活化因子XI在人深静脉血栓中的定位及在静脉血栓形成和止血中的作用

IF 3.4 3区 医学 Q2 HEMATOLOGY
Nobuyuki Oguri , Toshihiro Gi , Eriko Nakamura , Kazunari Maekawa , Eiji Furukoji , Hoshimi Okawa , Sho Kouyama , Saki Horiuchi , Akira Sawaguchi , Tatefumi Sakae , Minako Azuma , Yujiro Asada , Atsushi Yamashita
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引用次数: 0

摘要

目前,针对凝血因子(F)XI/活化FXI (FXIa)的新型抗凝剂正在开发中。然而,FXI是否存在于人深静脉血栓形成(DVT)中,以及FXIa和激活的FX (FXa)在静脉血栓形成和止血中是否发挥不同的作用尚不清楚。目的探讨FXI在DVT中的存在,以及直接口服FXIa和FXa抑制剂对家兔静脉血栓形成和止血及体外血栓形成的影响。方法采用免疫组织化学方法评估FXI在人吸式DVT中的定位(n = 15)。此外,我们比较了直接使用FXa抑制剂(ONO-1600586)和FXa抑制剂(利伐沙班)治疗家兔的内皮剥落和颈静脉狭窄或瘀血诱导的血栓形成以及皮肤出血时间和体积。兔和人离体血液在低剪切速率(70/s)的流室中灌注。结果fxi定位于所有DVT,主要集中在富含纤维蛋白的区域。非组织区FXI免疫阳性面积大于组织区。虽然FXIa和FXa抑制剂对静脉血栓形成的抑制作用相当,但FXIa抑制剂对家兔出血时间和出血量没有影响。FXIa或FXa抑制剂分别在低剪切速率下轻度或强烈抑制纤维蛋白的形成。此外,FXIa抑制剂在灌注过程中抑制人FXIa活性、凝血酶生成和纤维蛋白形成。结论人类深静脉血栓的病理表现提示FXI在人类深静脉血栓中的作用。FXIa抑制剂可能比FXa抑制剂抑制更少的纤维蛋白形成,这可能解释了FXIa在止血中的次要作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Factor XI localization in human deep venous thrombus and function of activated factor XI on venous thrombus formation and hemostasis

Factor XI localization in human deep venous thrombus and function of activated factor XI on venous thrombus formation and hemostasis

Background

Novel anticoagulants targeting coagulation factor (F)XI/activated FXI (FXIa) are currently under development. However, whether FXI is present in human deep vein thrombosis (DVT) and whether FXIa and activated FX (FXa) play different roles in venous thrombus formation and hemostasis remain unclear.

Objectives

To determine the presence of FXI in DVT and the effects of direct oral FXIa and FXa inhibitors on venous thrombus formation and hemostasis in rabbits and on in vitro thrombus formation.

Methods

We immunohistochemically assessed FXI localization in human-aspirated DVT (n = 15). Additionally, we compared thrombus formation induced by endothelial denudation and stenosis or stasis in the jugular vein and skin bleeding time and volume between rabbits treated with direct FXIa inhibitors (ONO-1600586) and FXa inhibitors (rivaroxaban). Ex vivo rabbit and human blood were perfused in a flow chamber under low-shear rates (70/s).

Results

FXI was localized in all DVT, predominantly in fibrin-rich areas. The FXI immunopositive area in the nonorganizing area was greater than that in the organizing area. Although FXIa and FXa inhibitors comparably inhibited venous thrombus formation, FXIa inhibitors did not affect bleeding time or volume in rabbits. FXIa or FXa inhibitors mildly or strongly inhibited fibrin formation at low-shear rates, respectively. Furthermore, the FXIa inhibitor suppressed human FXIa activity, thrombin generation, and fibrin formation during perfusion.

Conclusion

The pathologic findings of human DVT suggest FXI’s role in human DVT. FXIa inhibitors may inhibit less fibrin formation than FXa inhibitors and may explain the minor role of FXIa in hemostasis.
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来源期刊
CiteScore
5.60
自引率
13.00%
发文量
212
审稿时长
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