Different doses of prophylactic platelet transfusion for preventing bleeding in people with haematological disorders after myelosuppressive chemotherapy or stem cell transplantation

Abstract

Background

Platelet transfusions are used in modern clinical practice to prevent and treat bleeding in people who are thrombocytopenic due to bone marrow failure. Although considerable advances have been made in platelet transfusion therapy in the last 40 years, some areas continue to provoke debate, especially concerning the use of prophylactic platelet transfusions for the prevention of thrombocytopenic bleeding.

This is an update of a Cochrane review first published in 2004, and updated in 2012 that addressed four separate questions: prophylactic versus therapeutic‐only platelet transfusion policy; prophylactic platelet transfusion threshold; prophylactic platelet transfusion dose; and platelet transfusions compared to alternative treatments. This review has now been split into four smaller reviews; this review compares different platelet transfusion doses.

Objectives

To determine whether different doses of prophylactic platelet transfusions (platelet transfusions given to prevent bleeding) affect their efficacy and safety in preventing bleeding in people with haematological disorders undergoing myelosuppressive chemotherapy with or without haematopoietic stem cell transplantation (HSCT).

Search methods

We searched for randomised controlled trials in the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library 2015, Issue 6), MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1937), the Transfusion Evidence Library (from 1950), and ongoing trial databases to 23 July 2015.

Selection criteria

Randomised controlled trials involving transfusions of platelet concentrates, prepared either from individual units of whole blood or by apheresis, and given to prevent bleeding in people with malignant haematological disorders or undergoing HSCT that compared different platelet component doses (low dose 1.1 x 10¹¹/m² ± 25%, standard dose 2.2 x 10¹¹/m² ± 25%, high dose 4.4 x 10¹¹/m² ± 25%).

Data collection and analysis

We used the standard methodological procedures expected by The Cochrane Collaboration.

Main results

We included seven trials (1814 participants) in this review; six were conducted during one course of treatment (chemotherapy or HSCT).

Overall the methodological quality of studies was low to moderate across different outcomes according to GRADE methodology. None of the included studies were at low risk of bias in every domain, and all the included studies had some threats to validity.

Five studies reported the number of participants with at least one clinically significant bleeding episode within 30 days from the start of the study. There was no difference in the number of participants with a clinically significant bleeding episode between the low‐dose and standard‐dose groups (four studies; 1170 participants; risk ratio (RR) 1.04, 95% confidence interval (CI) 0.95 to 1.13; moderate‐quality evidence); low‐dose and high‐dose groups (one study; 849 participants; RR 1.02, 95% CI 0.93 to 1.11; moderate‐quality evidence); or high‐dose and standard‐dose groups (two studies; 951 participants; RR 1.02, 95% CI 0.93 to 1.11; moderate‐quality evidence).

Three studies reported the number of days with a clinically significant bleeding event per participant. There was no difference in the number of days of bleeding per participant between the low‐dose and standard‐dose groups (two studies; 230 participants; mean difference ‐0.17, 95% CI ‐0.51 to 0.17; low quality evidence). One study (855 participants) showed no difference in the number of days of bleeding per participant between high‐dose and standard‐dose groups, or between low‐dose and high‐dose groups (849 participants).

Three studies reported the number of participants with severe or life‐threatening bleeding. There was no difference in the number of participants with severe or life‐threatening bleeding between a low‐dose and a standard‐dose platelet transfusion policy (three studies; 1059 participants; RR 1.33, 95% CI 0.91 to 1.92; low‐quality evidence); low‐dose and high‐dose groups (one study; 849 participants; RR 1.20, 95% CI 0.82 to 1.77; low‐quality evidence); or high‐dose and standard‐dose groups (one study; 855 participants; RR 1.11, 95% CI 0.73 to 1.68; low‐quality evidence).

Two studies reported the time to first bleeding episodes; we were unable to perform a meta‐analysis. Both studies (959 participants) individually found that the time to first bleeding episode was either the same, or longer, in the low‐dose group compared to the standard‐dose group. One study (855 participants) found that the time to the first bleeding episode was the same in the high‐dose group compared to the standard‐dose group.

Three studies reported all‐cause mortality within 30 days from the start of the study. There was no difference in all‐cause mortality between treatment arms (low‐dose versus standard‐dose: three studies; 1070 participants; RR 2.04, 95% CI 0.70 to 5.93; low‐quality evidence; low‐dose versus high‐dose: one study; 849 participants; RR 1.33, 95% CI 0.50 to 3.54; low‐quality evidence; and high‐dose versus standard‐dose: one study; 855 participants; RR 1.71, 95% CI 0.51 to 5.81; low‐quality evidence).

Six studies reported the number of platelet transfusions; we were unable to perform a meta‐analysis. Two studies (959 participants) out of three (1070 participants) found that a low‐dose transfusion strategy led to more transfusion episodes than a standard‐dose. One study (849 participants) found that a low‐dose transfusion strategy led to more transfusion episodes than a high‐dose strategy. One study (855 participants) out of three (1007 participants) found no difference in the number of platelet transfusions between the high‐dose and standard‐dose groups.

One study reported on transfusion reactions. This study's authors suggested that a high‐dose platelet transfusion strategy may lead to a higher rate of transfusion‐related adverse events.

None of the studies reported quality‐of‐life.

Authors' conclusions

In haematology patients who are thrombocytopenic due to myelosuppressive chemotherapy or HSCT, we found no evidence to suggest that a low‐dose platelet transfusion policy is associated with an increased bleeding risk compared to a standard‐dose or high‐dose policy, or that a high‐dose platelet transfusion policy is associated with a decreased risk of bleeding when compared to a standard‐dose policy.

A low‐dose platelet transfusion strategy leads to an increased number of transfusion episodes compared to a standard‐dose strategy. A high‐dose platelet transfusion strategy does not decrease the number of transfusion episodes per participant compared to a standard‐dose regimen, and it may increase the number of transfusion‐related adverse events.

Findings from this review would suggest a change from current practice, with low‐dose platelet transfusions used for people receiving in‐patient treatment for their haematological disorder and high‐dose platelet transfusion strategies not being used routinely.

Plain language summary

Different doses of platelet transfusion for preventing bleeding in people with low platelet counts due to treatment‐induced bone marrow failure

Review question

We evaluated the evidence about whether low‐dose platelet transfusions (platelet transfusions containing a lower number of platelets (1.1 x 10¹¹/m² ± 25%)) given to prevent bleeding in people with low platelet counts were as effective and safe as standard‐dose (2.2 x 10¹¹/m² ± 25%) or high‐dose platelet transfusions (platelet transfusions containing a larger number of platelets (4.4 x 10¹¹/m² ± 25%)) given regularly to prevent bleeding (prophylactically). Our target population was children and adults with blood cancers who were receiving intensive chemotherapy treatments or stem cell transplantation.

Background

Children and adults with blood cancers may have low platelet counts because of their underlying cancer. Blood cancers may be treated with chemotherapy and stem cell transplantation, and these treatments can also cause low platelet counts.

Platelet transfusions are used to prevent or treat bleeding in people with low platelet counts. Platelet transfusions are given to prevent bleeding when the platelet count falls below a prespecified threshold platelet count (for example 10 x 10⁹/L). Platelet transfusions are given to treat bleeding when the patient has bleeding (such as a prolonged nosebleed or multiple bruises).

Study characteristics

The evidence is current to July 2015. In this update, we identified seven randomised controlled trials that compared different doses of prophylactic platelet transfusions given to prevent bleeding in people with blood cancers. We reviewed seven randomised controlled trials with a total of 1814 participants. These trials were conducted between 1973 and 2015. Six of these trials were conducted during one course of treatment (chemotherapy or a stem cell transplant); the seventh trial was conducted over a longer time period involving several courses of chemotherapy and could not be included in any of the analyses. One trial contained only children, two trials contained adults and children, and four trials contained only adults.

Five of the seven studies reported funding sources. None of the studies that reported funding sources were industry sponsored.

Key results

Overall, platelet transfusions containing smaller number of platelets appeared to have similar effects to platelet transfusions containing larger numbers of platelets. There was no difference in the number of participants who bled, the frequency of bleeding, or the severity of bleeding between participants receiving a low, standard, or high number of platelets within each platelet transfusion. This was unaffected by the participant's age (children or adults), underlying treatment, or diagnosis.

There was a clear increase in the number of platelet transfusion episodes in the low‐dose group, compared to the standard‐dose and high‐dose groups. A high‐dose transfusion strategy did not lead to a decrease in the number of transfusion episodes in the largest study.

A high‐dose transfusion strategy may lead to an increase in transfusion‐related adverse events compared to a standard‐dose or low‐dose strategy.

None of the seven studies reported any quality‐of‐life outcomes.

Quality of the evidence

The evidence for most of the findings was of low or moderate quality because the studies were at risk of bias or the estimates were imprecise.

Background

Description of the condition

Haematological malignancies account for between 8% and 9% of all new cancers reported in the United Kingdom and United States (CDC 2012; ONS 2012), and their incidence is increasing (11% to 14% increase in new cases of lymphoma and myeloma between 1991 to 2001 and 2008 to 2010) (Cancer Research UK 2013). The prevalence of these disorders is also increasing due to increased survival rates (Coleman 2004; Rachet 2009). These improved survival rates are due to the introduction of myelosuppressive chemotherapy treatments and the use of stem cell transplantation (Burnett 2011; Fielding 2007; Patel 2009). Over 50,000 haematopoietic stem cell transplants (HSCTs) are carried out annually worldwide (Gratwohl 2010), and are used to treat both malignant and non‐malignant haematological disorders. Autologous HSCT is the most common type of HSCT (57% to 59%) (Gratwohl 2010; Passweg 2012). However, chemotherapy and stem cell transplantation can lead to prolonged periods of severe thrombocytopenia (De la Serna 2008; Heddle 2009a; Rysler 2010; Stanworth 2013; Wandt 2012).

Platelet transfusions are used in modern clinical practice to prevent and treat bleeding in thrombocytopenic patients with bone marrow failure secondary to chemotherapy or stem cell transplantation. The ready availability of platelet concentrates has undoubtedly made a major contribution in allowing the development of intensive treatment regimens for haematological disorders (malignant and non‐malignant) and other malignancies. The first demonstration of the effectiveness of platelet transfusions was performed in 1910 (Duke 1910). However, it was not until the 1970s and 1980s that the use of platelet transfusions became standard treatment for thrombocytopenic patients with bone marrow failure (Blajchman 2008). Alongside changes in supportive care, the routine use of platelet transfusions in people with haematological disorders since that time has led to a marked decrease in the number of haemorrhagic deaths associated with thrombocytopenia (Slichter 1980). This has resulted in a considerable increase in the demand for platelet concentrates. Currently, platelet concentrates are the second most frequently used blood component. Administration of platelet transfusions to people with haematological disorders now constitutes a significant proportion (up to 67%) of all platelets issued (Cameron 2007; Greeno 2007; Pendry 2011), and the majority of these (69%) are given to prevent bleeding (Estcourt 2012b).

Patients can become refractory to platelet transfusions. In an analysis of the TRAP 1997 study data, there was a progressive decrease in the post‐transfusion platelet count increments and time interval between transfusions as the number of preceding transfusions increased (Slichter 2005). This effect was seen irrespective of whether or not patients had developed detectable human leukocyte antigen (HLA) antibodies (Slichter 2005).

Platelet transfusions are also associated with adverse events. Mild to moderate reactions to platelet transfusions include rigors, fever, and urticaria (Heddle 2009b). Although these reactions are not life‐threatening, they can be extremely distressing for the patient. Rarer but more serious sequelae include: anaphylaxis; transfusion‐transmitted infections; transfusion‐related acute lung injury; and immunomodulatory effects (Benson 2009; Blumberg 2009; Bolton‐Maggs 2012; Heddle 2009b; Knowles 2010; Knowles 2011; Pearce 2011; Popovsky 1985; Silliman 2003).

Any strategy that can safely decrease the need for prophylactic platelet transfusions in haematology patients will have significant logistical and financial implications as well as decreasing patients’ exposure to the risks of transfusion.

Description of the intervention

Platelet transfusions have an obvious beneficial effect in the management of active bleeding in people with haematological malignancy and severe thrombocytopenia. However, questions still remain about how this limited resource should be used to prevent severe and life‐threatening bleeding (Estcourt 2011). Prophylactic platelet transfusions for people with chemotherapy‐induced thrombocytopenia became standard practice following the publication of several small randomised controlled trials (RCTs) in the late 1970s and early 1980s (Higby 1974; Murphy 1982; Solomon 1978). There are two main methods for producing platelet components. Apheresis platelet components (one donor per transfusion) requires platelet donors to be connected to a cell separator for at least 90 minutes. Pooled platelet components are derived from platelets within several whole‐blood donations.

Dose of prophylactic platelet transfusions

The platelet dose is the number of platelets contained within a standard platelet transfusion. For adults, the usual dose given is a single apheresis unit or a pool of four to six whole blood‐derived platelets, with the absolute number of platelets in the range of 300 x 10⁹ to 600 x 10⁹ (Stanworth 2005). The experimental interventions will be low‐dose or high‐dose platelet transfusion strategies. Low‐dose platelet transfusions will be platelet transfusions containing a similar dose to that given in the low‐dose arm of Slichter 2010 (1.1 x 10¹¹/m² ± 25%). High‐dose platelet transfusions will be platelet transfusions containing a similar dose to that given in the high‐dose arm of Slichter 2010 (4.4 x 10¹¹/m² ± 25%). If the exact dose is unknown, we will use the study's own definition of high dose or low dose.

How the intervention might work

Optimal dose of prophylactic platelets

The dose of the platelet product transfused was based upon the perceived need to raise the patient's platelet count above a certain safe threshold. Over the years, our understanding of bleeding in people with thrombocytopenia has advanced, and there is now evidence to suggest that patients require only approximately 7100 platelets/µL per day to maintain haemostasis (Hanson 1985). Platelets have been shown to provide an endothelial supportive function by plugging gaps in the endothelium of otherwise intact blood vessels. Animal studies have shown that thrombocytopenia is associated with the gradual thinning of the vessel wall endothelium over time and, that if thrombocytopenia persists, gaps gradually occur between adjacent endothelial cells (Blajchman 1981; Kitchens 1975; Nachman 2008). This thinning and fenestration of the endothelium is accompanied by the ongoing and increased use of circulating platelets to prevent the loss of red blood cells through these gaps.

A mathematical model predicted that smaller, more frequent doses of platelets would be as effective as higher doses of platelets in maintaining patients' platelet counts above an agreed threshold (Hersh 1998). This raised the question of whether thrombocytopenic bleeding could be prevented with a lower platelet dose (Tinmouth 2003). Such a strategy has potential economic and resource advantages, as fewer platelet transfusions might be required and donor exposures might be reduced.

Several studies have attempted to address this question. The two largest studies came to different conclusions (Heddle 2009a; Slichter 2010). One trial was stopped early because of an excess of World Health Organization (WHO) grade 4 bleeding (Heddle 2009a), and the other study found no difference in bleeding between treatment arms (Slichter 2010).

Assessment of bleeding

A bleeding assessment has been seen as a more clinically relevant measure of the effect of platelet transfusions than surrogate markers such as the platelet increment.

Any review that uses bleeding as a primary outcome measure needs to assess the way that the trials have recorded bleeding. Unfortunately, the way bleeding has been recorded and assessed has varied markedly between trials (Cook 2004; Estcourt 2013a; Heddle 2003).

Retrospective analysis of bleeding leads to a risk of bias because bleeding events may be missed, and only more severe bleeding is likely to have been documented. Prospective bleeding assessment forms provide more information and are less likely to miss bleeding events. However, different assessors may grade the same bleed differently, and it is very difficult to blind the assessor to the intervention.

The majority of trials have used the WHO system, or a modification of it, for grading bleeding (Estcourt 2013a; Koreth 2004; WHO 1979). One limitation of all the scoring systems based on the WHO system is that the categories are relatively broad and subjective, meaning that a small change in a participant's bleeding risk may not be detected. Another limitation is that the modified WHO categories are partially defined by whether a bleeding participant requires a blood transfusion. The threshold for intervention may vary between clinicians and institutions, and so the same level of bleeding may be graded differently in different institutions.

The definition of what constitutes clinically significant bleeding has varied between studies. Although the majority of more recent platelet transfusion studies have classified it as WHO grade 2 or above (Heddle 2009a; Slichter 2010; Stanworth 2010; Wandt 2012), in the past there has been greater heterogeneity (Cook 2004; Estcourt 2013a; Koreth 2004). The difficulties of assessing and grading bleeding may limit the ability to compare results between studies, and this needs to be kept in mind when reviewing the evidence for the effectiveness of prophylactic platelet transfusions at different doses.

Why it is important to do this review

Although considerable advances have been made in platelet transfusion therapy in the last 40 years, three major areas continue to provoke debate.

• Firstly, what is the optimal prophylactic platelet dose to prevent thrombocytopenic bleeding?

• Secondly, which threshold should be used to trigger the transfusion of prophylactic platelets?

• Thirdly, are prophylactic platelet transfusions superior to therapeutic platelet transfusions for the prevention or control, or both, of life‐threatening thrombocytopenic bleeding?

The initial formulation of this Cochrane review attempted to answer these questions, but the evidence at the time was insufficient for us to draw any definitive conclusions (Stanworth 2004). This review was updated (Estcourt 2012a). For clarity and simplicity, we have now split the review to answer each question separately.

This review focuses solely on the first question: What is the optimal prophylactic platelet dose to prevent thrombocytopenic bleeding?

Avoiding the need for unnecessary prophylactic platelet transfusions in haematology patients will have significant logistical and financial implications for national health services as well as decreasing patients' exposure to the risks of transfusion. These factors are perhaps even more important in the development of platelet transfusion strategies in low‐income countries, where access to blood components is much more limited than in high‐income countries (Verma 2009).

The previous version of this review showed that there was no difference in the number of participants who developed WHO grade 2 or above bleeding between a low‐dose, standard‐dose, or high‐dose platelet transfusion strategy (Estcourt 2012a). However, the review was unable to establish whether there was any difference in the number of days on which bleeding occurred or in the number of participants with severe or life‐threatening haemorrhage (WHO grade 3 to 4) between the various platelet dose strategies.

This review did not assess the evidence for the answers to the second and third questions, as these are the focus of separate Cochrane reviews, nor did it assess the use of alternative agents instead of prophylactic platelet transfusions because this is the focus of another review.

This review did not assess whether there are any differences in the efficacy of apheresis versus whole‐blood derived platelet products, the efficacy of pathogen‐reduced platelet components, the efficacy of HLA‐matched versus random‐donor platelets, or differences between ABO identical and ABO non‐identical platelet transfusions, as recent systematic reviews have covered these topics (Butler 2013; Heddle 2008; Pavenski 2013; Shehata 2009).

Objectives

To determine whether different doses of prophylactic platelet transfusions (platelet transfusions given to prevent bleeding) affect their efficacy and safety in preventing bleeding in people with haematological disorders undergoing myelosuppressive chemotherapy with or without haematopoietic stem cell transplantation (HSCT).

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs). There were no restrictions on language or publication status.

Types of participants

People with haematological disorders receiving treatment with myelosuppressive chemotherapy or stem cell transplantation, or both. We included people of all ages, in both inpatient and outpatient clinical settings. If trials consisted of mixed populations of patients, for example patients with diagnoses of solid tumours, we only used data from the haematological subgroups. If subgroup data for haematological patients were not provided (after contacting the authors of the trial), we excluded the trial if fewer than 80% of participants had a haematological disorder. We excluded any participants who were not being treated with myelosuppressive chemotherapy or a stem cell transplant. We included participants with non‐malignant haematological disorders (for example aplastic anaemia, congenital bone marrow failure syndromes) if they were being treated with an allogeneic stem cell transplant.

Types of interventions

Participants in both treatment arms received transfusions of platelet concentrates, prepared either from individual units of whole blood or by apheresis, and given prophylactically to prevent bleeding. Prophylactic platelet transfusions are typically given when blood platelet counts fall below a given trigger level. There was no restriction on the frequency of platelet transfusions, type of platelet component, or platelet count transfusion threshold, although we took this information into account in the analysis where available.

We included the following comparisons:

• Low‐dose versus standard‐dose platelet transfusions

• Low‐dose versus high‐dose platelet transfusions

• High‐dose versus standard‐dose platelet transfusions

Low‐dose platelet transfusions were platelet transfusions containing a similar dose to that given in the low‐dose arm of Slichter 2010 (1.1 x 10¹¹/m² ± 25%). Standard‐dose platelet transfusions were platelet transfusions containing a similar dose to that given in the intermediate‐dose arm of Slichter 2010 (2.2 x 10¹¹/m² ± 25%). High‐dose platelet transfusions were platelet transfusions containing a similar dose to that given in the high‐dose arm of Slichter 2010 (4.4 x 10¹¹/m² ± 25%). If the exact dose was unknown, we used the study's own definition of high dose, standard dose, or low dose.

Types of outcome measures

Primary outcomes

Number and severity of bleeding episodes within 30 days from the start of the study:

1. The number of participants with at least one bleeding episode.

2. The total number of days on which bleeding occurred per participant.

3. The number of participants with at least one episode of severe or life‐threatening haemorrhage.

4. Time to first bleeding episode from the start of the study.

Secondary outcomes

1. Mortality (all causes, secondary to bleeding, and secondary to infection) within 30 days and 90 days from the start of the study.

2. Number of platelet transfusions per participant and number of platelet components per participant within 30 days from the start of the study.

3. Number of red cell transfusions per participant and number of red cell units per participant within 30 days from the start of the study.

4. Platelet transfusion interval within 30 days from the start of the study.

5. Proportion of participants requiring additional interventions to stop bleeding (surgical; medical, e.g. tranexamic acid; other blood products, e.g. fresh frozen plasma, cryoprecipitate) within 30 days from the start of the study.

6. Overall survival within 30, 90, and 180 days from the start of the study.

7. Proportion of participants achieving complete remission within 30 days and 90 days from the start of the study.

8. The total time in hospital within 30 days from the start of the study.

9. Adverse effects of treatments (transfusion reactions, thromboembolism, transfusion‐transmitted infection, development of platelet antibodies, development of platelet refractoriness) within 30 days from the start of the study.

