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    Oral Communication

    Platelet Disorders, von Willebrand Disease and Thrombotic Microangiopathies

    Thrombotic Thrombocytopenic Purpura (TTP) Treatment

    OC 14.3 - A novel strategy to combat the procoagulant phenotype in immune thrombotic thrombocytopenia using 12-LOX inhibition

    Sunday, June 25, 2023
    11:15 – 11:30 ET
    Room: 520
    Session Available As: On-Demand
    Background: Immune thrombotic thrombocytopenia (ITT) disorders, including heparin-induced thrombocytopenia (HIT), are caused by IgG immune complexes that activate platelets through Fc Receptor for IgG IIA (FcγRIIA). ITTs, characterized by platelet-fibrin thrombi, are common and inadequately treated. Thrombotic events remain high following the standard of care treatment with anticoagulants, while increasing risk of bleeding complications.

    Aims: 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.

    Methods: 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). Furthermore, we assessed the procoagulant phenotype and efficacy to treat HIT utilizing inhibitor of 12(S)-lipoxygenase (12-LOX), VLX-1005, previously reported to decrease platelet activation downstream of FcγRIIA and PAR4, using the triple allele ‘HIT’ mouse model.

    Results: 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. In human platelets, we observed that PAR1, PAR4, and FcγRIIA each contributed to the procoagulant phenotype, via receptor-specific increases in cytosolic Ca2+. We observed that inhibition of 12-LOX resulted in a significant reduction in both platelet procoagulant phenotype ex vivo, and thrombocytopenia and thrombosis in our humanized mouse model of HIT in vivo.

    Conclusion(s): These data demonstrate for the first time the need for dual platelet receptor (PAR and FcγRIIA) stimulation for fibrin formation in ITT 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.

    Learning Objectives:

    • At the end of this session, participants will be able to differentiate markers for procoagulant platelets or activity from proaggregatory platelets.
    • At the end of this session, participants will be able to identify multiple mechanisms that 12-HETE contributes to Heparin-induced thrombocytopenia (HIT) pathology
    • At the end of this session, participants will be able to describe the putative mechanism of alleviating HIT using 12-LOX inhibition.