Pathogen‐reduced platelets for the prevention of bleeding

Abstract

Background

Platelet transfusions are used to prevent and treat bleeding in people who are thrombocytopenic. Despite improvements in donor screening and laboratory testing, a small risk of viral, bacterial, or protozoal contamination of platelets remains. There is also an ongoing risk from newly emerging blood transfusion‐transmitted infections for which laboratory tests may not be available at the time of initial outbreak.

One solution to reduce the risk of blood transfusion‐transmitted infections from platelet transfusion is photochemical pathogen reduction, in which pathogens are either inactivated or significantly depleted in number, thereby reducing the chance of transmission. This process might offer additional benefits, including platelet shelf‐life extension, and negate the requirement for gamma‐irradiation of platelets. Although current pathogen‐reduction technologies have been proven to reduce pathogen load in platelet concentrates, a number of published clinical studies have raised concerns about the effectiveness of pathogen‐reduced platelets for post‐transfusion platelet count recovery and the prevention of bleeding when compared with standard platelets.

This is an update of a Cochrane review first published in 2013.

Objectives

To assess the effectiveness of pathogen‐reduced platelets for the prevention of bleeding in people of any age requiring platelet transfusions.

Search methods

We searched for randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 9), MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1937), the Transfusion Evidence Library (from 1950), and ongoing trial databases to 24 October 2016.

Selection criteria

We included RCTs comparing the transfusion of pathogen‐reduced platelets with standard platelets, or comparing different types of pathogen‐reduced platelets.

Data collection and analysis

We used the standard methodological procedures expected by Cochrane.

Main results

We identified five new trials in this update of the review. A total of 15 trials were eligible for inclusion in this review, 12 completed trials (2075 participants) and three ongoing trials. Ten of the 12 completed trials were included in the original review. We did not identify any RCTs comparing the transfusion of one type of pathogen‐reduced platelets with another.

Nine trials compared Intercept® pathogen‐reduced platelets to standard platelets, two trials compared Mirasol® pathogen‐reduced platelets to standard platelets; and one trial compared both pathogen‐reduced platelets types to standard platelets. Three RCTs were randomised cross‐over trials, and nine were parallel‐group trials. Of the 2075 participants enrolled in the trials, 1981 participants received at least one platelet transfusion (1662 participants in Intercept® platelet trials and 319 in Mirasol® platelet trials).

One trial included children requiring cardiac surgery (16 participants) or adults requiring a liver transplant (28 participants). All of the other participants were thrombocytopenic individuals who had a haematological or oncological diagnosis. Eight trials included only adults.

Four of the included studies were at low risk of bias in every domain, while the remaining eight included studies had some threats to validity.

Overall, the quality of the evidence was low to high across different outcomes according to GRADE methodology.

We are very uncertain as to whether pathogen‐reduced platelets increase the risk of any bleeding (World Health Organization (WHO) Grade 1 to 4) (5 trials, 1085 participants; fixed‐effect risk ratio (RR) 1.09, 95% confidence interval (CI) 1.02 to 1.15; I² = 59%, random‐effect RR 1.14, 95% CI 0.93 to 1.38; I² = 59%; low‐quality evidence).

There was no evidence of a difference between pathogen‐reduced platelets and standard platelets in the incidence of clinically significant bleeding complications (WHO Grade 2 or higher) (5 trials, 1392 participants; RR 1.10, 95% CI 0.97 to 1.25; I² = 0%; moderate‐quality evidence), and there is probably no difference in the risk of developing severe bleeding (WHO Grade 3 or higher) (6 trials, 1495 participants; RR 1.24, 95% CI 0.76 to 2.02; I² = 32%; moderate‐quality evidence).

There is probably no difference between pathogen‐reduced platelets and standard platelets in the incidence of all‐cause mortality at 4 to 12 weeks (6 trials, 1509 participants; RR 0.81, 95% CI 0.50 to 1.29; I² = 26%; moderate‐quality evidence).

There is probably no difference between pathogen‐reduced platelets and standard platelets in the incidence of serious adverse events (7 trials, 1340 participants; RR 1.09, 95% CI 0.88 to 1.35; I² = 0%; moderate‐quality evidence). However, no bacterial transfusion‐transmitted infections occurred in the six trials that reported this outcome.

Participants who received pathogen‐reduced platelet transfusions had an increased risk of developing platelet refractoriness (7 trials, 1525 participants; RR 2.94, 95% CI 2.08 to 4.16; I² = 0%; high‐quality evidence), though the definition of platelet refractoriness differed between trials.

Participants who received pathogen‐reduced platelet transfusions required more platelet transfusions (6 trials, 1509 participants; mean difference (MD) 1.23, 95% CI 0.86 to 1.61; I² = 27%; high‐quality evidence), and there was probably a shorter time interval between transfusions (6 trials, 1489 participants; MD ‐0.42, 95% CI ‐0.53 to ‐0.32; I² = 29%; moderate‐quality evidence). Participants who received pathogen‐reduced platelet transfusions had a lower 24‐hour corrected‐count increment (7 trials, 1681 participants; MD ‐3.02, 95% CI ‐3.57 to ‐2.48; I² = 15%; high‐quality evidence).

None of the studies reported quality of life.

We did not evaluate any economic outcomes.

There was evidence of subgroup differences in multiple transfusion trials between the two pathogen‐reduced platelet technologies assessed in this review (Intercept® and Mirasol®) for all‐cause mortality and the interval between platelet transfusions (favouring Intercept®).

Authors' conclusions

Findings from this review were based on 12 trials, and of the 1981 participants who received a platelet transfusion only 44 did not have a haematological or oncological diagnosis.

In people with haematological or oncological disorders who are thrombocytopenic due to their disease or its treatment, we found high‐quality evidence that pathogen‐reduced platelet transfusions increase the risk of platelet refractoriness and the platelet transfusion requirement. We found moderate‐quality evidence that pathogen‐reduced platelet transfusions do not affect all‐cause mortality, the risk of clinically significant or severe bleeding, or the risk of a serious adverse event. There was insufficient evidence for people with other diagnoses.

All three ongoing trials are in adults (planned recruitment 1375 participants) with a haematological or oncological diagnosis.

Platelet transfusions treated to reduce transfusion‐transmitted infections for the prevention of bleeding in people with low platelet counts

Review question

The aim of this review was to assess whether specially treated pathogen‐reduced platelets, work as well as normal platelets when transfused. Specifically, do they stop or prevent bleeding as well as standard platelets; do they produce the same increase in platelet count; and does their use affect further transfusion requirements? This review also assessed whether pathogen‐reduced platelets are as safe as normal platelets, for example are they associated with any difference in the rate of death following transfusion, and are there any side effects associated with the use of these products.

Our target population was people of any age with a low platelet count who would usually be treated with platelet transfusions.

Background

Blood for transfusion is collected from donors and then processed and stored as bags of different blood components. One of these components is platelets. Platelets are cells that help the body to form clots and prevent bleeding. Platelet transfusions may be given to prevent bleeding when the platelet count falls below a prespecified threshold platelet count (e.g. 10 x 10⁹/L), or may be given to treat bleeding (such as a prolonged nosebleed or multiple bruises). As for all transfusions, there are risks related to giving platelets transfusions, including a small risk of transfusion‐transmitted infections. A number of methods are used to minimise the risk of transfusion‐transmitted infections, including careful selection of people who donate blood and rigorous testing of the donated blood. One method of preventing infection is pathogen reduction by which, through a process of adding chemicals to the donated platelets and exposing them to a wavelength of ultraviolet light, the number of infecting organisms can be reduced. We have included two types of pathogen‐reduction technique in this review, Intercept® and Mirasol®.

Study characteristics

The evidence is current to October 2016. We found five new studies eligible for inclusion in this update of the review, three of which are still ongoing. We included 12 randomised controlled trials in this review; in 10 trials the Intercept® method of pathogen‐reduction was compared with standard platelets and in two trials the Mirasol® method of pathogen‐reduction was compared with standard platelets. All trials were conducted between 2003 and 2016 and included a total of 2075 participants. The sources of funding were reported in 12 studies. Most of the included studies were conducted in adults with blood cancers.

Key results

In people with cancer who have a low platelet count due to their disease or its treatment, we found that pathogen‐reduced platelet transfusions lead to an increase in the number of platelet transfusions required and an increase in the risk of no longer achieving a rise in the platelet count after a transfusion (platelet refractoriness). Pathogen‐reduced platelet transfusions probably do not affect the risk of death, bleeding, or a serious side effect. None of the studies reported on quality of life. No bacterial transfusion‐transmitted infections occurred in the six trials that reported this outcome.

There was insufficient evidence for people with other diagnoses.

All three ongoing studies are in adults with blood disorders (planned recruitment 1375 participants), there are no ongoing studies in children or in adults with other diagnoses.

Findings from this review were based on 12 studies and the 1981 participants who received a platelet transfusion.

We did not evaluate any economic outcomes.

Quality of the evidence

The overall quality of the evidence was low to high, as the estimates were imprecise (risk of death or a serious side effect), and there were differences in estimates for the risk of bleeding between studies.

Summary of findings

Summary of findings for the main comparison.

Pathogen‐reduced platelets versus standard platelets for the prevention of bleeding

Pathogen‐reduced platelets versus standard platelets for the prevention of bleeding in thrombocytopenia
Patient or population: thrombocytopenia Settings: hospital Intervention: pathogen‐reduced platelets
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Pathogen‐reduced platelets
Number of participants with 'any bleeding' event(s) (WHO grade 1 to 4 or equivalent) ‐ follow‐up > 7 days Follow‐up: 8 to 70 days	Study population		RR 1.09 (1.02 to 1.15)	1085 (5 studies)	⊕⊕⊝⊝ low1,2	Random‐effects analysis: RR 1.14, 95% CI 0.93 to 1.38; I2 = 59%
	696 per 1000	758 per 1000 (710 to 800)
	Moderate
	800 per 1000	872 per 1000 (816 to 920)
Number of participants with 'clinically significant' bleeding event(s) (WHO grade ≥ 2 or equivalent) ‐ follow‐up > 7 days Follow‐up: 8 to 70 days	Low		RR 1.10 (0.97 to 1.25)	1392 (5 studies)	⊕⊕⊕⊝ moderate2	Assumed risks from published data3
	570 per 1000	627 per 1000 (553 to 712)
	Moderate
	700 per 1000	770 per 1000 (679 to 875)
	High
	790 per 1000	869 per 1000 (766 to 988)
Number of participants with 'severe' bleeding event(s) (WHO grade ≥ 3 or equivalent) ‐ follow‐up > 7 days Follow‐up: 8 to 70 days	Study population		RR 1.24 (0.76 to 2.02)	1495 (6 studies)	⊕⊕⊕⊝ moderate4	Medium‐risk data taken from PLADO trial (Slichter 2010).
	36 per 1000	44 per 1000 (27 to 72)
	Moderate
	100 per 1000	124 per 1000 (76 to 202)
All‐cause mortality Follow‐up: 4 to 12 weeks	Study population		RR 0.81 (0.50 to 1.29)	1509 (6 studies)	⊕⊕⊕⊝ moderate5
	54 per 1000	43 per 1000 (27 to 69)
	Moderate
	25 per 1000	20 per 1000 (12 to 32)
Number of participants with a serious adverse event Follow‐up: 15 to 84 days	Study population		RR 1.09 (0.88 to 1.35)	1340 (7 studies)	⊕⊕⊕⊝ moderate5
	179 per 1000	196 per 1000 (158 to 242)
	Moderate
	204 per 1000	222 per 1000 (180 to 275)
Number of participants experiencing platelet refractoriness Follow‐up: 0 to 24 hours	Study population		RR 2.94 (2.08 to 4.16)	1525 (7 studies)	⊕⊕⊕⊕ high	4 studies defined refractoriness as 2 successive 1‐hour CCIs below 5 x 103 (Cazenave 2010; Janetzko 2005; McCullough 2004; van Rhenen 2003), while Kerkhoffs 2010 defined refractoriness as 2 successive 1‐hour CCIs below 7.5 x 103 or 24‐hour CCIs below 4.5 x 103 and presence of antibodies against platelets.
	51 per 1000	149 per 1000 (106 to 212)
Number of platelet transfusions per participant Multiple platelet transfusion trials	The mean number of platelet transfusions per participant was 4.7 to 8.4 platelet transfusions.	MD 1.23 platelet transfusions higher (0.86 to 1.61 higher)	‐	1509 (6 studies)	⊕⊕⊕⊕ high
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CCI: corrected count increment; CI: confidence interval; MD: mean difference; RR: risk ratio; WHO: World Health Organization.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

¹Downgraded one point due to inconsistency. ²Downgraded one point due to risk of other bias (differences in the assessment and grading of bleeding) ³Low risk = data taken from autologous transplantation participants from PLADO (PLAtelet DOse) trial (Slichter 2010). Medium risk = overall bleeding rate for all participants in the PLADO trial (Slichter 2010). High risk = data taken from allogeneic transplantation participants in PLADO trial (Slichter 2010). ⁴Downgraded one point due to inconsistency. One large study (McCullough 2004) had proportionately more events in the control group than the other five studies. Although the studies within this subgroup had similar follow‐up periods and to our knowledge there are no other major differences between them, the difference in the event rate may nevertheless be due to undetected methodological differences between the studies. ⁵Downgraded one point due to imprecision. Wide confidence intervals that include the risk of significant harm or benefit.

Background

Platelet transfusions are used to prevent and treat bleeding in people who are thrombocytopenic. Despite improvements in donor screening and laboratory testing, a small risk of transfusion‐transmitted infections (TTIs) remains. One solution to minimise the risk of TTIs from platelet transfusion is pathogen reduction, a process by which pathogens are either inactivated or significantly depleted in number, thereby reducing the chance of transmission. A number of published clinical studies have raised concerns about the effectiveness of pathogen‐reduced platelets for post‐transfusion platelet recovery and the prevention of bleeding when compared with standard platelets. The objective of this review was to evaluate the evidence from randomised controlled trials (RCTs) assessing the effectiveness of pathogen‐reduced platelets compared with standard platelets for the prevention of bleeding in people requiring platelet transfusion(s).

See Published notes for explanation of some technical terms and abbreviations.

Description of the condition

Significant progress has been made in recent years to improve the safety of blood transfusion with regard to transfusion‐transmitted infections (TTIs). Consequently the risk of viral TTIs (e.g. human immunodeficiency virus (HIV), hepatitis B (HBV), hepatitis C (HCV), and human T‐cell lymphotropic virus (HTLV) type I and II) is now considered to be low in high‐income countries (Zou 2012). Nevertheless, there remains the threat both of newly emerging blood‐transmitted infections (e.g. from viruses such as Zika, prions, and protozoa) and of TTIs caused by bacterial contamination of blood products. Platelet concentrates in particular are more vulnerable to bacterial contamination owing to their higher storage temperature (22°C) in comparison to other blood components (Blajchman 2006). The UK's Serious Hazards of Blood Transfusion (SHOT) programme reported that overall a total of 36 out of 43 bacterial transfusion‐transmissions to individual recipients (33 incidents) were caused by the transfusion of platelets between 1996 and 2014 (Bolton‐Maggs 2015). In the USA between January 2007 and December 2011, 38 episodes of probable or definite post‐transfusion sepsis including four fatalities were reported after transfusion of an apheresis platelet component to their haemovigilance programme (Benjamin 2014). In 2011, over 90% of all platelet components issued in the USA were apheresis platelet components (Whitaker 2011). For pools of whole blood‐derived platelet components prepared by the platelet‐rich plasma method and constituted just prior to transfusion, the rate for sepsis is approximately five times higher than in apheresis platelets (Jacobs 2008).

Both the UK and the USA use passive reporting systems, which may under‐report the number of cases. Using active reporting (based on prospective follow‐up of transfused recipients), single‐centre studies have identified higher rates of transfusion‐associated septic reactions that are up to 10 times that identified by passive reporting (Hong 2015; Jacobs 2008). The World Health Organization has therefore actively issued a recommendation of haemovigilance programmes to monitor and prevent unwanted transfusion events and increase safety and efficacy of blood transfusion (WHO 2016).

Description of the intervention

There are a number of current interventions that aim to reduce the risk of TTIs from platelet transfusion. These include improved donor screening, registries of previously deferred donors, single‐donor apheresis platelets, improved laboratory testing including the use of nucleic acid amplification testing, optimised skin preparation, removal of the first 10 to 30 mL of donated blood, and limited storage duration of platelet units. Some countries also carry out routine bacterial screening (Benjamin 2014; Pearce 2011). These methods have reduced but not eliminated the risk of both bacterial and viral TTIs from platelet transfusion, for example viral contamination can still occur during the 'window period' when the pathogen load is low enough to escape detection (Bolton‐Maggs 2015). The appearance of new blood‐borne viruses, such as West Nile virus (WNV), severe acute respiratory syndrome (SARS), and most recently the Zika virus, has highlighted the ongoing need to prevent the transmission of emerging pathogens.

It is against this background that photochemical pathogen‐reduction technologies have been developed and tested. Although solvent‐detergent treatment of pooled plasma for fractionation and transfusion has effectively eliminated the transmission of HIV, HBV, and HCV (Goodnough 2003; Pelletier 2006), these methods are cytocidal and therefore incompatible with cellular blood components. Pathogen‐reduction technology uses photochemical processes either entirely to inactivate or significantly reduce a broad spectrum of infectious agents such as viruses, fungi, bacteria and parasites within cellular blood components, including platelet concentrates. In addition, pathogen reduction should increase the availability of platelet concentrates by retarding bacterial growth, thereby extending platelet storage life from five to seven days and reducing costs.

How the intervention might work

Pathogen reduction uses photochemical treatment (PCT) to prevent replication of nucleic acid‐containing microbes whilst aiming to preserve cellular function and minimising toxicity. Two pathogen‐reduction systems for the treatment of platelet concentrates are currently available commercially. These utilise either a synthetic psoralen compound (amotosalen) or riboflavin (vitamin B₂), both in the presence of ultraviolet (UV) light.

Amotosalen

Amotosalen hydrochloride acts by selectively binding to nucleic acids within DNA and RNA and forming cross‐links upon photoactivation by exposure to long‐wave ultraviolet A (UVA) light. The UVA light induces a photochemical reaction that transforms the pre‐existing noncovalent link between pyrimidic base residues in DNA and RNA chains into irreversible. Such cross‐links render nucleic acids, and thus pathogens and white blood cells, incapable of replication (Grass 1998; Pelletier 2006). Amotosalen additionally binds to ribosomal RNA, inhibiting synthesis of proteins such as cytokines, and thus may also reduce the incidence of platelet transfusion reactions (McCullough 2007). The Intercept blood system (Cerus Corporation, Concord, CA, USA) achieves pathogen reduction through a combination of amotosalen and UVA light. It also employs a compound absorption device to scavenge unwanted postproduction residual amotosalen and photoproducts.

Amotosalen has been shown to inactivate 10³ to 10⁶ of enveloped viruses (HIV, WNV, HBV, HCV), both gram‐negative (Escherichia coli, Klebsiella pneumoniae) and gram‐positive bacteria (Staphylococcus aureus, Staphylococcus epidermidis), plus protozoa commonly implicated in TTIs (Lin 2004; Lin 2005). However, it has variable efficacy against non‐enveloped viruses, parvovirus is partially resistant, and hepatitis A and E viruses are resistant to inactivation by amotosalen (Hauser 2014; Kwon 2014).

In vitro data have demonstrated that in platelets treated with amotosalen plus UVA light, platelet function is comparable following storage for five and seven days despite transient platelet activation (Janetzko 2002; Lin 1998; Moog 2004; Van Rhenen 2000). Two phase II studies reported that although platelet viability was found to be significantly reduced in vivo in terms of recovery, survival, and corrected count increments, there was no significant difference in correction of bleeding time and transfusion interval (Slichter 2006; Snyder 2004). The Intercept® pathogen‐reduced products have demonstrated sufficient safety in terms of genotoxicity, carcinogenicity, and phototoxicity in single and repeated doses in both in vivo and in vitro studies (Ciaravino 2003; Tice 2007). This was also shown from combined seven‐year prospectively collected data from a cohort of 4067 participants receiving 19,175 transfusions as reported by the haemovigilance programme across 11 countries (Knutson 2015).

Riboflavin

Mirasol® pathogen‐reduction technology (CaridianBCT, Lakewood, CO, USA) reduces pathogens in platelet concentrates by utilising UVA light in the presence of riboflavin (vitamin B₂). This combination introduces intercalations with nucleic acids which, through photolysis upon exposure to UV light, promotes guanine oxidation and single‐strand breaks of nucleic acids (Kumar 2004). The riboflavin in conjunction with UV light associates with nucleic acids and mediates an oxygen‐independent electron transfer process leading to the oxidation of guanine residues and strand breaks. Each treated platelet unit with Mirasol Pathogen Reduction Technology has a fixed amount of riboflavin (35 mL) and can be used without the removal of residual riboflavin or its photoproduct. The Mirasol method causes irreversible damage to the RNA and DNA of of viruses, bacteria, and parasites, stopping them from replicating and causing infection.

Pathogens and white blood cells are thereby rendered inactive and effectively incapable of replication (Goodrich 2006; Kumar 2004). Riboflavin is a naturally occurring compound that does not require postproduction removal, and the breakdown products resulting from photolysis have been demonstrated to be satisfactorily safe (Hardwick 2004; Reddy 2008).

In vitro studies have shown that riboflavin inactivates viruses including HIV, WNV, and a number of bacteria commonly implicated in causing TTIs, including S epidermidis, S aureus, and E coli by 10³ to 10⁶ (Goodrich 2006; Ruane 2004). It may be effective against hepatitis E (Owada 2014), however it has variable efficacy against other viruses, including parvovirus, dengue virus, and hepatitis A virus (Faddy 2016; Kwon 2014).

Why it is important to do this review

Both systems are widely used in Europe, although there is a greater uptake of amotosalen, which is routinely used in 18 countries, and riboflavin, which is routinely used in 15 countries. For example, from 2011, Intercept was implemented nationwide in Switzerland, and amotosalen is widely used in Belgium. Advances in haematological treatments have led to an increased need for safer platelets transfusion strategies, and therefore motivated the development of pathogen inactivation products in order to reduce the risk of contamination. Functional and biochemical studies have revealed that pathogen inactivation may have some impact on the platelets' function, generating concerns about the haemostatic abilities of the inactivated platelets. Although the haemostatic function of the pathogen‐reduced platelets appeared to be preserved (AuBuchon 2005; Goodrich 2006; Lin 2004; Perez‐Pujol 2005; Picker 2009), some reduction in post‐transfusion recovery and survival in vivo were suggested (AuBuchon 2005; Slichter 2006; Snyder 2004).

Although current pathogen‐reduction technologies are very effective in reducing viruses and bacteria in platelet concentrates, concern remains about the haemostatic effectiveness of platelets treated in this way. While some studies have suggested that cell quality and platelet function are largely comparable between pathogen‐reduced and standard platelets (AuBuchon 2005; Goodrich 2006; Lin 2004; Perez‐Pujol 2005; Picker 2009), other studies have reported that current methods of pathogen reduction appear to reduce significantly post‐transfusion platelet recovery and survival in vivo when compared with standard platelets (AuBuchon 2005; Slichter 2006; Snyder 2004). Moreover, a recent RCT found Intercept® PCT pooled platelets to be less clinically effective at preventing bleeding than standard pooled platelets (Kerkhoffs 2010). As pathogen‐reduced platelets must be found to be safe and effective in achieving haemostasis prior to their introduction into routine clinical use, a systematic review of RCTs in this area was required.

Subsequently, results from an active haemovigilance programme across 11 countries involving 19,175 Intercept® transfusions, predominantly in a haemato‐oncology population, confirmed the Intercept® safety profile (Knutson 2015). However, the efficacy and safety of pathogen‐reduced platelets methods have not been systematically compared to standard platelets in people with thrombocytopenia.

Objectives

To assess the effectiveness of pathogen‐reduced platelets for the prevention of bleeding in people of any age requiring platelet transfusions.

Methods

Criteria for considering studies for this review

Types of studies

RCTs only (including cross‐over and multicentre, but excluding quasi‐randomised trials), irrespective of language or publication status.

Types of participants

People of any age requiring platelet transfusion(s).

Types of interventions

We included the following comparisons:

• Pathogen‐reduced platelets (either Intercept® pathogen‐reduction technology (PCT) or Mirasol® PCT or other pathogen‐reduction technologies) versus 'standard platelets' in people requiring platelet transfusion(s) (note that for the purposes of this review, we have used each trial's definition of 'standard platelets', and have described these differences in detail in the Characteristics of included studies section).

• Intercept® PCT versus Mirasol® PCT versus other pathogen‐reduced platelets in people requiring platelet transfusion(s). (We found no trials including this comparison.)

Types of outcome measures

Primary outcomes

1. Number, type, and severity of bleeding episodes. Bleeding was measured at up to 48 hours, 48 hours to 7 days, and more than 7 days.

2. All‐cause mortality. Mortality was measured at up to 4 weeks, 4 to 12 weeks, and more than 12 weeks. Of particular interest were deaths from platelet transfusion‐related complications such as bleeding, infection, thromboembolism, or transfusion reactions.

Secondary outcomes

1. Adverse events: recognised complications of platelet transfusions, e.g. mild transfusion reactions (rigors, fever, skin rash, urticaria) and platelet refractoriness.

2. Other adverse events, e.g. anaphylaxis, transfusion‐related acute lung injury (TRALI), infection, arterial or venous thromboembolism.

3. Laboratory assessment of response to platelet transfusion by post‐transfusion platelet count increment and corrected count increment (CCI).

4. Platelet and red cell transfusion requirement and interval.

5. Quality of life measured using validated scales.

Search methods for identification of studies

Electronic searches

The Systematic Review Initiative Information Specialist (CD) formulated updated search strategies in collaboration with the Cochrane Haematological Malignancies Review Group based on those used in previous versions of this review. In this update we searched the following databases for RCTs.

• Cochrane Central Register of Controlled Trials on 24 October 2016 (CENTRAL, the Cochrane Library 2016, Issue 9) (www.cochranelibrary.com/) (Appendix 1)

• MEDLINE (OvidSP Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE Daily & Ovid MEDLINE 1946 to 24 October 2016) (Appendix 2)

• Embase (OvidSP 1974 to 24 October 2016) (Appendix 3)

• CINAHL (Cumulative Index to Nursing and Allied Health Literature) (EBSCOhost 1937 to 24 October 2016) (Appendix 4)

• PubMed (for e‐publications ahead of print, in‐process and other non‐indexed citations only on 24 October 2016) (www.ncbi.nlm.nih.gov/pubmed) (Appendix 5)

• Transfusion Evidence Library (1950 to 24 October 2016) (www.transfusionevidencelibrary.com) (Appendix 6)

• LILACS (Latin American and Caribbean Health Sciences Literature) (1982 to 24 October 2016) (lilacs.bvsalud.org/en/) (Appendix 7)

• KoreaMed (1958 to 24 October 2016) (koreamed.org/) (Appendix 8)

• IndMED (1986 to 24 October 2016) (indmed.nic.in/indmed.html) (Appendix 9)

• Web of Science Conference Proceedings Citation Index‐Science (CPCI‐S) (1990 to 24 October 2016) (Appendix 10)

We searched the following ongoing trial databases (all years to 24 October 2016).

• World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (apps.who.int/trialsearch/) (Appendix 11)

• ClinicalTrials.gov (www.clinicaltrials.gov/) (Appendix 12)

We combined the search strategies in MEDLINE and Embase with adaptations of the Cochrane sensitive RCT search filter as detailed in Chapter 6 of the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2011), and in CINAHL with the RCT filter designed by the Scottish Intercollegiate Guidelines Network (SIGN) (www.sign.ac.uk/methodology/filters.html). We conducted our original search on 18 February 2013 (Butler 2013); search strategies for each database from the original review are available in Appendix 13, Appendix 14, Appendix 15, Appendix 16, Appendix 17, and Appendix 18.

Searching other resources

Handsearching of reference lists

We checked and citation‐tracked the reference lists of all identified trials, relevant review articles, and current treatment guidelines for further literature, but limited these searches to the 'first‐generation' reference lists.

Personal contacts

We contacted lead authors of relevant studies, study groups, and international experts known to be active in the field to request any unpublished material, missing data, or further information on ongoing trials. This included making contact with Dr Laurence Corash (Intercept, Cerus Corporation), Dr Raymond Goodrich (Mirasol®, CaridianBCT), and Dr Paolo Rebulla.

Data collection and analysis

Selection of studies

The Systematic Review Initiative Information Specialist (CD) initially removed all duplicate records. Two review authors (LE, RM) then independently screened all the remaining references for relevance against the full eligibility criteria using Covidence software. We obtained full‐text papers of all references for which eligibility could not be verified based on title and abstract alone in addition to records meeting the review inclusion criteria. It was necessary to seek further information from several authors, as most articles of interest contained insufficient data to make a decision about eligibility. Differences of opinion were resolved through discussion and consensus within the review team. Details of the studies that did not meet our eligibility criteria are recorded in the Characteristics of excluded studies table.

Data extraction and management

We updated the data extraction performed for the previous version of this review (Butler 2013), including data extraction for all new studies included since the previous review, all new review outcomes that were not part of the previous review (e.g. quality of life), and information on trial registration.

Two review authors (LE, RM) conducted the data extraction according to the guidelines proposed by The Cochrane Collaboration (Higgins 2011a). Any disagreements between the review authors were resolved by consensus. The review authors were not blinded to names of authors, institutions, journals, or the outcomes of the trials.

The agreed data extraction form included the following.

1. General information: study ID, first author of study, author's contact address (if available), citation of paper, objectives of the trial.

2. Trial details: trial design, location, setting, sample size, power calculation, trial registration, methods of treatment allocation, randomisation and blinding, inclusion and exclusion criteria, reasons for exclusion, comparability of groups, length of follow‐up, stratification, stopping rules described, method of statistical analysis used, and funding.

3. Characteristics of participants: age, gender, ethnicity, total number recruited, total number randomised, total number analysed, types of underlying condition(s), losses to follow‐up, dropouts (percentage in each arm) with reasons, protocol violations, current treatment, previous treatments, prognostic factors.

4. Interventions: experimental and control interventions, type of platelet given, method of platelet production (e.g. apheresis or pooled buffy‐coat derived), type and dosage of platelet given, timing of intervention, compliance with interventions, additional interventions given (especially with regard to red cell transfusions), any other differences between interventions.

5. Outcomes: mortality due to bleeding, long‐term morbidity due to bleeding (e.g. stroke, myocardial infarction, pulmonary embolism), number and severity of bleeding episodes, laboratory assessment of response to platelet transfusion by post‐transfusion platelet count increment, platelet and red cell transfusion interval, platelet and red cell transfusion requirement, recognised complications of platelet transfusion (e.g. transfusion reaction, TTI, platelet refractoriness, thromboembolism, development of platelet antibodies), and any adverse or other serious adverse event (e.g. anaphylaxis, acute lung injury).

Assessment of risk of bias in included studies

Two review authors (LE, RM) independently applied the Cochrane 'Risk of bias' tool per Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions to assess potential biases across the included studies (Higgins 2011b). We rated each domain of the tool as 'high', 'low', or 'unclear' risk of bias, and provided a brief description to support our judgement for each rating. We compared our statements, involving a third review author when agreement could not be reached. We used the assessment of risk of bias in each trial to conduct sensitivity analyses where appropriate as part of the exploration of heterogeneity among included trials. Details of the potential bias for each individual study are presented in the Characteristics of included studies tables.

The Cochrane 'Risk of bias' tool addresses the following domains.

• Selection bias: random sequence generation and allocation

• concealment.

• Performance bias: blinding of participants and personnel.

• Detection bias: blinding of outcome assessment.

• Attrition bias: incomplete outcome data.

• Reporting bias: selective reporting.

• Other bias.

Measures of treatment effect

For continuous outcomes, we extracted the mean, standard deviation, and total number of participants in both the treatment and control groups. For continuous outcomes using the same scale, we performed analyses using the mean difference (MD) with 95% confidence intervals (CI). When different scales were used to measure the same outcomes, we applied the standardised mean difference (SMD) when data were pooled.

For dichotomous outcomes, we recorded the number of events and the total number of participants in both the treatment and control groups. We reported the pooled risk ratios (RR) with a 95% CI using the Mantel‐Haenszel method. Where the number of observed events was small (less than 5% of sample per group) and trials had balanced treatment groups, we applied the Peto odds ratio (OR) with 95% CI (Deeks 2011).

If available, we planned to extract and report hazard ratios (HR) for mortality data. If HRs were not available, we made every effort to estimate as accurately as possible the HR using the available data and a purpose‐built method based on the Parmar and Tierney tool (Parmar 1998; Tierney 2007). However, we were unable to estimate any hazard ratios.

We planned to report the number needed to treat for an additional beneficial outcome (NNTB) and the number needed to treat for an additional harmful outcome (NNTH) with CIs for outcomes that showed a benefit or harm for transfusion‐related adverse events.

We also reported data in a narrative synthesis when data were not available in a usable format.

We applied the generic inverse variance method when pooling data from cross‐over design trials if period effects had been appropriately adjusted for.

Unit of analysis issues

We included no cluster‐randomised trials in this review.