10. Quality of life, as defined by the individual studies.

We expressed all primary and secondary outcomes in the formats defined in the Measures of treatment effect section of this review if data were available, except for two of our outcomes, which we planned to be only narrative reports. These were:

• Platelet transfusion interval, as this can be calculated in many different ways and it was unlikely that the exact methodology would be reported sufficiently to allow us to combine the data, the data was therefore reported in a table.

• Assessment of quality of life. We planned to use the study's own measure as there is no definitive patient‐reported outcome measure for this patient group (Estcourt 2014e). However, no study reported quality of life.

Search methods for identification of studies

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 (Estcourt 2012a; Stanworth 2004).

Electronic searches

Bibliographic databases

We searched for RCTs in the following databases:

• CENTRAL (Cochrane Library 2015, Issue 6, 23 July 2015) (Appendix 1)

• MEDLINE (OvidSP, 1946 to 23 July 2015) (Appendix 2)

• PubMed (epublications only, on 23 July 2015) (Appendix 3)

• Embase (OvidSP, 1974 to 23 July 2015) (Appendix 4)

• CINAHL (EBSCOhost, 1937 to 23 July 2015) (Appendix 5)

• UKBTS/SRI Transfusion Evidence Library (www.transfusionevidencelibrary.com) (1950 to 23 July 2015) (Appendix 6)

• Web of Science: Conference Proceedings Citation Index‐Science (CPCI‐S) (Thomson Reuters, 1990 to 23 July 2015) (Appendix 7)

• LILACS (BIREME/PAHO/WHO, 1982 to 23 July 2015) (Appendix 8)

• IndMed (ICMR‐NIC, 1985 to 23 July 2015) (Appendix 9)

• KoreaMed (KAMJE, 1997 to 23 July 2015) (Appendix 10)

• PakMediNet (2001 to 23 July 2015) (Appendix 10)

We updated searches from the original search in January 2002, Stanworth 2004, and the updated search on 10 November 2011, Estcourt 2012a. We combined searches in MEDLINE, Embase, and CINAHL with adaptations of the Cochrane RCT search filters, as detailed in the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2011).

Databases of ongoing trials

We also searched ClinicalTrials.gov (http://clinicaltrials.gov/ct2/search) (Appendix 11), the WHO International Clinical Trials Registry (ICTRP) (http://apps.who.int/trialsearch/) (Appendix 11), the ISRCTN Register (http://www.controlled‐trials.com/isrctn/) (Appendix 12), the EU Clinical Trials Register (https://www.clinicaltrialsregister.eu/ctr‐search) (Appendix 12), and the Hong Kong Clinical Trials Register (http://www.hkclinicaltrials.com/) (Appendix 13) in order to identify ongoing trials to 23 July 2015.

All new search strategies are presented as indicated in Appendices 1‐13. Search strategies for both the original (2002) and update (2011) searches are presented in Appendix 14.

Searching other resources

We augmented database searching with the following:

Handsearching of reference lists

We checked references lists of all included trials, relevant review articles, and current treatment guidelines for further literature. We limited these searches to the 'first generation' reference lists.

Personal contacts

We contacted authors of relevant studies, study groups, and experts worldwide known to be active in the field for unpublished material or further information on ongoing studies.

Data collection and analysis

Selection of studies

Two independent review authors (LE, PB) initially screened all electronically derived citations and abstracts of papers identified by the review search strategy for relevance. We excluded studies clearly irrelevant at this stage.

Two independent review authors (LE, PB) then formally assessed the full texts of all potentially relevant trials for eligibility against the criteria outlined above. We resolved all disagreements by discussion without the need to consult a third review author (SS). We sought further information from study authors if the article contained insufficient data to make a decision about eligibility. We designed a study eligibility form for trials of platelet transfusion to help in the assessment of relevance, which included ascertaining whether the participants had haematological disorders, and whether the two groups could be defined in the trial on the basis of differences in use of prophylactic platelet transfusion doses. We recorded the reasons why potentially relevant studies failed to meet the eligibility criteria.

Data extraction and management

We updated the data extraction performed for the previous version of this review (Estcourt 2012a). This included data extraction for all new studies that we have included since the previous review and also for all new review outcomes that were not part of the previous review (for example platelet transfusion interval, quality of life).

Two review authors (LE, PB) 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 data extraction forms had been piloted in the previous version of this review (Estcourt 2012a). Due to minor changes in the format, the forms were piloted on a further study; thereafter the two review authors (LE, PB) independently extracted data for all the studies. We extracted the following data.

General information

Review author's name, date of data extraction, study ID, first author of study, author's contact address (if available), citation of paper, objectives of the trial. 

Trial details

Trial design, location, setting, sample size, power calculation, treatment allocation, randomisation, blinding, inclusion and exclusion criteria, reasons for exclusion, comparability of groups, length of follow‐up, stratification, stopping rules described, statistical analysis, results, conclusion, and funding.

Characteristics of participants

Age, gender, ethnicity, total number recruited, total number randomised, total number analysed, types of haematological disease, lost to follow‐up numbers, dropouts (percentage in each arm) with reasons, protocol violations, previous treatments, current treatment, prognostic factors.

Interventions

Experimental and control interventions, type of platelet given, timing of intervention, dosage of platelet given, compliance to interventions, additional interventions given especially in relation to red cell transfusions, any differences between interventions.

Assessment of bias

Sequence generation, allocation concealment, blinding (participants, personnel, and outcome assessors), incomplete outcome data, selective outcome reporting, other sources of bias.

Outcomes measured

• Number and severity of bleeding episodes.

• Mortality (all causes), and mortality due to bleeding.

• Overall survival.

• Proportion of participants achieving complete remission.

• Time in hospital.

• Number of platelet transfusions and platelet components.

• Number of red cell transfusions and red cell components.

• Adverse effects of treatments (e.g. transfusion reactions, thromboembolism, transfusion‐transmitted infection, development of platelet antibodies or platelet refractoriness).

• Quality of life.

We used both full‐text versions and abstracts to retrieve the data. We extracted publications reporting on more than one trial using one data extraction form for each trial. We extracted trials reported in more than one publication on one form only. When these sources provided insufficient information, we contacted the authors and study groups for additional details.

One review author performed data entry into software, which a second review author checked for accuracy.

Assessment of risk of bias in included studies

We updated the 'Risk of bias' assessment to include study funding from the 'Risk of bias' assessment performed for the previous version of this review (Estcourt 2012a).

The assessment included information about the design, conduct, and analysis of the trial. We evaluated each criterion on a three‐point scale: low risk of bias, high risk of bias, or unclear (Higgins 2011c). To assess risk of bias, we addressed the following questions in the 'Risk of bias' table for each included study:

• Was the allocation sequence adequately generated?

• Was allocation adequately concealed?

• Was knowledge of the allocated intervention adequately prevented during the study (including an assessment of blinding of participants, personnel, and outcome assessors)?

• Were incomplete outcome data adequately addressed (for every outcome separately)?

• Are reports of the study free of selective outcome reporting?

• Was the study apparently free of other problems that could put it at risk of bias? This included assessing whether the protocol deviation was balanced between treatment arms.

Measures of treatment effect

For dichotomous outcomes, we recorded the number of outcomes in the treatment and control groups and estimated the treatment effect measures across individual studies as the relative effect measures (risk ratio with 95% confidence intervals (CIs)).

For continuous outcomes, we recorded the mean and standard deviations. For continuous outcomes measured using the same scale, the effect measure was the mean difference with 95% CIs, or the standardised mean difference for outcomes measured using different scales. For time‐to‐event outcomes, we extracted the hazard ratio from published data according to Parmar 1998 and Tierney 2007.

We did not report the number needed to treat to benefit with CIs and the number needed to treat to harm with CIs because there we saw no differences between any of the bleeding outcomes.

If we could not report the available data in any of the formats described above, we performed a narrative report.

Unit of analysis issues

We did not pre‐specify in the protocol how we would deal with any unit of analysis issues. There were no unit of analysis issues within the included studies.

Dealing with missing data

We dealt with missing data according to the recommendations in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). We contacted nine authors in order to obtain information that was missing or unclear in the published report.

Three authors supplied missing data (Heddle 2009; Slichter 2010; Tinmouth 2004). One author searched for missing data, but it was no longer available (Steffens 2002).

In trials that included people with haematological disorders as well as those with solid tumours or non‐malignant haematological disorders, we extracted data for the malignant haematology subgroup from the general trial data. We could not do this in two studies (Klumpp 1999; Lu 2011); we contacted the authors but they did not respond. We therefore excluded these studies from the review.

Within an outcome, the preferred analysis was an intention‐to‐treat analysis. Where data were missing, we recorded the number of participants lost to follow‐up for each trial.

Assessment of heterogeneity

If we considered studies to be sufficiently homogenous in their design, we conducted a meta‐analysis and assessed the statistical heterogeneity (Deeks 2011). We assessed 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 possible heterogeneity (I² > 50% moderate heterogeneity, I² > 80% considerable heterogeneity). We explored potential causes of heterogeneity by sensitivity and subgroup analyses where possible.

Assessment of reporting biases

We did not perform a formal assessment of potential publication bias (small trial bias) (Sterne 2011), because the review included fewer than 10 trials.

Data synthesis

We performed analyses according to the recommendations of The Cochrane Collaboration (Deeks 2011). We used aggregated data for analysis. For statistical analysis, we entered data into Review Manager 2014.

Where meta‐analysis was feasible, we used the fixed‐effect model for pooling the data. We used the Mantel‐Haenszel method for dichotomous outcomes, and the inverse‐variance method for continuous outcomes. We used the generic inverse‐variance method for time‐to‐event outcomes.

We used the random‐effects model for sensitivity analyses as part of the exploration of heterogeneity. If we found heterogeneity, as expressed by the I², to be above 50%, we reported both the fixed‐effect and random‐effects models. If we found heterogeneity to be above 80%, we did not perform a meta‐analysis and commented on results as a narrative.

Summary of findings tables

We used GRADE 2014 to create 'Summary of findings' tables as suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2011). This included the number and severity of bleeding episodes within 30 days from the start of the study (number of participants with at least one bleeding episode; number of days on which bleeding occurred; number of participants with severe or life‐threatening bleeding; time to first bleeding episode), number of platelet transfusions within 30 days from the start of the study, 30‐day mortality, and quality of life.

Subgroup analysis and investigation of heterogeneity

We considered performing subgroup analysis on the following characteristics, if appropriate:

• Presence of fever (> 38^oC)

• Underlying disease

• Type of treatment (autologous HSCT, allogeneic HSCT, or chemotherapy alone)

• Age of the participant (paediatric, adults, older adults (> 60 years))

Due to lack of data, we performed only three of these four subgroup analyses: underlying disease, type of treatment, and age of the participant.

We did not perform meta‐regression because no subgroup contained more than 10 studies (Deeks 2011). We commented on differences between subgroups as a narrative.

Investigation of heterogeneity between studies also included, if appropriate:

• Age of the study (as the type of platelet component has changed over the last 40 years)

• Different prophylactic platelet transfusion thresholds

Only one study was performed more than 20 years ago (Roy 1973). We could not incorporate any of the data from this study into any of the meta‐analyses, and therefore we did not perform this investigation of heterogeneity.

Sensitivity analysis

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

• Including only those trials at low risk of bias

• Including only those trials in which 20% of participants or less were lost to follow‐up.

None of the seven included trials had more that 20% of participants lost to follow‐up, and all of the trials had some threats to validity, therefore we performed neither pre‐planned sensitivity analysis.

Results

Description of studies

See Characteristics of included studies and Characteristics of excluded studies.

Results of the search

See PRISMA flow diagram Figure 1.

1.

Study flow diagram.

The original search (conducted January 2002) identified a total of 3196 potentially relevant records (Stanworth 2004). After duplicates were removed, there were 2380 records; we excluded 2343 records on the basis of the abstract. Using the original inclusion/exclusion criteria, the original systematic review identified 37 studies that appeared relevant on the basis of their full text or abstract (Stanworth 2004). This was performed by one review author.

The updated search (conducted November 2011) identified a total of 2622 potentially relevant records. After duplicates were removed, there were 2054 records; two review authors excluded 1865 records on the basis of the abstract. We retrieved 152 full‐text articles for relevance. Two review authors reviewed these full‐text articles and those from the original review (a total of 189 records) (Estcourt 2012a).

The latest update of the search (conducted 23 July 2015) identified a total of 4923 potentially relevant records. After duplicates were removed, there were 3927 records; two of three review authors (LE, PB, CD) excluded 3921 records on the basis of the abstract. Two review authors (LE, PB) retrieved and reviewed for relevance 26 full‐text articles.

The previous systematic review, Estcourt 2012a, identified seven trials that compared different platelet transfusion doses (six completed trials (Heddle 2009; Roy 1973; Sensebe 2004; Slichter 2010; Steffens 2002; Tinmouth 2004) and one ongoing trial (Lu 2011)). This updated search identified one additional study (Akay 2015). In total, we assessed and deemed eligible for inclusion seven studies (Akay 2015; Heddle 2009; Roy 1973; Sensebe 2004; Slichter 2010; Steffens 2002; Tinmouth 2004).

Included studies

See Characteristics of included studies for full details of each study.

Ongoing studies

This updated review identified no ongoing studies that were eligible for inclusion. The previous systematic review, Estcourt 2012a, identified one potentially relevant trial that compared different doses of platelets; this has now been excluded from our review because more than 20% of study participants had a solid tumour, and no subgroup data were available (Lu 2011).

Studies contributing to the main outcomes

The seven RCTs (20 publications) were published between 1973 and 2015. There were 13 secondary citations of included studies (cited as secondary references for the relevant included studies).

See Table 4 for study characteristics, including number and type of participants, type of intervention (actual doses used), prophylactic platelet transfusion thresholds used, duration of study, type of platelet product, and primary outcome.

1. Characteristics of studies.

Study	Participants	Number	Intervention	Intervention adjusted to BSA ranges of Slichter 2010a	Platelet count threshold for prophylactic transfusions	Duration of study	Type of platelet product	Primary outcome
Akay 2015	Adults with haematological malignancies	100	"Low dose" 3‐unit pooled product, or 1/2‐unit apheresis product "Standard dose" 6‐unit pooled product or single‐unit apheresis product	Actual dose not reported	Plt count ≤ 10 x 109/L	Not reported	Apheresis and pooled platelet products	Not reported
Heddle 2009	Adults with hypoproliferative thrombocytopenia	129	(1.5 to 3.0 x 1011 platelets/product) versus (3.0 to 6.0 x 1011 platelets/product)	Low dose 0.8 to 1.7 x 1011/m2 BSA versus Standard dose 1.7 to 3.4 x 1011/m2 BSA	Depended on local transfusion trigger. Usually 10 x 109/L	Mean of 14 to 15.8 days	Apheresis and pooled platelet products	Occurrence of a WHO grade 2 bleed or above
Roy 1973	Children with acute leukaemia	62	(0.5 x 1011/10 kg) versus (0.9 to 1.1 x 1011/10 kg)b	0 to 4 years Low dose 1.1 x 1011/m2 BSA versus Standard dose 2.0 to 2.4 x 1011/m2 BSA 5 to 9 years Low dose 1.3 x 1011/m2 BSA versus Standard dose 2.4 to 2.9 x 1011/m2 BSA 10 to 18 years Standard dose 1.7 x 1011/m2 BSA versus High dose 3.1 to 3.7 x 1011/m2 BSA	Plt count ≤ 25 x 109/L	Follow‐up for 24 hours post platelet transfusion	ABO‐identical pooled products	Not reported
Sensebe 2004	People with acute leukaemia or undergoing autologous SCT	101	(0.5 x 1011/10 kg) versus (1.0 x 1011/10 kg)c	Standard dose 1.9 x 1011/m2 BSA versus High dose 3.9 x 1011/m2 BSA	Plt count < 20 x 109/L	Not stated	Leucodepleted ABO‐compatible apheresis	Time between first transfusion and daily platelet count reaching 20 x 109/L
Slichter 2010	People of any age receiving SCT or myelosuppressive chemotherapy	1351	(1.1 x 1011/m2 BSA ± 25%) versus (2.2 x 1011/m2 BSA ± 25%) versus (4.4 x 1011/m2 BSA ± 25%)	Low dose (1.1 x 1011/m2 BSA) (range 0.8 to 1.4 x 1011/m2 BSA) versus Intermediate dose (2.2 x 1011/m2 BSA) (range 1.7 to 2.8 x 1011/m2 BSA) versus High dose (4.4 x 1011/m2 BSA) (range 3.3 to 5.5 x 1011/m2 BSA)	Plt count ≤ 10 x 109/L	Mean number of days 19.1	Apheresis and pooled platelet products	Grade 2 or higher bleeding
Steffens 2002	People age > 16 yrs with AML or undergoing an allogeneic SCT	54	(single apheresis unit) versus (triple apheresis unit)	Actual dose not reported. Study definition was standard versus high dose	Plt count ≤ 10 x 109/L	Median time for people with AML 25.1 to 25.8 days. Median time for SCT 14.1 to 15.9 days	Apheresis	Not reported
Tinmouth 2004	People age > 16 yrs with acute leukaemia or receiving an autologous SCT	111	(1.9 to 2.5 x 1011 platelets/transfusion) versus (3.4 to 4.4 x 1011 platelets/transfusion)	Low dose 1.1 to 1.4 x 1011/m2 BSA versus Standard dose 1.9 to 2.5 x 1011/m2 BSA	Plt count < 10 x 109/L	Median time 15 days	Leucodepleted random‐donor pooled platelets (PRP method)	Bayesian design. Lower dose of platelets would be safe and effective in preventing major bleeding events and would decrease total utilisation of platelets

AML: acute myeloid leukaemia
 BSA: body surface area
 Plt: platelet
 PRP: platelet‐rich plasma
 SCT: stem cell transplant

^a For adult participants, the average body surface area (BSA) was assumed to be 1.79 using data from Sacco 2010. In all studies containing adult participants we used this number to compare study doses to the Slichter 2010 study. For Roy 1973, the BSA was calculated for each age group: 0 to 4 years, 5 to 9 years, and 10 to 18 years. Approximate body weights were estimated for each age group and the BSA estimated using Sharkey 2001. The approximate weights were 0 to 4 years (13.5 kg), 5 to 9 years (23.3 kg), and 10 to 18 years (50.9 kg). These equate to approximate BSA of 0.62 (0 to 4 years), 0.87 (5 to 9 years), and 1.5 (10 to 15 years).

^b The original study stated that "higher dose" platelet transfusions = 0.06 to 0.07 units/lb and "lower dose" platelet transfusions = 0.03 units/lb (Roy 1973). The average platelet yield reported in the study was 7 x 10¹⁰ platelets per unit. Therefore "higher dose" platelets = 0.9 to 1.1 x 10¹¹platelets/10 kg and "lower dose" platelets = 0.46 x 10¹¹ platelets/10 kg.

^c Mean weight in both arms of the study was 69 kg.

Of the seven RCTs, four were single‐centre parallel RCTs (Akay 2015; Roy 1973; Steffens 2002; Tinmouth 2004), and three were multicentre parallel RCTs (Heddle 2009; Sensebe 2004; Slichter 2010). The number of participants randomised ranged from 54 in Steffens 2002 to 1351 in Slichter 2010.

One study was conducted in the 1970s (Roy 1973), five studies were conducted in the early to late 2000s (Heddle 2009; Sensebe 2004; Slichter 2010; Steffens 2002; Tinmouth 2004), and one study was conducted in the 2010s (Akay 2015). Two studies were conducted in the United States (Roy 1973; Slichter 2010), one in Canada (Tinmouth 2004), one in France (Sensebe 2004), one in Turkey (Akay 2015), and one in the United Kingdom (Steffens 2002), and one study was a multinational trial with centres in Canada, Norway, and the United States (Heddle 2009).

This updated review included one new study (Akay 2015). The original review identified two platelet dose studies (Klumpp 1999; Roy 1973). The previous update of this review identified five platelet dose studies (Heddle 2009; Sensebe 2004; Slichter 2010; Steffens 2002; Tinmouth 2004).

Participants

In total 1908 participants were randomised; of these, we included 1814 in the analyses. 91 participants (seven in Heddle 2009, five in Sensebe 2004, and 79 in Slichter 2010) were excluded from these studies because they did not receive a platelet transfusion. Three further patients were excluded from the Heddle 2009 study because there was no bleeding assessment data available.

Four of the studies included only adults (Akay 2015; Heddle 2009; Steffens 2002; Tinmouth 2004). Two of the studies included both adults and children (Sensebe 2004; Slichter 2010), and one study included only children (Roy 1973). All of the participants had hypoproliferative thrombocytopenia, but the cause of this varied between studies. All of the studies included participants with acute leukaemia, however only four of the studies specifically stated that acute promyelocytic leukaemia was an exclusion criteria (Heddle 2009; Sensebe 2004; Slichter 2010; Tinmouth 2004). Four of the studies included participants receiving an autologous stem cell transplant (Heddle 2009; Sensebe 2004; Slichter 2010; Tinmouth 2004). Three of the studies included participants receiving an allogeneic stem cell transplant (Heddle 2009; Slichter 2010; Steffens 2002).

Intervention

Five studies specified the dose of platelets used in each arm of the study (Heddle 2009; Roy 1973; Sensebe 2004; Slichter 2010; Tinmouth 2004), and we approximated the doses to the doses specified in Slichter 2010; and in two studies we used the study's own definition of whether it was a low‐dose, standard‐dose, or high‐dose transfusion (Akay 2015; Steffens 2002) (see Table 4).

Three studies compared low‐dose versus standard‐dose platelet transfusions (Akay 2015; Heddle 2009; Tinmouth 2004) (Table 4). One study compared low‐dose versus high‐dose platelet transfusions (Slichter 2010). Two studies compared standard‐dose versus high‐dose platelet transfusions (Sensebe 2004; Steffens 2002). Slichter 2010 performed a comparison between low‐dose, standard‐dose, and high‐dose platelet transfusions. Roy 1973 compared low‐dose versus standard‐dose platelet transfusions in the two younger age groups (0 to 4 and 5 to 9 years) and standard‐dose versus high‐dose platelet transfusions in the oldest age group (10 to 18 years).

