Assessing the influence of diurnal variations and selective Xa inhibition on whole blood aggregometry

Abstract

A biological rhythm in platelet function is well known. Multiple electrode aggregometry (MEA) is a widely used assay to measure platelet aggregability. Rivaroxaban is a new oral anticoagulant frequently used in an increasing number of indications. In this randomized, crossover trial we investigated whether a biological rhythm exists in MEA measurements and potential effects of rivaroxaban on platelet aggregation. Sixteen healthy volunteers were included in the study and blood samples were obtained at 08:00, 12:00, 16:00 and 20:00 h. Each subject was tested without rivaroxaban intake first and randomly assigned to 3 days of rivaroxaban intake at 08:00 or 3 days of rivaroxaban intake at 20:00 h and vice versa. In MEA measurements, a significant increase in platelet aggregation after addition of ristocetin at 12:00 h compared to other investigated time-points (122 ± 8 AU at 12:00 h vs. 109 ± 9 AU at 08:00 h, 114 ± 10 AU at 16:00 h and 103 ± 8 AU at 20:00 h, p = 0.027) could be detected. There was no biological rhythm detectable using other agonists (ADP, arachidonic acid, thrombin-receptor activating peptide-6). After rivaroxaban intake at 08:00 h an increased ristocetin-induced platelet aggregation was measured in the next morning (126 ± 4 AU (rivaroxaban at 08:00 h) vs. 109 ± 9 AU (no rivaroxaban), 111 ± 6 AU (rivaroxaban at 20:00 h; p = 0.002). No other effects of rivaroxaban on platelet function were found. We detected a biological rhythm in ristocetin-induced platelet aggregation with a peak at 12:00 h (noon). No influence of selective Xa inhibition on platelet aggregation was detected.

Noncanonical Effects of Oral Thrombin and Factor Xa Inhibitors in Platelet Activation and Arterial Thrombosis

“…65 A study by Schoergenhofer et al analyzed diurnal variation in platelet reactivity by MEA following 3 days of intermediate dose (10 mg) rivaroxaban treatment, but did not find any impact on platelet reactivity. 66 Limitations While reviewing the current knowledge we found partially contradicting reports regarding the effects of FIIa and FXa inhibitors on platelet function in the context of atherothrombosis. Although the origin of these discrepancies remained in parts elusive, some aspects have to be considered while interpreting the data.…”

Circadian Regulation of Drug Responses: Toward Sex-Specific and Personalized Chronotherapy

“…More recent trials involving direct oral anticoagulants inhibiting factor X, such as rivaroxaban, demonstrated circadian-related changes in pharmacokinetic and pharmacodynamic end points. Thus, 8:00 AM dosing of rivaroxaban was associated with both nearly halved plasma concentrations at 12:00 PM ( 152) and reduced platelet aggregation in response to the ex vivo platelet activator ristocetin (153) in comparison to its administration at 8:00 PM. These clinical observations are supported by experimental evidence, with factor X activity displaying a significant circadian rhythm in male rats, with a peak at ZT4, in the early rest span (154).…”