title: 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.affiliation: Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Marchioninistraße 15, 81377 Munich, Germany. tobias.petzold@med.uni-muenchen.de.|DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802 Munich, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Petzold
authors.affiliation: Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Marchioninistraße 15, 81377 Munich, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802 Munich, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Thienel
authors.affiliation: Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Marchioninistraße 15, 81377 Munich, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802 Munich, Germany.
authors.forename: Ildiko
authors.initials: I
authors.lastname: Konrad
authors.affiliation: Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Marchioninistraße 15, 81377 Munich, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802 Munich, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: Schubert
authors.affiliation: Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Marchioninistraße 15, 81377 Munich, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802 Munich, Germany.
authors.forename: Ron
authors.initials: R
authors.lastname: Regenauer
authors.affiliation: Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Marchioninistraße 15, 81377 Munich, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802 Munich, Germany.
authors.forename: Boj
authors.initials: B
authors.lastname: Hoppe
authors.affiliation: Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Marchioninistraße 15, 81377 Munich, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802 Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Lorenz
authors.affiliation: Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Marchioninistraße 15, 81377 Munich, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802 Munich, Germany.
authors.forename: Annekathrin
authors.initials: A
authors.lastname: Eckart
authors.affiliation: Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Marchioninistraße 15, 81377 Munich, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802 Munich, Germany.
authors.forename: Sue
authors.initials: S
authors.lastname: Chandraratne
authors.affiliation: DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802 Munich, Germany.|Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Elektrophysiologie, Technische Universität München, Lazarettstraße 36, 80636 Munich, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Lennerz
authors.affiliation: DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802 Munich, Germany.|Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Elektrophysiologie, Technische Universität München, Lazarettstraße 36, 80636 Munich, Germany.
authors.forename: Christof
authors.initials: C
authors.lastname: Kolb
authors.affiliation: Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Marchioninistraße 15, 81377 Munich, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802 Munich, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Braun
authors.affiliation: DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802 Munich, Germany.|Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, Klinikum der Universität München, Pettenkoferstraße 9, 80336 Munich, Germany.
authors.forename: Janina
authors.initials: J
authors.lastname: Jamasbi
authors.affiliation: St. Mary's Square Institute for Vascular Surgery and Phlebology, Rindermarkt 17/III, 80331 Munich, Germany.
authors.forename: Richard
authors.initials: R
authors.lastname: Brandl
authors.affiliation: Deutsches Herzzentrum München, Institut für Laboratoriumsmedizin, Technische Universität München, Lazarettstraße 36, 80636 Munich, Germany.
authors.forename: Siegmund
authors.initials: S
authors.lastname: Braun
authors.affiliation: DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802 Munich, Germany.|Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, Klinikum der Universität München, Pettenkoferstraße 9, 80336 Munich, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Siess
authors.affiliation: Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Marchioninistraße 15, 81377 Munich, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802 Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Schulz
authors.affiliation: Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Marchioninistraße 15, 81377 Munich, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802 Munich, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Massberg
mesh_terms: D054058:Acute Coronary Syndrome / Q000473:pathology; D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001158:Arteries / Q000473:pathology; D001241:Aspirin / Q000494:pharmacology; D050197:Atherosclerosis / Q000473:pathology; D001665:Binding Sites; D001792:Blood Platelets / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006801:Humans; D051379:Mice; D010973:Platelet Adhesiveness / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D016032:Randomized Controlled Trials as Topic; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000473:pathology*; D014812:Vitamin K / Q000037:antagonists & inhibitors
chemical_list: D000925:Anticoagulants; D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D014812:Vitamin K; D013917:Thrombin; D001241:Aspirin