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. Author manuscript; available in PMC: 2023 Jan 1.
Published in final edited form as: Pediatr Crit Care Med. 2022 Jan 1;23(13 SUPPLE 1 1 Suppl):e63–e73. doi: 10.1097/PCC.0000000000002859

Research Priorities for Plasma and Platelet Transfusion Strategies in Critically Ill Children: From the Transfusion and Anemia EXpertise Initiative – Control/Avoidance of Bleeding (TAXI-CAB)

Marianne E Nellis 1, Kenneth E Remy 2, Jacques Lacroix 3, Jill M Cholette 4, Melania M Bembea 5, Robert T Russell 6, Marie E Steiner 7, Susan M Goobie 8, Adam M Vogel 9, Gemma Crighton 10, Stacey L Valentine 11, Meghan Delaney 12, Robert I Parker 13, Pediatric Critical Care Transfusion and Anemia Expertise Initiative – Control/Avoidance of Bleeding (TAXI-CAB), in collaboration with the Pediatric Critical Care Blood Research Network (BloodNet), and the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network
PMCID: PMC8769351  NIHMSID: NIHMS1746611  PMID: 34989706

Abstract

Objectives:

To present a list of high priority research initiatives for the study of plasma and platelet transfusions in 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 13 experts developed research priorities for the study of plasma and platelet transfusions in critically ill children which were reviewed and ratified by the 29 TAXI-CAB experts. The specific priorities focused on the following sub-populations: severe trauma, traumatic brain injury, intracranial hemorrhage, cardiopulmonary bypass surgery, extracorporeal membrane oxygenation, oncologic diagnosis or stem cell transplantation, acute liver failure and/or liver transplantation, non-cardiac surgery, invasive procedures outside of the operating room and sepsis and/or disseminated intravascular coagulation. In addition, tests to guide plasma and platelet transfusion, as well as component selection and processing, were addressed. We developed four general overarching themes and fourteen specific research priorities using modified Research and Development (RAND)/University of California, Los Angeles (UCLA) methodology.

Conclusions:

Studies are needed to focus on the efficacy/harm, dosing, timing and outcomes of critically ill children who receive plasma and/or platelet transfusions. The completion of these studies will facilitate the development of evidence-based recommendations.

Keywords: platelet transfusion, plasma, hemostasis, critical illness, child, thrombocytopenia, coagulopathy

INTRODUCTION

Plasma and platelet transfusions are relatively common interventions prescribed in the pediatric intensive care unit (PICU); 3.5% of all admissions receive at least one transfusion of either of the two blood components [1,2]. Plasma and platelet transfusions have been independently associated with increased morbidity, such as acute lung injury [3], increased organ dysfunction [4] and immunomodulation [5], as well as mortality [2]. Despite the frequency of use and associated harms, recommendations for plasma and platelet transfusions specific to critically ill children are limited. While the aim of the Transfusion-Anemia eXpert Initiative – Control/Avoidance of Bleeding (TAXI-CAB) was to provide guidance to clinicians [6], the lack of high-quality evidence in critically ill children limited the program to four recommendations, five good practice statements, and forty-four expert consensus statements.

We therefore sought to develop a compilation of high priority research topics for the study of plasma and platelet transfusions in critically ill children.

METHODS

The methodology for TAXI-CAB is described in both the main paper describing the recommendations [6] as well as the detailed methodology of the TAXI program from which it was modeled [7]. Briefly, experts were chosen based on publication history in pediatric hemostasis and/or plasma and platelet transfusions along with clinical practice and experience. The experts participated in a systematic review and two virtual consensus conferences. Subtopics were identified for investigation. Eight of these subtopics focused on plasma and platelet transfusion strategies in specific groups of critically ill pediatric patients: 1) traumatic brain injury (TBI) or non-traumatic intracranial hemorrhage (ICH), and/or severe trauma; 2) post-cardiac surgery with cardiopulmonary bypass (CPB); 3) supported with extracorporeal membrane oxygenation (ECMO); 4) oncologic diagnosis with or without stem cell transplantation; 5) acute liver failure and/or liver transplantation; 6) following non-cardiac surgery; 7) patients undergoing invasive procedures outside of the operating room; and 8) sepsis and/or disseminated intravascular coagulation (DIC). Additionally, two subtopics focused on laboratory tests and product selection and processing including: 9) laboratory tests employed to identify the need and/or efficacy of platelet or plasma transfusion; and 10) the effect of product selection and processing on clinical outcome were investigated.

We performed comprehensive searches in the following databases: Ovid MEDLINE® (1946 to December 16, 2020), Ovid EMBASE (1974 to December 16, 2020), and Cochrane Library (Wiley). All experts worked together to develop general research priorities and each subgroup developed a list of research priorities specific to their subtopic. To limit redundancy, all proposed research priorities were reviewed by the Executive Committee prior to voting and those with similar themes were merged. Using the Research and Development/University of California, Los Angeles (UCLA) Appropriateness Method [8], the research priorities were scored anonymously using an online tool (Survey Monkey, San Mateo, CA). Using a 9-point Likert scale, ratings of 1-3 indicated disagreement, 4-6 represented neutrality and 7-9 represented agreement. Expert consensus agreement was defined a priori as 80% of the experts rating the research priority a 7, 8, or 9. The use of the word “recommend” in the research priorities denotes the study topics that the group believes to be essential in the field of transfusion medicine research in pediatrics. The word “recommend” does not denote an evidence-based process using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system [9].

RESULTS

The group developed general overarching research priorities applicable across all critically ill children, as well as some research priorities specific to subgroups.

GENERAL OVERARCHING THEMES

We identified four overarching themes that can be applied across all subgroups of critically ill patients.

