Download PDF
Aktuelle Neurologie 2018; 45(07): 534-541
DOI: 10.1055/a-0597-8699
Übersicht
© Georg Thieme Verlag KG Stuttgart · New York

Thromboinflammation beim ischämischen Schlaganfall – pathophysiologisches Konzept und translationale Relevanz

Thrombo-Inflammation in Ischemic Stroke – Pathophysiologic Concept and Translational Relevance
Peter Kraft   *
1   Universitätsklinikum Würzburg
2   Klinikum Main-Spessart Lohr
3   Deutsches Zentrum für Herzinsuffizienz Würzburg
,
Friederike Langhauser   *
4   Universitätsklinikum Essen
,
Christoph Kleinschnitz
4   Universitätsklinikum Essen
› Author Affiliations
Further Information

Publication History

Publication Date:
25 April 2018 (online)

Also available at
    Permissions and Reprints

Zusammenfassung

Noch vor wenigen Jahren galt der ischämische Schlaganfall pathophysiologisch gesehen als Prototyp einer rein thrombotischen Erkrankung. Dies veränderte sich sukzessive, da klar wurde, dass Immunzellen im ischämischen Hirngewebe nicht nur vorhanden sind, sondern überraschenderweise sogar eine maßgebliche pathophysiologische Rolle spielen. Mittlerweile weiß man, dass viele Bestandteile des Immunsystems an der Entwicklung eines ischämischen Schlaganfalls beteiligt sind. Von größtem Interesse ist die Beobachtung, dass sich thrombotische und inflammatorische Vorgänge bei der Schlaganfallentstehung gegenseitig beeinflussen. Ein Phänomen, das unter dem Begriff Thromboinflammation Einzug in die Literatur gefunden hat. Die vorhandene Datenlage basiert im Wesentlichen auf tierexperimentellen Studien. Erste klinische Studien deuten jedoch darauf hin, dass thromboinflammatorische Vorgänge auch beim humanen ischämischen Schlaganfall eine große pathophysiologische Relevanz haben könnten, sodass sich daraus innovative Therapiestrategien entwickeln könnten. Die vorliegende Übersichtsarbeit skizziert die wichtigsten Mechanismen der Thromboinflammation im Kontext des ischämischen Schlaganfalls und geht auf erste translationale Ansätze ein.

Abstract

Only a few years ago ischemic stroke has been pathophysiologically classified as a prototype of a merely thrombotic disease. This assumption changed step-wise after the surprising finding that immune cells do not only infiltrate ischemic brain parenchyma but even play a fundamental pathophysiologic role. Meanwhile it is widely accepted that various components of the immune system contribute to ischemic stroke development. Of utmost importance, thrombotic and inflammatory processes influence each other, a phenomenon in recent literature called thrombo-inflammation. Data regarding thrombo-inflammation in ischemic stroke mainly derive from experimental rodent studies but according to the results of first clinical trials a pathophysiological relevance of thrombo-inflammatory mechanisms can be assumed also in human stroke. Therefore, anti-thrombo-inflammatory strategies could become novel treatment approaches in the future. This review aims to address the most important mechanisms of thrombo-inflammation in ischemic stroke. In addition, the first translational results, i. e. clinical trials, will be outlined.

Schlüsselwörter

ischämischer Schlaganfall - Thromboinflammation - Thrombozyten - Immunzellen

Keywords

ischemic stroke - thrombo-inflammation - platelets - immune cells

* Gleicher Beitrag


 