The type of platelet product varied between studies: Roy 1973 and Tinmouth 2004 used pooled random‐donor platelets; Akay 2015, Heddle 2009, and Slichter 2010 used both apheresis and pooled platelet components; and Sensebe 2004 and Steffens 2002 used apheresis platelet components.

Six of the seven studies defined the platelet count threshold for prophylactic platelet transfusions: Akay 2015, Slichter 2010, Steffens 2002, and Tinmouth 2004 used a platelet count threshold of 10 x 10⁹/L; Sensebe 2004 used a platelet count threshold of 20 x 10⁹/L; and Roy 1973 used a platelet count threshold of 25 x 10⁹/L. In Heddle 2009, the prophylactic platelet transfusion threshold depended on local guidelines, but this was usually a platelet count threshold of 10 x 10⁹/L. In Akay 2015, the threshold was raised to 20 x 10⁹/L if the participants had WHO grade 1 bleeding or a fever.

Co‐interventions

None of the studies reported any co‐interventions. Five of the seven studies did not report a red cell transfusion policy, and two studies (unpublished data of Heddle 2009; Slichter 2010) reported that local practice at each centre determined the red cell transfusion policy.

Outcomes

Four of the seven studies defined a primary outcome (Heddle 2009; Sensebe 2004; Slichter 2010; Tinmouth 2004). In three of these studies, bleeding was the primary outcome measure (Heddle 2009; Slichter 2010; Tinmouth 2004), whereas in the fourth study the primary outcome was the time between the first platelet transfusion and the daily platelet count reaching 20 x 10⁹/L (Sensebe 2004), with bleeding reported as an adverse event. Only one of the seven studies reported on adverse events associated with platelet transfusions (Slichter 2010).

Excluded studies

See Characteristics of excluded studies for further details.

• Twelve excluded studies compared different participant groups (Andrew 1993; Arnold 2006; Bai 2004; Fanning 1995; Gajic 2006; Gerday 2009; Hillbom 2008; Johansson 2007; Julmy 2009; Reed 1986; Spiess 2004; Vadhan‐Raj 2002).

• Sixty‐four excluded studies compared different types of platelet formulations with outcome measures not relevant to the eligibility criteria (Agliastro 2006; Akkök 2007; Anderson 1997; Arnold 2004; Bentley 2000; Blumberg 2002; Blumberg 2004; Blundell 1996; Carr 1990; Couban 2002; De Wildt‐Eggen 2000; Diedrich 2005; Diedrich 2009; Dumont 2011; Gmur 1983; Goodrich 2008; Grossman 1980; Gurkan 2007; Harrup 1999; Heal 1993; Heckman 1997; Heddle 1994; Heddle 1999; Heddle 2002; Higby 1974; ISRCTN49080246; Kakaiya 1981; Kerkhoffs 2010; Lapierre 2003; Leach 1991; Lee 1989; Lozano 2010; Lozano 2011; McCullough 2004; Messerschmidt 1988; Mirasol 2010; Murphy 1982; Murphy 1986; NCT00180986; Oksanen 1991; Oksanen 1994; OPTIMAL Pilot Study; Pamphilon 1996; Rebulla 1997; Schiffer 1983; Shanwell 1992; Singer 1988; Sintnicolaas 1981; Sintnicolaas 1982; Sintnicolaas 1995; Slichter 1998; Slichter 2006; Solomon 1978; Stanworth 2013; Strindberg 1996; Sweeney 2000; TRAP 1997; van Marwijk 1991; van Rhenen 2003; Wandt 2012; Wang 2002; Williamson 1994; Zhao 2002; Zumberg 2002).

• Three citations were guidelines (Follea 2004; Samama 2005; Tosetto 2009).

• One citation was an audit (Qureshi 2007).

• Thirty‐nine citations were reviews (including four systematic reviews) (Andreu 2009; Avvisati 2003; Benjamin 2002; Blajchman 2008; Buhrkuhl 2010; Casbard 2004; Cid 2007; Dzik 2004; Goodnough 2002; Goodnough 2005; Heal 2004; Heddle 2003; Heddle 2007; Jelic 2006; Levi 2002; Lordkipanidze 2009; Lozano 2003; Martel 2004; McNicol 2003; Paramo 2004; Poon 2003; Rabinowitz 2010; Rayment 2005; Razzaghi 2012; Roberts 2003; Sakakura 2003; Shehata 2009; Shen 2007; Slichter 2004; Slichter 2007; Slichter 2012; Sosa 2003; Strauss 2004; Strauss 2005; Tinmouth 2003; Wandt 2010; Wang 2005; Woodard 2002; Zeller 2014).

• Twenty‐six studies were not RCTs (Aderka 1986; Callow 2002; Cameron 2007; Chaoui 2005; Chaurasia 2012; Decaudin 2004; Eder 2007; Elting 2002; Elting 2003; Friedmann 2002; Gil‐Fernandez 1996; Gmur 1991; Greeno 2007; Hardan 1994; Lawrence 2001; Navarro 1998; Nevo 2007; Norol 1998; Paananen 2009; Sagmeister 1999; Verma 2008; Wandt 1998; Wandt 2005; Wandt 2006; Weigand 2009; Zahur 2002).

• Forty‐four citations were secondary citations of excluded studies (cited as secondary references for the relevant excluded studies).

• In three studies fewer than 80% of the participants were haematological patients, and no data were available on the haematological subgroup (Goodnough 2001; Klumpp 1999; Lu 2011). We had included Klumpp 1999 in the original review, Stanworth 2004, but have now excluded it from the review because fewer than 80% of the participants were haematological patients, and no data were available on the haematological subgroup.

Risk of bias in included studies

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

2.

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

3.

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

All seven studies had some threats to validity (Akay 2015; Heddle 2009; Roy 1973; Sensebe 2004; Slichter 2010; Steffens 2002; Tinmouth 2004). The one study published in the 1970s had significant threats to validity; the majority of these were due to a lack of detail provided on the specific criteria and were thus judged as 'unclear' using the Cochrane 'Risk of bias' tool.

Allocation

Sequence generation

Three of the studies described adequate methods of sequence generation with computer‐generated block design (Heddle 2009; Slichter 2010; Tinmouth 2004). The other four studies were insufficiently reported for an adequate assessment to be made (Akay 2015; Roy 1973; Sensebe 2004; Steffens 2002).

Allocation concealment

Two of the studies described adequate allocation concealment (Heddle 2009; Tinmouth 2004). Heddle 2009 used a secure web‐based randomisation system, and Tinmouth 2004 used a sealed envelope system administered by blood bank staff. The other five studies were insufficiently reported for an adequate assessment to be made (Akay 2015; Roy 1973; Sensebe 2004; Slichter 2010; Steffens 2002).

Blinding

In two of the seven studies (Sensebe 2004; Tinmouth 2004), the medical staff were not blinded to the intervention. A further three studies could not be assessed for blinding of medical staff due to lack of information (Akay 2015; Roy 1973; Steffens 2002). The final two studies were designed as blinded studies, but the authors of both studies led us to believe that blinding was inadequate (Heddle 2009; Slichter 2010). In Heddle 2009, this was due to unbalanced early withdrawal of participants from the study by physicians (seven participants were withdrawn early from the study: one in the standard‐dose arm and six in the low‐dose arm). In Slichter 2010, it was noted that differences in the volume of platelets transfused led to loss of blinding.

Three studies were designed so that the bleeding assessors were blinded to the intervention (Heddle 2009; Roy 1973; Slichter 2010). Three studies provided insufficient information to determine whether bleeding assessors were blinded to the intervention (Akay 2015; Sensebe 2004; Steffens 2002). In one study (Tinmouth 2004), the bleeding assessor was unblinded to the outcome measure.

In four of the seven studies (Heddle 2009; Roy 1973; Slichter 2010; Tinmouth 2004), the final allocation of bleeding grade was performed by individuals blinded to the intervention (Heddle 2009; Roy 1973; Tinmouth 2004), or by the use of a computer algorithm (Slichter 2010). Akay 2015, Sensebe 2004 and Steffens 2002 provided insufficient information to determine whether individuals who graded bleeding were blinded to the intervention.

Incomplete outcome data

Two of the studies were at high risk of bias due to an imbalance in the amount of missing data between the arms of the study (Heddle 2009; Slichter 2010). In Slichter 2010, complete data were available on 71%, 82%, and 83% of platelet transfusions in the low‐dose, standard‐dose, and high‐dose arms of the study, respectively (this was a statistically significant difference). In Heddle 2009, more participants were withdrawn early from the study in the low‐dose arm.

Three of the studies were deemed as at low risk of bias due to incomplete outcome data (Roy 1973; Sensebe 2004; Tinmouth 2004), and two studies were not reported in enough detail for this to be assessed (Akay 2015; Steffens 2002).

Selective reporting

Only one of the seven studies was free of selective reporting (Slichter 2010). In three studies (Akay 2015; Sensebe 2004; Tinmouth 2004), we could not make an assessment due to a lack of information. Three studies were at risk of significant bias due to selective reporting (Heddle 2009; Roy 1973; Steffens 2002). In Heddle 2009, not all of the prespecified outcomes were reported (including platelet response; pre‐ and post‐transfusion bleeding grade in response to dose of therapeutic platelets transfused; cost analysis). In Roy 1973, a large amount of data had been collected, as demonstrated by the following sentence: "No correlation of the incidence of bleeding with sex, pre‐transfusion haematocrit, concomitant corticosteroid therapy or the use of anti‐neoplastic drugs was found". However, none of these results were reported. Steffens 2002 has only ever been reported as an abstract, although the abstract mentions that further outcomes (such as clinical efficacy and bleeding episodes) would be reported in more detail in the future this never occurred.

Other potential sources of bias

Protocol deviation

We considered three of the seven studies to be at a high risk of bias due to an imbalance in protocol deviations between the different arms of the studies (Heddle 2009; Slichter 2010; Tinmouth 2004). The other four studies were not reported in enough detail for an assessment to be made (Akay 2015; Roy 1973; Sensebe 2004; Steffens 2002).

In Heddle 2009, the platelet count that triggered a transfusion was higher in the low‐dose treatment group (35.9% of transfusions (158/440) given at a trigger of 16 x 10⁹/L or more) than in the standard‐dose group (24.7% of transfusions (66/267) given at a trigger of 16 x 10⁹/L or more). In Slichter 2010, a significantly smaller proportion of transfusions were within the assigned dose range when platelet counts were compared between low‐dose and standard‐dose groups (71% versus 80%) and between high‐dose and standard‐dose groups (70% versus 80%). In Tinmouth 2004, a total of 15 out of 164 transfusions contravened the protocol in the low‐dose arm, but only three out of 147 transfusions contravened the protocol in the standard‐dose arm.

Assessment and grading of bleeding

Six studies reported bleeding outcomes (Table 5). It was the primary outcome in three of these studies (Heddle 2009; Slichter 2010; Tinmouth 2004). These three studies all reported the method of assessing bleeding and the bleeding severity scale used. However, although in two of these three studies red blood cell usage was used to partially grade bleeding severity, neither study reported a definitive red cell transfusion policy, and both studies left the decision to transfuse up to local policies (Heddle 2009; Slichter 2010). 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 transfusions between studies could affect the results of any meta‐analysis.

2. Assessment and grading of bleeding within the included studies.

Study	Bleeding primary outcome of study	Method of bleeding assessment reported	Frequency of assessment of bleeding	Bleeding severity scale used	RBC usage part of bleeding severity assessment	RBC transfusion policy
Akay 2015	No	No	For 48 hours after first platelet transfusion	WHO 1979	No	Not reported
Heddle 2009	Yes	Yes	Daily	Adapted WHO	Yes	Local practice at each centre (unpublished)
Slichter 2010	Yes	Yes	Daily	Adapted WHO	Yes	Local practice at each centre
Tinmouth 2004	Yes	Yes	Daily	Adapted Rebulla	No	Not reported
Roy 1973	Not reported	Yes	For 24 hours after each platelet transfusion	Study specific	No	Not reported
Sensebe 2004	No	No	Daily	WHO 1979	No	Not reported

RBC: red blood cell
 WHO: World Health Organization

Other potential sources

Only two of the seven studies had further potential sources of bias (Roy 1973; Heddle 2009). Three of the studies were free of any other obvious sources of bias (Sensebe 2004; Slichter 2010; Tinmouth 2004), and two studies were reported in insufficient detail for an assessment to be made (Akay 2015; Steffens 2002).

In Roy 1973, there was a marked difference in population age groups between the two arms of the study; other baseline characteristics were not reported in sufficient detail for an assessment to be made. In Heddle 2009, discrepancies in the adjudication of bleeding grade occurred in 39% (433 out of 1150) of the bleeding days analysed, with most of these discrepancies occurring between the grade 1 and 2 classifications. However, agreement was eventually reached in most cases through consensus. Heddle 2009 was also stopped early due to a prespecified stopping guideline.

Effects of interventions

See: Table 1; Table 2; Table 3

Summary of findings for the main comparison. Prophylactic platelet transfusions with low‐dose schedule compared to prophylactic platelet transfusions with standard‐dose schedule for people with a haematological disorder.

Prophylactic platelet transfusions with a low‐dose schedule compared to prophylactic platelet transfusions with a standard‐dose schedule for prevention of haemorrhage after chemotherapy and stem cell transplantation
Patient or population: People with a haematological disorder Settings: After chemotherapy or a stem cell transplant Intervention: Prophylactic platelet transfusions with low‐dose schedule versus standard‐dose schedule
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Prophylactic platelet transfusions with standard‐dose schedule	Prophylactic platelet transfusions with low‐dose schedule
Number of participants with at least 1 clinically significant bleeding event up to 30 days from study entry	605 per 1000	629 per 1000 (575 to 684)	RR 1.04 (0.95 to 1.13)	1170 (4 studies)	⊕⊕⊕⊝ moderate1
Number of days on which bleeding occurred per participant up to 30 days from study entry	The mean number of days with clinically significant bleeding per participant was 0.17 days lower (0.51 lower to 0.17 higher) (fixed effect)			230 (2 studies)	⊕⊕⊝⊝ low1,2	We could not incorporate the largest study (840 participants) into the meta‐analysis (Slichter 2010); this also showed no difference in the number of days of bleeding between study arms (Table 6)
Number of participants with WHO grade 3 or 4 bleeding up to 30 days from study entry	91 per 1000	122 per 1000 (83 to 176)	RR 1.33 (0.91 to 1.92)	1059 (3 studies)	⊕⊕⊝⊝ low1,2
Time to first bleeding episode (days)	Not estimable	Not estimable	Not estimable	959 (2 studies)	See comment	The 2 studies reported the outcome in different formats, and the results could not be integrated into a meta‐analysis (Table 7). The largest study (840 participants) showed no difference between study arms (Slichter 2010)
Number of platelet transfusions per participant up to 30 days from study entry	Not estimable	Not estimable	Not estimable	1070 (3 studies)	See comment	The 3 studies reported the outcome in different formats, and results could not be integrated into a meta‐analysis (Table 8). 2 of the 3 studies (959 participants) showed that a low‐dose transfusion strategy led to significantly more transfusion episodes (Heddle 2009; Slichter 2010)
Mortality from all causes up to 30 days from study entry	9 per 1000	19 per 1000 (6 to 55)	RR 2.04 (0.70 to 5.93)	1070 (3 studies)	⊕⊕⊝⊝ low1,2
Quality of life ‐ not reported	Not estimable	Not estimable	Not estimable	‐	See comment	None of the studies reported quality of life
*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). CI: Confidence interval; RR: Risk ratio
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.

¹ The studies were at risk of bias. Sources of bias were due to lack of blinding, protocol deviation, and attrition bias. The quality of the evidence was downgraded by 1 due to risk of bias.
 ² The number of cases was very low, the quality of the evidence was downgraded by 1 due to imprecision.

Summary of findings 2. Prophylactic platelet transfusions with low‐dose schedule versus high‐dose schedule for preventing bleeding in people with haematological disorders after chemotherapy or stem cell transplantation.

Prophylactic platelet transfusion with low‐dose schedule versus high‐dose schedule for preventing bleeding in people with haematological disorders after chemotherapy or stem cell transplantation
Patient or population: People with a haematological disorder Settings: After chemotherapy or a stem cell transplant Intervention: Prophylactic platelet transfusions with a low‐dose schedule versus high‐dose schedule
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Prophylactic platelet transfusions with a high‐dose schedule	Prophylactic platelet transfusions with a low‐dose schedule
Number of participants with at least 1 clinically significant bleeding event up to 30 days from study entry	699 per 1000	713 per 1000 (650 to 776)	RR 1.02 (0.93 to 1.11)	849 (1 study)	⊕⊕⊕⊝ moderate1
Number of days on which bleeding occurred per participant up to 30 days from study entry	Not estimable	Not estimable	Not estimable	849 (1 study)	See comment	There was no significant difference between the study arms, according to the study authors (Table 6)
Number of participants with WHO grade 3 or 4 bleeding up to 30 days from study entry	100 per 1000	119 per 1000 (82 to 170)	RR 1.20 (0.82 to 1.77)	849 (1 study)	⊕⊕⊝⊝ low1,2
Time to first bleeding episode	Not estimable	Not estimable	Not estimable	849 (1 study)	See comment	There was no significant difference between the study arms, according to the study authors (Table 7)
Mortality from all causes up to 30 days from study entry	16 per 1000	22 per 1000 (8 to 57)	RR 1.33 (0.50 to 3.54)	849 (1 study)	⊕⊕⊝⊝ low1,2
Number of platelet transfusions per participant	Not estimable	Not estimable	Not estimable	849 (1 study)	See comment	There was a significant increase in the number of platelet transfusions between the study arms, according to the study authors (Table 8)
Quality of life ‐ not reported	Not estimable	Not estimable	Not estimable	‐	See comment	None of the studies reported quality of life
*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). CI: Confidence interval; RR: Risk ratio
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.

¹ The study was at risk of bias. Sources of bias were due to lack of blinding, protocol deviation, and attrition bias. The quality of the evidence was downgraded by 1 due to risk of bias.

² The number of cases was very low, the quality of the evidence was downgraded by 1 due to imprecision.

Summary of findings 3. Prophylactic platelet transfusions with high‐dose schedule versus standard‐dose schedule for preventing bleeding in people with haematological disorders after chemotherapy or stem cell transplantation.

Prophylactic platelet transfusion with high‐dose schedule versus standard‐dose schedule for preventing bleeding in participants with haematological disorders after chemotherapy or stem cell transplantation
Patient or population: People with a haematological disorder Settings: After chemotherapy or a stem cell transplant Intervention: Prophylactic platelet transfusions with a high‐dose schedule versus standard‐dose schedule
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Prophylactic platelet transfusions with standard‐dose schedule	Prophylactic platelet transfusions with a high‐dose schedule
Number of participants with at least 1 clinically significant bleeding event up to 30 days from study entry	624 per 1000	637 per 1000 (581 to 693)	RR 1.02 (0.93 to 1.11)	951 (2 studies)	⊕⊕⊕⊝ moderate1
Number of days on which bleeding occurred per participant up to 30 days from study entry	Not estimable	Not estimable	Not estimable	855 (1 study)	See comment	There was no significant difference between the study arms, according to the study authors (Table 6)
Number of participants with WHO grade 3 or 4 bleeding up to 30 days from study entry	90 per 1000	100 per 1000 (66 to 151)	RR 1.11 (0.73 to 1.68)	855 (1 study)	⊕⊕⊝⊝ low1,2
Time to first bleeding episode (days)	Not estimable	Not estimable	Not estimable	855 (1 study)	See comment	There was no significant difference between the study arms, according to the study authors (Table 7)
Number of platelet transfusions per participant up to 30 days from study entry	Not estimable	Not estimable	Not estimable	1005 (3 studies)	See comment	The studies reported the results in different formats, therefore the results could not be integrated (Table 8). The largest study (855 participants) showed no difference in the number of platelet transfusions between a standard‐ and high‐dose transfusion regimen (Slichter 2010)
Mortality from all causes up to 30 days from study entry	9 per 1000	16 per 1000 (5 to 55)	RR 1.71 (0.51 to 5.81)	855 (1 study)	⊕⊕⊝⊝ low1,2	The number of deaths was very low in both study arms
Quality of life ‐ not reported	Not estimable	Not estimable	Not estimable	‐	See comment	None of the studies reported quality of life
*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). CI: Confidence interval; RR: Risk ratio
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.

¹ The studies were at risk of bias. Sources of bias were due to lack of blinding, protocol deviation, and attrition bias. The quality of the evidence was downgraded by 1 due to risk of bias.

² The number of cases was very low, the quality of the evidence was downgraded by 1 due to imprecision.

In all the included studies, the study's own definition of clinically significant bleeding was used, unless otherwise stated. If the study did not explicitly define clinically significant bleeding, we assumed that WHO grade 2 or above bleeding was clinically significant bleeding, because this definition has been used by the majority of newer studies (Heddle 2009; Slichter 2010; Stanworth 2013).

Primary outcomes

Six of the seven studies reported bleeding as an outcome (Akay 2015; Heddle 2009; Roy 1973; Sensebe 2004; Slichter 2010; Tinmouth 2004). Four of these six studies assessed bleeding on a daily basis (Heddle 2009; Sensebe 2004; Slichter 2010; Tinmouth 2004); one study assessed bleeding for 48 hours after the first platelet transfusion (Akay 2015); and one study only assessed bleeding for 24 hours after each platelet transfusion (Roy 1973) (see Table 5).

Five studies compared a low‐dose versus standard‐dose platelet transfusion strategy (Akay 2015; Heddle 2009; Roy 1973; Slichter 2010; Tinmouth 2004); one study compared a low‐dose versus high‐dose platelet transfusion strategy (Slichter 2010); and three studies compared a standard‐dose versus high‐dose platelet transfusion strategy (Roy 1973; Sensebe 2004; Slichter 2010).

Bleeding outcomes were reported within 30 days from the start of the study for five of the six studies (Akay 2015; Heddle 2009; Sensebe 2004; Slichter 2010; Tinmouth 2004); in the fifth study it was unclear how long the study lasted (Roy 1973).

Number of participants with at least one bleeding episode (within 30 days from the start of the study)

This was reported for five of the seven studies (Akay 2015; Heddle 2009; Sensebe 2004; Slichter 2010; Tinmouth 2004).

