Effect of the FXa inhibitors Rivaroxaban and Apixaban on platelet activation in patients with atrial fibrillation

Abstract

Rivaroxaban and Apixaban, increasingly used for stroke prevention in non-valvular atrial fibrillation (AF), might impact platelet reactivity directly or indirectly. By inhibition of Factor Xa (FXa) they preclude not only generation of relevant thrombin amounts but also block signalling of FXa via protease activated receptors. However, weather FXa-inhibition affects platelet haemostasis remains incompletely known. One hundred and twenty-eight patients with AF on chronic anticoagulation with either Rivaroxaban or Apixaban for at least 4 weeks were included in the study. In a time course group (25 on Rivaroxaban, 13 on Apixaban) venous blood samples were taken before NOAC medication intake in the morning as well as 2 and 6 h afterwards. In 90 patients (Rivaroxaban n = 73, Apixaban n = 17) blood samples were drawn during left atrial RFA procedures before as well as 10 and 60 min after the first heparin application (RFA group). Platelet reactivity analyzed by whole blood aggregometry (Multiplate Analyzer, Roche) in response to ADP, Collagen, TRAP and ASPI (arachidonic acid) was not altered by Rivaroxaban or Apixaban neither in the time course nor in the RFA group. Moreover, soluble P-selectin, Thrombospondin, von Willebrand Factor and beta thromboglobulin plasma levels, measured by ELISA, showed no statistically significant changes in both clinical settings for either FXa-inhibitor. The present study fails to demonstrate any significant changes on platelet reactivity in patients with AF under chronic Rivaroxaban or Apixaban medication, neither for trough or peak levels nor in case of a haemostatic activation in vivo as depicted by RFA procedures.

Inhibitory mechanisms of very low–dose rivaroxaban in non–ST-elevation myocardial infarction

“…32,33 HMGB-1 is highly expressed in platelet-rich human coronary artery thrombi 34 and a key mediator of reciprocal communication between platelet and neutrophils, as well as monocytes facilitating formation of prothrombotic neutrophil extracellular traps and production of monocyte-derived tissue factor. 33 We found that P-selectin exposure was not affected by VLD rivaroxaban treatment, findings that are in line with previous studies 35,36 that both found no significant effect of rivaroxaban on platelet P-selectin expression and release. However, in the present study, we could show that platelet surface abundance of HMGB-1 was significantly reduced after treatment with VLD rivaroxaban pointing to a potential effect on thrombo-inflammatory processes triggered by platelets in patients with coronary artery disease.…”

Apixaban enhances endogenous fibrinolysis in patients with atrial fibrillation

“…Even at the very low dose of 2.5 mg b.i.d., rivaroxaban reduced platelet-dependent thrombin generation and coagulation-dependent thrombus-formation in patients treated with aspirin plus P2Y 12 inhibitor, whereas pure platelet-dependent thrombus formation was not affected 14 . Indeed, FXa inhibition appears to have no significant effect on platelets 14 including in response to adenosine diphosphate, collagen, thrombin receptor-activating peptide, or arachidonic acid 15 . Apixaban may therefore favourably enhance endogenous fibrinolysis through reduction in platelet-dependent and non-platelet-dependent thrombin generation, which directly impact on the structure and stability of the thrombus and its resistance to fibrinolysis.…”

Type 2 Diabetes, Atrial Fibrillation, and Direct Oral Anticoagulation

“…However, its activity might be affected with strong induction/inhibition of CYP enzymes or due to severe reduction of the kidney functions [39]. Rivaroxaban probably does not affect platelet aggregation [41, 42]. Several previously published studies [43–45] pointed on the fact that diabetes modulates the activity of CYP enzymes; hence, this modulation can, in theory, lead to changed rivaroxaban activity in T2D subjects.…”