For cross‐over trials, we included data from both trial periods if period effects had been appropriately adjusted for (more than 24‐hour washout period), using the generic inverse variance method. Otherwise we used data only from the first trial period, if data from the two trial periods were reported separately. If they were not reported separately, we reported data narratively. We included three cross‐over trials (Johansson 2013; Simonsen 2006; Slichter 2006). We were unable to use data provided by Johansson 2013 in any of the meta‐analyses as there was no clear washout period between the two trial phases. In Simonsen 2006 and Slichter 2006, we assessed dichotomous outcomes that included data from one or both of these trials using the generic inverse variance model. It should therefore be noted that we could not include outcomes with a zero value result in this type of analysis. Furthermore, for continuous outcomes for which data were available from the cross‐over trials, it was necessary to include data from the first period of each trial only. As Slichter 2006 reported only combined results for both periods of the two trial arms, we could not include these data in any of the meta‐analyses of continuous outcomes and have therefore reported them narratively throughout.

We identified duplication of participants through inclusion in more than one study cycle in three Intercept trials (McCullough 2004; Simonsen 2006; van Rhenen 2003). McCullough 2004 reported data from only the first cycle of the study, whilst we extracted the data for van Rhenen 2003 from cycle 1 only, either from the published literature or obtained through direct author contact. In Simonsen 2006, 1 participant out of 20 received both study transfusions on 2 separate occasions. We did not consider this as having a significant impact on the accuracy of this cross‐over trial's outcomes, despite its small size, and we included data for this participant in the analyses.

Dealing with missing data

We dealt with missing data according to the recommendations in Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011c). We attempted to contact the authors of all 12 included trials via email in order to request additional information and data that were either missing or unclear in the published papers. We received additional data for 10 of the 12 included trials (Cazenave 2010; Janetzko 2005; Johansson 2013; Kerkhoffs 2010; Lozano 2011; McCullough 2004; Rebulla 2016; Simonsen 2006; Slichter 2006; van Rhenen 2003). We recorded the number of participants lost to follow‐up for each trial. Where possible, we used intention‐to‐treat data, but if not available, we reported per‐protocol data.

Assessment of heterogeneity

The decision to combine the results of individual trials depended on an assessment of heterogeneity, which we performed according to the recommendations of The Cochrane Collaboration (Deeks 2011). If we considered trials to be sufficiently homogeneous in terms of their clinical and methodological characteristics, we carried out a meta‐analysis and assessed the statistical heterogeneity of treatment effects between trials using a Chi² test with a significance level at P < 0.1. We used the I² statistic to quantify the degree of possible heterogeneity, considering an I² > 30% as moderate heterogeneity and I² > 75% as considerable heterogeneity. Where there was moderate heterogeneity, we conducted both fixed‐effect and random‐effects analyses, presenting the former but reporting results for both in the text.

Assessment of reporting biases

We had intended in meta‐analyses of more than 10 trials to explore potential publication bias (small‐trial bias) by generating a funnel plot and using a linear regression test. However, the number of trials included in any of our meta‐analyses was insufficient to perform this analysis, per Chapter 10 of the Cochrane Handbook for Systematic Reviews of Interventions (Sterne 2011).

Data synthesis

We performed analyses according to the recommendations of The Cochrane Collaboration using aggregated data (Deeks 2011). For statistical analysis, we entered data into the Cochrane statistical package Review Manager 5 (Review Manager 2014). One review author performed data entry, and another review author checked the data entry for accuracy. We performed meta‐analyses using the Mantel‐Haenszel method with the fixed‐effect model. Where data did not allow for meta‐analysis, we reported outcome data descriptively within the Results section of the review. For the three included cross‐over trials (Johansson 2013; Simonsen 2006; Slichter 2006), if they appropriately adjusted for period effects, for dichotomous outcomes we included data from the trial periods using the generic inverse variance method, as described above. For continuous outcomes, we included data only from the first period, if available, as these data cannot be analysed using the generic inverse variance method. Where data were not reported separately, we reported these narratively. However, we used no data from Johansson 2013, as the washout period between the two phases was less than 24 hours, and data from phase one were not available.

For each outcome, we combined data to compare pathogen‐reduced platelets with standard platelet transfusion in the meta‐analyses. We made no comparisons between pathogen‐reduced products, as no completed or ongoing trials assessed this.

'Summary of findings' table

We used the GRADE profiler to create a 'Summary of findings' table, as suggested in Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2011), based on our primary outcomes and adverse events. These included the following.

• Number of participants with any bleeding

• Number of participants with clinically significant bleeding

• Severe bleeding

• All‐cause mortality (4 to 12 weeks)

• Serious adverse events

• Platelet refractoriness

• Number of platelet transfusions per participant

The outcomes within the 'Summary of findings' table had not been prespecified in the protocol.

Subgroup analysis and investigation of heterogeneity

Sufficient data were not available to perform our prespecified subgroup analyses relating to length of platelet storage and the underlying diagnosis of participants.

In the previous version of this review, Butler 2013, it became apparent upon the completion of searches that two different trial designs were used for the Intercept PCT versus standard platelet trials: single or multiple study platelet transfusions. In the previous version of this review a post hoc division of trials was performed, separating the trials according to the pathogen‐reduced platelet technique employed (as predefined) and transfusion exposure.

In this version of the review we prespecified these subgroups:

• a single transfusion of Intercept PCT versus standard platelets;

• multiple transfusions of Intercept PCT versus standard platelets;

• a single transfusion of Mirasol PCT versus standard platelets;

• multiple transfusions of Mirasol PCT versus standard platelets.

Sensitivity analysis

We intended to assess the robustness of our findings by performing the following two sensitivity analyses:

• including only those trials at low risk of bias;

• including only those trials in which 25% participants or less were lost to follow‐up.

However, we only carried out the first analysis, as the loss to follow‐up was not significantly high for any of the 10 completed trials included in the meta‐analyses.

Results

Description of studies

See Characteristics of included studies; Characteristics of ongoing studies; and Characteristics of excluded studies.

Results of the search

The original search (conducted February 2013) identified a total of 1138 potentially relevant records. After removal of duplicates 863 records remained, of which 812 records were excluded on the basis of the abstract. The original systematic review identified 51 records that appeared relevant on the basis of their full text or abstract using the original inclusion/exclusion criteria (Butler 2013). Ten studies were identified and included in the previous version of the review (Agliastro 2006; Cazenave 2010; De Francisci 2004; Janetzko 2005; Kerkhoffs 2010; Lozano 2011; McCullough 2004; Simonsen 2006; Slichter 2006; van Rhenen 2003).

The latest update of the search (conducted October 2016) identified a total of 1407 potentially relevant records. After the removal of duplicates 474 records remained. Two review authors (LE, RM) excluded 441 records on the basis of the abstract using Covidence software. Two review authors (LE, RM) retrieved for relevance and reviewed 33 full‐text articles. We identified two new completed studies, Johansson 2013 and Rebulla 2016, and three ongoing studies (EUCTR2015‐001035‐20‐DE; Kerkhoffs 2013; NCT01789762) (see the PRISMA study flow diagram in Figure 1).

Figure 1.

Updated review study flow diagram.

For this 2017 update, we have included the previous two ongoing trials in the review (Johansson 2013; Rebulla 2016), for a total of 12 included completed studies (Agliastro 2006; De Francisci 2004; Janetzko 2005; Johansson 2013; Kerkhoffs 2010; Lozano 2011; McCullough 2004; Rebulla 2016; Simonsen 2006; Slichter 2006; van Rhenen 2003), as well as three ongoing trials (EUCTR2015‐001035‐20‐DE; Kerkhoffs 2013; NCT01789762).

Included studies

All 12 trials were published in English between 2003 and 2016. The included trials were grouped by the type of the PCT product type: Intercept PCT and Mirasol PCT. Of the 12 included trials, no trials compared different types of pathogen‐reduced platelets with each other.

Ten of the 12 included trials compared the Intercept PCT product with standard platelets (Agliastro 2006; De Francisci 2004; Janetzko 2005; Kerkhoffs 2010; Lozano 2011; McCullough 2004; Rebulla 2016; Simonsen 2006; Slichter 2006; van Rhenen 2003). Of these 10 trials, eight were published as full papers (Janetzko 2005; Kerkhoffs 2010; Lozano 2011; McCullough 2004; Rebulla 2016; Simonsen 2006; Slichter 2006; van Rhenen 2003), and two as abstracts only (Agliastro 2006; De Francisci 2004).

Three of the 12 included trials compared the Mirasol PCT product with standard platelets (Cazenave 2010; Johansson 2013; Rebulla 2016). All three trials were reported in full (Cazenave 2010; Johansson 2013; Rebulla 2016).

In one trial (Rebulla 2016), three centres compared Intercept PCT to standard platelets, and another three centres compared Mirasol PCT to standard platelets. Consequently, in this review, we have reported data from the Rebulla 2016 trial separately for Intercept PCT versus standard platelets (three centres) and Mirasol PCT versus standard platelets (three centres).

Trial settings

All included studies were set in high‐income countries according to the World Bank classification (WB 2016).

Intercept PCT platelet trials

The 10 trials comparing Intercept PCT with standard platelets were conducted across 10 countries: Denmark, the Netherlands, Italy, Spain, Germany, France, Switzerland, Sweden, the UK, and the USA. Three trials were multinational: Janetzko 2005 (Germany, France, and Switzerland); Lozano 2011 (Spain, the UK, France, and Sweden); and van Rhenen 2003 (the Netherlands, Sweden, France, and the UK). Five were multicentre trials conducted in a single country: Cazenave 2010 (six centres in France); Kerkhoffs 2010 (eight centres in the Netherlands); McCullough 2004 (12 centres in the USA); Rebulla 2016 (three centres in Italy); and Slichter 2006 (two centres in the USA). One included trial was conducted in a single centre in Denmark (Simonsen 2006). Two trials conducted in Italy did not report the number of participating centres (Agliastro 2006; De Francisci 2004).

Mirasol PCT platelet trials

Of the three trials comparing Mirasol PCT with standard platelets, two were multicentre trials (Cazenave 2010 (six centres in France); Rebulla 2016 (three centres in Italy)), and the third was a single‐centre trial in Denmark (Johansson 2013).

Trial design

Three included trials had a cross‐over design (Johansson 2013; Simonsen 2006; Slichter 2006), while the other nine trials were parallel‐group RCTs (Agliastro 2006; Cazenave 2010; De Francisci 2004; Janetzko 2005; Kerkhoffs 2010; Lozano 2011; McCullough 2004; Rebulla 2016; van Rhenen 2003).

None of the three cross‐over studies reported the pre‐defined washout period to minimise the carry‐over effects due to transfusion sequences. However, there was at least a 24‐hour period between study transfusions in Simonsen 2006 and Slichter 2006. In Johansson 2013 no information with regard to the period between the two transfusion types was provided.

Intercept PCT platelet trials

Of the 10 RCTs comparing Intercept PCT with standard platelets (Agliastro 2006; De Francisci 2004; Janetzko 2005; Kerkhoffs 2010; Lozano 2011; McCullough 2004; Simonsen 2006; Slichter 2006; Rebulla 2016; van Rhenen 2003), two were cross‐over design trials (Simonsen 2006; Slichter 2006), and the rest were parallel design trials. Three trials were two‐arm non‐inferiority design trials (Lozano 2011; McCullough 2004; Rebulla 2016). Two trials were two‐arm equivalence trials (Janetzko 2005; van Rhenen 2003). One trial was a three‐arm non‐inferiority trial (Kerkhoffs 2010), in which Intercept PCT platelets were compared with platelets stored in both plasma and InterSol platelet additive solution. We selected the plasma arm as the control group (i.e. as the 'standard' platelet product) for comparison in this review. Two trials were parallel design trials that were only reported as an abstract, with no further details given (Agliastro 2006; De Francisci 2004).

Mirasol PCT platelet trials

Of the three trials comparing Mirasol PCT with standard platelets, one was a cross‐over equivalence trial (Johansson 2013), and two were parallel design non‐inferiority trials (Cazenave 2010; Rebulla 2016).

Trial size

The size of included trials varied from 16 participants in Johansson 2013 to 671 participants in McCullough 2004. Six trials included more than 100 participants (Cazenave 2010; Kerkhoffs 2010; Lozano 2011; McCullough 2004; Rebulla 2016; van Rhenen 2003).

Two trials were stopped early (Kerkhoffs 2010; Rebulla 2016). In Rebulla 2016, the initial target was to enrol 828 participants, but the study was stopped early for administrative reasons with only 424 participants included. The independent data safety monitoring board for the Kerkhoffs 2010 study recommended early stopping of the study, as significantly higher bleeding rates and lower one‐hour corrected count increments (CCIs) were identified in the Intercept PCT platelets arm.

Intercept PCT platelet trials

The size of the included trials varied from 28 participants in Simonsen 2006 to 671 participants in McCullough 2004. Five trials included more than 100 participants (Kerkhoffs 2010; Lozano 2011; McCullough 2004; Rebulla 2016; van Rhenen 2003). Two studies were stopped early (Kerkhoffs 2010; Rebulla 2016).

Mirasol PCT platelet trials

The size of the included trials varied from 16 participants in Johansson 2013 to 194 participants in Rebulla 2016. Two trials included more than 100 participants (Cazenave 2010; Rebulla 2016). One study was stopped early (Rebulla 2016).

Participant

Overall, 2075 participants were randomised in the 12 included trials, with only 1981 participants receiving at least one study platelet transfusion. However, we only included data from the 1887 participants in two arms of the three‐arm Kerkhoffs 2010 trial.

All participants, apart from those recruited to one trial (De Francisci 2004), were thrombocytopenic individuals who had a haematological or oncological diagnosis and were either in need of, or expected to be in need of, platelet transfusion. The exception, De Francisci 2004, explored two different groups: one adult group awaiting liver transplantation requiring platelet support before invasive procedures, and one paediatric group with congenital cyanotic cardiopathy undergoing cardiac surgery requiring per‐protocol platelet transfusions during extracorporeal circulation due to platelet consumption.

The age of participants ranged from 4 to 85 years. Two trials recruited only children (Agliastro 2006 and the cardiac group of De Francisci 2004), whilst two other trials included children from the age of 6 or 12 years (McCullough 2004; van Rhenen 2003). The remaining eight trials recruited adults aged over 16 or 18 years (Cazenave 2010; Janetzko 2005; Johansson 2013; Kerkhoffs 2010; Lozano 2011; Rebulla 2016; Simonsen 2006; Slichter 2006).

All trials had comparable proportions of males and females, except for Johansson 2013, in which almost all included participants were male.

Seven trials excluded individuals with a previous history of alloimmunisation, antibodies formed against human leukocyte antigens or human platelet antigens, or positive lymphocytotoxic antibody panels with high reactivity (Cazenave 2010; Johansson 2013; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; Slichter 2006; van Rhenen 2003). Nine trials excluded individuals with a previous history of clinical refractoriness to platelet transfusions (Cazenave 2010; Janetzko 2005; Johansson 2013; Kerkhoffs 2010; Lozano 2011; McCullough 2004; Rebulla 2016; Simonsen 2006; van Rhenen 2003). Five of the 12 included trials excluded from enrolment people who were actively bleeding (Cazenave 2010; Janetzko 2005; Johansson 2013; Simonsen 2006; Slichter 2006), whilst another study postponed the study transfusion if the person had evidence of active bleeding within the last 12 hours (Lozano 2011). In Rebulla 2016, participants with active bleeding were not excluded.

Intercept PCT platelet trials

A total of 1740 participants were enrolled in the Intercept PCT versus standard platelets trials, of which 1662 received at least one study platelet transfusion, and 1568 were included in our analyses.

Four trials included children (Agliastro 2006; De Francisci 2004; McCullough 2004; van Rhenen 2003), and six trials included only adults (Janetzko 2005; Kerkhoffs 2010; Lozano 2011; Rebulla 2016; Simonsen 2006; Slichter 2006). All participants, apart from those recruited to one trial (De Francisci 2004), were thrombocytopenic individuals who had a haematological or oncological diagnosis and were either in need of, or expected to be in need of, platelet transfusion.

Mirasol PCT platelet trials

A total of 335 participants were enrolled in the Mirasol PCT versus standard platelets trials (Cazenave 2010; Johansson 2013; Rebulla 2016), of which 319 received at least one study platelet transfusion. All three trials included adults (aged 18 years or older) with thrombocytopenic haematology or oncology conditions that required platelet transfusions.

Interventions

For full details of the source (apheresis or buffy coat), storage solution, mean storage duration and mean platelet dose of the study and standard platelet products for each of the included trials see the Characteristics of included studies section and Table 3. The transfusion triggers used were either prophylactic (generally a platelet count of 10 to 20 x 10⁹/L or prior to invasive procedures) or therapeutic due to bleeding, the details of which are given (where reported) in the Characteristics of included studies section and Table 4.

Table 1.

Trial characteristics

Study (publication)	Study design (analysis)	Total no. of participants (PCT plts/std plts)	Underlying disease	Type of treatment received for underlying disease (%)		Type of platelet component	Follow‐up periods for mortality (days)	Mean plt storage duration (days)	Platelet dosea (Mean plt transfusion dose) (1011/unit)
				PCT plts	Std plts
Single‐transfusion studies ‐ Intercept
De Francisci 2004 (A)	P2 (NR)	44 (22/22)	Adult liver transplant/ paediatric cardiac surgery	Liver: 14 Cardiac: 8	Liver: 14 Cardiac: 8	NR	NR	NR	NR
Lozano 2011 (F)	P2 (Non‐I)	211 (105/106)	Adult haemato‐ oncological disease	Auto: 42 Allo: 29 Ch: 27 Other: 3	Auto:40 Allo: 25 Ch: 34 Other: 2	86% BC 14% Aph	15	6.8	Intermediate   (4.2)
Simonsen 2006 (F)	C‐O (Non‐I)	20 PCT‐std: 9 std‐PCT: 11	Adult haemato‐ oncological disease	PCT‐std	Std‐PCT	BC	1	7	Low/intermediate   (2.9)
				Allo: 33 Ch: 67	Allo: 64 Ch: 36
Slichter 2006 (F)	C‐O (E)	32 PCT‐std: NR std‐PCT: NR	Adult haemato‐ oncological disease	NR	NR	Aph	42b	3	High   (7.5)
Multiple‐transfusion studies – Intercept
Agliastro 2006 (A)	P2 (NR)	30 (19/11)	Paediatric haemato‐ oncological disease	NR		PCT plts: BC Std plts: Aph	NR	NR	Low/intermediate   (2.9)
Janetzko 2005 (F)	P2 (E)	43 (22/21)	Adult haemato‐ oncological disease	SCT: 68 Ch: 27 Other: 5	SCT: 62 Ch: 38	Aph	35	3.1	Intermediate   (4.0)
Kerkhoffs 2010 (F)	P3 (Non‐I)	184 (85/99)	Adult haemato‐ oncological disease	Auto:  39 Allo: 7 Ch: 49 Other: 5	Auto:32 Allo: 12 Ch: 53 Other: 3	BC	42	4	Intermediate   (3.7c)
McCullough 2004 (F)	P2 (Non‐I)	645 (318/327)	Paediatric + adult haemato‐oncological disease	Auto:  48 Allo:  28 Ch: 21 Other: 3	Auto: 52 Allo: 28 Ch: 18 Other: 2	Aph	35	3.5d	Intermediate   (3.9c)
Rebulla 2016 (F)	P2 (Non‐I)	228 (113/115)	Adult haemato‐ oncological disease	Ch: 101 Allo: 12	Ch: 102 Allo: 13	1% Aph 99% BC	28	1.29 PR 1.48 C	Low/intermediate (2.9)
van Rhenen 2003 (F)	P2 (E)	103 (52/51)	Paediatric + adult haemato‐oncological disease	SCT: 37 Ch: 63	SCT: 37 Ch: 63	BC	84	3.5	Intermediate   (4.1c)
Single‐transfusion studies ‐ Mirasol
Johansson 2013 (F)	C‐O (NR)	15 PCT‐std: 8 std‐PCT: 7	Adult haemato‐ oncological disease	NR		BC	1	2.8 PR 2.3 C	Low/intermediate (3.0c)
Multiple‐transfusion studies – Mirasol
Cazenave 2010 (F)	P2 (Non‐I)	110 (56/54)	Adult haemato‐ oncological disease	NR		25% BC 75% Aph	56	2.7	Intermediate   (5.2)
Rebulla 2016 (F)	P2 (Non‐I)	196 (99/97)	Adult haemato‐ oncological disease	Ch: 85 Allo: 14	Ch: 83 Allo: 14	49% Aph 51% BC	28	1.66 PR 1.73 C	Low/intermediate (3.3)

Key: A: abstract only Allo: treated with allogeneic stem cell transplantation Aph: apheresis Auto: treated with autologous stem cell transplantation BC: buffy coats C: control Ch: treated with chemotherapy, but without stem cell transplantation C‐O: cross‐over trial E: equivalence trial F: full paper Non‐I: non‐inferiority NR: not reported P2: parallel, 2 arms P3: parallel, 3 arms PCT: photochemically treated Plt: platelet PR: pathogen‐reduced SCT: treated with stem cell transplantation (undifferentiated) Std: standard

^aPlatelet dose has been categorised according to the low‐, intermediate‐, and high‐dose categories in the PLADO study (Slichter 2010). Low/intermediate means that the dose was between the low and intermediate categories of PLADO. ^bCross‐over design means adverse events (including mortality) were not specifically attributed to either PCT or standard transfusion. ^cStatistically significant lower mean platelet doses were issued for PCT versus standard platelet transfusions (P < 0.001 for Kerkhoffs 2010, McCullough 2004, and van Rhenen 2003). However, the doses in both arms were within the intermediate dose category of the PLADO study in all of these studies (Slichter 2010). Although these differences were statistically significant overall there was less than a 10% difference in dose between the study arms in the three trials (range 8% in McCullough 2004 to 15% in Kerkhoffs 2010). ^dStatistically significant difference between treatment arms for duration of platelet storage in McCullough 2004 (P = 0.03).

Table 2.

Platelet transfusion data

Study	Platelet transfusion protocol	No. of plt transfusions/participant (mean ± SD)		Total % (no.) of off‐protocol transfusions
		PCT plts	Std plts	PCT plts	Std plts
Single‐transfusion studies ‐ Intercept
De Francisci 2004	P (NR)	1	1	NR	NR
Lozano 2011	P (10 to 20)	1	1	NA	NA
Simonsen 2006	P (10 to 20)	1	1	(2/25)	(1/25)
Slichter 2006	P (20)	1	1	NA	NA
Multiple‐transfusion studies ‐ Intercept
Agliastro 2006	T	NR	NR	NR	NR
Janetzko 2005	P (20); PP (NR) or T	4.7 ± 3.3	5.5 ± 4.7	16.5% (17/103)	7% (8/115)
Kerkhoffs 2010	P (10 to 40); PP (40 to 100) or T	5 ± 2a	4 ± 2a	34% (134/391)	18% (65/357)
McCullough 2004	P (NR) or T	8.4 ± 8.6a	6.2 ± 7.0a	8.5% (232/2715)	4.8% (101/2092)
Rebulla 2016	P (10 to 20) or T	5.9 ± 5.8a	3.8 ± 3.4a	2.8% (19/667)	2.0% (9/441)
van Rhenen 2003	P (20) or T	7.5 ± 5.8	5.6 ± 5.5	20.3% (79/390)	10.5% (30/286)
Single‐transfusion studies ‐ Mirasol
Johansson 2013	P (10 to 50)	1	1	NA	NA
Multiple‐transfusion studies ‐ Mirasol
Cazenave 2010	P (10 to 20); PP (50) or T	5.4 ± 3.4b 1.2 ± 2.3c	4.4 ± 3.4b 1.3 ± 3.6c	17.7% (65/368)	23.2% (72/310)
Rebulla 2016	P (10 to 20) or T	4.6 ± 4.0a	3.4 ± 2.1a	6.3% (29/457)	0% (0/334)

Key:       

NA: not applicable NR: not reported P: prophylactic transfusion (threshold plt count x 10⁹/L) PCT: photochemically treated plt: platelet PP: pre‐procedure transfusion (threshold plt count x 10⁹/L) SD: standard deviation Std: standard T: therapeutic transfusion

^aStatistically significant difference in the number of platelet transfusions received per participant. ^bOn‐protocol transfusions only. ^cOff‐protocol transfusions only.   

Intercept PCT platelet trials

Single transfusion

Three trials involved a single study platelet transfusion exposure (Lozano 2011; Simonsen 2006; Slichter 2006). De Francisci 2004 did not report the number of study platelets received, but as these were given to cover a single exposure period (surgery/pre‐procedure), we included them in the single study platelet transfusion exposure group (see Table 3).

Lozano 2011 and Simonsen 2006 stored their standard platelet products in platelet additive solution (PAS) rather than plasma. Slichter 2006 stored both Intercept platelets and standard platelets in plasma. De Francisci 2004 was only available as an abstract, and did not provide information related to the storage solution.

Multiple transfusion

Six trials involved multiple study platelet transfusion exposures (Agliastro 2006; Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; van Rhenen 2003). In Kerkhoffs 2010, Intercept PCT platelets were compared with PASIII (platelets stored in PAS) and plasma (standard platelets suspended in plasma). van Rhenen 2003 and Rebulla 2016 stored standard platelet products in PAS rather than in plasma. Janetzko 2005 and McCullough 2004 stored standard platelet products in plasma. Agliastro 2006 was only available as an abstract, and did not provide information related to the storage solution.

Mirasol PCT platelet trials

Single transfusion

In Johansson 2013, a cross‐over design study, each participant received two prophylactic transfusions of buffy‐coat derived platelets, one Mirasol and one control platelets, stored in PAS solution for two to four days.

Multiple transfusion

In Rebulla 2016, participants were assigned to receive multiple platelets transfusions of Mirasol or standard platelets derived by buffy‐coat method or apheresis and stored in PAS for a maximum of five days. Cazenave 2010 stored standard platelet products in plasma.

Off‐protocol transfusions

Off‐protocol transfusions were permitted in all trials, including two of the cross‐over trials (Simonsen 2006; Slichter 2006), with a defined, 24‐hour washout period between study transfusions in Simonsen 2006. No information was given with regard to the proportion of participants who received off‐protocol transfusions in three trials (Agliastro 2006; De Francisci 2004; Johansson 2013).

Co‐interventions

Red cell transfusions

Participants in all trials received red cell transfusions as required. Only two trials reported red cell transfusion protocols (Rebulla 2016; Slichter 2006). In Slichter 2006, red blood cell transfusions were given to maintain a minimum haematocrit of 25% across both trial arms. In Rebulla 2016, red blood cell transfusions were given when the haemoglobin dropped below 80 g/L.

Outcomes

Of the 12 included trials, only three trials reported bleeding as a primary outcome measure (McCullough 2004; Rebulla 2016; Slichter 2006).

On the other hand, six included trials used CCI as a primary outcome measure (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; Lozano 2011; Simonsen 2006; van Rhenen 2003). In two trials the primary outcome measures were not clear (Agliastro 2006; De Francisci 2004), although both trials reported bleeding and CCI.

Intercept PCT platelet trials

All 10 included trials comparing Intercept PCT to standard platelets stated bleeding and severity of bleeding complications as outcomes. However, in the two trials reported as abstracts (Agliastro 2006; De Francisci 2004), information relevant to participants' haemostatic status, bleeding scale assessment, and the timing of bleeding observation was not provided. The World Health Organization (WHO) and the Common Terminology Criteria for Adverse Events (CTCAE) were used to assess bleeding across the remaining eight trials (Janetzko 2005; Kerkhoffs 2010; Lozano 2011; McCullough 2004; Simonsen 2006; Slichter 2006; Rebulla 2016; van Rhenen 2003). Based on the WHO bleeding classification, four trials reported on bleeding grade 2 and above (Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016), and five trials reported bleeding grade 3 and above (Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; van Rhenen 2003).

The period during which bleeding assessments were performed varied between trials. In four trials (Janetzko 2005; Lozano 2011; McCullough 2004; Slichter 2006), bleeding assessments were made six hours before and six hours after platelet transfusions. The longest monitoring period was reported in the Kerkhoffs 2010 trial, in which the bleeding assessment was made daily over the 42‐day study period.

Mirasol PCT platelet trials

All three trials comparing Mirasol PCT to standard platelets reported bleeding (Cazenave 2010; Johansson 2013; Rebulla 2016). Bleeding was a primary outcome measure in one trial (Rebulla 2016). The primary outcome measure in the other two trials was the platelet CCI measured one hour post‐transfusion (Cazenave 2010; Johansson 2013).

In all three trials bleeding was reported according to WHO bleeding grades. The period during which bleeding assessments were performed varied between trials. In Cazenave 2010, bleeding assessments were performed 1 hour and 24 hours after each study transfusion and on the final follow‐up visit. In Johansson 2013, bleeding assessments were performed 12 hours before and after the platelet transfusion. In Rebulla 2016, a daily bleeding assessment was made during the 28‐day study period.

Authorship and funding sources

Intercept PCT platelet trials

Only one Intercept trial, Kerkhoffs 2010, was established to be independently financed and published without connection to either Cerus Corporation (manufacturers of the Intercept PCT platelet product) or Baxter Healthcare Corporation (manufacturer of InterSol PAS), or both. Six Intercept trials were supported by either one or both of these companies, with the data held by Cerus Corporation (Janetzko 2005; Lozano 2011; McCullough 2004; Simonsen 2006; Slichter 2006; van Rhenen 2003). The author and critical reviewer of many of these trials, Dr Larry Corash, an employee of Cerus Corporation, provided additional data for all six trials. The funding source was not reported for the two abstracts (Agliastro 2006; De Francisci 2004).

The Italian Platelet Technology Assessment Study (IPTAS) study comparing both Intercept and Mirasol was sponsored by the Italian Ministry of Health (Grant Ricerca Finalizzata 2009) and cofunded by Cerus and Terumo BCT (Rebulla 2016).

Mirasol PCT platelet trials

One Mirasol trial, Cazenave 2010, was supported by CaridianBCT (manufacturers of Mirasol PCT platelets), of which the corresponding author, Dr Raymond Goodrich, is an employee. Additional information was again provided through direct contact with the Mirasol study group to supplement the published data.

Four authors in Johansson 2013 were employees of Terumo BCT. The IPTAS study comparing both Intercept and Mirasol was sponsored by the Italian Ministry of Health (Grant Ricerca Finalizzata 2009) and cofunded by Cerus and Terumo BCT (Rebulla 2016)

Ongoing studies

We identified three ongoing RCTs, two have been completed but has not yet published (NCT01789762; Kerkhoffs 2013). Both trials were non‐inferiority, parallel‐group, multicentre RCTs, one comparing Mirasol and the other comparing Intercept. The third RCT, EUCTR2015‐001035‐20‐DE, will compare Theraflex pathogen inactivation technology to standard platelets. See Characteristics of ongoing studies for details.

Intercept PCT platelet trials

NCT01789762 was conducted in France and recruited 842 adults hospitalised for bone marrow aplasia from May 2013 to January 2016.The study compared Intercept platelets with platelets prepared in PAS, with bleeding as the primary outcome. This study has not yet been published.

Mirasol PCT platelet trials

Kerkhoffs 2013 was conducted in the Netherlands and recruited 567 participants with acute myeloid leukaemia (personal communication from study author). The study is comparing pooled buffy coat‐derived Mirasol pathogen‐reduced platelets with standard plasma platelets. The trial stopped enrolling participants in May 2016 and has not yet been published (personal communication from study authors).

Theraflex PCT platelet trials

EUCTR2015‐001035‐20‐DE will be conducted in Germany in adults with haematological malignancies. The study will compare Theraflex ultraviolet platelets with plasma‐reduced platelet concentrates stored in SSP+ additive solution.

Excluded studies

We excluded 21 studies from the review following full‐text eligibility assessment (see Characteristics of excluded studies).

The reasons for exclusion were as follows.

• Nine were not RCTs (Ayupova 2014; Berger 2013; Corash 2012; Drawz 2015; Infanti 2011; NCT00742001; NCT02330081; Rummler 2013; Sigle 2013).

• Four were studies in healthy donors (AuBuchon 2005; Corash 2000; Dumont 2010; NCT02653443).

• Five studies used the wrong intervention (Andreu 1993; Blundell 1996; MacLennan 2015; NCT01615146; TRAP 1997). Three studies compared treatment with ultraviolet B irradiation only (Andreu 1993; Blundell 1996; TRAP 1997). Ultraviolet B irradiation has been used to prevent the formation of antiplatelet alloantibodies and refractoriness to platelet transfusions (Blundell 1996), but not to reduce or remove pathogens. MacLennan 2015 compared platelets stored two to five days with platelets stored for six or seven days. NCT01615146 compared a therapeutic versus prophylactic platelet transfusion policy.

• Three studies were reviews (Cid 2012; Cook 2013; Vamvakas 2012).

Risk of bias in included studies

See Figure 2 and Figure 3 for visual representations of the ’Risk of bias’ assessments across all included trials and for each individual item in the included trials. See the Characteristics of included studies section ’Risk of bias’ table for further information about the bias identified within the individual trial.

Figure 2.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

Figure 3.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

The overall risk of bias was generally low, with much of the methodological information confirmed through direct contact with the trial authors or study group in addition to the published data. Two of the included trials were available only as abstracts (Agliastro 2006; De Francisci 2004), and therefore were often rated as at unclear risk of bias due to insufficient information.

