Thromboinflammation in stroke brain damage

Stroke

Volumn 47, Issue 4, 2016, Pages 1165-1172

  De Meyer, Simon F ^a   Denorme, Frederik ^a   Langhauser, Friederike ^b   Geuss, Eva ^b   Fluri, Felix ^b   Kleinschnitz, Christoph ^b  

^a UNIVERSITY OF LEUVEN   (Belgium)

^b UNIVERSITY HOSPITAL WÜRZBURG   (Germany)

Author keywords

Blood platelets; Factor XII; Neutrophils; Stroke; T lymphocytes; Von Willebrand factor

Indexed keywords

COLLAGEN; GLYCOPROTEIN IB; KININ; VON WILLEBRAND FACTOR; THROMBIN RECEPTOR;

ARTICLE; BLOOD CLOTTING; BLOOD VESSEL INJURY; BRAIN DAMAGE; BRAIN ISCHEMIA; HUMAN; INFLAMMATION; INFLAMMATORY CELL; META ANALYSIS (TOPIC); MIDDLE CEREBRAL ARTERY OCCLUSION; NONHUMAN; PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; THROMBOCYTE ACTIVATION; THROMBOSIS; BRAIN; CEREBROVASCULAR ACCIDENT; METABOLISM; PATHOLOGY; THROMBOCYTE;

BLOOD PLATELETS; BRAIN; BRAIN ISCHEMIA; COLLAGEN; HUMANS; INFLAMMATION; PLATELET GLYCOPROTEIN GPIB-IX COMPLEX; STROKE; VON WILLEBRAND FACTOR;

EID: 84954503110     PISSN: 00392499     EISSN: 15244628     Source Type: Journal    
DOI: 10.1161/STROKEAHA.115.011238     Document Type: Article

References (94)

