Ayesha A Baig1, Elizabeth J Haining1, Eva Geuss1, Sarah Beck1, Frauke Swieringa1, Podchanart Wanitchakool1, Michael K Schuhmann1, David Stegner1, Karl Kunzelmann1, Christoph Kleinschnitz1, Johan W M Heemskerk1, Attila Braun1, Bernhard Nieswandt2. 1. From the Rudolf Virchow Center for Experimental Biomedicine (A.A.B., E.J.H., D.S., B.N.), Institute of Experimental Biomedicine (A.A.B., E.J.H., S.B., D.S., A.B., B.N.), and Department of Neurology (E.G., M.K.S., C.K.), University Hospital of Würzburg and University of Würzburg, Germany; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, The Netherlands (F.S., J.W.M.H.); Department of Physiology, University of Regensburg, Germany (P.W., K.K.); and Clinic for Neurology, University of Duisburg-Essen Medical Facility, Essen, Germany (C.K.). 2. From the Rudolf Virchow Center for Experimental Biomedicine (A.A.B., E.J.H., D.S., B.N.), Institute of Experimental Biomedicine (A.A.B., E.J.H., S.B., D.S., A.B., B.N.), and Department of Neurology (E.G., M.K.S., C.K.), University Hospital of Würzburg and University of Würzburg, Germany; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, The Netherlands (F.S., J.W.M.H.); Department of Physiology, University of Regensburg, Germany (P.W., K.K.); and Clinic for Neurology, University of Duisburg-Essen Medical Facility, Essen, Germany (C.K.). bernhard.nieswandt@virchow.uni-wuerzburg.de.
Abstract
OBJECTIVE: It is known that both platelets and coagulation strongly influence infarct progression after ischemic stroke, but the mechanisms and their interplay are unknown. Our aim was to assess the contribution of the procoagulant platelet surface, and thus platelet-driven thrombin generation, to the progression of thromboinflammation in the ischemic brain. APPROACH AND RESULTS: We present the characterization of a novel platelet and megakaryocyte-specific TMEM16F (anoctamin 6) knockout mouse. Reflecting Scott syndrome, platelets from the knockout mouse had a significant reduction in procoagulant characteristics that altered thrombin and fibrin generation kinetics. In addition, knockout mice showed significant defects in hemostasis and arterial thrombus formation. However, infarct volumes in a model of ischemic stroke were comparable with wild-type mice. CONCLUSIONS: Platelet TMEM16F activity contributes significantly to hemostasis and thrombosis but not cerebral thromboinflammation. These results highlight another key difference between the roles of platelets and coagulation in these processes.
OBJECTIVE: It is known that both platelets and coagulation strongly influence infarct progression after ischemic stroke, but the mechanisms and their interplay are unknown. Our aim was to assess the contribution of the procoagulant platelet surface, and thus platelet-driven thrombin generation, to the progression of thromboinflammation in the ischemic brain. APPROACH AND RESULTS: We present the characterization of a novel platelet and megakaryocyte-specific TMEM16F (anoctamin 6) knockout mouse. Reflecting Scott syndrome, platelets from the knockout mouse had a significant reduction in procoagulant characteristics that altered thrombin and fibrin generation kinetics. In addition, knockout mice showed significant defects in hemostasis and arterial thrombus formation. However, infarct volumes in a model of ischemic stroke were comparable with wild-type mice. CONCLUSIONS: Platelet TMEM16F activity contributes significantly to hemostasis and thrombosis but not cerebral thromboinflammation. These results highlight another key difference between the roles of platelets and coagulation in these processes.
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