Obstructive Sleep Apnea and Hypercoagulability: Combining Observational and Mendelian Randomization Analyses to Explore Causal Relationships

Purpose: The relationship between Obstructive sleep apnea (OSA) and hypercoagulability remains unclear. To address this uncertainty, the present study combined observational and Mendelian randomization (MR) analyses to assess the associations of OSA and coagulation markers. Patients and Methods: We conducted an observational study of 790 patients with OSA, evaluating associations between OSA severity and coagulation markers, including activated partial thromboplastin time (APTT), prothrombin time (PT), and fibrinogen (Fib). Multivariate linear regression adjusted for age, gender, body mass index (BMI), and comorbidities. Additionally, we performed a large-scale Mendelian randomization analysis using two East Asian OSA genome-wide association study (GWAS) datasets (Million Veteran Program MVP, n=6550; Taiwan Precision Medicine Initiative TPMI, n=316351) as exposures, and East Asian coagulation GWAS data from BioBank Japan (BBJ) as outcomes (APTT: n=37767; Fib: n=18348; PT: n=58110). Multivariable MR (MVMR) with body mass index (BMI)(TPMI GWAS, n=191458) was performed to assess residual direct effects of OSA. Results: Severe OSA showed higher Fib ( p -value< 0.01) and shorter PT ( p -value< 0.05) and APTT ( p -value< 0.05) than mild-moderate OSA. Multivariate regression analysis showed T90 (the percentage of time oxygen saturation is below 90%) and MSaO2 (mean oxygen saturation) were associated with Fib (β=− 0.259; β=− 0.224, p -value< 0.001). While OSA severity is observationally associated with subclinical hypercoagulability, these significances vanished after adjusting for BMI and are not supported by genetic evidence since MR analyses provide no evidence for a moderate or clinically meaningful independent causal effect between genetic OSA liability and coagulation markers. MVMR confirmed no residual direct effect of OSA on coagulation after accounting for BMI. Conclusion: Severe OSA is associated with subclinical hypercoagulability, but this relationship is confounded by BMI. Genetic evidence does not support a moderate or clinically meaningful causal role for OSA in coagulation dysfunction, urging a paradigm shift toward obesity management as the primary strategy to reduce thrombotic risk in OSA patients. Keywords: obstructive sleep apnea, hypercoagulability, Mendelian randomization, chronic intermittent hypoxia, obesity