S. Carandina

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

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 cm2,± 23.6; VL = 6.1 cm2,± 6.9; LL = 4.1 cm2,± 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 cm2, ± 20.2 vs. 9.0 cm2, ± 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 XIII contrasts the effects of metalloproteinases in human dermal fibroblast cultured cells

Matrix metalloproteinases (MMPs) are overexpressed in venous leg ulcers, determining a breakdown of the main extracellular matrix (ECM) components owing mainly to collagenase activities, and so playing a crucial role in ulcer pathogenesis. The authors studied the effects of coagulation factor XIII (FXIII), which cross-links collagen and other ECM components, in human fibroblast cultured cells in the presence and in the absence of matrix metalloproteinases from Clostridium histolyticum collagenase. Clostridium collagenase at concentrations of 2.0, 1.0, and 0.5 mg/mL was added to normal human dermal fibroblasts cultured in the presence of 0.0, 1.0, and 5.0 U/mL of FXIII concentrate (Fibrogammin P, Aventis Behring). Cell counting and metabolically active fibroblast evaluation in the cultures were monitored for 72 hours, by means of trypan-blue dye and MTT test, respectively. The MTT test showed that at the highest collagenase concentration (2.0 mg/mL), the cell number decreased more than 95% in 72 hours of treatment and no significant differences were observed regardless of the FXIII concentrations utilized. At lower collagenase concentration (1.0 mg/mL), in absence or in presence of FXIII (1.0 U/mL), the cell number decreased by about 80% in 72 hours. In contrast, in the presence of higher FXIII levels (5.0 U/mL), cells suffered globally significantly less collagenase effects (p=0.011) and the gain was appreciable at each time tested. Finally, at 0.5 mg/mL of collagenase concentration, in the absence of FXIII, the cell number decreased by about 60% in 72 hours, whereas in presence of FXIII 1.0 U/mL and 5.0 U/mL, cells decreased significantly less, by about 35% and 20%, respectively (p<0.025 and p<0.01, respectively). These data were also confirmed by direct cell counting utilizing the trypan-blue test. Factor XIII contrasts effectively the detrimental action of Clostridium collagenases in human fibroblast cultured cells. These results support several in vivo reports about the effectiveness of its topical application in order to enhance the venous ulcer healing processes.

Haemodynamic CHIVA correction surgery versus compression for primary venous ulcers: first year results

Objective: To compare two different treatments for primary venous ulcers: a minimally invasive surgical technique for the haemodynamic correction of reflux, versus a traditional compression treatment. Method: From a cohort of 87 lower extremities affected by the first episode of venous ulcers, 45 mobile patients affected by primary chronic venous insufficiency were randomized to receive either the haemodynamic correction procedure (CHIVA) or compression treatment. Results: Mean follow up lasted one year. The rate of healing in the surgical group was 100% in a mean time of 29 days with a velocity of 2.86 mm2/day,and in the conservative group the rate was 96% in 61 days, with a velocity of 1.66 mm2/day (P<0.02). All air plethysmographic parameters, with the exception of ejection fraction, significantly improved at six months in the surgical group. Finally, quality of life significantly improved in both groups, but in the surgical group the following domains were significantly different compared with the compression group: RP, role limitations due to physical problems; VT, energy/vitality; SF, social functioning; RE, role limitations due to emotional problems; and MH, mental health. Conclusions: Surgical haemodynamic correction of reflux has been demonstrated to improve venous function, time to ulcer healing and quality of life when compared with compression treatment.

Perforator of the popliteal fossa and short saphenous vein insufficiency

Objectives: To assess the preoperative frequency of reflux from the perforator of the popliteal fossa (PPF) in cases of short saphenous vein insufficiency. Methods: Short saphenous vein insufficiency cases were carefully investigated in 590 consecutive patients affected by primary chronic venous insufficiency. PPF was identified in accordance with anatomical criteria translated in ultrasonic anatomy. Reflux was elicited in standing both by squeezing and active manoeuvres. Results: Short saphenous vein insufficiency occurred in 77/590 cases (13%). In 15/77 cases (19%) short saphenous insufficiency was fed by reflux from the PPF, with a competent saphenopopliteal junction, and this finding was confirmed at surgical exploration. PPF superficial outlet was found on the inferior aspect of the short saphenous main trunk (type 1 presentation, 11 cases) and on a varicous tributary (type 2, four cases). Conclusions: PPF is a neglected entity, but often is the only source of the reflux in the short saphenous vein system. The lack of preoperative awareness of its presence could lead to an increased rate of saphenopopliteal recurrences, especially in case of type 1 presentation.