Circadian clock regulation of hemostasis: a systematic review of molecular pathways

Thrombotic events such as myocardial infarction and stroke exhibit circadian variation with early-morning peaks, implicating intrinsic biological regulation, yet the molecular mechanisms coordinating hemostatic function remain unclear. This systematic review synthesizes evidence linking circadian rhythms and clock genes to hemostatic regulation and highlights the underlying molecular pathways. A comprehensive literature search of PubMed, Scopus, and Web of Science was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Human and animal studies evaluating circadian rhythm, circadian clock genes, or clock-modulating interventions in relation to platelet function, coagulation, fibrinolysis, or thrombosis were included. Of the 1048 articles screened at the level of title and abstract independently by 2 authors, 26 studies met the inclusion criteria and were categorized into 4 major thematic domains of circadian hemostatic regulation as follows: (1) circadian orchestration of hemostasis across populations and experimental models; (2) genetic and pharmacologic modulation of circadian clock components; (3) circadian gene expression in platelets and megakaryocytes; and (4) environmental and lifestyle influences on circadian hemostatic coordination. Collectively, the evidence demonstrates that circadian clocks function as active regulators of thrombotic homeostasis. Core clock components, particularly BMAL1 and CLOCK, orchestrate rhythmic expression of coagulation factors and platelet activation pathways, while CRY, PER, and REV-ERBα critically govern fibrinolytic balance through time-of-day-dependent regulation of plasminogen activator inhibitor 1. Circadian disruptions, such as shift work, altered light exposure, dietary patterns, and pharmacologic timing, disrupt these rhythms and promote a persistent prothrombotic state. Circadian clock genes critically regulate platelet activity, coagulation, and fibrinolysis, positioning circadian biology as a translational target for chronotherapy and timing-based strategies to reduce thrombotic and cardiovascular risk.