Beck Sarah, Öftering Patricia, Li Renhao, Hemmen Katherina, Nagy Magdolna, Wang Yingchun, Zarpellon Alessandro, Schuhmann Michael K, Stoll Guido, Ruggeri Zaverio M, Heinze Katrin G, Heemskerk Johan W M, Ruf Wolfram, Stegner David, Nieswandt Bernhard
Julius-Maximilians-Universität Würzburg, Rudolf Virchow Center for Integrative and Translational Bioimaging, Würzburg, Germany.
University Hospital Würzburg, Institute of Experimental Biomedicine, Würzburg, Germany.
Nat Cardiovasc Res. 2023 Apr;2(4):368-382. doi: 10.1038/s44161-023-00254-6. Epub 2023 Mar 23.
The activation of platelets and coagulation at vascular injury sites is crucial for haemostasis but can promote thrombosis and inflammation in vascular pathologies. Here, we delineate an unexpected spatio-temporal control mechanism of thrombin activity that is platelet orchestrated and locally limits excessive fibrin formation after initial haemostatic platelet deposition. During platelet activation, the abundant platelet glycoprotein (GP) V is cleaved by thrombin. We demonstrate with genetic and pharmacological approaches that thrombin-mediated shedding of GPV does not primarily regulate platelet activation in thrombus formation, but rather has a distinct function after platelet deposition and specifically limits thrombin-dependent generation of fibrin, a crucial mediator of vascular thrombo-inflammation. Genetic or pharmacologic defects in haemostatic platelet function are unexpectedly attenuated by specific blockade of GPV shedding, indicating that the spatio-temporal control of thrombin-dependent fibrin generation also represents a potential therapeutic target to improve haemostasis.
血小板的激活以及血管损伤部位的凝血对于止血至关重要，但在血管病变中会促进血栓形成和炎症反应。在此，我们描述了一种由血小板精心编排的凝血酶活性的意外时空控制机制，该机制在最初的止血性血小板沉积后局部限制过量纤维蛋白的形成。在血小板激活过程中，丰富的血小板糖蛋白（GP）V被凝血酶切割。我们通过基因和药理学方法证明，凝血酶介导的GPV脱落主要不是调节血栓形成中血小板的激活，而是在血小板沉积后具有独特功能，并特别限制凝血酶依赖性纤维蛋白的生成，纤维蛋白是血管血栓炎症的关键介质。止血性血小板功能的基因或药理学缺陷通过特异性阻断GPV脱落意外地得到缓解，这表明凝血酶依赖性纤维蛋白生成的时空控制也代表了改善止血的潜在治疗靶点。
