What laboratory tests and physiologic triggers should guide the decision to administer a platelet or plasma transfusion in critically ill children and what product attributes are optimal to guide specific product selection? From the Transfusion and Anemia EXpertise Initiative – Control/Avoidance of Bleeding (TAXI-CAB)

Abstract

Objectives:

To present consensus statements and supporting literature for plasma and platelet product parameters and related laboratory testing for transfusions in general critically ill children from the Transfusion and Anemia EXpertise Initiative – Control/Avoidance of Bleeding (TAXI-CAB).

Design:

Systematic review and consensus conference of international, multidisciplinary experts in platelet and plasma transfusion management of critically ill children.

Setting:

Not applicable.

Patients:

Critically ill pediatric patients at risk of bleeding and receiving plasma and/or platelet transfusions.

Interventions:

None

Measurements and Main Results:

A panel of 10 experts developed evidence-based and, when evidence was insufficient, expert based statements for laboratory testing and blood product attributes for platelet and plasma transfusions. These statements were reviewed and ratified by the 29 TAXI-CAB experts. A systematic review was conducted using MEDLINE, EMBASE, and Cochrane Library databases, from inception to December 2020. Consensus was obtained using the Research and Development/University of California, Los Angeles (UCLA) Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. We developed 5 expert consensus statements and 2 recommendations in answer to two questions: what laboratory tests and physiologic triggers should guide the decision to administer a platelet or plasma transfusion in critically ill children; and what product attributes are optimal to guide specific product selection?

Conclusions:

The TAXI-CAB program provides some guidance and expert consensus for the laboratory and blood product attributes used for decision making for plasma and platelet transfusions in critically ill pediatric patients.

INTRODUCTION

The Joint Commission on Accreditation of Health Care Organization has identified blood transfusion as a top five overused treatment that reduced patient safety [1]. Historically, platelet and plasma transfusions have been used to treat or prevent bleeding. However, balancing transfusion associated risks and the potential of overuse with benefit from treatment is challenging. As reported in a large national survey [2], platelet transfusions are the second most commonly prescribed blood product in pediatric patients with 19.3% of pediatric inpatients receiving platelets. Notably, platelet usage in all inpatients has increased nationwide from 1993 to 2014 [3].

Adverse events related to blood transfusion are an important clinical concern and result in increased healthcare cost [4]. Pediatric patients are more at risk for acute transfusion reactions than adults. In a study of >130,000 blood transfusions, given to pediatric and adult patients, the rate of acute transfusion reactions was higher in the pediatric patients compared to the adult patients (6.2 versus 2.1 per 1000 transfusions, respectively) [5]. The excess incidence of transfusion related reactions included three of the most common events; 1.9 vs 0.47 per 1000 transfusions for febrile non-hemolytic, 0.29 vs 0.078 per 1000 transfusions for hypotension, and 2.7 vs 1.1 per 1000 transfusions for allergic transfusion reactions, respectively. Transfusion reactions are most common following platelet transfusions, possibly as a result of the plasma contained in the products. However, the current literature for these reactions is limited in children [6, 7].

Multiple reports describe specific laboratory or clinical physiologic parameters to guide transfusion decisions in children admitted to the Pediatric Intensive Care Unit. Large-scale studies using objective measures evaluating laboratory and product attributes as efficacious in reducing bleeding are limited, as is research into development of functional hemostatic or coagulation parameters. Numerous studies have demonstrated that protocols, guidelines and/or decision trees improve clinical management and/or patient outcomes of critically ill children [8, 9]. The objective of the ‘Transfusion and Anemia EXpertise Initiative – Control/Avoidance of Bleeding’ (TAXI-CAB)” was to rigorously and methodologically develop guidelines that can support clinicians (e.g. pediatric intensivists, cardiologists, anesthesiologists, transfusion medicine specialists, etc.) in their decision-making about platelet and plasma transfusion in critically ill children. This sub-group of TAXI-CAB evaluated and summarized the current literature and ‘state of the science’ on the questions: what laboratory tests and physiologic triggers should guide the decision to administer a platelet or plasma transfusion in critically ill children and what product attributes are optimal to guide specific product selection?

