Antithrombotic Efficacy and Bleeding Risks of Vaccine-Induced Immune Thrombotic Thrombocytopenia Treatments

Abstract

Current guidelines for treating vaccine-induced immune thrombotic thrombocytopenia (VITT) recommend non-heparin anticoagulants and intravenous immunoglobulin (IVIg). However, the efficacy of these treatments remains uncertain due to a lack of comparative clinical trials or animal studies. A recent study proposed danaparoid and heparin as potential VITT therapies due to their ability to disrupt VITT IgG-PF4 binding. Here, we examined the effects of various anticoagulants (including unfractionated (UF) heparin, danaparoid, bivalirudin, fondaparinux, and argatroban), IVIg, and the Fc{gamma}RIIa receptor-blocking antibody, IV.3, in relation to VITT pathophysiology. Our investigation focused on VITT IgG-PF4 binding, platelet activation, thrombocytopenia, and thrombosis. Danaparoid, at therapeutic doses, was the sole anticoagulant that reduced VITT IgG-PF4 binding, verified by purified anti-PF4 specific VITT IgG. Low-dose UF heparin (< 2U/mL) augmented VITT IgG binding to PF4 on platelets. While danaparoid and high-dose UF heparin (10 U/mL) inhibited platelet activation, none of the anticoagulants significantly affected thrombocytopenia in our VITT animal model, and all prolonged bleeding time. IVIg and all anticoagulants, except UF heparin, protected VITT mice from thrombosis. Direct Fc{gamma}RIIa receptor inhibition with IV.3 antibody proved the most effective approach for managing both thrombosis and thrombocytopenia in VITT. Our results underscore the necessity of animal model investigations to inform patient treatment strategies. This study provides compelling evidence for developing Fc{gamma}RIIa receptor blockers to treat VITT and other Fc{gamma}RIIa-related thrombotic inflammatory disorders. Key pointsO_LINon-heparin anticoagulants and IVIg reduce thrombosis in vivo by varying degrees whereas heparin exacerbates thrombosis. C_LIO_LIDirect blocking of Fc{gamma}RIIa receptor is the most effective strategy to treating both thrombosis and thrombocytopenia in VITT. C_LI