1. Eltzschig HK, Eckle T. Ischemia and reperfusion-from mechanism to translation. Nat Med. 2011;17:1391-1401. doi: 10.1038/nm.2507.
2. Stoll G, Kleinschnitz C, Nieswandt B. Molecular mechanisms of thrombus formation in ischemic stroke: novel insights and targets for treatment. Blood. 2008;112:3555-3562. doi: 10.1182/blood-2008-04-144758.
3. Stoll G, Kleinschnitz C, Nieswandt B. Combating innate infamma-tion: a new paradigm for acute treatment of stroke? Ann N Y Acad Sci. 2010;1207:149-154. doi: 10.1111/j.1749-6632.2010.05730.x.
4. Broos K, Feys HB, De Meyer SF, Vanhoorelbeke K, Deckmyn H. Platelets at work in primary hemostasis. Blood Rev. 2011;25:155-167. doi: 10.1016/j.blre.2011.03.002.
5. De Meyer SF, Stoll G, Wagner DD, Kleinschnitz C. von Willebrand factor: an emerging target in stroke therapy. Stroke. 2012;43:599-606. doi: 10.1161/STROKEAHA.111.628867.
6. Kleinschnitz C, Pozgajova M, Pham M, Bendszus M, Nieswandt B, Stoll G. Targeting platelets in acute experimental stroke: impact of glycopro-tein Ib, VI, and IIb/IIIa blockade on infarct size, functional outcome, and intracranial bleeding. Circulation. 2007;115:2323-2330. doi: 10.1161/CIRCULATIONAHA.107.691279.
7. De Meyer SF, Schwarz T, Deckmyn H, Denis CV, Nieswandt B, Stoll G, et al. Binding of von Willebrand factor to collagen and glycoprotein Ibalpha, but not to glycoprotein IIb/IIIa, contributes to ischemic stroke in mice-brief report. Arterioscler Thromb Vasc Biol. 2010;30:1949-1951. doi: 10.1161/ATVBAHA.110.208918.
8. Zhao BQ, Chauhan AK, Canault M, Patten IS, Yang JJ, Dockal M, et al. von Willebrand factor-cleaving protease ADAMTS13 reduces ischemic brain injury in experimental stroke. Blood. 2009;114:3329-3334. doi: 10.1182/blood-2009-03-213264.
9. Kleinschnitz C, De Meyer SF, Schwarz T, Austinat M, Vanhoorelbeke K, Nieswandt B, et al. Defciency of von Willebrand factor protects mice from ischemic stroke. Blood. 2009;113:3600-3603. doi: 10.1182/blood-2008-09-180695.
10. Verhenne S, Denorme F, Libbrecht S, Vandenbulcke A, Pareyn I, Deckmyn H, et al. Platelet-derived VWF is not essential for normal thrombosis and hemostasis but fosters ischemic stroke injury in mice. Blood. 2015;126:1715-1722. doi: 10.1182/blood-2015-03-632901.
11. Fujioka M, Hayakawa K, Mishima K, Kunizawa A, Irie K, Higuchi S, et al. ADAMTS13 gene deletion aggravates ischemic brain damage: a possible neuroprotective role of ADAMTS13 by ameliorating post-ischemic hypoperfusion. Blood. 2010;115:1650-1653. doi: 10.1182/blood-2009-06-230110.
12. Khan MM, Motto DG, Lentz SR, Chauhan AK. ADAMTS13 reduces VWF-mediated acute infammation following focal cerebral ischemia in mice. J Thromb Haemost. 2012;10:1665-1671. doi: 10.1111/j.1538-7836.2012.04822.x.
13. Pham M, Helluy X, Kleinschnitz C, Kraft P, Bartsch AJ, Jakob P, 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:e18386. doi: 10.1371/journal.pone.0018386.
14. De Meyer SF, Schwarz T, Schatzberg D, Wagner DD. Platelet glycopro-tein Ibα is an important mediator of ischemic stroke in mice. Exp Transl Stroke Med. 2011;3:9. doi: 10.1186/2040-7378-3-9.
15. Elvers M, Stegner D, Hagedorn I, Kleinschnitz C, Braun A, Kuijpers ME, et al. Impaired alpha(IIb)beta(3) integrin activation and shear-dependent thrombus formation in mice lacking phospholipase D1. Sci Signal. 2010;3:ra1. doi: 10.1126/scisignal.2000551.
16. Samai A, Monlezun D, Shaban A, George A, Dowell L, Kruse-Jarres R, et al. Von Willebrand factor drives the association between elevated factor VIII and poor outcomes in patients with ischemic stroke. Stroke. 2014;45:2789-2791. doi: 10.1161/STROKEAHA.114.006394.