Allocation

Intercept PCT platelet trials

Eight trials were at low risk of selection bias due to adequate methods of sequence generation and allocation concealment (Janetzko 2005; Kerkhoffs 2010; Lozano 2011; McCullough 2004; Rebulla 2016; Simonsen 2006; Slichter 2006; van Rhenen 2003). We sought additional information from the authors of five trials in order to support the published information and confirm the method of randomisation or allocation concealment, or both (Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Simonsen 2006; van Rhenen 2003).

The two trials published as an abstract did not report their method of randomisation or allocation concealment and were therefore judged to be at unclear risk of selection bias (Agliastro 2006; De Francisci 2004).

Mirasol PCT platelet trials

All three trials were at low risk of selection bias due to adequate methods of sequence generation and allocation concealment (Cazenave 2010; Johansson 2013; Rebulla 2016).

Blinding

Intercept PCT platelet trials

Blinding of participants and personnel (performance bias)

Six trials were at low risk of performance bias because both treatment providers and participants were blinded to the intervention status (Lozano 2011; McCullough 2004; Rebulla 2016; Simonsen 2006; Slichter 2006; van Rhenen 2003).

Two trials were at unclear risk of performance bias because they did not provide information on blinding (Agliastro 2006; De Francisci 2004)

Two trials were at high risk of performance bias. Janetzko 2005 was at high risk due to the lack of uniformity in the handling and blinding of the study transfusions, which could have had an impact on self reporting of bleeding, for example. Kerkhoffs 2010 was at high risk of performance and detection bias because no blinding of any kind was implemented.

Blinding of outcome assessors (detection bias)

Seven trials were at low risk of detection bias because outcome assessors were blinded (Lozano 2011; Janetzko 2005; McCullough 2004; Rebulla 2016; Simonsen 2006; Slichter 2006; van Rhenen 2003).

Two trials were at unclear risk of detection bias because they did not provide information on blinding (Agliastro 2006; De Francisci 2004).

One trial was at high risk of detection bias because no blinding of any kind was implemented (Kerkhoffs 2010).

Mirasol PCT platelet trials

Blinding of participants and personnel (performance bias)

One trial was at low risk of performance bias because both trial participants and personnel were unaware of the intervention status (Rebulla 2016).

One trial was at unclear risk of performance bias because no clear information was provided (Johansson 2013).

One trial was at high risk of performance bias because the lack of blinding of the pathogen‐reduced platelet appearance could have affected ordering of additional platelets transfusions by the attending physician (Cazenave 2010).

Blinding of outcome assessors

All three trials were at low risk of detection bias because outcome assessors were blinded (Cazenave 2010; Johansson 2013; Rebulla 2016).

Incomplete outcome data

Intercept PCT platelet trials

Seven trials were at low risk of attrition bias because no participants were lost to follow‐up (De Francisci 2004); all participants who received a platelet transfusion were included in the analysis (Janetzko 2005; Kerkhoffs 2010; Rebulla 2016); all participants who received a platelet transfusion using the modified method of production were included in the analysis (Slichter 2006); or there was balanced loss to follow‐up between treatment arms, and the numbers lost to follow‐up were low (Lozano 2011; McCullough 2004).

Three trials were at unclear risk of attrition bias. Agliastro 2006 was only reported as an abstract, and no information was provided about whether any randomised participants were lost to follow‐up or withdrawn from treatment. In van Rhenen 2003, more participants receiving the intervention completed cycle 1 of the study than those receiving standard platelet transfusions (83% versus 67% completed cycle 1; P = 0.06). In Simonsen 2006, 28 participants were randomised, but only 20 were included in the per‐protocol analysis (3 did not receive a platelet transfusion; 3 received only 1 of the 2 types of platelet transfusion; and there were 2 major protocol violations). The number of participants who received a platelet transfusion that were lost to follow‐up was balanced between treatment arms (3 out of 12 randomised to receive an Intercept PCT platelet transfusion first and 2 out of 13 randomised to receive a standard platelet transfusion first).

Mirasol PCT platelet trials

Two trials were at low risk of attrition bias because all participants who received a platelet transfusion were included in the analysis (Cazenave 2010; Rebulla 2016).

One trial was at unclear risk of attrition bias. Johansson 2013 enrolled 16 participants, but only 10 participants were included in the study's primary outcome; 12 participants were included in other efficacy outcomes; and 15 participants were included in safety outcomes.

Selective reporting

Intercept PCT platelet trials

Seven trials were at low risk of reporting bias because all prespecified outcomes were reported in the publications or provided via direct author contact (Janetzko 2005; Kerkhoffs 2010; Rebulla 2016; Simonsen 2006; Slichter 2006; van Rhenen 2003).

One trial reported only as an abstract was at unclear risk of reporting bias (Agliastro 2006).

One trial was at high risk of reporting bias. In De Francisci 2004, the 1‐hour CCI was not reported for the adult cirrhotic group; no standard deviations were reported for the mean 1‐ and 24‐hour CCIs for either group, and pre‐ and post‐transfusion platelet counts for both groups were missing despite their inclusion as outcomes in the trial's methods section.

Mirasol PCT platelet trials

Two trials were at low risk of reporting bias because all prespecified outcomes were reported in the publications or provided via direct author contact (Cazenave 2010; Rebulla 2016).

One trial was at unclear risk of reporting bias because the trial protocol was not available, and trial registration occurred after the trial had been completed (Johansson 2013).

Other potential sources of bias

Intercept PCT platelet trials

Eight trials were at low risk of other potential sources of bias apart from the outcome of bleeding (Janetzko 2005; Kerkhoffs 2010; Lozano 2011; McCullough 2004; Rebulla 2016; Simonsen 2006; Slichter 2006).

Six trials reported on red cell transfusions received as an indirect measure of bleeding (Janetzko 2005; Kerkhoffs 2010; Lozano 2011; McCullough 2004; van Rhenen 2003; Slichter 2006), but only one of these reported a red cell transfusion policy of maintaining a haematocrit of at least 25% across both trial arms (Slichter 2006). Variations in red cell transfusion policies across centres within a trial could affect the assessment of bleeding grade and therefore lead to bias. Also, variations in the use of red cell transfusions between trials could affect the results of any meta‐analysis (Estcourt 2012).

Duplication of participants through inclusion in more than one study cycle was identified in three Intercept trials (McCullough 2004; Simonsen 2006; van Rhenen 2003). One participant out of 20 received both study transfusions on two separate occasions in Simonsen 2006. This was not thought to pose a high risk of bias, as a single participant included twice should not have a significant impact on the accuracy of the trial's outcomes, despite the small size of the study. McCullough 2004 reported data from only the first cycle of study, whilst the data for van Rhenen 2003 were extracted from cycle 1 only, either from the published literature or obtained through direct author contact.

Two trials were at unclear risk of other bias because they were only reported as abstracts (Agliastro 2006; De Francisci 2004).

Mirasol PCT platelet trials

Two trials were at low risk of other potential sources of bias (Cazenave 2010; Rebulla 2016).

Johansson 2013 was at unclear risk of other potential sources of bias because the trial was conducted mainly on male participants, and the study registration was made after trial completion.

Effects of interventions

See: Table 1

For an overview of the main findings of the review, please see Table 1.

We included three cross‐over trials (Johansson 2013; Simonsen 2006; Slichter 2006). We were unable to use data provided by Johansson 2013 in any of the meta‐analyses as there was no clear washout period between the two trial phases.

Where possible, for all outcomes we reported on overall differences between pathogen‐reduced platelet transfusions compared with standard platelet transfusions, then afterward reported the same outcomes for Intercept platelets and Mirasol platelets individually.

Primary outcomes

Number, type, timing, and severity of bleeding episodes

All 12 trials stated bleeding as an outcome. Bleeding was the primary outcome measure in two trials (McCullough 2004; Rebulla 2016). The duration of bleeding assessment varied between trials. Five trials reported bleeding events for up to 48 hours (De Francisci 2004; Johansson 2013; Lozano 2011; Simonsen 2006; Slichter 2006), and 7 trials reported bleeding events for more than 7 days (Table 5) (Agliastro 2006; Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; van Rhenen 2003). No trials reported bleeding between 48 hours and 7 days.

Table 3.

Bleeding assessment

Study	Bleeding scale used	Duration of bleeding assessment	Timing of bleeding assessment(s)	Maximum number of days of on‐study plt transfusion support	Bleeding results reported in meta‐analysis
Single‐transfusion studies ‐ Intercept
De Francisci 2004	NR	S	NR	1	NR
Lozano 2011	WHO1	S	6 hrs pre‐ and 6 hrs post‐Tx	1	Post‐Tx bleeding score
Simonsen 2006	WHO1 (m)	S	≤ 12 hrs post‐Tx	1	Post‐Tx bleeding score
Slichter 2006	WHO1 (m)	S	6 hrs pre‐ and 6 hrs post‐Tx	1	Post‐Tx bleeding score
Multiple‐transfusion studies ‐ Intercept
Agliastro 2006	NR	L	NR	NR	NR
Janetzko 2005	WHO1	L	6 hrs pre‐ and post‐ each plt Tx + daily	35	Max bleeding score/participant
Kerkhoffs 2010	CTCAE2	L	Post‐1st Tx + daily	42	Max bleeding score/participant
McCullough 2004	WHO1 (e)	L	12 hrs post‐Tx + daily	28	Max bleeding score/participant
Rebulla 2016	WHO1	L	Post‐1st Tx + daily	28	Max bleeding score/participant
van Rhenen 2003	WHO1 (m)	L	6 hrs pre‐ and 6 hrs post‐Tx	56	Max bleeding score/participant
Single‐transfusion studies ‐ Mirasol
Johansson 2013	WHO1	S	12 hours pre‐ and post‐Tx	1	NR
Multiple‐transfusion studies ‐ Mirasol
Cazenave 2010	WHO1	L	1 hr pre‐ and post‐Tx + 24 hrs post‐Tx +  final follow‐up visita	28	Max bleeding score/participant
Rebulla 2016	WHO1	L	Post‐1st Tx + daily	28	Max bleeding score/participant

Key:

(e): scale expanded (more specifically defined WHO grades, including sites of bleeding) L: long‐term bleeding assessment (> 7 days) post‐transfusion (m): scale modified (only 3 scores: none = 0, minor = 1 (equivalent  to WHO grades 1 and 2), major = 2 (equivalent to WHO grades 3 and 4)) NA: not applicable NR: not reported plt: platelet S: short‐term bleeding assessment (up to 48 hours) post‐transfusion M: medium‐term bleeding (2 to 7 days) post‐transfusion Tx: transfusion

^aOn‐protocol platelet transfusions only.

References:

1. WHO scale – WHO. WHO Handbook for Reporting Results of Cancer Treatment. Geneva: World Health Organization; 1979. 2. U.S. Dept of Health and Human Services (National Institutes of Health and National Cancer Institute). Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0, September 2006.

For trials that reported bleeding for up to 48 hours, we extracted the post‐transfusion bleeding assessment data from the trial reports.

For trials that reported bleeding for more than seven days, we extracted the number of participants with bleeding documented during a specific bleeding assessment. These bleeding assessments were reported to be undertaken on at least a daily basis in four trials (Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016); pre‐ and post‐platelet transfusion in two trials (Cazenave 2010; van Rhenen 2003); and were not described in two trials (Agliastro 2006; De Francisci 2004). We did not extract bleeding data reported within a trial's adverse event data.

We undertook meta‐analyses for 'any bleeding' (WHO grades 1 to 4, CTCAE 1 to 5 or equivalent), 'clinically significant bleeding' (WHO/CTCAE grade 2 and above or equivalent), and 'severe bleeding' (WHO/CTCAE grade 3 and above or equivalent), with trials grouped according to the duration of bleeding assessment.

As might be expected, the single platelet transfusion trials assessed bleeding for up to 48 hours, while the multiple platelet transfusion trials assessed bleeding over a period of more than seven days.

Any bleeding (WHO) grades 1 to 4 ‐ assessed at up to 48 hours

Four trials assessed the risk of any bleeding at less than 48 hours (Johansson 2013; Lozano 2011; Simonsen 2006; Slichter 2006). One cross‐over trial did not report a washout period (Johansson 2013). Post‐transfusion, there were three bleeding events (petechiae or purpura) after both pathogen‐reduced platelet transfusions and standard platelet transfusions. The three remaining trials all compared Intercept and standard platelets (Lozano 2011; Simonsen 2006; Slichter 2006).

There was no evidence of a difference in the risk of any bleeding between the Intercept and standard platelets (3 trials, 309 participants; risk ratio (RR) 0.86, 95% confidence interval (CI) 0.63 to 1.19; P = 0.38; I² = 0%) (Analysis 1.1).

Analysis 1.1.

Comparison 1 Pathogen‐reduced platelets versus standard platelets for the prevention of bleeding, Outcome 1 Number of participants with 'any bleeding' event(s) (WHO grade 1 to 4 or equivalent) ‐ follow‐up less than 48 hrs.

Any bleeding (WHO) grades 1 to 4 ‐ assessed at more than 7 days

Five trials reported this outcome (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; McCullough 2004; van Rhenen 2003).

We are very uncertain as to whether recipients of pathogen‐reduced platelets have a higher risk of any bleeding. Using a fixed‐effect analysis, recipients of pathogen‐reduced platelets were at a higher risk of any bleeding when compared with standard platelets (5 trials, 1085 participants; RR 1.09, 95% CI 1.02 to 1.15; P = 0.007; I² = 59%) (Analysis 1.2). However, using a random‐effects model, there was no longer any evidence of a difference between treatment arms (5 trials, 1085 participants; RR 1.14, 95% CI 0.93 to 1.38; P = 0.20; I² = 59%) (analysis not shown).

Analysis 1.2.

Comparison 1 Pathogen‐reduced platelets versus standard platelets for the prevention of bleeding, Outcome 2 Number of participants with 'any bleeding' event(s) (WHO grade 1 to 4 or equivalent) ‐ follow‐up more than 7 days.

Intercept PCT platelet trials

Four Intercept trials reported this outcome (Janetzko 2005; Kerkhoffs 2010; McCullough 2004; van Rhenen 2003).

We are very uncertain as to whether recipients of Intercept platelet transfusions have a higher risk of any bleeding. Using a fixed‐effect analysis, recipients of Intercept platelet transfusions were at a higher risk of any bleeding when compared with standard platelets (4 trials, 975 participants; RR 1.07, 95% CI 1.01 to 1.13; P = 0.03; I² = 47%) (Analysis 1.2). However, using a random‐effects model, there was no longer any evidence of a difference between treatment arms (4 trials, 975 participants; RR 1.08, 95% CI 0.91 to 1.30; P = 0.37; I² = 47%) (analysis not shown).

Mirasol PCT platelet trials

One Mirasol trial reported the risk of any bleeding (Cazenave 2010). There was no evidence of a difference between the Mirasol and control platelets (1 trial, 110 participants; RR 1.38, 95% CI 0.95 to 2.02; P = 0.09) (Analysis 1.2).

There was no evidence of subgroup differences between studies of Intercept and Mirasol platelets (test for subgroup differences: Chi² = 1.78, df = 1, P = 0.18, I² = 43.8%).

Clinically significant bleeding WHO grade 2 or above ‐ assessed at up to 48 hours

We could not incorporate data from three trials into an analysis. Slichter 2006 reported bleeding events as either minor or major and, as minor bleeding could not be split into the equivalent WHO/CTCAE grades 1 and 2, these results were not included in this outcome. In Johansson 2013 there was one bleeding event (WHO grade 2 petechiae or purpura) after a standard platelet transfusion. In Simonsen 2006 there was one bleeding event (WHO grade 2) in the Intercept PCT platelets arm and no bleeding events in the standard platelet transfusion arm. We could not include data from these two trials in a meta‐analysis using the generic inverse variance method because no events occurred in one of the study arms (Johansson 2013; Simonsen 2006).

In Lozano 2011 there was no evidence of a difference in clinically significant bleeding between treatment arms (1 trial, 211 participants; RR 1.01, 95% CI 0.34 to 3.03; P = 0.99) (Analysis 1.3).

Analysis 1.3.

Comparison 1 Pathogen‐reduced platelets versus standard platelets for the prevention of bleeding, Outcome 3 Number of participants with 'clinically significant' bleeding (WHO grade ≥ 2 or equivalent ‐ follow‐up less than 48 hours.

Clinically significant bleeding WHO grade 2 or above ‐ assessed at more than 7 days

van Rhenen 2003 reported bleeding events as either minor or major and, as minor bleeding could not be split into the equivalent WHO/CTCAE grades 1 and 2, these results could not be included in this outcome.

Five trials reported this outcome (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016). There was no evidence of a difference in the risk of clinically significant bleeding between recipients of pathogen‐reduced platelets and recipients of standard platelets (5 trials, 1392 participants; RR 1.10, 95% CI 0.97 to 1.25; P = 0.15; I² = 0%) (Analysis 1.4).

Analysis 1.4.

Comparison 1 Pathogen‐reduced platelets versus standard platelets for the prevention of bleeding, Outcome 4 Number of participants with 'clinically significant' bleeding (WHO grade ≥ 2 or equivalent) ‐ follow‐up more than 7 days.

Intercept PCT platelet trials

Four Intercept trials reported this outcome (Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016). There was no evidence of a difference in the risk of clinically significant bleeding between recipients of Intercept platelets and standard platelets (4 trials, 1088 participants; RR 1.06, 95% CI 0.94 to 1.21; P = 0.34; I² = 0%) (Analysis 1.4). However, this analysis was dominated by the large McCullough 2004 study (over 80% of weighting).

Mirasol PCT platelet trials

Two trials reported this outcome (Cazenave 2010; Rebulla 2016).

There was no evidence of a difference in the risk of clinically significant bleeding between recipients of Mirasol platelets and standard platelets (2 trials, 304 participants; RR 1.54, 95% CI 0.86 to 2.76; P = 0.15; I² = 0%) (Analysis 1.4).

There was no evidence of subgroup differences between studies of Intercept and Mirasol platelets (test for subgroup differences: Chi² = 1.44, df = 1, P = 0.23, I² = 30.8%).

Severe bleeding (WHO) grade 3 or above ‐ assessed at up to 48 hours

Four trials reported this outcome (Johansson 2013; Lozano 2011; Simonsen 2006; Slichter 2006). No severe bleeding events occurred in three trials (Johansson 2013; Simonsen 2006; Slichter 2006).

In Lozano 2011 there was no evidence of a difference in severe bleeding outcomes between treatment arms (1 trial, 211 participants; RR 2.02, 95% CI 0.19 to 21.93; P = 0.56) (Analysis 1.5).

Analysis 1.5.

Comparison 1 Pathogen‐reduced platelets versus standard platelets for the prevention of bleeding, Outcome 5 Number of participants with 'severe' bleeding (WHO grade ≥ 3 or equivalent) ‐ follow‐up less than 48 hours.

Severe bleeding (WHO) grade 3 or above ‐ assessed at more than 7 days

Six trials reported this outcome (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; van Rhenen 2003).

There was no evidence of a difference in the risk of developing clinically severe bleeding between recipients of pathogen‐reduced platelets and standard platelets (6 trials, 1495 participants; RR 1.24, 95% CI 0.76 to 2.02; P = 0.39; I² = 32%) (Analysis 1.6). This analysis was dominated by the large McCullough 2004 study (over 70% of weighting).

Analysis 1.6.

Comparison 1 Pathogen‐reduced platelets versus standard platelets for the prevention of bleeding, Outcome 6 Number of participants with 'severe' bleeding (WHO grade ≥ 3 or equivalent) ‐ follow‐up more than 7 days.

We defined an I² value higher than 30% as moderate statistical heterogeneity. Applying the random‐effects model did not alter the results (6 trials, 1495 participants; RR 1.51, 95% CI 0.67 to 3.40; P = 0.32; I² = 32%) (analysis not shown).

In McCullough 2004 more participants in the standard platelet transfusion arm had severe bleeding, whereas in the other three trials the results favoured PCT platelets. Removing McCullough 2004 data from the analysis removed all statistical heterogeneity, and suggested that participants receiving PCT platelets in the other three trials may be at a higher risk of developing severe bleeding (5 trials, 850 participants; RR 2.64, 95% CI 1.19 to 5.86; P = 0.02; I² = 0%) (analysis not shown).

Intercept PCT platelet trials

Five trials reported this outcome (Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; van Rhenen 2003). There was no evidence of a difference in the risk of developing clinically severe bleeding between recipients of Intercept and standard platelets (5 trials, 1191 participants; RR 1.21, 95% CI 0.70 to 2.09; P = 0.49; I² = 48%) (Analysis 1.6). This analysis was dominated by the large McCullough 2004 study (over 85% of weighting).

We defined an I² value higher than 30% as moderate statistical heterogeneity. Applying the random‐effects model did not alter the results (5 trials, 1191 participants; RR 2.08, 95% CI 0.60 to 7.20; P = 0.25; I² = 48%) (analysis not shown).

Removing McCullough 2004 data from the analysis removed all statistical heterogeneity, and suggested that participants receiving Intercept platelets in the remaining trials may be at a higher risk of developing severe bleeding (4 trials, 546 participants; RR 4.84, 95% CI 1.41 to 16.60; P = 0.01; I² = 0%) (analysis not shown).

Mirasol PCT platelet trials

Two multiple‐transfusion trials reported this outcome (Cazenave 2010;Rebulla 2016). There was no evidence of a difference in the risk of developing clinically severe bleeding between recipients of Mirasol and standard platelets (2 trials, 304 participants; RR 1.36, 95% CI 0.45 to 4.16; P = 0.59; I² = 0%) (Analysis 1.6).

There was no evidence of subgroup differences between studies of Intercept and Mirasol platelets (test for subgroup differences: Chi² = 0.03, df = 1, P = 0.85, I² = 0%).

Type of bleeding

Six trials reported the sites of bleeding with very variable methods of assessment and reporting, and so we have reported them narratively here (Janetzko 2005; Lozano 2011; McCullough 2004; Rebulla 2016; van Rhenen 2003).

Where reported, the majority of bleeding occurred at mucocutaneous sites (Janetzko 2005; Johansson 2013; Lozano 2011; McCullough 2004; Rebulla 2016; van Rhenen 2003). Invasive, gastrointestinal, and genitourinary WHO grade 2 or more bleeding events were seen quite frequently in McCullough 2004 (18.9% to 32.7%), although few such episodes were reported by the three other trials. However, McCullough 2004 was a larger trial that reported on bleeding daily and did not exclude people with active bleeding.

Mortality

Ten trials reported mortality over a variety of time periods (Table 3) (Cazenave 2010; Janetzko 2005; Johansson 2013; Kerkhoffs 2010; Lozano 2011; McCullough 2004; Rebulla 2016; Simonsen 2006; Slichter 2006; van Rhenen 2003). Two trials did not report this outcome (Agliastro 2006; De Francisci 2004).

As Johansson 2013 (no deaths), Simonsen 2006 (no deaths), and Slichter 2006 (three deaths) were cross‐over trials, it was not possible to assign deaths to a single trial arm, therefore we could not include these data in any meta‐analysis. We have not reported data from these cross‐over trials further in this section on mortality.

We defined short‐term mortality as up to 4 weeks, medium‐term mortality as 4 weeks to 12 weeks, and long‐term mortality as greater than 12 weeks. One trial (a single‐transfusion trial) reported all‐cause mortality for up to 4 weeks after the start of the study period (Lozano 2011), and six trials (all multiple‐transfusion trials) reported all‐cause mortality for 4 to 12 weeks (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; van Rhenen 2003).

All‐cause mortality (up to 4 weeks)

One single‐transfusion trial reported this outcome (Lozano 2011).

There was no evidence of a difference in all‐cause mortality between the two study arms (1 trial, 211 participants; RR 0.14, 95% CI 0.01 to 2.76) (Analysis 1.7).

Analysis 1.7.

Comparison 1 Pathogen‐reduced platelets versus standard platelets for the prevention of bleeding, Outcome 7 All‐cause mortality (follow‐up 0 to < 4 weeks).

Mortality due to bleeding, thromboembolism, or transfusion reactions (up to 4 weeks)

One single‐transfusion trial reported these outcomes (Lozano 2011). No deaths occurred due to bleeding, thromboembolism, or transfusion reactions.

Mortality due to infection (up to 4 weeks)

One single‐transfusion trial reported these outcomes (Lozano 2011). There was no evidence of a difference in mortality due to infection between the two study arms (1 trial, 211 participants; RR 0.20, 95% CI 0.01 to 4.16) (Analysis 1.7).

All‐cause mortality (4 weeks to 12 weeks)

Six multiple‐transfusion trials reported this outcome (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; van Rhenen 2003).

There was no evidence of a difference in all‐cause mortality between participants receiving pathogen‐reduced platelets and participants receiving standard platelets (6 trials, 1509 participants; RR 0.81, 95% CI 0.50 to 1.29; P = 0.37; I² = 26%) (Analysis 1.8).

Analysis 1.8.

Comparison 1 Pathogen‐reduced platelets versus standard platelets for the prevention of bleeding, Outcome 8 All‐cause mortality (follow‐up 4 to 12 weeks).

Intercept PCT platelet trials

There was no evidence of a difference in all‐cause mortality between participants receiving Intercept PCT platelets and participants receiving standard platelets (5 trials, 1203 participants; RR 0.62, 95% CI 0.37 to 1.05; P = 0.07; I² = 0%) (Analysis 1.8).

Mirasol PCT platelet trials

There was no evidence of a difference in all‐cause mortality between participants receiving Mirasol PCT platelets and participants receiving standard platelets (2 trials, 306 participants; RR 2.92, 95% CI 0.81 to 10.59; P = 0.10; I² = 0%) (Analysis 1.8).

There was evidence of subgroup differences between studies of multiple Intercept and Mirasol platelets transfusions (test for subgroup differences: Chi² = 4.93, df = 1, P = 0.03, I² = 79.7%).

Mortality due to bleeding (4 weeks to 12 weeks)

Six multiple‐transfusion trials reported mortality due to bleeding (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; van Rhenen 2003), and there was no evidence of a difference between treatment arms (6 trials, 1509 participants; RR 1.23, 95% CI 0.38 to 3.96; P = 0.73, I² = 0%) (Analysis 1.9).

Analysis 1.9.

Comparison 1 Pathogen‐reduced platelets versus standard platelets for the prevention of bleeding, Outcome 9 Mortality due to bleeding (follow‐up 4 to 12 weeks).

Intercept PCT platelet trials

There was no evidence of a difference in mortality due to bleeding between participants receiving Intercept PCT platelets and participants receiving standard platelets (5 trials, 1203 participants; RR 1.04, 95% CI 0.29 to 3.75; P = 0.96; I² = 0%) (Analysis 1.9).

Mirasol PCT platelet trials

There was no evidence of a difference in mortality due to bleeding between participants receiving Mirasol PCT platelets and participants receiving standard platelets (2 trials, 306 participants; RR 2.89, 95% CI 0.12 to 69.55; P = 0.51; I² = 0%) (Analysis 1.9).

There was no evidence of subgroup differences between studies of multiple Intercept and Mirasol platelets transfusions (test for subgroup differences: Chi² = 0.34, df = 1, P = 0.56, I² = 0%).

Mortality due to infection (4 weeks to 12 weeks)

Six multiple‐transfusion trials reported mortality due to infection (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; van Rhenen 2003), and there was no evidence of a difference between treatment arms (6 trials, 1509 participants; RR 0.94, 95% CI 0.42 to 2.09; P = 0.88; I² = 0%) (Analysis 1.10).

Analysis 1.10.

Comparison 1 Pathogen‐reduced platelets versus standard platelets for the prevention of bleeding, Outcome 10 Mortality due to infection (follow‐up 4 to 12 weeks).

Intercept PCT platelet trials

There was no evidence of a difference in mortality due to infection between participants receiving Intercept PCT platelets and participants receiving standard platelets (5 trials, 1203 participants; RR 0.84, 95% CI 0.35 to 2.03; P = 0.70; I² = 0%) (Analysis 1.10).

Mirasol PCT platelet trials

There was no evidence of a difference in mortality due to infection between participants receiving Mirasol PCT platelets and participants receiving standard platelets (2 trials, 306 participants; RR 1.62, 95% CI 0.22 to 12.07; P = 0.63; I² = 0%) (Analysis 1.10).

There was no evidence of subgroup differences between studies of multiple Intercept and Mirasol platelets transfusions (test for subgroup differences: Chi² = 0.36, df = 1, P = 0.55, I² = 0%).

Mortality due to thromboembolism (4 weeks to 12 weeks)

Five multiple‐transfusion trials reported on the incidence of thromboembolism (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; van Rhenen 2003). No deaths were attributed to thromboembolism in any of the trials.

Mortality due to transfusion reactions (4 weeks to 12 weeks)

Six multiple‐transfusion trials reported anaphylaxis reactions (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; van Rhenen 2003). No deaths were attributed to transfusion reactions.

Secondary outcomes

Adverse events

All 12 trials reported adverse events. Six trials included bleeding, platelet refractoriness, and/or acute transfusion reactions within the definition of adverse or serious adverse events (Cazenave 2010; Kerkhoffs 2010; Lozano 2011; McCullough 2004; Rebulla 2016; van Rhenen 2003).

Due to the difficulties of assigning an adverse event to a product within cross‐over trials, Simonsen 2006 and Slichter 2006 did not report adverse events in detail. Slichter 2006 reported safety outcomes for all 50 randomised participants, although 18 participants received Intercept PCT platelets prepared using a different protocol and were excluded in the clinical efficacy outcomes.

The duration of follow‐up for adverse events varied widely. Participants in Johansson 2013 were observed for acute transfusion reactions and transfusion‐related serious adverse events over the 24 hours after platelet transfusion. De Francisci 2004 reported events up to six months after the single study transfusion episode, whilst Lozano 2011 reported any adverse event until four days post‐transfusion, but serious adverse events up to 15 days post‐transfusion. Rebulla 2016, Janetzko 2005, McCullough 2004, Cazenave 2010, and van Rhenen 2003 reported both any adverse events and serious adverse events that occurred during the study and follow‐up periods (a maximum of 28, 35, 70, and 84 days after the start of the study period).

Frequently, studies reported 'any adverse events' or 'serious adverse events' only if they affected more than a certain proportion of the trial population. In order to extract data on the frequency of specific adverse events, we attempted direct author contact and were successful in all but two cases (Agliastro 2006; De Francisci 2004).

Recognised complications of platelet transfusions

Acute (mild) transfusion reactions

Twelve trials reported on acute transfusion reactions (defined in our protocol as rigors, fever, skin rash, and urticaria) (Agliastro 2006; Cazenave 2010; De Francisci 2004; Janetzko 2005; Johansson 2013; Kerkhoffs 2010; Lozano 2011; McCullough 2004; Rebulla 2016; Simonsen 2006; Slichter 2006; van Rhenen 2003). Three multiple Intercept transfusion trials reported transfusion reactions within six hours post‐transfusion (Janetzko 2005; McCullough 2004; van Rhenen 2003). Three single‐transfusion trials reported transfusion reactions within 24 hours post‐transfusion (Johansson 2013; Lozano 2011; Simonsen 2006). The remaining six trials did not report the timing for this outcome (Agliastro 2006; Cazenave 2010; De Francisci 2004; Kerkhoffs 2010; Rebulla 2016; Slichter 2006).

We could include data from seven trials in the meta‐analysis for this outcome (Janetzko 2005; Kerkhoffs 2010; Lozano 2011; McCullough 2004; Rebulla 2016; Simonsen 2006; van Rhenen 2003), which we combined (due to the inclusion of data from a cross‐over trial) using the generic inverse variance method. There was no difference between treatment groups for the risk of an acute transfusion reaction (7 trials, 1636 participants; RR 0.96, 95% CI 0.75 to 1.24; P = 0.77; I2 = 0%) (Analysis 1.11).

Analysis 1.11.

Comparison 1 Pathogen‐reduced platelets versus standard platelets for the prevention of bleeding, Outcome 11 Number of participants with an acute transfusion reaction.

Five trials could not be included in the meta‐analysis, as trials with zero events in one or both treatment arms cannot be included when using the generic inverse variance method of analysis (Agliastro 2006; Cazenave 2010; De Francisci 2004; Johansson 2013; Slichter 2006). Three studies reported no acute transfusion reactions in either trial arm (Agliastro 2006; De Francisci 2004; Johansson 2013). Slichter 2006 reported no events in the PCT platelets arm (although this trial reported acute transfusion reactions with a broader definition than our protocol and included nausea, which was experienced by 5.2% of the Intercept PCT platelets arm) versus five participants (13%) experiencing six events in the standard platelets arm (chills, rash/urticaria, hypertension, bronchospasm, and fever). Cazenave 2010 did not report the total number of participants with acute transfusion reactions. However, it should be noted that Cazenave 2010 did report the number of participants experiencing adverse events that were considered "very likely" to be related to the study platelet transfusions, with no participants in the PCT platelets arm experiencing such an adverse event versus two participants in the standard platelets arm (recorded as anaphylaxis, hypersensitivity, and eyelid oedema), but with no difference between groups (P = 0.28).

Intercept PCT platelet trials

Two single Intercept PCT platelet transfusion trials reported on this outcome with no difference between the two arms (2 trials, 251 participants; RR 1.57, 95% CI 0.71 to 3.48; P = 0.27; I² = 0%) (Analysis 1.11) (Lozano 2011; Simonsen 2006).

Five multiple Intercept PCT platelet transfusion trials reported this outcome (Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; van Rhenen 2003). There was no evidence of a difference between recipients of Intercept or standard platelets on acute transfusion reactions (5 trials, 1191 participants; RR 0.91, 95% CI 0.69 to 1.18, P = 0.46; I² = 0%) (Analysis 1.11).