Four studies compared a low‐dose versus standard‐dose platelet transfusion strategy (Akay 2015; Heddle 2009; Slichter 2010; Tinmouth 2004). A meta‐analysis of this data showed no difference in the number of participants who had clinically significant bleeding (risk ratio (RR) 1.04, 95% confidence interval (CI) 0.95 to 1.13) with relatively narrow 95% confidence interval (Analysis 1.1).

1.1. Analysis.

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 1 Number of participants with at least one clinically significant bleeding event ‐ low dose versus standard dose.

One study compared a low‐dose versus high‐dose platelet transfusion strategy (Slichter 2010), hence we carried out no meta‐analysis. The study showed no difference in the number of participants who had clinically significant bleeding (RR 1.02, 95% CI 0.93 to 1.11) ((study data shown in Analysis 1.2).

1.2. Analysis.

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 2 Number of participants with at least one clinically significant bleeding event ‐ low dose versus high dose.

Two studies compared a high‐dose versus standard‐dose platelet transfusion strategy (Sensebe 2004; Slichter 2010). A meta‐analysis of this data showed no difference in the number of participants who had clinically significant bleeding (RR 1.02, 95% CI 0.93 to 1.11) with relatively narrow 95% confidence interval (Analysis 1.3).

1.3. Analysis.

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 3 Number of participants with at least one clinically significant bleeding event ‐ high dose versus standard dose.

Total number of days on which bleeding occurred per participant (within 30 days from the start of the study)

Three of the studies reported on the number of days with a clinically significant bleeding event (Roy 1973; Heddle 2009; Slichter 2010, and a fourth study provided unpublished data (Tinmouth 2004). Only three of these four studies reported on the number of days on which bleeding occurred per patient (Heddle 2009; Slichter 2010; Tinmouth 2004) (Table 6).

3. Number of days with a clinically significant bleeding event/participant.

Study	Low dose		P value Low dose vs standard dose	Standard dose		P value Standard dose vs high dose	High dose
	Number of participants	Days		Number of participants	Days		Number of participants	Days
Heddle 2009	58	Mean 1.8 ± SD 3.23a	Not reported	61	Mean 1.2 ± SD 2.02a	NA	NA	NA
Slichter 2010	417	Median 1 IQR 0 to 4	0.9b	423	Median 1 IQR 0 to 4	0.91b	432	Median 1 IQR 0 to 4
Tinmouth 2004c	56	Mean 0.375 ± SD 0.93a	Not reported	55	Mean 0.65 ± SD 1.0a	NA	NA	NA

IQR: interquartile range
 NA: not applicable
 SD: standard deviation

^aunpublished data
 ^bP value is not statistically significant.
 ^cTo improve comparison with the other studies, significant bleeding in this analysis was the number of days with bleeding that required a therapeutic platelet transfusion or local intervention. This differs from the study's definition of significant bleeding.

Slichter 2010 reported this as the median number of days with WHO grade 2 or above bleeding per participant (Table 6); no significant difference was seen between the three arms of the study.

Authors of two studies provided unpublished data on the mean number of days with bleeding per participant (Heddle 2009;Tinmouth 2004) (Analysis 1.4). In Tinmouth 2004 we re‐classified clinically significant bleeding as the number of days with bleeding that required an intervention or a therapeutic platelet transfusion (rather than the study definition, so as to decrease the differences in how bleeding events were defined between studies). Despite this, there was still moderate heterogeneity (I² = 63%) when we attempted to combine the data (Analysis 1.4). The results of the fixed‐effect (mean difference (MD) ‐0.17, 95% CI ‐0.51 to 0.17) and random‐effects (MD 0.04, 95% CI ‐0.78 to 0.86) meta‐analyses were similar (Analysis 1.4; Analysis 1.5).

1.4. Analysis.

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 4 Number of days with clinically significant bleeding per participant low dose versus standard dose (fixed effect).

1.5. Analysis.

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 5 Number of days with clinically significant bleeding per participant low dose versus standard dose (random effects).

There were several possible reasons for the quantitative differences observed in this analysis between the studies and hence the heterogeneity observed. Firstly, Tinmouth 2004 included 24 participants who never received a platelet transfusion; these participants were specifically excluded from analysis of Heddle 2009. Secondly, Tinmouth 2004 randomised participants at initiation of chemotherapy, and the study was stopped when they had a clinically significant bleed, whereas in Heddle 2009 participants were randomised when they received their first prophylactic platelet transfusion, and they remained within the study until platelet count recovery or discharge from hospital. Thirdly, the majority of participants in Tinmouth 2004 were receiving an autologous stem cell transplant (77/111), whereas in Heddle 2009 the majority of participants had acute leukaemia (103/119).

Number of participants with at least one episode of severe or life‐threatening haemorrhage (within 30 days from the start of the study)

Three of the studies reported the number of participants with WHO grade 3 or 4 bleeding (Heddle 2009; Slichter 2010). We performed a meta‐analysis that compared low‐dose versus standard‐dose platelet transfusion strategies and saw no difference (RR 1.33, 95% CI 0.91 to 1.92) (Analysis 1.6).

1.6. Analysis.

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 6 Number of participants with WHO Grade 3 or 4 bleeding ‐ low dose versus standard dose.

In Slichter 2010 (a three‐arm trial), no significant difference was seen between low‐dose and high‐dose platelet transfusion strategies in the incidence of grade 3 and 4 bleeding (RR 1.20, 95% CI 0.82 to 1.77) ((study data shown in Analysis 1.7), or between high‐dose and standard‐dose platelet transfusion strategies in the incidence of grade 3 and 4 bleeding (RR 1.11, 95% CI 0.73 to 1.68) (study data shown in Analysis 1.8).

1.7. Analysis.

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 7 Number of participants with WHO Grade 3 or 4 bleeding ‐ low dose versus high dose.

1.8. Analysis.

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 8 Number of participants with WHO Grade 3 or 4 bleeding ‐ high dose versus standard dose.

Three of the studies reported the number of participants who could be classified as having grade 4 bleeding (Heddle 2009; Slichter 2010; Tinmouth 2004) (Analysis 1.9). We performed a meta‐analysis that compared low‐dose versus standard‐dose platelet transfusions and saw no significant difference (RR 1.87, 95% CI 0.86 to 4.08) (Analysis 1.9). In Slichter 2010, no significant difference was seen between low‐dose and high‐dose platelet transfusions in the incidence of grade 4 bleeding (RR 1.50, 95% CI 0.65 to 3.46) (study data shown in Analysis 1.10), or between high‐dose and standard‐dose platelet transfusions in the incidence of grade 4 bleeding (RR 1.10, 95% CI 0.43 to 2.83) (Analysis 1.11).

1.9. Analysis.

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 9 Number of participants with WHO Grade 4 bleeding ‐ low dose versus standard dose.

1.10. Analysis.

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 10 Number of participants with WHO Grade 4 bleeding ‐ low dose versus high dose.

1.11. Analysis.

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 11 Number of participants with WHO Grade 4 bleeding ‐ high dose versus standard dose.

One of the studies reported the number of participants with bleeding that required a red cell transfusion (Heddle 2009). There was no statistically significant difference between the two arms of the study (RR 0.86, 95% CI 0.25 to 3.0) (Analysis 1.12).

1.12. Analysis.

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 12 Number of participants with bleeding requiring a red cell transfusion.

One of the studies reported the number of participants with bleeding that caused cardiovascular compromise (Tinmouth 2004). There was no statistically significant difference between the two arms of the study (RR 2.95, 95% CI 0.12 to 70.82) ((study data shown in Analysis 1.13).

1.13. Analysis.

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 13 Number of participants with bleeding causing cardiovascular compromise.

Time to first bleeding episode from the start of the study

Two of the seven studies reported this outcome (Heddle 2009; Slichter 2010). We could not perform a meta‐analysis because the studies reported the data in different formats. In Heddle 2009, no significant difference was seen in the time it took for participants receiving low‐dose or standard‐dose platelets to develop bleeding of WHO grade 2 or above. In Slichter 2010, there was no significant difference in the time to first significant bleeding event (Table 7).

4. Time to first clinically significant bleeding event.

Study	Low dose		P value Low dose vs standard dose	Standard dose		P value Standard dose vs high dose	High dose
	Number of participants	Days		Number of participants	Days		Number of participants	Days
Heddle 2009	58	Mean 11.2 ± SD 9.18a	Not reported	61	Mean 9.7 ± SD 8.39a	NA	NA	NA
Slichter 2010	417	Median 7 IQR 3 to 18	0.85b	423	Median 7 IQR 3 to 19	0.66b	432	Median 8 IQR 3 to 19

IQR: interquartile range
 NA: not applicable
 SD: standard deviation

^aunpublished data
 ^bP value is not statistically significant.

Secondary outcomes

Mortality

All‐cause mortality within 30 and 90 days from the start of the study

No studies reported hazard ratios for all‐cause mortality. Data on all‐cause mortality within 30 days were available for four of the studies. In two of these studies, this was published data (Sensebe 2004; Slichter 2010); in the other two studies, this was unpublished data (Heddle 2009; Tinmouth 2004). In Sensebe 2004, three deaths occurred over both arms of the study, all in participants with acute leukaemia, but no further details were given. In the other three studies, there was no significant difference in the mortality rates between the low‐dose versus standard‐dose arms (RR 2.04, 95% CI 0.70 to 5.93) (Analysis 1.14). In Slichter 2010, there was no difference between the low‐dose and high‐dose arms of the study (RR 1.33, 95% CI 0.50 to 3.54) (Analysis 1.15), or between the high‐dose versus standard‐dose arms of the study (RR 1.71, 95% CI 0.51 to 5.81) (Analysis 1.16).

1.14. Analysis.

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 14 Mortality from all causes ‐ low dose vs. standard dose.

1.15. Analysis.

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 15 Mortality from all causes ‐ low dose vs. high dose.

1.16. Analysis.

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 16 Mortality from all causes ‐ high dose vs. standard dose.

No studies reported all‐cause mortality within 90 days.

Mortality secondary to bleeding within 30 and 90 days from the start of the study

No studies reported hazard ratios for mortality secondary to bleeding. Four of the six studies reported data on mortality secondary to bleeding within 30 days (Heddle 2009; Sensebe 2004; Slichter 2010; Tinmouth 2004). The mortality rate secondary to bleeding was very low. In all four studies, there was only one death attributable to bleeding (Slichter 2010); this was a participant in the high‐dose platelet transfusion arm who died secondary to a pulmonary haemorrhage (Analysis 1.17).

1.17. Analysis.

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 17 Mortality from bleeding.

No studies reported mortality secondary to bleeding within 90 days.

Mortality secondary to infection within 30 and 90 days from the start of the study

No studies reported hazard ratios for mortality secondary to infection. Only one study reported data on mortality secondary to infection within 30 days (Tinmouth 2004). No deaths occurred in either study arm.

No studies reported mortality secondary to infection within 90 days.

Number of platelet transfusions per participant and number of platelet components per participant within 30 days from the start of the study

Six of the seven studies reported on the number of platelet transfusions per participant (Table 8). The duration of the study was unclear for Roy 1973, and was more than 30 days.

5. Number of platelet transfusions and red cell transfusions.

Study	Intervention	Number of participants	Number of platelet transfusion episodes/participant	P value	Total platelet utilisation	P value	Number of red cell transfusions/participant	P value
Low‐dose versus standard‐dose platelets (within 30 days)
Heddle 2009	Low dose 0.8 to 1.7 x 1011/m2	58	Mean 9.5 ± SD 7.8	< 0.001	Number of donor exposures MD 4.1; 95% CI ‐4.3 to 12.4	0.335a	Mean 6.1 ± SD 4.19b	Not reported
	Standard dose 1.7 to 3.4 x 1011/m2	61	Mean 5.3 ± SD 3.2				Mean 5.23 ± SD 3.58b
Slichter 2010	Low dose 1.1 x 1011 platelets/m2 ± 25%	417	Median 5 IQR 3 to 9	< 0.001	Median 9.3 x 1011 IQR 4.9 to 17.9	0.002	Median 4 IQR 2 to 8	0.62a
	Standard dose 2.2 x 1011 platelets/m2 ± 25%	423	Median 3 IQR 2 to 6		Median 11.3 x 1011 IQR 7.0 to 22.8		Median 4 IQR 2 to 8
Tinmouth 2004	Low dose 1.1 to 1.4 x 1011/m2	56	Median 1 IQR 0.75 to 5	Not reported	Median 3 WBD units Range 0 to 49	Bayesian analysis 89% probability low‐dose platelets reduce total number of units transfused per participant	Median 4.5 Range 0 to 16	Not reported
	Standard dose 1.9 to 2.5 x 1011/m2	55	Median 1 IQR 1 to 4		Median 5 WBD units Range 0 to 110		Median 4 Range 0 to 12
Low‐dose versus standard‐dose platelets (duration of study unclear)
Roy 1973 (Aged 0 to 9)	Low dose 1.1 to 1.3 x 1011/m2	17	Mean 4.8	Not reported	Not reported	Not reported	Not reported	Not reported
	Standard dose 2.0 to 2.9 x 1011/m2	28	Mean 5.5
Low‐dose versus high‐dose platelets (within 30 days)
Slichter 2010	Low dose 1.1 x 1011 platelets/m2 ± 25%	417	Median 5 IQR 3 to 9	< 0.001	Median 9.3 x 1011 IQR 4.9 to 17.9	< 0.001	Median 4 IQR 2 to 8	0.90a
	High dose 4.4 x 1011 platelets/m2 ± 25%	432	Median 3 IQR 2 to 6		Median 19.6 x 1011 IQR 10.6 to 37.4		Median 4 IQR 2 to 8
Standard‐dose versus high‐dose platelets (within 30 days)
Sensebe 2004	Standard dose 1.9 x 1011/m2	48	Median 3 Range 1 to 12	0.037	Mean 14.9 x 1011	0.156a	Not reported	Not reported
	High dose 3.9 x 1011/m2	48	Median 2 Range 1 to 13		Mean 18.5 x 1011
Slichter 2010	Standard dose 2.2 x 1011 platelets/m2 ± 25%	423	Median 3 IQR 2 to 6	0.09a	Median 11.3 x 1011 IQR 7.0 to 22.8	< 0.001	Median 4 IQR 2 to 8	0.70a
	High dose 4.4 x 1011 platelets/m2 ± 25%	432	Median 3 IQR 2 to 6		Median 19.6 x 1011 IQR 10.6 to 37.4		Median 4 IQR 2 to 8
Steffens 2002	Standard dose (Single apheresis unit)	28	Median 6 Range 1 to 14	Not reported	Mean 6.0 units Range 1 to 14	Not reported	Not reported	Not reported
	High dose (Triple apheresis unit)	26	Median 3.23 Range 1 to 8		Mean 9.7 units Range 3 to 23
Standard‐dose versus high‐dose platelets (duration of study unclear)
Roy 1973 (Aged 10 to 18)	Standard dose 1.7 x 1011/m2	15	Mean 4	Not reported	Not reported	Not reported	Not reported	Not reported
	High dose 3.1 to 3.7 x 1011/m2	2	Mean 7

CI: confidence interval
 IQR: interquartile range
 MD: mean difference
 SD: standard deviation
 WBD: whole blood derived

^aP value is not statistically significant.
 ^bunpublished data

We could not perform a meta‐analysis because the studies reported data in different ways (Table 8). Two of the three studies comparing a low‐dose versus standard‐dose platelet transfusion showed a significantly smaller number of platelet transfusion episodes in the standard‐dose arm (Heddle 2009; Slichter 2010). Only two of the four studies comparing a high‐dose versus standard‐dose platelet transfusion reported P values (Sensebe 2004; Slichter 2010). Sensebe 2004 showed a significant difference in the number of platelet transfusion episodes, whereas Slichter 2010 did not. Overall, it appears that higher platelet doses led to fewer platelet transfusion episodes.

Four of the seven studies reported on the number of platelet components per participant within 30 days; again, we could not perform a meta‐analysis because the studies reported the data in different ways (Table 8).

Two of the three studies comparing a low‐dose versus standard‐dose platelet transfusion strategy showed a significant reduction in the total amount of platelets used (Slichter 2010; Tinmouth 2004). Only two of the four studies comparing a high‐dose versus standard‐dose platelet transfusion reported P values (Sensebe 2004; Slichter 2010). Slichter 2010 showed a significant difference in the total platelet utilisation, whereas Sensebe 2004 did not. Overall, it appears that higher platelet doses led to a higher total platelet utilisation.

Number of red cell transfusions per participant and number of red cell units per participant within 30 days from the start of the study

Three of the seven studies reported on the number of red cell transfusions per participant (Heddle 2009; Slichter 2010; Tinmouth 2004) (Table 8). We could not perform a meta‐analysis because the studies reported the data in different ways. In Heddle 2009, the mean difference in red cell transfusions per thrombocytopenic day was reported and showed no significant difference between low‐dose versus standard‐dose platelet transfusions (Table 8). In Slichter 2010, no significant difference was seen between the various arms of the study in the number of red cell transfusions participants received (Table 8). In Tinmouth 2004, no formal statistical analysis was reported.

Platelet transfusion interval within 30 days from the start of the study

Five of the seven studies reported the platelet transfusion interval (Heddle 2009; Sensebe 2004; Slichter 2010; Steffens 2002; Tinmouth 2004) (Table 9). All of the studies that reported on statistical significance showed that there was a significantly shorter transfusion interval in the low‐dose arm compared to the standard‐dose arm (Table 9), and a significantly shorter transfusion interval in the standard‐dose arm compared to the high‐dose arm (Table 9).

6. Platelet transfusion interval.

Study	Intervention	Number of participants	Platelet transfusion interval/participant (days)	P value
Low‐dose versus standard‐dose platelets (within 30 days)
Heddle 2009	Low dose 0.8 to 1.7 x 1011/m2	58	Mean 1.8 SD 1.1	< 0.001
	Standard dose 1.7 to 3.4 x 1011/m2	61	Mean 2.8 SD 1.8
Slichter 2010	Low dose 1.1 x 1011 platelets/m2 ± 25%	417	Median 1.1 IQR 0.7 to 2.1	< 0.001
	Standard dose 2.2 x 1011 platelets/m2 ± 25%	423	Median 1.9 IQR 0.9 to 3.1
Tinmouth 2004	Low dose 1.1 to 1.4 x 1011/m2	56	Median 2 Range 1 to 4.5	Not reported
	Standard dose 1.9 to 2.5 x 1011/m2	55	Median 3 Range 1 to 5
Low‐dose versus high‐dose platelets (within 30 days)
Slichter 2010	Low dose 1.1 x 1011 platelets/m2 ± 25%	417	Median 1.1 IQR 0.7 to 2.1	< 0.001
	High dose 4.4 x 1011 platelets/m2 ± 25%	432	Median 2.9 IQR 1.2 to 4.7
High‐dose versus standard‐dose platelets (within 30 days)
Sensebe 2004	Standard dose 1.9 x 1011/m2	48	Median time 2.6 95% CI 1.9 to 2.7	0.001
	High dose 3.9 x 1011/m2	48	Median time 4.0 95% CI 3.5 to 4.7
Slichter 2010	Standard dose 2.2 x 1011 platelets/m2 ± 25%	423	Median 1.9 IQR 0.9 to 3.1	< 0.001
	High dose 4.4 x 1011 platelets/m2 ± 25%	432	Median 2.9 IQR 1.2 to 4.7
Steffens 2002	Standard dose (Single apheresis unit)	28	3.1 days	Not reported
	High dose (Triple apheresis unit)	26	4.9 days

CI: confidence interval
 IQR: interquartile range

SD: standard deviation

Proportion of patients requiring additional interventions to stop bleeding (surgical; medical, e.g. tranexamic acid; other blood products, e.g. fresh frozen plasma, cryoprecipitate) within 30 days from the start of the study

None of the seven studies reported additional interventions to stop bleeding.

Overall survival within 30, 90, and 180 days from the start of the study

None of the seven studies reported overall survival rates.

Proportion of participants achieving complete remission within 30 and 90 days from the start of the study

None of the seven studies reported complete remission rates.

Total time in hospital within 30 days from the start of the study

None of the seven studies reported the length of time that the participants were in hospital.

Adverse effects of treatments within 30 days from the start of the study

Transfusion reactions

Only Slichter 2010 reported on transfusion reactions secondary to platelet transfusions (study data shown in Analysis 1.18), and documented a large number of events that occurred during or within four hours of a platelet transfusion. Wheezing was the only adverse event that occurred more frequently in the high‐dose arm compared to the standard‐dose arm (RR 6.85, 95% CI 1.57 to 29.98). However, there was no significant difference in the frequency of wheezing when the low‐dose arm was compared with the high‐dose arm (RR 0.52, 95% CI 0.21 to 1.27), therefore it is possible that this is a type I error (i.e. a false positive). The study authors have now published an analysis based on a proportion of transfusions in which there was no missing data (5034 platelet transfusions to 1102 participants from a total of 8158 platelet transfusions to 1231 participants) (Slichter 2010). In a multivariate analysis taking into account platelet source, platelet storage duration, ABO matching, sex of recipient, number of previous transfusions, type of treatment, and age of participants, participants assigned to high‐dose platelet components were more likely to experience any transfusion‐related adverse event than participants assigned to standard‐dose or low‐dose component groups (odds ratio for high‐dose versus standard‐dose, 1.50, 95% CI 1.10 to 2.05; three‐group comparison P = 0.02).

1.18. Analysis.

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 18 Number of participants with platelet transfusion reactions.

Thromboembolic disease

Only one study reported on thromboembolic disease (Slichter 2010), documenting three episodes of venous thromboembolism in the low‐dose platelet transfusion arm and none in the standard‐dose or high‐dose platelet transfusion arms. There was no significant difference between the arms of the study in the frequency of thromboembolic disease (study data shown in Analysis 1.19). Slichter 2010 also reported veno‐occlusive disease of the liver, with six cases in the low‐dose arm, five cases in the standard‐dose arm, and two cases in the high‐dose arm. There was no significant difference in the frequency of veno‐occlusive disease between the low‐dose and standard‐dose arms of the study, or between the standard‐dose and high‐dose arms of the study.

1.19. Analysis.

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 19 Thromboembolic disease.

Human leukocyte antigen (HLA) antibodies/platelet refractoriness

None of the seven studies reported on the development of HLA antibodies or platelet refractoriness.