  • Literatur

  • 1 Kraft P, De Meyer SF, Kleinschnitz C. Next-generation antithrombotics in ischemic stroke: preclinical perspective on ‘bleeding-free antithrombosis’. J Cereb Blood Flow Metab 2012; 32: 1831-1840
    PubMedSearch in Google Scholar
  • 2 Fujioka M, Hayakawa K, Mishima K. et al. ADAMTS13 gene deletion aggravates ischemic brain damage: a possible neuroprotective role of ADAMTS13 by ameliorating postischemic hypoperfusion. Blood 2010; 115: 1650-1653
    CrossrefPubMedSearch in Google Scholar
  • 3 Kleinschnitz C, Pozgajova M, Pham M. et al. 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: 2323-2330
    CrossrefPubMedSearch in Google Scholar
  • 4 Kleinschnitz C, De Meyer SF, Schwarz T. et al. Deficiency of von Willebrand factor protects mice from ischemic stroke. Blood 2009; 113: 3600-3603
    CrossrefPubMedSearch in Google Scholar
  • 5 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: ra1
    PubMedSearch in Google Scholar
  • 6 Adams Jr HP, Effron MB, Torner J. et al. 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: 87-99
    CrossrefPubMedSearch in Google Scholar
  • 7 Bernardo A, Ball C, Nolasco L. et al. 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
    CrossrefPubMedSearch in Google Scholar
  • 8 Petri B, Broermann A, Li H. et al. von Willebrand factor promotes leukocyte extravasation. Blood 2010; 116: 4712-4719
    CrossrefPubMedSearch in Google Scholar
  • 9 Boilard E, Nigrovic PA, Larabee K. et al. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 2010; 327: 580-583
    CrossrefPubMedSearch in Google Scholar
  • 10 Gros A, Syvannarath V, Lamrani L. et al. Single platelets seal neutrophil-induced vascular breaches via GPVI during immune-complex-mediated inflammation in mice. Blood 2015; 126: 1017-1026
    CrossrefPubMedSearch in Google Scholar
  • 11 De Meyer SF, Savchenko AS, Haas MS. et al. Protective anti-inflammatory effect of ADAMTS13 on myocardial ischemia/reperfusion injury in mice. Blood 2012; 120: 5217-5223
    CrossrefPubMedSearch in Google Scholar
  • 12 Kraft P, Drechsler C, Gunreben I. et al. Von Willebrand factor regulation in patients with acute and chronic cerebrovascular disease: a pilot, case-control study. PLoS One 2014; 9: e99851
    CrossrefPubMedSearch in Google Scholar
  • 13 Denorme F, Kraft P, Pareyn I. et al. Reduced ADAMTS13 levels in patients with acute and chronic cerebrovascular disease. PLoS One 2017; 12: e0179258
    CrossrefPubMedSearch in Google Scholar
  • 14 Wieberdink RG, van Schie MC, Koudstaal PJ. et al. High von Willebrand factor levels increase the risk of stroke: the Rotterdam study. Stroke 2010; 41: 2151-2156
    CrossrefPubMedSearch in Google Scholar
  • 15 Lip GY, Lane D, Van Walraven C. et al. Additive role of plasma von Willebrand factor levels to clinical factors for risk stratification of patients with atrial fibrillation. Stroke 2006; 37: 2294-2300
    CrossrefPubMedSearch in Google Scholar
  • 16 Sanders YV, Eikenboom J, de Wee EM. et al. Reduced prevalence of arterial thrombosis in von Willebrand disease. J Thromb Haemost 2013; 11: 845-854
    CrossrefPubMedSearch in Google Scholar
  • 17 Baker RI, Eikelboom J, Lofthouse E. et al. Platelet glycoprotein Ibalpha Kozak polymorphism is associated with an increased risk of ischemic stroke. Blood 2001; 98: 36-40
    CrossrefPubMedSearch in Google Scholar
  • 18 Hanson E, Jood K, Nilsson S. et al. Association between genetic variation at the ADAMTS13 locus and ischemic stroke. J Thromb Haemost 2009; 7: 2147-2148
    CrossrefPubMedSearch in Google Scholar
  • 19 Wagner S, Kalb P, Lukosava M. et al. Activation of the tissue kallikrein-kinin system in stroke. J Neurol Sci 2002; 202: 75-76