METHODS

The search strategy, item selection and recommendation generation used to identify and select references for systematic review and to develop recommendation are detailed in the general manuscript of TAXI-CAB [10]. Briefly, we searched Ovid MEDLINE®, Ovid EMBASE, and Cochrane Library (Wiley) from inception through December 2020 using a combination of medical subject heading terms and text words to define concepts of plasma or platelet transfusion, transfusion triggers, laboratory tests to assess efficacy of transfusion in children admitted to the pediatric intensive care unit (PICU). For articles selected for inclusion, reference lists and citing articles were selected from Scopus (Elsevier) and screened. Two reviewers independently reviewed all citations and performed data extraction and assessments of bias. Literature was reviewed for relevance to laboratory testing and blood product attributes. Research Electronic Data Capture (REDCap) hosted at Weill Cornell Medicine was used for standardized data extraction. We used a standardized data extraction form to construct evidence tables and graded the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system [11].

Ten experts participated in the development of recommendations from this subgroup. A panel of 29 experts convened in an on-line format over 18 months to develop good practice statements, recommendations and, when evidence was lacking, expert consensus statements. Good practice statements are those in which there is high-level of certainty that the practice will do more good than harm, but there is little in the way of supporting literature evidence. Expert consensus statements are based on the expert opinion of the group, but in areas where research is likely needed. All statements from each subgroup were reviewed by the full panel of experts and voted on using the Research and Development/University of California, Los Angeles (UCLA) Appropriateness Method. Agreement was defined a priori as >80% of all experts. The recommendations and statements are intended to apply to infants, children and adolescents. Prophylactic transfusions are those prescribed to patients at risk of bleeding, whereas therapeutic transfusions are given to those with active bleeding.

RESULTS

Searching laboratory parameters and blood product attributes identified 4031 and 5476 abstracts, respectively. After duplicates were removed, a total of 3446 and 4921 abstracts were screened. Then, out of 291 and 462 full text manuscripts about laboratory parameters and blood product attributes, respectively, we selected 49 and 88 papers for detailed review (see Figures 1 and 2). These papers underwent data extraction and assessment of bias in order to generate recommendations and statements (see Supplemental Data Tables 1 and 2); five 5 expert consensus statements and 2 graded recommendations were produced. The voting data, including the number of voting experts and median score, are provided for each statement and recommendation.

Figure 1. papers flow chart.

PRISMA diagram for studies on laboratory assays to guide plasma and platelet transfusion

Figure 2. papers flow chart.

PRISMA diagram for studies on product selection

Laboratory Tests for Guiding Plasma and Platelet Transfusions

Expert Consensus Statements

1. In critically ill pediatric patients, there is insufficient evidence to recommend a specific laboratory test as a threshold or as a target for platelet transfusion for prophylactic or therapeutic indications. 92% Agreement (n=24), Median 8, IQR 7–9.

Rationale: Over 50% of platelet transfusions in the pediatric ICU are given as prophylaxis [12,13]. Thus, platelet count alone determines whether a platelet transfusion will be administered. The risks associated with bleeding from thrombocytopenia have been evaluated in numerous studies with inconclusive findings [14–17]. Furthermore, the understanding of bleeding in certain types of adult thrombocytopenic patients suggests that patients only require a platelet level of approximately 7×10⁹ cells/L to maintain effective hemostasis [18]. Likewise, to minimize bleeding, a specific platelet count to trigger a prophylactic platelet transfusion has been controversial. Although studies have included children with cancer or undergoing hematopoietic stem cell transplant, very few recommendations have been made that are relevant to critically ill children. However, guidance from the American Association of Blood Banks (AABB) state platelet transfusions are indicated in adults for: 1) prophylactic transfusion when total platelet count (TPC) < 10×10⁹ cells/L due to hypoproliferative thrombocytopenia; 2) prophylactic transfusion when elective central venous catheter placement < 20×10⁹ cells/L; 3) prophylactic transfusion when elective lumbar puncture < 50×10⁹ cells/L; and 4) prophylactic transfusion when patient having major elective non-neuraxial surgery < 50×10⁹ cells/L. In addition, the AABB recommends against routine prophylactic transfusion in adult patients who are not thrombocytopenic and undergoing cardiopulmonary bypass surgery, but recommends platelet transfusions when bleeding or when there is evidence of platelet function defect [19]. Nonetheless, studies to assess quantitative platelet counts as targets to stop bleeding are lacking, particularly in the pediatric population.

