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CORRESPONDENCE Given the multifactorial aspect of venous thrombophilia,
identification of combined genetic factors in Factor V Leiden carriers is important to a more accurate risk assessment. Recently, a common point mutation (G The population consisted of all consecutive heterozygous FV Leiden
carriers (n = 308) from 220 unrelated families diagnosed between 1995 and 1998 in the Laboratorie Hématology of CHU Timone (Marseilles,
France) and without antithrombin, protein C, or protein S deficiency
and lupus anticoagulant. This population was more extensively described
in a previous report.2 Briefly, 168 patients (68 men and 100 women; age range, 18-86 years;
mean age, 47 years) underwent at least one objectively confirmed venous
thrombosis (VT), 155 with a deep-vein thrombosis complicated or not by
pulmonary embolism (VTE) and 13 with superficial thrombophlebitis
(STP). Asymptomatic FV Leiden carriers included 145 asymptomatic
relatives of patients with VT or individuals with familial but no
personal history of VT (61 men and 84 women; age range, 15-77 years;
mean age, 35 years). Asymptomatic carriers at the time of blood
sampling were younger than patients with VT. But the mean age of first
VT was not statistically different from the mean age of asymptomatic
carriers at the time of the study (38 versus 35, respectively; P
= .2). The 20210G>A mutation of the prothrombin gene was
present in 11 (7%) patients with VT and in 10 (7%) asymptomatic
participants. In all the subjects, the FXIIIV34L was checked as
previously described.3 Because individuals within a family
are not independent, conventional statistical procedures could not be
used. Thus statistical analyses were carried out using the
estimating-equations technique.2,4 Genotype frequencies
for symptomatic and asymptomatic individuals are shown in Table
1. The factor XIII mutation was found in
136 of 313 (43%) FV Leiden carriers, representing an allele frequency of 0.25. This frequency was similar to that previously reported in the
Marseilles area.3 The distribution of factor XIII genotype was not significantly different between symptomatic and asymptomatic individuals (P = .68). Moreover, the age of the
first VT in patients carrying the L allele was not different from those
homozygous for the V allele (36 versus 38 years, respectively;
P = .5). The results were not modified by exclusion of the
carriers of the prothrombin mutation.
Factor XIIIV34L has been shown to be protective for thromboembolic disease. This role has been reported in myocardial infarction,5-7 brain infarction,8 and VT.1,9 But it is noteworthy that some studies found negative results.10,11 In the study herein, the factor XIII polymorphism does not seem to influence the risk of VT in factor VL carriers, as no difference in prevalence of the V34L has been observed between symptomatic and asymptomatic carriers. Screening for this polymorphism does not seem to be useful to assess more accurately the risk of venous thrombosis or to manage better prophylactic and diagnostic measures in FV Leiden carriers.
Pierre E. Morange, Mireille Henry, Dominique Brunet, Marie-Françoise Aillaud, and Irène Juhan-Vague
References
1.
Catto AJ, Kohler HP, Coore J, Mansfield MW, Stickland MH, Grant PJ.
Association of a common polymorphism in the factor XIII gene with venous thrombosis.
Blood.
1999;93:906-908
2.
Morange PE, Henry M, Tregouët D, et al.
The A-844G polymorphism in the PAI-1 gene is associated with a higher risk of venous thrombosis in Factor V Leiden carriers.
Arterioscler Thromb Vasc Biol.
2000;20:1387-1391 3. Henry M, Morange PE, Canavy I, Alessi MC, Juhan-Vague I. Rapid detection of Factor XIII Val 34 Leu by allele specific PCR [letter]. Thromb Haemost. 1999;81:463[Medline] [Order article via Infotrieve]. 4. Trégouët DA, Ducimetière P, Tiret L. Testing association between candidate-gene markers and phenotype in related individuals, by use of estimating equations. Am J Human Genet. 1997;61:189-199[Medline] [Order article via Infotrieve]. 5. Kohler H, Stickland M, Ossei-Gerning N, Carter A, Mikkola H, Grant P. Association of a common polymorphism in the factor XIII gene with myocardial infarction. Thromb Haemost. 1998;79:8-13[Medline] [Order article via Infotrieve]. 6. Wartiovaara U, Perola M, Mikkola H, et al. Association of FXIII Val34Leu with decresed risk of myocardial infarction in Finnish males. Atherosclerosis. 1999;142:295-300[CrossRef][Medline] [Order article via Infotrieve].
7.
Franco RF, Pazin-Filho A, Tavella MH, Simoes MV, Martin-Neto J, Zago MA.
Factor XIII Val34Leu and the risk of myocardial infarction.
Haematologica.
2000;85:67-71
8.
Elbaz A, Poirier O, Canaple S, Chedru F, Cambien F, Amarenco P.
The association between the Val34Leu polymorphism in the factor XIII and brain infarction.
