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Excessively activated plasminogen in human plasma cleaves VWF multimers and reduces collagen-binding activity.
The Journal of Biochemistry ( IF 2.1 ) Pub Date : 2020 , DOI: 10.1093/jb/mvaa053
Kenshi Togashi 1 , Satoshi Suzuki 2 , Sae Morita 3 , Yuki Ogasawara 4 , Yasutada Imamura 1, 2, 3 , Yongchol Shin 1, 2, 3
Affiliation  

Abstract
Plasmin (Pm) is a serine protease that can dissolve fibrin clots. Several possible functions of Pm in blood other than fibrinolysis have been proposed. To explore the effects of Pm on primary haemostasis, we evaluated the cleavage of von Willebrand factor multimers (VWFMs) in human plasma by streptokinase (SK)-activated plasminogen (Pg) and the binding ability of the digested VWFMs to collagen. SK-activated Pg and ADAMTS13 (a VWF-cleaving enzyme) in human plasma cleaved VWFMs in conformation-dependent manners through dialysis to the urea-containing buffer. However, VWFMs in human plasma under vortex-based shear stress were cleaved by SK-activated Pg but not by ADAMTS13. These results suggested that the VWFM-cleavage sites in human plasma are exposed to some extent by vortex-based shear stress for Pm but not for ADAMTS13. Additionally, we revealed that cleavage by SK-activated Pg reduced VWFMs’ binding ability to collagen, and VWFMs in human plasma were cleaved by Pm at several sites. These results suggest that SK-activated Pg degrades VWFMs, reduces their binding abilities to collagen and affects primary haemostasis. Because excessive Pg activation can degrade fibrinogen/fibrin, we propose that SK-activated Pg in blood may cause impaired primary and secondary haemostasis.


中文翻译:

人血浆中过度激活的纤溶酶原会裂解VWF多聚体并降低胶原结合活性。

摘要
纤溶酶(Pm)是一种丝氨酸蛋白酶,可以溶解纤维蛋白凝块。已经提出了Pm在血液中除了纤维蛋白溶解以外的几种可能功能。为了探索Pm对原发性止血的影响,我们评估了链激酶(SK)激活的纤溶酶原(Pg)对人血浆中的von Willebrand因子多聚体(VWFM)的裂解以及消化的VWFM与胶原蛋白的结合能力。人血浆中的SK激活的Pg和ADAMTS13(一种VWF裂解酶)通过依赖尿素的缓冲液透析,以构象依赖性方式裂解VWFM。然而,在人类血浆中基于涡旋剪切应力的VWFMs被SK激活的Pg裂解,而ADAMTS13则未裂解​​。这些结果表明,人血浆中的VWFM裂解位点在一定程度上受到Pm涡旋剪切应力的影响,而ADAMTS13没有。另外,我们发现,SK激活的Pg裂解会降低VWFM与胶原蛋白的结合能力,而人血浆中的VWFM会在多个部位被Pm裂解。这些结果表明SK激活的Pg降解VWFM,降低其与胶原蛋白的结合能力并影响原发性止血。由于过度的Pg激活会降解纤维蛋白原/纤维蛋白,因此我们建议血液中SK激活的Pg可能导致原发性和继发性止血功能受损。
更新日期:2020-10-27
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