Oral thrombin inhibitor aggravates platelet adhesion and aggregation during arterial thrombosis.

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.

• Authors: Tobias Petzold, Manuela Thienel, Ildiko Konrad, Irene Schubert, Ron Regenauer, Boj Hoppe, Michael Lorenz, Annekathrin Eckart, Sue Chandraratne, Carsten Lennerz, Christof Kolb, Daniel Braun, Janina Jamasbi, Richard Brandl, Siegmund Braun, Wolfgang Siess, Christian Schulz, Steffen Massberg
• Journal: Science translational medicine (Sci Transl Med) Vol. 8 Issue 367 Pg. 367ra168 (11 30 2016) ISSN: 1946-6242 [Electronic] United States
• PMID: 27903864 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016, American Association for the Advancement of Science.

Chemical References

• Anticoagulants
• Fibrinolytic Agents
• Platelet Aggregation Inhibitors
• Vitamin K
• Thrombin
• Aspirin

Topics

• Acute Coronary Syndrome (pathology)
• Administration, Oral
• Animals
• Anticoagulants (pharmacology)
• Arteries (pathology)
• Aspirin (pharmacology)
• Atherosclerosis (pathology)
• Binding Sites
• Blood Platelets (drug effects)
• Fibrinolytic Agents (pharmacology)
• Humans
• Mice
• Platelet Adhesiveness (drug effects)
• Platelet Aggregation (drug effects)
• Platelet Aggregation Inhibitors (pharmacology)
• Randomized Controlled Trials as Topic
• Thrombin (antagonists & inhibitors)
• Thrombosis (pathology)
• Vitamin K (antagonists & inhibitors)