1. We recommend studies to validate definitions of bleeding and blood loss with specific impact of the location of bleeding in critically ill children. 82% agreement (n=22), Median 9, IQR 7.75-9.

2. We recommend studies to examine the mechanisms driving both efficacy and harm in critically ill children receiving plasma and/or platelet transfusions. 82% agreement (n=22), Median 8, IQR 7.75-9.

3. We recommend studies that describe thresholds or triggers to weigh the risk/benefit ratio in tolerating a coagulation abnormality or thrombocytopenia versus the risk/benefit ratio of giving a plasma or platelet transfusion in critically ill children. 86% agreement (n=22), Median 9, IQR 8-9.

4. We recommend studies that seek to determine the optimal dose, timing and order in which plasma and platelet transfusions are administered, with respect to each other and to other hemostatic interventions in order to decrease the risk of bleeding or stop active bleeding in critically ill children. 91% agreement (n=22), Median 8, IQR 8-9.

The following are the research priorities identified by the subgroups.

SEVERE TRAUMA, TBI AND NON-TRAUMATIC ICH

1.1. In children with traumatic injury and/or TBI and massive bleeding, we recommend future studies to determine if goal directed resuscitation compared to an empiric ratio approach may provide benefit in pre-determined patient-centered outcomes. 95% agreement (n=21), Median 8, IQR 8-9.

Rationale:

Trauma continues to be the most common cause of mortality in pediatric patients and coagulopathy is independently associated with poor outcomes [10]. Through appropriately designed and powered studies, trauma-induced coagulopathy and outcomes following massive transfusion in adults is relatively well characterized; however, quality pediatric data are less robust [11]. The current principles of resuscitation following trauma in many centers employ volume repletion with component-based administration of products to mimic whole blood, the aim being ratios close to 1:1:1 of transfused plasma, red blood cell (RBC), and platelets while minimizing crystalloid administration. Unfortunately, the results of studies in adults have been extrapolated to pediatric trauma protocols without appropriate corroborative data. Military and civilian pediatric trauma studies evaluating empiric ratio driven resuscitation for hemorrhagic shock have produced conflicting results [12–15] and, to our knowledge, no prospective goal directed studies have been performed.

While the specific research priority is made in reference to TBI, there was strong agreement within the Expert Panel that resuscitation strategies should be studied in different populations of critically ill children as the pathophysiology of bleeding and hemostasis may require different therapeutic approaches. For example, resuscitation in traumatic hemorrhagic shock might need to be substantially different than that in severe TBI. Lastly, children requiring massive transfusion outside of the trauma/TBI setting should be studied. For example, children with hypoproliferative thrombocytopenia or platelet refractoriness in need of massive transfusion may need a higher ratio of platelet products to improve hemostatic efficacy.

1.2. In children with severe TBI, we recommend future studies to determine if, and at what laboratory cutoff, platelets or plasma should be administered to ensure safe placement of an intracranial pressure (ICP) monitor. 95% agreement (n=22), Median 8.5, IQR 7.75-9.

Rationale:

ICP monitors are frequently placed in children with severe TBI [16]. Pediatric patients with severe TBI may also experience trauma-induced coagulopathy and thrombocytopenia. Placement of ICP monitors in the setting of coagulopathy may be further complicated by bleeding complications. Although monitoring does not affect outcomes directly, the data obtained may influence patient treatment decisions and consequently outcomes. Observational data in adults have been reported [17,18], though, to our knowledge, specific platelet or prothrombin time/international normalized ratio (PT/INR) thresholds for placement of ICP monitoring following pediatric TBI have neither been studied nor established. Studies evaluating specific laboratory values prior and subsequent to ICP monitor placement linked to bleeding outcome should be initiated.

CPB

2.1. In infants and children undergoing cardiac surgery with CPB, further research is needed to determine the benefits and risks associated with the administration of platelet and plasma transfusions in the CPB-prime, on-bypass and after separation of CPB, taking into account patient age and weight. 95% agreement (n=22), Median 8.5, IQR 7–9.

Rationale:

CPB management in neonates and small children is complicated by larger circuit volume relative to patient blood volume and by the prolonged by-pass times often required. Decisions regarding composition of CPB prime, regarding inclusion of whole blood vs. component therapy, are dependent upon multiple patient variables including weight, hemoglobin, cardiac morphology and function, presence/degree of cyanosis, pulmonary vascular resistance, and type of cardiac surgical repair or palliation. The complex interplay between the blood-circuit interface, inflammation, temperature, hemostasis, coagulant factor and platelet consumption and hemodilution contributes to bleeding and thrombotic risk, making intra-operative transfusion management challenging.

CPB initiation, maintenance, and separation all require careful consideration of right and left ventricle systolic and diastolic function, afterload, preload and pulmonary vascular resistance. Specifics of the CPB, cardiac function (global and regional), and ease of achieving intra-operative hemostasis, in the setting of thrombocytopenia and/or coagulopathy is also factored into the decision to transfuse platelets and/or plasma.

Children undergoing cardiac surgery receive large numbers of blood components [19] with post-operative hemostatic transfusions being independently associated with worse clinical outcomes [20]. However, priming composition and transfusions during CPB varies across surgeons and institutions with varying results on bleeding [21–23]. Additional research examining risk and benefit of platelet and/or plasma transfusions during the various stages of CPB are necessary to inform intra-operative transfusion decisions making in this patient population.

ECMO

3.1. In critically ill neonatal and pediatric patients on ECMO, we recommend that all blood product exposure (including plasma and platelets) within the circuit prime be reported in pediatric ECMO transfusion studies and quality improvement projects. 91% agreement (n=22), Median 9, IQR 8-9.

