medwireNews: The oral thrombin inhibitor (OTI) dabigatran may actually increase thrombus formation, suggest the results of a translational study conducted in human arterial plaque and mouse models of blood clotting.
Study author Tobias Petzold (Klinikum der Universität München, Germany) and colleagues note that this prothrombotic effect “might contribute to the increase” in acute coronary syndromes (ACS) that has been observed in patients receiving OTI treatment.
However, they explain that “OTI treatment shows a clear overall clinical net benefit” when compared with vitamin K antagonist (VKA) therapy, and the overall frequency of ACS with dabigatran is low, with “a number needed to treat of 188 to observe one additional myocardial infarction.”
As reported in Science Translational Medicine, the authors analyzed whole blood from 95 patients with nonvalvular atrial fibrillation or flutter, and performed aggregation experiments under arterial flow conditions.
They found a significant increase in platelet aggregate formation 3 minutes after exposure to von Willebrand factor in blood from patients treated with OTI compared with that from VKA-treated patients or healthy controls, with mean total surface coverage of approximately 190,000 µm2, 160,000 µm2, and 155,000 µm2, respectively.
Similarly, thrombus formation on a human atherosclerotic plaque homogenate – consisting of various matrix proteins that are exposed upon plaque rupture and cause atherothrombosis – was significantly enhanced in blood from patients treated with OTI compared with that from VKA-treated patients and controls (approximate surface coverage: 90,000 vs 60,000 vs 55,000 µm2).
Petzold and colleagues validated their findings in vivo using two mouse models. In a carotid ligation injury model, platelet aggregation formation was significantly higher following treatment with a single dose of OTI versus a single dose of the vehicle control dimethyl sulfoxide (DMSO).
Additionally, the team used a carotid artery wire injury model, in which rapid thrombotic vessel occlusion partially resolves over time, to establish the effect of OTI on thrombus formation at later stages of arterial thrombosis. All vessels were occluded among mice treated with OTI, and blood flow was restored within 30 minutes in only one of nine animals. In comparison, blood flow was restored within 15 minutes in all six mice treated with DMSO, and occlusive thrombus formation did not occur in mice treated with a VKA.
In the in vitro experiments, excess thrombus formation with OTI treatment was abolished in the presence of aspirin, suggesting that “OTI exerts its prothrombotic effects through alterations of platelet function that are sensitive to aspirin,” say the authors. However, concomitant treatment with OTI and aspirin in mice resulted in excessive bleeding.
Although Petzold and colleagues highlight the difficulty in translating the results of in vitro and animal studies into the clinic, they conclude that their study provides evidence for “assessment of the individual coronary artery disease and myocardial infarction risk” before initiation of OTI treatment.
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