TY - JOUR
T1 - Platelet glycoprotein V spatio-temporally controls fibrin formation
AU - Beck, Sarah
AU - Öftering, Patricia
AU - Li, Renhao
AU - Hemmen, Katherina
AU - Nagy, Magdolna
AU - Wang, Yingchun
AU - Zarpellon, Alessandro
AU - Schuhmann, Michael K.
AU - Stoll, Guido
AU - Ruggeri, Zaverio M.
AU - Heinze, Katrin G.
AU - Heemskerk, Johan W.M.
AU - Ruf, Wolfram
AU - Stegner, David
AU - Nieswandt, Bernhard
N1 - Funding Information:
We thank F. Lanza (Strasbourg, France) for providing Gp5 mice, J. Pinnecker (Julius-Maximilians-Universität Würzburg, Würzburg, Germany) for assistance in LSFM image acquisition, S. Hartmann and J. Goldmann for excellent technical assistance (both from University Hospital Würzburg, Institute of Experimental Biomedicine, Würzburg, Germany) and M. Spindler for excellent graphical assistance (University Hospital Würzburg, Institute of Experimental Biomedicine, Würzburg, Germany). Funding was provided by the German Research Foundation (Ni556/14-1, B.N.; SFB 1525, project number 453989101; TR240, project number 374031971; INST 93/1022-1), the National Institutes of Health (HL082808, R.L.; UM1 HL120877, W.R.), the European Union (Thrombo-Inflame, EFRE–Europäischer Fonds für regionale Entwicklung, Bavaria) and the Rudolf Virchow Centre for Integrative and Translational Bioimaging. -/-
Funding Information:
We thank F. Lanza (Strasbourg, France) for providing Gp5-/-mice, J. Pinnecker (Julius-Maximilians-Universität Würzburg, Würzburg, Germany) for assistance in LSFM image acquisition, S. Hartmann and J. Goldmann for excellent technical assistance (both from University Hospital Würzburg, Institute of Experimental Biomedicine, Würzburg, Germany) and M. Spindler for excellent graphical assistance (University Hospital Würzburg, Institute of Experimental Biomedicine, Würzburg, Germany). Funding was provided by the German Research Foundation (Ni556/14-1, B.N.; SFB 1525, project number 453989101; TR240, project number 374031971; INST 93/1022-1), the National Institutes of Health (HL082808, R.L.; UM1 HL120877, W.R.), the European Union (Thrombo-Inflame, EFRE–Europäischer Fonds für regionale Entwicklung, Bavaria) and the Rudolf Virchow Centre for Integrative and Translational Bioimaging.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/4/1
Y1 - 2023/4/1
N2 - The activation of platelets and coagulation at vascular injury sites is crucial for hemostasis 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 hemostatic 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 hemostatic 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 hemostasis.
AB - The activation of platelets and coagulation at vascular injury sites is crucial for hemostasis 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 hemostatic 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 hemostatic 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 hemostasis.
U2 - 10.1038/s44161-023-00254-6
DO - 10.1038/s44161-023-00254-6
M3 - Article
SN - 2731-0590
VL - 2
SP - 368
EP - 382
JO - Nature cardiovascular research
JF - Nature cardiovascular research
IS - 4
ER -