Effects of the direct thrombin inhibitor dabigatran etexilate vs warfarin on platelet function in patients with atrial fibrillation

Purpose: The impact of novel anticoagulants on platelet function is largely unknown. We characterized the effects of dabigatran etexilate (DE) compared with warfarin (W). Methods: We evaluated 22 atrial fibrillation (AF) patients treated with DE enrolled in the RELY-ABLE study, 26 AF patients treated with W, and 22 control age- and sex-matched non-anticoagulated non-AF patients. We assessed light transmittance platelet aggregation with 2 and 5 μM ADP, 5 and 10 μM thrombin-activated peptide (TRAP), and 1.5 and 6 ng/mL human γ-thrombin. We quantified platelet membrane thrombin protease-activated receptor (PAR)-1 expression by flow-cytometry. Results: We found no inhibition of ADP-induced aggregation in the DE or W groups vs control. γ-thrombin-induced aggregation (1.5 ng/mL) was significantly reduced by 90% in DE and 18% in W (P<0.001 and P<0.01) vs control, and by 88% in DE vs W (P<0.001). TRAP-induced aggregation (5 μM) was reduced in the W (by 60%, P<0.01) and DE (by 36%, P=NS) groups vs control (Figure, left). PAR-1 expression (mean fluorescence intensity, MFI ratio) was higher in the DE and W groups vs control (Figure, right). ![Figure][1] Conclusions: Both DE and W inhibit γ-thrombin-induced aggregation. W also reduces TRAP-induced aggregation. These findings were unexpected, since W is not known to affect γ-thrombin-induced aggregation, and TRAP-induced aggregation should bypass any indirect effect of W on thrombin generation (and direct effects of DE on thrombin activity). The higher platelet PAR-1 expression in platelets of anticoagulated patients suggests that reduced PAR-1 expression on the platelet surface does not explain these reduced platelet responses, which likely involve post-receptor changes. Such effects may contribute to the differential in vivo antithrombotic profile of DE vs W. [1]: pending:yes