Rationale:

Neonates and small infants requiring ECMO traditionally require a blood prime due to size discrepancy between their blood volume and volume of the ECMO circuit [24,25]. The priming volume and specific components (e.g., whole blood, RBCs, plasma) differs between institutions and specifics of the components administered are not consistently documented on registry databases. Transfusion thresholds during initiation of ECMO, maintenance on ECMO, and during decannulation depend on clinical factors and presence of coagulopathy and bleeding [26]. Studies examining indications for plasma and platelet transfusions linked to bleeding outcomes in children maintained on ECMO will be more informative if details regarding blood products utilized to prime the ECMO circuit are included.

ONCOLOGY/HSCT

4.1. We recommend investigations surrounding continuous vs. bolus infusion of platelets, various platelet products, and indications for and efficacy of transfusion (not just platelet count) in pediatric oncology/HSCT patients with hypoproliferative thrombocytopenia and evidence of refractoriness to platelet transfusions. 91% agreement (n=22), Median 9, IQR 7.75-9.

Rationale:

Platelet transfusion strategies for pediatric oncology/HSCT patients with hypoproliferative thrombocytopenia and evidence of transfusion refractoriness have yet to be established. Transfusion refractoriness can be due to immunologic factors or to more common non-immune platelet consumption. A subset of patients will not have adequate responses to transfusion with compatible platelet products, to treatments to enhance platelet survival (such steroids, rituximab, intravenous immunoglobulin, splenic radiation), or to medications to enhance platelet production (such as various thrombopoietins) [27,28]. Transfusion strategies to improve transfusion response, such as cross-matched or human leukocyte antigen (HLA)-matched platelets vs. standard issue platelets, continuous infusion vs. intermittent bolus infusion(s), room temperature stored platelets vs. cold stored platelets, and other platelet products should be studied [29]. Measures of platelet transfusion effectiveness should include bleeding related outcomes rather than measures of post-transfusion increment such as improvement in traditional World Health Organization (WHO) bleeding score or the new Bleeding Assessment Scale in Critically Ill Children (BASIC) definition [30].

4.2. We recommend studies to determine optimal platelet and plasma transfusion strategies for: a) prophylaxis and b) control of clinically relevant bleeding in pediatric oncology/HSCT patients with nervous system pathologies (including brain tumors, ischemic/hemorrhagic strokes, subdural hematomas, spinal cord tumors/metastases, orbit/sinus tumors, and orbit/sinus hemorrhage). 91% agreement (n=22), Median 9, IQR 7.75-9.

Rationale:

Platelet and plasma dosing strategies for pediatric oncology/HSCT patients often vary depending on the site and vulnerability of the bleeding tissue. Crucial areas affected by even milliliters of extravascular bleeding include the central nervous system and the head/neck. These tissues may be weakened by prior tumor infiltration, injury or infection and may be prone to bleed. Additionally, the unique tissue-specific regulation of hemostasis present in the central nervous system favors thrombogenesis [31,32]. The transfusion thresholds assumed to be necessary to maintain hemostasis to prevent even mild bleeding, including the thresholds targeted to resolve or stabilize bleeding in these areas, are more stringent than in other organ systems and common practice is to maintain/target traditional hemostasis measures in ranges closer to “normal”. However, neither the ability, nor necessity, of achieving “normal” platelet count and plasma-based assay values to manage bleeding in vivo is clear [31]. Clinical trials designed to determine optimal prophylaxis and control of bleeding in these areas should evaluate the utility of viscoelastic testing, hemostatic adjuncts, imaging strategies, novel interventional techniques and functional outcomes.

LIVER FAILURE/TRANSPLANT

5.1. We recommend investigations evaluating optimal diagnosis and treatment of coagulopathic bleeding and transfusion indications (including specific targets and thresholds) in bleeding and non-bleeding critically ill infants or children with acute liver failure and/or following liver transplantation. This approach should include an individualized patient approach to diagnosis and management of coagulopathic bleeding with an emphasis on tolerating coagulopathy and on promoting restrictive transfusion strategies when indicated. 91% agreement (n=22), Median 8, IQR 8-9.

Rationale:

Infants and children with acute liver failure and/or those undergoing liver transplantation represent a unique group of patients in whom the hemostatic system has changed. Because the liver is responsible for both pro-coagulant, as well as anti-coagulant, proteins, in addition to other factors such as thrombopoietin and von Willebrand factor, patients with liver failure have decreased production of both and therefore have a “rebalanced” although abnormal, hemostatic system [33]. Thrombosis is more common than bleeding in these children; as laboratory measures such as PT and INR only assay the pro-coagulant factors, they are poor predictors of bleeding risk [34]. Additionally, retrospective studies in adults have shown that the transfusion of platelets (or RBCs) is independently associated with poorer 1-year survival and graft failure [35]. The expert consensus statements from TAXI-CAB for this population are based on little evidence [36]. Studies are needed to 1) define laboratory tests that can predict bleeding in this rebalanced hemostatic state, and 2) direct clinicians when the transfusion of hemostatic products is necessary and the risk of bleeding outweighs the risk of thrombosis.

NON-CARDIAC SURGERY

6.1. We recommend research that seeks to evaluate optimal plasma and platelet transfusion thresholds/targets and transfusion strategies for critically ill children undergoing non-cardiac surgical procedures involving vascular anastomoses (liver and renal transplantation, plastic surgical free-flap procedures) with the objective of minimizing the risk of vascular thrombosis. This approach should consider an individualized patient approach to diagnosis and management of coagulopathic bleeding with emphasis on promoting restrictive transfusion strategies. 95% agreement (n=22), Median 8, IQR 7-9.

