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→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),1 carriership of the L allele leading to an OR of 0.63 (95% CI: 0.47 to 0.87). In Catto et al1 no interaction between FV Leiden and FXIIIV34L was found, but the small number of individuals with FV Leiden could have led to a lack of power. Therefore we decided to evaluate the role of the FXIIIV34L in the thrombophilic phenotype in a large population of FV Leiden carriers.
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 Table1. 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.
Prevalence of FXIII34L allele carriers among asymptomatic and symptomatic FV Leiden carriers
| . | FXIIIV34L present . | FXIIIV34L absent . | P . |
|---|---|---|---|
| Without VT (n = 145) | 65 (45) | 80 (55) | NA |
| VT (VTE + STP) (n = 168) | 71 (42) | 97 (58) | .68 |
| VTE (DVT + PE) (n = 155) | 89 (57) | 66 (43) | .72 |
| DVT (n = 113) | 63 (56) | 50 (44) | .93 |
| PE (n = 42) | 26 (62) | 16 (38) | .46 |
| . | FXIIIV34L present . | FXIIIV34L absent . | P . |
|---|---|---|---|
| Without VT (n = 145) | 65 (45) | 80 (55) | NA |
| VT (VTE + STP) (n = 168) | 71 (42) | 97 (58) | .68 |
| VTE (DVT + PE) (n = 155) | 89 (57) | 66 (43) | .72 |
| DVT (n = 113) | 63 (56) | 50 (44) | .93 |
| PE (n = 42) | 26 (62) | 16 (38) | .46 |
Numbers of carriers given; percentages are in parentheses.
VT indicates venous thrombosis; VTE, venous thromboembolism; STP, superficial thrombophlebitis; DVT, patients with at least one episode of deep venous thrombosis; and PE, patients with at least one episode of pulmonary embolism associated or not with DVT.
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.
Relationship between FXIIIV34L and Factor V Leiden in patients with venous thrombosis
The 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.1-1,1-2 FXIIIV34L, on the other hand, was recently described to be protective against VTE1-3,1-4 and arterial thrombosis.1-5-1-7 FVL exerts its effects by promoting thrombin generation, whereas V34L is sensitive to thrombin, thereby influencing fibrin structure and function.1-8 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.1-3 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,1-3 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.
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