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• W4387253125 abstract "The risk of stroke or other thrombotic complications following vaccination of SARS-CoV-2 has been extensively reported since widespread vaccination efforts began in early 2021. This disorder, termed vaccine-induced immune thrombotic thrombocytopenia (VITT), has remarkable overlap in clinical manifestations to that of heparin-induced thrombocytopenia (HIT). HIT and VITT are pathologies caused by IgG immune complexes that activate platelets via Fc Receptor for IgG IIA (FcγRIIA), which are collectively categorized as immune thrombotic thrombocytopenia (ITT) disorders. Thrombotic events remain high following the standard of care treatment with concurrent risk of bleeding complications. This study sought to investigate a novel approach to treatment of ITT. Recent reports demonstrate increased procoagulant activity in ITT. However, these reports required ex vivo analysis, and in vivo relevance remains unclear. Using human and mouse model systems, we investigated the cooperativity of protease activated receptors (PARs) and FcγRIIA in ITT. We challenged humanized FcγRIIA transgenic mice with or without endogenous mouse Par4 (denoted as IIA-Par4 +/+ or IIA-Par4 -/- , respectively) with a well-established model IgG immune complex (αCD9). IIA-Par4 +/+ mice given αCD9 were severely thrombocytopenic, with extensive platelet-fibrin deposition in the lung. In contrast, IIA-Par4 -/- mice had negligible thrombocytopenia or pulmonary platelet-fibrin thrombi. These data demonstrate for the first time the need for dual platelet receptor (PAR and FcγRIIA) stimulation for fibrin formation in ITT in vivo . In human platelets, we observed that PAR1, PAR4, and FcγRIIA each contributed to the procoagulant phenotype, via receptor-specific increases in cytosolic Ca 2+ . As inhibition of 12(S)-lipoxygenase has been reported to decrease platelet activation downstream of FcγRIIA and PAR4, we used inhibitor VLX-1005 and observed significant reduction in both platelet procoagulant phenotype ex vivo , and thrombocytopenia and thrombosis in our humanized mouse model of HIT in vivo . These results extend our understanding of ITT pathophysiology and provide a scientific rationale for targeting the procoagulant phenotype as a possible therapeutic strategy in ITT." @default.
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• W4387253125 date "2023-05-01" @default.
• W4387253125 modified "2023-10-03" @default.
• W4387253125 title "Abstract 242: A Novel Strategy To Combat The Procoagulant Phenotype In Immune Thrombotic Thrombocytopenia Using 12-LOX Inhibition" @default.
• W4387253125 doi "https://doi.org/10.1161/atvb.43.suppl_1.242" @default.
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