Mirasol PCT platelet trials

One multiple‐transfusion trial reported this outcome with no evidence of a difference between the two groups (1 trial, 194 participants; RR 1.99, 95% CI 0.18 to 21.78; P = 0.57) (Analysis 1.11) (Rebulla 2016).

Johansson 2013 reported no adverse transfusion reactions or transfusion‐related serious adverse events within the 24 hours after study transfusions.

There was no evidence of subgroup differences between studies of multiple Intercept and Mirasol platelets transfusions (test for subgroup differences: Chi² = 0.41, df = 1, P = 0.52, I² = 0%).

Platelet refractoriness

Seven trials reported refractoriness to platelet transfusions (Agliastro 2006; Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; van Rhenen 2003). Five trials defined refractoriness as two successive one‐hour post‐transfusion CCIs below 5 x 10³ (Cazenave 2010; Janetzko 2005; McCullough 2004; Rebulla 2016; van Rhenen 2003), while Kerkhoffs 2010 defined refractoriness as two successive one‐hour or 24‐hour CCIs below 7.5 x 10³ or 4.5 x 10³, respectively, and the presence of antibodies against platelets. Agliastro 2006 did not define refractoriness.

In six trials people with a previous history of clinical refractoriness to platelet transfusions were not eligible for inclusion (Cazenave 2010; Janetzko 2005; Johansson 2013; Kerkhoffs 2010; McCullough 2004; van Rhenen 2003). Agliastro 2006 was only available as an abstract and did not report the study inclusion and exclusion criteria.

Combining data from seven multiple platelet transfusion trials showed that recipients of pathogen‐reduced platelets were at a higher risk of developing refractoriness compared with recipients of standard platelets (7 trials, 1525 participants; RR 2.94, 95% CI 2.08 to 4.16; P < 0.001; I² = 0%) (Analysis 1.12) (Agliastro 2006; Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; van Rhenen 2003). It should be noted that one large study dominated the analysis (57.9% of overall study weighting) (McCullough 2004), and for one other trial an effect could not be estimated (Agliastro 2006).

Analysis 1.12.

Comparison 1 Pathogen‐reduced platelets versus standard platelets for the prevention of bleeding, Outcome 12 Number of participants experiencing platelet refractoriness.

Intercept PCT platelet trials

Six Intercept multiple‐transfusion trials contributed to this outcome (Agliastro 2006; Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; van Rhenen 2003). Refractoriness to platelet transfusions was more common in Intercept platelet recipients than standard platelet recipients (6 trials, 1221 participants; RR 2.85, 95% CI 1.96 to 4.15; P < 0.001; I² = 0%) (Analysis 1.12).

Three trials assessed whether amotosalen neoantigens were formed following exposure to Intercept PCT platelets, but no neoantigens were identified (Janetzko 2005; McCullough 2004; van Rhenen 2003).

Mirasol PCT platelet trials

Two Mirasol multiple‐transfusion trials reported this outcome (Cazenave 2010; Rebulla 2016). Refractoriness to platelet transfusions was more common in Mirasol platelet recipients than standard platelet recipients (2 trials, 304 participants; RR 3.47, 95% CI 1.44 to 8.34; P = 0.005; I² = 17%) (Analysis 1.12). Johansson 2013 did not report this outcome.

There was no evidence of subgroup differences between studies of multiple Intercept and Mirasol platelets (test for subgroup differences: Chi² = 0.16, df = 1, P = 0.69, I² = 0%) (Analysis 1.12).

Platelet refractoriness and platelet alloimmunisation

The CCIs formed the basis of most trials' definitions of refractoriness, therefore, in order to explore the development of platelet refractoriness specifically due to alloimmunisation, we performed a further analysis including only data from trials that reported on participants diagnosed both with their trial's definition of clinical refractoriness and with the presence of platelet alloantibodies.

Six multiple‐transfusion trials reported this outcome (Agliastro 2006; Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; van Rhenen 2003). Five trials excluded people with a previous history of platelet alloimmunisation (Kerkhoffs 2010; Johansson 2013; McCullough 2004; Rebulla 2016; van Rhenen 2003). Janetzko 2005 did not exclude people with a previous history of alloimmunisation, and Agliastro 2006 did not report their inclusion and exclusion criteria.

Participants receiving pathogen‐reduced platelet transfusions were at a higher risk of developing platelet refractoriness due to platelet alloimmunisation (6 trials, 1415 participants; RR 2.35, 95% CI 1.46 to 3.76; P < 0.001; I² = 0%) (Analysis 1.13).

Analysis 1.13.

Comparison 1 Pathogen‐reduced platelets versus standard platelets for the prevention of bleeding, Outcome 13 Number of participants experiencing platelet refractoriness and platelet alloimmunisation.

Intercept PCT platelet trials

We combined data from six Intercept multiple‐transfusion trials (Agliastro 2006; Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; van Rhenen 2003). Participants receiving Intercept platelet transfusions were at a higher risk of developing platelet refractoriness due to platelet alloimmunisation (6 trials, 1221 participants; RR 1.90, 95% CI 1.11 to 3.26; P = 0.02; I² = 0%) (Analysis 1.13).

Mirasol PCT platelet trials

One multiple‐transfusion trial reported this outcome (Rebulla 2016), and participants receiving Mirasol platelet transfusions were at a higher risk of developing platelet refractoriness due to platelet alloimmunisation (1 trial, 194 participants; RR 4.50, 95% CI 1.58 to 12.81; P = 0.005) (Analysis 1.13).

There was no evidence of subgroup differences between studies of multiple Intercept and Mirasol platelets transfusions (test for subgroup differences: Chi² = 2.06, df = 1, P = 0.15, I² = 51.5%).

All adverse events

Nine trials reported on all adverse events, five of which used the CTCAE Version 3.0, National Cancer Institute ‐ Common Toxicity Criteria (NCI‐CTC), and Medical Dictionary for Regulatory Activities (MedDRA) standards to categorise the adverse events (Cazenave 2010; Janetzko 2005; Lozano 2011; McCullough 2004; van Rhenen 2003), and three of which failed to state how adverse events were defined (De Francisci 2004; Simonsen 2006; Slichter 2006). In Rebulla 2016 participants were evaluated for adverse events, which were assessed for relation to the platelet transfusion and graded for clinical severity by the study clinical investigator. Although we had intended to exclude bleeding, transfusion reactions, and mortality data from the adverse events data for each trial, most trials did not present their data in a way that allowed for this, and so we have included all adverse events.

Regarding the three cross‐over trials, Simonsen 2006 reported one adverse event in the standard platelets arm during the 24‐hour post‐transfusion period; Slichter 2006 simply reported adverse events as "common" in both treatment arms during the entire follow‐up period of four weeks, with no additional details given; and in Johansson 2013, adverse transfusion reactions were assessed through physical examination and interviews with the study participants, but no adverse events were reported. Neither Agliastro 2006 nor Kerkhoffs 2010 provided usable data on all adverse events.

When we combined all of the adverse events data that were available from seven trials (Cazenave 2010; De Francisci 2004; Janetzko 2005; Lozano 2011; McCullough 2004; Rebulla 2016; van Rhenen 2003), there was no evidence of a difference between treatment arms (7 trials, 1566 participants; RR 1.01, 95% CI 0.97 to 1.05; P = 0.67; I² = 0%) (Analysis 1.14).

Analysis 1.14.

Comparison 1 Pathogen‐reduced platelets versus standard platelets for the prevention of bleeding, Outcome 14 Number of participants with an adverse event.

Intercept PCT platelet trials

Data from two single‐transfusion trials showed no evidence of a difference between the two arms (2 trials, 255 participants; RR 0.98, 95% CI 0.87 to 1.09; P = 0.68) (Analysis 1.14) (De Francisci 2004; Lozano 2011).

When we combined data from four multiple‐transfusion trials (Janetzko 2005; McCullough 2004; Rebulla 2016; van Rhenen 2003), there was no evidence of a difference between treatment arms (4 trials, 1007 participants; RR 1.01, 95% CI 0.97 to 1.05; P = 0.61; I² = 0%) (Analysis 1.14).

Mirasol PCT platelet trials

There was no evidence of a difference in the number of adverse events between the recipients of Mirasol and standard platelet transfusions (2 trials, 304 participants; RR 1.04, 95% CI 0.89 to 1.21; P = 0.65; I² = 0%) (Analysis 1.14).

There was no evidence of subgroup differences between studies of multiple Intercept and Mirasol platelets transfusions (test for subgroup differences: Chi² = 0.11, df = 1, P = 0.74, I² = 0%)

Serious adverse events

Nine of the 12 trials reported all serious adverse events (Cazenave 2010; De Francisci 2004; Janetzko 2005; Kerkhoffs 2010; Lozano 2011; McCullough 2004; Simonsen 2006; Slichter 2006; van Rhenen 2003), with six trials providing a definition of a serious adverse event that conformed either to the European Medicines Agency's, EMEA 1995, or the US Food and Drug Administration's, US FDA 2012, definition of a serious adverse event (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; Lozano 2011; McCullough 2004; van Rhenen 2003). Although we had intended to exclude bleeding and mortality data from the serious adverse events data for each trial, most trials did not present their data in a way that allowed for this, and so we have included all serious adverse events. In addition, it should be noted that, with the exception of infection, these were all rare events for which the trials were not sufficiently powered to identify differences between treatment arms.

Regarding the two cross‐over trials that reported this outcome (Simonsen 2006; Slichter 2006), Simonsen 2006 reported one serious adverse event (hypotension) in the standard platelet transfusion arm during the 24‐hour period post‐transfusion, and Slichter 2006 reported one serious adverse event (severe hypertension) in the standard platelet transfusion arm.

When we combined data from the remaining seven trials (Cazenave 2010; De Francisci 2004; Janetzko 2005; Kerkhoffs 2010; Lozano 2011; McCullough 2004; van Rhenen 2003), there was no evidence of a difference in the frequency of serious adverse events between the trial arms (7 trials, 1340 participants; RR 1.09, 95% CI 0.88 to 1.35; P = 0.44; I² = 0%) (Analysis 1.15).

Analysis 1.15.

Comparison 1 Pathogen‐reduced platelets versus standard platelets for the prevention of bleeding, Outcome 15 Number of participants with a serious adverse event.

Intercept PCT platelet trials

Data extracted from two single‐transfusion trials showed no evidence of a difference in the frequency of serious adverse events between recipients of Intercept and standard platelets (2 trials, 255 participants; RR 1.21, 95% CI 0.55 to 2.68; P = 0.64; I² = 0%) (Analysis 1.15) (De Francisci 2004; Lozano 2011).

Four multiple‐transfusion trials reported serious adverse events (Janetzko 2005; Kerkhoffs 2010; McCullough 2004; van Rhenen 2003), and combined results showed no evidence of a difference in the frequency of serious adverse events between recipients of Intercept and standard platelets (4 trials, 975 participants; RR 1.07, 95% CI 0.84 to 1.36; P = 0.57; I² = 0%) (Analysis 1.15).

Mirasol PCT platelet trials

Data from one multiple‐transfusion trial did not show any evidence of a difference in the incidence of serious adverse events between recipients of Mirasol and standard platelets (1 trial, 110 participants; RR 1.14, 95% CI 0.56 to 2.32; P = 0.72) (Analysis 1.15).

There was no evidence of subgroup differences between studies of multiple Intercept and Mirasol platelets transfusions (test for subgroup differences: Chi² = 0.03, df = 1, P = 0.87, I² = 0%).

Transfusion‐related acute lung injury

For the purposes of this review, we assumed that transfusion‐related acute lung injury (TRALI) (generally defined as new‐onset acute lung injury within six hours of transfusion with associated hypoxia and bilateral pulmonary infiltrates) was a serious adverse event related to transfusion, therefore if a trial reported that no serious adverse events related to transfusion had occurred, we assumed that no TRALI had occurred.

Eleven trials reported this outcome (Agliastro 2006; Cazenave 2010; De Francisci 2004; Janetzko 2005; Johansson 2013; Kerkhoffs 2010; Lozano 2011; McCullough 2004; Rebulla 2016; Simonsen 2006; Slichter 2006). van Rhenen 2003 did not report this outcome.

Ten trials reported no cases of TRALI (Agliastro 2006; Cazenave 2010; De Francisci 2004; Janetzko 2005; Johansson 2013; Kerkhoffs 2010; Lozano 2011; Rebulla 2016; Simonsen 2006; Slichter 2006). In McCullough 2004 there were no cases of TRALI with associated cognate antigen‐antibody mismatch.

Transfusion‐transmitted infections

Six trials reported this outcome (Cazenave 2010; Janetzko 2005; Lozano 2011; McCullough 2004; Simonsen 2006; van Rhenen 2003). No episodes of bacterial TTI occurred in any of these six trials.

Anaphylaxis

Seven trials reported anaphylaxis (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; Lozano 2011; McCullough 2004; Slichter 2006; van Rhenen 2003).

Combining data from six trials showed no evidence of a difference between treatment arms (6 trials, 1296 participants; RR 1.03, 95% CI 0.26 to 4.06; P = 0.97; I² = 0%) (Analysis 1.16) (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; Lozano 2011; McCullough 2004; van Rhenen 2003). Slichter 2006, a cross‐over trial, reported no anaphylaxis cases in either group.

Analysis 1.16.

Comparison 1 Pathogen‐reduced platelets versus standard platelets for the prevention of bleeding, Outcome 16 Number of participants with anaphylaxis.

Infections

Six trials reported the incidence of post‐transfusion infection (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; Lozano 2011; McCullough 2004; van Rhenen 2003). Pathogen‐reduced platelet transfusions increased the risk of developing an infection (6 trials, 1296 participants; RR 1.27, 95% CI 1.09 to 1.48; P = 0.002; I² = 39%) (Analysis 1.17). In the review protocol we stated that we would investigate any statistical heterogeneity over 30%. Removing Cazenave 2010 from the analysis (the only Mirasol PCT trial in the analysis) eliminated the heterogeneity (5 trials, 1186 participants; RR 1.35, 95% CI 1.14 to 1.60; P < 0.001; I² = 0%) (Analysis 1.17).

Analysis 1.17.

Comparison 1 Pathogen‐reduced platelets versus standard platelets for the prevention of bleeding, Outcome 17 Number of participants with infection.

Intercept PCT platelet trials

One single Intercept PCT platelet transfusion trial showed no evidence of a difference in the number of infections between treatment arms (1 trial, 211 participants; RR 1.18, 95% CI 0.57 to 2.43; P = 0.66) (Analysis 1.17).

Four multiple Intercept PCT platelet transfusion trials showed an increase in the number of infections in the Intercept PCT platelet transfusion arm (4 trials, 975 participants; RR 1.36, 95% CI 1.14 to 1.62; P < 0.001; I² = 28%) (Analysis 1.17) (Janetzko 2005; Kerkhoffs 2010; Lozano 2011; McCullough 2004; van Rhenen 2003).

Mirasol PCT platelet trials

One multiple‐transfusion trial reported this outcome (Cazenave 2010), and there was no evidence of a difference between the two treatment arms (1 trial, 110 participants; RR 0.90, 95% CI 0.63 to 1.28; P = 0.56) (Analysis 1.17).

There was evidence of a subgroup difference between studies of multiple Intercept and Mirasol platelets transfusions (test for subgroup differences: Chi² = 4.21, df = 1, P = 0.04, I² = 76.2%).

Venous thromboembolic events

Six trials reported venous thromboembolic events (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; Lozano 2011; McCullough 2004; van Rhenen 2003), and they showed no evidence of a difference between treatment arms (6 trials, 1296 participants; RR 1.23, 95% CI 0.67 to 2.26; P = 0.50; I² = 0%) (Analysis 1.18).

Analysis 1.18.

Comparison 1 Pathogen‐reduced platelets versus standard platelets for the prevention of bleeding, Outcome 18 Number of participants with venous thromboembolism (follow‐up 0 to 12 weeks).

Intercept PCT platelet trials

There was no evidence of a difference when we combined data from from the five Intercept platelet transfusion trials (5 trials, 1186 participants; RR 1.33, 95% CI 0.71 to 2.50; P = 0.38; I² = 17%) (Analysis 1.18). There was no change to the combined effect when we performed a sensitivity analysis excluding Lozano 2011 (single‐transfusion trial with no venous thromboembolic events among participants).

Mirasol PCT platelet trials

One multiple‐transfusion trial reported this outcome, finding no evidence of a difference between the two treatment arms (1 trial, 110 participants; RR 0.48, 95% CI 0.05 to 5.16; P = 0.38) (Analysis 1.18) (Cazenave 2010).

There was no evidence of subgroup differences between studies of multiple Intercept and Mirasol platelets transfusions (test for subgroup differences: Chi² = 0.66, df = 1, P = 0.42, I² = 0%).

Arterial thromboembolic events

Seven trials reported arterial thromboembolic events (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; Lozano 2011; McCullough 2004; Rebulla 2016; van Rhenen 2003); when we combined the data in a meta‐analysis, we found no difference between treatment arms (7 trials, 1706 participants; RR 0.44, 95% CI 0.14 to 1.42; P = 0.17; I² = 0%) (Analysis 1.19).

Analysis 1.19.

Comparison 1 Pathogen‐reduced platelets versus standard platelets for the prevention of bleeding, Outcome 19 Number of participants with arterial venous thromboembolism (follow‐up 0 to 12 weeks).

Intercept PCT platelet trials

Six Intercept trials contributed to this outcome (Janetzko 2005; Kerkhoffs 2010; Lozano 2011; McCullough 2004; Rebulla 2016; van Rhenen 2003), and combining data across the trials resulted in no evidence of a difference between the two treatment arms (6 trials, 1402 participants; RR 0.47, 95% CI 0.13 to 1.64; P = 0.23; I² = 0%) (Analysis 1.19). There was no change to the combined effect when we performed a sensitivity analysis excluding Lozano 2011 (single‐transfusion trial with no arterial thromboembolic events among participants).

Mirasol PCT platelet trials

Two multiple Mirasol transfusion trials reported this outcome (Cazenave 2010; Rebulla 2016), and there was no evidence of a difference between the two treatment arms (2 trials, 304 participants; RR 0.32, 95% CI 0.01 to 7.73; P = 0.48; I² = 0%) (Analysis 1.19).

There was no evidence of a subgroup difference between studies of multiple intercept and Mirasol platelets transfusions (test for subgroup differences: Chi² = 0.04, df = 1, P = 0.83, I² = 0%).

Laboratory assessment of response to platelet transfusion

All trials reported this outcome as a count increment and/or CCI at one hour or 24 hours, or both, post‐transfusion. There was variability between trials in a number of areas, including the mean study platelet transfusion dose (see Table 3), the timings of the platelet dose measurement, and the timings of the pre‐transfusion platelet counts (see Table 6). Furthermore, three of the seven multiple platelet transfusion trials restricted their primary analysis to include only the first five or eight study transfusions (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010), while the other four trials based their analyses on all transfusions (Agliastro 2006; McCullough 2004; Rebulla 2016; van Rhenen 2003).

Table 4.

Laboratory data

Study	Timing of pre‐Tx plt count from Tx	Timing of 1‐hr post‐Tx plt count (mins)	Timing of 24‐hr post‐Tx plt count (hrs)	Timing of plt dose measurement	CCI calculation
Single‐transfusion studies ‐ Intercept®
De Francisci 2004	NR	NR	NR	NR	NR
Lozano 2011	Same day	10 to 240	16 to 24	Day 5 of storage	NR
Simonsen 2006	≤ 6 hrs OR same day	10 to 90	NR	Prior to storage	CI x BSA/plt dose
Slichter 2006	NR	60 to 120	18 to 24	NR	CI x BSA/plt dose
Multiple‐transfusion studies ‐ Intercept®
Agliastro 2006	NR	NR	NR	NR	NR
Janetzko 2005	≤ 6 hrs	NR	NR	At issue	CI x BSA/plt dose
Kerkhoffs 2010	≤ 6 hrs	10 to 120	16 to 28	Prior to storage	CI x BSA/plt dose
McCullough 2004	Same day	10 to 240	10 to 24	NR	CI x BSA/plt dose
Rebulla 2016	Same day	10 to 60	16 to 24	At issue	CI x BSA/plt dose
van Rhenen 2003	NR	10 to 240	18 to 24	At issue	CI x BSA/plt dose
Single‐transfusion studies ‐ Mirasol®
Johansson 2013	< 60 min	30 to 60	8 to 26	NR	NR
Multiple‐transfusion studies ‐ Mirasol®
Cazenave 2010	≤ 12 hrs	30 to 90	18 to 26	At issue	CI x BSA/plt dose
Rebulla 2016	Same day	10 to 60	16 to 24	At issue	CI x BSA/plt dos

BSA: body surface area CCI: corrected count increment           CI: count increment NR: not reported plt: platelet Tx: transfusion                                        

Two of the single study platelet transfusion exposure trials, Lozano 2011 and Simonsen 2006, and four of the multiple study platelet exposure trials, Cazenave 2010, Janetzko 2005, Kerkhoffs 2010, and van Rhenen 2003, used the one‐hour CCI or count increment, or both, as their primary outcome.

Although all trials reported the one‐hour and/or 24‐hour count increments and/or CCIs, we could not include data from four trials in meta‐analyses. Two trials published as abstracts did not report standard deviations (Agliastro 2006; De Francisci 2004), and two cross‐over trials did not report data from the first trial period only (Johansson 2013; Slichter 2006).

One‐hour count increment

When we combined data from the seven trials with data that could be incorporated into a meta‐analysis, there was considerable statistical heterogeneity (I² = 85%) (Janetzko 2005; Kerkhoffs 2010; Lozano 2011; McCullough 2004; Rebulla 2016; Simonsen 2006; van Rhenen 2003). We therefore did not combine data for single‐ and multiple‐transfusion trials (test for subgroup differences: Chi² = 23.96, df = 2, P < 0.001, I² = 91.7%).

Single‐transfusion trials

We combined data from two single Intercept platelet transfusion trials (Lozano 2011; and the first period of Simonsen 2006). There was no evidence of a difference between treatment arms for the one‐hour count increment (2 trials, 219 participants; mean difference (MD) ‐1.39 x 10⁹/L, 95% CI ‐4.81 to 2.02; P = 0.42; I² = 0%) (Analysis 1.20).

Analysis 1.20.

Comparison 1 Pathogen‐reduced platelets versus standard platelets for the prevention of bleeding, Outcome 20 Lab response ‐ 1‐hour count increment [x 10⁹/L].

Multiple‐transfusion trials

When we combined data from the five multiple‐transfusion trials that reported this outcome (Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; van Rhenen 2003), there was still considerable statistical heterogeneity (I² = 79%). We noted a significant difference with regard to the platelet doses received by the pathogen‐reduced group and the standard group across three trials (Kerkhoffs 2010; McCullough 2004; van Rhenen 2003), in which lower mean platelet doses were issued to the pathogen‐reduced transfusion group versus the standard platelet transfusion group (P < 0.001) (Table 6). We subsequently decided to pool results from trials with and without a significant difference in platelet doses transfused by the two groups separately.

• No difference in platelet dose between treatment arms

We combined data from two multiple‐transfusion trials (Janetzko 2005; Rebulla 2016). Participants who received pathogen‐reduced platelet transfusions had a lower one‐hour count increment (2 trials, 467 participants; MD ‐4.96, 95% CI ‐7.64 to ‐2.28; P < 0.001; I² = 0%) (Analysis 1.20).

Similar results were seen when data for Intercept (2 trials, 271 participants; MD ‐4.63, 95% CI ‐7.42 to ‐1.83; P = 0.001; I² = 0%) and Mirasol (1 trial, 196 participants; MD ‐8.90, 95% CI ‐18.47 to 0.67; P = 0.07) were analysed separately (Analysis 1.20).

There was no evidence of a difference between the two subgroups: Intercept multiple platelet transfusion and Mirasol multiple platelet transfusion (test for subgroup differences: Chi² = 0.71, df = 1, P = 0.40, I² = 0%).

• Difference in platelet dose between treatment arms

Combining data from three Intercept PCT multiple‐transfusion trials in which a significant difference in transfused platelet doses was found showed that participants who received Intercept platelet transfusions had a lower one‐hour count increment (3 trials, 932 participants; MD ‐12.72, 95% CI ‐14.66 to ‐10.77; P < 0.001; I² = 20%) (Analysis 1.20) (Kerkhoffs 2010; McCullough 2004; van Rhenen 2003).

One‐hour corrected count increment

When we combined data from eight trials into a meta‐analysis there was considerable statistical heterogeneity (I² = 75%) (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; Lozano 2011; McCullough 2004; Rebulla 2016; Simonsen 2006; van Rhenen 2003). We therefore did not combine data for single‐ and multiple‐transfusion trials (test for subgroup differences: Chi² = 15.01, df = 2, P < 0.001; I² = 86.7%).

Single‐transfusion trials

We combined data from two Intercept PCT single‐transfusion trials (Lozano 2011; Simonsen 2006). There was no evidence of a difference in the one‐hour CCI between Intercept platelets and standard platelets (2 trials, 219 participants; MD ‐0.89, 95% CI ‐2.35 to 0.58; P = 0.23; I² = 23%) (Analysis 1.21).

Analysis 1.21.

Comparison 1 Pathogen‐reduced platelets versus standard platelets for the prevention of bleeding, Outcome 21 Lab response ‐ 1‐hour corrected count increment [x 10³/L].

Multiple‐transfusion trials

We combined data from six multiple‐transfusion trials (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; van Rhenen 2003). Participants who received pathogen‐reduced platelet transfusions had a lower one‐hour CCI (6 trials, 1495 participants; MD ‐4.11, 95% CI ‐4.83 to ‐3.39; P < 0.001; I² = 61%) (Analysis 1.21).

We defined an I² value higher than 30% as moderate statistical heterogeneity. Applying the random‐effects model did not alter the results (6 trials, 1495 participants; MD ‐3.81, 95% CI ‐5.15 to ‐2.46; P < 0.001; I² = 61%) (analysis not shown). Four trials measured the platelet dose at issue (Cazenave 2010; Janetzko 2005; Rebulla 2016; van Rhenen 2003), and two studies measured the platelet dose either prior to storage, in Kerkhoffs 2010, or did not report when it was measured (McCullough 2004). When we included only the four trials that measured the platelet dose at issue in the analysis there was no evidence of statistical heterogeneity (4 trials, 666 participants; MD ‐2.60, 95% CI ‐3.74 to ‐1.46; P < 0.001; I² = 0%) (analysis not shown).

• Intercept PCT platelet trials

We combined data from five Intercept multiple platelet transfusion trials (Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; van Rhenen 2003). Participants who received Intercept platelet transfusions had a lower one‐hour CCI (5 trials, 1191 participants; MD ‐4.11, 95% CI ‐4.87 to ‐3.35; P < 0.001; I² = 74%) (Analysis 1.21).

When we only included studies that measured platelet dose at issue there was no longer any statistical heterogeneity (3 studies, 362 participants; MD ‐1.99, 95% CI ‐3.34 to ‐0.64; P = 0.004; I² = 0%) (analysis not shown) (Janetzko 2005; Rebulla 2016; van Rhenen 2003).

• Mirasol PCT platelet trials

Two Mirasol trials reported this outcome (Cazenave 2010; Rebulla 2016). Participants who received Mirasol platelet transfusions had a lower one‐hour CCI (2 trials, 304 participants; MD ‐4.14, 95% CI ‐6.29 to ‐1.99; P < 0.001; I² = 0%) (Analysis 1.21).

There was no evidence of a difference between studies of multiple Intercept platelet transfusions and Mirasol platelet transfusions (test for subgroup differences: Chi² = 0.00, df = 1, P = 0.98, I² = 0%).

24‐hour count increment

Six studies reported on this outcome: one single platelet transfusion trial, Lozano 2011, and five multiple platelet transfusion trials (Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; van Rhenen 2003).

Combining data across six trials showed that participants who received pathogen‐reduced platelet transfusions had a lower 24‐hour count increment (6 trials, 1571 participants; MD ‐7.12, 95% CI ‐8.32 to ‐5.93; P < 0.001; I² = 55%) (Analysis 1.22) (Janetzko 2005; Kerkhoffs 2010; Lozano 2011; McCullough 2004; Rebulla 2016; van Rhenen 2003).

Analysis 1.22.

Comparison 1 Pathogen‐reduced platelets versus standard platelets for the prevention of bleeding, Outcome 22 Lab response ‐ 24‐hour count increment [x 10⁹/L].

Due to the moderate heterogeneity we have also reported single‐ and multiple‐transfusion trials separately.

Single platelet transfusion trials

In Lozano 2011 participants who received Intercept platelet transfusions had a lower 24‐hour count increment (1 trial, 186 participants; MD ‐4.10 x 10⁹/L, 95% CI ‐7.16 to ‐1.04; P = 0.009) (Analysis 1.22).

Multiple platelet transfusion trials

The five multiple‐transfusion studies that reported on this outcome also showed that participants receiving pathogen‐reduced platelet transfusions had a lower 24‐hour count increment (5 trials, 1385 participants; MD ‐7.67, 95% CI ‐8.96 to ‐6.37; P < 0.001; I² = 44%) (Analysis 1.22) (Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; van Rhenen 2003). Due to the moderate statistical heterogeneity, we also applied the random‐effects model, which did not alter the results (5 trials, 1385 participants; MD ‐7.59, 95% CI ‐9.52 to ‐5.67; P < 0.001; I² = 44%) (analysis not shown). We noticed a significant difference with regard to the platelet doses received by the pathogen‐reduced group and the standard group across three trials (Kerkhoffs 2010; McCullough 2004; van Rhenen 2003), in which lower mean platelet doses were issued to the pathogen‐reduced transfusion group versus the standard platelet transfusion group (P < 0.001) (Table 6). Combining results from the two multiple‐transfusion trials with no significant difference in platelet doses between the two study arms did not alter the results, but did remove any statistical heterogeneity (2 trials, 453 participants; MD ‐5.66, 95% CI ‐7.77 to ‐3.56; P < 0.001; I² = 0%) (analysis not shown) (Janetzko 2005; Rebulla 2016).

• Intercept PCT platelet trials

We combined data from five Intercept multiple platelet transfusion trials (Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; van Rhenen 2003). Participants who received Intercept platelet transfusions had a lower 24‐hour count increment (5 trials, 1191 participants; MD ‐8.39, 95% CI ‐9.82 to ‐6.96; P < 0.001; I² = 0%) (Analysis 1.22).

• Mirasol PCT platelet trials

One Mirasol multiple platelet transfusion trial reported this outcome (Rebulla 2016). Participants who received Mirasol platelet transfusions had a lower 24‐hour count increment (1 trial, 194 participants; MD ‐4.30, 95% CI ‐7.38 to ‐1.22; P = 0.006) (Analysis 1.22).

There was evidence of a difference between studies of multiple Intercept platelet transfusions and Mirasol platelet transfusions (test for subgroup differences: Chi² = 5.59, df = 1, P = 0.02, I² = 82.1%).

24‐hour corrected count increment

We combined data from seven trials in a meta‐analysis (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; Lozano 2011; McCullough 2004; Rebulla 2016; van Rhenen 2003). Participants who received pathogen‐reduced platelet transfusions had a lower 24‐hour CCI (7 trials, 1681 participants; MD ‐3.02, 95% CI ‐3.57 to ‐2.48; P < 0.001; I² = 15%) (Analysis 1.23). There was evidence of subgroup differences (test for subgroup differences: Chi² = 5.52, df = 2, P = 0.06, I² = 63.8%).

Analysis 1.23.

Comparison 1 Pathogen‐reduced platelets versus standard platelets for the prevention of bleeding, Outcome 23 Lab response ‐ 24‐hour corrected count increment [x 10³/L].

Single platelet transfusion trials

In Lozano 2011 participants who received Intercept platelet transfusions had a lower 24‐hour CCI (1 trial, 186 participants; MD ‐1.96 x 10³/L, 95% CI ‐3.24 to ‐0.68; P = 0.003) (Analysis 1.23).

Multiple platelet transfusion trials

Six multiple platelet transfusion trials reported this outcome (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; van Rhenen 2003). Participants who received pathogen‐reduced platelet transfusions had a lower 24‐hour CCI (6 trials, 1495 participants; MD ‐3.26, 95% CI ‐3.86 to ‐2.66; P < 0.001; I² = 0%).

• Intercept PCT platelet trials

A meta‐analysis of five Intercept PCT platelets trials showed that participants who received Intercept PCT platelets had a lower 24‐hour CCI (5 trials, 1191 participants; MD ‐3.50, 95% CI ‐4.18 to ‐2.82; P < 0.001; I² = 0%) (Analysis 1.23) (Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; van Rhenen 2003).

• Mirasol PCT platelet trials

A meta‐analysis of two Mirasol PCT platelets trials showed that participants who received Intercept PCT platelets had a lower 24‐hour CCI (2 trials, 304 participants; MD ‐2.37, 95% CI ‐3.68 to ‐1.06; P < 0.001; I² = 0%) (Analysis 1.23) (Cazenave 2010; Rebulla 2016).

There was no evidence of a difference between studies of multiple Intercept platelet transfusions and Mirasol platelet transfusions (test for subgroup differences: Chi² = 2.26, df = 1, P = 0.13, I² = 55.8%).

