Destabilization of PF4-antigenic complexes in heparin-induced thrombocytopenia
Abstract
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 UFH 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 (antigenic) complexes (ULCs), dissociated ULICs composed of the HIT-like monoclonal antibody KKO and ULCs, blocked binding of human HIT immunoglobulin G 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 nonheparin 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, postviral, and autoimmune HIT.
Article Details
Authors (13)
Lubica Rauova
4Hematology Division, Children’s Hospital of Philadelphia, Philadelphia, PA
Khalil Bdeir
University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
Ann H. Rux
3Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
Manu Thomas Kalathottukaren
4Department of Pathology and Laboratory Medicine, Center for Blood Research and Life Sciences Institute, The University of British Columbia, Vancouver, Canada
Jenna Oberg
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
Chanel C. La
4Department of Pathology and Laboratory Medicine, Center for Blood Research and Life Sciences Institute, The University of British Columbia, Vancouver, Canada
David T. E. Lim
4Department of Pathology and Laboratory Medicine, Center for Blood Research and Life Sciences Institute, The University of British Columbia, Vancouver, Canada
Vincent Hayes
1Hematology Division, Children’s Hospital of Philadelphia, Philadelphia, PA
Gavin T. Koma
1Hematology Division, Children’s Hospital of Philadelphia, Philadelphia, PA
Amrita Sarkar
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
Mortimer Poncz
Jayachandran N. Kizhakkedathu
4Department of Pathology and Laboratory Medicine, Center for Blood Research and Life Sciences Institute, The University of British Columbia, Vancouver, Canada
Douglas B. Cines
Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, Philadelphia, Pennsylvania, United States