Quality of life (as defined by the individual studies)

None of the seven studies reported quality of life.

Prespecified subgroup analyses

Presence of fever

None of the studies commented on an association between fever and bleeding risk.

Underlying disease

One study commented on disease subgroup and bleeding risk (Tinmouth 2004).

Number of participants with at least one clinically significant bleeding episode (within 30 days from the start of the study)

In Tinmouth 2004, eight out of 34 participants with acute leukaemia had significant bleeding, whereas only two out of 77 participants receiving an autologous transplant (myeloma, non‐Hodgkin's lymphoma, and Hodgkin's lymphoma) had significant bleeding (both of these participants bled when the platelet counts were greater than 100 x 10⁹/L).

Type of treatment

Two of the studies commented on treatment subgroup and bleeding risk (Slichter 2010; Tinmouth 2004).

Number of participants with at least one clinically significant bleeding episode (within 30 days from the start of the study)

In Tinmouth 2004, eight out of 34 participants receiving chemotherapy had significant bleeding, whereas only two out of 77 participants receiving an autologous transplant had significant bleeding (both of these participants bled when the platelet counts were greater than 100 x 10⁹/L). In Slichter 2010, bleeding of WHO grade 2 or greater occurred in 79% of recipients of allogeneic stem cell transplants (413 participants), 73% of participants with haematological cancers receiving chemotherapy (228 participants), and 57% of participants undergoing autologous or syngeneic stem cell transplantation (245 participants).

Only Tinmouth 2004 reported the number of participants who bled for each treatment category for each treatment arm (Analysis 1.20).

1.20. Analysis.

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 20 Number of participants with a significant bleeding episode ‐ autologous stem cell transplant versus intensive chemotherapy.

Total number of days on which bleeding occurred per participant (within 30 days from the start of the study)

In Tinmouth 2004, the total number of days on which bleeding occurred per participant was mean 1.5 days in the low‐dose arm versus 2.4 days in the standard‐dose arm for participants receiving chemotherapy. In participants receiving an autologous stem cell transplant, the total number of days on which bleeding occurred per participant was mean 0.2 days in the low‐dose arm versus 0.6 days in the standard‐dose arm. This included minor bleeding (unpublished data provided by the author).

Age of participant

One study included both children and adults and commented on bleeding risk and the age of the participant (Slichter 2010). This study analysed 1272 participants, including 200 paediatric participants, who had at least one study platelet transfusion. Similar numbers of patients were enrolled in each of the paediatric groups: 0 to 5 years (N = 66), 6 to 12 years (N = 69), and 13 to 18 years (N = 65), while the majority of participants were adults aged 19 years or older (N = 1072). The minimum age was 9 months, and the maximum age was 83 years.

Number of participants with at least one clinically significant bleeding episode (within 30 days from the start of the study)

In Slichter 2010, younger children were significantly more likely than adults to have at least one day of grade 2 or higher bleeding while on study (86%, 88%, 77%, and 67%, for ages 0 to 5, 6 to 12, 13 to 18, and 19+ years, respectively) (P < 0.001). The effect of age on the bleeding outcome was not affected by the assigned platelet dose, according to the study authors.

Total number of days on which bleeding occurred per participant (within 30 days from the start of the study)

In Slichter 2010, the median number of days with WHO grade 2 or higher bleeding was 3 (interquartile range (IQR) 1 to 6.5) in children aged 0 to 5; 3 (IQR 1 to 6) in children aged 6 to 12; and 3 (IQR 0 to 9.5) in children aged 13 to 18 versus 1 (IQR 0 to 4) in adults (P < 0.001). The effect of age on the bleeding outcome was not affected by the assigned platelet dose, according to the study authors.

Number of participants with at least one episode of severe or life‐threatening bleeding (within 30 days from the start of the study)

In Slichter 2010, the percentage of participants with WHO grade 3 or higher bleeding was 6%, 18%, 20%, and 10% for ages 0 to 5, 6 to 12, 13 to 18, and 19+ years, respectively (data derived from figure).

Time to first bleeding episode from the start of the study (within 30 days from the start of the study)

In Slichter 2010, the time to first episode of WHO grade 2 or higher bleeding (days) was median 3.0, 5.5, 6.0, and 11.0 for the four age groups, respectively; P < 0.001 in participants receiving a haematopoietic stem cell transplant. The effect of age on the bleeding outcome was not affected by the assigned platelet dose, according to the study authors.

Platelet transfusion threshold

Three of the six included studies used a threshold of 10 x 10⁹/L (Slichter 2010; Steffens 2002; Tinmouth 2004), and one of the studies used a threshold of 10 x 10⁹/L at the majority of study sites (Heddle 2009). One of the studies used a platelet transfusion threshold of 20 x 10⁹/L (Sensebe 2004), and one of the studies used a platelet count transfusion threshold of 25 x 10⁹/L (Roy 1973). Of the two studies that used a different platelet count threshold (Roy 1973; Sensebe 2004), only data from one of these studies, Sensebe 2004, were incorporated into any of the meta‐analyses. Exclusion of data from this study had no effect on the results of the meta‐analyses (Analysis 1.1; Analysis 1.17).

Discussion

The main objective of this review of prophylactic platelet transfusions was to answer the question what is the optimal prophylactic platelet dose to prevent thrombocytopenic bleeding in people with haematological disorders undergoing myelosuppressive chemotherapy or stem cell transplantation.

Summary of main results

Seven RCTs met our inclusion criteria for this review; all had data available. Five compared a low‐dose versus standard‐dose platelet transfusion, one compared a low‐dose versus high‐dose platelet transfusion, and four compared a standard‐dose versus a high‐dose platelet transfusion strategy.

These trials were carried out over a 42‐year time period and enrolled 1908 participants from fairly comparable patient populations. All of these studies contained separate data for each arm and could be critically appraised. One of these studies was conducted over an uncertain time period that included more than one course of chemotherapy; because of this none of the study data could be included into any of the analyses (Roy 1973).

The findings of the review led to the following main conclusions:

Overall, a low‐dose prophylactic platelet transfusion policy appears to be as effective as a standard‐dose or high‐dose prophylactic platelet transfusion policy with regard to rates of clinically significant bleeding. This included:

• Number of participants with a clinically significant bleeding event (WHO grade 2 or above)

• Number of days with clinically significant bleeding per participant

• Number of participants with severe or life‐threatening bleeding

• Time to first clinically significant bleeding episode

We saw this effect irrespective of the participant's age, underlying treatment, or diagnosis.

There was a clear increase in the number of platelet transfusion episodes in the low‐dose group; however there was a significant reduction in the total number of platelets used per participant in the low‐dose group. A high‐dose transfusion strategy led to a longer transfusion interval than the standard dose strategy; however, in the largest study (Slichter 2010), this did not lead to an increase in the number of transfusion episodes.

There is some evidence that a high‐dose transfusion strategy may lead to an increase in transfusion‐related adverse events compared to a standard‐ or low‐dose strategy.

There was no evidence of any difference in overall mortality between treatment arms.

Quality of life was not reported for any of the studies.

Overall completeness and applicability of evidence

The large number of participants within these studies provided strong evidence of no difference in the proportion of participants with bleeding between low‐dose, standard‐dose, and high‐dose platelet transfusions. This is reflected in the narrow confidence intervals around the point estimates.

Although Heddle 2009 and Slichter 2010 both used a WHO grading system for bleeding, the categorisation of bleeding varied between the studies. In Slichter 2010, less severe bleeding was categorised as grade 2. For example, in Heddle 2009 epistaxis that lasted for more than an hour or required packing was classed as grade 2 bleeding, whereas in Slichter 2010 if a participant had epistaxis that lasted for more than 30 minutes in any given 24‐hour period, it was classified as grade 2 bleeding. Also, in Heddle 2009, ecchymoses larger than 10 cm in size were classified as grade 2 bleeding, whereas in Slichter 2010 purpura greater than 2.54 cm (1 inch) in diameter were classified as grade 2 bleeding.

We only included data from Akay 2015 in the number of participants with bleeding; however, no participants in either of the study arms had bleeding that was greater than WHO grade 1 within 48 hours of the first platelet transfusion.

We did not include data from Roy 1973 within any of the analyses because the time frame over which data were reported was very unclear; the study was not conducted over one course of chemotherapy and appeared to be longer than the prespecified time frame of 30 days from the start of the study for all bleeding and platelet transfusion outcomes (the only outcomes that Roy 1973 reported). Also, assessment of bleeding was not performed on a daily basis during the study, but only for the 24 hours following each platelet transfusion.

Data from Steffens 2002 was limited because the study has only been published as an abstract, and the authors were unable to provide any additional information.

Five of the seven studies reported the number of platelets in the platelet component (Heddle 2009; Roy 1973; Sensebe 2004; Slichter 2010; Tinmouth 2004), and therefore we could approximate the doses used in these studies to the doses in Slichter 2010 using an average body surface area for adults (Sacco 2010) and children (Sharkey 2001). The only study that changed the dose categorisation using these estimates from the study's original definition of low dose, standard dose, or high dose was Roy 1973. However, we did not include Roy 1973 in any of this review's analyses.

Quality of the evidence

GRADE assessment

The GRADE quality of evidence was moderate due to a serious risk of bias for:

• Number of participants with at least one clinically significant bleeding event up to 30 days from study entry (low dose versus standard dose; low dose versus high dose; and high dose versus standard dose)

The GRADE quality of evidence was low due to a serious risk of imprecision and a serious risk of bias for:

• Number of days on which bleeding occurred per participant up to 30 days from study entry (low dose versus standard dose and high dose versus standard dose)

• Number of participants with WHO grade 3 or 4 bleeding up to 30 days from study entry (low dose versus standard dose; low dose versus high dose; and high dose versus standard dose)

• Mortality from all causes up to 30 days from study entry (low dose versus standard dose; low dose versus high dose; and high dose versus standard dose)

We did not downgrade the quality of evidence due to a serious risk of heterogeneity because:

• Participants within the studies were from similar patient groups.

• This review assessed all platelet doses within the review against the low dose, standard dose, and high dose defined in this review and based on the doses within the Slichter 2010 study; we have reported these adjusted doses in Table 4.

• Two studies used a different platelet count threshold to the other studies (Roy 1973; Sensebe 2004). However, we only incorporated data from Sensebe 2004 into any of the meta‐analyses. Exclusion of data from this study had no effect on the results of the meta‐analyses (Analysis 1.1; Analysis 1.17).

Risk of bias assessment

The ability to assess the quality of the evidence due to risk of bias was limited due to most of the studies not reporting study methodology in adequate detail. For example, only two of the seven studies reported allocation concealment as adequate (Heddle 2009; Tinmouth 2004), and and only three of the seven studies reported sequence generation as adequate (Heddle 2009; Slichter 2010; Tinmouth 2004).

Two studies that reported adequate blinding of the bleeding assessor documented compromise to the blinding process of participants and clinicians due to the different volumes of platelets to be transfused (Heddle 2009; Slichter 2010). Therefore, none of the studies reported adequate blinding of participants or clinicians.

Two studies were at high risk of bias due to an imbalance in the amount of missing data between the arms of the study (Heddle 2009; Slichter 2010).

We considered three of the seven studies as at high risk of bias due to an imbalance in protocol deviations between the different arms of the studies (Heddle 2009; Slichter 2010; Tinmouth 2004).

Potential biases in the review process

There were no obvious biases within the review process. We conducted a wide search, carefully assessed the relevance of each paper identified, and placed no restrictions on the language in which the paper was originally published. We included studies that had not been published or had only been published as an abstract and were not expected to be published in full. In this review, one study fulfilled this criterion (Steffens 2002).

We did not perform a formal assessment of potential publication bias (small‐trial bias), because we included only seven trials within this review.

Agreements and disagreements with other studies or reviews

One platelet transfusion review has recently been published in this area (Kumar 2014).

Kumar 2014 performed a systematic review of the use of platelet transfusions in common clinical settings, including the comparison of different platelet transfusion doses. Their review identified five studies with "analysable data" (Heddle 2009; Roy 1973; Sensebe 2004; Slichter 2010; Tinmouth 2004).

Our review agreed with the Kumar 2014 review, both reviews found that there was no difference in the risk of a significant bleeding event between a low‐dose and standard‐dose and high‐dose and standard‐dose platelet transfusion policy. Nor was any difference found in all‐cause mortality or mortality due to bleeding. Our review agreed with the Kumar review in finding that participants in the low‐dose platelet transfusion group underwent a greater number of platelet transfusion episodes than participants in the standard‐dose group, however overall platelet usage was lower.

Our review is more comprehensive than the Kumar 2014 review. We identified a study not previously reviewed (Akay 2015), as well as including study data from a study only published as an abstract (Steffens 2002). We included outcomes not assessed within the Kumar 2014 review. These included: time to first bleeding episode; total number of days on which bleeding occurred per participant; number of participants with severe or life‐threatening bleeding; number of days with clinically significant bleeding; overall survival; proportion of participants achieving complete remission; time in hospital; number of platelet transfusions and platelet components; number of red cell transfusions and red cell components; adverse effects of treatments (for example transfusion reactions, thromboembolism, transfusion‐transmitted infection, development of platelet antibodies or platelet refractoriness); and quality of life. The Kumar 2014 review authors performed meta‐analyses when the included studies had different durations of observation (for example one course of chemotherapy, in Heddle 2009, Sensebe 2004, Slichter 2010, and Tinmouth 2004, versus several courses of chemotherapy, in Roy 1973. Their review did not perform a detailed assessment of the risk of bias of the included studies, nor did it consider reasons for heterogeneity between the included studies. We performed a detailed quality assessment of all identified studies and highlighted their weaknesses and shortcomings.

Authors' conclusions

Implications for practice.

Most published clinical practice guidelines do not suggest an optimal platelet dose for transfusion. The findings from this updated review suggest that use of low‐dose prophylactic platelet transfusions for intensively treated inpatients should be considered. This would decrease the total platelet utilisation for inpatients. For outpatients, standard‐dose prophylactic platelet transfusions would decrease the frequency of day‐unit attendances for transfusions compared to a low‐dose regimen, which may lead to an improvement in quality of life. A high‐dose platelet transfusion regimen cannot be recommended routinely because there is no evidence of an effect on bleeding or the total number of platelet transfusions the patient receives, and a high‐dose strategy may increase the risk of transfusion‐related adverse events.

Implications for research.

Assessment of bleeding in future trials

One of the difficulties within this review was the variability between studies in assessing and grading bleeding. The WHO classification of bleeding, although widely used, has never been validated, and therefore the assumption that all WHO grade 2 bleeding is clinically significant has been brought into question. For future studies, an agreed international consensus on assessing and grading bleeding would greatly enhance the ability to compare platelet transfusion trials. This would need to be validated and to take into account the impact bleeding has upon the patient from both a medical perspective and with regard to their quality of life. The Biomedical Excellence for Safer Transfusion (BEST) Collaborative is currently developing a standardised bleeding assessment form.

It is acknowledged that blinding in platelet transfusion trials is difficult. However, whenever possible, the bleeding assessor should be blinded to the intervention.

What's new

Date	Event	Description
23 July 2015	New search has been performed	New search, and new citation (Akay 2015).
6 March 2014	New citation required but conclusions have not changed	The previous review (Estcourt 2012a) has now been split into four separate reviews. Protocols have been published for these four separate reviews (Estcourt 2014a; Estcourt 2014b; Estcourt 2014c; Estcourt 2014d). Two new outcomes have been added to the protocol (platelet transfusion interval, quality of life) (Estcourt 2014a). The primary and secondary outcomes have been reported over time frames prespecified within the protocol (Estcourt 2014a). The platelet doses within each study in the review have been compared to the doses used in Slichter 2010.

Appendices

Appendix 1. CENTRAL (Cochrane Library) 2015 search strategy

#1 MeSH descriptor: [Blood Platelets] explode all trees
 #2 (platelet* or thrombocyte*):ti
 #3 #1 or #2
 #4 MeSH descriptor: [Blood Transfusion] explode all trees
 #5 transfus*:ti
 #6 #4 or #5
 #7 #3 and #6
 #8 MeSH descriptor: [Platelet Transfusion] explode all trees
 #9 MeSH descriptor: [Plateletpheresis] explode all trees
 #10 ((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))
 #11 thrombocytopheres* or plateletpheres*
 #12 ((platelet* or thrombocyte*) near/5 (protocol* or trigger* or threshold* or schedul* or dose* or dosing or usage or utilisation or utilization))
 #13 #7 or #8 or #9 or #10 or #11 or #12
 #1 MeSH descriptor: [Blood Platelets] explode all trees
 #2 (platelet* or thrombocyte*):ti
 #3 #1 or #2
 #4 MeSH descriptor: [Blood Transfusion] explode all trees
 #5 transfus*:ti
 #6 #4 or #5
 #7 #3 and #6
 #8 MeSH descriptor: [Platelet Transfusion] explode all trees
 #9 MeSH descriptor: [Plateletpheresis] explode all trees
 #10 ((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))
 #11 thrombocytopheres* or plateletpheres*
 #12 ((platelet* or thrombocyte*) near/5 (protocol* or trigger* or threshold* or schedul* or dose* or dosing or usage or utilisation or utilization))
 #13 #7 or #8 or #9 or #10 or #11 or #12
 #14 MeSH descriptor: [Hematologic Neoplasms] explode all trees
 #15 MeSH descriptor: [Hematologic Diseases] this term only
 #16 MeSH descriptor: [Leukemia] explode all trees
 #17 MeSH descriptor: [Lymphoma] explode all trees
 #18 MeSH descriptor: [Neoplasms, Plasma Cell] explode all trees
 #19 MeSH descriptor: [Anemia, Aplastic] explode all trees
 #20 MeSH descriptor: [Bone Marrow Diseases] explode all trees
 #21 MeSH descriptor: [Thrombocytopenia] explode all trees
 #22 (thrombocytopeni* or thrombocytopaeni* or leukemi* or leukaemi* or lymphom* or aplast* anemi* or aplast* anaemi* or myelodysplas* or myeloproliferat* or myelom* or plasm??ytom*)
 #23 (lymphogranulomato* or histiocy* or granulom* or thrombocythemi* or thrombocythaemi* or polycythemi* or polycythaemi* or myelofibros* or AML or CLL or CML or Hodgkin* or nonhodgkin* or reticulosis or reticulosarcom*)
 #24 (burkitt* next (lymph* or tumo?r)) or lymphosarcom* or brill‐symmer* or sezary
 #25 ((haematolog* or hematolog* or blood or red cell* or white cell* or lymph* or marrow or platelet*) near/3 (malignan* or oncolog* or cancer* or neoplasm* or carcinoma*))
 #26 MeSH descriptor: [Antineoplastic Agents] explode all trees
 #27 MeSH descriptor: [Remission Induction] explode all trees
 #28 MeSH descriptor: [Antineoplastic Protocols] explode all trees
 #29 MeSH descriptor: [Stem Cell Transplantation] explode all trees
 #30 MeSH descriptor: [Bone Marrow Transplantation] this term only
 #31 MeSH descriptor: [Radiotherapy] explode all trees
 #32 MeSH descriptor: [Lymphatic Irradiation] this term only
 #33 (chemotherap* or antineoplast* or anti‐neoplast* or radiotherap* or radio‐therap* or chemoradiotherap* or chemo‐radiotherap* or stem cell* or progenitor cell* or (bone marrow near/2 (transplant* or graft* or engraft* or rescu*)))
 #34 ((haematolog* or hematolog* or hemato‐oncolog* or haemato‐oncolog*) near/2 patients)
 #35 (ASCT or ABMT or PBPC or PBSCT or PSCT or BMT or SCT or HSCT)
 #36 (malignan* or oncolog* or cancer*):ti
 #37 #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36
 #38 #13 and #37

Appendix 2. MEDLINE (OvidSP) search strategy (Nov 2011‐2015)

1. BLOOD PLATELETS/
 2. (platelet* or thrombocyte*).ti.
 3. 1 or 2
 4. exp BLOOD TRANSFUSION/
 5. transfus*.ti.
 6. 4 or 5
 7. 3 and 6
 8. PLATELET TRANSFUSION/
 9. PLATELETPHERESIS/
 10. ((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.
 11. (thrombocytopheres* or plateletpheres*).tw.
 12. ((platelet* or thrombocyte*) adj5 (protocol* or trigger* or threshold* or schedul* or dose* or dosing or usage or utili?ation)).tw.
 13. or/7‐12
 14. exp Hematologic Neoplasms/ or Hematologic Diseases/
 15. exp Leukemia/ or exp Lymphoma/
 16. exp Neoplasms, Plasma Cell/
 17. exp Anemia, Aplastic/
 18. exp Bone Marrow Diseases/
 19. exp Thrombocytopenia/
 20. (thrombocytopeni* or thrombocytopaeni* or leukemi* or leukaemi* or lymphom* or aplast* anemi* or aplast* anaemi* or myelodysplas* or myeloproliferat* or myelom* or plasm??ytom*).tw,kf,ot.
 21. (lymphogranulomato* or histiocy* or granulom* or thrombocythemi* or thrombocythaemi* or polycythemi* or polycythaemi* or myelofibros* or AML or CLL or CML or Hodgkin* or nonhodgkin* or reticulosis or reticulosarcom*).tw,kf,ot.
 22. (burkitt* adj (lymph* or tumo?r)) or lymphosarcom* or brill‐symmer* or sezary).tw,kf,ot.
 23. ((haematolog* or hematolog* or blood or red cell* or white cell* or lymph* or marrow or platelet*) adj3 (malignan* or oncolog* or cancer* or neoplasm* or carcinoma*)).tw,kf,ot
 24. exp Antineoplastic Agents/ or exp Remission Induction/ or exp Antineoplastic Protocols/
 25. exp Stem Cell Transplantation/ or Bone Marrow Transplantation/ or exp Radiotherapy/ or Lymphatic Irradiation/
 26. (chemotherap* or antineoplast* or anti‐neoplast* or radiotherap* or radio‐therap* or chemoradiotherap* or chemo‐radiotherap* or stem cell* or progenitor cell* or (bone marrow adj2 (transplant* or graft* or engraft* or rescu*))).tw,kf,ot.
 27. ((haematolog* or hematolog* or haemato‐oncolog* or hemato‐oncolog*) adj2 patients).tw,kf,ot.
 28. (ASCT or ABMT or PBPC or PBSCT or PSCT or BMT or SCT or HSCT).tw,kf,ot.
 29. (malignan* or oncolog* or cancer*).ti.
 30. or/14‐29
 31. 13 and 30
 32. randomized controlled trial.pt.
 33. controlled clinical trial.pt.
 34. randomi*.tw.
 35. placebo.ab.
 36. clinical trials as topic.sh.
 37. randomly.ab.
 38. groups.ab.
 39. trial.ti.
 40. or/32‐39
 41. exp animals/ not humans/
 42. 40 not 41
 43. 31 and 42