Rationale:

Transfusions are common in operative repairs involving vascular anastomosis, especially in solid organ transplants. In a large database study of Korean adults, nearly 96% of liver transplant and 60% of kidney transplant recipients received at least one transfusion, most which were plasma and/or platelets [37]. Intra-operative RBC transfusions have been associated with post-operative thrombosis in general surgeries and in those involving free flaps [38,39]. This clinical observation is thought to be related to the changes in RBC deformability and accumulation of pro-inflammatory markers that occur during storage [40]. Plasma and platelet transfusions are also at risk of storage lesions [41], but resulting morbidities have not been studied in pediatric populations of interest. The risk/benefit ratio balancing the risk of bleeding vs. thrombosis with the possible loss of the graft should be explored.

INVASIVE PROCEDURES

7.1. We recommend studies in critically ill children undergoing lumbar puncture (LP) to understand the relationship between abnormal hemostasis or coagulopathy (e.g. acquired coagulation factor deficiency) and the risk of bleeding (e.g. spinal hematoma) or other adverse event and the effect of plasma transfusions on these outcomes. 95% agreement (n=21), Median 9, IQR 7-9.

Rationale:

LP is commonly performed in critically ill children, for the evaluation of suspected sepsis or meningitis/encephalitis, investigation of neurological or metabolic disorders, assessment of intracranial pressure, diagnostic evaluation in pediatric malignancy or for the administration of chemotherapy [42]. While spinal hematoma is a very rare complication [43,44], several retrospective studies have examined platelet thresholds and the safety of LPs in children with hematologic malignancy [45–47]. However, there is no high-quality evidence to guide plasma transfusion in coagulopathic children undergoing LP. Spinal epidural hematoma has been reported in patients with coagulopathy undergoing LP [43,44,48], but it is unknown how coagulopathy influences this bleeding risk in children and how plasma may or may not reduce the risk.

7.2. We recommend studies in critically ill infants and children undergoing central venous line (CVL) insertion to determine whether prophylactic platelet or plasma transfusions are needed and to determine the minimum platelet count, the maximum INR/PT ratio and maximum aPTT for safe central venous catheter placement. 90% agreement (n=21), Median 8, IQR 7.5-9.

Rationale:

CVL insertion is an essential and common procedure performed in the management of critically ill children [49,50]. Perioperative complications in children are rare, bleeding complications are even rarer and are likely to be multi-factorial [50–54]. There is limited high-quality evidence to define safe thresholds for CVL insertion in children. Studies performed in children have included those with surgically placed CVLs where platelet transfusions are routinely given if the pre-procedure platelet count is ≤ 50 x 109/L [55,56]. Further studies are needed to understand how platelet count and coagulopathy correlate with bleeding risk in critically ill children undergoing CVL insertion and if prophylactic platelet and plasma transfusions are needed, and at what threshold. The safety contribution of direct imaging with techniques such as ultrasound during the procedure should also be considered.

DIC/SEPSIS

8.1. We recommend studies to evaluate specific indications and/or transfusion strategies to direct platelet and/or plasma transfusion in patients with all degrees of bleeding (minimal, moderate and severe) in the setting of sepsis and/or disseminated intravascular coagulation (DIC). 91% agreement (n=22), Median 9, IQR 8-9.

Rationale:

DIC, induced by sepsis or any other cause, represents a unique coagulopathy within critically ill children. The syndrome involves the activation of the coagulation system with excessive thrombin generation. Microthrombi are formed with the subsequent activation of fibrinolysis and the consumption of clotting factors and platelets [57]. Plasma and platelet transfusions can be considered in these patients when significant bleeding is present but appropriate thresholds for transfusion are unknown [58]. A recent systematic review reported three RCTs (involving fewer than 100 patients in total); the use of plasma and/or platelet transfusions in DIC was not associated with any improvement in clinical outcomes [59]. Given the high frequency in which sepsis is associated with coagulopathy in pediatric septic shock, estimated recently to be as high as 90% [60], the risk/benefit ratio of the use of hemostatic transfusions must be explored.

LABORATORY ASSAYS TO PREDICT NEED FOR PLASMA OR PLATELET TRANSFUSION

9.1. We recommend investigations to determine the efficacy of functional tests of hemostasis and coagulation (both standard coagulation assessment and viscoelastometric testing) in predicting bleeding in critically ill children and in developing test-based triggers for both platelet and plasma transfusions. 91% agreement (n=22), Median 9, IQR 8-9.

Rationale:

Pediatric critical illness is a dynamic process with alterations in physiology changing quickly in disease evolution. Not surprisingly, hemostasis and coagulation are complex, dynamic processes that include changes in adhesion of platelets to damaged endothelium, formation of a platelet plug (aggregation), formation of a fibrin network to stabilize the plug, clot retraction, fibrinolysis, and endothelial changes affecting vascular regulation of flow [61]. Quantitation of platelet numbers or measuring of clotting times (i.e. activated partial thromboplastin time, aPTT or PT) only reflect one aspect of these complex processes without an understanding of clot strength and clot dissolution. These tests may also underestimate coagulopathy [62]. Likewise, a ‘transfusion trigger’ is generally one that indicates a value of the platelet count or PT/INR above/below which prophylactic transfusion may not be indicated. Studies have shown that counting numbers of platelets or in vitro time to clot formation may not correlate with risk of bleeding or, as a target, cessation of bleeding since these measures do not reflect the complexity within the hemostatic cascade [63].

Further evaluation of platelet and coagulation functional assays are needed to determine efficacy and in vivo performance to mitigate bleeding in critically ill children. Newer tests that allow for more complex cell-based evaluations of hemostasis on multiple cellular surfaces are becoming increasingly used in research and clinical settings [64]. These include thromboelastometry and thromboelastography, platelet aggregation via impedance, thrombin generation, and many others [61,65–70]. The ideal test to guide platelet or plasma transfusion would have a dynamic range with identified limits precisely defining the risk for bleeding or thrombosis.

