PHYSIOPATHOLOGY OF VENOUS THROMBOEMBOLISM IN PATIENTS WITH HYPERCOAGULABLE STATE RELATED TO INHERITED AND ACQUIRED THROMBOPHILIAS AND CLINICAL IMPLICATIONS

Background Venous thromboembolism (VTE) is a multifactorial disorder resulting from the interaction between genetic predisposition, acquired risk factors, and environmental triggers. Conventional thrombophilia screening identifies a limited number of high-risk conditions, thus many young patients with unprovoked or provoked thrombotic events remain unexplained. Next-generation sequencing (NGS) offers the opportunity to explore a broader genetic spectrum underlying hypercoagulability. Aims This study aimed to characterize the genetic background of young patients with unprovoked or disproportionate VTE using a targeted NGS panel, to assess the prevalence and spectrum of pathogenic variants and risk alleles, and to explore genotype–phenotype associations with clinical outcomes. Material and methods We enrolled consecutive, unrelated patients aged 18–50 years with objectively documented VTE, referred to the Thrombotic and Hemorrhagic Diseases Unit and Clinical Medicine 1 of the University Hospital of Padova between January 2014 and December 2023. Eligible patients had unprovoked VTE or severe VTE with only weak provoking factors, and a negative standard thrombophilia work-up for both inherited and acquired causes. Patients were included irrespective of family history of VTE. Variants were classified according to ACMG/AMP criteria, and common risk alleles were systematically recorded. Clinical and genetic data were analyzed, and logistic regression was applied across the whole cohort and all defined subpopulations. Results A total of 100 patients were included (45% women, mean age 33 years). Most were Caucasian, with a mean BMI of 25.5 kg/m², and half reported a family history of VTE. The index event was unprovoked in 67% of cases, while 33% were associated with weak provoking factors. DVT was the most frequent phenotype (54%), followed by isolated PE (27%) and combined PE+DVT (19%); 11% had thrombosis at unusual sites. Recurrent VTE occurred in 42% of patients, and bleeding during anticoagulation in 19%, including two major events. From the genetic perspective, pathogenic or likely pathogenic variants (class 4–5) were identified in 12% of patients, while 47% carried variants of uncertain significance (class 3). Overall, 59% of the cohort had at least one potentially relevant variant, and 26% harbored multiple alterations across distinct genes, supporting the hypothesis of oligogenic inheritance. Recurrent pathogenic mutations included SERPINC1 Budapest 3, PROS1 Heerlen, and F2 Arg541Trp. Approximately 11.8% of the detected variants had no rs identifier (reference SNP cluster ID) in public databases and may represent novel findings. Risk alleles were found in 65% of patients, with F2 c.1726-59G>A being the most prevalent (>40%), often in homozygosis and frequently coexisting with rare variants. Additional alleles included TFPI rs8176592, F12 c.-4T, PROZ c.-13G, PROCR rs867186, and SERPINA10 rs31336516. Patients without any identifiable genetic variant accounted for about one third of the cohort, suggesting the existence of additional mechanisms not captured by the current panel. Conclusions Extended NGS revealed a substantial burden of pathogenic and uncertain variants in young patients with VTE, supporting the polygenic/oligogenic model of thrombophilia. The frequent coexistence of rare variants and common risk alleles underscores the complexity of genetic predisposition. Beyond molecular testing, family history remains a fundamental element in assessing thrombotic risk. Future multicenter studies integrating genetic, functional, clinical, and familial data are warranted to refine variant interpretation and move toward precision medicine in VTE management.