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SummaryActivated protein C resistance (APCR) is a major risk factor for venous thromboembolism (VTE). Although the factor V (FV) Leiden mutation accounts for the vast majority of APCR cases, other polymorphisms may contribute to the APCR phenotype. Genetic components of APCR and thrombophilia were investigated by two dinucleotide repeats, characterized in introns 2 and 11 of the FV gene. Only the intron 11 marker was genetically stable and thus suitable for further analysis. Its allelic frequencies were found to differ significantly (P=0.003) between subjects selected for increased APCR in the absence of the FV R506Q mutation (n=70, normalized ratios ≤0.80), and for increased APC sensitivity (n=98, normalized ratios ≥1.31). Genotype differences were also found (P=0.017) between FV R506Q heterozygotes (n=100) who had experienced previous VTE and those (n=100), who were still asymptomatic for VTE. Significance was mostly driven by the relative over-representation of the 12R allele and to a minor extent by the under-representation of the 15R allele among the symptomatic versus the asymptomatic FV Leiden carriers.Two SNPs (4070A/G and 2391A/G) were found to underlie the 12R and 15R alleles respectively, and marked extended haplo-types, previously (HR2) or newly (HT2) identified. Only the FV HR2 differed (P=0.002) in frequency between the two groups of FV R506Q heterozygotes, suggesting that it represents the most relevant FV genetic component of APCR or VTE detectable by this experimental and clinical approach. Our analysis indicates that frequent FV genetic components might contribute to shape the risk for VTE in FV Leiden carriers.