Other measures of laboratory assessment of response to platelet transfusion

In addition to count increments, Slichter 2006 reported bleeding time assessments at one to two and 18 to 24 hours' post‐study transfusion as the trial's primary outcome, with paired results available for only 10 of the 32 participants who received both study products after a change in platelet production protocol. There was no evidence of a difference between the bleeding times when Intercept PCT and standard platelet transfusion responses were compared (P = 0.25 for one‐ to two‐hour and P = 0.82 for 18‐ to 24‐hour bleeding time assessments).

Platelet transfusion requirement

Eight studies reported on this outcome, two single study platelet transfusion trials, Lozano 2011 and Simonsen 2006, and six multiple platelet transfusion trials (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; van Rhenen 2003).

Similar prophylactic transfusion thresholds were applied across the trials (platelet count < 10 to 20 x 10⁹/L), although therapeutic platelet transfusion protocols were frequently not reported and follow‐up periods varied (see Table 4).

Number of additional platelet transfusions (single‐transfusion studies)

Two single platelet transfusion studies reported this outcome (Lozano 2011; Simonsen 2006). In Lozano 2011 the number of additional platelet transfusions within the 24 hours post‐study transfusion was similar in both arms (15.2% versus 11.3%, P = 0.398). In Simonsen 2006 6/13 participants in the PCT arm and 4/13 in the standard arm required an additional platelet transfusion between the two study transfusions (unpublished data) (no analysis presented).

Number of platelet transfusions per participant (multiple‐transfusion studies)

Six trials reported this outcome as the number of platelet transfusions received per participant over various follow‐up periods (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; van Rhenen 2003), and three trials also reported the number of platelet transfusions received per participant per day of platelet support (Cazenave 2010; Janetzko 2005; McCullough 2004).

Participants who received pathogen‐reduced platelet transfusions required more platelet transfusions (6 trials, 1509 participants; MD 1.23, 95% CI 0.86 to 1.61; P < 0.001; I² = 27%) (Analysis 1.24). Due to the greater comparability of the data, we combined data from the three trials that reported the number of platelet transfusions received per day of platelet support; this also showed that participants who received pathogen‐reduced platelet transfusions required more platelet transfusions (3 trials, 798 participants; MD 0.07, 95% CI 0.03 to 0.11; P < 0.001; I² = 21%) (analysis not shown).

Analysis 1.24.

Comparison 1 Pathogen‐reduced platelets versus standard platelets for the prevention of bleeding, Outcome 24 Number of platelet transfusions per participant.

Intercept PCT platelet trials

Participants who received Intercept platelet transfusions required more platelet transfusions (5 trials, 1203 participants; MD 1.30, 95% CI 0.84 to 1.77; P < 0.001; I² = 49%) (Analysis 1.24). This was also seen for those studies that reported the number of platelet transfusions per day of platelet support (2 trials, 688 participants; MD 0.09, 95% CI 0.04 to 0.13; P < 0.001; I² = 22%) (analysis not shown).

Mirasol PCT platelet trials

Participants who received Mirasol platelet transfusions required more platelet transfusions (2 trials, 306 participants; MD 1.09, 95% CI 0.44 to 1.75; P = 0.001; I² = 0%) (Analysis 1.24). There was insufficient evidence to assess the effect from the only study that reported the number of platelet transfusions per day of platelet support (1 trial, 110 participants; MD 0.04, 95% CI ‐0.03 to 0.11; P = 0.23; I² = 0%) (analysis not shown).

There was no evidence of a subgroup difference between studies of multiple Intercept PCT and Mirasol PCT platelet transfusions (test for subgroup differences: Chi² = 0.27, df = 1, P = 0.60, I² = 0%)

Off‐protocol transfusions

For a variety of reasons, including a shortage of pathogen‐reduced platelet transfusions, five of the six multiple study platelet transfusion trials reported a fairly high use of off‐protocol platelets during their trial periods (see Characteristics of included studies and Table 4). The use of off‐protocol platelet transfusions was uneven between arms, with approximately double the number of off‐protocol transfusions in the PCT platelets arm of four of the five studies (Janetzko 2005; Kerkhoffs 2010; McCullough 2004; van Rhenen 2003). Cazenave 2010 reported a slightly higher use of off‐protocol platelets in the standard platelets arm (23.2%) when compared with the Mirasol PCT platelets arm (17.7%). In Rebulla 2016, off‐protocol transfusion occurred in 10.3% of the Intercept PCT recipients and 6.4% of the Mirasol PCT recipients. Off‐protocol transfusions were not an issue for the single platelet transfusion trials. However, in Simonsen 2006 there were three protocol violations in which two participants did not receive PCT platelets, and one participant did not receive standard platelets. No off‐protocol violation was reported in Johansson 2013.

Platelet transfusion interval

Nine trials measured the interval between platelet transfusions as days to the next platelet transfusion (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; Lozano 2011; McCullough 2004; Rebulla 2016; Simonsen 2006; Slichter 2006; van Rhenen 2003). We could incorporate data from eight trials into meta‐analyses (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; Lozano 2011; McCullough 2004; Rebulla 2016; van Rhenen 2003; and the first period of Simonsen 2006). Due to moderate statistical heterogeneity (I² = 68%) and considerable differences between subgroups (I² = 91.2%), we did not combine the data, but analysed the subgroups single‐ and multiple‐transfusions separately.

Single platelet transfusion trials

We combined data from two single Intercept platelet transfusion trials (Lozano 2011; and the first period of Simonsen 2006); we found no evidence of a difference in the platelet transfusion interval between treatment arms (2 trials, 194 participants; MD 0.10 days, 95% CI ‐0.13 to 0.34; P = 0.39; I² = 0%) (Analysis 1.25).

Analysis 1.25.

Comparison 1 Pathogen‐reduced platelets versus standard platelets for the prevention of bleeding, Outcome 25 Platelet transfusion interval (days to next platelet transfusion).

Of the data that could not be included in the meta‐analysis, Slichter 2006 reported the mean time to the next platelet transfusion following both sequences of study platelet transfusions as 2.9 ± 1.2 days (N = 26) for the Intercept PCT arm versus 3.4 ± 1.3 days (N = 26) for the standard platelets arm, with no difference between treatment arms (P = 0.18). In the second period of Simonsen 2006, the mean time to the next platelet transfusion following the second single study platelet transfusion was reported as 0.86 ± 0.23 days (N = 11) for the PCT platelets arm versus 1.41 ± 0.22 days (N = 9) for the standard platelets arm, favouring the standard platelets arm (P < 0.001). Nevertheless, despite a minimum washout period of 24 hours, the trial authors reported a significant period‐by‐treatment interaction between study transfusions for the second period of the trial (Simonsen 2006).

Multiple platelet transfusion trials

We combined data from six multiple platelet transfusion trials (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; van Rhenen 2003). Participants who received pathogen‐reduced platelet transfusions had a shorter platelet transfusion interval (6 trials, 1489 participants; MD ‐0.42 days, 95% CI ‐0.53 to ‐0.32; P < 0.001; I² = 29%) (Analysis 1.25).

We combined data from the five Intercept multiple platelet transfusion trials (Janetzko 2005; Kerkhoffs 2010; McCullough 2004; Rebulla 2016; van Rhenen 2003). Participants who received Intercept PCT platelet transfusions had a shorter platelet transfusion interval (5 trials, 1197 participants; MD ‐0.50, 95% CI ‐0.61 to ‐0.38; P < 0.001; I² = 0%) (Analysis 1.25).

When we combined data from two Mirasol multiple platelet transfusion trials (Cazenave 2010; Rebulla 2016), there was no evidence of a difference in the platelet transfusion interval between the two treatment arms (2 trials, 306 participants; MD ‐0.16, 95% CI ‐0.38 to 0.07; P = 0.17; I² = 0%) (Analysis 1.25).

There was evidence of a difference between studies of multiple Intercept PCT and Mirasol PCT platelet transfusions (test for subgroup differences: Chi² = 6.78, df = 1, P = 0.009, I² = 85.3%).

Red cell transfusion requirement and interval

Red cell transfusion requirement

Seven trials reported this outcome as the number of red cell transfusions received per participant over various follow‐up periods (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; Lozano 2011; McCullough 2004; Rebulla 2016; van Rhenen 2003); five trials also reported the number of red cells received per participant per day of platelet support (Cazenave 2010; Janetzko 2005; Lozano 2011; McCullough 2004; van Rhenen 2003).

There was no evidence of a difference between the pathogen‐reduced platelets arm and the standard platelets arm in the number of red cell transfusions participants received (7 trials, 1720 participants; MD 0.13, 95% CI ‐0.07 to 0.33; P = 0.07; I² = 24%) (Analysis 1.26). Due to the greater comparability of the data, we combined data from the five trials that reported the number of red cell transfusions received per day of platelet support, which also showed that there is probably no difference in the number of red cell transfusions participants received (5 trials, 1112 participants; MD 0.00, 95% CI ‐0.02 to 0.03; P = 0.72; I² = 0%) (analysis not shown).

Analysis 1.26.

Comparison 1 Pathogen‐reduced platelets versus standard platelets for the prevention of bleeding, Outcome 26 Number of red cell transfusions per participant.

Intercept PCT platelet trials

Six Intercept trials contributed to this outcome (Janetzko 2005; Kerkhoffs 2010; Lozano 2011; McCullough 2004; Rebulla 2016; van Rhenen 2003); combining data across the trials resulted in no evidence of a difference between the two treatment arms (6 trials, 1414 participants; MD 0.07, 95% CI ‐0.15 to 0.28; P = 0.54; I² = 22%) (Analysis 1.26). There was no change to the combined effect when we performed a sensitivity analysis excluding the only single‐transfusion trial, Lozano 2011 (5 trials, 1203 participants; MD 0.38, 95% CI ‐0.08 to 0.85; P = 0.11; I² = 4%) (Analysis 1.26).

Mirasol PCT platelet trials

Two multiple Mirasol transfusion trials reported this outcome (Cazenave 2010; Rebulla 2016), and there was no evidence of a difference between the two treatment arms (2 trials, 306 participants; MD 0.47, 95% CI ‐0.05 to 0.99; P = 0.07; I² = 0%) (Analysis 1.26).

There was no evidence of a difference between studies of multiple Intercept PCT and Mirasol PCT platelet transfusions (test for subgroup differences: Chi² = 0.07, df = 1, P = 0.80, I² = 0%).

Red cell transfusion interval

Kerkhoffs 2010 was the only trial reporting the interval between red cell transfusions, again with no evidence of a difference between intervention arms (P = 0.15).

Sensitivity analyses

Only one of our intended sensitivity analyses was required as, having received additional data from several trial authors, there were no trials in which 25% of participants or more were lost to follow‐up. We identified Cazenave 2010, Kerkhoffs 2010, and Janetzko 2005 as at a high risk of performance or detection bias, or both (Risk of bias in included studies; Figure 2), thus we performed sensitivity analyses. However, upon exclusion of these trials there was no change in the overall effect estimates for any of the outcomes for which they reported data, and thus no impact was detected from these potential sources of bias.

Discussion

The main aims of this review were to comprehensively assess the effectiveness and safety of pathogen‐reduced platelets compared with standard platelets for the prevention of bleeding. We identified 12 completed RCTs involving 2045 participants assessing two commercially available pathogen‐reduction systems (1981 received at least one platelet transfusion): 10 studies compared Intercept PCT platelets with standard platelets (1662 participants), and three studies compared Mirasol PCT platelets with standard platelets (319 participants). All studies were performed in high‐income countries. We also identified three ongoing trials comparing three different types of pathogen‐reduced platelets, Intercept PCT, Mirasol PCT, and Theraflex UV, to standard platelets.

The main rationale for introducing pathogen reduction of platelets is to further reduce the risk of transfusion‐transmitted infection (TTI) from both known and future pathogens. In high‐income countries that perform bacterial screening, the current risks of TTI are exceedingly small, as bacterial screening has proved highly effective in removing platelets contaminated with pathogenic bacteria from the blood supply. In the UK since the introduction of bacterial screening in 2011, there has been only one case of proven bacterial TTI (Bolton‐Maggs 2016).

It is highly unlikely that the sample sizes of any RCTs of pathogen‐reduced platelets would inform these outcomes. However, RCTs of pathogen‐reduced platelets would be expected to address other safety issues and to assess efficacy, including the prevention and treatment of bleeding, which are the major clinical reasons for using platelet transfusions.

Summary of main results

• We are very uncertain as to whether pathogen‐reduced platelets increase the risk of any bleeding (WHO grade 1 to 4). There was no evidence of a difference between pathogen‐reduced platelets and standard platelets in the incidence of clinically significant bleeding complications (WHO grade 2 to 4), and there is probably no difference in the incidence of severe or life‐threatening bleeding (WHO grade 3 to 4).

• There is probably no difference between pathogen‐reduced platelets and standard platelets in the incidence of all‐cause mortality (4 to 12 weeks). However, there was evidence of a subgroup difference between multiple‐transfusion trials of Intercept and Mirasol (Intercept 5 trials, 1203 participants; RR 0.62, 95% CI 0.37 to 1.05; Mirasol 2 trials, 306 participants; RR 2.92, 95% CI 0.81 to 10.59; test for subgroup differences: Chi² = 4.78, df = 1, P = 0.03, I² = 79.1%).

• There is probably no difference between pathogen‐reduced platelets and standard platelets in the incidence of serious adverse events, acute transfusion reactions, or adverse events.

• Participants who received pathogen‐reduced platelet transfusions required more platelet transfusions and probably had a shorter time interval between platelet transfusions.

• Participants who received pathogen‐reduced platelet transfusions had a lower 24‐hour corrected count increment (CCI).

• Participants who received pathogen‐reduced platelet transfusions had an increased risk of developing platelet refractoriness, including an increased risk due to alloimmunisation.

• No bacterial TTIs occurred in the six trials that reported this outcome.

Overall completeness and applicability of evidence

This review provides the most up‐to‐date assessment of the effectiveness and safety of pathogen‐reduced platelet transfusions versus standard platelet transfusions.

No studies directly compared different types of pathogen‐reduced platelet transfusions. There are three ongoing studies comparing pathogen‐reduced platelets versus standard platelets; none of these trials will directly compare different pathogen‐reduction technologies (EUCTR2015‐001035‐20‐DE is assessing Theraflex UV platelets (166 participants); Kerkhoffs 2013 is assessing Mirasol PCT platelets (375 participants); and NCT01789762 is assessing Intercept PCT platelets (810 participants)).

There are a number of limitations that may affect the strength of any conclusions in this review. They are as follows.

• The majority of the evidence applies to Intercept PCT platelets alone, with only three trials comparing Mirasol PCT platelets with standard platelets (319 participants).

• Although platelet transfusions are used in many different clinical settings, the predominantly investigated group in this review were people with haemato‐oncological malignancies. De Francisci 2004 was the only trial including participants with other diagnoses (adults requiring a liver transplant and children requiring cardiac surgery). Although individuals with haemato‐oncological malignancies represent a large proportion of people receiving platelet transfusions, we cannot extrapolate these finding to individuals with other diagnoses (Charlton 2014; Fedele 2016; Fillet 2016; Jones 2013).

• Only three trials included children (De Francisci 2004; McCullough 2004; van Rhenen 2003).

• It was not possible to extract data on outcomes for all trials, even after contact with the trial authors.

• There was considerable variability in the reporting of the methodology of recording and grading bleeding between trials; this included the use of different bleeding scales or bleeding scales that had been modified in different ways (Table 5). Details, such as training of outcome assessors, were often poorly described, which may limit the comparison of bleeding outcomes between trials. Bleeding was assessed in relation to three different bleeding scales in the identified trials: WHO (four‐point scale), CTCAE version 3 (five‐point scale), and a three‐point scale of no bleeding, minor, or major bleeding used in two trials (Slichter 2006; van Rhenen 2003). There remains uncertainty in the literature regarding the clinical importance of detecting, recording, and reporting minor severity of bleeding in trials (such as WHO grade 1), although all types of bleeding may be of concern to patients. Furthermore, the data from the SPRINT trial as reported by McCullough 2004 used an expanded version of the WHO scale, but with the same bleeding events additionally reported and assessed by Snyder 2004 using the CTCAE scale (version 2).

• Many participants in these trials received off‐protocol transfusions, with uneven use noted between study arms in four trials (Table 4) (Janetzko 2005; Kerkhoffs 2010; McCullough 2004; van Rhenen 2003). Off‐protocol transfusions could additionally be prescribed during the minimum 24‐hour washout period of two of the cross‐over trials, and hence more than one platelet product type would have been received during the short follow‐up period of these studies (Simonsen 2006; Slichter 2006).

• Significantly lower platelet doses were received per transfusion in the pathogen‐reduced platelet transfusion arm of four of the 11 trials that reported this measure (Table 3). As platelet losses are frequently seen during the processing of pathogen‐reduced platelets, one study permitted centres to either increase their apheresis collection dose by 10% or to add an additional buffy coat during the production of the Intercept PCT platelet product (Lozano 2011); despite this adjustment, laboratory responses were still significantly lower following PCT platelet transfusion for both the 24‐hour count increment and CCI in this trial.

• Five of the 12 included trials were single‐transfusion trials. The power of these single‐dose trials to identify clinically significant outcomes and safety issues is likely to be considerably reduced compared to trials that evaluated multiple platelet transfusions, in which the follow‐up periods were generally longer.

• The comparator standard platelet component in all trials varied by platelet collection method, storage duration, platelet dose, and storage solution (Table 3). Finally, changes in platelet function related to the pathogen‐reduction technologies have been less clearly investigated and were not studied in the trials included in this review.

Quality of the evidence

All included studies were RCTs, of which three were cross‐over trials. Through direct author contact for nine of the 12 included studies we obtained sufficient information to allow us to evaluate the quality of evidence. Due to the limitations of information reported in the two trials published only as abstracts and our inability to contact these trial authors, much of their study methodology remains unclear (Agliastro 2006; De Francisci 2004). The impact on the pooled results of the potentially high risk of performance and or detection bias present in three trials was shown to be insignificant when tested by a series of sensitivity analyses (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010). The usefulness of this method in meta‐analyses involving small numbers of trials is, however, limited. Participants were aware of the intervention status in three trials (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010), and in Kerkhoffs 2010 the outcome assessors were not blinded.

We assessed the quality of the evidence using the GRADE approach, and this ranged from low to high quality (see Table 1).

We assessed the GRADE quality of evidence as high for the following.

• Number of participants experiencing platelet refractoriness.

• 24‐hour CCI.

We assessed the GRADE quality of evidence as moderate for the following.

• Number of participants with a clinically significant bleeding event (WHO grade ≥ 2 or equivalent) ‐ follow‐up more than seven days.

• Number of participants with a severe bleeding event (WHO grade ≥ 3 or equivalent) ‐ follow‐up more than seven days. We downgraded the evidence because there was inconsistency between the McCullough 2004 trial and the other trials. In McCullough 2004, the number of severe bleeding events in the standard platelet transfusion arm was higher than in the pathogen‐reduced platelet transfusion arm, whereas all of the other studies showed a lower incidence in the standard platelet arm. Also, the incidence of severe bleeding was much higher in the McCullough 2004 study than in the other trials. Although the studies within this subgroup had similar follow‐up periods, and to our knowledge there were no other major differences between them, the difference in the event rate may nevertheless be due to undetected methodological differences between the studies.

• All‐cause mortality post‐transfusion. We downgraded the evidence because there was inconsistency between the trials; part of this may have been due to different follow‐up durations between the trials.

• Number of participants with a serious adverse event. We downgraded the evidence because there was inconsistency between the trials in the number of serious adverse events; part of this may have been due to different follow‐up durations between the trials.

We assessed the GRADE quality of evidence as low for the following.

• Number of participants with any bleeding event(s) (WHO grade 1 to 4 or equivalent) ‐ follow‐up more than seven days. We downgraded the evidence because there was inconsistency between the trials, and results differed depending on whether a fixed‐effect or random‐effects analysis was performed.

Assessing the methodological quality across the included studies was a complex task, as the included studies differed in their design, primary outcomes, transfusion frequency, timing of the assessment, and scales used to document bleeding signs and symptoms. Similar methodological challenges were reported in another review (Cook 2013) that included six of the trials included in this review (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; Lozano 2011; McCullough 2004; van Rhenen 2003). Cook 2013 provided recommendations on how to design future clinical trials of pathogen‐reduced platelets, including: a parallel RCT design should be used for trials with clinical outcomes (e.g. bleeding), whereas a randomised block design should be used for trials with transfusion‐based outcomes (e.g. CCI); "bleeding status should be assessed on a daily basis using a valid and reliable bleeding assessment instrument"; "bleeding data should be analyzed based on the time to the first bleed as well as using the daily bleeding data"; and transfusion‐based outcome data (such as CCIs) should be interpreted with caution "since they are susceptible to selection effects" (Cook 2013). Cook 2013 also highlighted a recently devised universal bleeding assessment tool for use in future platelet transfusion trials (Webert 2012). Meanwhile, the Biomedical Excellence for Safer Transfusion (BEST) Collaborative Study Group has developed "consensus bleeding definitions, a standardized approach to record and grade bleeding, and guidance notes to educate and train bleeding assessors" for use in future platelet transfusion trials.

Potential biases in the review process

There were no obvious biases within the review process. We conducted a wide search that included ongoing trial databases and contact with researchers in the field; we carefully assessed the relevance of each paper identified; and we used no restrictions on the language in which the paper was originally published or its publication status. We performed all screening and data extractions in duplicate. We prespecified all outcomes and subgroups prior to analysis. The numbers of included studies were insufficient for us to combine to complete a funnel plot in order to examine the risk of publication bias.

Although two different methods of platelet pathogen‐reduction were included and their results pooled in this review, subgroups of trials evaluating the different pathogen‐reduction technologies with single or multiple platelet transfusion exposures were described and presented separately. This enabled assessment of differences between study subgroups where identified in addition to assessing the pooled effect.

Agreements and disagreements with other studies or reviews

Comparison with non‐randomised trials

Both pathogen‐reduction technologies have been introduced into routine practice in a number of countries worldwide. A number of surveillance and observational studies have reported on haemovigilance of pathogen‐reduced platelets; there was no increase in the adverse event reporting rate for the Mirasol PCT platelet product, Łętowska 2016, or Intercept PCT platelet products (Cazenave 2011; Osselaer 2008).

An international survey of current practice and concerns or opinions regarding pathogen‐reduced platelets was performed by Reesink 2010. Of the nine responding countries, pathogen‐reduced platelets were already employed by four (Intercept PCT platelets: France, Spain, Kuwait; Mirasol PCT platelets: Norway). No TTIs were identified in these centres, in which approximately 190,000 pathogen‐reduced platelet products had been transfused, with observational reports of fewer febrile, allergic reactions after transfusion of pathogen‐reduced versus standard platelets, assumed to be due to the reduced plasma content of the pathogen‐reduced platelets. Limitations of these studies include non‐standardised reporting by non‐research staff. The findings of these countries support our findings that adverse events are infrequent and not increased by the use of pathogen‐reduced platelets when compared with standard platelets.

Cazenave 2011 showed an increase in the number of platelet components per participant when pathogen‐reduced platelet components were used (mean 5.2 platelet components per participant (platelets in plasma) to mean 6.4 platelet components per participant (Intercept PCT platelets)). This is consistent with the findings of this review, but is inconsistent with another observational study that found no difference in platelet component demand (Osselaer 2009).

Cazenave 2011, conducted in France (control 2050 participants, pathogen‐reduced 2069 participants), was a much bigger study than Osselaer 2009, conducted in Belgium (control 699 participants, pathogen‐reduced 795 participants), but there were no other obvious differences between the two studies.

Comparison with other meta‐analyses

According to the Transfusion Evidence Library, there have been no systematic reviews published since the previous version of this review (Butler 2013). The reviews identified in the previous version of this review, Cid 2012, Vamvakas 2011, and Vamvakas 2012, only included five, Cid 2012 and Vamvakas 2011, or six, Vamvakas 2012, of this review's 12 included trials.

Vamvakas 2011 identified five trials (Cazenave 2010; Janetzko 2005; Kerkhoffs 2010; McCullough 2004; van Rhenen 2003), and, similar to our review, reported a significant reduction of the 1‐ and 24‐hour CCI (1‐hour CCI: MD 3.26, 95% CI 2.45 to 4.79; 24‐hour CCI: MD 3.31, 95% CI 2.03 to 4.60); an increased platelet transfusion requirement (MD 0.93, 95% CI 0.16 to 1.7); and reduced platelet transfusion interval for PCT platelets (MD 0.41, 95% CI 0.13 to 0.67). Unlike our review, Vamvakas 2011 reported an increase in "all bleeding" (odds ratio (OR) 1.58, 95% CI 1.1 to 2.25; estimated to cause a 58% increase) and "clinically significant" bleeding (OR 1.54, 95% CI 1.11 to 2.13; estimated to cause a 54% increase) with the use of pathogen‐reduced platelets. Vamvakas 2011 used the CTCAE‐graded haemorrhagic adverse event data from the largest included study (SPRINT) reported by Snyder 2004 to assess bleeding, whereas our review used the original WHO grading of bleeding rather than data from adverse event reporting. Methodological issues were discussed in the updated review (Vamvakas 2012), which applied different eligibility criteria and included a different additional trial, Lozano 2011 (although again, quantitative results were based on five trials).

Cid 2012 compared Intercept PCT to standard platelet transfusions and included five trials in their meta‐analysis. The authors concluded that the transfusion of Intercept PCT platelets was associated with lower CCIs and a shorter transfusion interval when compared with the transfusion of standard platelets, but there was no difference in the odds ratio of bleeding.

Comparison with other trials

As mentioned above, there are concerns that pathogen‐reduction technologies may affect platelet dose. The question of the effectiveness of different doses of prophylactic platelet transfusions has been addressed by Slichter 2010, which randomly assigned 1272 haematopoietic stem cell transplantation or chemotherapy recipients to receive either low‐, medium‐, or high‐dose platelet transfusions (1.1 x 10¹¹, 2.2 x 10¹¹, or 4.4 x 10¹¹ platelets per square metre of body surface area). Fewer platelets were transfused per participant in the group randomised to low‐dose platelets when compared with medium‐ (P = 0.002) or high‐dose (P < 0.001) platelets, but an increased number of transfusions was required (P < 0.001). The number of platelets within the transfused product did not translate into a difference in the incidence of bleeding. Overall, the platelet dose in the 10 trials included in our review ranged from a mean of 2.8 x 10¹¹ to 7.6 x 10¹¹ per transfusion (see Table 3), which is generally in line with the medium‐ to high‐dose categories identified by the PLADO study (Slichter 2010). Although we did not perform a post hoc analysis to assess our review's outcomes by platelet transfusion dose, participants of three trials (which recruited approximately two‐thirds of the participants included in this review) received a lower platelet dose in the PCT platelets arm (Kerkhoffs 2010; McCullough 2004; van Rhenen 2003). Despite these differences being statistically significant overall, there was less than a 10% difference in dose between the study arms in these three trials (range 8% in McCullough 2004 to 15% in Kerkhoffs 2010). The PLADO study also raised uncertainties about the relationship between the one‐hour count increment and risk of bleeding, reaffirming the need for trials evaluating clinical haemostatic outcomes (Triulzi 2012).

Authors' conclusions

Different implications for practice will apply to hospitals and countries already using pathogen‐reduced platelets and those considering using these platelets.

For those countries and hospitals already using pathogen‐reduced platelets, it is important that adverse event and transfusion usage data are prospectively and systematically collected, preferably by establishing a collaborative central registry system. Risks of bleeding and adverse events may differ between different systems of pathogen‐reduction technology, reflecting their different mechanisms of action.

For centres considering the introduction of pathogen‐reduced platelets, priority should be given to supporting the research agenda in order to address uncertainties in their effectiveness (bleeding risk), cost‐effectiveness (platelet transfusion demand, refractoriness to platelet transfusions), and safety (risk of infection).

No trials compared different types of pathogen‐reduced platelets with each other.

• Three ongoing randomised controlled trials use bleeding as their primary outcome; we will incorporate their results in the update of this review when they become available (Kerkhoffs 2013; NCT01789762; NCT02653443).

• We have not addressed cost implications in this review, and cost‐effectiveness modelling needs to be completed in order to address such factors as the cost of the pathogen‐reduction technology, the possible requirement for higher platelet dose thresholds at collection, and the potential for an increased platelet demand if bleeding risks differ. These models would establish whether any increase in costs could be offset by reduced requirements for bacterial screening, gamma irradiation, or potential for shelf life extension and any reduced risks of future pathogens that may enter the transfusion chain.

• Further trials of effectiveness are needed in order to understand the differences in bleeding outcomes, if any, between pathogen‐reduced platelets and standard platelets. Obtaining consensus and agreement on methodologies for standardised reporting and grading of bleeding for trials of platelet transfusions would be valuable (Estcourt 2013). Recent work in this area includes the creation of a new universal bleeding assessment tool, Webert 2012, and the development of consensus bleeding definitions, standardised approaches to recording and grading bleeding, and guidance notes to educate and train bleeding assessors by the Biomedical Excellence for Safer Transfusion (BEST) Collaborative Study Group.

• Trials that directly compare different pathogen‐reduction techniques are required to assess their clinical effectiveness.

• Trials of pathogen‐reduced platelets are required in non‐haemato‐oncological malignancy populations.

• Future trials need to collect data on quality of life measures.