Appendix 3. PubMed search strategy (epublications only)

#1 ((platelet* OR thrombocyte*) AND (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 OR protocol* OR trigger* OR threshold* OR schedul* OR dose OR doses OR dosing OR usage OR utilisation OR utilization))
 #2 thrombocytopheres* OR plateletpheres*
 #3 #1 OR #2
 #4 (thrombocytop* OR leukemi* OR leukaemi* OR lymphoma* OR aplastic anemia OR aplastic anaemia OR myelodysplas* OR myeloproliferat* OR multiple myeloma OR plasma cell myeloma OR plasmacytoma OR thrombocythemi* OR thrombocythaemi* OR polycythemi* OR polycythaemi* OR myelofibros* OR hodgkin* OR nonhodgkin*)
 #5 ((haematolog* OR hematolog* OR blood OR red cell* OR white cell* OR lymphom* OR marrow OR platelet*) AND (malignan* OR oncolog* OR cancer OR cancers OR neoplasm*))
 #6 #4 OR #5
 #7 #3 AND #6
 #8 (random* OR blind* OR control group* OR placebo OR controlled trial OR controlled study OR trials OR systematic review OR meta‐analysis OR metaanalysis OR literature OR medline OR cochrane OR embase) AND ((publisher[sb] OR inprocess[sb]) NOT pubstatusnihms)
 #9 #7 AND #8

Appendix 4. Embase (OvidSP) search strategy (Nov 2011‐2015)

1. Thrombocyte/
 2. (platelet* or thrombocyte*).ti.
 3. 1 or 2
 4. Blood Transfusion/
 5. transfus*.ti.
 6. 4 or 5
 7. 3 and 6
 8. Thrombocyte Transfusion/
 9. Thrombocytopheresis/
 10. ((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.
 11. (thrombocytopheres* or plateletpheres*).tw.
 12. ((platelet* or thrombocyte*) adj5 (protocol* or trigger* or threshold* or schedul* or dose* or dosing or usage or utili?ation)).tw.
 13. or/7‐12
 14. Hematologic Malignancy/
 15. Lymphoma/
 16. NonHodgkin Lymphoma/ or Hodgkin Disease/
 17. Plasmacytoma/
 18. exp Myeloproliferative Disorder/
 19. exp Aplastic Anemia/
 20. exp Thrombocytopenia/
 21. (thrombocytopeni* or thrombocytopaeni* or leukemi* or leukaemi* or lymphom* or aplast* anemi* or aplast* anaemi* or myelodysplas* or myeloproliferat* or myelom* or plasm??ytom*).tw,kf,ot.
 22. (lymphogranulomato* or histiocy* or granulom* or thrombocythemi* or thrombocythaemi* or polycythemi* or polycythaemi* or myelofibros* or AML or CLL or CML or Hodgkin* or nonhodgkin* or reticulosis or reticulosarcom*).tw,kf,ot.23. ((burkitt* adj (lymph* or tumo?r)) or lymphosarcom* or brill‐symmer* or sezary).tw,kf,ot.
 24. ((haematolog* or hematolog* or blood or red cell* or white cell* or lymph* or marrow or platelet*) adj3 (malignan* or oncolog* or cancer* or neoplasm*)).tw,kf,ot.
 25. exp Chemotherapy/
 26. exp Stem Cell Transplantation/
 27. exp Bone Marrow Transplantation/
 28. exp Radiotherapy/
 29. (chemotherap* or antineoplast* or anti‐neoplast* or radiotherap* or radio‐therap* or chemoradiotherap* or chemo‐radiotherap* or stem cell* or progenitor cell* or (bone marrow adj2 (transplant* or graft* or engraft* or rescu*))).tw,kf,ot.
 30. ((haematolog* or hematolog* or haemato‐oncolog* or hemato‐oncolog*) adj2 patients).tw,kf,ot.
 31. (ASCT or ABMT or PBPC or PBSCT or PSCT or BMT or SCT or HSCT).tw,kf,ot.
 32. (malignan* or oncolog* or cancer*).ti.
 33. or/14‐32
 34. 13 and 33
 35. Randomized Controlled Trial/
 36. Randomization/
 37. Single Blind Procedure/
 38. Double Blind Procedure/
 39. Crossover Procedure/
 40. Placebo/
 41. exp Clinical Trial/
 42. Prospective Study/
 43. (randomi* or double‐blind* or single‐blind* or RCT*).tw.
 44. (random* adj2 (allocat* or assign* or divid* or receiv*)).tw.
 45. (crossover* or cross over* or cross‐over* or placebo*).tw.
 46. ((treble or triple) adj blind*).tw.
 47. or/35‐46
 48. Case Study/
 49. case report*.tw.
 50. (note or editorial).pt.
 51. or/48‐50
 52. 47 not 51
 53. (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.
 54. 52 not 53
 55. 34 and 54
 56. limit 55 to embase

Appendix 5. CINAHL (EBSCOhost) search strategy (Nov 2011‐2015)

S1 (MH "Blood Platelets")
 S2 TI (platelet* or thrombocyte*)
 S3 S1 OR S2
 S4 (MH "Blood Transfusion+")
 S5 TI transfus*
 S6 S4 or S5
 S7 S3 and S6
 S8 (MH "Platelet Transfusion")
 S9 (MH Plateletpheresis)
 S10 ((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))
 S11 (thrombocytopheres* or plateletpheres*)
 S12 ((platelet* or thrombocyte*) N5 (protocol* or trigger* or threshold* or schedul* or dose* or dosing or usage or utili?ation))
 S13 S7 OR S8 OR S9 OR S10 OR S11 OR S12
 S14 (MH "Hematologic Neoplasms+")
 S15 (MH "Hematologic Diseases")
 S16 (MH Leukemia+)
 S17 (MH Lymphoma+)
 S18 (MH "Plasmacytoma+")
 S19 (MH "Anemia, Aplastic+")
 S20 (MH "Bone Marrow Diseases+")
 S21 (MH Thrombocytopenia+)
 S22 (thrombocytopeni* or thrombocytopaeni* or leukemi* or leukaemi* or lymphom* or aplast* anemi* or aplast* anaemi* or myelodysplas* or myeloproliferat* or myelom* or plasm??ytom*)
 S23 (lymphogranulomato* or histiocy* or granulom* or thrombocythemi* or thrombocythaemi* or polycythemi* or polycythaemi* or myelofibros* or AML or CLL or CML or Hodgkin* or nonhodgkin* or reticulosis or reticulosarcom*)
 S24 (burkitt* lymph* or burkitt* tumo?r or lymphosarcom* or brill‐symmer* or sezary)
 S25 ((haematolog* or hematolog* or blood or red cell* or white cell* or lymph* or marrow or platelet*) N3 (malignan* or oncolog* or cancer* or neoplasm* or carcinoma*))
 S26 ((haematolog* or hematolog* or blood or red cell* or white cell* or lymph* or marrow or platelet*) N3 (malignan* or oncolog* or cancer* or neoplasm* or carcinoma*))
 S27 (MH "Antineoplastic Agents+")
 S28 (MH "Hematopoietic Stem Cell Transplantation")
 S29 (MH "Bone Marrow Transplantation")
 S30 (MH Radiotherapy+)
 S31 (chemotherap* or antineoplast* or anti‐neoplast* or radiotherap* or radio‐therap* or chemoradiotherap* or chemo‐radiotherap* or stem cell* or progenitor cell* or (bone marrow N2 (transplant* or graft* or engraft* or rescu*)))
 S32 ((haematolog* or hematolog* or haemato‐oncolog* or hemato‐oncolog*) N2 patients)
 s33 (ASCT or ABMT or PBPC or PBSCT or PSCT or BMT or SCT or HSCT)
 S34 TI (malignan* or oncolog* or cancer*)
 S35 S14 OR S15 OR S16 OR S17 OR S18 OR S19 OR 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
 S36 S13 and S35
 S37 (MH CLINICAL TRIALS+)
 S38 PT Clinical Trial
 S39 TI ((controlled trial*) or (clinical trial*)) OR AB ((controlled trial*) or (clinical trial*))
 S40 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*))
 S41 TI randomi* OR AB randomi*
 S42 MH RANDOM ASSIGNMENT
 S43 TI ((phase three) or (phase III) or (phase three)) or AB ((phase three) or (phase III) or (phase three))
 S44 TI (random* N2 (assign* or allocat*)) ) OR ( AB (random* N2 (assign* or allocat*))
 S45 MH PLACEBOS
 S46 MH QUANTITATIVE STUDIES
 S47 TI placebo* OR AB placebo*
 S48 S37 OR S38 OR S39 OR S40 OR S41 OR S42 OR S43 OR S44 OR S45 OR S46 OR S47
 S49 S36 AND S48

Appendix 6. TRANSFUSION EVIDENCE LIBRARY search strategy (2015)

Clinical Specialty: Haematology and Oncology AND Subject Area: Blood Components/Platelets
 OR
 All fields: (haematology OR haematological OR hematology OR hematological OR malignancy OR malignancies OR leukemia OR leukaemia OR lymphoma OR hodgkin OR hodgkins OR nonhodgkin OR aplastic OR thrombocytopenia OR thrombocytopenic OR myeloma OR plasmacytoma OR myelodysplasia) AND title:(platelet OR platelets OR thrombocyte OR thrombocytes) OR keywords:(platelet transfusion)

Appendix 7. Web of Science (CPCI‐S) search strategy (2015)

Topic: (platelet*) AND Topic: (prophyla* OR transfus* OR products OR component* OR concentrate* OR apheres* OR pooled OR single donor OR random donor OR protocol* OR trigger* OR threshold*) AND Topic: (thrombocytop* OR leukemi* OR leukaemi* OR lymphoma* OR aplastic OR myelodysplas* OR myeloproliferat* OR myeloma OR plasmacytoma OR thrombocythemi* OR thrombocythaemi* OR polycythemi* OR polycythaemi* OR myelofibros* OR hodgkin* OR haematological OR hematological)) AND Topic: (systematic* OR random* OR blind* OR trial* OR control*)

Appendix 8. LILACS search strategy (2015)

((platelet* AND (prophyla* OR transfus* OR products OR component*  OR concentrate* OR apheres* OR pooled OR single donor OR random donor OR protocol* OR trigger* OR threshold*)) AND (thrombocytop* OR leukemi* OR leukaemi* OR lymphoma* OR aplastic OR myelodysplas* OR myeloproliferat* OR myeloma OR plasmacytoma OR thrombocythemi* OR thrombocythaemi* OR polycythemi* OR polycythaemi* OR myelofibros* OR hodgkin* OR haematological OR hematological)) AND db:("LILACS") AND type_of_study:("clinical_trials" OR "systematic_reviews")

Appendix 9. INDMED search strategy (2015)

(platelet OR platelets OR thrombocyte$ OR thrombocytopheres$ OR plateletpheres$) AND (thrombocytop$ OR leukemi$ OR leukaemi$ OR lymphoma$ OR aplastic OR myelodysplas$ OR myeloproliferat$ OR myeloma OR thrombocythemi$ OR thrombocythaemi$ OR polycyth$ OR myelofibros$ OR Hodgkin$ OR haematological OR hematological OR hematopoietic OR haematopoietic) AND (random$ OR blind$ OR trial$ OR control$)

Appendix 10. KoreaMed & PakMediNet search strategy (2015)

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

Appendix 11. ClinicalTrials.gov & ICTRP search strategy (2015)

Search Terms/Title: randomized OR randomised
 Conditions: hematological neoplasm OR hematological malignancies OR leukemia OR lymphoma OR thrombocytopenia OR multiple myeloma OR plasmacytoma OR aplastic anemia OR thrombocythemia OR polycythemia OR myelofibrosis OR hodgkins disease
 Intervention: platelets OR platelet transfusion

Appendix 12. ISRCTN & EU Clinical Trials Register search strategy (2015)

(hematological OR haematological OR leukemi* OR leukaemi* OR lymphoma OR thrombocytopeni* OR myeloma OR plasmacytoma OR aplastic OR thrombocythemia OR polycythemia OR myelofibrosis OR hodgkin*) AND platelet* transfus* AND random*

Appendix 13. Hong Kong Clinical Trials Register search strategy (2015)

Disease Group: Blood and blood‐forming organs
 Title: randomized OR randomised

Appendix 14. Previous searches: original (Jan 2002) & update (Nov 2011) search strategies

CENTRAL search strategy (Issue 4, 2011) 
 #1 MeSH descriptor Blood Platelets explode all trees
 #2 platelet* or thrombocyte*
 #3 (#1 OR #2)
 #4 MeSH descriptor Blood Transfusion explode all trees
 #5 transfus*
 #6 (#4 OR #5)
 #7 (#3 AND #6)
 #8 MeSH descriptor Platelet Transfusion explode all trees
 #9 (platelet* or thrombocyte*) NEAR/5 (transfus* or infus* or administ* or requir*)
 #10 (#7 OR #8 OR #9)
 #11 prophylactic* or prophylax* or prevent*
 #12 (#10 AND #11)

MEDLINE (Ovid) search strategy (Jan 2002‐Nov 2011) 
 1. BLOOD PLATELETS/
 2. (platelet* or thrombocyte*).tw.
 3. 1 or 2
 4. exp BLOOD TRANSFUSION/
 5. transfus*.tw.
 6. 4 or 5
 7. 3 and 6
 8. PLATELET TRANSFUSION/
 9. ((platelet* or thrombocyte*) adj5 (transfus* or infus* or administ* or requir*)).tw.
 10. or/7‐9
 11. (prophylactic* or prophylax* or prevent*).tw.
 12. 10 and 11

Embase (Ovid) search strategy (Jan 2002‐Nov 2011) 
 1. THROMBOCYTE/
 2. (platelet* or thrombocyte*).tw.
 3. 1 or 2
 4. exp BLOOD TRANSFUSION/
 5. transfus*.tw.
 6. 4 or 5
 7. 3 and 6
 8. THROMBOCYTE TRANSFUSION/
 9. ((platelet* or thrombocyte*) adj5 (transfus* or infus* or administ* or requir*)).tw.
 10. or/7‐9
 11. (prophylactic* or prophylax* or prevent*).tw.
 12. 10 and 11
 
 CINAHL (NHS Evidence) search strategy (Jan 2002‐Nov 2011) 
 1. BLOOD PLATELETS/
 2. (platelet* or thrombocyte*).ti,ab
 3. 1 or 2
 4. exp BLOOD TRANSFUSION/
 5. transfus*.ti,ab
 6. 4 or 5
 7. 3 and 6
 8. PLATELET TRANSFUSION/
 9. ((platelet* adj5 transfus*) or (platelet* adj5 infus*) or (platelet* adj5 administ*) or (platelet* adj5 requir*)).ti,ab
 10. ((thrombocyte* adj5 transfus*) or (thrombocyte* adj5 infus*) or (thrombocyte* adj5 administ*) or (thrombocyte* adj5 requir*)).ti,ab
 11. 7 or 8 or 9 or 10
 12. (prophylactic* or prophylax* or prevent*).ti,ab
 13. 11 and 12

Free text search strategy for other databases (Nov 2011) 
 (platelet* OR thrombocyte*) AND (transfus* OR infus* OR administ* OR requir*) AND (prophylactic* OR prophylaxis OR prevent OR prevention OR preventing)

MEDLINE & Embase search strategy (Jan 2002) 
 1. Platelet Transfusion.mh.
 2. platelet$ adj10 (substitute$ or transfusion$ or prophyla$).tw.
 3. 1 or 2
 4. haemorrhage.mh.
 5. platelet$.tw.
 6. 4 and 5
 7. exp Blood Transfusion/
 8. 5 and 7
 9. 3 or 6 or 8

Data and analyses

Comparison 1. Prophylactic platelet transfusion with one dose schedule versus another dose schedule.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number of participants with at least one clinically significant bleeding event ‐ low dose versus standard dose	4	1170	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.95, 1.13]
2 Number of participants with at least one clinically significant bleeding event ‐ low dose versus high dose	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
3 Number of participants with at least one clinically significant bleeding event ‐ high dose versus standard dose	2	951	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.93, 1.11]
4 Number of days with clinically significant bleeding per participant low dose versus standard dose (fixed effect)	2	230	Mean Difference (IV, Fixed, 95% CI)	‐0.17 [‐0.51, 0.17]
5 Number of days with clinically significant bleeding per participant low dose versus standard dose (random effects)	2	230	Mean Difference (IV, Random, 95% CI)	0.04 [‐0.78, 0.86]
6 Number of participants with WHO Grade 3 or 4 bleeding ‐ low dose versus standard dose	3	1059	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [0.91, 1.92]
7 Number of participants with WHO Grade 3 or 4 bleeding ‐ low dose versus high dose	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
8 Number of participants with WHO Grade 3 or 4 bleeding ‐ high dose versus standard dose	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
9 Number of participants with WHO Grade 4 bleeding ‐ low dose versus standard dose	3	1070	Risk Ratio (M‐H, Fixed, 95% CI)	1.87 [0.86, 4.08]
10 Number of participants with WHO Grade 4 bleeding ‐ low dose versus high dose	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
11 Number of participants with WHO Grade 4 bleeding ‐ high dose versus standard dose	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
12 Number of participants with bleeding requiring a red cell transfusion	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
13 Number of participants with bleeding causing cardiovascular compromise	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
14 Mortality from all causes ‐ low dose vs. standard dose	3	1070	Risk Ratio (M‐H, Fixed, 95% CI)	2.04 [0.70, 5.93]
15 Mortality from all causes ‐ low dose vs. high dose	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
16 Mortality from all causes ‐ high dose vs. standard dose	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
17 Mortality from bleeding	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
17.1 Low dosage platelet transfusions versus standard dose platelet transfusions	3	859	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
17.2 High dosage platelet transfusions versus standard dosage platelet transfusions	2	739	Risk Ratio (M‐H, Fixed, 95% CI)	1.47 [0.06, 35.90]
18 Number of participants with platelet transfusion reactions	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
18.1 Allergic reaction or hypersensitivity: Low dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.2 Allergic reaction or hypersensitivity: High dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.3 Hypotension: Low dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.4 Hypotension: High dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.5 Dyspnoea: Low dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.6 Dyspnoea: High dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.7 Hypoxia: Low dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.8 Hypoxia: High dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.9 Wheezing: Low dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.10 Wheezing: High dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.11 Wheezing: Low dosage platelet transfusions versus high dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.12 Haemolysis: Low dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.13 Haemolysis: High dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.14 Rigors or chills: Low dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.15 Rigors or chills: High dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.16 Fever: Low dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.17 Fever: High dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.18 Infection: Low dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.19 Infection: High dosage platelet transfusions versus standard dosage platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
19 Thromboembolic disease	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
19.1 Low dose platelet transfusions versus standard dose platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
19.2 Low dose platelet transfusions versus high dose platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
19.3 High dose platelet transfusions versus standard dose platelet transfusions	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
20 Number of participants with a significant bleeding episode ‐ autologous stem cell transplant versus intensive chemotherapy	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
20.1 Autologous HSCT	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
20.2 Intensive chemotherapy	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
21 Number of participants with a significant bleeding episode ‐ autologous stem cell transplant versus allogeneic stem cell transplant	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
22 Time to first significant bleeding event	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.21. Analysis.

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 21 Number of participants with a significant bleeding episode ‐ autologous stem cell transplant versus allogeneic stem cell transplant.

1.22. Analysis.

Comparison 1 Prophylactic platelet transfusion with one dose schedule versus another dose schedule, Outcome 22 Time to first significant bleeding event.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Akay 2015.

Methods	Parallel RCT. Randomised into 4 parallel groups. (Enrolled 2011 to 2013). Single centre (Turkey)
Participants	Inclusion criteria: People between the ages of 18 and 80, receiving chemotherapy for newly diagnosed haematological malignancy and were expected to have a platelet count ≤ 20 x 109/L for ≥ 10 days Exclusion criteria: People who within the last 14 days used medications that can affect platelet function; people who have evidence of WHO ≥ grade 2 bleeding; people who have systemic disorders (renal, hepatic, endocrinological) or haemostatic disorders or history N = 100 randomised and analysed Arm 1: N = 24 (AML N = 17; ALL N = 1; MDS N = 4; primary myelofibrosis N = 1; AA N = 1) Arm 2: N = 24 (AML N = 14; ALL N = 2; MDS N = 1; NHL N = 7) Arm 3: N = 28 (AML N = 17; ALL N = 2; MDS N = 2; NHL N = 5; primary myelofibrosis N = 1; AA N = 1) Arm 4: N = 24 (AML N = 14; ALL N = 3; MDS N = 2; NHL N = 5)
Interventions	Arm 1: 6 unit random‐donor platelet transfusions Arm 2: 3 unit random‐donor platelet transfusions Arm 3: 1 unit apheresis platelet transfusions Arm 4: 1/2 unit apheresis platelet transfusions Transfusion thresholds: Prophylactic platelet transfusion given when platelet count ≤ 10 x 109/L. They were also given when platelet count ≤ 20 x 109/L if participant had a fever or WHO grade 1 bleeding or both. Type of platelet transfusion: Depended on the arm to which the participant was randomised
Outcomes	Primary outcome: Not reported Secondary outcomes: Before and 15 minutes after transfusion, peripheral blood was taken and complete blood count and rotation thromboelastography were performed by standard device (Pentapharm GmbH, Munich, Germany). Clotting time, clot formation time, and maximum clot firmness were evaluated by 2 methods, in‐TEM and ex‐TEM. Participants were followed up during study by using clinical bleeding signs based on WHO bleeding grade. Number of days of thrombocytopenia (mean ± SD) Not reported
Bleeding scale	WHO grading system not further defined Definition of significant haemorrhage: Not reported Definition of life‐threatening haemorrhage: Not reported Assignment of bleeding grade: Not reported
Bleeding assessment	Not reported
Red cell transfusion policy	Not reported
Notes	Participants randomised at: Not reported Follow‐up of participants: Not reported Stopping guideline: Not reported Funding: Not reported Declarations of interest: Not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of sequence generation was not commented on
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment was not commented on
Blinding (performance bias and detection bias) Assessor of bleeding assessment	Unclear risk	Method of blinding assessor not reported
Blinding (performance bias and detection bias) Physician/Medical Staff	Unclear risk	Method of blinding clinician not reported
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Loss to follow‐up was not reported
Selective reporting (reporting bias)	Unclear risk	Insufficient information to say. No protocol available
Other bias	Unclear risk	The study was insufficiently reported to exclude any significant bias
Protocol Deviation balanced?	Unclear risk	Not reported

Heddle 2009.