    CrossrefPubMedSearch in Google Scholar
  • 20 Müller F, Mutch NJ, Schenk WA. et al. Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo. Cell 2009; 139: 1143-1156
    CrossrefPubMedSearch in Google Scholar
  • 21 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: 513-518
    CrossrefPubMedSearch in Google Scholar
  • 22 Pham M, Kleinschnitz C, Helluy X. et al. Enhanced cortical reperfusion protects coagulation factor XII-deficient mice from ischemic stroke as revealed by high-field MRI. Neuroimage 2010; 49: 2907-2914
    CrossrefPubMedSearch in Google Scholar
  • 23 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: 1510-1517
    CrossrefPubMedSearch in Google Scholar
  • 24 Krupka J, May F, Weimer T. et al. The coagulation factor XIIa inhibitor rHA-Infestin-4 improves outcome after cerebral ischemia/reperfusion injury in rats. PLoS One 2016; 11: e0146783
    CrossrefPubMedSearch in Google Scholar
  • 25 Choudhri TF, Hoh BL, Prestigiacomo CJ. et al. Targeted inhibition of intrinsic coagulation limits cerebral injury in stroke without increasing intracerebral hemorrhage. J Exp Med 1999; 190: 91-99
    CrossrefPubMedSearch in Google Scholar
  • 26 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
    CrossrefPubMedSearch in Google Scholar
  • 27 Göb E, Reymann S, Langhauser F. et al. Blocking of plasma kallikrein ameliorates stroke by reducing thromboinflammation. Ann Neurol 2015; 77: 784-803
    CrossrefPubMedSearch in Google Scholar
  • 28 Simão F, Ustunkaya T, Clermont AC. et al. Plasma kallikrein mediates brain hemorrhage and edema caused by tissue plasminogen activator therapy in mice after stroke. Blood 2017; 129: 2280-2290
    CrossrefPubMedSearch in Google Scholar
  • 29 Langhauser F, Göb E, Kraft P. et al. Kininogen deficiency protects from ischemic neurodegeneration in mice by reducing thrombosis, blood-brain barrier damage, and inflammation. Blood 2012; 120: 4082-4092
    CrossrefPubMedSearch in Google Scholar
  • 30 Siegerink B, Rosendaal FR, Algra A. High-molecular-weight kininogen and the risk of a myocardial infarction and ischemic stroke in young women: the RATIO case-control study. J Thromb Haemost 2012; 10: 2409-2412
    CrossrefPubMedSearch in Google Scholar
  • 31 Leeb-Lundberg LM, Marceau F, Müller-Esterl W. et al. International union of pharmacology. XLV. Classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences. Pharmacol Rev 2005; 57: 27-77
    CrossrefPubMedSearch in Google Scholar
  • 32 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: 285-293
    CrossrefPubMedSearch in Google Scholar
  • 33 Sang H, Liu L, Wang L. et al. Opposite roles of bradykinin B1 and B2 receptors during cerebral ischaemia-reperfusion injury in experimental diabetic rats. Eur J Neurosci 2016; 43: 53-65
    CrossrefPubMedSearch in Google Scholar
  • 34 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: 2457-2467
    CrossrefPubMedSearch in Google Scholar
  • 35 Chen X, Arumugam TV, Cheng YL. et al. Combination therapy with low-dose IVIG and a C1-esterase inhibitor ameliorates brain damage and functional deficits in experimental ischemic stroke. Neuromolecular Med 2018; 20: 63-72
    CrossrefPubMedSearch in Google Scholar
  • 36 Gelderblom M, Leypoldt F, Steinbach K. et al. Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke 2009; 40: 1849-1857
    CrossrefPubMedSearch in Google Scholar
  • 37 Jickling GC, Liu D, Ander BP. et al. Targeting neutrophils in ischemic stroke: translational insights from experimental studies. J Cereb Blood Flow Metab 2015; 35: 888-901
    PubMedSearch in Google Scholar