Recent advances in platelet function testing (PFT) instead of reliance on platelet number alone, have made this assessment more widely available, albeit not at all centers. These have previously included bleeding time by various methodologies, platelet aggregometry, and studies of activated platelets via flow cytometry [20]. Although these tests may become available in the future, at present there is insufficient information to support a recommendation or consensus statement about routine use. Moreover, the platelet count does not correlate well with risk of bleeding or represent a functional hemostatic marker [21].

We evaluated studies with platelet transfusion alone (n=34), platelet and RBC (n=2), or platelet and plasma (n=7) using platelet count (n=26), platelet aggregation (n=2), thrombin generation (n=1), closure time (n=1), or platelet mass index (n=2) in surgical, neonatal, pediatric ICU, oncology, trauma, extracorporeal membrane oxygenation (ECMO), or dengue patients. Given the available laboratory testing, platelet count has been incorporated into decision trees based on expert consensus to help practitioners in the decision to transfuse platelets to critically ill children in eight pre-defined clinical settings [10]. However, similar to current British guidelines [22], we concluded that pediatric intensivists should not use platelet count alone to drive the decision to administer platelet transfusions in PICU patients as the overall general health and acuity of the patient may govern bleeding tolerance more than a pretransfusion threshold. The tolerance of thrombocytopenia and risk of bleeding varies with contextual patient circumstances, e.g., a child following a traumatic brain injury with intracranial hemorrhage is different from a patient with disseminated intravascular coagulation or bone marrow failure. It is the presence of thrombocytopenia, and other risk factors that should prompt the practitioner to prescribe a platelet transfusion, such as presence of severe bleeding, severity and type of illness, patient trajectory of illness (deteriorating or recovering), hemodynamic instability, and other related conditions.

2. In critically ill pediatric patients, there is insufficient evidence to recommend a specific laboratory test as a threshold or as a target for plasma transfusion for prophylactic or therapeutic indications. 96% Agreement (n=24), Median 8.5, IQR 7.25–9.

Rationale: Plasma contains all coagulation factors present in whole blood. Thirty to 50% of plasma transfusions given in the PICU are prophylactic (3, 23–26). In patients on extracorporeal membrane oxygenation, almost 60% of plasma transfusions are given prophylactically even though conventional coagulation tests (prothrombin time (PT), international normalized ratio (INR) or activated partial thromboplastin time (aPTT)) are unchanged after transfusion [12]. A retrospective study found that plasma transfusion is independently associated with adverse outcomes including transfusion-related acute lung injury, anaphylaxis, and venous thrombosis [27]. Finding relevant laboratory tests to indicate which patients may benefit from plasma transfusion to minimize bleeding risk or stop active bleeding is paramount.

PT and/or aPTT are the conventional clot-based tests that measure the time it takes for blood to form a clot after in vitro incubation with thromboplastin. INR is calculated from PT and used to monitor the intensity of warfarin-induced anticoagulation. The PT and aPTT results are used as an estimation of coagulation efficiency. Viscoelastic tests (VET) are clot-based assays (thromboelastometry (ROTEM^™) or thromboelastography (TEG^™)) that measure various parameters regarding clot formation. However, studies evaluating the use of traditional and viscoelastic test parameters in critically ill children to minimize bleeding are inconclusive and these values alone may not be reliable triggers for transfusion. Furthermore, due to changes in hemostasis during development, the neonatal coagulation values differ from those in children and adults and therefore measured values must be interpreted against age-specific norms.

