Abstract Number: PB1430
Meeting: ISTH 2020 Congress
Background: Heparin-induced thrombocytopenia (HIT) is a highly prothrombotic, antibody-mediated disorder that develops during anticoagulation therapy in ~1% of adults exposed to therapeutic doses of unfractionated heparin. Ultra-large immune complexes (ULICs) composed of HIT antibody, PF4 and heparin, glycosaminoglycans or polyanions such as polyphosphates, von Willebrand factor or DNA are central to the pathogenesis of HIT. Recently, we developed and reported highly biocompatible cationic polyanion inhibitors composed of a dendritic polyglycerol core assembled with trivalent cationic ligands with high charge densities (R) (Figure 1) that are protected with short polyethylene glycol (PEG) to generate a protective shell (a brush layer) against nonspecific interactions named as UHRAs.
Aims: The aim of this study was to evaluate the capacity of representative compounds to disrupt ULICs as potential therapeutic in HIT.
Methods: We characterized UHRA binding properties using isothermal titration calorimetry, their capacity to disrupt formation of ULICs by dynamic light scattering and their effect on antigen recognition by HIT antibodies by ELISA. Flow cytometry was used to assess the effect on platelet activation and the membrane-bound antigenic complex. A murine model of HIT employing transgenic mice expressing hPF4 and hFcγRIIA was used to assess the in vivo effect.
Results: UHRAs caused extensive, dynamic changes within multimolecular PF4 antigenic complexes that prevented or disrupted formation of the epitope necessary for binding of multiple pathogenic antibodies in vitro. Selected UHRAs were able to prevent thrombocytopenia in a murine passive model of HIT. Intravital imaging of cremaster muscle vasculature showed disruption of HIT antigenic complex assembled on arteriolar endothelium (Figure 2) and prevention of thrombus growth induced by HIT like monoclonal antibody KKO in murine model of HIT.
Conclusions: Disrupting ULIC formation prevents antibody-mediated cell activation and the subsequent development of a prothrombotic state in HIT and could potentially be used as a new therapeutic approach for HIT alternative to anticoagulation.
To cite this abstract in AMA style:Kizhakkedathu JN, La C, Kalathottukaren MT, Yarovoi SV, Hayes V, Koma GT, Abbina S, Morrissey JH, Haynes CA, Cines DB, Rauova L. Effect of Synthetic Inhibitors on HIT Antigenic Complex – Therapeutic Approach Alternative to Anticoagulation [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/effect-of-synthetic-inhibitors-on-hit-antigenic-complex-therapeutic-approach-alternative-to-anticoagulation/. Accessed January 28, 2022.
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