17. Wieberdink RG, van Schie MC, Koudstaal PJ, Hofman A, Witteman JC, de Maat MP, et al. High von Willebrand factor levels increase the risk of stroke: the Rotterdam study. Stroke. 2010;41:2151-2156. doi: 10.1161/STROKEAHA.110.586289.
18. Lip GY, Lane D, Van Walraven C, Hart RG. Additive role of plasma von Willebrand factor levels to clinical factors for risk stratifcation of patients with atrial fbrillation. Stroke. 2006;37:2294-2300. doi: 10.1161/01.STR.0000236840.00467.84.
19. Sanders YV, Eikenboom J, de Wee EM, van der Bom JG, Cnossen MH, Degenaar-Dujardin ME, et al; WiN Study Group. Reduced prevalence of arterial thrombosis in von Willebrand disease. J Thromb Haemost. 2013;11:845-854. doi: 10.1111/jth.12194.
20. Seaman CD, Yabes J, Comer DM, Ragni MV. Does defciency of von Willebrand factor protect against cardiovascular disease? Analysis of a national discharge register. J Thromb Haemost. 2015;13:1999-2003. doi: 10.1111/jth.13142.
21. van Schie MC, de Maat MP, Isaacs A, van Duijn CM, Deckers JW, Dippel DW, et al. Variation in the von Willebrand factor gene is associated with von Willebrand factor levels and with the risk for cardiovascular disease. Blood. 2011;117:1393-1399. doi: 10.1182/blood-2010-03-273961.
22. Dai K, Gao W, Ruan C. The Sma I polymorphism in the von Willebrand factor gene associated with acute ischemic stroke. Thromb Res. 2001;104:389-395.
23. Baker RI, Eikelboom J, Lofthouse E, Staples N, Afshar-Kharghan V, López JA, et al. Platelet glycoprotein Ibalpha Kozak polymorphism is associated with an increased risk of ischemic stroke. Blood. 2001;98:36-40.
24. Reiner AP, Kumar PN, Schwartz SM, Longstreth WT Jr, Pearce RM, Rosendaal FR, et al. Genetic variants of platelet glycoprotein receptors and risk of stroke in young women. Stroke. 2000;31:1628-1633.
25. Hanson E, Jood K, Nilsson S, Blomstrand C, Jern C. Association between genetic variation at the ADAMTS13 locus and ischemic stroke. J Thromb Haemost. 2009;7:2147-2148. doi: 10.1111/j.1538-7836.2009.03617.x.
26. Adams HP Jr, Effron MB, Torner J, Dávalos A, Frayne J, Teal P, et al; AbESTT-II Investigators. Emergency administration of abcix-imab 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;39:87-99. doi: 10.1161/STROKEAHA.106.476648.
27. Pendu R, Terraube V, Christophe OD, Gahmberg CG, de Groot PG, Lenting PJ, et al. P-selectin glycoprotein ligand 1 and beta2-integrins cooperate in the adhesion of leukocytes to von Willebrand factor. Blood. 2006;108:3746-3752. doi: 10.1182/blood-2006-03-010322.
28. Bernardo A, Ball C, Nolasco L, Choi H, Moake JL, Dong JF. Platelets adhered to endothelial cell-bound ultra-large von Willebrand factor strings support leukocyte tethering and rolling under high shear stress. J Thromb Haemost. 2005;3:562-570. doi: 10.1111/j.1538-7836.2005.01122.x.
29. Petri B, Broermann A, Li H, Khandoga AG, Zarbock A, Krombach F, et al. von Willebrand factor promotes leukocyte extravasation. Blood. 2010;116:4712-4719. doi: 10.1182/blood-2010-03-276311.
30. De Meyer SF, Savchenko AS, Haas MS, Schatzberg D, Carroll MC, Schiviz A, et al. Protective anti-infammatory effect of ADAMTS13 on myocardial ischemia/reperfusion injury in mice. Blood. 2012;120:5217-5223. doi: 10.1182/blood-2012-06-439935.
