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Acetylsalicylsäure im Kardiovaskulären System pp 36–61Cite as

Grundlagen der antithrombotischen Wirkung von Acetylsalicylsäure

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Zusammenfassung

Grundlage der antithrombotischen Wirkung von Acetylsalicylsäure ist die Hemmung der Thrombozytenfunktion. Diese beruht auf einer irreversiblen Hemmung der Thrombozyten-Cyclooxygenase nach Acetylierung einer funktionell wichtigen Aminosäure im Cyclooxygenasemolekül. Acetylsalicylsäure ist ein ca. 150-fach stärker wirksamer Inhibitor der (konstitutiven) Isoform der Thrombozyten-Cyclooxygenase (COX-1) als der (induzierbaren) Isoform (COX-2), die u.a. in Gefäßwandzellen unter Einfluß von Zytokinen und Wachstumsfaktoren exprimiert wird. Dies erklärt die unterschiedlichen Dosierung von Acetylsalicylsäure als Antithrombotikum bzw. Antiphlogistikum. Klinisch relevante prostaglandinunabhängige Mechanismen der plättchenfunktionshemmenden Wirkungen von Acetylsalicylsäure sind nicht bekannt.

Die Antiplättchenwirkungen von Acetylsalicylsäure beinhalten ausschließlich eine Hemmung der thrombo-zytären Thromboxansynthese nach Inhibition der COX-1. Andere Mechanismen der Plättchenaktivierung werden nicht beeinflußt. Daraus resultiert eine Resistenz gegenüber der Acetylsalicylsäure-vermittelten Hemmung der Thrombozytenfunktion bei allen Aktivierungsvorgängen, die nicht über die COX-1 verlaufen. Hierzu gehört die Aktivierung durch Scherstreß, ADP aber wahrscheinlich auch die Thromboxansynthese aus Vorstufen, die von der induzierbaren COX-2 der Gefäßwand stammen. Umgekehrt ist auch ein „sparing“ der endothelialen Prostacyclinsynthese durch low-dose Acetylsalicylsäure unter klinischen Bedingungen einer atherosklerotischen Gefäßwandschädigung nicht zu erwarten: Hemmung der COX-1 durch Acetylsalicylsäure hemmt auch die Vorstufenbereitstellung für die vaskuläre Prostacyclinsynthese für adhärente Thrombozyten.

Acetylsalicylsäure ist der „golden standard“ der Thrombozytenfunktionshemmer zur Prävention arterieller Thrombosen. Andere Wirkprinzipien sind allerdings denkbar und könnten als mögliche Alternativen zu Acetylsalicylsäure angesehen werden. Hierzu gehören GP IIb/IIIa-Antagonisten bei schweren akuten Plättchensyndromen und Thienopyridine bei ADP- oder scherstreßinduzierter Thrombozytenaktivierung. Auch stellt sich erneut die Frage nach klinischen Bedeutung von selektiven Thromboxaninhibitoren, die unabhängig vom Cy-clooxygenasetyp die Thromboxansynthese hemmen bzw.- Wirkung blockieren.

Summary

The antithrombotic action of acetylsalicylic acid is due to inhibition of platelet function. This is caused by an irreversible inhibition of the platelet cyclooxygenase subsequent to acetylation of a functionally important amino acid in the cyclooxygenase enzyme. Acetylsalicylic acid is an approximately 150-times more potent inhibitor of the (constitutive) isoform of the platelet enzyme (COX-1) as compared to the (inducible) isoform (COX-2) which is expressed in vascular cells by cytokines and growth factors. This explains the different dosage requirements of acetylsalicylic acid as antithrombotic and antiinflammtory drug (COX-2), respectively. There are no known prostaglandin-independent mechanisms for the antithrombotic action of acetylsalicylic acid in clinical use.

The antiplatelet effects of acetylsalicylic acid are exclusively due to inhibition of platelet-dependent thromboxane formation via inhibition of COX-1. Other pathways of platelet activation remain unchanged. This eventually results in a resistance against inhibition of platelet function by acetylsalicylic acid if platelets are stimulated by COX-1-independent factors. This involves activation by shear-stress, ADP but possibly also activation by thromboxane A2 if the precursors are provided via COX-2-regulated pathways. On the other hand, there is no „sparing“ of endothelial prostacyclin synthesis in clinical conditions of atherosclerotic endothelial injury. In this case, inhibition of COX-1 by acetylsalicylic acid will also reduce the amount of precursors for vascular pro-stacyclinsynthese, provided for example from adhering platelets.

Acetylsalicylic acid is the „golden standard“ antiplatelet agent to prevent arterial thromboses. However, a number of pharmacological alternatives exists and might compete with acetylsalicylic acid in certain indications, for example GPIIb/IIIa antagonists in severe acute platelet syndroms and thienopyridines in case of ADP-induced platelet activation and/or platelet activation by shear-stress. Finally, the clinical use of thromboxane inhibitors might be revisited: These compounds block thromboxane synthesis and/or -action independent of the source of the cyclooxvgenase.

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Authors and Affiliations

  1. Institut für Pharmakologie, Heinrich-Heine-Universität Düsseldorf, Moorenstr. 5, D-40225, Düsseldorf, Germany

    K. Schrör

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  1. Institutes für Pharmakologie, Heinrich-Heine-Universität Düsseldorf, Universitätsstr. 1, D-40225, Düsseldorf, Deutschland

    K. Schrör (Direktor) (Direktor)

  2. International Institute of Thrombosis and Vascular Diseases, Ferdinand-Schrey-Weg 6, D-60598, Frankfurt am Main, Deutschland

    H. K. Breddin

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Schrör, K. (1996). Grundlagen der antithrombotischen Wirkung von Acetylsalicylsäure. In: Schrör, K., Breddin, H.K. (eds) Acetylsalicylsäure im Kardiovaskulären System. Birkhäuser Basel. https://doi.org/10.1007/978-3-0348-7574-5_3

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  • DOI: https://doi.org/10.1007/978-3-0348-7574-5_3

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