Research ArticleCardiovascular Disease

Oral thrombin inhibitor aggravates platelet adhesion and aggregation during arterial thrombosis

+ See all authors and affiliations

Science Translational Medicine  30 Nov 2016:
Vol. 8, Issue 367, pp. 367ra168
DOI: 10.1126/scitranslmed.aad6712

You are currently viewing the abstract.

View Full Text

The hidden side of an anticoagulant

For patients with atrial fibrillation and other conditions that predispose them to thrombosis, long-term anticoagulation treatment is the norm. Surprisingly, oral thrombin inhibitors, one of the types of anticoagulants used in humans, slightly increased the risk of acute coronary syndromes in clinical studies. To understand this apparent paradox, Petzold et al. compared the effects of treatment with oral thrombin inhibitors, treatment with vitamin K antagonists (another class of anticoagulants), or no treatment at all in patients’ blood and in mouse models of arterial thrombosis, confirming the observations from clinical studies and identifying some of the underlying mechanisms.

Abstract

In patients with atrial fibrillation, oral anticoagulation with oral thrombin inhibitors (OTIs), in contrast to vitamin K antagonists (VKAs), associates with a modest increase in acute coronary syndromes (ACSs). Whether this observation is causatively linked to OTI treatment and, if so, whether OTI action is the result of a lower antithrombotic efficacy of OTI compared to VKA or reflects a yet undefined prothrombotic activity of OTI remain unclear. We analyzed platelet function in patients receiving OTI or dose-adapted VKA under static and flow conditions. In vivo, we studied arterial thrombosis in OTI-, VKA-, and vehicle-treated mice using carotid ligation and wire injury models. Further, we examined thrombus formation on human atherosclerotic plaque homogenates under arterial shear to address the relevance to human pathology. Under static conditions, aggregation in the presence of ristocetin was increased in OTI-treated blood, whereas platelet reactivity and aggregation to other agonists were only marginally affected. Under flow conditions, firm platelet adhesion and thrombus formation on von Willebrand factor, collagen, and human atherosclerotic plaque were increased in the presence of OTI in comparison to VKA. OTI treatment was associated with increased thrombus formation in injured carotid arteries of mice. Inhibition or ablation of GPIbα-thrombin interactions abolished the effect of OTI on thrombus formation, suggesting a mechanistic role of the platelet receptor GPIbα and its thrombin-binding site. The effect of OTI was also abrogated in the presence of aspirin. In summary, OTI treatment has prothrombotic activity that might contribute to the increase in ACS observed clinically in patients.

View Full Text