COVID-19 as a Modifier of Genetically Determined Coagulation Phenotype: Implications for Precision Risk...

Persistent endothelial dysfunction and coagulation abnormalities are increasingly recognized as central components of post-COVID syndrome. However, substantial interindividual variability in long-term coagulation biomarkers suggests the presence of genetically determined susceptibility factors capable of modulating post-infectious thromboinflammatory responses. To determine whether common prothrombotic genetic variants modify long-term D-dimer and INR levels after COVID-19 and to assess their value for precision risk stratification. A controlled observational cohort study included 504 adults aged 18-50 years examined more than two years after PCR-confirmed COVID-19 and 270 control individuals without clinically significant SARS-CoV-2 infection. Genotyping of F2 c.20210G > A, F5 c.1691G > A (Factor V Leiden), and MTHFR c.C677T was performed using real-time PCR. D-dimer and international normalized ratio (INR) were measured monthly for 12 months and averaged. Log-transformed D-dimer was analyzed using multivariable linear regression with interaction terms. All three variants were independent predictors of D-dimer. In adjusted models, F2 GA (+ 31%), F5 GA (+ 37%), MTHFR CT (+ 34%), and MTHFR TT (+ 67%) were associated with higher D-dimer levels (all p < 0.001). Significant amplification of genetic effects was observed in post-COVID individuals (Group × Genotype interaction p < 0.01). INR showed no genotype association. COVID-19 acts as a long-term modifier of inherited thrombophilia phenotypes. Incorporating genetic profiling into post-COVID evaluation may enable precision identification of individuals at risk for persistent hypercoagulability.