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Direkte orale Antikoagulanzien und akuter Schlaganfall

Einblicke in translationale Forschungsarbeiten

Direct oral anticoagulants and acute stroke

Insights into translational research studies

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Zusammenfassung

In den letzten Jahren wurden zahlreiche translationale Forschungsarbeiten über die Hirnblutung und den Hirninfarkt veröffentlicht, die durch eine besondere Nähe zu konkreten klinischen Fragestellungen gekennzeichnet sind. Tierexperimentelle Studien gewährten hierbei Einblicke in pathophysiologische Vorgänge und Therapieeffekte, die bislang in klinischen Studien nur unzureichend untersucht wurden. Hierzu zählen u. a. die Wirksamkeit einer raschen Normalisierung der Gerinnungshemmung bei der antikoagulanzienassoziierten Hirnblutung und die Sicherheit einer Thrombolysetherapie bei Hirninfarkten, die unter Einnahme von Antikoagulanzien auftreten. Im Zuge der Zulassung der direkten oralen Antikoagulanzien kommt diesen Fragestellungen eine besondere Aktualität zu. Selbstredend können Ergebnisse aus der experimentellen Schlaganfallforschung nicht unmittelbar in die Klinik übertragen werden. Dennoch helfen sie, grundlegende Vorgänge und Mechanismen zu verstehen und Behandlungsansätze konzeptionell zu überprüfen. Diese Übersichtsarbeit fasst die im Hinblick auf klinische Fragestellungen relevanten Ergebnisse dieses Forschungsgebietes zusammen.

Abstract

In recent years a considerable number of translational research studies on intracerebral hemorrhage and ischemic stroke have been published, which are characterized by a particular proximity to practical clinical questions. Animal research has provided insights into the pathophysiological processes and therapy effects, which have so far only been insufficiently investigated in clinical studies. This includes the effectiveness of a rapid reversal of anticoagulation in cases of anticoagulation-associated intracerebral hemorrhage and the safety of thrombolytic treatment in ischemic stroke occurring during treatment with anticoagulants. With the approval of the direct oral anticoagulants these problems have become of particular contemporary relevance. Of course, results from experimental translational studies on stroke cannot be directly translated into clinical routine. Nevertheless, these investigations help to understand the underlying processes and mechanisms and provide proof of concept data for new treatment strategies. This review summarizes the most relevant results in this field of research with a particular focus on practical clinical questions.

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Literatur

  1. Aguilar MI, Hart RG, Kase CS et al (2007) Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion. Mayo Clin Proc 82:82–92

    Article  CAS  PubMed  Google Scholar 

  2. Alvarez-Sabin J, Maisterra O, Santamarina E et al (2013) Factors influencing haemorrhagic transformation in ischaemic stroke. Lancet Neurol 12:689–705

    Article  PubMed  Google Scholar 

  3. Berrouschot J, Stoll A, Hogh T et al (2016) Intravenous thrombolysis with recombinant tissue-type plasminogen activator in a stroke patient receiving dabigatran anticoagulant after antagonization with idarucizumab. Stroke 47:1936–1938

    Article  CAS  PubMed  Google Scholar 

  4. Bohmann F, Mirceska A, Pfeilschifter J et al (2012) No influence of dabigatran anticoagulation on hemorrhagic transformation in an experimental model of ischemic stroke. PLOS ONE 7:e40804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cheng T, Petraglia AL, Li Z et al (2006) Activated protein C inhibits tissue plasminogen activator-induced brain hemorrhage. Nat Med 12:1278–1285

    Article  CAS  PubMed  Google Scholar 

  6. Demaerschalk BM, Kleindorfer DO, Adeoye OM et al (2016) Scientific rationale for the inclusion and exclusion criteria for intravenous alteplase in acute Ischemic stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 47:581–641

    Article  PubMed  Google Scholar 

  7. Diener HC, Bernstein R, Butcher K et al (2016) Thrombolysis and thrombectomy in patients treated with dabigatran with acute ischemic stroke: expert opinion. Int J Stroke 30. doi:10.1177/1747493016669849

