Defective thrombus formation in mice lacking endogenous factor VII activating protease (FSAP)
Defective thrombus formation in mice lacking endogenous factor VII activating protease (FSAP)
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缺乏内源性VII因子激活蛋白酶（FSAP）的小鼠中的缺陷性血栓形成
DOI：
10.1160/th14-06-0519
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发表时间：
2015
影响因子：
6.7
通讯作者：
Kanse SM
中科院分区：
文献类型：
--
作者：
Subramaniam S;Thielmann I;Morowski M;Pragst I;Sanset PM;Nieswandt B;Etscheid M;Kanse SM
因子VII（FVII）活化蛋白酶（FSAP）是一种循环蛋白酶，在凝血和纤维蛋白溶解中具有推定的功能。遗传流行病学研究已经暗示FSAP在颈动脉狭窄、中风和血栓形成中的作用。到目前为止，没有体内证据支持这些说法。我们首次使用FSAP-/-小鼠来确定其在体内血栓形成和止血中的作用，并阐明所涉及的分子机制。FeCl 3诱导的颈动脉和肠系膜动脉血栓形成显示，FSAP-/-小鼠的闭塞时间显著增加（p< 0.01），一些FSAP-/-小鼠根本没有闭塞。FSAP-/-小鼠免受胶原/肾上腺素输注诱导的致死性肺血栓栓塞（p< 0.01）。尽管没有明显的自发性出血，但在尾部出血试验中，在FSAP-/-小鼠中观察到再出血模式。为了在机制水平上解释这些观察结果，我们随后确定了FSAP-/-小鼠中止血因子和推定的FSAP底物是如何改变的。与WT小鼠相比，FSAP-/-小鼠中的组织因子途径抑制物（TFPI）水平更高，而FVIIa水平不变。其他凝血因子以及血小板活化和功能的标志物显示WT和FSAP-/-小鼠之间没有显著差异。FSAP-/-小鼠的这种表型可以通过应用外源性FSAP来逆转。总之，内源性FSAP的缺乏损害了小鼠中稳定的闭塞性血栓的形成。FSAP的潜在体内作用更可能与TFPI而不是FVIIa的调节相关。
Factor VII (FVII) activating protease (FSAP) is a circulating protease with a putative function in blood coagulation and fibrinolysis. Genetic epidemiological studies have implied a role for FSAP in carotid stenosis, stroke and thrombosis. To date, no in vivo evidence is available to support these claims. We have, for the first time, used FSAP-/-mice to define its role in thrombosis and haemostasis in vivo and to characterise the molecular mechanisms involved. FeCl3–induced arterial thrombosis in carotid and mesenteric artery revealed that the occlusion time was significantly increased in FSAP-/-mice (p< 0.01) and that some FSAP-/-mice did not occlude at all. FSAP-/-mice were protected from lethal pulmonary thromboembolism induced by collagen/ epinephrine infusion (p< 0.01). Although no spontaneous bleeding was evident, in the tail bleeding assay a re-bleeding pattern was observed in FSAP-/-mice. To explain these observations at a mechanistic level we then determined how haemostasis factors and putative FSAP substrates were altered in FSAP-/-mice. Tissue factor pathway inhibitor (TFPI) levels were higher in FSAP-/-mice compared to WT mice whereas FVIIa levels were unchanged. Other coagulation factors as well as markers of platelet activation and function revealed no significant differences between WT and FSAP-/-mice. This phenotype of FSAP-/-mice could be reversed by application of exogenous FSAP. In conclusion, a lack of endogenous FSAP impaired the formation of stable, occlusive thrombi in mice. The underlying in vivo effect of FSAP is more likely to be related to the modulation of TFPI rather than FVIIa.
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DOI：
10.1084/jem.20052546
发表时间：
2006-12-25
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Sedding D;Daniel JM;Muhl L;Hersemeyer K;Brunsch H;Kemkes-Matthes B;Braun-Dullaeus RC;Tillmanns H;Weimer T;Preissner KT;Kanse SM
通讯作者：
Kanse SM
影响因子：
4.4
作者：
Kanse, Sandip M.;Gallenmueller, Andrea;Huber-Lang, Markus
通讯作者：
Huber-Lang, Markus
因子 VII 激活蛋白酶的马尔堡 I 多态性和静脉血栓栓塞的风险。
影响因子：
20.3
作者：
F. Franchi;I. Martinelli;E. Biguzzi;P. Bucciarelli;P. Mannucci
通讯作者：
P. Mannucci
影响因子：
20.3
作者：
Girard, Thomas J.;Tuley, Elodee;Broze, George J., Jr.
通讯作者：
Broze, George J., Jr.
影响因子：
10.4
作者：
Stavenuiter, F.;Dienava-Verdoold, I.;Mertens, K.
通讯作者：
Mertens, K.