31. Gandhi C, Motto DG, Jensen M, Lentz SR, Chauhan AK. ADAMTS13 defciency exacerbates VWF-dependent acute myocardial ischemia/reperfusion injury in mice. Blood. 2012;120:5224-5230. doi: 10.1182/blood-2012-06-440255.
32. Boilard E, Nigrovic PA, Larabee K, Watts GF, Coblyn JS, Weinblatt ME, et al. Platelets amplify infammation in arthritis via collagen-dependent microparticle production. Science. 2010;327:580-583. doi: 10.1126/science.1181928.
33. Gros A, Syvannarath V, Lamrani L, Ollivier V, Loyau S, Goerge T, et al. Single platelets seal neutrophil-induced vascular breaches via GPVI during immune-complex-mediated infammation in mice. Blood. 2015;126:1017-1026. doi: 10.1182/blood-2014-12-617159.
34. Duerschmied D, Bode C, Ahrens I. Immune functions of platelets. Thromb Haemost. 2014;112:678-691. doi: 10.1160/TH14-02-0146.
35. Thornton P, McColl BW, Greenhalgh A, Denes A, Allan SM, Rothwell NJ. Platelet interleukin-1alpha drives cerebrovascular infammation. Blood. 2010;115:3632-3639. doi: 10.1182/blood-2009-11-252643.
36. Ishikawa M, Vowinkel T, Stokes KY, Arumugam TV, Yilmaz G, Nanda A, et al. CD40/CD40 ligand signaling in mouse cerebral microvasculature after focal ischemia/reperfusion. Circulation. 2005;111:1690-1696. doi: 10.1161/01.CIR.0000160349.42665.0C.
37. Henn V, Slupsky JR, Gräfe M, Anagnostopoulos I, Förster R, Müller-Berghaus G, et al. CD40 ligand on activated platelets triggers an infam-matory reaction of endothelial cells. Nature. 1998;391:591-594. doi: 10.1038/35393.
38. Albert-Weißenberger C, Sirén AL, Kleinschnitz C. Ischemic stroke and traumatic brain injury: the role of the kallikrein-kinin system. Prog Neurobiol. 2013;101-102:65-82. doi: 10.1016/j.pneurobio.2012.11.004.
39. Müller F, Mutch NJ, Schenk WA, Smith SA, Esterl L, Spronk HM, et al. Platelet polyphosphates are proinfammatory and procoagulant mediators in vivo. Cell. 2009;139:1143-1156. doi: 10.1016/j.cell.2009.11.001.
40. Björkqvist J, Nickel KF, Stavrou E, Renné T. In vivo activation and functions of the protease factor XII. Thromb Haemost. 2014;112:868-875. doi: 10.1160/TH14-04-0311.
41. Renné T, Pozgajová M, Grüner S, Schuh K, Pauer HU, Burfeind P, et al. Defective thrombus formation in mice lacking coagulation factor XII. J Exp Med. 2005;202:271-281. doi: 10.1084/jem.20050664.
42. Kleinschnitz C, Stoll G, Bendszus M, Schuh K, Pauer HU, Burfeind P, et al. Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis. J Exp Med. 2006;203:513-518. doi: 10.1084/jem.20052458.
43. Hagedorn I, Schmidbauer S, Pleines I, Kleinschnitz C, Kronthaler U, Stoll G, et al. Factor XIIa inhibitor recombinant human albumin Infestin-4 abolishes occlusive arterial thrombus formation without affecting bleeding. Circulation. 2010;121:1510-1517. doi: 10.1161/CIRCULATIONAHA.109.924761.
44. Choudhri TF, Hoh BL, Prestigiacomo CJ, Huang J, Kim LJ, Schmidt AM, et al. Targeted inhibition of intrinsic coagulation limits cerebral injury in stroke without increasing intracerebral hemorrhage. J Exp Med. 1999;190:91-99.
45. Göb E, Reymann S, Langhauser F, Schuhmann MK, Kraft P, Thielmann I, et al. Blocking of plasma kallikrein ameliorates stroke by reducing thromboinfammation. Ann Neurol. 2015;77:784-803. doi: 10.1002/ana.24380.
46. Langhauser F, Göb E, Kraft P, Geis C, Schmitt J, Brede M, et al. Kininogen defciency protects from ischemic neurodegeneration in mice by reducing thrombosis, blood-brain barrier damage, and infammation. Blood. 2012;120:4082-4092. doi: 10.1182/blood-2012-06-440057.