PRODUCT SELECTION/PROCESSING

10.1. We recommend studies to investigate how physiological measures and outcomes are affected by the transfusion of different types of plasma and platelet products. Specifically, we recommend investigations that examine the effects of different types of plasma and platelet products on endothelial function, as well as the occurrence of adverse transfusion reactions. 90% agreement (n=21), Median 8, IQR 7-9.

Rationale:

The inflammatory process is usually a significant part of pediatric critical illness. Inflammation affects the microvasculature at the level of the endothelium leading to microscopic disruption. Platelets play a key role in healing the disruptions and coordinating the host leukocyte recruitment and local environmental inflammatory cascades [71]. Experimental models have investigated how platelets achieve hemostasis in inflamed or non-inflamed tissues or under conditions with immune clearance of platelets [72,73]. These findings could provide insight for further investigations into platelet transfusion in these settings. Clinical markers of endothelial damage in thrombocytopenic patients should also be studied. As a next step, if endothelial damage can be measured clinically, the changes in endothelial function following platelet transfusion, or platelet reconstitution in the case of an immune process, or when there are platelet transfusion reactions, should be studied to determine if endothelial dysfunction could be induced under these different clinical situations [74]. Finally, different methods of platelet production, storage and selection, such as whole blood derived versus apheresed, cold storage, and pathogen reduction can be explored in these models.

10.2. We recommend studies to determine if there is a physiological impact in children transfused with plasma or platelet products that are donated by adults. 86% agreement (n=22), Median 8, IQR 7-9.

Rationale:

Certain drugs, native metabolites and environmental elements have been found in donated blood, which can impact the viability of the blood in storage [75,76]. Large studies have found RBCs from male donors are more prone to hemolysis, while those donors of African ancestry were relatively resistant to osmotic hemolysis [77,78]. These and other findings may be due to the underlying genetic traits of the donors. While platelets and plasma products have not been studied to the degree RBCs have, characteristics of the donor, including age and sex have been shown to lead to different functional levels of platelets [79]. These changes may have an impact on the transfusion product.

CONCLUSIONS

Though plasma and platelet transfusions are administered frequently to critically ill children, evidence to guide this practice is lacking. After a thorough systematic review, the TAXI-CAB investigators could only develop four clinical recommendations, with the remainder of the program only identifying good practice or expert consensus statements. In addition, the development of decision trees to guide plasma and platelet transfusions was greatly hampered by the paucity of studies. There is a clear need for large scale studies of plasma and platelet transfusion strategies in critically ill children. Future studies should be focused on efficacy/harm, thresholds to balance risk/benefit, optimal dosing and timing, as well as validated outcomes in critically ill children receiving plasma and/or platelet transfusions.

ACKNOWLEDGMENTS

We would like to thank all members of TAXI-CAB for their support and input, especially during the COVID-19 pandemic. In addition, we thank the Chaire Héma-Québec-Bayer en médecine transfusionnelle de l’Université de Montréal, the Society for the Advancement of Blood Management, the Network for the Advancement of Patient Blood Management, Haemostasis and Thrombosis, the International Society of Blood Transfusion, the Society for Critical Care Medicine, and the AABB for their support.

Financial Support:

The Transfusion and Anemia EXpertise Initiative – Control/Avoidance of Bleeding (TAXI-CAB) was supported, in part, by the National Institutes of Health National Heart, Lung and Blood Institute under award number R13 HL154544-01.

Copyright Form Disclosure:

Dr. Bembea’s institution received funding from the National Institute of Neurological Disorders and Stroke (R01NS106292), the National Institute of Child Health and Human Development, and Grifols Investigator Sponsored Research Grant. Drs. Bembea and Russell received support for article research from the National Institutes of Health. Dr. Steiner received funding from PumpKIN DSMB and HealthCore. Dr. Crighton disclosed that she is employed by the Royal Children’s Hospital of Melbourne, Australia and was the Australian and New Zealand Society of Blood Transfusion President. The remaining authors have disclosed that they do not have any potential conflicts of interest.

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.

Footnotes

Transfusion and Anemia EXpertise Initiative – Control/Avoidance of Bleeding (TAXI-CAB) Members are listed in Appendix 1