After evaluation of studies reporting plasma transfusion alone (n=13) or platelet and plasma (n=7) using INR (n=6), VET (n=4), in surgical, neonatal, pediatric ICU, oncology, trauma, ECMO, or dengue patients, we agreed that pediatric intensivists should not use PT (INR) cutoffs or VET R times alone to drive the decision to administer plasma transfusions in PICU patients; they should be guided by clinical assessment. Given the available laboratory testing, PT (INR) has been incorporated into decision trees based on expert consensus to help practitioners in the decision to transfuse plasma to critically ill children in eight pre-defined clinical settings [10]. Nonetheless, current level of evidence is insufficient to recommend a PT (INR) threshold as a guide for plasma transfusion. Plasma transfusion may be indicated in clinical situations such as invasive procedures in patients with major alterations in coagulopathy testing (INR, PT, and VET).

Blood Product Attributes for Plasma and Platelet Components

Clinical Recommendations

1. In critically ill neonatal and pediatric patients, the use of leukocyte reduced cellular blood components is recommended. GRADE 1C (strong recommendation, Low quality of pediatric evidence), 96% Agreement (n=23), Median 9, IQR 8–9.

Rationale: Leukocyte reduction for cellular blood products is now standard in transfusion practice due to compelling evidence of safety improvements they produce. Specifically, studies have demonstrated leukocyte reduced blood products are associated with 1) decreased alloimmunization to foreign human leukocyte antigens (HLA), 2) fewer febrile transfusion reactions and 3) less risk of transfusion transmitted cytomegalovirus (CMV) compared to non-leukocyte reduced blood products [28–30]. Studies in adult patients not included in the selected articles find similar results [31]. Lastly, leukocyte reduction is also a reliable mechanism to decrease the rate of febrile non-hemolytic transfusion reactions and should be employed for this reason alone whenever possible [32]. The timing of leukocyte reduction is important; products leukocyte reduced before storing (i.e. prestorage) are less likely to cause a febrile reaction than those that are filtered after storage [33]. In pediatric patients, there is an association of allergic and febrile reactions with non-leukoreduced blood product administration, thus attributing the reaction to the leukocytes or secreted mediators [34].

2. In a critically ill RhD negative neonate, infant or child in need of a platelet transfusion, RhD positive platelets should be used if an RhD negative platelet component is not available. GRADE 1C (strong recommendation, Low quality of pediatric evidence), 95% Agreement (n=20), Median 8, IQR 8–9.

Rationale: RhD is a membrane protein restricted to the surface of RBCs that functions to support membrane integrity and transport. Approximately 7–15% of the population is lacking the RhD protein on the RBC, i.e. are “Rh negative” and are at risk of forming anti-D antibody if exposed to RhD positive RBCs through transfusion or pregnancy [35]. While platelets do not express the RhD protein, platelet concentrates can provide RhD via RBC contamination during donation or by shed antigen adsorbed to the platelet membrane. Whole blood derived platelet concentrates are estimated to have an average of 0.036 mL per full adult dose, while apheresis platelets have 0.00043 mL [36]. There is a theoretical concern that the very low amount of RhD positive RBCs in a platelet product could cause the patient to become alloimmunized to RhD (i.e., form anti-D antibodies).

As RhD negative individuals are relatively uncommon in the population, ensuring an ample supply of RhD negative platelets for RhD negative patients can be difficult. Additionally, the platelet supply is often low due to seasonal and local shortages, further affecting availability of all platelet products. When this occurs, transfusion services may issue RhD positive platelets to RhD negative patients, particularly when a patient requires multiple platelet transfusions.

Real world, clinical studies have found the risk of RhD alloimmunization due to platelet transfusion to be very low. In a single center study, 315 RhD negative patients (aged 0–103 years) were tested for anti-D antibodies 4+ weeks after receiving a RhD positive product, 89% of which were platelet concentrates [36]. There were 12 of 303 recipients who formed anti-D antibodies for a 3.8% alloimmunization rate. In a retrospective multicenter study of RhD negative patients (aged 2 – 100 years) who received RhD+ platelets, only 7 of 485 patients (1.44%; 95% CI 0.58–2.97%) had evidence of anti-D alloimmunization following RhD+ platelet transfusion. Diagnoses included hematologic (203/485, 42%), oncologic (64/485, 13%) and other disorders (218/485, 45%). There were no differences between patients who formed anti-D antibodies from non-responders (gender, age, immunosuppressive therapy, type and number of platelet products) [36]. In a study of RhD negative pediatric oncology and stem cell transplant patients receiving over 200 RhD positive apheresis platelet “units”, authors found no evidence of anti-D alloimmunization [37]. Using available evidence, the transfusion of RhD positive platelets, especially apheresis products to RhD negative patients who are bleeding or have met clinical or laboratory criteria for a platelet transfusion, appears to be safe, particularly if platelet supply is limited.

