RSS-Feed abonnieren
DOI: 10.1055/a-1151-9519
Platelets in Thrombo-Inflammation: Concepts, Mechanisms, and Therapeutic Strategies for Ischemic Stroke
Publikationsverlauf
17. Dezember 2019
18. März 2020
Publikationsdatum:
26. Mai 2020 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00034925/202002/lookinside/thumbnails/10-1055-a-1151-9519_190062-1.jpg)
Abstract
Platelets are anucleate cells known for their essential function in hemostasis and formation of thrombi under pathologic conditions. In recent years, strong evidence emerged demonstrating the critical involvement of platelets in inflammatory processes including acute ischemic stroke (AIS), which is one of the leading causes of death and disability worldwide. Recanalization of the occluded brain artery to reconstitute cerebral blood flow is the primary goal in the treatment of stroke patients. However, despite successful reperfusion many patients show progression of infarct sizes, a phenomenon referred to as ischemia/reperfusion injury (I/RI). Cerebral I/RI involves both thrombotic as well as inflammatory pathways acting in concert to cause tissue damage, defining AIS as a prototypic thrombo-inflammatory disease. Currently used antiplatelet drugs applied to AIS patients eventually increase the risk of partially life-threatening hemorrhages, making more targeted pharmacological intervention necessary. Experimental evidence indicates that inhibition of platelet surface receptors that regulate initial platelet adhesion and activation might be suitable targets in thrombo-inflammatory settings, while inhibitors of platelet aggregation are not. In this review, we will summarize the recent developments in elucidating the role of the main platelet receptors in AIS and discuss their potential as pharmaceutical targets. Furthermore, we will also briefly discuss the important platelet-triggered intrinsic coagulation pathway with the pro-inflammatory kallikrein–kinin system in the context of ischemic stroke.
Zusammenfassung
Thrombozyten sind anukleäre Zellen, die für ihre entscheidende Bedeutung in der Hämostase, aber auch für die Bildung von gefäßverschließenden Thromben unter pathologischen Bedingungen bekannt sind. In den letzten Jahren belegten jedoch einige Studien auch eine wichtige Rolle von Thrombozyten bei inflammatorischen Prozessen. Zu diesen gehört auch der ischämische Schlaganfall (acute ischemic stroke - AIS) - eine der häufigsten Todesursachen und Verursacher von Behinderungen weltweit. Bei dessen Behandlung ist das primäre Ziel die Rekanalisierung des verschlossenen Gefäßes, durch die der Blutfluss wiederhergestellt wird. Dennoch vergrößern sich bei vielen Patienten trotz erfolgreicher Reperfusion des betroffenen Areals die Infarktgebiete weiter. Dieses Phänomen wird Ischämie-Reperfusionsschaden (ischemia / reperfusion injury - I/RI) genannt. Bei dem zerebralen I/RI sind ineinandergreifende pro-thrombotische als auch inflammatorische Mechanismen an der Entstehung von Gewebeschäden beteiligt – AIS gilt daher als Prototyp thrombo-inflammatorischer Erkrankungen. Der Einsatz von gängigen Thrombozytenfunktionshemmern in AIS Patienten führt häufig zu - in Einzelfällen lebensgefährlichen - Blutungen, was die Notwendigkeit einer neuen, zielgerichteteren pharmakologischen Intervention verdeutlicht. Experimentelle Daten zeigen, dass die Inhibition von Thrombozytenrezeptoren, die an der initialen Adhäsion und Aktivierung der Zellen beteiligt sind, möglicherweise gute Angriffspunkte zur Behandlung thrombo-inflammatorischer Erkrankungen darstellen - klassische Thrombozytenaggregationshemmer jedoch nicht. In diesem Übersichtsartikel fassen wir die neuesten Entwicklungen der Forschung über die Funktion der wichtigsten Thrombozytenrezeptoren im AIS zusammen und diskutieren deren Eignung als neue pharmakologische Zielstrukturen. Darüber hinaus diskutieren wir kurz die Rolle der von Thrombozyten induzierten Kontaktaktivierung im AIS, die Startpunkt der intrinsischen Kaogulationskaskade und des inflammatorischen Kallikrein-Kinin-Systems ist.
