Publication date: Jul 16, 2026
Direct oral anticoagulants (DOACs) – dabigatran (a thrombin inhibitor) and rivaroxaban, apixaban, and edoxaban (factor Xa [FXa] inhibitors) – modify oxidative stress, endothelial inflammation, and barrier integrity beyond anticoagulation. We ask whether this reflects distinct pharmacology or silencing of proteases at protease-activated receptors (PARs), and propose a three-condition framework for when it becomes clinically measurable. Narrative review (PubMed, Scopus, Web of Science; primary search 2019-2026, with foundational earlier references retained) with claims graded on a six-tier hierarchy; A‡ marks trials formally negative or inconclusive owing to insufficient statistical power. DOAC effects largely converge on one node – reduced PAR-1 signalling under thrombin inhibition and dual PAR-1/PAR-2 blockade under FXa inhibition – rather than independent targets; the FXa-PAR-2 axis is cross-validated across macrophages, liver sinusoidal endothelial cells, and neutrophils; and dabigatran plausibly differs qualitatively rather than only in degree – a working hypothesis whose mechanistic linchpin (residual exosite-I signalling) currently rests on a single unreplicated in-vitro study (level D). Clinically the signal sorts by phenotype and disease phase, not class: low-dose rivaroxaban benefits stable atherosclerosis (COMPASS) but not heart failure in sinus rhythm (COMMANDER-HF), and COVID-19 benefit appears only in convalescence (MICHELLE), not acutely or in outpatients (ACTIV-4B, A‡). A nationwide cohort linked DOACs to lower acute kidney injury and chronic kidney disease progression than vitamin K antagonists, pending separation from their nephrotoxicity. Pleiotropy emerges where three conditions coincide – the protease is available at PARs, its generation is chronic, and PAR signalling is rate-limiting. This supports within-indication molecule selection (selection, not extension) and biomarker co-primary trials, not extension of indications.
| Concepts | Keywords |
|---|---|
| Direct oral anticoagulants | |
| Factor Xa | |
| Phenotype-stratified medicine | |
| Pleiotropic effects | |
| Protease-activated receptors | |
| Thromboinflammation |
Semantics
| Type | Source | Name |
|---|---|---|
| disease | MESH | inflammation |
| drug | DRUGBANK | Dabigatran |
| drug | DRUGBANK | Thrombin |
| drug | DRUGBANK | Rivaroxaban |
| drug | DRUGBANK | Apixaban |
| drug | DRUGBANK | Edoxaban |
| disease | MESH | atherosclerosis |
| disease | MESH | heart failure |
| disease | MESH | COVID-19 |
| disease | MESH | convalescence |
| disease | MESH | acute kidney injury |
| disease | MESH | chronic kidney disease |
| drug | DRUGBANK | Phylloquinone |
| disease | MESH | Thromboinflammation |