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    Oral Communication

    Venous Thromboembolism

    Molecular Insights in Cancer Associated Thrombosis

    OC 46.3 - Jak2V617F-positive myeloproliferative neoplasms are associated with impaired fibrinolysis both in mice and humans

    Monday, June 26, 2023
    15:15 – 15:30 ET
    Room: 510
    Session Available As: On-Demand
    Background: Myeloproliferative neoplasms (MPNs) are characterized by a high rate of thrombotic complications that contribute to morbi-mortality. MPN-related thrombogenesis is assumed to be multifactorial involving pro-coagulant and pro-inflammatory processes. In this context, fibrinolysis has been poorly investigated, despite its major role in thrombus resolution. Impaired fibrinolysis could participate to pro-thrombotic phenotype of MPNs.

    Aims: To determine whether the presence of JAK2V617F mutation affects fibrinolysis.

    Methods: Using a hematopoietic-restricted JAK2V617F expression mouse model (Jak2V617F) compared to WT mice (Jak2WT), tissue plasminogen activator (tPA)-mediated fibrinolysis was evaluated both in whole blood and plasma using different assays: (1) halo clot lysis, (2) front lysis and (3) plasmin generation. The tPA-clot lysis assay was also performed in 50 MPN patients with JAK2V617F mutation compared to 28 healthy controls.

    Results: In whole blood from Jak2V617F mice, we observed an impaired fibrinolysis characterized by a significant lower halo clot lysis rate compared to Jak2WT (95±22 vs 147±39 UA/min, p< 0.05). Similar results were observed in plasma (halo clot lysis rate: 130±27 vs 186±29 UA/min; front lysis rate: 2.8±1.6 vs 6.1±1.2 µm.min-1 p< 0.05). Plasmin generation was also significantly decreased both on plasma clots or standardized fibrin clots from Jak2V617F mice (p < 0.05). In MPN patients with JAK2V617F mutation, impaired tPA-related fibrinolysis was confirmed by an increased clot lysis time (135,2 ±20,2 vs 118,2 ± 13,7 min; p< 0.001). Plasminogen activator inhibitor-1 (PAI-1), the main inhibitor of t-PA, was significantly increased in plasma from both Jak2V617F mice and MPN patients compared to controls.

    Conclusion(s): Altogether, our results suggest that impaired tPA-mediated fibrinolysis could represent a significant pro-thrombotic mechanism and a potential new therapeutic target in MPN-related thrombosis.

    Learning Objectives:

    • to evoke fibrinolytic disorders during myeloproliferative neoplasms in case of thrombotic or hemorrhagic phenotype
    • to propose a fibrinolysis test panel to detect both hyperfibrinolysis and hypofibrinolysis states
    • to develop new techniques in the mouse model to study fibrinolysis