Describing the Epitopes of Pathogenic Antibodies in Heparin-induced Thrombocytopenia

Abstract

Heparin is an anticoagulant widely administered to patients undergoing major orthopedic or cardiac surgery. Though heparin is effective at preventing thrombosis, it is paradoxically associated with the development of heparin-induced thrombocytopenia (HIT). HIT is strongly associated with thrombotic complications and is an adverse drug reaction that occurs when heparin binds to the self-protein, platelet factor 4 (PF4) and forms immunogenic multimolecular complexes. As a result, anti-PF4/heparin antibodies are formed, which bind to these complexes, and can cross-linking Fc receptors on platelets and monocytes causing intense platelet activation, thrombocytopenia, and thrombosis. Patients who receive heparin frequently form antibodies against these PF4/heparin complexes; however, most of these antibodies do not cause HIT. Over-diagnosis of HIT is common due to the detection of clinically insignificant non-pathogenic anti-PF4/heparin antibodies. Current enzyme immunoassays (EIAs) cannot distinguish between pathogenic and non-pathogenic anti-PF4/heparin antibodies and will give a false positive result in the presence of the clinically insignificant non-pathogenic anti-PF4/heparin antibodies. Further functional testing is required to identify samples containing the pathogenic anti-PF4/heparin antibodies that will lead to HIT; however, these tests are not readily available in most centres, and delay timely diagnosis. There is little known about the differences between pathogenic and non-pathogenic HIT antibodies. The identification of antigenic determinations of pathogenic HIT antibodies binding to PF4 from this project will have direct implications for patient care. We will be able to accurately and rapidly identify “true” HIT patients from learning more about the pathogenic HIT antibody epitope.