Title: Molecular basis of the humoral immune response in heparin-induced thrombocytopenia Heparin induced thrombocytopenia (HIT) is the most common adverse drug reaction affecting blood cells. Although heparin is an important anticoagulant widely used in many clinic settings, heparin exposure often leads to production of antibodies (Abs) specific for conformational epitopes expressed by the platelet alpha granule chemokine, platelet factor 4 (PF4) when it binds to heparin to form a complex (PF4/H). In some patients, particularly after surgery, these Abs provoke HIT, characterized by thrombocytopenia and often life- threatening arterial or venous thrombosis/thromboembolism. This complication is thought to result, at least in part, from PF4-dependent Ab binding to platelets, monocytes and possibly other target cells, leading to cell activation via Fc receptors and generation of procoagulant activity. The mechanisms by which heparin-induced Abs cause thrombocytopenia and thrombosis are partially understood, but very little is known about the molecular basis of the underlying immune response itself. One unique feature of HIT is that 25-50% of patients exposed to heparin produce Abs that recognize PF4/H but only 0.1-1.0% experience the classical HIT syndrome. Why some heparin-induced Ab are ?benign? or ?non-pathogenic? and others are ?pathogenic? cannot be accounted for on the basis of Ab potency alone. In this application, we propose to provide a molecular explanation for why some heparin-induced Abs cause pathology whereas others that may recognize PF4/H equally well fail to cause disease. Our studies will be facilitated by close collaboration with clinicians and translational scientists engaged in research to improve understanding of HIT pathogenesis and improve diagnosis and treatment of this condition.
This proposal aims to study the molecular mechanism underlying the pathogenesis of heparin-induced thrombocytopenia and the molecular basis of the pathogenicity of disease-causing PF/heparin-specific antibodies, and holds great promise in improving diagnosis and treatment of this complication.