    Google Scholar 

  8. Diener HC, Foerch C, Riess H et al (2013) Treatment of acute ischaemic stroke with thrombolysis or thrombectomy in patients receiving anti-thrombotic treatment. Lancet Neurol 12:677–688

    Article  CAS  PubMed  Google Scholar 

  9. Dirnagl U (2006) Bench to bedside: the quest for quality in experimental stroke research. J Cereb Blood Flow Metab 26:1465–1478

    Article  PubMed  Google Scholar 

  10. Dittmeier M, Kraft P, Schuhmann MK et al (2016) Pretreatment with rivaroxaban attenuates stroke severity in rats by a dual antithrombotic and anti-inflammatory mechanism. Thromb Haemost 115:835–843

    Article  PubMed  Google Scholar 

  11. Dittmeier M, Wassmuth K, Schuhmann MK et al (2016) Dabigatran etexilate reduces thrombin-induced inflammation and thrombus formation in experimental ischemic stroke. Curr Neurovasc Res 13:199–206

    Article  CAS  PubMed  Google Scholar 

  12. Flaherty ML, Adeoye O, Sekar P et al (2009) The challenge of designing a treatment trial for warfarin-associated intracerebral hemorrhage. Stroke 40:1738–1742

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Foerch C, Arai K, Jin G et al (2008) Experimental model of warfarin-associated intracerebral hemorrhage. Stroke 39:3397–3404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Foerch C, Arai K, Van Cott EM et al (2009) Rapid reversal of anticoagulation reduces hemorrhage volume in a mouse model of warfarin-associated intracerebral hemorrhage. J Cereb Blood Flow Metab 29:1015–1021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gliem M, Hermsen D, Van Rooijen N et al (2012) Secondary intracerebral hemorrhage due to early initiation of oral anticoagulation after ischemic stroke: an experimental study in mice. Stroke 43:3352–3357

    Article  CAS  PubMed  Google Scholar 

  16. Hicks T, Stewart F, Eisinga A (2016) NOACs versus warfarin for stroke prevention in patients with AF: a systematic review and meta-analysis. Open Heart 3:e000279

    Article  PubMed  PubMed Central  Google Scholar 

  17. Hogan KA, Weiler H, Lord ST (2002) Mouse models in coagulation. Thromb Haemost 87:563–574

    CAS  PubMed  Google Scholar 

  18. Illanes S, Zhou W, Heiland S et al (2010) Kinetics of hematoma expansion in murine warfarin-associated intracerebral hemorrhage. Brain Res 1320:135–142

    Article  CAS  PubMed  Google Scholar 

  19. Illanes S, Zhou W, Schwarting S et al (2011) Comparative effectiveness of hemostatic therapy in experimental warfarin-associated intracerebral hemorrhage. Stroke 42:191–195

    Article  CAS  PubMed  Google Scholar 

  20. Jalini S, Jin AY, Taylor SW (2012) Reversal of warfarin anticoagulation with prothrombin complex concentrate before thrombolysis for acute stroke. Cerebrovasc Dis 33:597

    Article  PubMed  Google Scholar 

  21. Kafke W, Kraft P (2016) Intravenous thrombolysis after reversal of dabigatran by idarucizumab: a case report. Case Rep Neurol 8:140–144

    Article  PubMed  PubMed Central  Google Scholar 

  22. Kilkenny C, Browne WJ, Cuthill IC et al (2010) Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLOS Biol 8:e1000412

    Article  PubMed  PubMed Central  Google Scholar 

  23. Kono S, Deguchi K, Omote Y et al (2014) Reducing hemorrhagic complication by dabigatran via neurovascular protection after recanalization with tissue plasminogen activator in ischemic stroke of rat. J Neurosci Res 92:46–53

    Article  CAS  PubMed  Google Scholar 

  24. Kono S, Yamashita T, Deguchi K et al (2014) Rivaroxaban and apixaban reduce hemorrhagic transformation after thrombolysis by protection of neurovascular unit in rat. Stroke 45:2404–2410

