High Incidence of Alloimmunization to Platelets and Platelet Transfusion Refractoriness during Induction Therapy in Patients Diagnosed with Acute Myeloid Leukemia

Introduction: Patients with acute myeloid leukemia (AML) are treated with intensive chemotherapeutic protocols. They are known to suffer from protracted pancytopenia and need prolonged transfusion support. Despite the administration of leukocyte-reduced and irradiated blood products, long-term transfusion dependency predisposes these patients to alloimmunization to both leukocyte (HLA) and platelet (HPA) antigens, leading to  immune platelet transfusion refractoriness, which is a major risk factor for bleeding-associated morbidity and mortality, to longer hospitalizations and higher inpatient hospital costs. The published incidence of immune platelet refractoriness in patients with hematologic malignancies ranges between 7% and 34%. The Rambam Health Care Campus is the only tertiary care medical center in Northern Israel providing services to over 2 million citizens. This population is highly heterogeneous in terms of ethnic and religious background and has a relatively high birth rate (3.2 versus 1.75 in other developed countries). The majority of AML patients in the region are treated at the Rambam Department of Hematology. To the best of our knowledge, the incidence of alloimmunization to platelet antigens and immune platelet refractoriness in this population has never been studied. The aims of the current study were: to estimate the incidence of immune platelet transfusion refractoriness among AML patients in Northern Israel, to define the onset of alloimmunization during the treatment course and to evaluate the efficacy of antibody screening by platelet immunofluorescent test (PIFT) as a follow-up tool to predict the risk for alloimmunization and immune platelet transfusion refractoriness in these patients.

Methods: Newly diagnosed AML patients were screened every two weeks for two months since diagnosis and throughout induction therapy for the presence of anti-HPA and anti-HLA antibodies using flow cytometry (PIFT assay). Antibodies were identified by the monoclonal-specific immobilization of platelet antigens (MAIPA) assay. Clinical parameters of patients were consecutively registered. Patients received platelet transfusions according to the institutional transfusion policy, including continuous platelet increment monitoring. Blood counts and platelet transfusion requirements were followed weekly; platelet refractoriness was determined when no increment (defined as an increase <5x10⁹ platelets/L after a single transfusion of 3x10¹¹platelets) was documented following two consecutive platelet transfusions.

Results:One hundred newly diagnosed AML patients (56 males and 44 females; age range 25-60 years) of various ethnic origins were included in the analysis. Platelet refractoriness was revealed in 49 (49%) patients (20 males and 29 females). Forty four (44%) patients developed anti-HLA and/or anti-HPA antibodies, 32/44 (73%) were females, 27 of them with more than two children. Immune platelet refractoriness was revealed in 34/49 (69%) refractory patients (8 males and 26 females); 13/34 (38%) had anti-HPA with (11) or without (2) anti-HLA antibodies and 21/34 (62%) had only anti-HLA antibodies. The average period from the beginning of treatment to antibody appearance was 26 days. The PIFT was found to be a sensitive, specific and efficient method for screening and detection of all anti-platelet antibodies, while MAIPA was found to be the preferred method for anti-platelet antibody identification.

Conclusions: Women with more than two children were found to have a significantly higher risk to develop alloantibodies and transfusion refractoriness. Our findings demonstrating a higher incidence of immune platelet refractoriness compared to that reported in the     literature may be attributed to the increased prevalence of multiparous women inhabiting our region. Routine antibody screening by PIFT appears to be an efficient tool for early detection of alloimmunized patients.