REFERENCES

  • 1.Karam O, Demaret P, Shefler A, et al. Indications and Effects of Plasma Transfusions in Critically Ill Children. Am J Respir Crit Care Med 2015, 191:1395–1402. [DOI] [PubMed] [Google Scholar]
  • 2.Nellis ME, Karam O, Mauer E, et al. Platelet Transfusion Practices in Critically Ill Children. Crit Care Med 2018, 46:1309–1317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Toy P, Gajic O, Bacchetti P, et al. Transfusion-related acute lung injury: incidence and risk factors. Blood 2012, 119:1757–1767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Karam O, Lacroix J, Robitaille N, Rimensberger PC, Tucci M. Association between plasma transfusions and clinical outcome in critically ill children: a prospective observational study. Vox Sang 2013, 104:342–349. [DOI] [PubMed] [Google Scholar]
  • 5.Muszynski JA, Spinella PC, Cholette JM, et al. Transfusion-related immunomodulation: review of the literature and implications for pediatric critical illness. Transfusion 2017, 57:195–206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Nellis ME, Karam O, Valentine S, et al. Executive Summary of Recommendations and Expert Consensus for Plasma and Platelet Transfusion Practice in Critically Ill Children: From the Transfusion and Anemia EXpertise Initiative – Control/Avoidance of Bleeding (TAXI-CAB). Pediatr Crit Care Med to complete [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Bembea MM, Valentine SL, Bateman ST, et al. The Pediatric Critical Care Transfusion and Anemia Expertise Initiative Consensus Conference Methodology. Pediatr Crit Care Med 2018, 19:S93–s97. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Fitch KBS, Aguilar M. The RAND/UCLA Appropriateness Method User’s Manual. Arlington, VA; 2001. [Google Scholar]
  • 9.Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ (Clinical research ed) 2008, 336:924–926. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Christiaans SC, Duhachek-Stapelman AL, Russell RT, Lisco SJ, Kerby JD, Pittet JF. Coagulopathy after severe pediatric trauma. Shock 2014, 41:476–490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Davenport R Pathogenesis of acute traumatic coagulopathy. Transfusion 2013, 53:23s–27s. [DOI] [PubMed] [Google Scholar]
  • 12.Butler EK, Mills BM, Arbabi S, et al. Association of Blood Component Ratios With 24-Hour Mortality in Injured Children Receiving Massive Transfusion. Crit Care Med 2019, 47:975–983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Cannon JW, Johnson MA, Caskey RC, Borgman MA, Neff LP. High ratio plasma resuscitation does not improve survival in pediatric trauma patients. J Trauma Acute Care Surg 2017, 83:211–217. [DOI] [PubMed] [Google Scholar]
  • 14.Cunningham ME, Rosenfeld EH, Zhu H, Naik-Mathuria BJ, Russell RT, Vogel AM. A High Ratio of Plasma: RBC Improves Survival in Massively Transfused Injured Children. J Surg Res 2019, 233:213–220. [DOI] [PubMed] [Google Scholar]
  • 15.Edwards MJ, Lustik MB, Clark ME, Creamer KM, Tuggle D. The effects of balanced blood component resuscitation and crystalloid administration in pediatric trauma patients requiring transfusion in Afghanistan and Iraq 2002 to 2012. J Trauma Acute Care Surg 2015, 78:330–335. [DOI] [PubMed] [Google Scholar]
  • 16.Kochanek PM, Carney N, Adelson PD, et al. Guidelines for the acute medical management of severe traumatic brain injury in infants, children, and adolescents--second edition. Pediatr Crit Care Med 2012, 13:S1–82. [DOI] [PubMed] [Google Scholar]
  • 17.Bauer DF, McGwin G, Melton SM, George RL, Markert JM. The relationship between INR and development of hemorrhage with placement of ventriculostomy. J Trauma 2011, 70:1112–1117. [DOI] [PubMed] [Google Scholar]
  • 18.Davis JW, Davis IC, Bennink LD, et al. Placement of intracranial pressure monitors: are “normal” coagulation parameters necessary? J Trauma 2004, 57:1173–1177. [DOI] [PubMed] [Google Scholar]
  • 19.Nellis ME, Goel R, Hendrickson JE, et al. Transfusion Practices in a Large Cohort of Hospitalized Children. Transfusion 2021; 61:2042–2053. [DOI] [PubMed] [Google Scholar]
  • 20.Closson R, Mauer E, Stock A, et al. The Use of Hemostatic Blood Products in Children Following Cardiopulmonary Bypass and Associated Outcomes. Crit Care Explor 2020; 2:e0172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Petäjä J, Lundström U, Leijala M, Peltola K, Siimes MA. Bleeding and use of blood products after heart operations in infants. J Thorac Cardiovasc Surg 1995; 109:524–529. [DOI] [PubMed] [Google Scholar]
  • 22.Dieu A, Rosal Martins M, Eeckhoudt S, et al. Fresh Frozen Plasma versus Crystalloid Priming of Cardiopulmonary Bypass Circuit in Pediatric Surgery: A Randomized Clinical Trial. Anesthesiology 2020; 132:95–106. [DOI] [PubMed] [Google Scholar]
  • 23.Gautam NK, Pierre J, Edmonds K, et al. Transfusing Platelets During Bypass Rewarming in Neonates Improves Postoperative Outcomes: A Randomized Controlled Trial. World J Pediatr Congenit Heart Surg 2020; 11:71–76. [DOI] [PubMed] [Google Scholar]
  • 24.Yuan S, Tsukahara E, De La Cruz K, Kelly RB. How we provide transfusion support for neonatal and pediatric patients on extracorporeal membrane oxygenation. Transfusion 2013; 53:1157–1165. [DOI] [PubMed] [Google Scholar]
