Impaired fibrinolysis in JAK2V617F-related myeloproliferative neoplasms

Abstract

Background: Myeloproliferative neoplasms (MPNs) are characterized by a high rate of thrombotic complications that contribute to morbidity and mortality. MPN-related thrombogenesis is assumed to be multifactorial, involving both procoagulant and proinflammatory processes. Whether impaired fibrinolysis also participates in the prothrombotic phenotype of MPN has been poorly investigated.

Objectives: We determined whether MPN, particularly JAK2V617F-positive MPN, is associated with fibrinolytic changes.

Methods: Tissue-type plasminogen activator (tPA)-mediated fibrinolysis was evaluated both in whole blood and plasma from mice with a hematopoietic-restricted Jak2^V617F expression compared with wild-type (WT) mice (Jak2^WT) 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 with 28 healthy controls.

Results: In whole blood from Jak2^V617F mice, we observed a decreased fibrinolysis characterized by a significantly lower halo clot lysis rate compared with Jak2^WT (95 ± 22 vs 147 ± 39 AU/min; P < .05). Similar results were observed in plasma (halo clot lysis rate, 130 ± 27 vs 186 ± 29 AU/min; front lysis rate, 2.8 ± 1.6 vs 6.1 ± 1.2 μm.min^-1; P < .05). Plasmin generation was significantly decreased both in plasma clots and standardized fibrin clots from Jak2^V617F mice compared with Jak2^WT 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 α2-antiplasmin were significantly increased in plasma from JAK2V617F patients compared with controls.

Conclusion: Our results suggest that impaired tPA-mediated fibrinolysis represents an important prothrombotic mechanism in MPN patients that requires confirmation in larger studies.

Keywords: JAK2 protein; fibrin clot lysis time; fibrinolysis; myeloproliferative disorders.