Appendices

Appendix 1. CENTRAL (the Cochrane Library) search strategy 2013 to 2016

#1 MeSH descriptor: [Blood Preservation] this term only #2 MeSH descriptor: [Virus Inactivation] this term only #3 MeSH descriptor: [Decontamination] this term only #4 MeSH descriptor: [Disinfection] this term only #5 MeSH descriptor: [Photochemistry] this term only #6 MeSH descriptor: [Photosensitizing Agents] this term only #7 MeSH descriptor: [Ultraviolet Rays] this term only #8 MeSH descriptor: [Ultraviolet Therapy] explode all trees #9 MeSH descriptor: [Psoralens] explode all trees #10 MeSH descriptor: [Riboflavin] this term only #11 (photochemical* or photoinactivat* or photosensiti* or intercept* or amotosalen* or "S‐59" or riboflavin* or "vitamin b2" or ultraviolet* or ultra‐violet* or "UV light" or "UV therapy" or UVA or UVB or UVC or actinotherapy or mirasol* or eurosprite* or hovon* or "sprint trial" or theraflex* or "methylene blue" or "MD light" or macopharma) #12 photo* next (chemical* or inactivat* or sensiti*) #13 (pathogen* or virus* or viral* or infect*) near/3 (inactivat* or reduc* or remov*) #14 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 #15 MeSH descriptor: [Blood Platelets] explode all trees #16 MeSH descriptor: [Platelet Transfusion] explode all trees #17 MeSH descriptor: [Plateletpheresis] explode all trees #18 ((platelet* or thrombocyte*) near/5 (prophyla* or transfus* or infus* or administ* or requir* or need* or product or products or component* or concentrate* or apheres* or pooled or single donor* or random donor*)) #19 thrombocyt?pheres* or plateletpheres* #20 ((platelet* or thrombocyte*) near/5 (protocol* or trigger* or threshold* or schedul* or dose* or dosing or usage or utilisation or utilization)) #21 (platelet* or thrombocyte*):ti #22 (((septic or transmit*) near/3 transfus*) or (platelet* near/5 (infect* or pathogen* or bacter*))) #23 #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 #24 #14 and #23

Appendix 2. MEDLINE (OvidSP) search strategy 2013 to 2016

1. Platelet Transfusion/ 2. Plateletpheresis/ 3. Blood Platelets/ 4. ((platelet* or thrombocyte*) adj5 (prophyla* or transfus* or infus* or administ* or requir* or need* or product* or component* or concentrate* or apheres* or pooled or single donor or random donor)).tw. 5. (thrombocytopheres* or plateletpheres*).tw. 6. ((platelet* or thrombocyte*) adj5 (protocol* or trigger* or threshold* or schedul* or dose* or dosing or usage or utili?ation)).tw. 7. (platelet* or thrombocyte*).ti. 8. (((septic or transmit*) adj3 transfus*) or (platelet* adj5 (infect* or pathogen* or bacter*))).tw. 9. or/1‐8 10. Blood Preservation/ 11. Virus Inactivation/ 12. Decontamination/ 13. Disinfection/ 14. Photochemistry/ 15. Photosensitizing Agents/ 16. Ultraviolet Rays/ 17. exp Ultraviolet Therapy/ 18. Psoralens/ 19. Riboflavin/ 20. (photochemical* or photoinactivat* or photosensiti* or intercept* or amotosalen* or S‐59 or riboflavin* or vitamin b2 or ultraviolet* or ultra violet* or UV light* or UV therap* or UVA or UVB or UVC or actinotherapy or mirasol* or eurosprite* or hovon* or sprint trial or theraflex* or methylene blue or MD light or macopharma).tw. 21. (photo adj (chemical* or inactivat* or sensiti*)).tw. 22. ((pathogen* or virus* or viral* or infect*) adj3 (inactivat* or reduc* or remov*)).tw. 23. or/10‐22 24. 9 and 23 25. Meta‐Analysis.pt. 26. ((meta analy* or metaanaly*) and (trials or studies)).ab. 27. (meta analy* or metaanaly* or evidence‐based).ti. 28. ((systematic* or evidence‐based) adj2 (review* or overview*)).tw. 29. (cochrane or embase or cinahl or cinhal or lilacs or citation index or psyclit or psychlit or psycinfo or psychinfo or "web of science" or scopus).ab. 30. Cochrane Database of systematic reviews.jn. 31. ((literature or systematic* or comprehensive* or electronic*) adj2 search*).ab. 32. (additional adj (papers or articles or sources)).ab. 33. (bibliograph* or handsearch* or hand search* or manual* search* or searched or reference list*).ab. 34. (relevant adj (journals or articles)).ab. 35. or/25‐34 36. Review.pt. 37. RANDOMIZED CONTROLLED TRIALS AS TOPIC/ 38. selection criteria.ab. or critical appraisal.ti. 39. (data adj (extraction or analys$)).ab. 40. RANDOMIZED CONTROLLED TRIALS/ 41. or/37‐40 42. 36 and 41 43. 35 or 42 44. randomized controlled trial.pt. 45. controlled clinical trial.pt. 46. randomi*.tw. 47. placebo.ab. 48. clinical trials as topic.sh. 49. randomly.ab. 50. groups.ab. 51. trial.tw. 52. or/44‐51 53. 43 or 52 54. (ANIMALS/ or exp ANIMAL EXPERIMENTATION/ or exp MODELS, ANIMAL/) not HUMANS/ 55. (Comment or Editorial).pt. 56. 54 or 55 57. 53 not 56 58. 24 and 57

Appendix 3. Embase (OvidSP) search strategy 2013 to 2016

1. exp Thrombocyte Preservation/ 2. Virus Inactivation/ 3. Infection Control/ 4. Phototherapy/ 5. Photochemistry/ 6. PUVA/ 7. exp Photosensitizing Agent/ 8. exp Ultraviolet Radiation/ 9. Amotosalen/ 10. Pathogen Reduction/ 11. Psoralen/ 12. Riboflavin/ 13. (photochemical* or photoinactivat* or photosensiti* or intercept* or amotosalen* or S‐59 or riboflavin* or vitamin b2 or ultraviolet* or ultra violet* or UV light* or UV therap* or UVA or UVB or UVC or actinotherapy or mirasol* or eurosprite* or hovon* or sprint trial or theraflex* or methylene blue or MD light or macopharma).tw. 14. (photo adj (chemical* or inactivat* or sensiti*)).ti. 15. ((pathogen* or virus* or viral* or infect*) adj3 (inactivat* or reduc* or remov*)).tw. 16. or/1‐15 17. Thrombocyte Transfusion/ 18. Thrombocytopheresis/ 19. Thrombocyte/ 20. ((platelet* or thrombocyte*) adj5 (prophyla* or transfus* or infus* or administ* or requir* or need* or product* or component* or concentrate* or apheres* or pooled or single donor or random donor)).tw. 21. (thrombocyt?pheres* or plateletpheres*).tw. 22. ((platelet* or thrombocyte*) adj5 (protocol* or trigger* or threshold* or schedul* or dose* or dosing or usage or utili?ation)).tw. 23. (platelet* or thrombocyte*).ti. 24. (((septic or transmit*) adj3 transfus*) or (platelet* adj5 (infect* or pathogen* or bacter*))).tw. 25. or/17‐24 26. 16 and 25 27. Randomized Controlled Trial/ 28. Randomization/ 29. Single Blind Procedure/ 30. Double Blind Procedure/ 31. Crossover Procedure/ 32. Placebo/ 33. exp Clinical Trial/ 34. Prospective Study/ 35. (randomi* or double‐blind* or single‐blind* or RCT*).tw. 36. (random* adj2 (allocat* or assign* or divid* or receiv*)).tw. 37. (crossover* or cross over* or cross‐over* or placebo*).tw. 38. ((treble or triple) adj blind*).tw. 39. or/27‐38 40. Case Study/ 41. case report*.tw. 42. (note or editorial).pt. 43. or/40‐42 44. 39 not 43 45. (animal* or cat or cats or dog or dogs or pig or pigs or sheep or rabbit* or mouse or mice or rat or rats or feline or canine or porcine or ovine or murine or model*).ti. 46. 44 not 45 47. limit 46 to embase 48. 26 and 47

Appendix 4. CINAHL (EBSCOhost) search strategy 2013 to 2016

S1 MH BLOOD PLATELETS S2 MH PLATELET TRANSFUSION S3 MH PLATELETPHERESIS S4 TI (platelet* OR PLT or PLTs OR thrombocyte*) OR (thrombocytopheres* or plateletpheres*) S5 ((platelet* or thrombocyte*) N5 (prophyla* or transfus* or infus* or administ* or requir* or need* or product* or component* or concentrate* or apheres* or pooled or single donor or random donor or protocol* or trigger* or threshold* or schedul* or dose* or dosing or usage or utili?ation)) S6 (((septic or transmit*) N3 transfus*) or (platelet* N5 (infect* or pathogen* or bacter*))) S7 S1 OR S2 OR S3 OR S4 OR S5 OR S6 S8 MH BLOOD PRESERVATIO S9 MH PHOTOSENSITIZING AGENTS S10 MH ULTRAVIOLET RAYS S11 MH ULTRAVIOLET THERAPY S12 MH RIBOFLAVIN S13 TI ( (photochemical* or photoinactivat* or photosensiti* or intercept* or amotosalen* or "s‐59" or riboflavin or "vitamin b2" or ultraviolet or "ultra violet" or "UV light*" or "UV therap*" or UVA or UVB or UVC or actinotherapy or mirasol* or eurosprite* or hovon* or "sprint trial" or theraflex* or methylene blue or MD light or macopharma) ) OR AB ( (photochemical* or photoinactivat* or photosensiti* or intercept* or amotosalen* or "s‐59" or riboflavin or "vitamin b2" or ultraviolet or "ultra violet" or "UV light*" or "UV therap*" or UVA or UVB or UVC or actinotherapy or mirasol* or eurosprite* or hovon* or "sprint trial" or theraflex* or methylene blue or MD light or macopharma) ) S14 TI ( ("photo chemical*" or "photo inactivat*" or "photo sensiti*") ) OR AB ( ("photo chemical*" or "photo inactivat*" or "photo sensiti*") ) S15 TI ( ((pathogen* or virus* or viral* or infect*) and (inactivat* or reduc* or remov*)) ) OR AB ( ((pathogen* or virus* or viral* or infect*) and (inactivat* or reduc* or remov*)) ) S16 (MH "Virus Inactivation") S17 (MH "PUVA Therapy") S18 S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 S19 S7 AND S18 S20 (MH Clinical Trials+) S21 PT Clinical Trial S22 TI ((controlled trial*) or (clinical trial*)) OR AB ((controlled trial*) or (clinical trial*)) S23 TI ((singl* blind*) OR (doubl* blind*) OR (trebl* blind*) OR (tripl* blind*) OR (singl* mask*) OR (doubl* mask*) OR (tripl* mask*)) OR AB ((singl* blind*) OR (doubl* blind*) OR (trebl* blind*) OR (tripl* blind*) OR (singl* mask*) OR (doubl* mask*) OR (tripl* mask*)) S24 TI randomi* OR AB randomi* S25 MH RANDOM ASSIGNMENT S26 TI ((phase three) or (phase III) or (phase three)) or AB ((phase three) or (phase III) or (phase three)) S27 ( TI (random* N2 (assign* or allocat*)) ) OR ( AB (random* N2 (assign* or allocat*)) ) S28 MH PLACEBOS S29 MH META ANALYSIS S30 MH SYSTEMATIC REVIEW S31 TI ("meta analys*" OR metaanalys* OR "systematic review" OR "systematic overview" OR "systematic search*") OR AB ("meta analys*" OR metaanalys* OR "systematic review" OR "systematic overview" OR "systematic search*") S32 TI ("literature review" OR "literature overview" OR "literature search*") OR AB ("literature review" OR "literature overview" OR "literature search*") S33 TI (cochrane OR embase OR cinahl OR cinhal OR lilacs OR BIDS OR science AND citation AND index OR cancerlit) OR AB (cochrane OR embase OR cinahl OR cinhal OR lilacs OR BIDS OR science AND citation AND index OR cancerlit) S34 TI placebo* OR AB placebo* S35 MH QUANTITATIVE STUDIES S36 S20 or S21 or S22 or S23 or S24 or S25 or S26 or S27 or S28 or S29 or S30 or S31 or S32 or S33 or S34 or S35 S37 S19 AND S36

Appendix 5. PubMed (for epublications ahead of print) search strategy 2013 to 2016

#1 (photochemical* or photoinactivat* or photosensiti* or intercept* or amotosalen* or "S‐59" or riboflavin* or "vitamin b2" or ultraviolet* or "ultra violet" or "UV light" or "UV therapy" or "UV therapies" OR UVA or UVB or UVC or actinotherapy or mirasol* or eurosprite* or hovon* or theraflex* or "methylene blue" or "MD light" or macopharma) #2 (photo chemical* or photo inactivat* or photo sensiti*) #3 ((pathogen* or virus or viruses or viral* or infect*) AND (inactivat* or reduc* or remov*)) #4 #1 OR #2 OR #3 #5 ((platelet* OR thrombocyte*) AND (prophyla* OR transfus* OR infus* OR administ* OR requir* OR need* OR product* OR component* OR concentrate* OR apheres* OR pooled OR single donor* OR random donor* OR protocol* OR trigger* OR threshold* OR schedul* OR dose* OR dosing OR usage OR utilisation OR utilization)) #6 (thrombocytopheres* OR plateletpheres*) #7 platelet*[TI] OR thrombocyte*[TI] #8 (((septic OR transmit*) AND transfus*) OR (platelet* AND (infect* OR pathogen* OR bacteria OR bacterium))) #9 #5 OR #6 OR #7 OR #8 #10 #4 AND #9 #11 (random* OR blind* OR control group OR placebo OR controlled trial OR controlled study OR groups OR trials OR systematic review OR meta‐analysis OR metaanalysis OR literature search OR medline OR cochrane OR embase) AND (publisher[sb] OR inprocess[sb] OR pubmednotmedline[sb]) #12 #10 AND #11

Appendix 6. Transfusion Evidence Library 2013 to 2016

Search: photochemical OR photoinactivation or photosensitized OR intercept OR amotosalen OR S‐59 OR riboflavin OR vitamin OR ultraviolet OR ultra violet OR UV light OR or UV therapy OR UVA OR UVB OR UVC OR actinotherapy OR mirasol OR eurosprite OR hovon OR sprint OR theraflex OR methylene blue OR MD light OR macopharma OR photo chemical OR photo inactivation or photo sensitized OR pathogen OR virus OR viruses OR viral OR infected OR infection Filter: Platelets

Appendix 7. LILACS search strategy 2013 to 2016

((platelet OR platelets OR thrombocyte OR thrombocytes) AND (photochemical OR photoinactivation OR photosensitized OR intercept OR amotosalen OR S‐59 OR riboflavin OR vitamin OR ultraviolet OR ultra violet OR UV light OR UV therapy OR UVA OR UVB OR UVC OR actinotherapy OR mirasol OR eurosprite OR hovon OR sprint OR theraflex OR methylene blue OR MD light OR macopharma OR photo‐chemical OR photo‐inactivation OR photo‐sensitized OR pathogen OR virus OR viruses OR viral OR infected OR infection) AND db:("LILACS") AND type_of_study:("clinical_trials" OR "systematic_reviews")

Appendix 8. KoreaMed search strategy 2013 to 2016

platelet*[ALL] AND "Randomized Controlled Trial" [PT] thrombocyt*[ALL] AND "Randomized Controlled Trial" [PT]

Appendix 9. IndMED search strategy 2013 to 2016

(platelet OR platelets OR thrombocyte OR thrombocytes OR thrombocytopheresis OR plateletpheresis) AND (randomized OR randomised OR randomly OR blind OR blinded OR trial OR control group OR controlled)

Appendix 10. Web of Science CPCI‐S search strategy 2013 to 2016

TS=(platelet OR platelets OR thrombocyte OR thrombocytes) AND TS=(photochemical OR photoinactivated OR photosensitized OR intercept OR amotosalen OR "S‐59" OR riboflavin OR vitamin OR ultraviolet OR "ultra violet" OR "UV light" OR "UV therapy" OR UVA OR UVB OR UVC OR actinotherapy OR mirasol OR eurosprite OR hovon OR sprint OR theraflex OR "methylene blue" OR "MD light" OR macopharma OR "photo chemical" OR "photo inactivated" or "photo sensitized" OR pathogen OR virus OR viruses OR viral OR infected OR infection OR infections) AND TS=(randomized OR randomised OR randomly OR blind OR blinded OR trial OR "control group" OR "controlled study")

Appendix 11. WHO ICTRP search strategy 2013 to 2016

(Title: platelet OR platelets OR thrombocyte OR thrombocytes) AND (Intervention: photochemical OR photoinactivated OR photosensitized OR inactivated OR intercept OR amotosalen OR S‐59 OR riboflavin OR vitamin OR ultraviolet OR ultra violet OR UV light OR UV therapy OR UVA OR UVB OR UVC OR actinotherapy OR mirasol OR hovon OR theraflex OR methylene blue OR MD light OR macopharma OR photo OR pathogen OR virus OR viruses OR viral OR infected OR infection) AND Recruitment Status: ALL

Appendix 12. ClinicalTrials.gov search strategy 2013 to 2016

Search Terms: (photochemical OR photoinactivated OR photosensitized OR inactivated OR intercept OR amotosalen OR "S‐59" OR riboflavin OR vitamin OR ultraviolet OR "ultra violet" OR "UV light" OR "UV therapy" OR UVA OR UVB OR UVC OR actinotherapy OR mirasol OR hovon OR theraflex OR "methylene blue" OR "MD light" OR macopharma OR photo OR pathogen OR virus OR viruses OR viral OR infected OR infection) Title: platelet OR platelets OR thrombocyte OR thrombocytes Study Design: Intervention Studies

Appendix 13. CENTRAL search strategy up to 2013

#1 Blood Platelets single term (MeSH) #2 Platelet Transfusion single term (MeSH) #3 Blood Component Transfusion single term (MeSH) #4 Blood Transfusion single term (MeSH) #5 Plateletpheresis single term (MeSH) #6 Antigens, Human Platelet single term (MeSH) #7 Blood Borne Pathogens single term (MeSH) #8 (platelet* or thrombocyte* or blood product* or blood component*):ti #9 (platelet* NEAR/2 (transfus* or concentrate* or component* or product*)) #10 "septic transfusion*" or (transfus* NEAR/2 transmit*) #11 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 #12 Blood Preservation single term (MeSH) #13 Virus Inactivation single term (MeSH) #14 Decontamination single term (MeSH) #15 Disinfection single term (MeSH) #16 Photochemistry single term (MeSH) #17 Photosensitizing Agents single term (MeSH) #18 Ultraviolet Rays single term (MeSH) #19 Ultraviolet Therapy explode all trees (MeSH) #20 Psoralens single term (MeSH) #21 Riboflavin single term (MeSH) #22 photochemical* or photoinactivat* or photosensiti* or Intercept* or amotosalen* or s‐59 or riboflavin or vitamin b2 or ultraviolet or ultra violet or UV light* or UV therap* or actinotherapy or Mirasol* or eurosprite* or hovon* or "sprint trial" #23 (photo NEXT (chemical* or inactivat* or sensiti*) #24 (pathogen* or virus* or viral* or infect*) NEAR/3 (inactivat* or reduc* or remov*) #25 #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 #26 #11 and #25

Appendix 14. MEDLINE (Ovid) search strategy up to 2013

1. Blood Platelets/ 2. Platelet Transfusion/ 3. Blood Component Transfusion/ 4. Blood Transfusion/ 5. Plateletpheresis/ 6. Antigens, Human Platelet/ 7. Blood Borne Pathogens/ 8. (platelet* or thrombocyte* or blood product* or blood component*).ti. 9. ((platelet* adj5 (transfus* or concentrate* or product* or component*)).tw. 10. (septic transfusion* or (transfus* adj2 transmit*)).tw. 11. or/1‐10 12. Blood Preservation/ 13. Virus Inactivation/ 14. Decontamination/ 15. Disinfection/ 16. Photochemistry/ 17. Photosensitizing Agents/ 18. Ultraviolet Rays/ 19. exp Ultraviolet Therapy/ 20. Psoralens/ 21. Riboflavin/ 22. (photochemical* or photoinactivat* or photosensiti* or Intercept®* or amotosalen* or s‐59 or riboflavin or vitamin b2 or ultraviolet or ultra violet or UV light* or UV therap* or actinotherapy or Mirasol®* or eurosprite* or hovon* or sprint trial).tw. 23. (photo adj (chemical* or inactivat* or sensiti*)).tw. 24. ((pathogen* or virus* or viral* or infect*) adj3 (inactivat* or reduc* or remov*)).tw. 25. or/12‐24 26. 11 and 25

Appendix 15. Embase (Ovid) search strategy up to 2013

1. Thrombocyte/ 2. Thrombocyte Transfusion/ 3. Blood Transfusion/ 4. Blood Component Therapy/ 5. Thrombocyte Concentrate/ 6. Thrombocyte Antigen/ 7. exp Blood Transfusion Reaction/ 8. (platelet* or thrombocyte* or blood product* or blood component*).ti. 9. (platelet* adj5 (transfus* or concentrate* or product* or component*)).tw. 10. (septic transfusion* or (transfus* adj2 transmit*)).tw. 11. or/1‐10 12. Thrombocyte Preservation/ 13. Virus Inactivation/ 14. Infection Control/ 15. Phototherapy/ 16. Photochemistry/ 17. PUVA/ 18. exp Photosensitizing Agent/ 19. exp Ultraviolet Radiation/ 20. Amotosalen/ 21. Pathogen Reduction/ 22. Psoralen/ 23. Riboflavin/ 24. (photochemical* or photoinactivat* or photosensiti* or Intercept* or amotosalen* or s‐59 or riboflavin or vitamin b2 or ultraviolet or ultra violet or UV light* or UV therap* or actinotherapy or Mirasol* or eurosprite* or hovon* or sprint trial).tw. 25. (photo adj (chemical* or inactivat* or sensiti*)).tw. 26. ((pathogen* or virus* or viral* or infect*) adj3 (inactivat* or reduc* or remov*)).tw. 27. or/12‐26 28. 11 and 27

Appendix 16. CINAHL & BNID (NHS Evidence) search strategy up to 2013

1. Blood Platelets/ 2. Platelet Transfusion/ 3. Blood Component Transfusion/ 4. Blood Transfusion/ 5. Plateletpheresis/ 6. (platelet* or PLT or PLTs or thrombocyte* or “blood product*” or “blood component*”).ti 7. ((platelet* AND (transfus* or concentrate* or product* or component*)).ti,ab 8. (“septic transfusion*” or (transfus* adj2 transmit*)).ti,ab 9. or/1‐8 10. Blood Preservation/ 11. Photosensitizing Agents/ 12. Ultraviolet Rays/ 13. Ultraviolet Therapy/ 14. Riboflavin/ 15. (photochemical* or photoinactivat* or photosensiti* or Intercept* or amotosalen* or "s‐59" or riboflavin or "vitamin b2" or ultraviolet or "ultra violet" or "UV light*" or "UV therap*" or actinotherapy or Mirasol* or eurosprite* or hovon* or "sprint trial").ti,ab 16. ("photo chemical*" or "photo inactivat*" or "photo sensiti*").ti,ab 17. ((pathogen* or virus* or viral* or infect*) and (inactivat* or reduc* or remov*)).ti,ab 18. or/10‐17 19. 9 and 18

Appendix 17. PubMed search strategy (epublications only) up to 2013

((platelet[ti] OR platelets OR thrombocyte[ti] OR thrombocytes) AND (reduction[ti] OR reduced[ti] OR inactivat*[ti] OR Intercept*[ti] OR amotosalen[ti] OR Mirasol*[ti] OR “sprint trial”[ti] OR eurosprite[ti] OR hovon[ti] OR riboflavin[ti])) AND (publisher[sb] NOT pubstatusnihms)

Appendix 18. Transfusion Evidence Library, international databases, and ongoing trial databases up to 2013

1. (platelet or platelets or thrombocyte or thrombocytes) AND (pathogen or pathogens) AND (reduction or reduced or inactivation or inactivated) 2. (platelet or platelets or thrombocyte or thrombocytes) AND (Intercept or amotosalen or Mirasol or Sprint or Eurosprite or Hovon or riboflavin) 3. 1 OR 2

Data and analyses

Comparison 1.

Pathogen‐reduced platelets versus standard platelets for the prevention of bleeding

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number of participants with 'any bleeding' event(s) (WHO grade 1 to 4 or equivalent) ‐ follow‐up less than 48 hrs	3		Risk Ratio (Fixed, 95% CI)	Subtotals only
1.1 Intercept plts vs standard plts ‐ single platelet transfusion studies	3	309	Risk Ratio (Fixed, 95% CI)	0.86 [0.63, 1.19]
2 Number of participants with 'any bleeding' event(s) (WHO grade 1 to 4 or equivalent) ‐ follow‐up more than 7 days	5	1085	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [1.02, 1.15]
2.1 Intercept plts vs standard plts ‐ multiple platelet transfusion studies	4	975	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [1.01, 1.13]
2.2 Mirasol plts vs standard plts ‐ multiple platelet transfusion studies	1	110	Risk Ratio (M‐H, Fixed, 95% CI)	1.38 [0.95, 2.02]
3 Number of participants with 'clinically significant' bleeding (WHO grade ≥ 2 or equivalent ‐ follow‐up less than 48 hours	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3.1 Intercept plts vs standard plts ‐ single platelet transfusion studies	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Number of participants with 'clinically significant' bleeding (WHO grade ≥ 2 or equivalent) ‐ follow‐up more than 7 days	5	1392	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.97, 1.25]
4.1 Intercept plts vs standard plts ‐ multiple platelet transfusion studies	4	1088	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.94, 1.21]
4.2 Mirasol plts vs standard plts ‐ multiple platelet transfusion studies	2	304	Risk Ratio (M‐H, Fixed, 95% CI)	1.54 [0.86, 2.76]
5 Number of participants with 'severe' bleeding (WHO grade ≥ 3 or equivalent) ‐ follow‐up less than 48 hours	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5.1 Intercept plts vs standard plts ‐ single platelet transfusion studies	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Number of participants with 'severe' bleeding (WHO grade ≥ 3 or equivalent) ‐ follow‐up more than 7 days	6	1495	Risk Ratio (M‐H, Fixed, 95% CI)	1.24 [0.76, 2.02]
6.1 Intercept plts vs standard plts ‐ multiple platelet transfusion studies	5	1191	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [0.70, 2.09]
6.2 Mirasol plts vs standard plts ‐ multiple platelet transfusion studies	2	304	Risk Ratio (M‐H, Fixed, 95% CI)	1.36 [0.45, 4.16]
7 All‐cause mortality (follow‐up 0 to < 4 weeks)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7.1 All‐cause mortality	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.2 Mortality due to bleeding	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.3 Mortality due to infection	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.4 Mortality due to thromboembolism	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.5 Mortality due to transfusion reactions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
8 All‐cause mortality (follow‐up 4 to 12 weeks)	6	1509	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.50, 1.29]
8.1 Intercept plts vs standard plts ‐ multiple platelet transfusion studies	5	1203	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.37, 1.05]
8.2 Mirasol plts vs standard plts ‐ multiple platelet transfusion studies	2	306	Risk Ratio (M‐H, Fixed, 95% CI)	2.92 [0.81, 10.59]
9 Mortality due to bleeding (follow‐up 4 to 12 weeks)	6	1509	Risk Ratio (M‐H, Fixed, 95% CI)	1.23 [0.38, 3.96]
9.1 Intercept plts vs standard plts‐multiple platelet transfusion studies	5	1203	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.29, 3.75]
9.2 Mirasol plts vs standard plts‐multiple platelet transfusion studies	2	306	Risk Ratio (M‐H, Fixed, 95% CI)	2.89 [0.12, 69.55]
10 Mortality due to infection (follow‐up 4 to 12 weeks)	6	1509	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.42, 2.09]
10.1 Intercept plts vs standard plts‐multiple platelet transfusion studies	5	1203	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.35, 2.03]
10.2 Mirasol plts vs standard plts‐multiple platelet transfusions studies	2	306	Risk Ratio (M‐H, Fixed, 95% CI)	1.62 [0.22, 12.07]
11 Number of participants with an acute transfusion reaction	7	1636	Risk Ratio (Fixed, 95% CI)	0.96 [0.75, 1.24]
11.1 Intercept plts vs standard plts ‐ single platelet transfusion studies	2	251	Risk Ratio (Fixed, 95% CI)	1.57 [0.71, 3.48]
11.2 Intercept plts vs standard plts ‐ multiple platelet transfusion studies	5	1191	Risk Ratio (Fixed, 95% CI)	0.91 [0.69, 1.18]
11.3 Mirasol plts vs standard plts‐multiple platelet	1	194	Risk Ratio (Fixed, 95% CI)	1.99 [0.18, 21.78]
12 Number of participants experiencing platelet refractoriness	7	1525	Risk Ratio (M‐H, Fixed, 95% CI)	2.94 [2.08, 4.16]
12.1 Intercept plts vs standard plts ‐ multiple platelet transfusion studies	6	1221	Risk Ratio (M‐H, Fixed, 95% CI)	2.85 [1.96, 4.15]
12.2 Mirasol plts vs standard plts ‐ multiple platelet transfusion studies	2	304	Risk Ratio (M‐H, Fixed, 95% CI)	3.47 [1.44, 8.34]
13 Number of participants experiencing platelet refractoriness and platelet alloimmunisation	6	1415	Risk Ratio (M‐H, Fixed, 95% CI)	2.35 [1.46, 3.76]
13.1 Intercept plts vs standard plts ‐ multiple platelet transfusion studies	6	1221	Risk Ratio (M‐H, Fixed, 95% CI)	1.90 [1.11, 3.26]
13.2 Mirasol plts vs standard plts‐multiple platelet transfusion studies	1	194	Risk Ratio (M‐H, Fixed, 95% CI)	4.5 [1.58, 12.81]
14 Number of participants with an adverse event	7	1566	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.97, 1.05]
14.1 Intercept plts vs standard plts ‐ single platelet transfusion studies	2	255	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.87, 1.09]
14.2 Intercept plts vs standard plts ‐ multiple platelet transfusion studies	4	1007	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.97, 1.05]
14.3 Mirasol plts vs standard plts ‐ multiple platelet transfusion studies	2	304	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.89, 1.21]
15 Number of participants with a serious adverse event	7	1340	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.88, 1.35]
15.1 Intercept plts vs standard plts ‐ single platelet transfusion studies	2	255	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [0.55, 2.68]
15.2 Intercept plts vs standard plts ‐ multiple platelet transfusion studies	4	975	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.84, 1.36]
15.3 Mirasol plts vs standard plts ‐ multiple platelet transfusion studies	1	110	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.56, 2.32]
16 Number of participants with anaphylaxis	6	1296	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.26, 4.06]
16.1 Intercept plts vs standard plts‐single platelet transfusion studies	1	211	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.06, 15.93]
16.2 Intercept plts vs standard plts‐ multiple platelet transfusion studies	4	975	Risk Ratio (M‐H, Fixed, 95% CI)	1.79 [0.23, 13.69]
16.3 Mirasol plts vs standard plts‐multiple platelet transfusion studies	1	110	Risk Ratio (M‐H, Fixed, 95% CI)	0.32 [0.01, 7.73]
17 Number of participants with infection	6	1296	Risk Ratio (M‐H, Fixed, 95% CI)	1.27 [1.09, 1.48]
17.1 Intercept plts vs standard plts‐ single platelet transfusion studies	1	211	Risk Ratio (M‐H, Fixed, 95% CI)	1.18 [0.57, 2.43]
17.2 Intercept plts vs standard plts‐multiple platelet transfusion studies	4	975	Risk Ratio (M‐H, Fixed, 95% CI)	1.36 [1.14, 1.62]
17.3 Mirasol plts vs standard plts‐multiple platelet transfusion studies	1	110	Risk Ratio (M‐H, Fixed, 95% CI)	0.9 [0.63, 1.28]
18 Number of participants with venous thromboembolism (follow‐up 0 to 12 weeks)	6	1296	Risk Ratio (M‐H, Fixed, 95% CI)	1.23 [0.67, 2.26]
18.1 Intercept plts vs standard plts‐single platelet transfusion studies	1	211	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.2 Intercept plts vs standard plts‐multiple platelet transfusion studies	4	975	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [0.71, 2.50]
18.3 Mirasol plts vs standard plts‐multiple platelet transfusion studies	1	110	Risk Ratio (M‐H, Fixed, 95% CI)	0.48 [0.05, 5.16]
19 Number of participants with arterial venous thromboembolism (follow‐up 0 to 12 weeks)	7	1706	Risk Ratio (M‐H, Fixed, 95% CI)	0.44 [0.14, 1.42]
19.1 Intercept plts vs standard plts‐single platelet transfusion studies	1	211	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
19.2 Intercept plts vs standard plts‐multiple platelet transfusion studies	5	1191	Risk Ratio (M‐H, Fixed, 95% CI)	0.47 [0.13, 1.64]
19.3 Mirasol plts vs standard plts‐multiple transfusion studies	2	304	Risk Ratio (M‐H, Fixed, 95% CI)	0.32 [0.01, 7.73]
20 Lab response ‐ 1‐hour count increment [x 109/L]	7		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
20.1 Intercept plts vs standard plts ‐ single platelet transfusion studies	2	219	Mean Difference (IV, Fixed, 95% CI)	‐1.39 [‐4.81, 2.02]
20.2 Intercept plts vs standard plts ‐ multiple platelet transfusion studies	5	1203	Mean Difference (IV, Fixed, 95% CI)	‐10.08 [‐11.67, ‐8.48]
20.3 Mirasol plts vs standard plts‐multiple platelet transfusion studies	1	196	Mean Difference (IV, Fixed, 95% CI)	‐8.90 [‐18.47, 0.67]
21 Lab response ‐ 1‐hour corrected count increment [x 103/L]	8		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
21.1 Intercept plts vs standard plts ‐ single platelet transfusion studies	2	219	Mean Difference (IV, Fixed, 95% CI)	‐0.89 [‐2.35, 0.58]
21.2 Intercept plts vs standard plts ‐ multiple platelet transfusion studies	5	1191	Mean Difference (IV, Fixed, 95% CI)	‐4.11 [‐4.87, ‐3.35]
21.3 Mirasol plts vs standard plts ‐ multiple platelet transfusion studies	2	304	Mean Difference (IV, Fixed, 95% CI)	‐4.14 [‐6.29, ‐1.99]
22 Lab response ‐ 24‐hour count increment [x 109/L]	6	1571	Mean Difference (IV, Fixed, 95% CI)	‐7.12 [‐8.32, ‐5.93]
22.1 Intercept plts vs standard plts ‐ single platelet transfusion studies	1	186	Mean Difference (IV, Fixed, 95% CI)	‐4.1 [‐7.16, ‐1.04]
22.2 Intercept plts vs standard plts ‐ multiple platelet transfusion studies	5	1191	Mean Difference (IV, Fixed, 95% CI)	‐8.39 [‐9.82, ‐6.96]
22.3 Mirasol plts vs standard plts‐multiple platelet transfusion studies	1	194	Mean Difference (IV, Fixed, 95% CI)	‐4.30 [‐7.38, ‐1.22]
23 Lab response ‐ 24‐hour corrected count increment [x 103/L]	7	1681	Mean Difference (IV, Fixed, 95% CI)	‐3.02 [‐3.57, ‐2.48]
23.1 Intercept plts vs standard plts ‐ single platelet transfusion studies	1	186	Mean Difference (IV, Fixed, 95% CI)	‐1.96 [‐3.24, ‐0.68]
23.2 Intercept plts vs standard plts ‐ multiple platelet transfusion studies	5	1191	Mean Difference (IV, Fixed, 95% CI)	‐3.50 [‐4.18, ‐2.82]
23.3 Mirasol plts vs standard plts ‐ multiple platelet transfusion studies	2	304	Mean Difference (IV, Fixed, 95% CI)	‐2.37 [‐3.68, ‐1.06]
24 Number of platelet transfusions per participant	6	1509	Mean Difference (IV, Fixed, 95% CI)	1.23 [0.86, 1.61]
24.1 Intercept plts vs standard plts ‐ multiple platelet transfusion studies	5	1203	Mean Difference (IV, Fixed, 95% CI)	1.30 [0.84, 1.77]
24.2 Mirasol plts vs standard plts ‐ multiple platelet transfusion studies	2	306	Mean Difference (IV, Fixed, 95% CI)	1.09 [0.44, 1.75]
25 Platelet transfusion interval (days to next platelet transfusion)	8	1697	Mean Difference (IV, Fixed, 95% CI)	‐0.34 [‐0.43, ‐0.24]
25.1 Intercept plts vs standard plts ‐ single platelet transfusion studies	2	194	Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.13, 0.34]
25.2 Intercept plts vs standard plts ‐ multiple platelet transfusion studies	5	1197	Mean Difference (IV, Fixed, 95% CI)	‐0.50 [‐0.61, ‐0.38]
25.3 Mirasol plts vs standard plts ‐ multiple platelet transfusion studies	2	306	Mean Difference (IV, Fixed, 95% CI)	‐0.16 [‐0.38, 0.07]
26 Number of red cell transfusions per participant	7	1720	Mean Difference (IV, Fixed, 95% CI)	0.13 [‐0.07, 0.33]
26.1 Intercept plts vs standard plts ‐ single platelet transfusion studies	1	211	Mean Difference (IV, Fixed, 95% CI)	‐0.02 [‐0.27, 0.23]
26.2 Intercept plts vs standard plts ‐ multiple platelet transfusion studies	5	1203	Mean Difference (IV, Fixed, 95% CI)	0.38 [‐0.08, 0.85]
26.3 Mirasol plts vs standard plts ‐ multiple platelet transfusion studies	2	306	Mean Difference (IV, Fixed, 95% CI)	0.47 [‐0.05, 0.99]

What's new

Date	Event	Description
31 August 2017	Amended	Typos corrected

History

Date	Event	Description
24 October 2016	New citation required but conclusions have not changed	New authorship: Lise J Estcourt, Reem Malouf, Marialena Trivella, Carolyn Doree, Sally Hopewell, Simon J Stanworth, Michael F Murphy
24 October 2016	New search has been performed	New search, 5 new studies identified (EUCTR2015‐001035‐20‐DE; Johansson 2013; Kerkhoffs 2013; NCT01789762; Rebulla 2016). Three of these are ongoing studies (EUCTR2015‐001035‐20‐DE; Kerkhoffs 2013; NCT01789762).

