Destabilization of PF4-antigenic complexes in heparin-induced thrombocytopenia.

Abstract

Heparin-induced thrombocytopenia (HIT) is initiated by antibodies that recognize large antigenic complexes composed of multiple molecules of cationic platelet factor 4 (PF4) and polyanions such as unfractionated heparin (UFH) that bind to each other primarily through electrostatic interactions. We asked whether the formation and stability of these HIT antigenic or ultralarge immune complexes (ULICs) would be inhibited by biocompatible synthetic polycationic molecules shown previously to dissociate unfractionated heparin from antithrombin III and to inhibit polyphosphates. Members of this family of molecules, designated Universal Heparin Reversal Agents (UHRAs), inhibited formation and dissociated preformed ultralarge PF4-UFH complexes (ULCs), dissociated ULICs composed of the HIT-like monoclonal antibody KKO and ULCs, blocked binding of human HIT IgG antibodies to PF4/heparin, binding of KKO to platelets, KKO-induced adhesion of platelets to activated human endothelium under flow, and microvascular thrombosis induced by KKO in a mouse model of HIT. These data suggest that UHRAs might provide a rationale intervention that acts at an early step in the pathogenesis of HIT to enhance the benefits and lessen the risks of non-heparin anticoagulants. Destabilization of immune complexes using polycationic inhibitors might also find a role in management of other polyanion-PF4-antibody-mediated conditions, including vaccine-induced thrombocytopenia/thrombosis, post-viral, and autoimmune HIT.