47. Austinat M, Braeuninger S, Pesquero JB, Brede M, Bader M, Stoll G, et al. Blockade of bradykinin receptor B1 but not bradykinin receptor B2 provides protection from cerebral infarction and brain edema. Stroke. 2009;40:285-293. doi: 10.1161/STROKEAHA.108.526673.
48. Heydenreich N, Nolte MW, Göb E, Langhauser F, Hofmeister M, Kraft P, et al. C1-inhibitor protects from brain ischemia-reperfusion injury by combined antiinfammatory and antithrombotic mechanisms. Stroke. 2012;43:2457-2467. doi: 10.1161/STROKEAHA.112.660340.
49. Wagner S, Kalb P, Lukosava M, Hilgenfeldt U, Schwaninger M. Activation of the tissue kallikrein-kinin system in stroke. J Neurol Sci. 2002;202:75-76.
50. Suri MF, Yamagishi K, Aleksic N, Hannan PJ, Folsom AR. Novel hemo-static factor levels and risk of ischemic stroke: the Atherosclerosis Risk in Communities (ARIC) Study. Cerebrovasc Dis. 2010;29:497-502. doi: 10.1159/000297966.
51. 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:e62-e66. doi: 10.1016/j.thromres.2011.06.010.
52. Undas A, Slowik A, Gissel M, Mann KG, Butenas S. Active tissue factor and activated factor XI in patients with acute ischemic cerebrovascular events. Eur J Clin Invest. 2012;42:123-129. doi: 10.1111/j.1365-2362.2011.02565.x.
53. Siegerink B, Rosendaal FR, Algra A. Antigen levels of coagulation factor XII, coagulation factor XI and prekallikrein, and the risk of myocardial infarction and ischemic stroke in young women. J Thromb Haemost. 2014;12:606-613.
54. Govers-Riemslag JW, Smid M, Cooper JA, Bauer KA, Rosenberg RD, Hack CE, et al. The plasma kallikrein-kinin system and risk of cardiovascular disease in men. J Thromb Haemost. 2007;5:1896-1903. doi: 10.1111/j.1538-7836.2007.02687.x.
55. Johnson CY, Tuite A, Morange PE, Tregouet DA, Gagnon F. The factor XII-4CT variant and risk of common thrombotic disorders: A HuGE review and meta-analysis of evidence from observational studies. Am J Epidemiol. 2011;173:136-144. doi: 10.1093/aje/kwq349.
56. Salomon O, Steinberg DM, Koren-Morag N, Tanne D, Seligsohn U. Reduced incidence of ischemic stroke in patients with severe factor XI defciency. Blood. 2008;111:4113-4117. doi: 10.1182/blood-2007-10-120139.
57. Hanson E, Nilsson S, Jood K, Norrving B, Engström G, Blomstrand C, et al. Genetic variants of coagulation factor XI show association with ischemic stroke up to 70 years of age. PLoS One. 2013;8:e75286. doi: 10.1371/journal.pone.0075286.
58. Jickling GC, Liu D, Ander BP, Stamova B, Zhan X, Sharp FR. Targeting neutrophils in ischemic stroke: translational insights from experimental studies. J Cereb Blood Flow Metab. 2015;35:888-901. doi: 10.1038/jcbfm.2015.45.
59. del Zoppo GJ, Mabuchi T. Cerebral microvessel responses to focal ischemia. J Cereb Blood Flow Metab. 2003;23:879-894. doi: 10.1097/01. WCB.0000078322.96027.78.
60. Darbousset R, Thomas GM, Mezouar S, Frère C, Bonier R, Mackman N, et al. Tissue factor-positive neutrophils bind to injured endothelial wall and initiate thrombus formation. Blood. 2012;120:2133-2143. doi: 10.1182/blood-2012-06-437772.
61. von Brühl ML, Stark K, Steinhart A, Chandraratne S, Konrad I, Lorenz M, et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med. 2012;209:819-835. doi: 10.1084/jem.20112322.
62. Massberg S, Grahl L, von Bruehl ML, Manukyan D, Pfeiler S, Goosmann C, et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med. 2010;16:887-896. doi: 10.1038/nm.2184.
63. Faraday N, Schunke K, Saleem S, Fu J, Wang B, Zhang J, et al. Cathepsin G-dependent modulation of platelet thrombus formation in vivo by blood neutrophils. PLoS One. 2013;8:e71447. doi: 10.1371/jour-nal.pone.0071447.
