Unraveling genetic contributors to bleeding events induced by rivaroxaban treatment

Rivaroxaban, a non-vitamin K antagonist oral anticoagulant, is a potent inhibitor of factor-Xa activity. As a direct oral anticoagulant (DOAC), it is commonly utilized for stroke prevention in patients with non-valvular atrial fibrillation, aiming to decrease the incidence of stroke and systemic embolism.1 The pharmacodynamics of rivaroxaban exhibit predictability irrespective of ethnic variations and demonstrate a robust linear correlation with plasma concentration, with no clinically significant gender-based differences observed.2, 3 Rivaroxaban monotherapy is preferred over combination therapy with antiplatelet agents in the management of cardiovascular disease and major bleeding events.4 While rivaroxaban demonstrates remarkable treatment efficacy, its clinical adoption requires caution. In a comparative study between rivaroxaban and apixaban, rivaroxaban therapy was associated with an increased risk of major ischemic or hemorrhagic events, particularly in elderly patients.5 Conversely, apixaban exhibited a lower incidence of both ischemic stroke or systemic embolism and bleeding in adults diagnosed with atrial fibrillation.6 Attention should be given to the potential side effects of rivaroxaban, which encompass both non-hemorrhagic adverse events and bleeding events.7 Non-hemorrhagic adverse events associated with rivaroxaban include regular occurrences of nausea, vomiting, and constipation. Regarding bleeding events, most studies have primarily focused on evaluating the clinical dosage of rivaroxaban. For instance, the off-label use of low-dose rivaroxaban increases vulnerability to ischemic stroke without reducing the risk of intracranial hemorrhage compared to on-label dosing.8 Furthermore, elderly individuals with atrial fibrillation are particularly susceptible to major bleeding events following rivaroxaban treatment, commonly exhibiting impaired renal function. Consequently, this medication is contraindicated in patients with severe kidney impairment and advanced hepatopathy.9, 10 DOACs have been preferred for prescription due to their favorable pharmacokinetics and pharmacodynamics. However, apart from determining the anticoagulant effects, the plasma concentrations of DOACs are also associated with major bleeding events and stroke prevention. Atrial fibrillation patients receiving DOAC treatment and experiencing bleeding complications have shown higher plasma levels of DOACs.11 Furthermore, inter-individual variations in plasma drug levels of DOACs can be attributed to genetic differences and drug interactions.12 Therefore, the identification of novel genetic variants to modify DOAC plasma levels holds promise for the prevention of related bleeding events. Genetic variants, particularly single nucleotide polymorphisms (SNPs), have the potential to modify disease risk and are often associated with various complications. Recent advances in pharmacogenetics have shed light on the intricate relationship between DOACs and genetic polymorphisms.13 For example, specific genotypes of ABCB1 rs3842 and APOB rs13306198 variants have been linked to an increased risk of bleeding events in patients receiving DOACs.14 In addition to ABCB1, emerging risk factors such as AKR7A3 and ABCA6 were observed; however, the role of genetic variations in bleeding events by rivaroxaban treatment remains unclear and has drawn limited attention15-18 (Table 1). In this issue of Clinical and Translational Medicine, the multicenter prospective cohort study focused on genetic polymorphisms, researchers identified 18 SNPs from 14 genes (including COL6A3, NCAM2, MMP3, VCAN, JCAD) as promising biomarkers for understanding the adverse effects of rivaroxaban. These candidate genes were found to influence multiple regulatory factors associated with bleeding events.18 COL6A3 encodes collagen VI, a cell-binding protein that plays a crucial role in the blood coagulation cascade. MARCH1 is a member of the MARCH family of membrane-bound E3 ubiquitin ligases, responsible for the ubiquitination of specific proteins such as major histocompatibility complex class II proteins. PSAP encodes prosaposin, a highly conserved preproprotein that generates four saposins (A, B, C, D), which act as lysosomal hydrolases involved in the breakdown of sphingolipids. JCAD encodes an endothelial intercellular junction protein, while MMP3 encodes proteins belonging to the matrix metalloproteinase family that play a role in the degradation of the extracellular matrix. NCAM2 encodes a type I membrane protein that is a member of the immunoglobulin superfamily and appears to be involved in selective fasciculation and zone-to-zone projection of primary olfactory axons. According to the Genome-wide Association Study Catalog, multiple polymorphisms in these candidate genes have been associated with various phenotypes, including coronary artery disease, large artery stroke, peripheral arterial disease and ischemic stroke. Taking advantage of their abundant presence in genomes, potential functional impact in coding regions and linkage disequilibrium-derived haplotypes, SNPs offer a distinct contribution to seek an instructive biotarget in the occurrence and progression of disease. For example, variant rs8400 has been demonstrated to affect the activity of miR-186-3p, thereby dysregulating ALKBH5 and promoting the progression of neuroblastoma through the ALKBH5-SPP1 axis.19 Therefore, it is advisable to further investigate the molecular mechanisms underlying disease etiology by focusing on informative SNPs. Additionally, the use of polygenic risk scores (PRS) as an alternative approach is available. By computing the weighted effects of relevant genotypes, PRS enables the prediction of individual susceptibility to bleeding events, offering significant implications for preventive strategies. In conclusion, the identification of genetic polymorphisms associated with bleeding events during rivaroxaban treatment provides potential biomarkers for mitigating adverse effects of direct factor Xa inhibitors. Furthermore, these biomarkers may have implications for other oral anticoagulant drugs such as Vitamin K antagonists and direct thrombin inhibitors. This work was supported by the National Natural Science Foundation of China (grant number: 82173593). The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.