Special Communication: Response to “Ensuring a Reliable Platelet Supply in the United States”

See Article, page 921 The recent "Perspective" published in the New England Journal of Medicine, on June 1, 2023, by Riley et al1 draws attention to the chronic and unreliable platelet supply and the need to expand technologies to collect and prepare platelet components more efficiently and rapidly. The coronavirus disease 2019 (COVID-19) pandemic, as the authors point out, saw the United States suffering from a lack of resources to secure an adequate blood supply for many reasons. Numerous publications, organizational press releases, alliances, and public forums focused on the supply chain and the same old strategies to mitigate this issue with very low yield. Blood components being perishable, and the short shelf-life of platelets certainly lend to the supply chain challenge. When coupled with natural or man-made disasters, this further limits resources to maintain inventory. Initiatives to increase the platelet shelf-life and the call for semiautomated and automated technologies to harvest platelets from whole blood mentioned by Riley et al1 serve to improve the availability of platelet components, streamline processes, and prepare for the ongoing need for rapid responses in times of crisis. These are sound and timely recommendations. Acknowledging the above, another critically important part of the problem still needs to and must be addressed. There has been a clear failure to recognize the opposite side of the proverbial coin. Much has been made of supply while the discussion regarding demand is marginalized at best, and often ignored entirely. The authors mention the steady increase in platelet transfusions from 2017 to 2019.2 They comment on the mismatch between the growing demand versus reduced collection, yet there needs to be an explanation for why the demand continues to rise. Is this statistic for platelet use based on rational care? Are these transfusions appropriate? Are they necessary? Are they in compliance with the current evidence-based transfusion practices? Does this increased demand represent the misutilization of a blood component while placing patients at risk and further depleting the supply? Current literature points to serious adverse events associated with the transfusion of blood components, and platelet transfusions are no exception. Poorer outcomes are seen in patients receiving platelet transfusions including significant transfusion reactions such as transfusion-related circulatory overload, transfusion-related acute lung injury, allergic/anaphylactic reactions, alongside increased nosocomial infections, admission to critical care units, thrombosis, length of stay, and mortality.3–8 Most platelet components are not administered therapeutically for hemorrhage; instead, they are commonly given prophylactically to nonbleeding patients before minimally invasive elective procedures or for various levels of thrombocytopenia not associated with bleeding risk.9 These prophylactic platelets do not assure the prevention of bleeding and have been associated with increased bleeding episodes in certain clinical scenarios.4,10–16 Additionally, even in bleeding patients, the etiology may be surgical or due to coagulopathy unrelated to platelet number or function. Variability of platelet count thresholds and dual-unit versus single-unit platelet transfusions in the outpatient arena also contribute to potential overuse and thus inadequate inventory. A recent survey across more than 40 states found that a platelet count threshold of ≤10,000/μL was utilized in approximately 50% of institutions.17 Current evidence exists that a 2-unit strategy provides no clear advantage over the transfusion of 1 unit of platelets in the outpatient setting.18 Applying more consistent evidence-based guidelines regarding outpatient transfusions could help secure platelet inventories. Transfusion of ABO-mismatched platelets also deserves comment. Supply constraints often necessitate the utilization of ABO-mismatched platelets. The incidence of hemolysis secondary to anti-A/anti-B is rare. However, studies in the early 1990s showed ABO-mismatched platelets to be associated with increased platelet refractoriness and increased platelet usage.19,20 A more recent study revealed increased mortality and poorer neurocognitive function in patients with spontaneous intracerebral hemorrhage (ICH) who received ABO-incompatible platelets.21 An additional study by Bougie et al22 identified ABO-identical platelets to minimize total platelet dosage. Additionally, 2 subpopulations, hematology/oncology and ICH patients, had increased mortality if transfused