-
References
- 1 Cameron SJ, Mix DS, Ture SK. , et al. Hypoxia and ischemia promote a maladaptive platelet phenotype. Arterioscler Thromb Vasc Biol 2018; 38 (07) 1594-1606
- 2 Nieswandt B, Pleines I, Bender M. Platelet adhesion and activation mechanisms in arterial thrombosis and ischaemic stroke. J Thromb Haemost 2011; 9 (Suppl. 01) 92-104
- 3 Chung T, Connor D, Joseph J. , et al. Platelet activation in acute pulmonary embolism. J Thromb Haemost 2007; 5 (05) 918-924
- 4 Jackson SP. Arterial thrombosis--insidious, unpredictable and deadly. Nat Med 2011; 17 (11) 1423-1436
- 5 Franks ZG, Campbell RA, Weyrich AS, Rondina MT. Platelet-leukocyte interactions link inflammatory and thromboembolic events in ischemic stroke. Ann N Y Acad Sci 2010; 1207: 11-17
- 6 Grommes J, Alard JE, Drechsler M. , et al. Disruption of platelet-derived chemokine heteromers prevents neutrophil extravasation in acute lung injury. Am J Respir Crit Care Med 2012; 185 (06) 628-636
- 7 Nieswandt B, Kleinschnitz C, Stoll G. Ischaemic stroke: a thrombo-inflammatory disease?. J Physiol 2011; 589 (17) 4115-4123
- 8 Feigin VL, Abajobir AA, Abate KH. , et al; GBD 2015 Neurological Disorders Collaborator Group. Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Neurol 2017; 16 (11) 877-897
- 9 Feigin VL, Lawes CM, Bennett DA, Anderson CS. Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurol 2003; 2 (01) 43-53
- 10 Saver JL, Gornbein J, Grotta J. , et al. Number needed to treat to benefit and to harm for intravenous tissue plasminogen activator therapy in the 3- to 4.5-hour window: joint outcome table analysis of the ECASS 3 trial. Stroke 2009; 40 (07) 2433-2437
- 11 de Los Ríos la Rosa F, Khoury J, Kissela BM. , et al. Eligibility for intravenous recombinant tissue-type plasminogen activator within a population: the effect of the European Cooperative Acute Stroke Study (ECASS) III Trial. Stroke 2012; 43 (06) 1591-1595
- 12 Leischner H, Flottmann F, Hanning U. , et al. Reasons for failed endovascular recanalization attempts in stroke patients. J Neurointerv Surg 2019; 11 (05) 439-442
- 13 Tsivgoulis G, Goyal N, Mikulik R. , et al. Eligibility for mechanical thrombectomy in acute ischemic stroke: a phase IV multi-center screening log registry. J Neurol Sci 2016; 371: 96-99
- 14 Nour M, Scalzo F, Liebeskind DS. Ischemia-reperfusion injury in stroke. Intervent Neurol 2013; 1 (3–4): 185-199
- 15 Mizuma A, You JS, Yenari MA. Targeting reperfusion injury in the age of mechanical thrombectomy. Stroke 2018; 49 (07) 1796-1802
- 16 Eltzschig HK, Eckle T. Ischemia and reperfusion--from mechanism to translation. Nat Med 2011; 17 (11) 1391-1401
- 17 Braeuninger S, Kleinschnitz C, Nieswandt B, Stoll G. Focal cerebral ischemia. Methods Mol Biol 2012; 788: 29-42
- 18 Kleinschnitz C, Schwab N, Kraft P. , et al. Early detrimental T-cell effects in experimental cerebral ischemia are neither related to adaptive immunity nor thrombus formation. Blood 2010; 115 (18) 3835-3842
- 19 Stoll G, Nieswandt B. Thrombo-inflammation in acute ischaemic stroke - implications for treatment. Nat Rev Neurol 2019; 15 (08) 473-481
- 20 Zrzavy T, Machado-Santos J, Christine S. , et al. Dominant role of microglial and macrophage innate immune responses in human ischemic infarcts. Brain Pathol 2018; 28 (06) 791-805
- 21 Yilmaz G, Arumugam TV, Stokes KY, Granger DN. Role of T lymphocytes and interferon-gamma in ischemic stroke. Circulation 2006; 113 (17) 2105-2112