Methods	Parallel RCT (enrolled October 2003 to June 2007). Multinational study (Canada 3 centres, Norway 1 centre, USA 2 centres)
Participants	Inclusion criteria: Hypoproliferative thrombocytopenia where platelet count was expected to be < 10 x 109/L for ≥ 10 days; receiving treatment as an inpatient; weight between 40 kg and 100 kg; minimum age 17 yrs Exclusion criteria: APL; pregnant; history or current diagnosis of ITP, TTP, or HUS; evidence of ≥ WHO grade 2 bleeding at time of study assessment; indication for bedside leukoreduced platelet components N = 129 randomised; 119 included in analysis (6 did not require platelet transfusions; 1 withdrew from trial before receiving platelets; 3 no bleeding assessment data) Arm 1: N = 58 (AL N = 51; lymphoma N = 4; carcinoma N = 1; MDS N = 1; plasma cell dyscrasia N = 1) N = 7 withdrew early (1 participant decision; 6 physician decision) Arm 2: N = 61 (AL N = 52; chronic leukaemia N = 2; lymphoma N = 3; MDS N = 2; plasma cell dyscrasia N = 1; other N = 1) N = 3 withdrew early (2 participant decision; 1 physician decision)
Interventions	Comparison between prophylactic platelet transfusions with different platelet doses Arm 1: low dose (1.5 to 3.0 x 1011 platelets/product) Arm 2: standard dose (3.0 to 6.0 x 1011 platelets/product) Transfusion thresholds: Prophylactic platelet transfusion threshold depended on local transfusion trigger. Most centres used trigger of 10 x 109/L. Higher triggers were used in special circumstances (e.g. sepsis) at the discretion of the treating physician. Type of platelet transfusion: Both US sites used leucodepleted apheresis platelets. Canadian sites used both apheresis and random‐donor pooled platelets (both leucodepleted). Norwegian site used apheresis and random‐donor pooled platelets.
Outcomes	Primary outcome: Occurrence of a WHO grade 2 or higher bleed Secondary outcomes: Frequency of individual grades of bleeding (grades 1 to 4) Time to first bleed Duration of thrombocytopenia Platelet transfusion requirements Red cell transfusion requirements Interval between platelet transfusions Modeling the recurrent event analysis to determine the mean number of bleeding days over time per 100 participants Number of days of thrombocytopenia (mean ± SD) Arm 1 = 15.8 ± 9.3 Arm 2 = 14.0 ± 9.0
Bleeding scale	Modified WHO Grade 1* Mucocutaneous haemorrhage (oral blood blisters); petechiae (lesions < 2 mm in size); purpura < 2.54 cm (1 inch) in diameter; ecchymosis (lesions < 10 cm in size); oropharyngeal bleeding; conjunctival bleeding; epistaxis < 1 hour in duration and not requiring intervention; abnormal vaginal bleeding (non‐menstrual) with spotting (< 2 pads per day). Grade 2* Ecchymosis (lesions > 10 cm in size); haematoma; epistaxis > 1 hour in duration or packing required; retinal haemorrhage without visual impairment; abnormal vaginal bleeding (not normal menses) using > 2 pads/day; melaena, haematemesis, haemoptysis, haematuria, haematochezia; bleeding from invasive sites; musculoskeletal bleeding. Grade 3ɫ Melaena; haematemesis; haemoptysis; haematuria, including intermittent gross bleeding without clots; abnormal vaginal bleeding; haematochezia; epistaxis; oropharyngeal; bleeding from invasive sites; musculoskeletal bleeding; or soft tissue bleeding. Grade 4ɫ Debilitating bleeding including retinal bleeding with visual impairment (defined as a field deficit and there must be a consult note documenting visual impairment); non‐fatal central nervous system bleeding with neurologic signs and symptoms; fatal bleeding from any source. * Does not require red cell transfusion ɫ Requiring red cell transfusion specifically for support of bleeding within 24 hours of onset Definition of significant haemorrhage: WHO grade 2 or above (unpublished, information supplied by author) Definition of life‐threatening haemorrhage: WHO grade 4 (unpublished, information supplied by author) Assignment of bleeding grade: Data from all bleeding assessments were reviewed independently by 2 trained adjudicators. If the 2 adjudicators disagreed in their assessments, the data were sent to another adjudicator. If agreement was not reached after 5 adjudicators, a meeting of adjudicators was held to achieve consensus.
Bleeding assessment	Daily. Physical examination for signs of petechiae, purpura, bruising; inspection of intravenous and central line sites for evidence of bleeding; and questioning the participant to determine whether any bleeding had occurred during the previous 24 hours. The participant’s chart was also reviewed to capture any documented information related to bleeding in the 24‐hour time period prior to the clinical assessment
Red cell transfusion policy	As per local red cell transfusion guidelines (unpublished, information supplied by author)
Notes	Participants randomised at: time of first prophylactic platelet transfusion (usually when platelet count < 10 x 109/L; depended on local trigger). Follow‐up of participants: until bone marrow recovery (unsupported platelet count > 50 x 109/L) OR 30 days from randomisation OR discharge from hospital OR participant withdrawal OR death. Stopping guideline: Study to be stopped if difference in the proportion of grade 4 bleeding between the 2 treatment arms exceeded 5% at any time after 50 patients had been enrolled per arm. Funding: Canadian Blood Services funded study coordination and participation by 3 Canadian sites. Funding of other sites not reported. Declarations of interest: The authors declared no competing financial interests
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated, stratified by centre and diagnostic group. Block randomisation was used with variable block sizes within strata to help conceal treatment allocation
Allocation concealment (selection bias)	Low risk	Allocated through a secure central web‐based randomisation system. Block randomisation was used with variable block sizes within strata to help conceal treatment allocation
Blinding (performance bias and detection bias) Assessor of bleeding assessment	Low risk	Bleeding assessment was performed each morning during the period of thrombocytopenia by personnel who were blinded to the platelet dose assigned to the participant
Blinding (performance bias and detection bias) Physician/Medical Staff	High risk	Although study was meant to be blinded, authors were concerned that this was not always the case. 7 participants withdrawn from the study early: 1 in standard‐dose arm and 6 in low‐dose arm.
Incomplete outcome data (attrition bias) All outcomes	High risk	2 participants in standard group and 1 participant in low‐risk group had missing data (not included in analysis). 10 participants withdrew from the study early for the following reasons: participant decision to withdraw (N = 3: 2 standard dose, 1 low dose); physician decision to withdraw (N = 7: 1 standard dose, 6 low dose). Early withdrawal was therefore unbalanced between the two groups
Selective reporting (reporting bias)	High risk	Not all of the prespecified outcomes were reported, including platelet response; pre‐ and post‐transfusion bleeding grade in response to dose of therapeutic platelets transfused; cost analysis
Other bias	High risk	Discrepancies in adjudication of bleeding grade between the first 2 adjudicators in 39% (433/1150) of the bleeding days adjudicated. However, agreement was reached through consensus. Most of the discrepancies occurred between the grade 1 and grade 2 classifications. Trial stopped early due to a prespecified stopping guideline. Higher rate of grade 4 bleeding in participants receiving low‐dose prophylactic platelet transfusions. Frequency of grade 4 bleeding 5.2% (3/58) in low‐dose arm and 0% (0/61) in standard‐dose arm. Risk of incomplete randomisation blocks
Protocol Deviation balanced?	High risk	The triggers used for prophylactic platelet transfusions tended to be higher in the low‐dose treatment group, with 35.9% of transfusions (158/440) given at a trigger of 16 x 109/L or more compared with 24.7% (66/267) in the standard‐dose group. In the low‐dose arm, 27.4% of the prophylactic platelet transfusions were outside the predesignated range: 2.7% below 150 x109 platelets/product (n = 10) and 24.7% above 300 x 109 platelets/product (n = 91) In the standard‐dose arm, 20% of the prophylactic platelet transfusions were outside the predesignated range: 6.7% below 300 x 109 platelets/product (n = 17) and 13.3% above 600 x 109 platelets/product (n = 34)

Roy 1973.

Methods	Parallel RCT (enrolment period not stated). Single centre. USA
Participants	Inclusion criteria: Hospitalised leukaemia patients (paediatric); platelet count ≤ 25 x 109/L; no active bleeding within the previous 5 days Exclusion criteria: Not stated N = 62 participants Arm 1: N = 30 participants having 167 transfusion episodes (age 0 to 4 yrs = 14; age 5 to 9 yrs = 14; age 10 to 14 yrs = 2) Arm 2: N = 32 participants having 141 transfusion episodes (age 0 to 4 yrs = 5; age 5 to 9 yrs = 12; age 10 to 14 yrs = 15)
Interventions	Comparison between prophylactic platelet transfusions with different platelet doses Arm 1: 'higher dose' platelets (dose: 0.06 to 0.07 units/lb) = 0.9 to 1.1 x 1011platelets/10 kg Arm 2: 'lower dose' platelets (dose: 0.03 units/lb) = 0.46 x 1011 platelets/10 kg (the average platelet yield reported in the study was 7 x 1010 platelets per unit) Transfusion thresholds: Prophylactic platelet transfusions given when platelet count ≤ 25 x 109/L When bleeding occurred despite prophylaxis, the participant was treated with larger platelet transfusions until all bleeding was arrested Platelet transfusion type: ABO‐identical pooled platelets
Outcomes	Main or primary outcome not stated. Aims of the trial: To assess the dose‐response relationship between transfused platelets and prevention of haemorrhage To investigate the needs and desirability of prophylactic platelet transfusion Number of days on study Participants were followed up for 24 hours after platelet transfusion.
Bleeding scale	Bleeding events for this study were descriptively classified: Mild: spontaneous appearance of petechiae or ecchymoses of skin or mucous membranes of mouth, gums, nose (epistaxis), or sclera of the eye, microscopic haematuria or guaiac‐positive stools. Severe: gross gastro‐intestinal bleeding or haematuria
Bleeding assessment	Prospective bleeding assessment by an investigator who was blinded to the platelet dose. Assessment of bleeding only occurred for 24 hours after each platelet transfusion
Red cell transfusion policy	Not reported
Notes	Participants randomised at: platelet count ≤ 25 x 109/L Follow‐up of participants: for 24 hours after platelet transfusion Stopping guideline: not reported If participant required further platelet transfusions during the same hospital admission, participant kept initial randomisation. On re‐admission to hospital participants were re‐randomised. Funding: Supported by research grants CAO‐8855 and C‐6526 from the National Cancer Institute and RRO‐5526 from the Division of Research Facilities and Resources, National Institutes of Health Declarations of interest: Not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Participants were assigned randomly to either dose group by drawing sealed envelopes. Method of sequence generation not reported
Allocation concealment (selection bias)	Unclear risk	Participants were assigned randomly to either dose group by drawing sealed envelopes. Does not say whether envelopes were opaque
Blinding (performance bias and detection bias) Assessor of bleeding assessment	Low risk	Participants were studied over 24 hours following transfusion for signs of bleeding by an investigator who was unaware of the platelet dose received
Blinding (performance bias and detection bias) Physician/Medical Staff	Unclear risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	No participants were lost to follow‐up
Selective reporting (reporting bias)	High risk	No protocol available to assess this, but in the report a lot of data has been collected but not reported on. "No correlation of the incidence of bleeding with sex, pre‐transfusion haematocrit, concomitant corticosteroid therapy or the use of anti‐neoplastic drugs was found". None of these results were reported
Other bias	High risk	Marked difference between population age groups. Other baseline characteristics not stated adequately to assess. There were only 2/30 children aged 10 to 18 yrs in the higher‐dose arm and 15/32 children in the same age group in the lower‐dose arm. Conversely, there were 14/30 children aged 0 to 4 yrs in the higher‐dose arm and 5/32 in the same age group in the lower‐dose arm. In this study, the age of the participant affected the incidence of bleeding. Overall, 13.6% of children aged 0 to 4 years bled, whereas only 2.7% of children aged 10 to 18 years bled
Protocol Deviation balanced?	Unclear risk	Not reported

Sensebe 2004.

Methods	Parallel RCT (enrolled from May 1999 to October 2001). Multicentre (4 centres). France
Participants	Inclusion criteria: People who had not undergone transfusion who had AL undergoing first‐line treatment; people undergoing autologous hematopoietic stem cell transplantation without criteria impairing platelet efficiency Exclusion criteria: People diagnosed with AML M3 N = 101 participants randomised (98 included in analysis; 5 never transfused). Arm 1 = 50 (AL = 17; AT = 33) (2 AT never transfused) Arm 2 = 51 (AL = 14; AT = 37) (2 AL never transfused; 1 AT never transfused)
Interventions	Comparison between prophylactic platelet transfusions with different platelet doses Arm 1: Single dose (0.5 x 1011/10 kg) Arm 2: Double dose (1.0 x 1011/10 kg) Platelet transfusion thresholds: Prophylactic platelet transfusions given if platelet count < 20 x 109/L. Therapeutic platelet transfusion trigger not stated. Platelet transfusion type: Leucodepleted, ABO‐compatible apheresis platelets
Outcomes	Primary outcome: Time between first transfusion and daily platelet reaching 20 x 109/L (allowed for calculating the risk of re‐transfusion and theoretical time between first and second transfusions). Secondary outcomes: Corrected count increment (CCI) calculated as: (post‐transfusion count ‐ pre‐transfusion count) x body surface area (m2)/ platelet dose (x 1011) Number of transfusions Number of transfused platelets Number of days on study Not reported
Bleeding scale	WHO Scale Grade 0 No bleeding Grade 1 Petechial Grade 2 Mild blood loss Grade 3 Gross blood loss Grade 4 Debilitating blood loss Definition of significant or life‐threatening blood loss: not reported
Bleeding assessment	Bleeding was assessed daily, but it was not stated how bleeding was assessed or who assessed the bleeding
Red cell transfusion policy	Not reported
Notes	Participants randomised at: not reported Follow‐up of participants: until platelet count > 25 x 109/L and stable OR discharge from hospital OR death Stopping guideline: not reported Funding: Supported by a grant from Etablissement Français du Sang (EFS; FORTS no. 99004250837) Declarations of interest: Not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of sequence generation was not commented on. Randomisation was based on the centre and type of pathology
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment was not commented on
Blinding (performance bias and detection bias) Assessor of bleeding assessment	Unclear risk	Bleeding was assessed daily, but it was not stated how bleeding was assessed or who assessed the bleeding. The main outcome parameter in this study was the platelet count, and the laboratory was blinded to the dose of platelets received, thus defining the study as a prospective, randomised, open, blinded end point (PROBE) study
Blinding (performance bias and detection bias) Physician/Medical Staff	High risk	Physicians and participants were not blinded to the randomisation arm
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data
Selective reporting (reporting bias)	Unclear risk	Insufficient information to say. No protocol available
Other bias	Low risk	The study appears to be free of other sources of biases
Protocol Deviation balanced?	Unclear risk	Protocol deviations or violations were not commented on

Slichter 2010.

Methods	Parallel RCT (enrolled from 2004 to 2007). Multicentre (26 centres). USA
Participants	Inclusion criteria: Inpatients of any age; receiving a stem cell transplant (for any diagnosis) or chemotherapy (for haematological cancers or solid tumours) and were expected to have a platelet count ≤ 10 x 109/L for ≥ 5 days. Weight 10 kg to 135 kg. PT and APTT < 1.3 x upper limit of normal. Fibrinogen ≥ 100 mg/dl. No previous platelet transfusions related to the current or planned course of therapy. Exclusion criteria: Evidence of WHO ≥ grade 2 bleeding; receiving antithrombotic/antiplatelet medications; bedside platelet leucoreduction; platelet refractoriness within previous 30 days; APL; idiopathic or thrombotic thrombocytopenic purpura; HUS; major surgery within previous 2 weeks; pregnancy; planned prophylactic transfusion of platelets at platelet counts > 10 x 109/L. N = 1351 participants randomised (1272 participants received at least 1 platelet transfusion; data analysis only on these participants) Arm 1: N = 417 (AL = 202; lymphoma = 91; myeloma = 39; chronic leukaemia = 24; MDS = 16; other = 45) Arm 2: N = 423 (AL = 186; lymphoma = 89; myeloma = 59; chronic leukaemia = 24; MDS = 26; other = 39) Arm 3: N = 432 (AL = 185; lymphoma = 84; myeloma = 56; chronic leukaemia = 33; MDS = 14; other = 60)
Interventions	Comparison between prophylactic platelet transfusions with different platelet doses Arm 1: 1.1 x 1011/m2 body surface area/transfusion ± 25% Arm 2: 2.2 x 1011/m2 body surface area/transfusion ± 25% Arm 3: 4.4 x 1011/m2 body surface area/transfusion ± 25% Platelet transfusion thresholds: Prophylactic platelet transfusions given when platelet count ≤ 10 x 109/L. Participant's physician could alter transfusion trigger or threshold if required by clinical indications. Therapeutic platelet transfusion trigger not reported. Platelet transfusion type: apheresis and random‐donor pooled products
Outcomes	Primary outcome: Grade 2 or higher bleeding as determined by the Platelet Dose Trial Bleeding Scale Secondary outcomes: Platelet utilisation rates (total number of platelets transfused x 1011) Number of platelet transfusion events (frequency of transfusions) Highest category of bleeding during time of study Bleeding severity based on number of days with bleeding, intensity of bleeding, and number of sites with bleeding Number of days on study 1272 participants were observed for a total of 24,309 days. Mean number of days 19.1
Bleeding scale	Modified WHO Scale Grade 1*: Oropharyngeal bleeding or epistaxis lasting < 30 minutes in previous 24 hours; petechiae of skin and oral mucosa; purpura < 2.54 cm in diameter; abnormal vaginal bleeding with spotting Grade 2*: Oropharyngeal bleeding or epistaxis for > 30 minutes in previous 24 hours; purpura > 2.54 cm in diameter; deep haematoma; joint bleeding; melaena; haematemesis; gross haematuria; abnormal vaginal bleeding consisting of more than spotting; haemoptysis, blood in bronchoalveolar lavage specimens; visible blood in body cavity fluids without symptoms; retinal bleeding without symptoms; LP specimens containing microscopic amounts of blood; bleeding at invasive sites for > 1 hour in previous 24 hours. Grade 3: Any bleeding requiring RBC transfusion over routine needs. Any bleeding associated with moderate haemodynamic instability (hypotension > 30 mmHg fall or > 30% fall in systolic or diastolic BP). Grossly bloody body cavity fluids and organ dysfunction with symptoms. Atraumatic LP with visible red colour in absence of symptoms. Grade 4: Any bleeding with severe haemodynamic instability (hypotension; > 50 mmHg fall or > 50% decrease in systolic or diastolic BP with associated tachycardia). Retinal bleeding with visual field impairment. Any CNS symptoms with LP evidence of bleeding. Any CNS bleeding on imaging with or without dysfunction. Fatal bleeding. *Bleeding does not require a red cell transfusion over routine needs. Definition of significant bleeding Not reported Definition of life threatening bleeding Not reported
Bleeding assessment	Daily bleeding assessment using physical examinations, interviews with participants, and chart reviews for bleeding events. Data was collected on all bleeding described in the WHO criteria (except no urine dipstick or stool guaiac tests were performed)
Red cell transfusion policy	Local practice at each centre determined red cell transfusion policy
Notes	Participants randomised at: not reported Follow‐up of participants: until a 10‐day period without a platelet transfusion OR 30 days from first platelet transfusion OR discharge from hospital OR withdrawal from study OR death Stopping guideline: Stopping boundaries for the comparison of the primary endpoint between each pair of treatment groups were calculated with the use of an alpha spending function similar to O'Brien‐Fleming boundaries Funding: Supported by grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health to the Data Coordinating Center at New England Research Institutes (HL072268), Case Western Reserve University (HL072033), Children’s Hospital Boston (HL072291), Cornell University (HL072196), Duke University (HL072289), Emory University (HL072248), Johns Hopkins University (HL072191), Massachusetts General Hospital (HL072299), Puget Sound Blood Center (HL072305), Tulane University (HL072274), University of Iowa (HL072028), University of Maryland (HL072359), University of Minnesota (HL072072), University of North Carolina (HL072355), University of Oklahoma (HL072283), University of Pennsylvania (HL072346), University of Pittsburgh (HL072331), and the Blood Center of Wisconsin (HL072290). Declarations of interest: Dr. Slichter reports receiving grant support from U.S. Army Medical Research Acquisition Activity (Department of Defense), Navigant Biotechnologies, and Pall Medical; Dr. Assmann, receiving grant support from Z‐Medica; Dr. Triulzi, receiving consulting fees from Fenwal Laboratories and Cerus and lecture fees from Pall; Dr. Strauss, receiving consulting fees from CaridianBCT; Dr. Ness, receiving consulting fees from Fenwal Laboratories and CaridianBCT; Dr. Brecher, receiving consulting fees from Fenwal Laboratories; Dr. Josephson, receiving lecture fees from Mediware; Dr. George, receiving consulting fees and grant support from Amgen; and Dr. Manno, receiving consulting fees and grant support from Baxter Healthcare, consulting fees from Bayer Healthcare, and lecture fees from EMD Healthcare Communications Scientific Communication Group. No other potential conflicts of interest relevant to this article were reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomly assigned in a 1:1:1 ratio, by means of computer‐generated permuted blocks, to receive platelets at 1 of 3 doses. Treatment groups were balanced within trial sites with the use of dynamic balancing
Allocation concealment (selection bias)	Unclear risk	Not explicitly reported
Blinding (performance bias and detection bias) Assessor of bleeding assessment	Low risk	Site staff were not told the participant’s assigned dose, but differences in transfusion volume prevented complete blinding. However, a computer algorithm assigned the final bleeding grade from the collected data, and this part of the process was at a low risk of bias
Blinding (performance bias and detection bias) Physician/Medical Staff	High risk	Site staff were not told the participant’s assigned dose, but differences in transfusion volume prevented complete blinding
Incomplete outcome data (attrition bias) All outcomes	High risk	Analysis of the number of platelet transfusions per participant was limited to participants who had no missing data on the number of transfusion events and number of platelets transfused (71%, 82%, and 83% of data were complete on low‐, medium‐, and high‐dose participants, respectively)
Selective reporting (reporting bias)	Low risk	Study protocol is available and has been reported in the prespecified way
Other bias	Low risk	The study appears to be free of other sources of bias
Protocol Deviation balanced?	High risk	A significantly smaller proportion of transfusions were within the assigned dose range when the “at‐issue” platelet counts were compared between low‐dose and medium‐dose groups (71% vs 80% (P = 0.007)) and between high‐dose and medium‐dose groups (70% vs 80% (P < 0.001)

Steffens 2002.

