GSK484

Heparin-caused thrombocytopenia/thrombosis (HIT) is really a serious immune response to heparins, characterised by thrombocytopenia and frequently severe thrombosis rich in morbidity and mortality. HIT is mediated by IgG antibodies against heparin/platelet factor 4 antigenic complexes. These complexes are believed to activate platelets resulting in thrombocytopenia and thrombosis. Ideas reveal that HIT immune complexes induce NETosis via interaction with FcγRIIa on neutrophils and thru neutrophil-platelet association. HIT immune complexes induce formation of thrombi that contains neutrophils, extracellular DNA, citrullinated histone H3 and platelets inside a microfluidics system as well as in vivo, while neutrophil depletion abolishes thrombus formation. Lack of PAD4 or PAD4 inhibition with GSK484 abrogates thrombus formation although not thrombocytopenia, suggesting they’re caused by separate mechanisms. NETs markers and neutrophils undergoing NETosis can be found in HIT patients. Our findings demonstrating the participation of NETosis in thrombosis will customize the current idea of HIT pathogenesis and can lead to new therapeutic strategies.