- 22 Caudrillier A, Kessenbrock K, Gilliss BM. , et al. Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury. J Clin Invest 2012; 122 (07) 2661-2671
- 23 McDonald B, Urrutia R, Yipp BG, Jenne CN, Kubes P. Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. Cell Host Microbe 2012; 12 (03) 324-333
- 24 Strecker J-K, Schmidt A, Schäbitz W-R, Minnerup J. Neutrophil granulocytes in cerebral ischemia - evolution from killers to key players. Neurochem Int 2017; 107: 117-126
- 25 Obrenovitch TP, Hallenbeck JM. Platelet accumulation in regions of low blood flow during the post-ischemic period. Stroke 1985; 16 (02) 224-234
- 26 Del Zoppo GJ, Copeland BR, Harker LA. , et al. Experimental acute thrombotic stroke in baboons. Stroke 1986; 17 (06) 1254-1265
- 27 Sandercock PA, Counsell C, Tseng MC, Cecconi E. Oral antiplatelet therapy for acute ischaemic stroke. Cochrane Database Syst Rev 2014; (03) CD000029
- 28 Zinkstok SM, Beenen LF, Majoie CB, Marquering HA, de Haan RJ, Roos YB. Early deterioration after thrombolysis plus aspirin in acute stroke: a post hoc analysis of the Antiplatelet Therapy in Combination with Recombinant t-PA Thrombolysis in Ischemic Stroke trial. Stroke 2014; 45 (10) 3080-3082
- 29 Savage B, Saldívar E, Ruggeri ZM. Initiation of platelet adhesion by arrest onto fibrinogen or translocation on von Willebrand factor. Cell 1996; 84 (02) 289-297
- 30 Kanaji S, Fahs SA, Shi Q, Haberichter SL, Montgomery RR. Contribution of platelet vs. endothelial VWF to platelet adhesion and hemostasis. J Thromb Haemost 2012; 10 (08) 1646-1652
- 31 Moroi M, Jung SM, Nomura S, Sekiguchi S, Ordinas A, Diaz-Ricart M. Analysis of the involvement of the von Willebrand factor-glycoprotein Ib interaction in platelet adhesion to a collagen-coated surface under flow conditions. Blood 1997; 90 (11) 4413-4424
- 32 Mammadova-Bach E, Ollivier V, Loyau S. , et al. Platelet glycoprotein VI binds to polymerized fibrin and promotes thrombin generation. Blood 2015; 126 (05) 683-691
- 33 Rayes J, Watson SP, Nieswandt B. Functional significance of the platelet immune receptors GPVI and CLEC-2. J Clin Invest 2019; 129 (01) 12-23
- 34 Alshehri OM, Hughes CE, Montague S. , et al. Fibrin activates GPVI in human and mouse platelets. Blood 2015; 126 (13) 1601-1608
- 35 Braun A, Vogtle T, Varga-Szabo D, Nieswandt B. STIM and Orai in hemostasis and thrombosis. Front Biosci 2011; 16: 2144-2160
- 36 Bergmeier W, Stefanini L. Platelet ITAM signaling. Curr Opin Hematol 2013; 20 (05) 445-450
- 37 Heemskerk JW, Mattheij NJ, Cosemans JM. Platelet-based coagulation: different populations, different functions. J Thromb Haemost 2013; 11 (01) 2-16
- 38 Stegner D, Nieswandt B. Platelet receptor signaling in thrombus formation. J Mol Med (Berl) 2011; 89 (02) 109-121
- 39 Suzuki-Inoue K, Kato Y, Inoue O. , et al. Involvement of the snake toxin receptor CLEC-2, in podoplanin-mediated platelet activation, by cancer cells. J Biol Chem 2007; 282 (36) 25993-26001
- 40 Müller F, Mutch NJ, Schenk WA. , et al. Platelet polyphosphates are pro-inflammatory and procoagulant mediators in vivo. Cell 2009; 139 (06) 1143-1156
- 41 Coller BS. Anti-GPIIb/IIIa drugs: current strategies and future directions. Thromb Haemost 2001; 86 (01) 427-443
- 42 Neri M, Riezzo I, Pascale N, Pomara C, Turillazzi E. Ischemia/reperfusion injury following acute myocardial infarction: a critical issue for clinicians and forensic pathologists. Mediators Inflamm 2017; 2017: 7018393