  • 38 del Zoppo GJ, Mabuchi T. Cerebral microvessel responses to focal ischemia. J Cereb Blood Flow Metab 2003; 23: 879-894
    PubMedSearch in Google Scholar
  • 39 Darbousset R, Thomas GM, Mezouar S. et al. Tissue factor-positive neutrophils bind to injured endothelial wall and initiate thrombus formation. Blood 2012; 120: 2133-2143
    CrossrefPubMedSearch in Google Scholar
  • 40 von Brühl ML, Stark K, Steinhart A. et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 2012; 209: 819-835
    CrossrefPubMedSearch in Google Scholar
  • 41 Massberg S, Grahl L, von Bruehl ML. et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med 2010; 16: 887-896
    CrossrefPubMedSearch in Google Scholar
  • 42 Sreeramkumar V, Adrover JM, Ballesteros I. et al. Neutrophils scan for activated platelets to initiate inflammation. Science 2014; 346: 1234-1238
    CrossrefPubMedSearch in Google Scholar
  • 43 Yilmaz G, Arumugam TV, Stokes KY. et al. Role of T lymphocytes and interferon-gamma in ischemic stroke. Circulation 2006; 113: 2105-2112
    CrossrefPubMedSearch in Google Scholar
  • 44 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: 3835-3542
    CrossrefPubMedSearch in Google Scholar
  • 45 Schuhmann MK, Langhauser F, Kraft P. et al. B cells do not have a major pathophysiologic role in acute ischemic stroke in mice. J Neuroinflammation 2017; 14: 112
    CrossrefPubMedSearch in Google Scholar
  • 46 Shichita T, Sugiyama Y, Ooboshi H. et al. Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury. Nat Med 2009; 15: 946-950
    CrossrefPubMedSearch in Google Scholar
  • 47 Kleinschnitz C, Kraft P, Dreykluft A. 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
    CrossrefPubMedSearch in Google Scholar
  • 48 Liesz A, Suri-Payer E, Veltkamp C. et al. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med 2009; 15: 192-199
    CrossrefPubMedSearch in Google Scholar
  • 49 Schuhmann MK, Kraft P, Stoll G. et al. CD28 superagonist-mediated boost of regulatory T cells increases thrombo-inflammation and ischemic neurodegeneration during the acute phase of experimental stroke. J Cereb Blood Flow Metab 2015; 35: 6-10
    PubMedSearch in Google Scholar
  • 50 Kraft P, Göb E, Schuhmann MK. et al. FTY720 ameliorates acute ischemic stroke in mice by reducing thrombo-inflammation but not by direct neuroprotection. Stroke 2013; 44: 3202-3210
    CrossrefPubMedSearch in Google Scholar
  • 51 Hasegawa Y, Suzuki H, Sozen T. et al. Activation of sphingosine 1-phosphate receptor-1 by FTY720 is neuroprotective after ischemic stroke in rats. Stroke 2010; 41: 368-374
    CrossrefPubMedSearch in Google Scholar
  • 52 O'Collins VE, Macleod MR, Donnan GA. et al. 1,026 experimental treatments in acute stroke. Ann Neurol 2006; 59: 467-477
    CrossrefPubMedSearch in Google Scholar
  • 53 Lees KR, Zivin JA, Ashwood T. et al. NXY-059 for acute ischemic stroke. N Engl J Med 2006; 354: 588-600
    CrossrefPubMedSearch in Google Scholar
  • 54 Shuaib A, Lees KR, Lyden P. et al. NXY-059 for the treatment of acute ischemic stroke. N Engl J Med 2007; 357: 562-571
    CrossrefPubMedSearch in Google Scholar
  • 55 Chronos NA, Wilson DJ, Janes SL. et al. Aspirin does not affect the flow cytometric detection of fibrinogen binding to, or release of alpha-granules or lysosomes from, human platelets. Clin Sci (Lond) 1994; 87: 575-580
    CrossrefPubMedSearch in Google Scholar
  • 56 Li N, Hu H, Hjemdahl P. Aspirin treatment does not attenuate platelet or leukocyte activation as monitored by whole blood flow cytometry. Thromb Res 2003; 111: 165-170
    CrossrefPubMedSearch in Google Scholar
