Precision Platelet Transfusion Medicine is Needed to Improve Outcomes

In this retrospective cohort study from a large administrative database in this issue of Hospital Pediatrics, Lang et al¹  examine epidemiologic trends and clinical outcomes of 4 million children hospitalized in tertiary care centers who received platelet transfusions during 244 464 hospitalizations. The data reveal 2 important findings: (1) rates of platelet transfusion have not declined in recent years and (2) increased platelet transfusion are associated with increased morbidity and mortality. On multivariate analysis, among patients who received platelet transfusions, each additional platelet transfusion was associated with increased risk of thrombus, nosocomial infection, and mortality even when adjusted for age, extracorporeal membrane oxygenation support, mechanical ventilation, need for surgical intervention, and presence of chronic conditions.

This report contributes to a growing field exploring the risks of platelet transfusions in pediatric patients. Recent recommendations from pediatric experts recognize the paucity of data on this topic, lack of agreement on platelet transfusion indications by clinicians, and discordance between clinical practice and evidence-based platelet guidelines.^2,3  The literature on this topic includes increased complications and mortality after platelet transfusion in the following cohorts: preterm infants with severe thrombocytopenia, pediatric patients receiving extracorporeal membrane oxygenation, children undergoing cardiopulmonary bypass, and in general populations in pediatric ICUs.^4–7 

The review by Lang et al¹  and the data cited could be a result of confounding by indication. It has been hypothesized that this confounding cannot be adjusted for with multivariate logistic regression because transfusion is so closely associated with severity of illness that even well-adjusted analyses cannot accurately separate the interdependence of the transfusion with severity of illness.⁸  Alternatively, it is quite possible that the association is real (or at the very least it is a little of both confounding by indication and causation). Platelets could be causing harm either because of patients receiving platelets that are not indicated, therefore exposing the patient to the risks of platelet transfusion without any potential for benefit or storage lesion effects such as microparticle generation that lead to immune dysfunction and prothrombotic complications could be harmful.⁹  This hypothesis is supported by randomized, controlled trials in both premature infants in whom increased platelet transfusions increased the risk of mortality or major bleeding¹⁰  and in an adult population with hemorrhagic stroke in which platelet transfusion caused increased risk of poor neurologic outcomes.¹¹  Additional trials in other patient populations are needed to more definitively assess causation; as discussed later, the specifics about how the platelets are manufactured and the patient cohort being studied is essential because data with 1 platelet product in 1 population may not be translatable to other platelet products in other patient populations.

These data by Lang et al¹  add to the literature that ultimately highlights the need for precision transfusion medicine, in which specific therapeutic interventions take into account the unique biology of each individual and the specific biologic effects of a blood product based on its manufacturing methods.¹²  In critically ill children who receive platelet transfusions, the ICU mortality rate is 25%.¹³  We must work toward improving the platelet products we provide and how we use them in this highly vulnerable population.

To achieve precision transfusion medicine for any blood product, but specifically for platelet transfusion, multiple areas of investigation are required. First, we must obtain a better understanding of the pathophysiology of the conditions in which platelet transfusion is considered. Platelets are mostly transfused to either prevent bleeding in the setting of severe thrombocytopenia or to control bleeding. The pathophysiology of both microvascular bleeding secondary to hypoproliferative thrombocytopenia and hemostatic dysfunction in the setting of hemorrhage from multiple etiologies such as trauma and gastrointestinal and obstetric bleeding are poorly understood. The vascular protective effects of platelets that maintain structural integrity are also mechanistically distinct compared with the mechanisms required for primary hemostasis.¹⁴  The mechanisms for how platelets maintain vascular integrity are not well known and need additional investigation.