    Article  CAS  PubMed  Google Scholar 

  25. Lauer A, Cianchetti FA, Van Cott EM et al (2011) Anticoagulation with the oral direct thrombin inhibitor dabigatran does not enlarge hematoma volume in experimental intracerebral hemorrhage. Circulation 124:1654–1662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lauer A, Pfeilschifter W, Schaffer CB et al (2013) Intracerebral haemorrhage associated with antithrombotic treatment: translational insights from experimental studies. Lancet Neurol 12:394–405

    Article  PubMed  PubMed Central  Google Scholar 

  27. Liu F, Mccullough LD (2014) The middle cerebral artery occlusion model of transient focal cerebral ischemia. Methods Mol Biol 1135:81–93

    Article  CAS  PubMed  Google Scholar 

  28. Maclellan CL, Silasi G, Poon CC et al (2008) Intracerebral hemorrhage models in rat: comparing collagenase to blood infusion. J Cereb Blood Flow Metab 28:516–525

    Article  CAS  PubMed  Google Scholar 

  29. Marsh EB, Llinas RH, Hillis AE et al (2013) Hemorrhagic transformation in patients with acute ischaemic stroke and an indication for anticoagulation. Eur J Neurol 20:962–967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Na SY, Mracsko E, Van Ryn J et al (2015) Idarucizumab improves outcome in murine brain hemorrhage related to dabigatran. Ann Neurol 78:137–141

    Article  CAS  PubMed  Google Scholar 

  31. O’donnell M, Oczkowski W, Fang J et al (2006) Preadmission antithrombotic treatment and stroke severity in patients with atrial fibrillation and acute ischaemic stroke: an observational study. Lancet Neurol 5:749–754

    Article  PubMed  Google Scholar 

  32. Pfeilschifter W, Bohmann F, Baumgarten P et al (2012) Thrombolysis with recombinant tissue plasminogen activator under dabigatran anticoagulation in experimental stroke. Ann Neurol 71:624–633

    Article  CAS  PubMed  Google Scholar 

  33. Pfeilschifter W, Spitzer D, Czech-Zechmeister B et al (2011) Increased risk of hemorrhagic transformation in ischemic stroke occurring during warfarin anticoagulation: an experimental study in mice. Stroke 42:1116–1121

    Article  CAS  PubMed  Google Scholar 

  34. Pfeilschifter W, Spitzer D, Pfeilschifter J et al (2011) Warfarin anticoagulation exacerbates the risk of hemorrhagic transformation after rt-PA treatment in experimental stroke: therapeutic potential of PCC. PLOS ONE 6:e26087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ploen R, Sun L, Zhou W et al (2014) Rivaroxaban does not increase hemorrhage after thrombolysis in experimental ischemic stroke. J Cereb Blood Flow Metab 34:495–501

    Article  CAS  PubMed  Google Scholar 

  36. Pollack CV Jr., Reilly PA, Eikelboom J et al (2015) Idarucizumab for dabigatran reversal. N Engl J Med 373:511–520

    Article  CAS  PubMed  Google Scholar 

  37. Schlunk F, Schulz E, Lauer A et al (2015) Warfarin pretreatment reduces cell death and mmp-9 activity in experimental intracerebral hemorrhage. Transl Stroke Res 6:133–139

    Article  CAS  PubMed  Google Scholar 

  38. Schlunk F, Van Cott EM, Hayakawa K et al (2012) Recombinant activated coagulation factor VII and prothrombin complex concentrates are equally effective in reducing hematoma volume in experimental warfarin-associated intracerebral hemorrhage. Stroke 43:246–249

    Article  CAS  PubMed  Google Scholar 

  39. Shahjouei S, Tsivgoulis G, Bavarsad Shahripour R et al (2015) Safety of intravenous thrombolysis among stroke patients taking new oral anticoagulants – case series and systematic review of reported cases. J Stroke Cerebrovasc Dis 24:2685–2693

