Molecular Mechanisms of Immune Thrombocytopenia in Transfusion Medicine - OVERALL COMPONENT – PROJECT SUMMARY/ABSTRACT This revised application for a Program Project seeks support for a coordinated, multi-disciplinary investigation of molecular mechanisms that underly clinically important immune-mediated thrombocytopenic and thrombotic disorders. The Program is housed at Versiti's Blood Research Institute and Children's Hospital of Philadelphia – both nationally renowned facilities with long-standing commitments to basic, translational, and clinical blood-rela- ted research, particularly in the areas of platelet immunology, platelet activation, thrombosis, and B cell immuno- biology. These disciplines are of programmatic significance to the NHLBI, and of central importance to trans- fusion medicine and classical hematology - disciplines that, despite their impact on the nation's health, are cur- rently underrepresented in both human and financial resources. Our application reflects ongoing, close collabor- ative ties amongst the Project Leaders, some for more than three decades, and is bolstered by a strong history of interdependence that has allowed us to tackle thematically related issues of clinical relevance and importance. The central unifying theme of our application is to build on and develop a deeper understanding of clinically rele- vant immunological insults that lead to thrombocytopenia and downstream pathophysiological sequelae in the fetus, newborn, and adult. The Program comprises three highly synergistic, interdependent Projects, each of which is characterized by (1) examination of an unpredictable pathology attributable to a subset of antigen-spe- cific antibodies that, in addition to causing thrombocytopenia, also adversely affect other cell types, and (2) judi- cious use of preclinical mouse models that are specifically designed to investigate the etiology of different forms of immune thrombocytopenia. Project 1: The Immunobiology of Fetal/Neonatal Alloimmune Thrombocytopenia (FNAIT) employs a novel antigen-specific mouse model and a battery of clinically relevant monoclonal antibodies to define the functional significance of specific maternal antibody subpopulations that contribute mechanistically to, and may be diagnostic of, the severity of FNAIT. The etiology of this disorder is examined by exploring routes of antigen exposure that cause maternal alloimmunization to occur unpredictably in first pregnancies. Project 2: The Immunobiology of Heparin-induced Thrombocytopenia (HIT) uses sophisticated human antibody cloning techniques and analysis to identify and characterize the specific pathogenic antibody subpopulations that cause HIT, and explores an intriguing role for the gut microbiome in the etiology of this man-made immunological dis- order. Project 3: The Immunobiology of Vaccine-induced Thrombotic Thrombocytopenia (VITT) examines novel mechanisms by which platelet factor 4, platelet basic protein, and neutrophil activating peptide 2 contribute to the etiology of this rare, but life-threatening, immunologically mediated disorder. Taken together, there is strong scientific and programmatic rationale for this comprehensive effort to examine molecular and cellular mechan- isms that underly the immune-mediated thrombocytopenias. Insights and concepts derived from these basic studies should enhance the development of novel, clinically relevant diagnostic and therapeutic applications.