with major mismatched platelet components. The methods suggested by Riley et al1 might allow for more adequate inventory and thus the ability to provide ABO-identical platelets in these particular patient groups. Patients with thrombocytopenia and/or platelet dysfunction should be evaluated thoroughly without transfusion as the default. Transfusion is a temporizing measure and will not address the abnormality in hemostasis if it indeed exists. We must identify the root cause, or causes, to allow for appropriate and targeted therapeutic interventions where possible. A thorough history, physical examination, and laboratory assessment are vital to identifying the etiology(ies) of thrombocytopenia or thrombocytopathy. Is the thrombocytopenia isolated or nonisolated? What is the platelet morphology as seen on the peripheral smear? Using mean platelet volume (MPV) and immature platelet fraction (IPF) can aid in assessing marrow production and peripheral destruction. Direct antiglobulin testing can differentiate between entities such as immune and drug-induced thrombocytopenia versus Evan syndrome. Platelet function testing via aggregometry or other platforms are available to assess platelet dysfunction, particularly in patients taking antiplatelet medications, a population most often, and unnecessarily transfused either prophylactically or therapeutically.23 These tests vary in laboratory methods, sensitivity and specificity, turn-around-times, and their interpretations. Nontransfusion alternatives, such as desmopressin, antifibrinolytics, thrombopoietin receptor agonists, and other drugs should be utilized when available and appropriate. Incorporation of all the approaches mentioned above represents the delivery of patient-centered care and avoids the risks and poor outcomes of transfusion as noted. Incorporation and adoption of the most current state of the science regarding the approach to thrombocytopenia and/or thrombocytopathy, understanding the various pathophysiologic mechanisms that may or may not be at play, is critical to decreasing the need for platelet transfusions and supporting patients' overarching blood health.24–27 Furthermore, expanding knowledge of platelet therapy through well-designed trials is essential for achieving the desired end state of optimal hemotherapy. One of the 4 foundational pillars of patient blood management (PBM) is the optimization of coagulation/hemostasis. This implies the empiric use of evidence-based transfusion practice, but far beyond this, it calls for implementing transfusion-avoidance and patient-oriented therapies to ensure better outcomes. We agree with Riley et al1 that attention to processes supporting supply are needed. Collaboration with the Food and Drug Administration (FDA) and donor centers will be necessary to expand these methods and services. We cannot, however, ignore the evidence-based interventions that prove to clearly reduce demand through embracing and implementing the practice of comprehensive PBM. This is simply good clinical medicine as well as solid economics. DISCLOSURES Name: Carolyn D. Burns, MD. Contribution: This author developed the initial concepts, reviewed the literature, prepared the initial draft, and managed the manuscript for approval and submission. Conflicts of Interest: President, Society for the Advancement of Patient Blood Management; CMO Collaborative Clinical Consulting, LLC; Consulting for Accumen, Octapharma, Hemosonics; Advisory Board, Werfen; Invited speaker for Zuellig Pharma, WellSky. Name: Arthur W. Bracey, MD. Contribution: This author helped develop further concepts, assisted with editing and final version for submission. Conflicts of Interest: Harris Health Board of Directors; Community Health Choice Board of Directors; Gulf Coast Regional Blood Center Board of Directors; American Red Cross Medical Advisory Committee; HHS Advisory Council on Blood Stem Cell Transplantation. Name: Aryeh Shander, MD, FCCM, FCCP, FASA. Contribution: This author helped develop further concepts, assisted with editing and final version for submission. Conflicts of Interest: Consulting and research fees for CSL Vifor, Pharmacosmos, Accumen, I-Sep, Grifols, Baxter, Lindis Corp, Octapharma CSL Behring, HbO2 Therapeutics LLC; Expert Witness – class action litigation. Name: Pierre R. Tibi, MD. Contribution: This author assisted with editing and final version for submission. Conflicts of Interest: Consulting for Accumen, Hemosonics, Baxter. Name: Sean G. Yates, MD. Contribution: This author helped develop further concepts, assisted with editing and final version for submission. Conflicts of Interest: None. This manuscript was handled by: Shannon L. Farmer, DHSc.