Cooperative effect between anti-PF4/H and anti-PF4 antibodies increases cell activation and thrombotic risk in HIT

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ABSTRACT: Heparin-induced thrombocytopenia (HIT) is a severe complication of heparin therapy, frequently associated with thrombosis. Immunoglobulin G (IgG) antibodies to heparin-platelet factor 4 (PF4/H) complexes play a central role in HIT by activating platelets and leukocytes via Fc gamma Receptor IIa (FcγRIIA). However, some patients also develop IgG against unmodified PF4 (anti-PF4), but their implication in the pathophysiology of HIT is unclear. Therefore, we assessed the impact of the joint presence of anti-PF4/H and anti-PF4 antibodies on cellular activation, platelet count, and thrombus formation, using chimeric monoclonal IgG1 antibodies specific for either PF4/H complexes (5B9) or PF4 alone (1E12). As expected, 5B9 coincubated with washed platelets without heparin did not induce platelet activation, but when a nonactivating concentration of 1E12 was present with 5B9, significant platelet activation was observed. This functional cooperation was Fc dependent and involved FcγRIIA receptors, given that it was no longer detectable with F(ab')2 fragments of 1E12 or 5B9 or with ibrutinib, which inhibits the FcγRIIA pathway. 5B9 at a nonactivating concentration of 1E12 also induced thrombus formation without heparin under flow conditions. Furthermore, when the 2 antibodies were injected together into human FcγRIIA/human PF4 transgenic mice, thrombocytopenia always occurred, with pulmonary thrombi in one-third of the injected mice, similar to that observed after injection of 5B9 and heparin. These results support that functional cooperation may exist between anti-PF4 antibodies of different specificity and promote cell activation, thrombocytopenia, and thrombosis. This process may also increase the risk of thrombosis in HIT even after heparin treatment has been discontinued.

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