Some centers use Rh immune globulin (RhIg) when RhD positive platelets are administered to certain RhD negative patients (for example, in females of childbearing potential and/or those who are pre-stem cell transplant). Given the low rate of RhD alloimmunization and limited evidence, this practice is variable. In a recent survey of 28 cancer centers who are members of the National Comprehensive Cancer Network, fifty-three percent of centers stated they would consider using RhIg in an RhD negative female patient of childbearing potential receiving RhD positive platelets [38]. Each institution may consider the development of institutional guidelines in collaboration with the transfusion service medical leadership to direct the use of RhIg.

Expert Consensus Statements

1. When considering pathogen reduction and selecting products for plasma transfusion, products may be selected that balance risk of transfusion-transmitted infection, hemostatic effects, and clinical outcomes, as well as feasibility. 92% Agreement (n=24), Median 9, IQR 8–9.

Rationale: Since coagulation factors are highly variable between single-donor plasma units pooling plasma from many donors provides a method to maintain a “normal” concentration of these factors [39]. However, pooling donors increases the odds of transmission of infectious diseases. To mitigate this risk, multiple pathogen inactivation methods are available including solvent/detergent (S/D) treatment, methylene blue (MB), ultraviolet light with riboflavin, and psoralens (amotosalen) [40].

Some coagulation factors are reduced in various products, including factor VIII (25% lower in MB plasma and 45% lower in amotosalen and S/D plasma), and fibrinogen (30% lower in MB and amotosalen plasma) [41]. Additionally, both Protein S and alpha-2 antiplasmin are lower in S/D plasma causing this product to be contraindicated in patients with Protein S deficiency. However, S/D plasma has been shown to have a better thrombin generation profile (total, lag time to peak, and peak thrombin formation), compared with regular plasma [42].

Safety of these products is supported by hemovigilance studies of over 10 million units administered to patients in Europe, although detailed information regarding children is not included [39]. In a retrospective study of adults with thrombotic thrombocytopenic purpura, patients younger than 40 years who underwent plasma exchange with S/D plasma exhibited a shorter time to platelet recovery [43]. Conversely, one randomized controlled trial (RCT) in adults undergoing liver transplantation, demonstrated lower transfusion volumes with regular plasma than with S/D or MB plasma [44]. In critically ill children, a secondary analysis of a prospective observational study suggested S/D plasma to be independently associated with a lower risk of mortality [45]. However, there are no multicenter RCTs comparing the efficacy of regular plasma compared to pooled products in critically ill children. Pathogen-reduced plasma may be safe and have appropriate hemostatic effects, but studies are needed in children for confirmation.

2. When considering pathogen reduction and selecting products for platelet transfusion, products may be selected that balance risk of transfusion-transmitted infection, hemostatic effects, and clinical outcomes, as well as feasibility. 87% Agreement (n=23), Median 9, IQR 8–9.

Rationale: Platelets are typically stored at a room temperature (20– 24°C) under gentle agitation, which, when compared to cold storage, improves circulation time. However, room temperature storage increases the risk of bacterial contamination [46]. Therefore, several pathogen reduction techniques have been developed to mitigate infection risk [47]. For example, amotosalen, a light-activated, DNA-, RNA-crosslinking psoralen compound, is able to neutralize pathogens, by preventing replication of DNA or RNA present in pathogens but not in the blood components being treated [48]. In addition to decreasing the risk of infections, pathogen reduction obviates the need for blood product irradiation to decrease the risk of transfusion associated graft versus host disease, as the pathogen reduction process irreversibly blocks DNA and RNA replication.

