Genetic risk assessment of pregnancy-associated venous thromboembolism: dual utility of maternal peripheral blood in NIPT and VTE evaluation.

OBJECTIVE

Venous thromboembolism (VTE) is a leading cause of maternal mortality, with pregnancy significantly increasing VTE risk due to physiological hypercoagulability. Current risk assessment methods, such as VTE scoring systems and D-dimer testing, have limitations in identifying high-risk individuals, highlighting the need for improved stratification.

METHODS

Whole genome sequencing (WGS) was performed on peripheral blood samples collected from 29 pregnant women with clinically diagnosed VTE during routine non-invasive prenatal testin (NIPT). The analysis focused on a curated list of 162 thrombosis-related genes (18 high-risk, 144 moderate/low-risk), incorporating detection of pathogenic variants, copy number variations (CNVs). Genetic risk factors were compared against conventional VTE risk scores and D-dimer levels. Additionally, a control group of 74 healthy pregnant women was included to enable allele frequency analyses.

RESULTS

Pathogenic/likely pathogenic variants were identified in 58.6% of cases (17/29), with TUBB1 and vWF as key contributors. 17 pathogenic CNVs were detected in 41.4% (12/29), involving PRSS1, C4A, etc. Allele frequency analysis highlighted 9 loci across 4 genes, indluding HLA-B, PRSS1, ACE, C4A linked to VTE susceptibility. Traditional VTE risk scores and D-dimer levels showed limited predictive ability, particularly in cases with low clinical risk scores but high genetic risk. Notably, among the 11 women with a pre-delivery VTE score of 0, 7 had genetic predispositions. Similarly, among the 15 women with low pre-delivery D-dimer levels, 9 had genetic risk, and among the 5 women with low D-dimer levels at 24 h postpartum, 3 had genetic risk. These findings collectively highlight the inability of traditional markers to capture hidden genetic risk in pregnancy-associated VTE.

CONCLUSIONS

The dual use of NIPT samples for VTE genetic assessment reduces invasive procedures and costs, offering a novel approach to optimize risk stratification, particularly for individuals with low traditional risk scores but high genetic susceptibility. These findings support integrating genetic screening into prenatal care to enable personalized prevention.