  • 25.Bembea MM, Cheifetz IM, Fortenberry JD, et al. Recommendations on the Indications for RBC Transfusion for the Critically Ill Child Receiving Support From Extracorporeal Membrane Oxygenation, Ventricular Assist, and Renal Replacement Therapy Devices From the Pediatric Critical Care Transfusion and Anemia Expertise Initiative. Pediatr Crit Care Med 2018; 19:S157–162. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Bembea MM, Annich G, Rycus P, Oldenburg G, Berkowitz I, Pronovost P. Variability in anticoagulation management of patients on extracorporeal membrane oxygenation: an international survey. Pediatr Crit Care Med 2013; 14:e77–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Stanworth SJ, Navarrete C, Estcourt L, Marsh J. Platelet refractoriness--practical approaches and ongoing dilemmas in patient management. Br J Haematol 2015; 171:297–305. [DOI] [PubMed] [Google Scholar]
  • 28.Hod E, Schwartz J. Platelet transfusion refractoriness. Br J Haematol 2008; 142:348–360. [DOI] [PubMed] [Google Scholar]
  • 29.Patel RM, Josephson C. Neonatal and pediatric platelet transfusions: current concepts and controversies. Curr Opin Hematol 2019; 26:466–472. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Nellis ME, Tucci M, Lacroix J, et al. Bleeding Assessment Scale in Critically Ill Children (BASIC): Physician-Driven Diagnostic Criteria for Bleeding Severity. Crit Care Med 2019; 47:1766–1772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Fager AM, Hoffman M. Biology of Coagulation and Coagulopathy in Neurologic Surgery. Neurosurg Clin N Am 2018; 29:475–483. [DOI] [PubMed] [Google Scholar]
  • 32.Grover SP, Mackman N. Tissue Factor: An Essential Mediator of Hemostasis and Trigger of Thrombosis. Arterioscler Thromb Vasc Biol 2018; 38:709–725. [DOI] [PubMed] [Google Scholar]
  • 33.Lisman T, Porte RJ. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences. Blood 2010; 116:878–885. [DOI] [PubMed] [Google Scholar]
  • 34.Lisman T, Porte RJ. Pathogenesis, prevention, and management of bleeding and thrombosis in patients with liver diseases. Res Pract Thromb Haemost 2017; 1:150–161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.de Boer MT, Christensen MC, Asmussen M, et al. The impact of intraoperative transfusion of platelets and red blood cells on survival after liver transplantation. Anesth Analg 2008; 106:32–44. [DOI] [PubMed] [Google Scholar]
  • 36.Lieberman L, Karam O, Stanworth SJ, et al. Plasma and Platelet Transfusion Strategies in Critically Ill Children with Malignancy, Acute Liver Failure and/or Liver Transplantation, or Sepsis: From the Transfusion and Anemia Expertise Initiative – Control/Avoidance of Bleeding (TAXI-CAB). Pediatr Crit Care Med to complete [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Park B, Yoon J, Kim HJ, Jung YK, Lee KG, Choi D. Transfusion Status in Liver and Kidney Transplantation Recipients-Results from Nationwide Claims Database. J Clin Med 2020; 9:3613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Goel R, Josephson CD, Patel EU, et al. Perioperative Transfusions and Venous Thromboembolism. Pediatrics 2020; 145:e20192351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Sanchez-Porro Gil L, Leon Vintro X, Lopez Fernandez S, et al. The Effect of Perioperative Blood Transfusions on Microvascular Anastomoses. J Clin Med 2021; 10:1333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Almac E, Ince C. The impact of storage on red cell function in blood transfusion. Best Pract Res Clin Anaesthesiol 2007; 21:195–208. [DOI] [PubMed] [Google Scholar]
  • 41.Ng MSY, Tung JP, Fraser JF. Platelet Storage Lesions: What More Do We Know Now? Transfus Med Rev 2018; S0887–7963. [DOI] [PubMed] [Google Scholar]
  • 42.Schulga P, Grattan R, Napier C, Babiker MO. How to use… lumbar puncture in children. Arch Dis Child Educ Pract Ed 2015; 100:264–271. [DOI] [PubMed] [Google Scholar]
  • 43.Bauer ME, Toledano RD, Houle T, et al. Lumbar neuraxial procedures in thrombocytopenic patients across populations: A systematic review and meta-analysis. J Clin Anesth 2020; 61:109666. [DOI] [PubMed] [Google Scholar]
  • 44.Bodilsen J, Mariager T, Vestergaard HH, et al. Association of Lumbar Puncture With Spinal Hematoma in Patients With and Without Coagulopathy. JAMA 2020; 324:1419–1428. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Chung HH, Morjaria S, Frame J, et al. Rethinking the need for a platelet transfusion threshold of 50 × 10(9) /L for lumbar puncture in cancer patients. Transfusion 2020; 60:2243–2249. [DOI] [PubMed] [Google Scholar]
  • 46.Howard SC, Gajjar A, Ribeiro RC, et al. Safety of lumbar puncture for children with acute lymphoblastic leukemia and thrombocytopenia. JAMA 2000; 284:2222–2224. [DOI] [PubMed] [Google Scholar]
  • 47.Foerster MV, Pedrosa Fde P, da Fonseca TC, Couceiro TC, Lima LC. Lumbar punctures in thrombocytopenic children with cancer. Paediatr Anaesth 2015; 25:206–210. [DOI] [PubMed] [Google Scholar]
  • 48.Brown MW, Yilmaz TS, Kasper EM. Iatrogenic spinal hematoma as a complication of lumbar puncture: What is the risk and best management plan? Surg Neurol Int 2016; 7:S581–589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Baarslag MA, Jhingoer S, Ista E, Allegaert K, Tibboel D, van Dijk M. How often do we perform painful and stressful procedures in the paediatric intensive care unit? A prospective observational study. Aust Crit Care 2019; 32:4–10. [DOI] [PubMed] [Google Scholar]
  • 50.Casado-Flores J, Barja J, Martino R, Serrano A, Valdivielso A. Complications of central venous catheterization in critically ill children. Pediatr Crit Care Med 2001; 2:57–62. [DOI] [PubMed] [Google Scholar]
  • 51.de Jonge RC, Polderman KH, Gemke RJ. Central venous catheter use in the pediatric patient: mechanical and infectious complications. Pediatr Crit Care Med 2005; 6:329–339. [DOI] [PubMed] [Google Scholar]
