Abstract 4359742: Thrombophilia Variants Do Not Predict Thrombotic Events in Congenital Heart Disease: Insights from the Pediatric Cardiac Genomics Consortium

Abstract

Background: Thrombotic events are a major complication in patients with congenital heart disease (CHD), particularly those with single ventricle physiology. The contribution of inherited thrombophilia variants—namely F2 c.*97G>A (Prothrombin G20210A) and F5 c.1601G>A (Factor V Leiden)—to thrombotic risk in this population remains unclear. Objective: To assess whether common thrombophilia variants are associated with increased risk of thrombotic events, including acute ischemic stroke, in individuals with CHD. Methods: We analyzed data from the Pediatric Cardiac Genomics Consortium (PCGC), including exome sequencing and electronic medical records. Thrombotic events were defined using PheCodes (e.g., 433.x for stroke). Single ventricle CHD was identified using Fyler codes. Variant prevalence in PCGC was compared to gnomAD v4.1. Pearson’s chi-squared test was used for statistical comparisons. Results: Among the 4,008 participants with EMR data, 737 (18%) had thrombotic events, including 93 (13%) with acute ischemic stroke. Thrombophilia variants were identified in 30 (4%) of these participants, with no significant difference in variant prevalence between those with and without thrombotic events or stroke. Of the 93 with stroke, two were Prothrombin G20210A heterozygotes and one was a Factor V Leiden heterozygote. Among the eight dual heterozygotes with EMR data, two (25%) had thrombotic events. Participants with single ventricle heart disease had a higher frequency of thrombosis compared to those with biventricular heart disease (32% vs. 16%, p ≤ 0.001), but thrombophilia variant prevalence did not differ by ventricular status. Conclusion: In this large, genomically characterized CHD cohort, common thrombophilia variants were not associated with thrombotic events, including ischemic stroke. These findings do not support routine thrombophilia screening to guide thromboprophylaxis in CHD. Future research should focus on hemodynamic, procedural, and environmental contributors to thrombotic risk in this population.