Association of a Common Polymorphism in the Factor XIII Gene With Venous Thrombosis

Catto, Andrew J.; Köhler, Hans Peter; Coore, Julie; Mansfield, Michael; Stickland, M. H.; Grant, Peter J.

doi:10.1182/blood.v93.3.906

Cited by 167 publications

(27 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is now well demonstrated that the FXIII V34L polymorphism associates with FXIII speci®c transglutaminase activity, due to the thrombin-activation rate of FXIII (3, 18±22). Paradoxically, the less frequent Leu 34 allele has been identi®ed as a protective genetic factor against coronary artery disease (4, 5) and venous thrombosis (6,7 ). Also, a preliminary study indicated a slightly higher incidence of the FXIII Leu 34 variant in 62 patients with primary intracerebral haemorrhage compared with controls (23).…”

Section: Discussionmentioning

confidence: 99%

Role of Factor Xiii Val 34 Leu Polymorphism in Patients with Migraine

et al. 2001

View full text Add to dashboard Cite

At present, it is contradictory to determine if the combination of certain prothrombotic polymorphisms and migraine increases the risk to develop ischaemic cerebrovascular disease. Recently, the common Val34Leu polymorphism of the A-chain factor XIII gene, associated with variations in factor XIII activity, has been suggested to play a significant role in the development of arterial and venous thrombotic disorders. We analysed the prevalence of this polymorphism in 17 patients with coexisting ischaemic cerebrovascular disease and migraine (5 with aura, and 12 without aura), 89 patients with migraine (43 with aura, and 46 without aura), 116 patients with ischaemic cerebrovascular disease, and 467 healthy Caucasian controls from the South of Spain. Genomic PCR amplification, using a mutated oligonucleotide, and allele-specific restriction assays were used for genotyping. The factor XIII Leu 34 variant was present in 47.1; 40.5; 34.9; and 35.1% of patients with coexisting ischaemic cerebrovascular disease and migraine, ischaemic cerebrovascular disease, migraine, and control subjects, respectively. These data suggest that the factor XIII Leu 34 allele does not play a protective role against these disorders in our population.

show abstract

Section: Discussionmentioning

confidence: 99%

Role of Factor Xiii Val 34 Leu Polymorphism in Patients with Migraine

et al. 2001

View full text Add to dashboard Cite

show abstract

“…To take into account the association strengths between the selected SNPs and VTE, we created a weighted GRS for each of the panels described ( Table 1). The weights assigned to each SNP were defined a priori and based on the results of published meta-analyses in the case of FVL 23 and PT 24 or data from individual reports for rs2232698, 13,25 rs1801020, 20,26,27 rs59852, 8,28,29 rs2289252, 30,31 and rs2036914 31,32 or meta-GWAS for the variants rs2066865, 19,33,34 AB0, 35 rs121909548, 14 and rs710446 36 (Tables S1 and S2). For FV Cambridge and Hong Kong, the same weights as FV Leiden were assigned.…”

Section: Genetic Risk Scorementioning

confidence: 99%

Multilocus Genetic Risk Scores for Venous Thromboembolism Risk Assessment

Soria

Morange

Vila

et al. 2014

JAHA

View full text Add to dashboard Cite

BackgroundGenetics plays an important role in venous thromboembolism (VTE). Factor V Leiden (FVL or rs6025) and prothrombin gene G20210A (PT or rs1799963) are the genetic variants currently tested for VTE risk assessment. We hypothesized that primary VTE risk assessment can be improved by using genetic risk scores with more genetic markers than just FVL‐rs6025 and prothrombin gene PT‐rs1799963. To this end, we have designed a new genetic risk score called Thrombo inCode (TiC).Methods and ResultsTiC was evaluated in terms of discrimination (Δ of the area under the receiver operating characteristic curve) and reclassification (integrated discrimination improvement and net reclassification improvement). This evaluation was performed using 2 age‐ and sex‐matched case–control populations: SANTPAU (248 cases, 249 controls) and the Marseille Thrombosis Association study (MARTHA; 477 cases, 477 controls). TiC was compared with other literature‐based genetic risk scores. TiC including F5 rs6025/rs118203906/rs118203905, F2 rs1799963, F12 rs1801020, F13 rs5985, SERPINC1 rs121909548, and SERPINA10 rs2232698 plus the A1 blood group (rs8176719, rs7853989, rs8176743, rs8176750) improved the area under the curve compared with a model based only on F5‐rs6025 and F2‐rs1799963 in SANTPAU (0.677 versus 0.575, P<0.001) and MARTHA (0.605 versus 0.576, P=0.008). TiC showed good integrated discrimination improvement of 5.49 (P<0.001) for SANTPAU and 0.96 (P=0.045) for MARTHA. Among the genetic risk scores evaluated, the proportion of VTE risk variance explained by TiC was the highest.ConclusionsWe conclude that TiC greatly improves prediction of VTE risk compared with other genetic risk scores. TiC should improve prevention, diagnosis, and treatment of VTE.