64. McCabe DJ, Harrison P, Mackie IJ, Sidhu PS, Purdy G, Lawrie AS, et al. Increased platelet count and leucocyte-platelet complex formation in acute symptomatic compared with asymptomatic severe carotid stenosis. J Neurol Neurosurg Psychiatry. 2005;76:1249-1254. doi: 10.1136/jnnp.2004.051003.
65. Sreeramkumar V, Adrover JM, Ballesteros I, Cuartero MI, Rossaint J, Bilbao I, et al. Neutrophils scan for activated platelets to initiate infam-mation. Science. 2014;346:1234-1238. doi: 10.1126/science.1256478.
66. Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD Jr, et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci USA. 2010;107:15880-15885. doi: 10.1073/pnas.1005743107.
67. Martinod K, Wagner DD. Thrombosis: tangled up in NETs. Blood. 2014;123:2768-2776. doi: 10.1182/blood-2013-10-463646.
68. Perez-de-Puig I, Miró-Mur F, Ferrer-Ferrer M, Gelpi E, Pedragosa J, Justicia C, et al. Neutrophil recruitment to the brain in mouse and human ischemic stroke. Acta Neuropathol. 2015;129:239-257.
69. De Meyer SF, Suidan GL, Fuchs TA, Monestier M, Wagner DD. Extracellular chromatin is an important mediator of ischemic stroke in mice. Arterioscler Thromb Vasc Biol. 2012;32:1884-1891. doi: 10.1161/ATVBAHA.112.250993.
70. Yilmaz G, Arumugam TV, Stokes KY, Granger DN. Role of T lymphocytes and interferon-gamma in ischemic stroke. Circulation. 2006;113:2105-2112. doi: 10.1161/CIRCULATIONAHA.105.593046.
71. Kleinschnitz C, Schwab N, Kraft P, Hagedorn I, Dreykluft A, Schwarz T, et al. Early detrimental T-cell effects in experimental cerebral ischemia are neither related to adaptive immunity nor thrombus formation. Blood. 2010;115:3835-3842. doi: 10.1182/blood-2009-10-249078.
72. Liesz A, Hu X, Kleinschnitz C, Offner H. Functional role of regulatory lymphocytes in stroke: facts and controversies. Stroke. 2015;46:1422-1430. doi: 10.1161/STROKEAHA.114.008608.
73. Kleinschnitz C, Kraft P, Dreykluft A, Hagedorn I, Göbel K, Schuhmann MK, et al. Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature. Blood. 2013;121:679-691. doi: 10.1182/blood-2012-04-426734.
74. Schuhmann MK, Kraft P, Stoll G, Lorenz K, Meuth SG, Wiendl H, et al. CD28 superagonist-mediated boost of regulatory T cells increases thrombo-infammation and ischemic neurodegeneration during the acute phase of experimental stroke. J Cereb Blood Flow Metab. 2015;35:6-10. doi: 10.1038/jcbfm.2014.175.
75. Liesz A, Suri-Payer E, Veltkamp C, Doerr H, Sommer C, Rivest S, et al. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med. 2009;15:192-199. doi: 10.1038/nm.1927.
76. Lukasik M, Dworacki G, Michalak S, Kufel-Grabowska J, Golanski J, Watala C, et al. Aspirin treatment influences platelet-related infammatory biomarkers in healthy individuals but not in acute stroke patients. Thromb Res. 2011;128:e73-e80. doi: 10.1016/j.thromres.2011.06.016.
77. Chronos NA, Wilson DJ, Janes SL, Hutton RA, Buller NP, Goodall AH. Aspirin does not affect the fow cytometric detection of fbrinogen binding to, or release of alpha-granules or lysosomes from, human platelets. Clin Sci (Lond). 1994;87:575-580.
78. Li N, Hu H, Hjemdahl P. Aspirin treatment does not attenuate platelet or leukocyte activation as monitored by whole blood fow cytometry. Thromb Res. 2003;111:165-170.
79. Xiao Z, Théroux P. Clopidogrel inhibits platelet-leukocyte interactions and thrombin receptor agonist peptide-induced platelet activation in patients with an acute coronary syndrome. J Am Coll Cardiol. 2004;43:1982-1988. doi: 10.1016/j.jacc.2003.10.071.
