Impaired fibrinolysis in JAK2V617F-related myeloproliferative neoplasms

• DOI: 10.1016/j.jtha.2024.07.031
• Publication Date: 2024-09-12T11:40:54Z
• Authors: Marie-Charlotte B...; Stéphane Loyau; Dorothée Faille; Juliette Gay; Séléna Akhenak; Carine Farkh; Véronique Ollivier; Mialitiana Solono...; Sébastien Dupont; Christine Choqueux; Jean-Luc Villeval; Isabelle Plo; Valérie Edmond; Benoît Ho-Tin-Noé; Nadine Ajzenberg; Mikaël Mazighi
• Keywords: Myeloproliferative Disorders

Myeloproliferative neoplasms (MPN) are characterized by a high rate of thrombotic complications that contribute to morbi-mortality. MPN-related thrombogenesis is assumed to be multifactorial involving both pro-coagulant and pro-inflammatory processes. Whether impaired fibrinolysis also participates in the pro-thrombotic phenotype of MPN has been poorly investigated.We determined whether MPN, particularly JAK2V617F-positive MPN, are associated with fibrinolytic changes.Tissue plasminogen activator (tPA)-mediated fibrinolysis was evaluated both in whole blood (WB) and plasma from mice with a hematopoietic-restricted Jak2V617F expression compared to wild type mice (Jak2WT) using: (1) halo clot lysis, (2) front lysis and (3) plasmin generation assays. tPA-clot lysis assay was performed in the plasma from 65 MPN patients (JAK2V617F mutation, n=50; CALR mutations, n=9) compared to 28 healthy controls.In WB from Jak2V617F mice, we observed a decreased 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 significantly decreased both in plasma clots and standardized fibrin clots from Jak2V617F mice compared to Jak2WT mice. Among MPN patients, impaired tPA-related fibrinolysis with prolonged clot lysis time was observed in JAK2V617F and CALR patients. Plasminogen activator inhibitor-1 and alpha 2-antiplasmin were significantly increased in plasma from JAK2V617F patients compared to controls.Our results suggest that impaired tPA-mediated fibrinolysis represents an important pro-thrombotic mechanism in MPN patients that requires confirmation on larger studies.