Optimum platelet therapy for thrombocytopenic leukemic patients is currently ill-defined. The issues to be addressed in the current proposal are: 1) Define the appropriate platelet transfusion level to prevent bleeding and how this level is effected by medications or concurrent illnesses; 2) Determine the best platelet and red cell transfusion programs to prevent platelet alloimmunization; 3) identify mechanisms and management o the platelet-refractory patient; 4) Determine the best methods of selecting compatible platelet donors for alloimmunized platelet refractory patients; and 5) Characterized mechanisms of spontaneous loss of platelet and lymphocytotoxic antibodies and evaluate techniques of active reversal of platelet alloimmunization in the chronically platelet-refractory patient. Patients will be randomized to receive prophylactic platelet transfusions at platelet counts of 5,000, 10,000 and 20,000/ul, and the associated bleeding risk will be assessed by red cell transfusion requirements, bleeding manifestations, hemorrhagic mortality, and 51CR- labeled stool blood loss measurements. The best methods of preventing platelet alloimmunization will be determined by a randomized prospective transfusion trial comparing the incidence of alloimmune platelet refractoriness in recipients of standard red cell and platelet products compared to those receiving leukocyte-poor red cells and either leukocyte-poor or UV-irradiated pooled random donor platelet concentrates, or leukocyte-poor single donor apheresis platelets. Primary endpoints will be: 1) clinical refractoriness to platelet transfusions; and 2) the development of broadly reactive alloantibodies. Secondary study endpoints will be: 1) influence of transfusion program on leukemia status (survival and remission duration); 2) evaluation of platelet alloantibody development and loss as a result of the transfusion program; 3) the association between medications and clinical conditions of the patient and the onset of refractoriness to platelet transfusions; and 4) the efficacy of leukocyte-poor transfusion products in preventing CMV infection in CMV seronegative transfusion recipients. Mechanisms of platelet refractoriness will be identified by a concurrent measurements of allo- and autoantibodies in association with fibrinogen survival and fibrin/fibrinogen degradation product assays to identify alloimmunization and platelet consumption as mechanisms of platelet refractoriness, respectively. The relative value of providing apheresis donor platelets to platelet-refractory patients on the basis of HLA- matching, HLA-matching plus platelet crossmatch testing, or matching for public HLA-specificities will be determined in a randomized fashion. Finally, a careful investigation of the role of suppressor cell induction in the observed loss of alloantibodies in some transfused patients over time will be evaluated. Active reversal of platelet alloimmunization in chronically platelet-refractory patients with cyclosporine A treatment will be determined by measuring transfusion responses to previously-incompatible platelet donors and by following platelet alloantibody levels. In summary, proposed is an organized, systematic, and rational approach for evaluating the critical issues regarding platelet therapy of leukemic patients.