80. Chen YG, Xu F, Zhang Y, Ji QS, Sun Y, Lü RJ, et al. Effect of aspirin plus clopidogrel on infammatory markers in patients with non-ST-segment elevation acute coronary syndrome. Chin Med J (Engl). 2006;119:32-36.
81. Salanova B, Choi M, Rolle S, Wellner M, Luft FC, Kettritz R. Beta2-integrins and acquired glycoprotein IIb/IIIa (GPIIb/IIIa) receptors cooperate in NF-kappaB activation of human neutrophils. J Biol Chem. 2007;282:27960-27969. doi: 10.1074/jbc.M704039200.
82. Ciccone A, Motto C, Abraha I, Cozzolino F, Santilli I. Glycoprotein IIb-IIIa inhibitors for acute ischaemic stroke. Cochrane Database Syst Rev. 2014;3:CD005208. doi: 10.1002/14651858.CD005208.pub3.
83. Yousuf O, Bhatt DL. The evolution of antiplatelet therapy in cardiovascular disease. Nat Rev Cardiol. 2011;8:547-559. doi: 10.1038/nrcardio.2011.96.
84. Fu Y, Zhang N, Ren L, Yan Y, Sun N, Li YJ, et al. Impact of an immune modulator fngolimod on acute ischemic stroke. Proc Natl Acad Sci USA. 2014;111:18315-18320. doi: 10.1073/pnas.1416166111.
85. Zhu Z, Fu Y, Tian D, Sun N, Han W, Chang G, et al. Combination of the Immune Modulator Fingolimod With Alteplase in Acute Ischemic Stroke: A Pilot Trial. Circulation. 2015;132:1104-1112. doi: 10.1161/CIRCULATIONAHA.115.016371.
86. Kraft P, Göb E, Schuhmann MK, Göbel K, Deppermann C, Thielmann I, et al. FTY720 ameliorates acute ischemic stroke in mice by reducing thrombo-infammation but not by direct neuroprotection. Stroke. 2013;44:3202-3210. doi: 10.1161/STROKEAHA.113.002880.
87. Becker K, Kindrick D, Relton J, Harlan J, Winn R. Antibody to the alpha4 integrin decreases infarct size in transient focal cerebral ischemia in rats. Stroke. 2001;32:206-211.
88. Relton JK, Sloan KE, Frew EM, Whalley ET, Adams SP, Lobb RR. Inhibition of alpha4 integrin protects against transient focal cerebral ischemia in normotensive and hypertensive rats. Stroke. 2001;32:199-205.
89. Langhauser F, Kraft P, Göb E, Leinweber J, Schuhmann MK, Lorenz K, et al. Blocking of α4 integrin does not protect from acute isch-emic stroke in mice. Stroke. 2014;45:1799-1806. doi: 10.1161/STROKEAHA.114.005000.
90. Liesz A, Zhou W, Mracskó É, Karcher S, Bauer H, Schwarting S, et al. Inhibition of lymphocyte traffcking shields the brain against deleterious neuroinfammation after stroke. Brain. 2011;134(pt 3):704-720. doi: 10.1093/brain/awr008.
91. Llovera G, Hofmann K, Roth S, Salas-Pérdomo A, Ferrer-Ferrer M, Perego C, et al. Results of a preclinical randomized controlled multi-center trial (pRCT): Anti-CD49d treatment for acute brain ischemia. Sci Transl Med. 2015;7:299ra121. doi: 10.1126/scitranslmed.aaa9853.
92. Jilma-Stohlawetz P, Gorczyca ME, Jilma B, Siller-Matula J, Gilbert JC, Knöbl P. Inhibition of von Willebrand factor by ARC1779 in patients with acute thrombotic thrombocytopenic purpura. Thromb Haemost. 2011;105:545-552. doi: 10.1160/TH10-08-0520.
93. Callewaert F, Ulrichts H, Hovinga JAK, De Swert K, Tersago D. The predictive value of ADAMTS13 activity for treatment monitoring of patients with acquired TTP: data from the phase II TITAN trial with caplacizumab. J Thromb Haemost. 2015;13:234-235.
94. Markus HS, McCollum C, Imray C, Goulder MA, Gilbert J, King A. The von Willebrand inhibitor ARC1779 reduces cerebral embolization after carotid endarterectomy: a randomized trial. Stroke. 2011;42:2149-2153. doi: 10.1161/STROKEAHA.111.616649.