TMEM16F-Mediated Platelet Membrane Phospholipid Scrambling Is Critical for Hemostasis and Thrombosis but not Thromboinflammation in Mice-Brief Report

被引：55

作者：

Baig, Ayesha A. ^{[1
,2
]}

Haining, Elizabeth J. ^{[1
,2
]}

Geuss, Eva ^{[3
]}

Beck, Sarah ^{[2
]}

Swieringa, Frauke ^{[4
]}

Wanitchakool, Podchanart ^{[5
]}

Schuhmann, Michael K. ^{[3
]}

Stegner, David ^{[1
,2
]}

Kunzelmann, Karl ^{[5
]}

Kleinschnitz, Christoph ^{[3
,6
]}

Heemskerk, Johan W. M. ^{[4
]}

Braun, Attila ^{[2
]}

Nieswandt, Bernhard ^{[1
,2
]}

机构：

[1] Univ Hosp Wurzburg, Rudolf Virchow Ctr Expt Biomed, Wurzburg, Germany

[2] Univ Hosp Wurzburg, Inst Expt Biomed, Wurzburg, Germany

[3] Univ Hosp Wurzburg, Dept Neurol, Wurzburg, Germany

[4] Maastricht Univ, Dept Biochem, Cardiovasc Res Inst Maastricht CARIM, Maastricht, Netherlands

[5] Univ Regensburg, Dept Physiol, Regensburg, Germany

[6] Univ Duisburg Essen, Med Facil, Neurol Clin, Essen, Germany

来源：

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY | 2016年 / 36卷 / 11期

关键词：

blood platelets; fibrin; stroke; thrombin; thrombosis; PHOSPHATIDYLSERINE EXPOSURE; SCOTT-SYNDROME; PROCOAGULANT ACTIVITY; GLYCOPROTEIN-VI; IN-VIVO; PROTEIN; COAGULATION; TMEM16F; ACTIVATION; EXPRESSION;

D O I：

10.1161/ATVBAHA.116.307727

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：2152 / +

页数：18

共 37 条

[11] Factor XIIa Inhibitor Recombinant Human Albumin Infestin-4 Abolishes Occlusive Arterial Thrombus Formation Without Affecting Bleeding [J].

Hagedorn, Ina ;

Schmidbauer, Stefan ;

Pleines, Irina ;

Kleinschnitz, Christoph ;

Kronthaler, Ulrich ;

Stoll, Guido ;

Dickneite, Gerhard ;

Nieswandt, Bernhard .

CIRCULATION, 2010, 121 (13) :1510-1517

[12] Collagen but not fibrinogen surfaces induce bleb formation, exposure of phosphatidylserine, and procoagulant activity of adherent platelets: Evidence for regulation by protein tyrosine kinase-dependent Ca2+ responses [J].

Heemskerk, JWM ;

Vuist, WMJ ;

Feijge, MAH ;

Reutelingsperger, CPM ;

Lindhout, T .

BLOOD, 1997, 90 (07) :2615-2625

[13] Spatiotemporal regulation of coagulation and platelet activation during the hemostatic response invivo [J].

Ivanciu, L. ;

Stalker, T. J. .

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 2015, 13 (11) :1949-1959

[14] New insights into the spatiotemporal localization of prothrombinase in vivo [J].

Ivanciu, Lacramioara ;

Krishnaswamy, Sriram ;

Camire, Rodney M. .

BLOOD, 2014, 124 (11) :1705-1714

[15] Intracerebral hirudin injection attenuates ischemic damage and neurologic deficits without altering local cerebral blood flow [J].

Karabiyikoglu, M ;

Hua, Y ;

Keep, RF ;

Ennis, SR ;

Xi, GH .

JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 2004, 24 (02) :159-166

[16] Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis [J].

Kleinschnitz, C ;

Stoll, G ;

Bendszus, M ;

Schuh, K ;

Pauer, HU ;

Burfeind, P ;

Renné, C ;

Gailani, D ;

Nieswandt, B ;

Renné, T .

JOURNAL OF EXPERIMENTAL MEDICINE, 2006, 203 (03) :513-518

[17] Collagen-platelet interaction: Gly-Pro-Hyp is uniquely specific for platelet Gp VI and mediates platelet activation by collagen [J].

Knight, CG ;

Morton, LF ;

Onley, DJ ;

Peachey, AR ;

Ichinohe, T ;

Okuma, M ;

Farndale, RW ;

Barnes, MJ .

CARDIOVASCULAR RESEARCH, 1999, 41 (02) :450-457

[18] The Coagulation Factor XIIa Inhibitor rHA-Infestin-4 Improves Outcome after Cerebral Ischemia/Reperfusion Injury in Rats [J].

Krupka, Jennifer ;

May, Frauke ;

Weimer, Thomas ;

Pragst, Ingo ;

Kleinschnitz, Christoph ;

Stoll, Guido ;

Panousis, Con ;

Dickneite, Gerhard ;

Nolte, Marc W. .

PLOS ONE, 2016, 11 (01)

[19] Molecular functions of anoctamin 6 (TMEM16F): a chloride channel, cation channel, or phospholipid scramblase? [J].

Kunzelmann, Karl ;

Nilius, Bernd ;

Owsianik, Grzegorz ;

Schreiber, Rainer ;

Ousingsawat, Jiraporn ;

Sirianant, Lalida ;

Wanitchakool, Podchanart ;

Bevers, Edouard M. ;

Heemskerk, Johan W. M. .

PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, 2014, 466 (03) :407-414

[20] Platelet membrane phospholipid asymmetry: from the characterization of a scramblase activity to the identification of an essential protein mutated in Scott syndrome [J].

Lhermusier, T. ;

Chap, H. ;

Payrastre, B. .

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 2011, 9 (10) :1883-1891

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