  • 52.Trieschmann U, Cate UT, Sreeram N. Central venous catheters in children and neonates - what is important? Images Paediatr Cardiol 2007; 9:1–8. [PMC free article] [PubMed] [Google Scholar]
  • 53.Karapinar B, Cura A. Complications of central venous catheterization in critically ill children. Pediatr Int 2007; 49:593–599. [DOI] [PubMed] [Google Scholar]
  • 54.Johnson EM, Saltzman DA, Suh G, Dahms RA, Leonard AS. Complications and risks of central venous catheter placement in children. Surgery 1998; 124:911–916. [PubMed] [Google Scholar]
  • 55.Olivieri C, Crocoli A, De Pasquale MD, Inserra A. Central venous catheter placement in children with thrombocytopenia. Minerva Pediatr 2016; 68:398–403. [PubMed] [Google Scholar]
  • 56.Elgendy AI, Ismail AM, Elhawary E, et al. Insertion of central venous catheters in children undergoing bone marrow transplantation: is there a platelet level for a safe procedure? Annals of Pediatric Surgery 2020; 16:46. [Google Scholar]
  • 57.Bick RL, Arun B, Frenkel EP. Disseminated intravascular coagulation. clinical and pathophysiological mechanisms and manifestations. Haemostasis 1999; 29:111–134. [DOI] [PubMed] [Google Scholar]
  • 58.Parker RI. Coagulopathies in the PICU: DIC and liver disease. Crit Care Clin 2013; 29:319–333. [DOI] [PubMed] [Google Scholar]
  • 59.Squizzato A, Hunt BJ, Kinasewitz GT, et al. Supportive management strategies for disseminated intravascular coagulation. An international consensus. Thromb Haemost 2016; 115:896–904. [DOI] [PubMed] [Google Scholar]
  • 60.Loberger JM, Aban IB, Prabhakaran P. Exploration of Sepsis-Associated Coagulopathy Severity and Pediatric Septic Shock Outcomes. J Pediatr Intensive Care 2021; 10:38–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Choi SY, Kim MH. Comparison of factors affecting platelet reactivity in various platelet function tests. Platelets 2019; 30:631–636. [DOI] [PubMed] [Google Scholar]
  • 62.Levi M, Opal SM. Coagulation abnormalities in critically ill patients. Crit Care 2006; 10:222. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Slichter SJ. Relationship between platelet count and bleeding risk in thrombocytopenic patients. Transfus Med Rev 2004; 18:153–167. [DOI] [PubMed] [Google Scholar]
  • 64.Shah A, Stanworth SJ, McKechnie S. Evidence and triggers for the transfusion of blood and blood products. Anaesthesia 2015; 70:10–19. [DOI] [PubMed] [Google Scholar]
  • 65.Just Vinholt P, Hojrup Knudsen G, Sperling S, Frederiksen H, Nielsen C. Platelet function tests predict bleeding in patients with acute myeloid leukemia and thrombocytopenia. Am J Hematol 2019; 94:891–901. [DOI] [PubMed] [Google Scholar]
  • 66.Lordkipanidze M Platelet Function Tests. Semin Thromb Hemost 2016; 42:258–267. [DOI] [PubMed] [Google Scholar]
  • 67.Frelinger AL, Grace RF, Gerrits AJ, et al. Platelet function tests, independent of platelet count, are associated with bleeding severity in ITP. Blood 2015; 126:873–879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Zhu M, Xu W, Wang BL, Su H. Hemostatic function and transfusion efficacy of apheresis platelet concentrates treated with gamma irradiation in use for thrombocytopenic patients. Transfus Med Hemother 2014; 41:189–196. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Karon BS, Tolan NV, Koch CD, et al. Precision and reliability of 5 platelet function tests in healthy volunteers and donors on daily antiplatelet agent therapy. Clin Chem 2014; 60:1524–1531. [DOI] [PubMed] [Google Scholar]
  • 70.Shah U, Ma A. Tests of platelet function. Curr Opin Hematol 2007; 14:432–437. [DOI] [PubMed] [Google Scholar]
  • 71.Ho-Tin-Noé B, Boulaftali Y, Camerer E. Platelets and vascular integrity: how platelets prevent bleeding in inflammation. Blood 2018; 131:277–288. [DOI] [PubMed] [Google Scholar]
  • 72.Le Chapelain O, Jadoui S, Boulaftali Y, Ho-Tin-Noé B. The reversed passive Arthus reaction as a model for investigating the mechanisms of inflammation-associated hemostasis. Platelets 2020; 31:455–460. [DOI] [PubMed] [Google Scholar]
  • 73.Xu XR, Gallant RC, Ni H. Platelets, immune-mediated thrombocytopenias, and fetal hemorrhage. Thromb Res 2016; 141:S76–79. [DOI] [PubMed] [Google Scholar]
  • 74.Wiel E, Vallet B, ten Cate H. The endothelium in intensive care. Crit Care Clin 2005; 21:403–416. [DOI] [PubMed] [Google Scholar]
  • 75.Alexander K, Hazegh K, Fang F, et al. Testosterone replacement therapy in blood donors modulates erythrocyte metabolism and susceptibility to hemolysis in cold storage. Transfusion 2021; 61:108–123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76.Hazegh K, Fang F, Bravo MD, et al. Blood donor obesity is associated with changes in red blood cell metabolism and susceptibility to hemolysis in cold storage and in response to osmotic and oxidative stress. Transfusion 2021; 61:435–448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Kanias T, Lanteri MC, Page GP, et al. Ethnicity, sex, and age are determinants of red blood cell storage and stress hemolysis: results of the REDS-III RBC-Omics study. Blood Adv 2017; 1:1132–1141. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.D’Alessandro A, Fu X, Kanias T, et al. Donor sex, age and ethnicity impact stored red blood cell antioxidant metabolism through mechanisms in part explained by glucose 6-phosphate dehydrogenase levels and activity. Haematologica 2021; 106:1290–1302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Davizon-Castillo P, McMahon B, Aguila S, et al. TNF-α-driven inflammation and mitochondrial dysfunction define the platelet hyperreactivity of aging. Blood 2019; 134:727–740. [DOI] [PMC free article] [PubMed] [Google Scholar]

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