Factor XIII V34L polymorphism modulates the risk of chronic venous leg ulcer progression and extension

Abstract

Low Factor XIII (FXIII) activity has been reported in the blood of patients with chronic venous leg ulcer (CVU). In vivo studies have described increased wound healing in CVU patients treated with FXIII concentrate, and in vitro studies have shown increased regenerative capacity in FXIII-treated fibroblasts. In addition, a common G-to-T polymorphism in the FXIIIA-subunit gene (V34L) significantly increases the activity and modifies the cross-linking properties of the FXIII molecule and this variant has been investigated as a protective factor against thrombosis, a recognized risk factor for CVU establishment. Therefore, the role of FXIII levels, FXIII V34L, FVR506Q, and FIIG20210A, common gene polymorphisms in the pathogenesis of CVU was investigated. Ninety-one patients with CVU and 195 healthy controls (91 of them sex- and age-matched) were PCR-genotyped for the FXIIIV34L, FVR506Q, and FIIG20210A substitutions and FXIIIA-subunit levels were determined by immuno-electrophoresis. The extent of the venous ulcer surface in patients was measured by computer software. The allele frequency and the genotype distribution of the FXIII polymorphism did not show significant differences between the whole group of cases and controls as well as prothrombin variants did. On the contrary, the FVR506Q variant (FV Leiden) allele was more frequent in patients, yielding a significant OR value of 5.93 (95 percent CI, 1.83-19.17; p= 0.003). Considering only CVU cases secondary to a post-thrombotic syndrome (n= 24), FV Leiden yielded a greater OR value of 16.08 (95 percent CI, 4.33-59.6; p < 0.0001). When the CVU cases were stratified by the three possible FXIII genotypes, a significant trend toward a lower mean value of the ulcerated area was clearly evident as the number of the polymorphic alleles (L34) increased in the genotype of patients (VV = 11.9 cm(2,)+/- 23.6; VL = 6.1 cm(2,)+/- 6.9; LL = 4.1 cm(2,)+/- 2.8; p= 0.01). On the other hand, FXIIIA antigen levels were similar between CVU cases and matched controls, but 11 percent of cases had FXIII deficiency (FXIIIA </= 0.65 U/ml; p= 0.003) and they showed a greater mean extension of the lesion if compared with the remaining cases without FXIIIA deficiency (14.5 cm(2), +/- 20.2 vs. 9.0 cm(2), +/- 6.3; p= 0.08). We conclude that FXIII antigen levels and FXIII V34L polymorphism may play a crucial role in the complex cascade of CVU pathophysiology, being significantly related to the CVU progression and extension because of the direct effects they have on the FXIII molecular activity.

Factor XIIIA-V34L and Factor XIIIB-H95R Gene Variants: Effects on Survival in Myocardial Infarction Patients

“…Key roles of FXIII in wound healing and tissue repair are strongly suggested by numerous observations, starting from its role in improving healing of cutaneous lesions to the beneficial effects on cell migration into the wound (5,6). We recently reported cases with chronic skin lesions had inverse association of the wound area with FXIII activity and that the lesion extension and progression increased as the number of a FXIII polymorphic allele decreased in the genotype of patients (7). In addition, carrier patients with chronic vascular insufficiency and venous leg ulcer had a significantly shorter mean healing time of the skin lesion after venous reflux correction.…”

“…FXIII molecule activity strongly depends from intragenic polymorphisms (31). The V34L is considered as the main functional locus (32) with stronger L34-associated increased activity being in L34-homozyogotes basically twice as high as VV34-wild-types (7,33). The prevalence of these polymorphisms is high in Caucasians (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), and no clear explanations exist for why variants at increased activity should be protective against atherothrombosis.…”

Genetic risk factors of chronic venous leg ulceration: Can molecular screening aid in the prevention of chronic venous insufficiency complications?

“…It has been proposed that the FXIII-A 34L variant displays improved crosslinking activity towards extracellular matrix components, thus further augmenting the antifibrinolytic properties of FXIII. Consequently, this modification should result in enhanced fibroblast migration followed by significantly improved ulcer healing (72)(73)(74). Indeed, these suggestions were confirmed by Gemmati et al (72) and Tognazzo et al (73), who found that 34LL homozygous patients displayed a 2-fold higher FXIII activity at the same FXIII blood level compared to wild-type 34VV homozygotous ones.…”

“…Consequently, this modification should result in enhanced fibroblast migration followed by significantly improved ulcer healing (72)(73)(74). Indeed, these suggestions were confirmed by Gemmati et al (72) and Tognazzo et al (73), who found that 34LL homozygous patients displayed a 2-fold higher FXIII activity at the same FXIII blood level compared to wild-type 34VV homozygotous ones. Furthermore, the 34L allele was associated with faster reduction of wound size and overall improved wound healing.…”

“…In contrast to the previously described CVU formation-inducing polymorphisms, variants of certain genes also facilitate wound healing. Among these is a polymorphism concerned with a gene encoding for coagulation factor XIII (FXIII) subunit A (72)(73)(74).…”