Studies of pathogen reduced platelets compared to conventional (untreated) platelets have not demonstrated an increase in acute transfusion adverse events. However, two retrospective cohort studies in children and infants suggested that pathogen reduction of platelets is associated with decreased post-transfusion platelet increments as compared to untreated platelet products. One study from the USA found that pediatric patients ages 1–18 years who were given Intercept® platelets (Cerus, CA, USA) required additional platelet transfusion(s) within 48 hours after the index transfusion suggesting that the target platelet count had not been achieved [49]. No such difference was found in infants < 1yr whether treated in a NICU or PICU. Additionally, the authors did not find any difference in bleeding in any of the age groups. There was no difference in the rate of allergic or febrile non-hemolytic transfusion reactions in those infants and children who received either conventional or Intercept® platelets. A second study from Spain found that neonatal patients exhibited increased usage of Mirasol® (Terumo BCT, CO, USA) pathogen reduced platelets (transfusion events and dose) when compared to historic controls who received conventional platelets [50]. The authors also found that adults and children had the same rate of acute transfusion reactions (1.3%) when using Mirasol® pathogen reduced platelets.

There are prospective studies that further support the retrospective studies in children. A RCT in adult hematology-oncology patients with chemotherapy-induced thrombocytopenia comparing untreated platelets with Mirasol® pathogen reduced platelets showed a 50% lower platelet count increment in the pathogen-reduced platelet arm (p<0.001), and shorter intervals between platelet transfusion (p<0.001) [51]. Nonetheless, pathogen-reduced platelets did not lead to increased bleeding events. Another RCT has just finished enrolling 3,070 children and adults with hematology-oncology disorders who were randomized to conventional vs pathogen-reduced platelet transfusions (ClinicalTrials.gov NCT02549222). The primary outcome was the proportion of patients requiring mechanical ventilation. A 2017 Cochrane systematic review, based on 12 trials and 1,981 participants, concluded that pathogen-reduced platelet transfusions do not affect all-cause mortality, risk of clinically significant or severe bleeding, or risk of a serious adverse event [52]. Therefore, while there is a benefit in terms of decreased risk of transfusion transmitted infection, pathogen-reduced platelets might have lower hemostatic effects, as measured by platelet increment count and requiring more frequent transfusions.

3. When a critically ill pediatric patient has persistently poor platelet count increments following platelet transfusion, a clinical and laboratory assessment for platelet refractoriness is suggested to elucidate the cause. 96% Agreement (n=23), Median 9, IQR 8–9.

Rationale: Platelet transfusion refractoriness (PTR) is generally defined as persistently insufficient post-transfusion platelet count increments following platelet transfusion from random donors [53] and is typically considered when the corrected count increment (CCI) is ≤7500/μL and absolute count increment less than 5000 per unit of platelets measured at 1-hour post-transfusion. PTR has been associated with adverse clinical outcomes including risk of bleeding, length of stay, survival and hospital cost [54,55].

PTR can be due to either immune or non-immune causes, with non-immune causes being more common. A detailed history, physical examination and laboratory testing help to distinguish between these potential causes. Non-immune factors include both patient and product related factors. Patient related factors include bleeding, medications, splenomegaly, or a consumptive etiology, e.g., diffuse intravascular coagulation. Product related factors may include the type of product received (buffy coat or apheresis), blood group ABO compatibility, or age [56]. The relative contribution of immune or non-immune factors can be challenging to separate when treating complex critically ill patients with underlying co-morbidities.

Prevalence estimates of PTR in adults are widely variable depending on the underlying disease and comorbidities and have been estimated to range from 1 in 20 to 1 in 5 in various observational studies [14,57]. The prevalence of PTR in critically ill children has not been assessed [58]. Fewer than ten studies have been published on PTR in children and rates of PTR have varied widely between 8–100% [56,58]. Experts suggest that PTR occurs less frequently in children when compared to adults due to decreased previous exposure to transfusions and pregnancy, which typically precedes immune PTR.