- 43 Safley DM, Venkitachalam L, Kennedy KF, Cohen DJ. Impact of glycoprotein IIb/IIIa inhibition in contemporary percutaneous coronary intervention for acute coronary syndromes: insights from the National Cardiovascular Data Registry. JACC Cardiovasc Interv 2015; 8 (12) 1574-1582
- 44 Barrabés JA, Inserte J, Mirabet M. , et al. Antagonism of P2Y12 or GPIIb/IIIa receptors reduces platelet-mediated myocardial injury after ischaemia and reperfusion in isolated rat hearts. Thromb Haemost 2010; 104 (01) 128-135
- 45 Cannon CP. Combination therapy for acute myocardial infarction: glycoprotein IIb/IIIa inhibitors plus thrombolysis. Clin Cardiol 1999; 22 (8, Suppl): IV37-IV43
- 46 Montalescot G, Barragan P, Wittenberg O. , et al; ADMIRAL Investigators. Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-Term Follow-up. Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction. N Engl J Med 2001; 344 (25) 1895-1903
- 47 Choudhri TF, Hoh BL, Zerwes HG. , et al. Reduced microvascular thrombosis and improved outcome in acute murine stroke by inhibiting GP IIb/IIIa receptor-mediated platelet aggregation. J Clin Invest 1998; 102 (07) 1301-1310
- 48 Abumiya T, Fitridge R, Mazur C. , et al. Integrin alpha(IIb)beta(3) inhibitor preserves microvascular patency in experimental acute focal cerebral ischemia. Stroke 2000; 31 (06) 1402-1409 , discussion 1409–1410
- 49 Lapchak PA, Araujo DM, Song D, Zivin JA. The nonpeptide glycoprotein IIb/IIIa platelet receptor antagonist SM-20302 reduces tissue plasminogen activator-induced intracerebral hemorrhage after thromboembolic stroke. Stroke 2002; 33 (01) 147-152
- 50 Kleinschnitz C, Pozgajova M, Pham M, Bendszus M, Nieswandt B, Stoll G. Targeting platelets in acute experimental stroke: impact of glycoprotein Ib, VI, and IIb/IIIa blockade on infarct size, functional outcome, and intracranial bleeding. Circulation 2007; 115 (17) 2323-2330
- 51 Kraft P, Schuhmann MK, Fluri F. , et al. Efficacy and safety of platelet glycoprotein receptor blockade in aged and comorbid mice with acute experimental stroke. Stroke 2015; 46 (12) 3502-3506
- 52 Adams Jr HP, Effron MB, Torner J. , et al; AbESTT-II Investigators. Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of an international phase III trial: Abciximab in Emergency Treatment of Stroke Trial (AbESTT-II). Stroke 2008; 39 (01) 87-99
- 53 Kellert L, Hametner C, Rohde S. , et al. Endovascular stroke therapy: tirofiban is associated with risk of fatal intracerebral hemorrhage and poor outcome. Stroke 2013; 44 (05) 1453-1455
- 54 Zhu YQ, Zhang YJ, Ruan HL, Liu Q, Zhan Q, Li Q. Safety of tirofiban for patients with acute ischemic stroke in routine clinical practice. Exp Ther Med 2015; 10 (01) 169-174
- 55 Chang Y, Kim BM, Bang OY. , et al. Rescue stenting for failed mechanical thrombectomy in acute ischemic stroke: a multicenter experience. Stroke 2018; 49 (04) 958-964
- 56 Pham M, Helluy X, Kleinschnitz C. , et al. Sustained reperfusion after blockade of glycoprotein-receptor-Ib in focal cerebral ischemia: an MRI study at 17.6 Tesla. PLoS One 2011; 6 (04) e18386
- 57 Schuhmann MK, Guthmann J, Stoll G, Nieswandt B, Kraft P, Kleinschnitz C. Blocking of platelet glycoprotein receptor Ib reduces “thrombo-inflammation” in mice with acute ischemic stroke. J Neuroinflammation 2017; 14 (01) 18
- 58 Kanaji T, Russell S, Ware J. Amelioration of the macrothrombocytopenia associated with the murine Bernard-Soulier syndrome. Blood 2002; 100 (06) 2102-2107
- 59 De Meyer SF, Schwarz T, Schatzberg D, Wagner DD. Platelet glycoprotein Ibα is an important mediator of ischemic stroke in mice. Exp Transl Stroke Med 2011; 3 (01) 9