    Article  PubMed  Google Scholar 

  40. Shang J, Yamashita T, Kono S et al (2016) Effects of pretreatment with warfarin or rivaroxaban on neurovascular unit dissociation after tissue plasminogen activator thrombolysis in ischemic rat brain. J Stroke Cerebrovasc Dis 25:1997–2003

    Article  PubMed  Google Scholar 

  41. Shirasaki Y, Morishima Y, Shibano T (2014) Comparison of the effect of edoxaban, a direct factor Xa inhibitor, with a direct thrombin inhibitor, melagatran, and heparin on intracerebral hemorrhage induced by collagenase in rats. Thromb Res 133:622–628

    Article  CAS  PubMed  Google Scholar 

  42. Steiner T, Poli S, Griebe M et al (2016) Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): a randomised trial. Lancet Neurol 15:566–573

    Article  CAS  PubMed  Google Scholar 

  43. Steiner T, Rosand J, Diringer M (2006) Intracerebral hemorrhage associated with oral anticoagulant therapy: current practices and unresolved questions. Stroke 37:256–262

    Article  CAS  PubMed  Google Scholar 

  44. Sun L, Zhou W, Ploen R et al (2013) Anticoagulation with dabigatran does not increase secondary intracerebral haemorrhage after thrombolysis in experimental cerebral ischaemia. Thromb Haemost 110:153–161

    Article  CAS  PubMed  Google Scholar 

  45. Tomita H, Hagii J, Metoki N et al (2015) Severity and functional outcome of patients with cardioembolic stroke occurring during non-vitamin K antagonist oral anticoagulant treatment. J Stroke Cerebrovasc Dis 24:1430–1437

    Article  PubMed  Google Scholar 

  46. Van Ryn JSJ, Fischer D (2016) No influence of dabigatran or its specific reversal agent, idarucizumab, on rTPA-induced thrombolysis of clots in human plasma: an in vitro study. Stroke 47:AWP73

    Article  Google Scholar 

  47. Veltkamp R, Juttler E, Pfefferkorn T et al (2012) Current registry studies of acute ischemic stroke. Nervenarzt 83:1270–1274

    Article  CAS  PubMed  Google Scholar 

  48. Wang X, Tsuji K, Lee SR et al (2004) Mechanisms of hemorrhagic transformation after tissue plasminogen activator reperfusion therapy for ischemic stroke. Stroke 35:2726–2730

    Article  CAS  PubMed  Google Scholar 

  49. Xian Y, Liang L, Smith EE et al (2012) Risks of intracranial hemorrhage among patients with acute ischemic stroke receiving warfarin and treated with intravenous tissue plasminogen activator. JAMA 307:2600–2608

    Article  CAS  PubMed  Google Scholar 

  50. Zhou W, Schwarting S, Illanes S et al (2011) Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke 42:3594–3599

    Article  PubMed  Google Scholar 

  51. Zhou W, Zorn M, Nawroth P et al (2013) Hemostatic therapy in experimental intracerebral hemorrhage associated with rivaroxaban. Stroke 44:771–778

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Klinik für Neurologie, Goethe-Universität, Schleusenweg 2–16, 60528, Frankfurt am Main, Deutschland

    C. Foerch, J. H. Schäfer, W. Pfeilschifter & F. Bohmann

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Correspondence to C. Foerch.

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Interessenkonflikt

C. Foerch erhielt Vortragshonorare und Forschungsmittel zur Durchführung einer translationalen Studie zu Dabigatran bei der traumatischen Hirnschädigung von der Fa. Boehringer Ingelheim. W. Pfeilschifter erhielt Vortragshonorare und Forschungsmittel von der Fa. Boehringer Ingelheim und Vortragshonorare von der Fa. Bayer. J. H. Schäfer und F. Bohmann geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

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Foerch, C., Schäfer, J.H., Pfeilschifter, W. et al. Direkte orale Antikoagulanzien und akuter Schlaganfall . Nervenarzt 88, 642–651 (2017). https://doi.org/10.1007/s00115-017-0282-6

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