Genetic risk score (GRS) analysis is an increasingly popular approach to derive individual risk prediction models for complex diseases. In the context of venous thrombosis (VT), any GRS shall integrate information at the ABO blood group locus, the latter being one of the major susceptibility locus for this disease. However, there is yet no consensus about which single nucleotide polymorphisms (SNPs) must be investigated when one is interested in properly assessing the association of ABO locus with VT risk. Using comprehensive haplotype analyses of ABO blood group tagging SNPs in up to 5,425 cases and 8,445 controls from 6 studies, we demonstrated that using only rs8176719 (tagging O1) to correctly assess the impact of ABO locus on VT risk is suboptimal as 5% of rs8176719-delG carriers are not exposed at higher VT risk. Instead, we recommend to use 4 SNPs, rs2519093 (tagging A1), rs1053878 (A2), rs8176743 (B) and rs41302905 (O2) in any analysis aimed at assessing the impact of ABO locus on VT risk to avoid any risk misestimation. Compared to O1 haplotype that can be inferred from these 4 SNPs, the A2 haplotype is associated with a modest increase in VT risk (odds ratio ~1.2), A1 and B haplotypes are associated with a ~1.8 fold increased risk while O2 tend to be slightly protective (odds ratio ~0.80). In addition, our analyses clearly showed that while the A1 an B blood group are associated with increased vWF and FVIII plasma levels only the A1 blood group is associated wih ICAM plasma levels but in an opposite direction, leaving additional avenues to be explored in order to fully understand the whole spectrum of biological effect of ABO locus on cardiovascular traits.

Background: Coagulation factor V (FV), present in plasma and platelets, has both proand anticoagulant functions. Objective:We investigated an FV-deficient patient (FV:C 3%, FV:Ag 4%) paradoxically presenting with recurrent venous thrombosis (11 events) instead of bleeding.Methods/Results: Thrombophilia screening revealed only heterozygosity for the F2 20210G>A mutation. Although thrombin generation in the patient's platelet-poor plasma was suggestive of a hypocoagulable state, thrombin generation in the patient's platelet-rich plasma (PRP) was higher than in control PRP and extremely resistant to activated protein C (APC). This was partially attributable to the complete abolition of the APC-cofactor activity of FV and a marked reduction of plasma tissue factor pathway inhibitor antigen and activity. The patient was homozygous for a novel missense mutation (Ala2086Asp, FV Besançon ) that favors a "closed conformation" of the C2 domain, predicting impaired binding of FV(a) to phospholipids. Recombinant FV Besançon was hardly secreted, indicating that this mutation is responsible for the patient's FV deficiency. Model system experiments performed using highly diluted plasma as a source of FV showed that, compared with normal FVa, FVa Besançon has slightly (≤1.5fold) unfavorable kinetic parameters (K m , V max ) of prothrombin activation, but also a lower rate of APC-catalyzed inactivation in the presence of protein S.Conclusions: FV Besançon induces a hypercoagulable state via quantitative (markedly decreased FV level) and qualitative (phospholipid-binding defect) effects that affect anticoagulant pathways (anticoagulant activities of FV, FVa inactivation, tissue factor pathway inhibitor α level) more strongly than the prothrombinase activity of FVa. A possible specific role of platelet FV cannot be excluded.