In addition to a comprehensive clinical assessment, laboratory tests are essential to confirm an immune mediated cause [59]. Immune causes include alloimmunization to human leucocyte antigen (HLA) and or human platelet antigen (HPA) antigens with HLA alloimmunization occurring more frequently. Other immune causes include ABO incompatibility, platelet autoantibodies and drug related platelet antibodies. Methods to screen for the presence of HLA antibodies include lymphocytotoxicity, enzyme-linked immunosorbent assay (ELISA), flow cytometric immunofluorescence tests or the newer multiplex flow cytometric bead-based assays. Due to technological aspects of testing, significant amount of discordance exists between methods, and consequently there is no recognized gold standard test.

Standard practice is to provide unselected or random platelet products for initial platelet transfusion support while awaiting results. Typically, ABO-identical, fresh platelet products are issued with assessment of a 1-hour post transfusion increment. If non-immune factors are suspected and treatment is essential, support may be continued with random donor platelets. Immune-based PTR can be managed by either crossmatch-compatible, HLA-matched or HLA-compatible platelet units than using random non-selected units [60,61]. Platelet crossmatching involves a match with antibodies against HLA or HPA bound to the donor platelets seen with indicator red cells coated with anti–immunoglobulin G. In HLA matching, donor HLA-A and HLA-B antigens can be matched with those of the patient aiming for a 4/4 match. When exact HLA matches are unavailable, antibody profile determined by the single-antigen bead test can be used to select donor units that lack the corresponding cognate antigens called as HLA compatible/HLA selected platelets. Response to HLA selected platelet transfusions should be carefully monitored, ideally with one-hour post transfusion platelet assessment. If responses are poor, additional rare etiologies including HPA antibodies may be considered.

DISCUSSION

In the TAXI-CAB program [10], the current report has sought to address the following two questions: 1) what laboratory tests and physiologic triggers should guide the decision to administer a platelet or plasma transfusion in critically ill children; and 2) what product attributes are optimal to guide specific product selection? The ensuing literature review and expert assessment produced two expert consensus statements about laboratory testing and three expert consensus statements and two graded recommendations about blood product attributes best suited for critically ill pediatric patients. Our extensive systematic review resulted in very few studies of high quality related to plasma and/or platelet transfusion strategies in critically ill children. Specifically, there are few RCTs in these two areas of medical science. Thus, many of the statements are derived from a mixture of retrospective studies and single center studies. There are some large population studies about blood safety that helped to develop blood product attribute statements. However, several are hemovigilance studies from European countries that lack detail on children and do not include efficacy outcomes.

CONCLUSIONS

This systematic review and assessment of the literature has yielded a robust set of two recommendations and five expert consensus statements that describe the current state of evidence-based practice of laboratory testing and blood products attributes for platelet and plasma transfusions for critically ill children. Further research, particularly to investigate appropriate laboratory parameters that correlate bleeding risks to guide transfusion therapy are urgently needed and discussed in the companion TAXI-CAB research-gaps article [62].

APPENDIX 1. Transfusion and Anemia EXpertise Initiative – Control/Avoidance of Bleeding (TAXI-CAB) Members