- 60 Kleinschnitz C, De Meyer SF, Schwarz T. , et al. Deficiency of von Willebrand factor protects mice from ischemic stroke. Blood 2009; 113 (15) 3600-3603
- 61 Verhenne S, Denorme F, Libbrecht S. , et al. Platelet-derived VWF is not essential for normal thrombosis and hemostasis but fosters ischemic stroke injury in mice. Blood 2015; 126 (14) 1715-1722
- 62 Zhao BQ, Chauhan AK, Canault M. , et al. von Willebrand factor-cleaving protease ADAMTS13 reduces ischemic brain injury in experimental stroke. Blood 2009; 114 (15) 3329-3334
- 63 Fujioka M, Hayakawa K, Mishima K. , et al. ADAMTS13 gene deletion aggravates ischemic brain damage: a possible neuroprotective role of ADAMTS13 by ameliorating post-ischemic hypoperfusion. Blood 2010; 115 (08) 1650-1653
- 64 Canobbio I, Balduini C, Torti M. Signalling through the platelet glycoprotein Ib-V-IX complex. Cell Signal 2004; 16 (12) 1329-1344
- 65 Elvers M, Stegner D, Hagedorn I. , et al. Impaired alpha(IIb)beta(3) integrin activation and shear-dependent thrombus formation in mice lacking phospholipase D1. Sci Signal 2010; 3 (103) ra1
- 66 Klier M, Gowert NS, Jäckel S, Reinhardt C, Elvers M. Phospholipase D1 is a regulator of platelet-mediated inflammation. Cell Signal 2017; 38: 171-181
- 67 Thielmann I, Stegner D, Kraft P. , et al. Redundant functions of phospholipases D1 and D2 in platelet α-granule release. J Thromb Haemost 2012; 10 (11) 2361-2372
- 68 Stegner D, Thielmann I, Kraft P, Frohman MA, Stoll G, Nieswandt B. Pharmacological inhibition of phospholipase D protects mice from occlusive thrombus formation and ischemic stroke--brief report. Arterioscler Thromb Vasc Biol 2013; 33 (09) 2212-2217
- 69 Maguire JM, Thakkinstian A, Sturm J. , et al. Polymorphisms in platelet glycoprotein 1balpha and factor VII and risk of ischemic stroke: a meta-analysis. Stroke 2008; 39 (06) 1710-1716
- 70 Nieswandt B, Watson SP. Platelet-collagen interaction: is GPVI the central receptor?. Blood 2003; 102 (02) 449-461
- 71 Nieswandt B, Schulte V, Bergmeier W. , et al. Long-term antithrombotic protection by in vivo depletion of platelet glycoprotein VI in mice. J Exp Med 2001; 193 (04) 459-469
- 72 Massberg S, Gawaz M, Grüner S. , et al. A crucial role of glycoprotein VI for platelet recruitment to the injured arterial wall in vivo. J Exp Med 2003; 197 (01) 41-49
- 73 Lockyer S, Okuyama K, Begum S. , et al. GPVI-deficient mice lack collagen responses and are protected against experimentally induced pulmonary thromboembolism. Thromb Res 2006; 118 (03) 371-380
- 74 Schuhmann MK, Kraft P, Bieber M. , et al. Targeting platelet GPVI plus rt-PA administration but not α2β1-mediated collagen binding protects against ischemic brain damage in mice. Int J Mol Sci 2019; 20 (08) 2019
- 75 van Eeuwijk JM, Stegner D, Lamb DJ. , et al. The novel oral Syk inhibitor, Bl1002494, protects mice from arterial thrombosis and thrombo-inflammatory brain infarction. Arterioscler Thromb Vasc Biol 2016; 36 (06) 1247-1253
- 76 Cherpokova D, Bender M, Morowski M. , et al. SLAP/SLAP2 prevent excessive platelet (hem)ITAM signaling in thrombosis and ischemic stroke in mice. Blood 2015; 125 (01) 185-194
- 77 Bigalke B, Stellos K, Geisler T. , et al. Expression of platelet glycoprotein VI is associated with transient ischemic attack and stroke. Eur J Neurol 2010; 17 (01) 111-117
- 78 Bender M, Hofmann S, Stegner D. , et al. Differentially regulated GPVI ectodomain shedding by multiple platelet-expressed proteinases. Blood 2010; 116 (17) 3347-3355