show abstract

“…8 Findings on the role of this polymorphism in thrombosis risk have been inconsistent; however, both independent studies and meta-analyses suggest the 34Leu variant offers modest but significant protection against venous thrombosis. [9][10][11][12][13][14] Discovery that the effects of the Val34Leu polymorphism are mediated by gene-environment interactions between FXIII-A genotype and plasma fibrinogen concentration has resolved some of the discord. 15 For example, in the Leiden Thrombophilia Study, although Leu homozygosity showed weak protection against venous thrombosis in men, 16 reanalysis adjusting for fibrinogen concentration strengthened the association for both men and women, especially in individuals older than 45 years.…”

Section: Introductionmentioning

confidence: 99%

“…27 By extension, one might speculate that individuals with the 34Leu variant and accelerated FXIII activation would produce larger clots carrying increased venous thrombosis risk. However, the paradoxical association of the 34Leu variant with decreased venous thrombosis risk [11][12][13][14] warrants an explicit analysis of the interaction between this polymorphism and fibrinogen concentration during whole blood clot formation. Determining the impact of the 34Leu variant on clot characteristics is essential for understanding the clinical significance of the FXIII-A Val34Leu polymorphism in thrombosis risk.…”

Section: Introductionmentioning

confidence: 99%

The factor XIII‐A Val34Leu polymorphism decreases whole blood clot mass at high fibrinogen concentrations

Kattula

Bagoly

Tóth

et al. 2020

Journal of Thrombosis and Haemostasis

View full text Add to dashboard Cite

Background Factor XIII (FXIII) promotes fibrin crosslinking and red blood cell (RBC) retention in clots. The FXIII‐A polymorphism, Val34Leu, is associated with protection against venous thrombosis. This effect is hypothesized to result from fibrinogen concentration‐dependent changes in fibrin structure. Effects of the FXIII‐A Val34Leu polymorphism in whole blood clots have not been investigated. Aim Characterize effects of FXIII‐A Val34Leu polymorphism and fibrinogen on whole blood clots. Methods We isolated platelet‐poor plasmas from human donors (FXIIIVal/Val, FXIIIVal/Leu, FXIIILeu/Leu), reconstituted plasmas with platelets and RBCs, and triggered clotting. We assessed contributions of gender, age, clotting times, thrombin generation, FXIII activity, FXIII‐A Val34Leu polymorphism, and fibrinogen to clot mass. We also reconstituted FXIII‐depleted plasma with platelets, RBCs, and purified FXIIIVal/Val or FXIIILeu/Leu, varied fibrinogen, and characterized effects on clot mass. Results Clot mass was associated with age, fibrinogen, prothrombin time, and thrombin generation. Clots reconstituted with plasmas from individuals with FXIII‐AVal/Val and FXIII‐AVal/Leu did not differ in mass from clots with FXIII‐ALeu/Leu. However, clots containing a 34Val allele demonstrated a fibrinogen concentration‐dependent increase in mass, whereas clots with homozygous 34Leu did not. In plasmas with high fibrinogen, mass was higher for clots with 34Val alleles compared with clots with homozygous 34Leu. In clots reconstituted with purified FXIII, increasing fibrinogen enhanced clot mass in the presence of 34Val, but decreased mass in the presence of 34Leu. Conclusions FXIII 34Leu mitigates the effect of elevated fibrinogen on whole blood clot mass. The Val34Leu polymorphism may protect against venous thrombosis by reducing clot mass.

show abstract

Association of a Common Polymorphism in the Factor XIII Gene With Venous Thrombosis

Cited by 167 publications

References 6 publications

Role of Factor Xiii Val 34 Leu Polymorphism in Patients with Migraine

Role of Factor Xiii Val 34 Leu Polymorphism in Patients with Migraine

Multilocus Genetic Risk Scores for Venous Thromboembolism Risk Assessment

The factor XIII‐A Val34Leu polymorphism decreases whole blood clot mass at high fibrinogen concentrations

Contact Info

Product

Resources

About