Occurring in approximately 1-3% of all transfusions, allergic transfusion reactions (ATRs) manifest primarily as urticarial and pruritic reactions, but more severe reactions with angioedema and anaphylaxis can occur. The mechanisms of ATRs are not known in the vast majority of cases. An understanding of these mechanisms is essential for determining how to prevent ATRs, as several randomized clinical trials have failed to show that interventions with antihistamines can prevent ATRs. Our overall hypothesis is that factors in donor plasma stimulate basophils in a susceptible transfusion recipient to release mediators that cause an ATR. Using apheresis platelet (AP) transfusions as a model, we will delineate mechanisms of common ATRs following these Specific Aims: 1) To determine if there is an atopic phenotype for subjects who experience ATRs from oncology subjects who experience ATRs (n=156), oncology subjects with no history of an ATR (n=78), and the donors of these AP products (n=234), using clinical and laboratory measures. Questionnaires will identify clinical atopic disease and clinically apparent allergies to food, environmental, and drug allergens;and subjects will have IgE testing of food and environmental allergens. We hypothesize that patients who experience ATRs have an underlying atopic tendency and are primed to experience ATRs. Additionally, in the setting of marrow aplasia from chemotherapy, we will explore whether this atopic tendency is increased through chemotherapy-induced elevations of IL-3 and GM-CSF, which prime recipient basophils for atopic mediator release;2) To determine if the candidate ATR mediators brain derived neurotrophic factor (BDNF), C5a, and CCL5 in AP products correlate with ATRs. We hypothesize that elevated concentrations of BDNF, C5a, and CCL5 will identify platelet products that have a greater risk of causing ATRs;3) To use the basophil activating potential of AP supernatants from products that cause ATRs to identify pro-allergic mediators released during an ATR. Products of basophil activation such as histamine and cysteinyl leukotrienes will be measured. We hypothesize that a quantitative, functional test for factors released after AP supernatant induced basophil activation will identify pathways that mediate ATRs in vivo. We will define a comprehensive mechanistic overview of ATRs by linking donor, recipient, and AP product factors in the same study. This proposal will also provide a detailed record of the associated clinical features and symptoms of ATRs, which have not been systematically investigated in depth. The long-term goal of this and subsequent projects is to provide a rationale for clinical trials that 1) prospectively identify patients and/or products at higher risk for ATRs and prospectively plasma reduce platelet products for these select patients to reduce the incidence of ATRs, or 2) define a mechanism involved in ATRs that would be amenable to a novel prophylactic treatment, e.g., a leukotriene receptor antagonist.
The overall goal of this proposal is to identify mechanisms of allergic transfusion reactions (ATRs), with the ultimate goal of a rationally designed clinical trial of ATR prevention strategies. ATRs cause itching, hives, and sometimes swelling and life-threatening reactions, and ATRs are a frequent morbidity for patients, typically those with cancer, who already bear significant burdens.
|Kacker, Seema; Ness, Paul M; Savage, William J et al. (2014) Cost-effectiveness of prospective red blood cell antigen matching to prevent alloimmunization among sickle cell patients. Transfusion 54:86-97|
|Savage, William J; Hamilton, Robert G; Tobian, Aaron A R et al. (2014) Defining risk factors and presentations of allergic reactions to platelet transfusion. J Allergy Clin Immunol 133:1772-5.e9|
|Savage, William J; Tobian, Aaron A R; Savage, Jessica H et al. (2013) Scratching the surface of allergic transfusion reactions. Transfusion 53:1361-71|