Methods	Parallel RCT (period of enrolment not stated). Single centre. UK
Participants	Inclusion criteria: People aged > 16 yrs receiving myelosuppressive chemotherapy for AML and SCT conditioning for allogeneic SCT Exclusion criteria: People with HLA antibodies. People with cardiovascular disease unable to tolerate a volume load N = 54 Arm 1: N = 28 participants. AML (21) allogeneic SCT (7) Arm 2: N = 26 participants. AML (19) allogeneic SCT (7)
Interventions	Comparison between prophylactic platelet transfusions with different platelet doses Arm 1: single adult unit (2.4 x 1011/L) Arm 2: 3 single adult units Transfusion thresholds: platelet count ≤ 10 x 109/L or higher if the participant was bleeding or febrile. Type of platelet transfusion: single‐donor apheresis platelets
Outcomes	No primary or secondary outcomes stated. Aim: compare the efficacy of single‐donor platelets given as either a single adult dose or a triple adult dose
Bleeding scale	Not reported
Bleeding assessment	Not reported
Red cell transfusion policy	Not reported
Notes	Participants randomised at: initiation of chemotherapy Participants followed up until: platelet transfusion independent (not further defined) Stopping guideline: not reported Funding: not reported Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random allocation not reported
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported
Blinding (performance bias and detection bias) Assessor of bleeding assessment	Unclear risk	Method of blinding assessor not reported
Blinding (performance bias and detection bias) Physician/Medical Staff	Unclear risk	Method of blinding clinician not reported
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficiently reported to allow an assessment to be made
Selective reporting (reporting bias)	High risk	No protocol available. However, mentions study will be reported in more detail in future including clinical efficacy, bleeding episodes, red cell requirements, and complications
Other bias	Unclear risk	Study not reported sufficiently to enable a comment to be made
Protocol Deviation balanced?	Unclear risk	Not reported

Tinmouth 2004.

Methods	Phase II Bayesian approach study (February 2001 to March 2002 (unpublished)). Single centre. Canada
Participants	Inclusion criteria: Consecutive participants > 16 yrs of age. Undergoing autologous SCT or induction chemotherapy for ALL or AML. Exclusion criteria: APL, active bleeding, abnormal coagulation tests, history of a bleeding diathesis, ITP, refractory to platelet transfusions, receiving anticoagulants, antifibrinolytics, desmopressin, or antiplatelet medication. N = 111 participants enrolled Arm 1: N = 56. AL (17); AT (39). 55 participants completed assessment (1 allergic transfusion reaction). 14 participants did not require any platelet transfusions. Arm 2: N = 55. AL (17); AT (38). 51 participants completed assessment (2 withdrawn when required antifibrinolytic or anticoagulant; 2 withdrawn when bleeding initially categorised as major was reclassified as minor). 10 participants did not require any platelet transfusions.
Interventions	Comparison between prophylactic platelet transfusions with different platelet doses Arm 1: 3 units/half single apheresis unit = 1.9 to 2.5 x 1011 platelets/transfusion Arm 2: 5 units/full single apheresis unit = 3.4 to 4.4 x 1011 platelets/transfusion Platelet yields were 6.73 x 1010 to 8.5 x 1010 per whole blood‐derived platelet unit and 3.85 x 1011 to 4.06 x 1011 per apheresis platelet unit Platelet transfusion thresholds: Prophylactic platelet threshold < 10 x 109/L. If minor bleeding, platelet threshold < 20 x 109/L. Prior to invasive procedures, platelet threshold < 50 x 109/L. Platelet transfusion type: Random‐donor pooled platelets (PRP method). Leucodepleted. Apheresis platelets only used if no whole blood‐derived platelets available.
Outcomes	Hypothesis: Lower dose of platelets would be safe and effective in preventing major bleeding events and would decrease total utilisation of platelets. Stopping criteria: Absolute increase in major bleeding in the low‐dose group of ≤ 10% was considered the range of equivalence a high probability (greater than 80%) of equivalence (i.e. the increase in major bleeding events with low‐dose platelet transfusions was less than 10%) a moderately high probability (greater than 60%) of nonequivalence (i.e. that the increase in major bleeding events was greater than 10%) Number of days on study Median time from start of chemotherapy to termination of the transfusion protocol was 15 days.
Bleeding scale	Modified Rebulla Scale Grade 0 No bleeding Grade 1 Petechiae or mucosal or vaginal bleeding that did not require a red cell transfusion and caused a fall in Hb by less than 20g/L in last 24 hours Grade 2 Melaena, haematemesis, haematuria, or haemoptysis Grade 3 Any bleeding that caused a fall in Hb by at least 20 g/L in last 24 hours Grade 4 Retinal bleeding (accompanied by visual impairment) Grade 5 Non‐fatal cerebral bleeding Grade 6 Fatal cerebral bleeding Grade 7 Fatal non‐cerebral bleeding. Definition of significant bleeding: ≥ grade 2 bleeding Definition of life‐threatening bleeding: not reported
Bleeding assessment	Daily examination by treating physician, any bleeding was graded initially by physician. Study personnel reviewed daily medical and nursing notes
Red cell transfusion policy	Not reported
Notes	Participant randomisation: within 72 hours of starting chemotherapy Follow‐up of participants: until platelet count > 20 x 109/L for 2 days spontaneously OR major bleeding event (determined by treating physician) OR refractoriness to platelet transfusions OR discharge from hospital OR transfer to intensive care unit OR administration of further chemotherapy OR failure of engraftment OR death Stopping guideline: not reported Funding: The project was funded by Canadian Blood Services Grant XT0026. AT Tinmouth was supported by a Canadian Blood Services transfusion medicine fellowship Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated, stratified by diagnostic group. Block randomisation was used with variable block sizes within strata to help conceal treatment allocation (unpublished, information supplied by the author)
Allocation concealment (selection bias)	Low risk	Sealed, consecutively numbered envelopes containing information about the platelet dose group were opened by the hospital blood bank staff who were not involved in the study design, clinical management, or data collection for the trial (unpublished, information supplied by the author)
Blinding (performance bias and detection bias) Assessor of bleeding assessment	High risk	Clinicians collected the data on bleeding, and they were unblinded to the dose of platelets transfused. "Ajudication committee of three physicians blinded to the platelet dose and physician assigned bleeding grade independently reviewed all bleeding events and assigned the final bleeding grade." Therefore the allocation of a bleeding grade was at a low risk of bias.
Blinding (performance bias and detection bias) Physician/Medical Staff	High risk	Medical and nursing staff were not blinded to the dose of platelet transfused
Incomplete outcome data (attrition bias) All outcomes	Low risk	Balanced withdrawal across groups
Selective reporting (reporting bias)	Unclear risk	No protocol available to assess
Other bias	Low risk	The study appears to be free of other sources of bias
Protocol Deviation balanced?	High risk	15/164 transfusions contravened protocol in Arm 1 3/147 transfusions contravened protocol in Arm 2

AA: aplastic anaemia

AL: acute leukaemia
 ALL : acute lymphocytic leukaemia
 AML: acute myeloid leukaemia
 APL: acute promyelocytic leukaemia
 APTT: activated partial thromboplastin time
 AT: autologous transplant
 BP: blood pressure

Hb: haemoglobin
 HLA: human leukocyte antigen
 HUS: haemolytic uraemic syndrome
 ITP: idiopathic thrombocytopenic purpura

LP: lumbar puncture
 MDS: myelodysplastic syndrome

NHL: Non‐Hodgkin lymphoma
 PRP: platelet‐rich plasma
 RBC: red blood cell
 RCT: randomised controlled trial
 PT: prothrombin time
 SCT: stem cell transplant
 SD: standard deviation
 TTP: thrombotic thrombocytopenic purpura
 WHO: World Health Organization

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Aderka 1986	A non‐randomised retrospective study
Agliastro 2006	Comparison of apheresis vs buffy coat platelet transfusions ( abstract)
Akkök 2007	Comparison of apheresis vs buffy coat platelet transfusions
Anderson 1997	Comparison of apheresis vs buffy coat ‐derived vs platelet rich plasma ‐derived platelet products
Andreu 2009	Review
Andrew 1993	Wrong patient group ‐ premature infants
Arnold 2004	Comparison of apheresis vs whole blood ‐derived platelet transfusions
Arnold 2006	Wrong patient group ‐ i ntensive therapy unit
Avvisati 2003	Review
Bai 2004	Wrong patient group ‐ solid tumours
Benjamin 2002	Review
Bentley 2000	Comparison of autologous vs allogeneic platelet transfusions
Blajchman 2008	Review
Blumberg 2002	Comparison of washed vs standard platelet transfusions
Blumberg 2004	Comparison of washed vs standard platelet transfusions
Blundell 1996	Comparison of standard vs pathogen ‐inactivated platelets
Buhrkuhl 2010	Review
Callow 2002	A non‐randomised prospective study with historical control
Cameron 2007	A non‐randomised prospective study
Carr 1990	Comparison of ABO‐matched vs mismatched platelet products
Casbard 2004	Systematic review and wrong patient group
Chaoui 2005	Observational prospective study
Chaurasia 2012	A non‐randomised prospective study
Cid 2007	Systematic review of differing platelet transfusion doses
Couban 2002	Comparison of plasma reduction and leucodepletion
De Wildt‐Eggen 2000	Comparison of platelet concentrates in plasma vs additive solution
Decaudin 2004	Non‐randomised prospective study
Diedrich 2005	Comparison of prophylactic platelet transfusions at different transfusion thresholds
Diedrich 2009	Comparison of platelet products stored 1 to 5 vs 6 to 7 days
Dumont 2011	Comparison of buffy coat vs platelet rich plasma platelet concentrates
Dzik 2004	Review
Eder 2007	Non‐randomised observational study
Elting 2002	Retrospective analysis ‐ lymphoma and solid tumours
Elting 2003	Non‐randomised retrospective cohort ‐ lymphoma and solid tumours
Fanning 1995	Wrong patient group ‐ gynaecological cancer
Follea 2004	Guideline
Franklin 1995	Comparison of different donor exposures
Friedmann 2002	A non‐randomised retrospective analysis
Gajic 2006	Wrong patient group ‐ intensive therapy unit
Gerday 2009	Wrong patient group ‐ neonates
Gil‐Fernandez 1996	A non‐randomised retrospective historical control study (different platelet transfusion thresholds)
Gmur 1983	Comparison of single ‐donor vs pooled platelet products
Gmur 1991	A non‐randomised prospective cohort observational study (different platelet transfusion thresholds)
Goodnough 2001	Fewer than 80% of participants diagnosed with a haematological disorder ‐ different platelet doses
Goodnough 2002	Review
Goodnough 2005	Review
Goodrich 2008	Comparison of pathogen ‐inactivated vs standard apheresis platelets
Greeno 2007	A non‐randomised prospective observational study (different platelet transfusion thresholds)
Grossman 1980	Comparison of a therapeutic vs prophylactic platelet transfusion policy
Gurkan 2007	Comparison of apheresis vs pooled platelet products
Hardan 1994	A non‐randomised observational study (therapeutic platelets only), historical control reported only as an abstract
Harrup 1999	Comparison of buffy coat plasma or T‐ Sol platelet transfusions
Heal 1993	Comparison of ABO ‐compatible vs mismatched platelet transfusions
Heal 2004	Review
Heckman 1997	Comparison of prophylactic platelet transfusions at different transfusion thresholds
Heddle 1994	Comparison of plasma from platelet concentrates vs platelets
Heddle 1999	Comparison of plasma removal vs leucodepletion
Heddle 2002	Comparison of plasma removal vs leucodepletion
Heddle 2003	Systematic review ‐ methods of assessing bleeding outcome
Heddle 2007	Review
Higby 1974	Comparison of a therapeutic vs prophylactic platelet transfusion policy
Hillbom 2008	Wrong patient group ‐ intracerebral haemorrhage
ISRCTN49080246	Comparison of 1‐ to 5‐ vs 6‐ to 7 ‐day ‐old platelet transfusions
Jelic 2006	Review
Johansson 2007	Wrong patient group ‐ ruptured abdominal aortic aneurysm
Julmy 2009	Wrong patient group ‐ ruptured abdominal aortic aneurysm
Kakaiya 1981	Comparison of apheresis vs pooled platelet concentrates
Kerkhoffs 2010	Comparison of standard platelets vs pathogen ‐inactivated platelets vs platelets stored in PAS II media
Klumpp 1999	A randomised cross‐over study. This study was included within the previous systematic review. However, because of stricter inclusion/exclusion criteria, it has now been excluded from the review. Only laboratory outcomes were reported. 37% of participants had a non‐haematological malignancy (breast cancer)
Kluter 1996	Comparison of random ‐donor platelet components from pooled buffy coats vs apheresis platelet components
Lapierre 2003	Comparison of standard apheresis platelet products vs a donor reduction policy
Lawrence 2001	A non‐randomised retrospective historical control study (different platelet transfusion thresholds)
Leach 1991	Comparison of warmed vs standard platelet transfusions
Lee 1989	Comparison of ABO ‐matched vs mismatched platelet transfusions
Levi 2002	Review
Lordkipanidze 2009	Review
Lozano 2003	Review
Lozano 2010	Efficacy of older platelet transfusions
Lozano 2011	Comparison of pathogen ‐inactivated vs conventional platelet products
Lu 2011	Fewer than 80% of participants diagnosed with a haematological disorder ‐ different platelet doses
Martel 2004	Review
McCullough 2004	Comparison of pathogen ‐inactivated vs conventional apheresis platelets
McNicol 2003	Review
Messerschmidt 1988	Comparison of HLA ‐matched vs mismatched platelet transfusions
Mirasol 2010	Comparison of pathogen ‐inactivated vs conventional platelet products
Murphy 1982	Comparison of a therapeutic vs prophylactic platelet transfusion policy
Murphy 1986	Comparison of HLA ‐matched and leucodepleted blood products
Navarro 1998	A non‐randomised retrospective historical control observational study (different platelet transfusion thresholds)
NCT00180986	Comparison of exposure of children to more or fewer donors
Nevo 2007	A non‐randomised retrospective analysis (different platelet thresholds)
Norol 1998	A non‐randomised prospective comparison ( 3 different doses of platelets)
Oksanen 1991	Comparison of pre‐ vs post ‐storage leucodepletion of PRP ‐derived platelet transfusions
Oksanen 1994	Comparison of leucodepleted buffy coat ‐derived platelet transfusions vs historical control
OPTIMAL Pilot Study	Comparison of a therapeutic vs prophylactic platelet transfusion policy
Paananen 2009	Non‐randomised study (unclear whether prospective or retrospective)
Pamphilon 1996	Comparison of buffy coat platelet components, single ‐donor apheresis non‐leucocyte depleted and single ‐donor apheresis leucocyte‐depleted platelet components
Paramo 2004	Review
Poon 2003	Review
Qureshi 2007	Audit of platelet transfusions in the UK
Rabinowitz 2010	Review
Rayment 2005	Review
Razzaghi 2012	Systematic review of platelet transfusion threshold in people with gastrointestinal bleeding
Rebulla 1997	Comparison of prophylactic platelet transfusions at different platelet transfusion thresholds
Reed 1986	Wrong patient group ‐ massive transfusion
Roberts 2003	Review
Sagmeister 1999	A non‐randomised retrospective study (aplastic anaemia)
Sakakura 2003	Review
Samama 2005	Guideline
Schiffer 1983	Comparison of leucodepleted vs standard platelet concentrates
Shanwell 1992	Comparison of fresh vs stored platelets
Shehata 2009	Systematic review ‐ ABO ‐identical vs non‐identical platelet transfusions
Shen 2007	Review
Singer 1988	Single ‐donor HLA ‐matched vs random ‐donor platelets
Sintnicolaas 1981	Comparison of single ‐donor and multiple ‐donor platelet components
Sintnicolaas 1982	Comparison of a prophylactic vs therapeutic platelet transfusion policy
Sintnicolaas 1995	Comparison of leucocyte depleted vs standard platelets
Slichter 1998	Comparison of apheresis vs pooled platelet components
Slichter 2004	Review
Slichter 2006	Comparison of pathogen ‐inactivated vs conventional apheresis platelets
Slichter 2007	Review
Slichter 2012	Review
Solomon 1978	Comparison of a prophylactic vs therapeutic platelet transfusion policy
Sosa 2003	Review
Spiess 2004	Wrong patient group ‐ cardiac
Stanworth 2013	Comparison of a therapeutic vs prophylactic platelet transfusion policy
Strauss 2004	Review
Strauss 2005	Review
Strindberg 1996	Comparison of apheresis vs buffy coat platelet products
Sweeney 2000	Comparison of pre‐storage leucodepleted vs bedside leucodepleted platelets
Tinmouth 2003	Review
Tosetto 2009	Guideline
TRAP 1997	Comparison of standard pooled platelet product vs irradiated pooled platelet product vs leucodepleted pooled platelet product vs apheresis platelet product
Vadhan‐Raj 2002	Wrong patient group ‐ gynaecological malignancy
van Marwijk 1991	Comparison of leucodepleted platelet products prepared by filtration or centrifugation
van Rhenen 2003	Comparison of pathogen ‐inactivated vs standard buffy coat ‐derived platelet transfusions
Verma 2008	A non‐randomised observational study
Wandt 1998	A non‐randomised prospective cohort study (not randomised at the participant level)
Wandt 2005	A non‐randomised prospective study with an historical case control (therapeutic vs prophylactic platelet transfusions)
Wandt 2006	A non‐randomised prospective study with an historical case control (therapeutic vs prophylactic platelet transfusions)
Wandt 2010	Review
Wandt 2012	Comparison of a therapeutic vs prophylactic platelet transfusion policy
Wang 2002	A comparison of acetaminophen and diphenhydramine vs placebo as premedication for platelet transfusions
Wang 2005	Review
Weigand 2009	Prospective observational study
Williamson 1994	Comparison of standard vs bedside leucodepleted platelet products
Woodard 2002	Review
Zahur 2002	Prospective observational study
Zeller 2014	Review
Zhao 2002	Comparison of leucodepleted vs standard platelet transfusions
Zumberg 2002	Comparison of prophylactic platelet transfusion policies using different platelet count thresholds

HLA: human leukocyte antigen 
 PAS: platelet additive solutions 
 PRP: platelet‐rich plasma

Differences between protocol and review

The previous review, Estcourt 2012a, has now been split into four separate reviews. We have published protocols for these four separate reviews (Estcourt 2014a; Estcourt 2014b; Estcourt 2014c; Estcourt 2014d). There have been no changes between the protocol for this review, Estcourt 2014a, and the completed review. As part of our assessment of other potential sources of bias, we assessed whether protocol deviation was balanced between treatment arms; this was not explicitly stated in the protocol.

Aspects of the protocol that were not implemented due to lack of data

Publication bias: We did not perform a formal assessment of potential publication bias (small‐trial bias) because we included fewer than 10 trials within this review (Sterne 2011).

Primary outcomes: We did not report the number needed to treat to benefit with CIs and the number needed to treat to harm with CIs because there were no significant differences between any of the bleeding outcomes.

Secondary outcomes: We planned to use the study's own measure, as there is no definitive patient‐reported outcome measure for this patient group (Estcourt 2014e). However, no study reported quality of life.

Subgroup analyses: Due to lack of data, we did not report one of the four prespecified subgroup analyses; this was presence of fever.

We did not perform meta‐regression because no subgroup contained more than 10 studies (Deeks 2011). We commented on differences between subgroups as a narrative.

Sensitivity analyses: None of the seven included trials had more that 20% of participants lost to follow‐up, and all of the trials had some threats to validity, therefore we performed neither pre‐planned sensitivity analysis.

Contributions of authors

Lise Estcourt: protocol development, searching, selection of studies, eligibility and quality assessment, data extraction and analysis, and content expert.

Simon Stanworth: protocol development, searching, selection of studies, eligibility and quality assessment, data extraction and analysis, and content expert.

Carolyn Doree: protocol development, searching, and selection of studies.

Marialena Trivella: protocol development and statistical expert.

Sally Hopewell: protocol development and methodological expert.

Patricia Blanco: searching and selection of studies.

Mike Murphy: protocol development and content expert.

Sources of support

Internal sources

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

  To fund the work of the Systematic Review Initiative (SRI)

External sources

• Cochrane Haematological Malignancies Group, Germany.

  For Editorial Support

• National Institute for Health Research (NIHR) Cochrane Programme Grant, UK.

  To provide funding for systematic reviewers and methodological support from the Centre for Statistics in Medicine, Oxford

Declarations of interest

Lise Estcourt is partly funded by NIHR Cochrane Programme Grant ‐ Safe and Appropriate Use of Blood Components.

Simon Stanworth: None declared.

Carolyn Doree: None declared.

Marialena Trivella is partly funded by NIHR Cochrane Programme Grant ‐ Safe and Appropriate Use of Blood Components.

Sally Hopewell is partly funded by NIHR Cochrane Programme Grant ‐ Safe and Appropriate Use of Blood Components.

Patricia Blanco is funded by NIHR Cochrane Programme Grant ‐ Safe and Appropriate Use of Blood Components.

Mike Murphy: None declared.

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