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

Jun 8, 2026Biochemical genetics

How COVID-19 Changes Genetic Blood Clotting Risk and What It Means for Personalized Risk Assessment After Infection

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Abstract

Common prothrombotic genetic variants are associated with increased D-dimer levels in individuals more than two years after COVID-19, with F2 GA linked to a 31% increase.

All three genetic variants (F2, F5, MTHFR) independently predict higher D-dimer levels in individuals post-COVID.
F2 GA is associated with a 31% increase, F5 GA with a 37% increase, MTHFR CT with a 34% increase, and MTHFR TT with a 67% increase in D-dimer levels.
Significant amplification of genetic effects occurs in individuals recovering from COVID-19.
No association between these genetic variants and INR levels was observed.
COVID-19 may modify inherited tendencies toward blood clotting, impacting long-term health.

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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.

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

Abstract

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