Elevated procoagulant levels are associated with an increased risk of venous thrombosis (VT). The dependency on concurrent increased factor levels and VT was analyzed in a large study. Factor VIII (FVIII) and von Willebrand factor (VWF) were associated with the highest VT risk. The risks for other procoagulant factor levels were largely explained by FVIII and VWF. Summary BackgroundCoagulation factors are essential for robust clot formation. However, elevated levels of procoagulant factors are associated with an increased risk of venous thrombosis (VT). The precise contribution of these factors to the development of VT is not yet understood. ObjectivesWe determined the thrombosis risk for the highest levels of eight selected coagulation factors. Furthermore, we analyzed which of these coagulation factors had the strongest impact on the supposed association. MethodsWe used data of 2377 patients with a first VT and 2940 control subjects in whom fibrinogen, von Willebrand factor (VWF), factor II, FVII, FVIII, FIX, FX and FXI levels were measured. ResultsThe odds ratios (ORs) for the various coagulation factor levels (> 99th percentile versus ≤ 25th percentile) varied between 1.8 and 4, except for FVIII (OR 23.0; 95% confidence interval [CI] 14.7–36.0) and VWF (OR 24.0; 95% CI 15.3–37.3). Adjustment for FVIII and VWF in a mediation analysis reduced the risks of the other factors to unity, with the exception of FIX and FXI (remaining ORs between 1.7 and 1.9). Conversely, the ORs for FVIII and VWF levels remained high after adjustment for all other procoagulant factors (FVIII: 16.0; 95% CI 9.7–26.3; VWF: 17.6; 95% CI 10.7–28.8). ConclusionsOur results imply that the observed relationship between VT and coagulation factor levels can be largely explained by FVIII and VWF. FVIII and VWF levels were also associated with the highest VT risk.

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To cite this article: Uitte de Willige S, Rietveld IM, de Visser MCH, Vos HL, Bertina RM. Polymorphism 10034C>T is located in a region regulating polyadenylation of FGG transcripts and influences the fibrinogen c¢/cA mRNA ratio. J Thromb Haemost 2007; 5: 1243-9.Summary. Background: Fibrinogen gamma haplotype 2 (FGG-H2) is associated with reduced fibrinogen c¢ levels and fibrinogen c¢/total fibrinogen ratios and with an increased deepvenous thrombosis (DVT) risk. Two FGG-H2 tagging single nucleotide polymorphisms (SNPs), 9615C>T and 10034C>T, are located in the region of alternative FGG pre-mRNA processing. 10034C>T is located in a GT-rich downstream sequence element (DSE) that comprises a putative cleavage stimulation factor (CstF) binding site. Objectives: To investigate the functionality of SNPs 9615C>T and 10034C>T, and the importance of the DSE containing 10034C>T. Methods: Different minigene constructs containing FGG exon 9, intron 9, exon 10 and the 3¢ region were transiently transfected into HepG2 cells and quantitative real-time polymerase chain reaction was used to measure relative polyadenylation (pA) signal usage (pA1/pA2 ratio). Results: Compared with the reference construct CC (9615C-10034C; FGG-H1; pA1/pA2 ratio set at 100%), the pA1/pA2 ratio of construct TT (9615T-10034T; FGG-H2) was 1.4-fold decreased (71.5%, P = 0.015). The pA1/pA2 ratio of construct CT (9615C-10034T) was almost 1.2-fold decreased (85.3%, P = 0.001), whereas the pA1/pA2 ratio of construct TC (9615T-10034C) did not differ significantly from the reference construct (101.6%, P = 0.890). Functionality of the putative CstF binding site was confirmed using constructs in which this site was deleted or its sequence altered by point mutations. Conclusions: SNP 10034C>T is located in a GT-rich DSE involved in regulating the usage of the pA2 signal of FGG, which may represent a CstF binding site. We propose that the 10034C>T change is the functional variation in FGG-H2 that is responsible for the reduction in the fibrinogen c¢/total fibrinogen ratio and the increased DVT risk.

Essentials No clear association between FV concentration and venous thrombosis (VT) has been described yet.This association was studied in a large case‐control study on VT (MEGA‐study).Both high and low FV levels were associated with VT risk.Association with high FV levels was dependent on FVIII levels, that with low FV levels was not. BackgroundBlood coagulation levels are associated with risk of venous thrombosis (VT). The role of factor (F)V is ambiguous since it plays a dual role in coagulation: it has a procoagulant role when it serves as a cofactor for the activation of thrombin and it has an anticoagulant role by enhancing the inactivation of activated FVIII.ObjectivesTo elucidate the association of FV levels with risk of VT.Patients/MethodsWe analyzed FV antigen levels in 2377 patients with VT and 2943 controls from the MEGA study. FV levels were categorized according using the 1st, 2.5th, 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles of FV levels in controls as cut‐off points. Odds ratios (ORs) were estimated using logistic regression models and adjusted for age and sex, liver disease, FVIII levels, FV Leiden, and TFPI.ResultsThe risk estimates were U‐shaped with increased ORs for the lowest (<0.57 U/dL) levels (OR 1.46; 95% CI 0.87‐2.43) as well as the highest (>1.22 U/dL) (OR 1.86; 95% CI 1.46‐2.37) levels as compared with the reference group (25th‐50th percentile). FVIII adjustment led to attenuation of the OR for high FV levels (OR 1.14; 95% CI 0.88‐1.48), with little change for low FV levels (OR 1.68; 95% CI 0.97‐2.91). Other adjustments had limited effects.ConclusionsWe found high FV levels to be associated with increased risk for VT, which was explained by concurrently raised FVIII levels. For low levels of factor V, the increased risk for VT could not be explained by the mechanisms we explored.

Altered levels of factor (F)VIII, prothrombin, or antithrombin have been associated with an increased risk for venous thromboembolism (VTE). However, the exact molecular mechanism by which these altered factor levels modulate the risk is incompletely understood. Here we hypothesize that elevated factor levels affect the pro-and anticoagulant balance in coagulation such that even minute amounts of tissue factor (TF) will initiate thrombin formation, thereby contributing to the VTE risk. Materials and methods:To test this so-called TF-threshold hypothesis, we monitored thrombin generation initiated by very low TF concentrations in FXII-deficient plasma, to avoid any contact pathway-mediated thrombin formation. Furthermore, similar experiments were performed in the presence of increasing concentrations of pro-and anticoagulant proteins.Results: A TF-threshold was established in the FXII-deficient plasma, which is subject to inter-individual variation. Elevated plasma levels of procoagulant factors, such as FVIII or prothrombin, enhanced thrombin generation and reduced the amount of TF required for the initiation of thrombin formation. Conversely, elevated levels of the coagulation inhibitor antithrombin increased the TF-threshold.Conclusions: Our findings support a mediating role for the TF-threshold in the association between high procoagulant factor levels and the risk for VTE. Furthermore, elevated levels of anticoagulants may have a protective effect on the development of VTE.