  • 57 Chen YG, Xu F. et al. Effect of aspirin plus clopidogrel on inflammatory markers in patients with non-ST-segment elevation acute coronary syndrome. Chin Med J (Engl) 2006; 119: 32-36
    PubMedSearch in Google Scholar
  • 58 Salanova B, Choi M, Rolle S. et al. 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
    CrossrefPubMedSearch in Google Scholar
  • 59 Ciccone A, Motto C, Abraha I. et al. Glycoprotein IIb-IIIa inhibitors for acute ischaemic stroke. Cochrane Database Syst Rev 2014; 3: CD005208
    PubMedSearch in Google Scholar
  • 60 Jilma-Stohlawetz P, Gorczyca ME, Jilma B. et al. Inhibition of von Willebrand factor by ARC1779 in patients with acute thrombotic thrombocytopenic purpura. Thromb Haemost 2011; 105: 545-552
    Thieme ConnectPubMedSearch in Google Scholar
  • 61 Peyvandi F, Scully M, Kremer Hovinga JA. et al. Caplacizumab for acquired thrombotic thrombocytopenic purpura. N Engl J Med 2016; 374: 511-522
    CrossrefPubMedSearch in Google Scholar
  • 62 Markus HS, McCollum C, Imray C. et al. The von Willebrand inhibitor ARC1779 reduces cerebral embolization after carotid endarterectomy: a randomized trial. Stroke 2011; 42: 2149-2153
    CrossrefPubMedSearch in Google Scholar
  • 63 Langhauser F, Kraft P, Göb E. et al. Blocking of α4 integrin does not protect from acute ischemic stroke in mice. Stroke 2014; 45: 1799-1806
    CrossrefPubMedSearch in Google Scholar
  • 64 Elkins J, Veltkamp R, Montaner J. et al. Safety and efficacy of natalizumab in patients with acute ischaemic stroke (ACTION): a randomised, placebo-controlled, double-blind phase 2 trial. Lancet Neurol 2017; 16: 217-226
    CrossrefPubMedSearch in Google Scholar
  • 65 Fu Y, Zhang N, Ren L. et al. Impact of an immune modulator fingolimod on acute ischemic stroke. Proc Natl Acad Sci USA 2014; 111: 18315-18320
    CrossrefPubMedSearch in Google Scholar
  • 66 Zhu Z, Fu Y, Tian D. et al. Combination of the immune modulator fingolimod with alteplase in acute ischemic stroke: a pilot trial. Circulation 2015; 132: 1104-1112
    CrossrefPubMedSearch in Google Scholar
  • 67 Zhang S, Zhou Y, Zhang R. et al. Rationale and design of combination of an immune modulator Fingolimod with Alteplase bridging with Mechanical Thrombectomy in Acute Ischemic Stroke (FAMTAIS) trial. Int J Stroke 2017; 12: 906-909
    CrossrefPubMedSearch in Google Scholar
  • 68 Prass K, Meisel C, Höflich C. et al. Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1-like immunostimulation. J Exp Med 2003; 198: 725-736
    CrossrefPubMedSearch in Google Scholar
  • 69 Lampl Y, Boaz M, Gilad R. et al. Minocycline treatment in acute stroke: an open-label, evaluator-blinded study. Neurology 2007; 69: 1404-1410
    CrossrefPubMedSearch in Google Scholar
  • 70 Emsley HC, Smith CJ, Georgiou RF. et al. A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients. J Neurol Neurosurg Psychiatry 2005; 76: 1366-1372
    CrossrefPubMedSearch in Google Scholar
  • 71 Enlimomab Acute Stroke Trial I. Use of anti-ICAM-1 therapy in ischemic stroke: results of the Enlimomab Acute Stroke Trial. Neurology 2001; 57: 1428-1434
    CrossrefPubMedSearch in Google Scholar
  • 72 Smith CJ, Denes A, Tyrrell PJ. et al. Phase II anti-inflammatory and immune-modulating drugs for acute ischaemic stroke. Exp Opin Invest Drugs 2015; 24: 623-643
    CrossrefPubMedSearch in Google Scholar
  • 73 del Zoppo GJ. Acute anti-inflammatory approaches to ischemic stroke. Ann N Y Acad Sci 2010; 1207: 143-148
    CrossrefPubMedSearch in Google Scholar
  • 74 Veltkamp R, Gill D. Clinical trials of immunomodulation in ischemic stroke. Neurotherapeutics 2016; 13: 791-800
    CrossrefPubMedSearch in Google Scholar