Differences between protocol and review

There have been several changes from the protocol due to findings from the previous version of the review (Butler 2011; Butler 2013).

We performed several post hoc subgroup analyses In the previous version of the review (Butler 2013). These were prespecified in this version of the review. The subgroups were:

• trials that exposed participants to a single transfusion of Intercept PCT versus standard platelets;

• trials that exposed participants to multiple transfusions of Intercept PCT versus standard platelets;

• trials that exposed participants to a single transfusion of Mirasol PCT versus standard platelets;

• trials that exposed participants to multiple transfusions of Mirasol PCT versus standard platelets.

In the previous version of the review for the outcomes assessing bleeding (Butler 2013), we combined data according to whether the follow‐up period was up to 48 hours, up to seven days, or more than seven days. We prespecified these categories in this version of the review.

The outcomes within the 'Summary of findings' table had not been prespecified in the protocol (Butler 2011). We prespecified the outcomes used in the previous version of this review, which included any bleeding, clinically significant bleeding, severe bleeding, mortality, serious adverse events, platelet refractoriness, and number of platelet transfusions per participant.

We have made an additional change that was not in the previous version of the review (Butler 2013). In this update of the review we:

• added quality of life as a secondary outcome.

Other adverse events

Although we had intended to exclude bleeding, transfusion reactions, and mortality data from the adverse events data for each trial, most trials did not present their data in a way that allowed for this, and so we have included all adverse events, and serious adverse events

Differences between the protocol and the review due to lack of data

Subgroup analysis

In the review protocol we planned to perform a subgroup analysis for the length of platelet storage and participants' underlying conditions. However, this was not possible due to lack of data. Not all included trials reported the duration of platelets storage, with two trials published as abstracts not providing relevant information (Agliastro 2006; De Francisci 2004). An additional example is for a number of meta‐analyses in which studies from two different platelets storage durations were combined, such as 'any bleeding' (Analysis 1.2), where the storage duration for all included studies in this meta‐analysis was five days except for one study (Kerkhoffs 2010), in which the platelets were stored for up to seven days. Subgroup analysis was also not possible in our meta‐analysis of 'all‐cause mortality' (Analysis 1.7), in which all the included studies reported a five‐day platelet storage duration apart from two studies, Kerkhoffs 2010 and Lozano 2011, for which combining was not possible, as Lozano 2011 was a single platelet transfusion study and Kerkhoffs 2010 was a multiple platelet transfusion study. Performing subgroup analysis based on the underlying conditions that required platelet transfusions was not possible, as the majority of the included studies were conducted on people with thrombocytopenia caused by haemato‐oncological diagnosis.

We were only able to categorise bleeding outcomes according to short‐term (up to 48 hours) and long‐term (more than seven days) after receiving the transfusion. We were not able to assess these outcomes at medium‐term follow‐up.

We were not able to perform subgroup analysis comparing single and multiple Intercept PCT transfusion strategies for all outcomes.

Sensitivity analysis

We had also planned to perform a sensitivity analysis to assess the robustness of our findings including only trials with low risk of bias. However, this was not required as all the included studies were generally at low risk of bias, and data from the two studies with unclear risk of bias did not contribute to any of the meta‐analyses in the review (Agliastro 2006; De Francisci 2004).

Publication bias

We were unable to detect publication bias due to insufficient numbers of included studies. The maximum number of included studies contributing to a meta‐analysis was seven.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Agliastro 2006

Methods	Type of study: parallel‐group, randomised controlled trial Type of publication: abstract Setting and country: hospital, Palermo, Italy Number of centres: unclear Dates of trial (start and end): July 2005 to not reported Treatment period + follow‐up: not reported Power calculation performed?: not reported
Participants	30 thrombocytopenic children with either solid or haematological malignancies were randomised to 1 of 2 intervention groups: PCT: Intercept PCT platelets (N = 19) Control: standard platelets (N = 11) Number analysed for primary outcome: 30 People who were actively bleeding excluded?: not reported People with platelet refractoriness or alloimmunisation excluded?: not reported
Interventions	PCT: Intercept PCT platelets produced from 5 pooled buffy coats, storage solution not reported Control: apheresis standard platelets, storage solution not reported Timing of measurement of platelet dose and gamma irradiation: not reported Storage duration of platelets: not reported Transfusion trigger: therapeutic ("bleeding symptomatology"), no further information reported % off‐protocol transfusions: not reported Red cell transfusion protocol specified: not reported
Outcomes	Study outcomes (primary outcome unclear): pre‐ and post‐transfusion platelet count; 24‐hr CCI; the continuing of bleeding (scale not reported); transfusion reactions; transfusion refractoriness
Notes	Trial registration: none found Source(s) of funding: not reported Conflicts of interest: not reported Intervention exposure: multiple dose
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information provided, only available as an abstract.
Allocation concealment (selection bias)	Unclear risk	No information provided, only available as an abstract.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	No information provided, only available as an abstract.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided, only available as an abstract.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear whether any randomised participants were lost to follow‐up or withdrawn from treatment. All participants enrolled were randomly divided between the 2 interventions and received at least 1 platelet transfusion.
Selective reporting (reporting bias)	Unclear risk	Study published as an abstract only, original study protocol not available for comparison. Minimal participant background characteristics reported. The average platelet dose of both interventions was reported, but no timings of platelet dose measurement or storage duration of platelets was reported. Comparability of interventions and participants unclear. All outcomes listed in methods section were reported, but no standard deviations were given for pre‐ and post‐transfusion platelet counts and 24‐hour CCI.
Other bias	Unclear risk	Only available as an abstract

Cazenave 2010

Methods	Type of study: parallel‐group, non‐inferiority, randomised controlled trial Type of publication: full Setting and country: blood transfusion centres and hospitals, France Number of centres: 6 Dates of trial: December 2005 to September 2007 (recruitment period only) Treatment period + follow‐up: maximum 28‐day treatment period with a 28‐day follow‐up period, starting the day after the last on‐protocol transfusion Power calculation performed?: yes. It was estimated that the mean CCI1hour in the reference group would be 14,700 (SD 5200; based on the results of TRAP 1997). With a Type 1 error of 2.5% and power of 80%, it was determined that 50 participants would be required per group to claim non‐inferiority of PRP‐platelet components compared to standard practice with a non‐inferiority margin of 20% (CCI difference of 2940). This sample size was increased to 118 to accommodate some loss to follow‐up.
Participants	118 adults (≥ 16 years of age) with thrombocytopenia and a haemato‐oncological diagnosis expected to receive at least 2 platelet transfusions were randomised to 1 of 2 intervention groups: PCT: Mirasol PCT platelets (N = 60) Control: standard platelets (N = 58) Number analysed for primary outcome: 110 (56/54), 8 participants were excluded as they did not require a platelet transfusion (4 from each study arm) People who were actively bleeding excluded?: yes; "Patients were excluded if any of the following criteria were present: ... active bleeding requiring one or more red cell transfusions; ... and any other medical condition that could compromise participation." People with platelet refractoriness or alloimmunisation excluded?: yes; "history of refractoriness to PLT transfusion (two successive CCI1hour < 5000); presence of HLA antibodies, positive lymphocytotoxicity test or previously documented alloimmunization to PLTS"
Interventions	PCT: apheresis or 6 pooled buffy coat Mirasol PCT platelets (riboflavin + ultraviolet light treatment), suspended in plasma Control: apheresis or 6 pooled buffy coat standard platelets suspended in plasma Timing of measurement of platelet dose and gamma irradiation: not reported Storage duration of platelets: up to 5 days Transfusion trigger: prophylactic or therapeutic: platelet count 10 x 109/L when clinical risk factors absent; 20 x 109/L when fever, hypertension, evidence of grade 2 mucositis, lesions with bleeding potential and/or a rapid decrease in platelet count occurring within 72 hrs; 50 x 109/L if antithrombotics were administered, there was evidence of fibrinolysis or coagulopathy, or invasive surgery required % off‐protocol transfusions: PCT platelets group: 17.7%; standard platelets group: 23.2% Red cell transfusion protocol specified: not reported
Outcomes	Primary: 1‐hour CCI for each of a maximum of 8 on‐protocol platelet transfusions per participant occurring within the 28‐day treatment period Secondary: 24‐hour CCI; interval between transfusions; number of platelet and red blood cell transfusions per participants during the treatment period; number of platelets transfused; evidence of refractoriness; frequency of transfusion‐associated infections and bleeding Safety outcomes: adverse events, serious adverse events, bleeding status on days of platelet transfusion, transfusion‐associated infections, and death
Notes	Trial registration: NCT00263809 on 7 December 2005 Source(s) of funding: CaridianBCT (Mirasol) Conflicts of interest: Raymond P Goodrich (corresponding author) is an employee of CaridianBCT Biotechnologies, LLC. Intervention exposure: multiple dose
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"The random treatment allocation scheme involved stratification by centre and blocking and was computer generated by the coordinating centre (MedPass International, Paris, France)."
Allocation concealment (selection bias)	Low risk	"Patient allocation was performed at each site using opaque envelopes containing the treatment assignment"
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding of participants and personnel was not possible due to slight yellow colour of the PCT platelets product.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Those individuals assessing PLT (platelet) counts and performing patient assessments were blinded to the patient's treatment allocation."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Clear CONSORT flow diagram identifying the number of participants withdrawn or lost to follow‐up. All participants who received a platelet transfusion were included in the analysis.
Selective reporting (reporting bias)	Low risk	All outcomes specified in methods were reported.
Other bias	Low risk	At least 15% of participants were re‐recruited to a second cycle with the same randomisation schedule. However, data from the second cycle were not reported.

De Francisci 2004

Methods	Type of study: parallel‐group, randomised controlled trial Type of publication: abstract Setting and country: hospital, Italy Number of centres: not reported Dates of trial (start and end): April 2003 to unclear Treatment period + follow‐up: platelet requirement observed for the first 2 weeks' post‐transfusion. Follow‐up for adverse events or side effects at 1, 3, and 6 months' post‐transfusion. Power calculation performed?: not reported
Participants	44 participants divided into 2 groups: 1st group: 28 adults (≥ 16 years of age) with cirrhosis who are thrombocytopenic and on a waiting list for liver transplantation, requiring platelet transfusions before invasive procedures, were divided into 2 random groups: PCT: Intercept PCT platelets (N = 14) Control: standard platelets (N = 14) Number analysed for primary outcome: 28 People who were actively bleeding excluded?: not reported People with platelet refractoriness or alloimmunisation excluded?: not reported 2nd group: 16 children with congenital cyanogen cardiopathy who underwent cardiac surgery and required platelet transfusions per protocol due to platelet consumption during extracorporeal circulation, were divided into 2 random groups: PCT: Intercept PCT platelets (N = 8) Control: standard platelets (N = 8) Number analysed for primary outcome: 16 People who were actively bleeding excluded?: not reported People with platelet refractoriness or alloimmunisation excluded?: not reported
Interventions	PCT: Intercept PCT platelets, prepared from an unreported number of buffy coats, storage solution and gamma irradiation not reported Control: standard platelets, method of platelet preparation, storage solution, and gamma irradiation not reported Timing of measurement of platelet dose and gamma irradiation: not reported Storage duration of platelets: not reported Transfusion trigger: prophylactic (prior to invasive procedure for cirrhotic group; perioperatively, according to protocol for paediatric cardiac participants), no further information reported % off‐protocol transfusions: not reported Red cell transfusion protocol specified: not reported
Outcomes	Study outcomes (primary outcome unclear): pre‐ and post‐transfusion platelet count; 1‐ and 24‐hour CCI; bleeding; transfusion reactions; requirement for additional platelet transfusions during the following 2 weeks
Notes	Trial registration: none found Source(s) of funding: not reported Conflicts of interest: not reported Intervention exposure: not reported but appears to be a single transfusion episode
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation not reported.
Allocation concealment (selection bias)	Unclear risk	No information provided.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	No information provided.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided.
Incomplete outcome data (attrition bias) All outcomes	Low risk	All randomised participants received the intervention, and no losses to follow‐up or treatment withdrawals were reported following randomisation.
Selective reporting (reporting bias)	High risk	Study published as an abstract only, original study protocol not available for comparison. Minimal participant background characteristics reported. 1‐hour CCI not reported for the cirrhotic group. No standard deviations reported for mean 1‐ and 24‐hour CCIs. Pre‐ and post‐transfusion platelet counts not reported for either intervention.
Other bias	Unclear risk	Only available as an abstract

Janetzko 2005

Methods	Type of study: parallel‐group, randomised controlled trial Type of publication: full Setting and country: hospitals in Germany, France, and Switzerland Number of centres: 3 Dates of trial (start and end): not reported Treatment period + follow‐up: maximum 28‐day treatment period (or until 7 days without platelet transfusion, "PLT transfusion independence") + 7‐day surveillance period Power calculation performed?: yes. A sample size of 20 participants in each group was estimated to provide a power of 80% to detect a difference in mean count increment of 13.6 x 109/L and a difference in CCI of 5.25 x 103 between reference and PRP platelet components.
Participants	44 adults (≥ 16 years of age) with thrombocytopenia and a haemato‐oncological diagnosis requiring platelet transfusions during medical treatment were randomised to 1 of 2 intervention groups: PCT: Intercept PCT platelets (N = 22) Control: standard platelets (N = 22) Number analysed for primary outcome: 43 (22/21) (1 did not require platelet transfusion) People who were actively bleeding excluded?: yes; "The following criteria results in exclusion from entry into the study, but did not constitute reasons for removing patients from the study once enrolled: ... active haemorrhage" People with platelet refractoriness or alloimmunisation excluded?: yes; "prior history of refractoriness to PLT transfusion"
Interventions	PCT: Intercept PCT platelets collected via apheresis, suspended in 30% to 45% plasma and 55% to 70% InterSol platelet additive solution. Gamma irradiated at discretion of investigators at 1 of 3 sites. Control: apheresis standard platelets, stored in 100% plasma. Gamma irradiated at discretion of the investigators at individual sites. Timing of platelet dose measurement: at time of issue Storage duration of platelets: up to 5 days Transfusion trigger: prophylaxis (platelet count 20 x 109/L or pre‐procedure); treatment of clinical bleeding; to prepare for an invasive therapeutic or diagnostic intervention % off‐protocol transfusions: PCT platelets group: 16.5%; standard PLT group: 7% Red cell transfusion protocol specified: not reported
Outcomes	Primary: 1‐hour count increment and CCI for the first 8 study platelet transfusions Secondary: 1‐ and 24‐hour count increment and CCI for all study platelet transfusions 24‐hour post‐transfusion platelet counts by longitudinal regression analysis frequency of and interval between study platelet transfusions clinical haemostasis after platelet transfusion number of red cell transfusions frequency of acute platelet transfusion reactions frequency of platelet transfusion–attributed bacteraemia frequency of refractoriness (clinical and immunologic) to platelet transfusion evidence of human leukocyte antigens alloantibody formation evidence for antibodies directed against potential amotosalen‐related neoantigens overall safety and tolerability
Notes	Trial registration: none found Sources of funding: Baxter Healthcare Corporation (InterSol) and Cerus Corporation (Intercept) Conflicts of interest: not reported Intervention exposure: multiple dose
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Confirmation received through direct author contact: use of an automated, interactive voice‐activated randomisation system by the Transfusion Co‐ordinator with secured access to treatment assignment. Access to the system required knowledge of a 4 digit site‐specific ID number.
Allocation concealment (selection bias)	Low risk	Confirmation received through direct author contact: only the Transfusion Co‐ordinator knew the randomisation assignment, as this person was charged with preparation of study platelet concentrates.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Confirmation received through direct author contact: participants, primary care physicians, investigators, and the sponsors were blinded as to the randomisation assignment in order to avoid bias. Photochemically treated and standard platelet concentrates were labelled and handled so as to maintain blinding of the participants and study including the use of brown overwrap. 1 site was unable to use the overwrap due to enforced haemovigilance programmes, and in all sites the overwrap could be lifted to check the platelet labelling or appearance prior to transfusion. Comment: unblinding of participants and personnel could affect self reporting of bleeding severity and ordering of further red cell or platelet transfusions.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Haemostatic assessments were performed ... by trained personnel blinded to the treatment assignment"; "AEs were assessed (and) graded ... by the study staff, blinded to treatment assignment"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Confirmation received through direct author contact of withdrawals, losses to follow‐up, and reasons for exclusion from randomisation.
Selective reporting (reporting bias)	Low risk	All outcomes specified in methods were reported, full details of the 24‐hour platelet counts, CIs and CCIs for all transfusions received through direct author contact.
Other bias	Low risk	None identified.

Johansson 2013

Methods	Type of study: cross‐over, randomised controlled trial Type of publication: full Setting and country: Transfusion Services of Rigshospitalet in Copenhagen, Denmark Number of centres: 1 Dates of trial (start and end): September 2010 to April 2011 Treatment period + follow‐up: 24‐hour surveillance period after each study transfusion Power calculation performed: not reported
Participants	16 adults with a haemato‐oncological diagnosis (majority had acute myeloid leukaemia (N = 9) or B‐cell lymphoma (N = 3)), age range 25 to 75 years, with or expected to develop thrombocytopenia requiring at least 3 platelet transfusions. All participants had a prior history of receiving platelet transfusions with no transfusion reaction. Number analysed for primary outcome: 10 (per‐protocol analysis), 1 enrolled participant was later found to have splenomegaly and was withdrawn from the study before receiving study treatment; 3 participants were excluded from the per‐protocol analysis because they did not require a second platelet transfusion; 2 participants had technical problems in collecting pre‐ or 1‐hour post‐transfusion thromboelastography data. People who were actively bleeding excluded?: yes; "active bleeding requiring one or more transfusions of red blood cells" was an exclusion criterion People with platelet refractoriness or alloimmunisation excluded?: yes; "history of refractoriness to PLT transfusions (two successive corrected count increments at 1 hr [CCI1hr] < 5000, presence of HLA antibodies, positive lymphocytotoxicity, or previously documented alloimmunization" were exclusion criteria
Interventions	Each participant to receive 2 prophylactic study transfusions of 2‐ to 4‐day‐old pooled buffy coat‐derived platelets ‐ 1 Mirasol PCT platelet transfusion and 1 control platelet transfusion PCT: Mirasol PCT platelets prepared from an unreported number of pooled buffy coats, suspended in SSP+ platelet additive solution. Platelet components were gamma irradiated when directed by the treating physician. Control: standard platelets, prepared from an unreported number of pooled buffy coats, suspended in InterSol platelet additive solution. Platelet components were gamma irradiated when directed by the treating physician. Timing of platelet dose measurement: platelet counts were performed after pooling and again before product release on Days 2 to 4 of storage, unclear which count was used to assess platelet dose Storage duration of platelets: 2 to 4 days Transfusion trigger: Prophylactic platelet transfusions were given when platelet counts < 10 x 109/L in non‐febrile, clinically stable participants or < 20 x 109/L in participants with fever. The transfusion trigger could be raised to 50 x 109/L for participants that were at high risk of bleeding. % off‐protocol transfusions: not reported Red cell transfusion protocol specified: not reported
Outcomes	Primary outcome measure: haemostatic function 1 hour pre‐ and post‐study platelet transfusions using computerised thromboelastography. Secondary outcome measures: bleeding assessments 12 hours pre‐ and post‐transfusions platelet counts 1 hour pre‐ and post‐transfusions adverse transfusion reactions (within 24 hours) serious adverse events (within 24 hours).
Notes	Trial registration: trial is part of the Pathogen Reduction Extended Storage Study (PRESS) registered at ClinicalTrials.gov ID: NCT01368211 on 6 June 2011 Sources of funding: research funding for this study was provided by Terumo BCT to PIJ. Conflicts of interest: LD, PVH, and RPG are employees of Terumo BCT. SSY is a contract employee of Terumo BCT. Intervention exposure: single dose
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was performed according to a computer‐generated randomisation scheme with a block size of 2.
Allocation concealment (selection bias)	Low risk	Allocation to interventions was performed randomly by computer.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	No information on blinding of participants was reported.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Clinical site personnel responsible for participant enrolment, physical examination, and safety monitoring were blinded.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	16 participants were initially randomised to receive the interventions, and the number of participants lost to follow‐up or treatment withdrawals were reported with reasons after randomisation. 1 enrolled participant was later found to have splenomegaly (an exclusion criterion) and was withdrawn from the study before receiving study treatment. Only 15 participants were included in the ITT analysis. 10 participants were included in the PP analysis including the study's primary outcome. 3 participants were excluded from the PP analysis because they did not require a second platelet transfusion (included in analysis of safety data, including bleeding); 2 participants had technical problems in collecting pre‐ or 1‐hour post‐transfusion thromboelastography data.
Selective reporting (reporting bias)	Unclear risk	Protocol not available, and trial registration was after the trial had been completed.
Other bias	Unclear risk	The majority of participants were male (14 out of 15 in ITT analysis and 11 out of 12 in PP analysis). The study was retrospectively registered on a trial database (study completed April 2011 and registered June 2011).

Kerkhoffs 2010

Methods	Type of study: parallel‐group, non‐inferiority, randomised controlled trial Type of publication: full Setting and country: haematology wards, the Netherlands Number of centres: 8 Dates of trial (start and end): March 2007 to May 2009 Treatment period + follow‐up: 5 platelet transfusions received over a maximum study period of 42 days after the first on‐protocol transfusion Power calculation performed?: yes, 100 participants required in each study arm. However, the recruitment to the PCT platelets arm was halted early on advice from the DSMB due to significantly more bleeding episodes and lower CCIs in the PCT platelets group. This arm of the trial was therefore underpowered, with only 84 participants receiving PCT platelets.
Participants	278 adults (≥ 18 years of age) with haemato‐oncological diagnosis and (or expected to have) thrombocytopenia and expected to require 2 or more platelet transfusions were randomised to 1 of 3 intervention groups: Intercept PCT platelets (PCT) (N = 85) standard platelets stored in InterSol PAS (PASIII) (N = 94) standard platelets stored in plasma (Plasma) (N = 99) Number analysed for primary outcome: 278 (17 of the recruited 295 were ineligible: 13 did not require transfusion; 4 had anti‐HLA antibodies) People who were actively bleeding excluded?: no People with platelet refractoriness or alloimmunisation excluded?: yes; "immunological refractoriness to random platelet transfusions due to human leucocyte antigen (HLA) ‐ and/or human platelet antigen (HPA) ‐ antibodies or clinical relevant auto‐antibodies"
Interventions	3 interventions, all produced from 5 whole‐blood buffy coats, gamma irradiated at the request of the hospital PCT: Intercept PCT platelets, stored in PAS (35% plasma; 65% InterSol) PASIII: platelets stored in PAS (35% plasma; 65% InterSol) Plasma (control): standard platelets suspended in 100% plasma Timing of platelet dose measurement: prior to storage Storage duration of platelets: up to 7 days Transfusion trigger: prophylactic and therapeutic (thresholds: platelet count 40 x 109/L in endoscopic evaluation of the gastrointestinal or respiratory tract (without biopsies), diagnostic puncture with a thin needle, lumbar puncture, extraction of a central venous catheter, and minor surgery; 60 x 109/L in cases of bleeding, endoscopic evaluation with biopsies, dental extraction, placement of central venous catheter, and major surgery (with exception of neurosurgery and cardiac surgery); 100 x 109/L in cases of cerebral bleeding, diffuse alveolar haemorrhage, neurosurgery, and cardiac surgery) % off‐protocol transfusions: PCT platelets group: 34%; standard PLT group: 18% Red cell transfusion protocol specified: not reported
Outcomes	Primary: 1‐hour CCI Secondary: 24‐hour CCI; bleeding; red cell transfusion requirement; platelet transfusion requirement; platelet transfusion interval; adverse transfusion reactions
Notes	Trial registration: yes. ISRCTN88278819 on 8 February 2007 Source(s) of funding: Sanquin Blood Bank Conflicts of interest: not reported Intervention exposure: multiple dose Additional notes: interim analysis planned after 300 transfusions: "Two criteria for early stopping of an experimental arm were defined: (i) a negative 24 hr CCI (decrement) not caused by immunological factors in more than 20% of transfusions; (ii) statistically significant more bleeding complications (CTCAE ≥ 2) compared with the Plasma arm."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Confirmation through direct author contact: randomisation was performed by computer (web‐based), stratified by centre on a 1:1:1 ratio
Allocation concealment (selection bias)	Low risk	Confirmation through direct author contact: randomisation performed by web‐based computer
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study, blinding not performed. High risk, as bleeding assessments potentially performed (or reported) by both participants and physicians and are necessarily subjective in nature.
Blinding of outcome assessment (detection bias) All outcomes	High risk	Open‐label study, blinding not performed.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Flow diagram from randomisation to end of follow‐up period provided.
Selective reporting (reporting bias)	Low risk	Protocol consulted and confirmation received through direct author contact clarifying bleeding grades, adverse events, laboratory response to platelet transfusions, and red cell/platelet transfusion requirements.
Other bias	Low risk	None identified.

Lozano 2011

Methods	Type of study: parallel‐group, non‐inferiority, randomised controlled trial Type of publication: full Setting and country: haematology‐oncology departments: Spain, UK, France, Sweden Number of centres: 4 Dates of trial (start and end): October 2005 to July 2009 Treatment period + follow‐up: 24‐hour study period with 15‐day follow‐up post‐transfusion (any adverse event followed up for 4 days' post‐transfusion, serious adverse events for 15 days' post‐transfusion) Power calculation performed?: yes
Participants	242 adults (≥ 16 years of age) with a haemato‐oncological diagnosis with (or expected to have) thrombocytopenia requiring platelet transfusion were randomised to 1 of 2 intervention groups: PCT: Intercept PCT platelets (N = 123) Control: standard platelet transfusion (N = 119) Number analysed for primary outcome: 211 (105/106) received study transfusion for ITT analysis, performed but not reported. 199 (101/98) included in reported PP analysis. 12 participants excluded from analysis: 2 control participants due to "invalid platelet counts [> 100 x 109/L]"; 3 control participants due to death; 7 missing platelet count or platelet count not taken in the correct time‐frame. People who were actively bleeding excluded?: not excluded at randomisation, but the study transfusion was postponed "if the subject had ... active haemorrhage associated with reduction in haemoglobin >1.0g/dL or 10% within 24 hours, in the previous 12 hours prior to study transfusion." People with platelet refractoriness or alloimmunisation excluded?: yes; "prior history of clinical refractoriness to platelet transfusion" Major protocol violations were reported for 7 participants (2 PCT, 5 standard platelets) who either did not fulfil the inclusion criteria or had reason for exclusion that was not detected prior to receiving the study transfusion.
Interventions	PCT: pooled buffy coat‐derived or apheresis Intercept PCT platelets, suspended in PAS (65% InterSol, 35% plasma). Gamma irradiated at the investigator's request. Bacterial culture performed if requested by study investigator. Control: standard platelets, collected from buffy coats or apheresis, suspended in PAS (65% T‐Sol/SSP, 35% plasma). Gamma irradiated at the investigator's request. Timing of platelet dose measurement: day 5 Storage duration of platelets: 6 or 7 days Transfusion trigger: prophylaxis (platelet count 10 to 20 x 109/L) % off‐protocol transfusions: 15.2% participants in the PCT platelets group received off‐protocol transfusions versus 11.3% in the standard PLT group. Red cell transfusion protocol specified: not reported
Outcomes	Primary: 1‐hour CCI Secondary: 1‐ and 24‐hour count increment; 24‐hour CCI; 1‐ and 24‐hour post‐transfusion platelet count; platelet and red cell transfusion requirement during 24‐hour post‐transfusion period; time interval between the study transfusion and the next platelet transfusion; clinical haemostatic assessments; acute transfusion reactions; adverse events
Notes	Trial registration: yes EudraCT 2005‐003183‐33 NCT00261924 on 5 December 2005 Source(s) of funding: Cerus Corporation (Intercept), of which at least 4 authors are employees Conflicts of interest: not reported Intervention exposure: single dose Additional notes: in order to reach a target threshold platelet content per transfusion (3.0 x 1011/unit), PCT platelet products collected by apheresis were produced by increasing the collection by 10% whilst an additional buffy coat could be added to the pooled PCT products to compensate for processing losses.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Confirmation through direct author contact: "Patients were randomly assigned to PRP [PCT platelets] or Reference in a 1:1 ratio (using a permuted block randomisation with fixed block sizes)". Randomisation was "computer generated using an IVRS (interactive voice recognition system)"
Allocation concealment (selection bias)	Low risk	Confirmation through direct author contact: randomisation was conducted by each study site Transfusion Co‐ordinator who opened the next randomisation code envelope to determine the treatment assignment. "They were instructed and signed an agreement not to discuss randomisation assignment with other study personnel"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Confirmation through direct author contact: "All study personnel and medical care personnel, except for the Transfusion Coordinator, were blinded to treatment assignment. ... Study PCs were in identical containers with identical labels" Study reported as double‐blinded.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Haemostatic assessments were performed by trained personnel blinded to treatment assignment."
Incomplete outcome data (attrition bias) All outcomes	Low risk	"A total of 242 patients were enrolled in four clinical sites." "A total of 211 patients received a study platelet transfusion [full analysis set (FAS) population]. Of the 211 patients who received a study platelet transfusion, 199 patients were eligible for the 1‐h CCI per protocol analyses and 186 patients were eligible for the 24‐h CCI per protocol analyses."
Selective reporting (reporting bias)	Low risk	All outcomes specified in methods were reported and supported by data received through direct author contact.
Other bias	Low risk	None identified.

McCullough 2004

Methods	Type of study: parallel‐group, non‐inferiority, randomised controlled trial Type of publication: full Setting and country: hospitals, USA Number of centres: 12 Dates of trial (start and end): July 1999 to February 2001 Treatment period + follow‐up: maximum 28‐day treatment period + 7‐day surveillance period Power calculation performed?: yes
Participants	671 adults and children (≥ 6 years of age) with a haemato‐oncological diagnosis and thrombocytopenia were randomised to 1 of 2 intervention groups to receive platelet transfusions for up to 28 days or until transfusion independence (7 days without platelet transfusion) prior to day 28: PCT: Intercept PCT platelets (N = 335) Control: standard platelets (N = 336) Number analysed (primary outcome): 645 (318/327) (26 participants did not require platelet transfusion and so were not included in the analysis) People who were actively bleeding excluded?: no People with platelet refractoriness or alloimmunisation excluded?: yes; "positive lymphocytotoxic antibody (> 20% panel reactive antibody at screening) or history of clinical refractoriness"
Interventions	PCT: apheresis Intercept PCT platelets suspended in 30% to 45% plasma and 70% to 55% InterSol PAS, gamma irradiated if required Control: apheresis standard platelets, stored in 100% plasma, gamma irradiated if required Timing of measurement of platelet dose: pre‐issue Storage duration of platelets: up to 5 days Transfusion trigger: prophylactic and therapeutic (overt bleeding or pre‐invasive procedure) % off‐protocol transfusions: PCT platelets group: 8.5%; standard platelets group: 4.8% Red cell transfusion protocol specified: not reported
Outcomes	Primary: proportion of participants with WHO grade 2 bleeding on any day during period of platelet support Secondary: number of participants with WHO grade 3 or 4 bleeding; number of days of WHO grade 2 bleeding; 1‐ and 24‐hour CIs and CCIs; number of days to next platelet transfusion; number of platelet transfusions; incidence of platelet refractoriness; number of red blood cell transfusions Safety endpoints: number of platelet transfusion reactions; development of antibody to potential amotosalen neoantigens; overall safety
Notes	Trial registration: none identified Source(s) of funding: Cerus Corporation and Baxter Healthcare Corporation Conflicts of interest: J‐SL, LL, PM, DHB, LC, and MGC are employees of Baxter Healthcare or Cerus. JM, SJS, and SM are members of the Cerus Medical Advisory Committee, for which USD 2500 per year is received. JM, ES, and SM are consultants for Baxter or served on the Fenwal Medical Advisory Committee, for which less than USD 10,000 was received in the past year. JM, RJB, AP, TR, ES, SM, and IL‐P participated in other clinical trials sponsored by Cerus or Baxter; they received funds only to support the cost of those studies. Intervention exposure: multiple dose
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Confirmation through direct author contact: "Randomization was conducted by authorized site personnel who telephoned a computerized, central, randomisation system (Interactive Voice Response System). The randomisation was stratified by site and blocked using variable block sizes."
Allocation concealment (selection bias)	Low risk	As above. Confirmation through direct author contact: "Platelet processing coordinators were the only personnel with a Personal Identification Number (PIN) that could be used to access the randomisation system"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"All individuals involved in the clinical care and assessment of patients were blinded to study treatment assignment. These individuals included the principal investigator, clinical study coordinators and nurses making haemostatic assessments, clinicians and nurses caring for the patient, and the study sponsor." Study participants also blinded, confirmed through direct author contact.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	See above
Incomplete outcome data (attrition bias) All outcomes	Low risk	18 participants (9 PCT platelets, 9 control) did not complete transfusion period for "other" reasons; author reported that a variety of non‐specific reasons were given, but no details reported. Comment: low risk of bias, as equal numbers of participants from both arms were involved
Selective reporting (reporting bias)	Low risk	All outcomes specified in methods were reported; missing standard deviations and other data provided by direct contact with author.
Other bias	Low risk	None identified.

