Antithrombotic efficacy and bleeding risks of vaccine-induced immune thrombotic thrombocytopenia treatments

Current guidelines for treating vaccine-induced immune thrombotic thrombocytopenia (VITT) recommend nonheparin anticoagulants and IV immunoglobulin (IVIg). However, the efficacy of these treatments remains uncertain due to case studies involving small patient numbers, confounding factors (eg, concurrent treatments), and a lack of animal studies. A recent study proposed danaparoid and heparin as potential VITT therapies because of their ability to disrupt VITT IgG-platelet factor 4 (PF4) binding. Here, we examined the effects of various anticoagulants (including unfractionated [UF] heparin, danaparoid, bivalirudin, fondaparinux, and argatroban), IVIg, and the FcγRIIa receptor-blocking antibody, IV.3. 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 affinity-purified anti-PF4 VITT IgG. Although 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 the VITT mice from thrombosis. Direct FcγRIIa receptor inhibition with IV.3 antibody is an effective approach for managing both thrombosis and thrombocytopenia in the VITT mouse model. Our results underscore the necessity of animal model investigations to inform and better guide clinicians on treatment choices. This study provides compelling evidence for the development of FcγRIIa receptor blockers to prevent thrombosis in VITT and other FcγRIIa-related inflammatory disorders.