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Plasma Kallikrein Contributes to Coagulation in the Absence of Factor XI by Activating Factor IX.
Arteriosclerosis, Thrombosis, and Vascular Biology ( IF 7.4 ) Pub Date : 2019-11-26 , DOI: 10.1161/atvbaha.119.313503
Mayken Visser 1, 2 , René van Oerle 2 , Hugo Ten Cate 2, 3 , Volker Laux 1 , Nigel Mackman 4 , Stefan Heitmeier 1 , Henri M H Spronk 2
Affiliation  

OBJECTIVES FXIa (factor XIa) induces clot formation, and human congenital FXI deficiency protects against venous thromboembolism and stroke. In contrast, the role of FXI in hemostasis is rather small, especially compared with FIX deficiency. Little is known about the cause of the difference in phenotypes associated with FIX deficiency and FXI deficiency. We speculated that activation of FIX via the intrinsic coagulation is not solely dependent on FXI(a; activated FXI) and aimed at identifying an FXI-independent FIX activation pathway. Approach and Results: We observed that ellagic acid and long-chain polyphosphates activated the coagulation system in FXI-deficient plasma, as could be demonstrated by measurement of thrombin generation, FIXa-AT (antithrombin), and FXa-AT complex levels, suggesting an FXI bypass route of FIX activation. Addition of a specific PKa (plasma kallikrein) inhibitor to FXI-deficient plasma decreased thrombin generation, prolonged activated partial thromboplastin time, and diminished FIXa-AT and FXa-AT complex formation, indicating that PKa plays a role in the FXI bypass route of FIX activation. In addition, FIXa-AT complex formation was significantly increased in F11-/- mice treated with ellagic acid or long-chain polyphosphates compared with controls and this increase was significantly reduced by inhibition of PKa. CONCLUSIONS We demonstrated that activation of FXII leads to thrombin generation via FIX activation by PKa in the absence of FXI. These findings may, in part, explain the different phenotypes associated with FIX and FXI deficiencies.

中文翻译:

在没有因子XI的情况下,血浆激肽释放酶通过激活因子IX促凝。

目的FXIa(因子XIa)诱导血凝块形成,而人类先天性FXI缺乏症可预防静脉血栓栓塞和中风。相反,FXI在止血中的作用很小,尤其是与FIX缺乏症相比。关于与FIX缺乏症和FXI缺乏症相关的表型差异的原因,人们所知甚少。我们推测,通过内在凝血激活FIX并不仅仅依赖于FXI(a;激活的FXI),其目的在于确定独立于FXI的FIX激活途径。方法和结果:我们观察到鞣花酸和长链多磷酸盐激活了缺乏FXI的血浆中的凝血系统,这可以通过测量凝血酶生成,FIXa-AT(抗凝血酶)和FXa-AT复合物水平来证明,这表明FIX激活的FXI绕过路线。向缺乏FXI的血浆中添加特定的PKa(血浆激肽释放酶)抑制剂可减少凝血酶生成,延长部分凝血活酶激活时间并减少FIXa-AT和FXa-AT复合物的形成,这表明PKa在FIX的FXI旁路途径中起作用激活。此外,与鞣花酸或长链多磷酸盐治疗的F11-/-小鼠相比,FIXa-AT复合物的形成显着增加,而这种增加通过抑制PKa而明显减少。结论我们证明了在没有FXI的情况下,FXII的激活通过PKa的FIX激活导致凝血酶的产生。这些发现可能部分解释了与FIX和FXI缺陷相关的不同表型。延长了激活的部分凝血活酶时间,并减少了FIXa-AT和FXa-AT复合物的形成,表明PKa在FIX激活的FXI旁路途径中起作用。此外,与鞣花酸或长链多磷酸盐治疗的F11-/-小鼠相比,FIXa-AT复合物的形成显着增加,而这种增加通过抑制PKa而明显减少。结论我们证明了在没有FXI的情况下,FXII的激活通过PKa的FIX激活导致凝血酶的产生。这些发现可能部分解释了与FIX和FXI缺陷相关的不同表型。延长了激活的部分凝血活酶时间,并减少了FIXa-AT和FXa-AT复合物的形成,表明PKa在FIX激活的FXI旁路途径中起作用。此外,与鞣花酸或长链多磷酸盐治疗的F11-/-小鼠相比,FIXa-AT复合物的形成显着增加,而这种增加通过抑制PKa而明显减少。结论我们证明了在没有FXI的情况下,FXII的激活通过PKa的FIX激活导致凝血酶的产生。这些发现可能部分解释了与FIX和FXI缺陷相关的不同表型。与对照相比,用鞣花酸或长链多磷酸盐处理的F11-/-小鼠的FIXa-AT复合物形成显着增加,并且这种抑制作用通过抑制PKa显着降低。结论我们证明了在不存在FXI的情况下,FXII的激活通过PKa的FIX激活导致凝血酶的产生。这些发现可能部分解释了与FIX和FXI缺陷相关的不同表型。与对照组相比,用鞣花酸或长链多磷酸盐处理的F11-/-小鼠的FIXa-AT复合物形成显着增加,并且通过抑制PKa显着降低了这种增加。结论我们证明了在没有FXI的情况下,FXII的激活通过PKa的FIX激活导致凝血酶的产生。这些发现可能部分解释了与FIX和FXI缺陷相关的不同表型。
更新日期:2019-12-25
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