Rebulla 2016

Methods	Multicentre (involving 6 large blood transfusion services), non‐inferiority, randomised, prospectively controlled study (confirmed through direct author contact). 3 sites participated in the study to evaluate Intercept platelets (Cerus, Concord, CA) and in 3 other sites Mirasol platelets (Terumo BCT, Lakewood, CO) were evaluated. Type of study: parallel‐group, non‐inferiority, randomised controlled trial Type of publication: full Setting and country: blood transfusion centres, hospitals, Italy Number of centres: 6 Dates of trial (start and end): October 2010 to March 2015 Treatment period + follow‐up: a maximum treatment period of 4 weeks (28 days), data on safety were collected at 5 to 8 weeks. First day of observation was first day of receiving platelets transfusion. If a participant did not receive platelets transfusion for 7 days, he or she was discharged or died. Power calculation performed?: yes; "It was estimated that the frequency of bleeding grade 2 in the reference group would be 20% (pre IPTAS pilot study). With a type I error of 0.025 and power of 80%, it was worked out that 207 patients per arm would be required to claim non‐inferiority of PRT‐PLTs compared to standard platelets with a non‐inferiority margin of 11%."
Participants	438 adults (> 18 years of age) with a haemato‐oncological diagnosis expected to require 2 or more PLT transfusions in 4 weeks, hospital admission (people admitted to outpatient clinics were excluded), negative pregnancy test in female participants Exclusion criteria: people with promyelocytic leukaemia; previously transfused people with historical documentation of 2 or more 1‐hour post‐transfusion platelet CCIs below 5000/μL; and anti‐HLA antibodies on admission with panel reactive antibodies greater than 20% PCT: Intercept PCT platelets "Intersol or SPP+ platelet additive solutions" (N = 118) Control: standard platelets (N = 119) PCT: Mirasol PCT platelets (Composol) (N = 102) Control: standard platelets (N = 99) Number analysed (primary outcome): 424; Intercept (N = 109), control (N = 107); Mirasol PCT (N = 97), control (N = 97) People who were actively bleeding excluded?: no information People with platelet refractoriness or alloimmunisation excluded?: yes, presence of HLA class I antibodies on admission with panel reactive antibody > 20% or historical documented record of 2 or more 1‐hour post‐ transfusion platelet CCIs < 5000 per microlitre were excluded
Interventions	Group 1: 3 centres received Intercept pathogen‐reduced platelets (the Intercept system for platelets and plasma uses a molecule, amotosalen hydrochloride solution and ultraviolet light (320 to 400 nm)) versus standard platelets (prepared with buffy coat method or by apheresis and resuspended in 30% autologous plasma/70% platelet additive solution). Group 2: 3 centres received Mirasol pathogen‐reduced platelets (PRT uses ultraviolet light 265 to 375 nm and riboflavin in 30% to 45% plasma) versus standard platelets (prepared with buffy coat method or by apheresis and resuspended in 30% autologous plasma/70% platelet additive solution). All participants scheduled to receive on‐protocol platelet transfusions until: 1) platelet transfusion independence; 2) detection of refractoriness; 3) discharge or death, for a maximum of 4 weeks. Timing of measurement of platelet dose: was determined in all platelet units at time of production Storage duration of platelets: a maximum of 5 days Transfusion trigger: prophylactic transfusion trigger of 10 x 109/L and 20 x 109/L for stable participants and participants with rapid fall of platelet count % off‐protocol transfusions: 10.3% in the Intercept group received standard platelets, and 6.4% in the Mirasol group received standard platelets. Red cell transfusion protocol specified: yes. The study sites used a red blood cell transfusion trigger of 80 g/L haemoglobin.
Outcomes	Primary outcome measure: incidence of bleeding of grade 2 or greater in recipients of PRT platelets versus recipients of control (standard) platelets. Daily bleeding assessments were performed by a clinical investigator at each clinical site by interviewing the participant, performing a clinical assessment, and by chart review. Secondary outcome measures: time to the first grade 2 or greater bleeding event after the first study transfusion; proportion of transfusions given to treat breakthrough bleeding; number of days with grade 2 or greater bleeding during the period of platelet transfusion support; number of platelet units transfused per day of thrombocytopenic platelet support; proportion of participants with acute transfusion reactions; post‐transfusion platelet count increments; total dose of platelets transfused per day of thrombocytopenic platelet support
Notes	Trial registration: yes, ClinicalTrials.gov ID: NCT01642563 on 13 July 2012 ISS‐2007646931 Source(s) of funding: Centro Nazionale Sangue in addition to grants from Cerus and Terumo BCT Conflicts of interest: Rebulla received research grant from Cerus and Terumo BCT. Milani received honoraria from Terumo BCT. Other authors declared no conflicts of interest. Intervention exposure: multiple dose The study was closed before reaching the planned sample size of 828 for administrative reasons.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomization to groups was generated by a computer at the co‐ordinating centre (CNS) using random permuted blocks. "Randomization will be prepared by the CNS office in Rome under the coordination of Stefania Vaglio. Randomization will occur by Random Permuted Blocks based on a random assignment list generated by a computer. Randomization will occur within the following strata: (a) chemotherapy, (b) allogeneic (related or unrelated) donor transplant." "There were 2 levels of randomization: sites and patients. The site allocation to the Intercept® or Mirasol® trial was randomly assigned by the administrative coordinating center (Centro Nazionale Sangue, Rome)" "Patients were assigned using a 1:1 ratio to one of the two study arms using random permuted blocks with block size equal to 8. Only the study data manager had knowledge of the randomization codes for both the sites and the patients". The investigators kept the treatment code envelopes in secured storage, to only be opened in an emergency.
Allocation concealment (selection bias)	Low risk	Allocation to treatment was performed at each study site using opaque envelopes containing the treatment assignment. "The treatment allocation schedule for patients was prepared by the Centro Nazionale Sangue using a computer generated assignment sequence stratified by site and whether the patient was receiving chemotherapy or allogeneic hemopoietic stem cell transplant (HSCT)"; "Patients were randomized at the time of their first platelet transfusion request by the local blood transfusion service staff using opaque envelopes containing the treatment assignment"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants were not aware of the intervention status. "IPTAS will be partially blinded, as: ‐ neither the patient nor their treating physician will be actively informed of the patient's treatment assigned; the IPTAS local coordinator will not know allocation arm; transfusion laboratories will be aware of the assigned allocation as they have to issue appropriate products and maintain adequate product inventory"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Physicians were not aware of the participants' intervention status. "IPTAS will be partially blinded, as: ‐ neither the patient nor their treating physician will be actively informed of the patient's treatment assigned; the IPTAS local coordinator will not know allocation arm; transfusion laboratories will be aware of the assigned allocation as they have to issue appropriate products and maintain adequate product inventory"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Number of participants who did not require platelets was reported, and these were excluded from the analysis.
Selective reporting (reporting bias)	Low risk	All prespecified outcomes in the study protocol were reported for all groups.
Other bias	Low risk	There were more male participants across the groups.

Simonsen 2006

Methods	Type of study: cross‐over, non‐inferiority, 2‐treatment period, randomised controlled trial Type of publication: full Setting and country: hospital, Denmark Number of centres: 1 Dates of trial (start and end): October 2003 to April 2004 Treatment period + follow‐up: maximum 45 days; 15 days from randomisation to first transfusion, minimum 24‐hour washout period between study transfusions, maximum 28 days until second study transfusion, and 24‐hour follow‐up following both study transfusions Power calculation performed?: yes
Participants	28 adults (≥ 18 years of age) with a haemato‐oncological diagnosis and (or expected to have) thrombocytopenia requiring platelet transfusions were randomly assigned to 1 of 2 treatment sequences: Sequence PCT‐Control: participants received a single Intercept PCT platelets transfusion followed by a single standard platelet transfusion when the participant's transfusion threshold was next reached with a minimum 24‐hour washout period between interventions Sequence Control‐PCT: participants received a single standard platelet transfusion followed by a single Intercept PCT platelet transfusion when the participant's transfusion threshold was next reached with a minimum 24‐hour washout period between interventions Number analysed for primary outcome: 20 for PP analysis, ITT analysis also performed but not reported (N = 25). 3 participants received neither intervention; 3 received only 1 intervention; 2 had major protocol violations (platelet dose missing and study platelets transfused in presence of postponement criteria). Actively bleeding participants excluded?: yes; "the inclusion criteria did not accept participants with severe bleeding" Participants with platelet refractoriness or alloimmunisation excluded?: yes; "history of refractoriness to PLT transfusion (defined by at least two successive PLT transfusions with a 1‐hr PLT corrected count increment [CCI] of <5000)"
Interventions	PCT: 4 pooled buffy coat collected Intercept PCT platelets suspended in PAS (30% to 45% plasma, 55% to 70% InterSol). Gamma irradiated at request of physician. Control: 4 pooled buffy coat collected platelets suspended in T‐Sol PAS (55% to 70% T‐Sol, 30% to 45% plasma). Gamma irradiated at request of physician. Timing of platelet dose measurement: measured at completion of processing and again at the time of issue on Day 7 (confirmed through direct author contact) Storage duration of platelets: 7 days Transfusion trigger: prophylactic (platelet count 10 to 20 x 109/L) % off‐protocol transfusions: 66.7% of participants received off‐protocol transfusions after PCT platelets in the PCT‐Control sequence versus 36.4% after standard PLTs in the Control‐PCT arm Red cell transfusion protocol specified: not reported
Outcomes	Primary: 1‐hour CCI Secondary: 1‐hour count increment; time to next platelet transfusion; change in haemostatic score before and after study platelet transfusion; frequency of acute platelet transfusion reactions up to 24 hours' post‐transfusion
Notes	Source(s) of funding: Cerus Corporation (Intercept) and Baxter Healthcare Corporation (InterSol and T‐Sol). 2 authors were employees of Cerus Corporation at the time of publication, and a further senior employee (L Corash) critically reviewed the manuscript. Intervention exposure: single dose Additional notes: a significant period‐by‐treatment effect was identified when both sequences were compared with a reduced 1‐hour CCI in the group that received PCT after standard platelets compared with those that received PCT platelets first. The study published data for both sequences combined as well as separately for each arm, however the baseline characteristics of the participants recruited to the 2 sequences were very different (e.g. post‐HSCT 33.3% PCT‐control, 64% control‐PCT; postchemotherapy 66.7% PCT‐control, 36% control‐PCT). This could in itself explain the differences in mean 1‐hour CCIs. The first period of this study was included in the meta‐analyses of this review where possible.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Confirmation through direct author contact: "Patients were randomized to receive, as first study transfusion, Intercept® or Reference treatment in a 1:1 ratio using a permuted block randomization with fixed block sizes". Randomisation was "computer generated using an IVRS (interactive voice recognition system)".
Allocation concealment (selection bias)	Low risk	Confirmation through direct author contact: "Upon enrolment of each new patient, the Transfusion Coordinator (or her back‐up) opened the code envelope identified by the next lowest available patient number"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Confirmation through direct author contact: "Patients, primary care physicians, the Clinical Coordinator, and the clinical monitor were blinded as to the randomisation assignment in order to avoid bias. INTERCEPT and Reference platelet concentrates were labelled and handled identically so as to maintain blinding for the patients and study personnel"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	See above, in addition: "Haemostatic assessments were performed by clinical personnel blinded to treatment sequence."
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Clear figures were reported for participants who did not complete transfusion period, including losses to follow‐up or withdrawal from study. 1 platelet dose measurement was not performed in the PCT‐control platelet sequence arm. 28 participants were randomised, only 20 were included in the PP analysis, ITT analysis was also performed but not reported (N = 25). 3 participants received neither intervention; 3 received only 1 intervention; 2 had major protocol violations (platelet dose missing and study platelets transfused in presence of postponement criteria).
Selective reporting (reporting bias)	Low risk	All outcomes specified in methods were reported.
Other bias	Low risk	1 participant received each study transfusion twice, as this participant was recruited to 2 separate cycles of the trial; this was not thought to pose a significant impact on the trial outcomes, as only a single participant was included twice. 1 participant received the study intervention despite postponement criteria being present. 2 participants (1 in each sequence) failed to receive both study transfusions.

Slichter 2006

Methods	Type of study: cross‐over, 2‐treatment period, randomised controlled trial Type of publication: full Setting and country: blood centres, USA Number of centres: 2 Dates of trial (start and end): not reported Treatment period + follow‐up: maximum 14‐day treatment + 28‐day observation period Power calculation performed: not done. "The study was designed to enrol at least 10 patients with paired bleeding time assessments."
Participants	60 adult (≥ 18 years of age) participants with a haemato‐oncological diagnosis and thrombocytopenic requiring prophylactic platelet transfusions, with a haematocrit level of at least 25%, were randomised to 1 of 2 treatment sequences: PCT‐Control: a single Intercept PCT platelet transfusion followed by a single standard platelet transfusion when the transfusion threshold was next reached (N = 16) Control‐PCT: a single standard platelet transfusion followed by a single Intercept PCT platelet transfusion when the transfusion threshold was next reached (N = 16) Number analysed for primary outcome: 32 (10 received no study transfusion, 18 participants excluded due to a mid‐study protocol amendment to "incorporate changes in PLT processing and inventory management") Actively bleeding patients excluded?: yes; "Patients were excluded from enrolment based on the presence of factors known to affect post‐transfusion PLT response or haemostasis: ... significant haemorrhage the day before enrolment" Patients with platelet refractoriness or alloimmunisation excluded?: yes; "lymphocytotoxic antibody panel reactivity of at least 20 percent"
Interventions	PCT: apheresis Intercept PCT platelets, suspended in PAS (35% plasma, 65% InterSol). Gamma irradiated at the request of the physician. Control: apheresis standard platelets stored in 100% plasma. Gamma irradiated at the request of the physician. Participants of both study arms received double platelet doses to attain a target dose of 6 x 1011/unit. Direct author contact confirmed that higher doses were required due to bleeding time measurements. Timing of platelet dose measurement: not reported Storage duration of platelets: up to 5 days Transfusion trigger: prophylaxis (platelet count < 20 x 109/L) % off‐protocol transfusions: not reported Red cell transfusion protocol specified: yes. Participants were given red blood cell transfusions to maintain haematocrit levels of at least 25% during the trial.
Outcomes	Primary: cutaneous template bleeding time assessments by 2 incisions made at 1 to 2 hours' and 18 to 24 hours' post‐transfusion Secondary: 1‐ to 2‐hour count increment and CCI; 18‐ to 24‐hour count increment and CCI; transfusion interval to next platelet transfusion; clinical haemostatic assessments; adverse events (combined unless acute transfusion reactions); pre‐ and post‐transfusion plasma amotosalen concentration
Notes	Source(s) of funding: Cerus Corporation (Intercept) and Baxter Healthcare Corporation (InterSol). At least 1 author, L Corash, is an employee of Cerus Corporation. Intervention exposure: single dose Participants received red cell transfusions during the study to maintain a haematocrit of at least 25% "because low Hct levels may cause prolonged bleeding times" Additional notes: a change of protocol for platelet preparation mid‐study required 18 of the 50 participants who received the study products to be removed from the efficacy outcomes. However, all 50 were included in the safety outcomes, therefore protocol violations were frequent.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Confirmation through direct author contact: Randomisation was "computer generated using an IVRS (interactive voice recognition system)" using a randomised sequence cross‐over design.
Allocation concealment (selection bias)	Low risk	"Randomisation to PCT or reference platelet transfusions as the first or second transfusion was provided by an interactive voice recognition system that was called by the research staff after each patient's enrolment in the study."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Hospital staff ... and study patients were blinded to the type of PLT transfusion given."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Principal Investigators, hospital staff, research staff performing the bleeding times, anyone evaluating clinical haemostasis, and study patients were blinded to the type of PLT transfusion given."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Clear figures were reported for participants who did not complete transfusion period, including losses to follow‐up or withdrawal from study. However, 1 participant was not assessed for post‐transfusion bleeding. "60 patients met the enrollment criteria and were randomly assigned. Ten randomly assigned patients, however, received no study PLT transfusions (4 withdrew consent, 2 became transfusion independent, 2 were withdrawn by their primary care physician, 1 because PCT PLTs were not available, and 1 because the sponsor terminated the study); these patients were not further analyzed." "Of the 50 randomly assigned patients who received one or more study PLT transfusions, 18 patients were entered under the original protocol. Because study PLTs for these patients were prepared differently, data from these 18 patients, as well as the remaining 32 patients, were included only in the safety analysis. All of the rest of the data presented are only for the 32 patients admitted to the amended protocol."
Selective reporting (reporting bias)	Low risk	All outcomes specified in methods were reported.
Other bias	Low risk	None identified.

van Rhenen 2003

Methods	Type of study: parallel‐group, randomised controlled trial Type of publication: full Setting and country: blood centres, the Netherlands, Sweden, France, and UK Number of centres: 4 Dates of trial (start and end): June 1998 to June 2000 Treatment period + follow‐up: 56‐day transfusion period + 28‐day surveillance period (Cycle 1). A second cycle was then commenced if participants continued to require platelet support for an additional 56‐day transfusion period + 28‐day surveillance period (Cycle 2). The same intervention was assigned for both cycles. Power calculation performed?: yes
Participants	106 children and adult participants (≥ 12 years of age) with a haemato‐oncological diagnosis and thrombocytopenia (or receiving therapy expected to cause thrombocytopenia) requiring platelet transfusions were randomised to 1 of 2 interventions: PCT: Intercept PCT platelets (N = 54) Control: standard platelets (N = 52) Number analysed (primary outcome): 103 (52/51) (3 did not require transfusion) Actively bleeding patients excluded?: no Participants with platelet refractoriness or alloimmunisation excluded?: yes; "history of alloimmunization or refractoriness to platelet transfusion"
Interventions	PCT: Intercept PCT platelets prepared from 5 to 6 pooled buffy coats and stored in PAS (65% InterSol, 35% plasma). Gamma irradiation not performed. Control: standard platelets prepared from 4 to 6 buffy coats, stored either in 100% plasma, or PAS (35% plasma, 65% T‐Sol). Gamma irradiated as requested by physician. Timing of platelet dose measurement: at issue Storage duration of platelets: up to 5 days Transfusion trigger: prophylactic (platelet count < 20 x 109/L) or therapeutic to treat active bleeding % off‐protocol transfusions: PCT platelets group: 20.3%; standard platelets group: 10.5% Red cell transfusion protocol specified: not reported
Outcomes	Primary: 1‐hour count increment and CCI Secondary: 24‐hour count increment and CCI; platelet transfusion requirement during platelet support period; interval between platelet transfusions; clinical haemostasis before and after transfusion; red cell transfusion requirement; incidence of refractoriness to platelet transfusion; incidence of alloimmunisation; transfusion‐related adverse events; all other adverse events
Notes	Source(s) of funding: Cerus Corporation (Intercept) and Baxter Healthcare Corporation (InterSol). 6 of the 20 authors were employed by 1 of these manufacturing companies at the time of publication. Intervention exposure: multiple dose
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Confirmation through direct author contact: "Upon enrolment, the Transfusion Coordinator for the site telephoned the central randomisation computer system (IVRS ‐ Interactive Voice Response System) to receive a site‐specific patient number and treatment assignment."
Allocation concealment (selection bias)	Low risk	Confirmation through direct author contact: "Access to the randomisation system required a site‐specific Personal Identification Number restricted to the Transfusion Coordinator. Only the transfusion coordinator and one alternate had access to this PIN at each site"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Confirmation through direct author contact: "Patients, primary care physicians, investigators and the Sponsors were blinded as to the randomisation assignment in order to avoid bias. PRP (PCT) and reference platelet concentrates were labelled and handled in identical containers so as to maintain blinding for the patients and study personnel."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	See above
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Through direct author contact, clear figures reported for participants who did not complete transfusion period including losses to follow‐up or withdrawal from study. "More test patients (83%) than reference patients (67%) completed cycle 1 (P = 0.06), and more test patients (10 of 52) than reference patients (2 of 51) received transfusions during cycle 2. This difference resulted in a greater number of study observation days for test patients than for reference patients (4081 vs 3633 days)."
Selective reporting (reporting bias)	Low risk	All outcomes specified in methods were reported.
Other bias	Low risk	12 participants were re‐recruited to a second cycle of the study with the same randomisation (10 PCT, 2 standard platelets). All study outcome data were either reported or available through direct author contact for Cycle 1 only.

AE: adverse event CCI: corrected count increment CI: count increment DSMB: data safety monitoring board Hct: haematocrit HLA: human leukocyte antigens HSCT: haematopoietic stem cell transplantation ITT: intention‐to‐treat PAS: platelet additive solution PCT: photochemically treated PLT: platelet PP: per‐protocol PRP: pathogen‐reduced platelets PRT: pathogen reduction technology SD: standard deviation WHO: World Health Organization

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Andreu 1993	Outcomes: measured human leukocyte antigen alloimmunisation, not clinical effectiveness
AuBuchon 2005	Participants: healthy people
Ayupova 2014	Non‐RCT: a retrospective cohort study included 33 people with malignant chronic lymphocytic leukaemia
Berger 2013	Non‐RCT: economic model calculations were structured to estimate the clinical and safety benefits of pathogen inactivation
Blundell 1996	Intervention: platelets were treated with ultraviolet B irradiation only. Ultraviolet B irradiation is used to prevent the formation of antiplatelet alloantibodies and refractoriness to platelet transfusions, not to reduce or remove pathogens.
Cid 2012	Review
Cook 2013	A review of 6 RCTs of pathogen‐inactivated platelets
Corash 2000	Participants: healthy people
Corash 2012	Case studies reporting on respiratory adverse events after transfusion of Intercept platelet components
Drawz 2015	Prospective cohort study
Dumont 2010	Participants: healthy people
Infanti 2011	Cohort study conducted on people requiring platelet support because of thrombocytopenia
MacLennan 2015	Intervention: cross‐over RCT involving thrombocytopenic haematology patients receiving 2‐ to 5‐ versus 6‐ or 7‐day‐stored platelets
NCT00742001	Non‐RCT: phase I study involving healthy participants to evaluate the recovery and survival of red blood cells retrieved from Mirasol‐treated whole blood
NCT01615146	RCT comparing therapeutic standard platelet transfusion with prophylactic standard platelet transfusion
NCT02330081	Non‐RCT: prospective, intra‐subject controlled, open‐label design Platelets were treated with Mirasol pathogen reduction technology; the recovery and survival of the platelets were measured in vitro.
NCT02653443	RCT comparing apheresis platelets prepared with the Intercept Blood System for Platelets versus apheresis conventional untreated platelets in healthy participants
Rummler 2013	Retrospective cohort study on pathogen‐reduced plasma in plasma therapy.
Sigle 2013	Non‐RCT: observational study involving haematologic participants assigned to receive platelets treated with amotosalen‐based pathogen reduction technology or conventional platelets.
TRAP 1997	Intervention: platelets were treated with ultraviolet B irradiation only. Ultraviolet B irradiation is used to prevent the formation of antiplatelet alloantibodies and refractoriness to platelet transfusions, not to reduce or remove pathogens.
Vamvakas 2012	Review including 5 RCTs evaluating the amotosalen‐hydrochloride/ultraviolet A light technology. Cross‐over studies were excluded.

RCT: randomised controlled trial

Characteristics of ongoing studies [ordered by study ID]

EUCTR2015‐001035‐20‐DE

Trial name or title	Phase III, randomised, double‐blind, multi‐centre clinical trial on clinical efficacy and safety of platelet concentrates treated with the THERAFLEX UV Platelets procedure in comparison to conventional platelet components (Capture)
Methods	Non‐inferiority, parallel‐group, multicentre RCT (5 planned centres in Germany)
Participants	166 participants Inclusion criteria: Haemato‐oncological patients with thrombocytopenia or expected to become thrombocytopenic Expected to receive at least 1 platelet transfusion during their hospital stay Aged at least 18 years Written informed consent Exclusion criteria: Known immunological refractoriness to platelet transfusions, i.e. HLA and/or HPA alloimmunisation (documented in the patient’s medical record) History or diagnosis of an autoimmune disease affecting haemostasis Acute or chronic disseminated intravascular coagulation History or diagnosis of thrombotic thrombocytopenic purpura or haemolytic uraemic syndrome Severe uncontrolled infection Positive serum or urine pregnancy test Lactation Simultaneous participation in another interventional trial Previous inclusion in this trial Acute promyelocytic leukemia (AML, FAB subtype M3) Active bleeding at time of enrolment requiring 1 or more red blood cell transfusions and/or therapeutic platelet transfusions Splenomegaly defined as a palpable spleen felt more than 4 cm below costal margin History of severe anaphylactic transfusion criteria Legal incapacity or other circumstances preventing the person from understanding the nature, meaning, and implications of the clinical trial
Interventions	Intervention: Theraflex UV platelets Comparator: Untreated plasma‐reduced platelet concentrates stored in SSP+ additive solution or gamma‐irradiated plasma‐reduced platelet concentrates stored in SSP+ additive solution
Outcomes	Primary outcome measure: The primary objective of the trial is to demonstrate the non‐inferiority of ultraviolet C‐treated plasma‐reduced platelet concentrates in comparison to untreated plasma‐reduced platelet concentrates stored for up to 5 days in adults with haematological or oncological diseases and thrombocytopenia based on the 1‐hour CCI of not more than 30% below the control. Secondary outcome measures: Mean 24‐hour CCI, mean 1‐hour CI, and mean 24‐hour CI calculated for each platelet transfusion on a maximum of 8 platelet transfusions Mean number of PLT transfusion episodes and units* Mean interval between PLT transfusions (days)* Mean number of red blood cell transfusion episodes and units* Rate of bleeding events ≥ WHO grade 3 and 4* Rate of clinical refractoriness defined as 2 consecutive transfusions with 1‐hour CCI < 7500* Rate of immunologic refractoriness defined as 2 consecutive transfusions with 1‐hour CCI < 7500 and serologic conversion to positive tests for HLA and/or HPA alloantibodies or antibodies to ultraviolet C‐related neoantigens* Frequency of alloimmunisation to neoantigens on PLTs** Rate of PLT transfusion‐related adverse events and serious adverse events** *assessed during treatment period only; **assessed during treatment and follow‐up periods
Starting date	June 2016
Contact information	Axel.Seltsam@bsd‐nstob.de +495041772455 Eldagsener Str. 38, 31832, Springe, Germany
Notes	Sponsor: DRK‐Blutspendedienst NSTOB Funding: Macopharma, France. Blood services of the German Red Cross, Germany

Kerkhoffs 2013

Trial name or title	PREPAReS (Pathogen Reduction Evaluation & Predictive Analytical Rating Score) Study
Methods	Non‐inferiority, parallel‐group, single‐blind, multicentre RCT
Participants	375 people with acute myeloid leukaemia (including those undergoing stem cell therapy) requiring platelet transfusion
Interventions	Pooled buffy coat‐derived Mirasol pathogen‐reduced platelet concentrates versus standard plasma platelet concentrates
Outcomes	Primary outcome measure: CTCAE bleeding grade ≥ 2 bleeding complications of people receiving platelet concentrates stored 1 to 5 days Secondary outcome measures: 1‐ and 24‐hour CI; 1‐ and 24‐hour CCI; adverse transfusion reactions; total transfusion requirement of red cells and platelets; platelet transfusion interval; rate of HLA alloimmunisation; in vitro quality markers related to the 1‐ or 24‐hour CCI; clinical factors interacting on primary endpoint, including in vivo variables of immunological responses and of haemostasis in the recipients after transfusion as compared prior to transfusion
Starting date	March 2010
Contact information	JLH Kerkhoffs, Haga Hospital, Leyweg 275, 2545 CH, Den Haag, the Netherlands j.kerkhoffs@hagaziekenhuis.nl
Notes	Estimated end date: January 2014 Netherlands Trial Register ID: NTR2106 Supported by: Sanquin Blood Bank; Terumo BCT International multicentre study based in the Netherlands and Canada

NCT01789762

Trial name or title	EFFIPAP (Evaluation of the Efficacy of Platelets Treated with Pathogen Inactivation Process)
Methods	Multicentre (9 centres in France), non‐inferiority, randomised, double‐blind, controlled trial
Participants	810 adults hospitalised for bone marrow aplasia expected to become thrombocytopenic
Interventions	Intercept pathogen‐reduced platelet concentrates versus standard platelet concentrates (in InterSol additive solution)
Outcomes	Primary outcome measure: Incidence of grade 2 or higher (WHO) haemorrhagic episodes Secondary outcome measures: Frequency incidence of haemorrhagic episodes (grade 1 and higher) Number of serious grade 3 to 4 haemorrhagic episodes Number of minor grade 1 haemorrhagic episodes Transfusion outcome in platelets (CCI) at 24 hours Number of transfusions of platelet concentrates and red blood cells Transfusion intervals Safety Occurrence of antiplatelet antibodies (anti‐HLA, anti‐HPA) Occurrence of platelet transfusions refractoriness Validation of a new haemorrhagic evaluation: EFS scale Variation in haematocrit and haemoglobin levels
Starting date	April 2013
Contact information	Contact: Pierre Tiberghien, MD, PhD; pierre.tiberghien@efs.sante.fr
Notes	Estimated end date: January 2016 Supported by Etablissement Français du Sang ClinicalTrials.gov ID: NCT01789762

CCI: corrected count increment CI: count increment CTCAE: Common Terminology Criteria for Adverse Events FAB: French‐American‐British HLA: human leukocyte antigens HPA: human platelet antigens PCT: photochemically treated PLT: platelet RCT: randomised controlled trial WHO: World Health Organization

Contributions of authors

Lise Estcourt undertook the screening and selection of trials, data extraction, assessment of risk of bias, analysis of results, and preparation of the protocol and final report in addition to being the content expert of the review.

Reem Malouf undertook the screening and selection of trials, data extraction, assessment of risk of bias, analysis of results, and drafted the final report.

Sally Hopewell is a methodological expert for this review and provided support with data analysis and contributed to the preparation of the protocol and final report.

Marialena Trivella is a methodological expert for this review and provided guidance with regard to the statistical analysis, formulation of the 'Summary of findings' table, and final report.

Carolyn Doree created the search strategies and contributed to the preparation of the protocol and final report.

Simon Stanworth is a content expert for this review and contributed to the preparation of the protocol and final report.

Michael Murphy is a content expert for this review and contributed to the preparation of the protocol and final report.

Sources of support

Internal sources

• NHS Blood and Transplant, Research and Development, UK.

External sources

• No sources of support supplied

Declarations of interest

Lise Estcourt is partly funded by NIHR Cochrane Programme Grant ‐ Safe and Appropriate Use of Blood Components. Award of this national government grant by NIHR does not lead to a conflict of interest.

Reem Malouf is partly funded by NIHR Cochrane Programme Grant ‐ Safe and Appropriate Use of Blood Components. Award of this national government grant by NIHR does not lead to a conflict of interest.

Sally Hopewell is partly funded by NIHR Cochrane Programme Grant ‐ Safe and Appropriate Use of Blood Components. Award of this national government grant by NIHR does not lead to a conflict of interest.

Marialena Trivella is partly funded by NIHR Cochrane Programme Grant ‐ Safe and Appropriate Use of Blood Components. Award of this national government grant by NIHR does not lead to a conflict of interest.

Carolyn Doree: None known.

Simon Stanworth: None known.

Michael Murphy: None known.

Notes

Apheresis The removal of blood from a patient for the purpose of removing certain blood components (such as platelets) before transfusion back to the donor Cytocidal Causing cell death Haemostatic (also spelled hemostatic) A haemostatic agent is a substance that promotes haemostasis (stops bleeding). It is also referred to as an antihaemorrhagic agent Pathogen A biological agent that causes disease or illness to its host (especially a virus, bacterium, or other micro‐organism) Photochemical Relating to, or produced by the effects of, light on chemical systems Psoralen A compound that sensitises mammalian cells to ultraviolet radiation

ACRONYMS USED IN THIS REVIEW: CAD compound absorption device CI confidence interval CCI corrected count increment CTCAE Common Toxicity Criteria for Adverse Events DSMB data safety monitoring board HBV hepatitis B virus HCV hepatitis C virus HIV human immunodeficiency virus HLA human leucocyte antigens HPA human platelet antigens HSCT haematopoietic stem cell transplantation HTLV human T‐cell lymphotropic virus MD mean difference OR odds ratio PAS platelet additive solution PCT photochemically treated RCT randomised controlled trial RR risk ratio TEG thromboelastography TTI transfusion‐transmitted infection WHO World Health Organization WNV West Nile virus

Edited (no change to conclusions)