Blood.
2000;95:586-591 9. Franco RF, Reitsma PH, Lourenco D, et al. Factor XIII Val34Leu is a genetic factor involved in the etiology of venous thrombosis. Thromb Haemost. 1999;81:676-679[Medline] [Order article via Infotrieve]. 10. Canavy I, Henry M, Morange PE, et al. Genetic polymorphisms and coronary artery disease in the south of France. Thromb Haemost. 2000;83:212-216[Medline] [Order article via Infotrieve].
11.
Corral J, Gonzales-Conejero R, Iniesta JA, Rivera J, Martinez C, Vicente V.
The FXIII Val34Leu polymorphism in venous and arterial thromboembolism.
Haematologica.
2000;85:293-297
Response:Relationship between FXIIIV34L and Factor V Leiden in patients with venous thrombosisThe recognition of Factor V Leiden (FVL) as a major risk factor in the development of venous thromboembolism (VTE) has emphasized the importance of genetic factors in the pathogenesis of this disorder. The high prevalence of FVL and an approximately 8-fold risk of thrombosis associated with the heterozygous state has demonstrated the potential for interaction of FVL with other inherited deficiencies of coagulation, including protein C, protein S, and antithrombin III.1,2 FXIIIV34L, on the other hand, was recently described to be protective against VTE3,4 and arterial thrombosis.5-7 FVL exerts its effects by promoting thrombin generation, whereas V34L is sensitive to thrombin, thereby influencing fibrin structure and function.8 A biochemical interaction between FVL and V34L might therefore be expected, with potential clinical implications, as has been investigated by Morange et al. In this study, however, no relationship was observed between FVL and V34L, which is in keeping with our preliminary observations.3 The overall size of the French population was larger than our own and differed in the sense that all of their subjects were FVL heterozygotes. These results, together with our own findings,3 provide fairly convincing evidence for a lack of interaction between FVL and V34L. But an interaction between V34L and FVL homozygous mutants (in which the risk of thrombosis is very significantly increased) cannot be excluded, as none were included in Morange et al's study or in our study. There are a number of plausible explanations to account for the apparent lack of association between FVL and V34L. It could be that in both studies, the population was insufficiently powered and/or characterized to demonstrate a significant effect. This would be unlikely, due to large numbers reported on this study. Alternatively, the protective effect exerted by V34L may be considerably weaker than the prothrombotic effect of FVL, and any protective effect conferred by the 34L allele may not be evident in combination with FVL. Finally, it is possible that as-yet-undefined mechanisms play a role in the phenotypic effect of the FXIIIV34L polymorphism, other than purely increased sensitivity to thrombin. This could include effects on FXIII A-B subunit dissociation, fibrin structure, and the cross-linking of other proteins to the developing clot. The clinical findings from these and other studies indicate the need for a better understanding of the biochemical interactions between FVL and FXIIIV34L in the genesis of a fibrin clot.
Andrew J. Catto, Robert A. S. Ariëns, and Peter J. Grant
References
1.
Koeleman BP, Reitsma PH, Allaart CF, Bertina RM.
Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families.
Blood.
1994;84:1031-1035
2.
Zoller B, Berntsdotter A, Garcia de Frutos P, Dahlback B.
Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S.
Blood.
1995;85:3518-3523 3. Catto AJ, Kohler HP, Coore J, Mansfield MW, Stickland MH, Grant PJ. Association of a common polymorphism in the Factor XIII gene with venous thrombosis. Blood. 1999;93:906-908. 4. Franco RF, Reitsma PH, Lourenco D, et al. Factor XIII Val34Leu is a genetic risk factor involved in the aetiology of venous thrombosis. Thromb Haemost. 1999;81:676-679. 5. Kohler HP, Stickland MH, Ossei-Gerning N, Carter A, Mikkola H, Grant PJ. Association of a common polymorphism in the factor XIII gene with myocardial infarction. Thromb Haemost. 1998;79:8-13. 6. Wartiovaara U, Perola M, Mikkola H, et al. Association of FXIII Val34Leu with decreased risk of myocardial infarction in Finnish males. Atherosclerosis. 1999;142:295-300. 7. Elbaz A, Poirier O, Canaple S, Chedru F, Cambien F, Amarenco P. The association between the Val34Leu polymorphism in the factor XIII gene and brain infarction. Blood. 2000;95:586-591.
8.
Ariens RA, Philippou H, Nagaswami C, Weisel JW, Lane DA, Grant PJ.
The factor XIII V34L polymorphism accelerates thrombin activation of factor XIII and affects cross-linked fibrin structure.
Blood.
2000;96:988-995   CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
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T) in exon 2 of the factor XIII A-subunit gene that codes for an amino acid change 3 amino acids from the
thrombin-activation site (Factor XIIIV34L) was reported to be
protective against venous thrombosis (VT),
