Anti-PF4 antibodies trigger a faster and stronger platelet procoagulant response than anti-heparin/PF4 antibodies

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Vaccine-induced immune thrombocytopenia and thrombosis (VITT) and "VITT-like" cases are an emerging cause of severe thrombocytopenia and thrombosis associated with IgG antibodies targeting platelet factor 4 (anti-PF4). These syndromes are characterized by more frequent and severe thrombosis than heparin-induced thrombocytopenia (HIT), which is typically caused by antibodies targeting heparin-modified PF4 (anti-PF4/H). In this study, we compared the intrinsic prothrombotic properties of anti-PF4 and anti-PF4/H IgG antibodies to identify mechanisms that may contribute to the severity of VITT/VITT-like syndromes. Using the monoclonal IgG1 antibodies 1E12 (anti-PF4) and 5B9 (anti-PF4/H), we showed that anti-PF4 IgG exhibited an increased propensity to induce the formation of fibrin-rich platelet/leukocytes aggregates in a microfluidic model of whole blood (WB) thrombosis. This phenomenon was related to a strong potentiation of thrombin generation in plasma by 1E12, but not by 5B9, and only in the presence of platelets and coagulation factors V and XI. We also demonstrated a substantially faster and stronger ability of 1E12 compared to 5B9 to activate platelets using the serotonin release assay, confirmed with human VITT and HIT samples. Furthermore, 1E12 was more likely than 5B9 to induce procoagulant platelets (CD62P+/phosphatidylserine+) in platelet-rich plasma (PRP) and to produce procoagulant microvesicles in WB and PRP. In conclusion, platelets are activated faster and exhibit more procoagulant activity in response to anti-PF4 antibodies than to anti-PF4/H antibodies, which may contribute to the severity of VITT and VITT-like syndromes.