(* for executive committee) Co-chairs: Marianne E. Nellis, MD, MS*, Weill Cornell Medicine, New York, NY, and Robert I. Parker, MD*, Renaissance School of Medicine, State University of New York at Stony Brook, Stony Brook, NY; Content Experts: Section 1. Laboratory assays used to assess need for plasma and/or platelet transfusions: Scot T. Bateman, MD*, University of Massachusetts Medical School, Worcester, MA, Meghan Delaney, DO, MPH, The George Washington University Health Sciences, Washington, DC, Kenneth E. Remy, MD, MHSc, MSCI, Washington University of St. Louis, St. Louis, MO, Katherine Steffen, MD, Stanford University, Palo Alto, CA; Section 2. Traumatic brain injury and intracranial hemorrhage: David F. Bauer, MD, MPH, Baylor College of Medicine, Houston, TX, Jacques Lacroix, MD, Université de Montréal, Montreal, QC, Canada, Daniel Nishijima, MD, Davis School of Medicine, Davis, CA; Section 3. Following cardiopulmonary bypass: Jill M. Cholette, MD, University of Rochester Golisano Children’s Hospital, Rochester, NY, Sitaram Emani, MD, Harvard Medical School, Boston, MA, Juan Ibla, MD, Harvard Medical School, Boston, MA, Marie E. Steiner, MD, MS, University of Minnesota, Minneapolis, MN; Section 4. Supported by extracorporeal membrane oxygenation: Melania M. Bembea, MD, PhD, Johns Hopkins University School of Medicine, Baltimore, MD, Jill M. Cholette, MD, University of Rochester Golisano Children’s Hospital, Rochester, NY, Jennifer A. Muszynski, MD, MPH, Nationwide Children’s Hospital, Columbus, OH, Adam M. Vogel, MD, Baylor College of Medicine, Houston, TX; Section 5. Following severe trauma: Susan M. Goobie, MD, Harvard Medical School, Boston, MA, Thorsten Haas, MD, University Children’s Hospital Zurich, Switzerland, Daniel Nishijima, MD, Davis School of Medicine, Davis, CA, Robert T. Russell, MD, MPH, University of Alabama Birmingham, Birmingham, AL, Adam M. Vogel, MD, Baylor College of Medicine, Houston, TX; Section 6. With oncologic diagnosis or following hematopoietic stem cell transplantation: Gemma Crighton, MD, Royal Children’s Hospital, Melbourne, Australia, Ruchika Goel, MD, MPH, Johns Hopkins University, Baltimore, MD, Jacques Lacroix, MD, Université de Montréal, Montreal, QC, Canada, Lani Lieberman, MD, University of Toronto, Canada, Simon J. Stanworth, MD, University of Oxford, UK, Marie E. Steiner, MD, MS, University of Minnesota, Minneapolis, MN; Section 7. With acute liver failure or following liver transplantation: Susan M. Goobie, MD, Harvard Medical School, Boston, MA, Oliver Karam, MD, PhD*, Children’s Hospital of Richmond at VCU, Richmond, VA, Paul A. Stricker, MD, Perelman School of Medicine at the University of Pennsylvania, PA; Section 8. Following non-cardiac surgery: Susan M. Goobie, MD, Harvard Medical School, Boston, MA, Thorsten Haas, MD, University Children’s Hospital Zurich, Switzerland, Marisa Tucci, MD, Université de Montréal, Montreal, QC, Canada, Adam M. Vogel, MD, Baylor College of Medicine, Houston, TX; Section 9. Invasive procedures outside of the operating room: Gemma Crighton, MD, Royal Children’s Hospital, Melbourne, Australia, Jacques Lacroix, MD, Université de Montréal, Montreal, QC, Canada, Robert T. Russell, MD, MPH, University of Alabama Birmingham, Birmingham, AL, Paul A. Stricker, MD, Perelman School of Medicine at the University of Pennsylvania, PA; Section 10. Sepsis and/or disseminated intravascular coagulation: Oliver Karam, MD, PhD*, Children’s Hospital of Richmond at VCU, Richmond, VA, Simon J. Stanworth, MD, University of Oxford, UK, Katherine Steffen, MD, Stanford University, Palo Alto, CA, Stacey L. Valentine, MD, MPH*, University of Massachusetts Medical School, Worcester, MA; Section 11. Product processing and selection: Meghan Delaney, DO, MPH, The George Washington University Health Sciences, Washington, DC, Ruchika Goel, MD, MPH, Johns Hopkins University, Baltimore, MD, Oliver Karam, MD, PhD*, Children’s Hospital of Richmond at VCU, Richmond, VA, Jennifer A. Muszynski, MD, MPH, Nationwide Children’s Hospital, Columbus, OH; Evidence-based medicine: Melania M. Bembea, MD, PhD, Johns Hopkins University School of Medicine, Baltimore, MD, Diana Delgado and Michelle Demetres, Weill Cornell Medicine, New York, NY; Implementation science: Katherine Steffen, MD, Stanford University, Palo Alto, CA.