- 79 Montague SJ, Andrews RK, Gardiner EE. Mechanisms of receptor shedding in platelets. Blood 2018; 132 (24) 2535-2545
- 80 Al-Tamimi M, Gardiner EE, Thom JY. , et al. Soluble glycoprotein VI is raised in the plasma of patients with acute ischemic stroke. Stroke 2011; 42 (02) 498-500
- 81 Ungerer M, Rosport K, Bültmann A. , et al. Novel antiplatelet drug revacept (dimeric glycoprotein VI-Fc) specifically and efficiently inhibited collagen-induced platelet aggregation without affecting general hemostasis in humans. Circulation 2011; 123 (17) 1891-1899
- 82 Goebel S, Li Z, Vogelmann J. , et al. The GPVI-Fc fusion protein Revacept improves cerebral infarct volume and functional outcome in stroke. PLoS One 2013; 8 (07) e66960
- 83 Lebozec K, Jandrot-Perrus M, Avenard G, Favre-Bulle O, Billiald P. Design, development and characterization of ACT017, a humanized Fab that blocks platelet's glycoprotein VI function without causing bleeding risks. MAbs 2017; 9 (06) 945-958
- 84 Voors-Pette C, Lebozec K, Dogterom P. , et al. Safety and tolerability, pharmacokinetics, and pharmacodynamics of ACT017, an antiplatelet GPVI (glycoprotein VI) Fab. Arterioscler Thromb Vasc Biol 2019; 39 (05) 956-964
- 85 Suzuki-Inoue K, Fuller GL, García A. , et al. A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2. Blood 2006; 107 (02) 542-549
- 86 Hughes CE, Pollitt AY, Mori J. , et al. CLEC-2 activates Syk through dimerization. Blood 2010; 115 (14) 2947-2955
- 87 Séverin S, Pollitt AY, Navarro-Nuñez L. , et al. Syk-dependent phosphorylation of CLEC-2: a novel mechanism of hem-immunoreceptor tyrosine-based activation motif signaling. J Biol Chem 2011; 286 (06) 4107-4116
- 88 Suzuki-Inoue K, Inoue O, Ding G. , et al. Essential in vivo roles of the C-type lectin receptor CLEC-2: embryonic/neonatal lethality of CLEC-2-deficient mice by blood/lymphatic misconnections and impaired thrombus formation of CLEC-2-deficient platelets. J Biol Chem 2010; 285 (32) 24494-24507
- 89 Lowe KL, Finney BA, Deppermann C. , et al. Podoplanin and CLEC-2 drive cerebrovascular patterning and integrity during development. Blood 2015; 125 (24) 3769-3777
- 90 Bertozzi CC, Schmaier AA, Mericko P. , et al. Platelets regulate lymphatic vascular development through CLEC-2-SLP-76 signaling. Blood 2010; 116 (04) 661-670
- 91 Finney BA, Schweighoffer E, Navarro-Núñez L. , et al. CLEC-2 and Syk in the megakaryocytic/platelet lineage are essential for development. Blood 2012; 119 (07) 1747-1756
- 92 Navarro-Núñez L, Pollitt AY, Lowe K, Latif A, Nash GB, Watson SP. Platelet adhesion to podoplanin under flow is mediated by the receptor CLEC-2 and stabilised by Src/Syk-dependent platelet signalling. Thromb Haemost 2015; 113 (05) 1109-1120
- 93 May F, Hagedorn I, Pleines I. , et al. CLEC-2 is an essential platelet-activating receptor in hemostasis and thrombosis. Blood 2009; 114 (16) 3464-3472
- 94 Hughes CE, Navarro-Núñez L, Finney BA, Mourão-Sá D, Pollitt AY, Watson SP. CLEC-2 is not required for platelet aggregation at arteriolar shear. J Thromb Haemost 2010; 8 (10) 2328-2332
- 95 Payne H, Ponomaryov T, Watson SP, Brill A. Mice with a deficiency in CLEC-2 are protected against deep vein thrombosis. Blood 2017; 129 (14) 2013-2020
- 96 Haining EJ, Cherpokova D, Wolf K. , et al. CLEC-2 contributes to hemostasis independently of classical hemITAM signaling in mice. Blood 2017; 130 (20) 2224-2228
