The Identification of PAI-1 4G Polymorphisms in a Family with Unexplained Venous Thromboembolic Disease: Implications for VTE Screening

Abstract

Research Question: In patients with venous thromboembolic disease and a negative standard hematologic evaluation, are there novel genetic factors associated with the development of venous thromboembolic disease?

Background and Significance: Venous thromboembolic disease (VTD), including deep vein thrombosis (DVT) and pulmonary embolism (PE), affects as many as 900,000 people each year in the United States. Among those with a history of VTD, approximately one third to one half develop longer term sequalae — venous insufficiency, intractable edema, and thromboembolic pulmonary hypertension [7]. Despite recent expansion of VTD risk-reduction criteria by way of reducing known in-hospital risk factors (recent surgery, immobilization, indwelling catheterization) and promotion of healthier living, no known efforts have been made to expand current VTD evaluation criteria. Standard hematological evaluation includes Antithrombin III Deficiency, Antiphospholipid Syndrome (autoimmune platelet destruction), Factor V Leiden (resistance to Factor V inactivation), Protein C/S Deficiency, and Prothrombin G20210A mutation (excess prothrombin production) [15]. This evaluation stratifies patients in view of Virchow’s triad — hypercoagulability, stasis of blood, endothelial injury— and their predisposition to the development of VTD.

Materials and Methods: The study enrolled 4 related subjects in a single family over the age of 18 who experienced a venous thromboembolic event (DVT or PE) and had undergone a standard hematologic evaluation excluding current factors associated with thrombophilia. The primary enrollment site was Consultants in Cardiovascular Medicine and Science – Fort Worth, PLLC. For subjects meeting enrollment criteria, DNA samples were collected prospectively. We used a standard oropharyngeal swab to collect DNA using standard methodology and collected 50 mL of whole blood to use for serum auto-antibody assessment. Analysis of Plasminogen Activator Inhibitor-1 (PAI-1) (SERPINE 1) for single nucleotide variants was performed using commercially available, CLIA certified genotyping assays through Quest diagnostics. Pedigree analysis was performed to identify the genetic inheritance of thrombophilia in each subject.

Results: The results confirmed our suspicion for genetic variance in the PAI-1 (SERPINE 1) gene, with at least one family member heterozygous for the 4G variant. Analyses for the remaining subjects are currently pending.

Conclusion: If verified by a larger cohort study, the results highlight the need to expand current hematologic evaluation criteria to include PAI-1 (SERPINE 1) and stress the importance of improved VTD screening and evaluation for at-risk family members.