Optimisation Thérapeutique en Neuropsychopharmacologie, INSERM U1144, Université Paris Cité, Paris, France; Laboratoire Hématologie, AP-HP, Hôpital Bichat-Claude Bernard, Paris, France.
Université Paris Cité and Université Sorbonne Paris Nord, INSERM, LVTS, Paris, France.
J Thromb Haemost. 2024 Nov;22(11):3199-3208. doi: 10.1016/j.jtha.2024.07.031. Epub 2024 Sep 12.
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.
We determined whether MPN, particularly JAK2V617F-positive MPN, is associated with fibrinolytic changes.
Tissue-type plasminogen activator (tPA)-mediated fibrinolysis was evaluated both in whole blood and plasma from mice with a hematopoietic-restricted Jak2 expression compared with wild-type (WT) mice (Jak2) 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.
In whole blood from Jak2 mice, we observed a decreased fibrinolysis characterized by a significantly lower halo clot lysis rate compared with Jak2 (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; P < .05). Plasmin generation was significantly decreased both in plasma clots and standardized fibrin clots from Jak2 mice compared with Jak2 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.
Our results suggest that impaired tPA-mediated fibrinolysis represents an important prothrombotic mechanism in MPN patients that requires confirmation in larger studies.
骨髓增殖性肿瘤（MPN）的特征是血栓并发症发生率高，导致发病率和死亡率增加。MPN 相关的血栓形成被认为是多因素的，涉及促凝和促炎过程。纤溶功能受损是否也参与 MPN 的血栓前表型尚未得到充分研究。
我们旨在确定 MPN，特别是 JAK2V617F 阳性 MPN 是否与纤溶变化有关。
使用（1）光环凝块溶解、（2）前缘溶解和（3）纤溶酶原生成测定法，比较具有造血受限 Jak2 表达的小鼠与野生型（WT）小鼠（Jak2）的全血和血浆中组织型纤溶酶原激活物（tPA）介导的纤溶作用。在来自 65 名 MPN 患者（JAK2V617F 突变，n=50；CALR 突变，n=9）的血浆中进行 tPA 凝块溶解试验，与 28 名健康对照者进行比较。
在 Jak2 小鼠的全血中，我们观察到纤溶作用降低，其特征是光环凝块溶解率明显低于 Jak2（95±22 对 147±39 AU/min；P<.05）。在血浆中也观察到类似的结果（光环凝块溶解率，130±27 对 186±29 AU/min；前缘溶解率，2.8±1.6 对 6.1±1.2 μm.min；P<.05）。与 Jak2 小鼠相比，Jak2 小鼠的血浆凝块和标准化纤维蛋白凝块中的纤溶酶原生成明显减少。在 MPN 患者中，JAK2V617F 和 CALR 患者观察到 tPA 相关纤溶作用受损，凝块溶解时间延长。与对照组相比，JAK2V617F 患者的血浆中纤溶酶原激活物抑制剂-1 和 α2-抗纤溶酶显著增加。
我们的研究结果表明，tPA 介导的纤溶作用受损是 MPN 患者重要的血栓前机制，需要在更大的研究中进行确认。