We also need to investigate how each of the manufacturing methods for platelets affect their biologic function and if these effects are clinically relevant. There are variations in the collection method (apheresis or whole blood derived), collection process (centrifugation or buffy coat), storage conditions (plasma or platelet additive solutions), storage temperature (–80°C, 4°C, 22°C), and processing differences (washing, irradiation, leukoreduction, pathogen reduction, lyophilization) of platelets. There are data indicating there are in vitro differences in hemostatic function between different methods to produce a platelet product, but the data are lacking regarding the clinical relevance of these differences.^15–18 

Potentially the most important factor in the manufacturing of platelet units is the donor. Donor variation related to platelet quality metrics has been reported.¹⁹  These differences are potentially from both genetic and environmental conditions such as diet. Recent data also suggest that platelet donor sex and that of the recipient may have implications for outcomes because sex-specific transfusions were associated with improved hemostatic capacity.^20,21  The donor provides the “raw material” for platelet products, and we should not discount the differences in platelet function at baseline before manufacturing methods alter platelet function.

We also need a better understanding of the ability of platelet products to maintain the many different functional aspects of endogenous platelets. Endogenous platelets, in addition to being central for the process of cell-based hemostasis are also integral for immune modulation, maintaining vascular integrity, and angiogenesis.¹⁴  There is very little known about the nonhemostatic function of platelet units for transfusion. Because platelets are most commonly used for patients with hypoproliferative thrombocytopenia, it is essential that we further investigate if a platelet products can provide vascular protective effects and which manufacturing method can enhance this function.

We should also try to triage donors to the manufacturing method that is optimal for specific function. For example, some donors inherently have improved maintenance of hemostatic function when their platelets are stored at 4 °C compared with other donors. Blood collection centers could prioritize using donors that store platelets better in the cold for their production rather than indiscriminately using any donor to make cold-stored platelets. To do this, we must start to pedigree donors to determine which manufacturing methods optimize a specific platelet function that is needed for patients.

We need more accurate assays and animal models to measure each functional aspect of platelet products. To gain a more in-depth understanding of either the pathophysiology of conditions requiring platelet transfusion or to explore the functional aspects of platelet products, we also need to develop better in vitro and ex vivo assays as well as in vivo models. The currently available in vitro assays for hemostasis are limited for multiple reasons to include the lack of incorporating flow and biologic surfaces that are essential for hemostasis.²²  The in vitro assays that evaluate endothelial function such as permeability are also quite limited and have questionable validity in representing in vivo function. In vivo models are hampered by the issues related to incompatibility of human platelets in animals or the difficulty in external validity of using animal platelets in models. More accurate assays and animal models of transfusion that reflect endothelial, immune, and hemostatic function will allow for establishing more precise indications for platelets and therefore allow for more benefit relative to risks that will hopefully translate to improved outcomes. Primate models that have successfully used human blood products in bleeding models hold promise for this need.²³ 

Methods to improve the indications to transfuse platelets and to reduce the need for platelet transfusions through blood management strategies may also improve outcomes. Viscoelastic hemostatic assays have been shown to reduce exposure to blood products while also improving outcomes in predominantly adult cardiac surgery patients and other surgical populations.²⁴  Viscoelastic assays can have also been used as a surrogate marker for clinical bleeding in children requiring cardiac surgery.²⁵  As whole blood becomes more widely available at hospitals across the country, data from surgical adult and pediatric patients also reveal that whole blood transfusion can ultimately reduce total blood product requirement and subsequent platelet transfusion-related complications.^26,27 

Improving outcomes for patients who may need a platelet transfusion will likely be enhanced by collecting platelets from donors that have specific qualities to address a specific deficit such as loss of endothelial structural integrity or adhesion/aggregation needed for primary hemostasis. Currently, we are collecting platelets from any donor, manufacturing it in any way, and then transfusing it to any patient. Until there is a better understanding of the pathophysiology of the conditions in which platelet transfusions are considered and how manufacturing methods to include donor variation affect specific platelet functions, it will remain challenging to improve outcomes for patients who may benefit from platelet transfusion.

This report by Lang et al¹  tells an important story about the heterogeneity of transfusion practices and the potential complications associated with platelet transfusions in hospitalized pediatric patients. It is further evidence that there is urgency to work toward precision transfusion medicine goals in which we understand the pathophysiology for specific patients and then manufacture platelets for a precise need. This may seem daunting, but we can start with manufacturing platelets geared toward supporting endothelial structural integrity and for hemostatic plug formation. We are currently transfusing products with different functional profiles based on different manufacturing methods for all different kinds of conditions, and change is clearly needed.