Platelet transfusion - the new immunology of an old therapy

Abstract

Platelet transfusion has been a vital therapeutic approach in patients with hematologic malignancies for close to half a century. Randomized trials show that prophylactic platelet transfusions mitigate bleeding in patients with acute myeloid leukemia. However, even with prophylactic transfusions, as many as 75% of patients, experience hemorrhage. While platelet transfusion efficacy is modest, questions and concerns have arisen about the risks of platelet transfusion therapy. The acknowledged serious risks of platelet transfusion include viral transmission, bacterial sepsis, and acute lung injury. Less serious adverse effects include allergic and non-hemolytic febrile reactions. Rare hemolytic reactions have occurred due to a common policy of transfusing without regard to ABO type. In the last decade or so, new concerns have arisen; platelet-derived lipids are implicated in transfusion-related acute lung injury after transfusion. With the recognition that platelets are immune cells came the discoveries that supernatant IL-6, IL-27 sCD40L, and OX40L are closely linked to febrile reactions and sCD40L with acute lung injury. Platelet transfusions are pro-inflammatory, and may be pro-thrombotic. Anti-A and anti-B can bind to incompatible recipient or donor platelets and soluble antigens, impair hemostasis and thus increase bleeding. Finally, stored platelet supernatants contain biological mediators such as VEGF and TGF-β1 that may compromise the host versus tumor response. This is particularly of concern in patients receiving many platelet transfusions, as for acute leukemia. New evidence suggests that removing stored supernatant will improve clinical outcomes. This new view of platelets as pro-inflammatory and immunomodulatory agents suggests that innovative approaches to improving platelet storage and pre-transfusion manipulations to reduce toxicity could substantially improve the efficacy and safety of this long-employed therapy.

Keywords: bleeding; immune response; platelets; storage; thrombosis; transfusion; transfusion reaction.

Figure 1

Unwanted passengers and events during platelet storage: Besides platelets, platelet concentrates contain “unwanted passengers” in the form of soluble mediators in the supernatant (in the case of unwashed platelet concentrates – which are still the routine product in virtually all US hospitals) and leukocytes (in the case of non-leukoreduced platelet concentrates – which are still an available product in some US hospitals). The supernatant (red background) contains substances which are secreted or shed into the plasma during storage containing soluble mediators, like sCD40L, PDGF, or sP-selectin. In addition, cytokines and cell fragments can be found. The platelet themselves (yellow background) change during storage. They become hyporesponsive (not depicted), and degranulate with increased expression of alpha granule contents (e.g., P-selectin). Platelets express ABO antigens, which lead to suboptimal results and complications if transfused into ABO-unmatched recipients. A marker for platelet activation is platelet leukocyte aggregate formation (white background). With prolonged storage, the number of platelet leukocyte aggregates increase. Leukocytes in the stored bag (gray background) release cytokines, which can induce febrile transfusion reactions. Passenger leukocytes lead to sensitization to HLA antigens with subsequent refractoriness.