Abstract
Dabigatran is an oral direct thrombin inhibitor, and rivaroxaban, a factor Xa inhibitor. Dabigatran has been implicated in the etiology of acute coronary syndromes and as these occur following inflammatory changes in the endothelium, we investigated the inflammatory potential of these agents in vitro. In order to do so, polymorphonuclear leukocytes (PMNL) were isolated from heparinized venous blood from non-smoking, healthy adults and exposed to dabigatran or rivaroxaban (0.5–10 µM). Generation of reactive oxygen species (ROS), elastase release, cytosolic Ca2+ fluxes, neutrophil extracellular trap (NET) formation and cell viability were measured using chemiluminescence, spectrophotometric and flow cytometric procedures respectively. However, with the exception of modest inhibitory effects on elastase release, neither agent at concentrations of up to 10 µM affected these markers of PMNL activation. Although no pro-inflammatory effects of dabigatran nor any difference between the two test agents were detected in vitro, the existence of a pro-inflammatory mechanism involving the generation of thrombin during dabigatran therapy cannot be fully excluded.
Highlights
Atherosclerosis is an inflammatory condition in which endothelial injury predisposes to endothelial lipid accumulation and plaque formation [1]
Neither of the test agents at the highest concentrations used (5 and 10 μM) affected either the generation of superoxide or myeloperoxidase-derived reactive oxygen species (ROS) by phorbol 12-myristate 13-acetate (PMA)-activated polymorphonuclear leukocyte (PMNL) (Figure 1). No effects on these PMA-activated responses of PMNL were detected at lower concentrations (0.5 and 1 μM) of either test agent, while basal responses were unaffected at all concentrations tested
These agents at higher concentrations, dabigatran (5 and 10 μM) and rivaroxaban (5 μM) did have a modest, albeit statistically significant, inhibitory effect on elastase release from fMLP/cytochalasin B (CB)-activated PMNL; p < 0.016 and p < 0.008 respectively for dabigatran and p < 0.04 for rivaroxaban. (Figure 2). No effects on these fMLP/CB-activated responses of PMNL were evident at lower concentrations (0.5 and 1 μM) of both test agents, while basal responses were unaffected at all concentrations tested
Summary
Atherosclerosis is an inflammatory condition in which endothelial injury predisposes to endothelial lipid accumulation and plaque formation [1]. NOACs have been used successfully in diverse conditions, including venous thromboembolism (both deep vein thrombosis and pulmonary embolism) and stroke prevention in atrial fibrillation, there have been concerns that direct thrombin inhibitors may predispose to, or cause, coronary thrombosis [8]. These concerns originated with the use of the intravenous thrombin inhibitors lepirudin, argatroban, desidurin and bivalirudin with several studies suggesting that bivalirudin is associated with coronary thromboses (number needed to harm (NNH) between 50 and 111) [8]. Boehringer-Ingelheim GmbH, the manufacturers of dabigatran, concluded that the incidence of MI with warfarin (when used to prevent stroke in patients with atrial fibrillation or for acute VTE treatment or prevention) is significantly lower than that observed with the higher dose of dabigatran (OR of 1.4 and 95% CI, 1.1–1.9)
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