Alloimmune platelet refractoriness (alloPR) among actively bleeding surgical patients with thrombocytopenia represents a life-threatening problem. Introduction Alloimmunization to human leukocyte antigens (HLA) remains a major hurdle in achieving successful transplantation and is the primary cause of alloimmune platelet refractoriness (alloPR) [1-3]. Platelet transfusion support of HLA allosensitized patients presents distinct problems for the blood transfusion service. Whereas patients are routinely tested for red blood cell (RBC) alloantibodies prior to blood transfusion no screening test is routinely performed for HLA alloantibodies prior to platelet transfusion. Moreover there are no data available validating the use of any screening test for HLA alloantibodies as a reliable predictor of platelet refractoriness [4 5 In the Trial to Reduce Alloimmunization to Platelets the incidence of HLA alloimmunization exceeded that of clinical platelet refractoriness by twofold . Thus alloPR is currently recognized when inadequate platelet increments are documented following platelet transfusion [1-3]. Furthermore while all blood banks have Gefitinib (Iressa) ready access to an inventory of antigen-typed RBC units that are compatible and available for transfusion to the majority of patients who are sensitized to red cell antigens very few blood banks have an inventory of HLA-typed platelet components. While alloPR due to HLA antibodies is well recognized among patients with chemotherapy-related thrombocytopenia [4 6 there are little data describing its frequency in other patient populations. The reported prevalence of detectable HLA antibodies in normal male and nulliparous female blood donors ranges from 1 to 17% and increases to 24-53% in females with prior pregnancy [7-10]. Pregnancy imparts a greater risk of HLA allosensitization compared with blood transfusion  and an increasing number of pregnancies is associated with higher HLA allosensitization rates [7 9 In addition there are data suggesting an increased prevalence of HLA alloantibodies among patients with antibodies to RBC antigens [11 12 Given these data it is reasonable to expect alloPR to occur outside of the setting of hematologic malignancies and that prior pregnancy and/or known RBC alloimmunization may identify at-risk patients. Here we present three surgical cases in which alloPR due to HLA antibodies compromised transfusion support for active bleeding and thrombocytopenia during major surgery and resulted in life-threatening hemorrhage. We show serologic evidence that HLA antibodies are found in much higher concentration than RBC Gefitinib (Iressa) antibodies and cannot be sufficiently “washed out” during massive transfusion or “adsorbed out” by transfusion of multiple doses of platelets. Given that alloPR is not typically considered in the context of intra-operative thrombocytopenia it may play an under-recognized role in bleeding morbidity and mortality in the surgical patient population. Patient 1 A male patient with Marfan’s syndrome and an extensive history of prior cardiac surgery and multiple blood transfusions presented for a repeat aortic arch repair. His pre-surgical platelet count was 106 0 A pre-operative specimen was noted to have anti-C and anti-Fya RBC antibodies. Intra-operatively 10 units of compatible packed RBCs (C- Fya -) were administered. Continued bleeding and depletion of all available Fya-negative RBCs necessitated switching to (C- Fya+) packed RBCs after an intra-operative specimen showed only weak reactivity with Fya+ cells. The patient also received numerous fresh Gefitinib (Iressa) frozen plasma (FFP) and platelet transfusions (see Table I). During surgery the patient’s platelet count dropped to 21 0 In response to a 6 unit dose of platelets the patient’s platelet count increased to 30 0 within minutes of platelet transfusion representing a corrected-count increment of 4950/μL. Transfusion of an Gefitinib (Iressa) additional 18 units of platelets increased the platelet count to only 46 0 and 45 min later the patient’s platelet count was only 30 0 despite transfusion of an additional 21 units of platelets. A presumptive diagnosis of alloPR was confirmed by detection of COL4A5 anti-HLA antibodies. Single antigen bead studies identified 68 different HLA Class I antigen specificities. The patient continued to bleed in the post-operative period despite administration of platelets plasma recombinant activated factor VII and epsilon aminocaproic acid (EACA) and required surgical re-exploration. The highest platelet count obtained during surgery or the post-operative period was 98 0 with a nadir of 10 Gefitinib (Iressa) 0 He.