Acute pulmonary embolism caused by highly aggregated intravenous immunoglobulin

Yu, Chuanfei; Hou, Jifeng; Shen, Lianzhong; Gao, Kai; Chun-ming, Rao; Yang, Peng; Fu, Zhihao; Wang, Q. Z.; Li, Y. H.; Wang, L.; Liu, F.; Zhang, L.; Qu, Zhe; Shen, Qi; Li, B.; Li, X. G.; Wang, J. Z.

doi:10.1111/vox.12307

Cited by 6 publications

(1 citation statement)

References 30 publications

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“…IVIg is derived from pooled plasma of 3,000-100,000 healthy donors 30 and very high concentrations are required for treatment to achieve the desired effect of non-specific inhibition of FcγRIIa. Aggregates of IVIg can be found in batches of IVIg and can cause paradoxical prothrombotic effects, platelet aggregation 31 , and potential thromboembolism 32,33 . In contrast, IV.3 requires doses 1000 times less than IVIg to achieve specific FcγRIIa inhibition to a greater extent.…”

Section: Discussionmentioning

confidence: 99%

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

Leung,

Ahmadi,

Casey

et al. 2024

Preprint

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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 FcγRIIa 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 (<2 U/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 FcγRIIa 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 FcγRIIa receptor blockers to treat VITT and other FcγRIIa-related thrombotic inflammatory disorders.

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