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Akuter ischämischer Schlaganfall

Neue Ansätze in der Antithrombosetherapie

Acute ischemic stroke

New approaches to antithrombotic treatment

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Zusammenfassung

Die derzeit einzige empfohlene medikamentöse Akuttherapie des ischämischen Schlaganfalls ist die Thrombolyse innerhalb des 4,5- (bis 6-)Stunden-Fensters. In der (frühen) Sekundärprophylaxe kommen Thrombozytenaggregationshemmer und, bei kardialer Emboliequelle, Antikoagulanzien zum Einsatz. Die genannten Substanzen sind jedoch entweder nur moderat wirksam (Thrombozytenaggregationshemmer) oder gehen mit einem signifikanten Blutungsrisiko einher (rt-PA, Antikoagulanzien). Obwohl der überwiegende Teil der Schlaganfälle durch lokale oder embolische Gefäßverschlüsse hervorgerufen wird, ist über die Rolle von Blutplättchen bei der akuten Schlaganfallentwicklung im Hirnkreislauf selbst bisher erstaunlich wenig bekannt. Die Entwicklung transgener Mauslinien ermöglichte es in den letzten Jahren, elementare Schritte der Thrombusbildung nach zerebraler Ischämie auf Ebene der Blutplättchen und der plasmatischen Blutgerinnung im Schlaganfallmodell zu analysieren. Dabei fand man, dass eine Verhinderung der frühen Adhäsion von Blutplättchen an die Gefäßwand über die Ausschaltung der Blutplättchenoberflächenrezeptoren GPIbα und GPVI dramatische Effekte auf die Schlaganfallgröße und das funktionelle Defizit hat, ohne dass dadurch die Blutungsgefahr ansteigt. Darüber hinaus konnte entgegen der vorherrschenden Lehrmeinung gezeigt werden, dass die Aktivierung des intrinsischen Gerinnungssystems über den Blutgerinnungsfaktor XIIa (FXIIa) entscheidend an der Thrombusbildung beim Schlaganfall beteiligt ist. Auf Grundlage dieser Beobachtungen wurden spezifische GPIbα- und FXIIa-Inhibitoren entwickelt, die im Experiment vor Schlaganfällen schützen, aber nicht mit den gefürchteten Blutungskomplikationen einhergehen. Diese Substanzen bilden die Basis für das neue Konzept einer „blutungsrisikofreien Antithrombose“ beim ischämischen Schlaganfall und anderen thrombembolischen Erkrankungen, welches derzeit die präklinische Entwicklung durchläuft.

Abstract

The only recommended therapy in the acute phase of ischemic stroke is thrombolysis within 4.5–(6) h after symptom onset. For secondary stroke prevention platelet inhibitors or, in cases of cardiac embolism, anticoagulants are used. However, these substances bear significant limitations: either they show only moderate efficacy (platelet inhibitors), or they are associated with a considerable bleeding risk (rt-PA, anticoagulants). Although the majority of strokes are caused by embolic or thrombotic vessel occlusion, strikingly little is known about the pathophysiological role of platelets and their local function in the brain vasculature. The recent development of novel transgenic mouse lines paved the way for the in-depth analysis of the different molecular steps of thrombus formation involving platelets and the plasma coagulation cascade in models of acute ischemic stroke. It was demonstrated that prevention of early platelet adhesion to the damaged vessel wall by blocking the platelet surface receptors GPIbα or GPVI dramatically protects against experimental stroke without increasing the frequency of intracranial hemorrhage. Moreover, the critical involvement of the blood coagulation factor XII (FXII)-driven intrinsic coagulation cascade in thrombus formation during the course of ischemic brain damage could be unraveled thereby disproving established concepts of hemostasis. Based on these findings novel pharmacological blockers of GPIbα and FXIIa were designed that likewise proved to be safe and effective in animal stroke studies. Those compounds now lay the groundwork for a novel and intriguing concept in ischemic stroke and other thromboembolic diseases: antithrombosis devoid of any bleeding complications. Further preclinical testing is currently ongoing.

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Danksagung

Einige der hier referierten Arbeiten wurden durch die Deutsche Forschungsgemeinschaft (DFG), SFB 688 (TP A13 und B1) unterstützt.

Interessenkonflikt

Der korrespondierende Autor weist auf folgende Beziehungen hin: BN, GS und CK halten Patente zur Therapie thrombembolischer Erkrankungen mit anti-GPIb und anti-GPVI sowie FXIIa Inhibitoren. BN, GS und CK erhalten Forschungsunterstützung von der CSL Behring GmbH, Marburg. PK gibt keine Interessenkonflikte an.

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  1. Neurologische Klinik und Poliklinik, Universitätsklinik Würzburg, Josef-Schneider Str. 11, 97080, Würzburg, Deutschland

    P. Kraft, G. Stoll &  C. Kleinschnitz

  2. DFG Forschungszentrum für Experimentelle Biomedizin und Rudolf-Virchow-Zentrum, Universität Würzburg, Würzburg, Deutschland

    B. Nieswandt

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  1. P. Kraft
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Kraft, P., Nieswandt, B., Stoll, G. et al. Akuter ischämischer Schlaganfall. Nervenarzt 83, 435–449 (2012). https://doi.org/10.1007/s00115-011-3368-6

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