- 97 Bender M, May F, Lorenz V. , et al. Combined in vivo depletion of glycoprotein VI and C-type lectin-like receptor 2 severely compromises hemostasis and abrogates arterial thrombosis in mice. Arterioscler Thromb Vasc Biol 2013; 33 (05) 926-934
- 98 Boulaftali Y, Hess PR, Getz TM. , et al. Platelet ITAM signaling is critical for vascular integrity in inflammation. J Clin Invest 2013; 123 (02) 908-916
- 99 Rayes J, Jadoui S, Lax S. , et al. The contribution of platelet glycoprotein receptors to inflammatory bleeding prevention is stimulus and organ dependent. Haematologica 2018; 103 (06) e256-e258
- 100 Rayes J, Lax S, Wichaiyo S. , et al. The podoplanin-CLEC-2 axis inhibits inflammation in sepsis. Nat Commun 2017; 8 (01) 2239
- 101 Lax S, Rayes J, Wichaiyo S. , et al. Platelet CLEC-2 protects against lung injury via effects of its ligand podoplanin on inflammatory alveolar macrophages in the mouse. Am J Physiol Lung Cell Mol Physiol 2017; 313 (06) L1016-L1029
- 102 Zhang X, Zhang W, Wu X. , et al. Prognostic significance of plasma CLEC-2 (C-type lectin-like receptor 2) in patients with acute ischemic stroke. Stroke 2018; 50 (01) A118022563
- 103 Wu X, Zhang W, Li H. , et al. Plasma C-type lectin-like receptor 2 as a predictor of death and vascular events in patients with acute ischemic stroke. Eur J Neurol 2019; 26 (10) 1334-1340
- 104 Müller F, Renné T. Novel roles for factor XII-driven plasma contact activation system. Curr Opin Hematol 2008; 15 (05) 516-521
- 105 Renné T, Pozgajová M, Grüner S. , et al. Defective thrombus formation in mice lacking coagulation factor XII. J Exp Med 2005; 202 (02) 271-281
- 106 Kleinschnitz C, Stoll G, Bendszus M. , et al. Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis. J Exp Med 2006; 203 (03) 513-518
- 107 Hagedorn I, Schmidbauer S, Pleines I. , et al. Factor XIIa inhibitor recombinant human albumin Infestin-4 abolishes occlusive arterial thrombus formation without affecting bleeding. Circulation 2010; 121 (13) 1510-1517
- 108 Wagner S, Kalb P, Lukosava M, Hilgenfeldt U, Schwaninger M. Activation of the tissue kallikrein-kinin system in stroke. J Neurol Sci 2002; 202 (1–2): 75-76
- 109 Austinat M, Braeuninger S, Pesquero JB. , et al. Blockade of bradykinin receptor B1 but not bradykinin receptor B2 provides protection from cerebral infarction and brain edema. Stroke 2009; 40 (01) 285-293
- 110 Davis III AE, Mejia P, Lu F. Biological activities of C1 inhibitor. Mol Immunol 2008; 45 (16) 4057-4063
- 111 Heydenreich N, Nolte MW, Göb E. , et al. C1-inhibitor protects from brain ischemia-reperfusion injury by combined antiinflammatory and antithrombotic mechanisms. Stroke 2012; 43 (09) 2457-2467
- 112 Göb E, Reymann S, Langhauser F. , et al. Blocking of plasma kallikrein ameliorates stroke by reducing thrombo-inflammation. Ann Neurol 2015; 77 (05) 784-803
- 113 Leung PY, Hurst S, Berny-Lang MA. , et al. Inhibition of Factor XII-mediated activation of factor XI provides protection against experimental acute ischemic stroke in mice. Transl Stroke Res 2012; 3 (03) 381-389
- 114 Undas A, Slowik A, Gissel M, Mann KG, Butenas S. Circulating activated factor XI and active tissue factor as predictors of worse prognosis in patients following ischemic cerebrovascular events. Thromb Res 2011; 128 (05) e62-e66
- 115 Kraft P, Drechsler C, Gunreben I, Heuschmann PU, Kleinschnitz C. Regulation of blood coagulation factors XI and XII in patients with acute and chronic cerebrovascular disease: a case-control study. Cerebrovasc Dis 2014; 38 (05) 337-343