Prognostic role of factor XIII gene variants in nonhealing venous leg ulcers

OBJECTIVE: Many factors impair healing of chronic venous ulcer (CVU), and many theories have been proposed to explain their pathogenesis. Coagulation factor XIII (FXIII) influences tissue regeneration and angiogenesis with effects on wound healing. Because FXIII properties depend upon its genetic variants, we investigated whether intragene polymorphisms may have modulating effects on the CVU area. METHODS: The study included 121 patients with nonhealing CVUs (CEAP clinical class C6) that included 67% with primary chronic venous disease (CVD), 26% with post-thrombotic ulcers, and 7% with mixed ulcer origin. Polymerase chain reaction was used to genotype them for Val34Leu, Pro564Leu, and Tyr204Phe variants in the FXIII-A subunit gene and for His95Arg variant in the FXIII-B subunit gene. The same variants were analyzed in 102 controls, healthy subjects who were case-matched by age and gender. RESULTS: Genotype distribution for all polymorphisms investigated was not significantly different between cases and controls. Conversely, our CVU cases had a mean ulcer area inversely related with the presence of both Leu34 and Leu564 alleles (ValVal, 12.3 +/- 22.4 cm2 vs LeuLeu, 3.9 +/- 2.6 cm2, P = .002; ProPro, 10.2 +/- 21.2 cm2 vs LeuLeu, 2.9 +/- 1.4 cm2, P = .002). In combined analysis, those cases who were wild-type for both variants (ValVal34/ProPro564) had a further increase in mean ulcer size compared with cases carrying both variants (Leu34/Leu564) (13.3 +/- 27.1 cm2 vs 5.2 +/- 5.6 cm2; P = .034). CONCLUSIONS: No correlation exists between FXIII genotypes and the prevalence of chronic venous ulcers, thus demonstrating that FXIII polymorphisms have no role in ulcer development. In contrast, FXIII-gene variants, in particular the non-wild-type alleles Leu34 and Leu564, were associated with a smaller venous ulcer surface and might have favorable effects on reparative processes.     

Increased angiogenic response but deficient arteriolization and abnormal microvessel ultrastructure in critical leg ischaemia

BACKGROUND: Ischaemia is known to induce angiogenesis, but the effects of critical leg ischaemia (CLI) on angiogenesis remain unclear. The aim of this study was to examine the physiological angiogenic response in CLI by investigating the extent of neovascularization, characterizing microvessel subtypes and determining the microvessel ultrastructure. METHODS: Gastrocnemius muscles were biopsied from 12 patients with CLI and 12 without leg ischaemia. Microvessels were evaluated immunohistochemically using three endothelial markers (anti-CD31, anti-CD34 and PAL-E) and anti-alpha smooth muscle actin (SMA) as a mural cell marker to label arterioles. Ki67 was used to demonstrate active cell proliferation. Further microvessel ultrastructural characteristics were determined by transmission electron microscopy. RESULTS: The CLI group had significantly higher microvessel density and microvessel : muscle fibre ratio for all endothelial subtypes examined (P < 0.001). PAL-E staining demonstrated the highest increase: 4.7 times higher in CLI muscle. There was no significant difference in alphaSMA-positive microvessel density (P = 0.118) or microvessel: muscle fibre ratio (P = 0.214). Ki67 staining showed no active cell proliferation. Transmission electron microscopy showed CLI microvessels had abnormal morphology, mainly a thick basement membrane. CONCLUSION: A physiological angiogenic response was found in CLI, but the microvessels had an abnormal ultrastructure. A lack of active cell proliferation suggests that the angiogenic response may have been exhausted.     

Compression and venous surgery for venous leg ulcers

This article reviews published data on the effects of surgery and compression in the treatment of venous ulcers and the best options for compression therapy. Randomized controlled studies reveal that surgery and compression have similar effectiveness in healing ulcers but surgery is more effective in preventing recurrence. Most leg ulcers have a venous pathophysiology and occur because of venous ambulatory hypertension caused by venous reflux and impairment of the venous pumping function. Proposed surgical interventions range from crossectomy and stripping to perforator vein interruption and endovascular procedures (laser, radiofrequency). More conservative procedures (foam sclerotherapy, conservative hemodynamic treatment) have also been proposed.     

A new approach in the management of chronic nonhealing leg ulcers.

Chronic leg ulcers are a major cause of mortality and morbidity. The efficacy of hyperbaric oxygen treatment is being evaluated in the management of nonhealing leg ulcers to improve skin graft survival. Twenty-seven patients with 36 chronic leg ulcers were examined. Each wound received 12 preoperative hyperbaric oxygen treatments, split-thickness skin grafting, followed by 12 postoperative hyperbaric oxygen treatments. Wound transcutaneous oxygen tension measurements (TCOM) were taken. The graft take was evaluated. At 18 months follow-up, 18 skin grafts (50%) showed complete take, 15 (41.7%) demonstrated partial take, and 3 (8.3%) failed. Hyperbaric oxygen treatment is an effective adjunct in the management of chronic leg ulcers, and its use resulted in increased graft take and survival.     

Surgery of venous leg ulcers.

Numerical data are presented to prove the endemic nature and importance of the varicose and postthrombotic syndrome. The fact that even in the most fortunate cases conservative therapy can bring about only temporary improvement, has directed attention to surgical methods. The surgical methods of treatment of varicos (VS) and postthrombotic (PS) syndrome are reviewed. The surgical procedure considered adequate is described. It consists of the following steps. After phlebography, in the case of satisfactorily functioning deep veins, the superficial venous system is extirpated according to Trendelenburg, Madelung and Babcock, the insufficient perforants are exposed and ligated, the ulcer is excised deeply and broadly into the intact tissue. The effect is covered at a later date with a semi-thick skin graft. The importance of supplemental conservative methods (preparation and postoperative treatment) is stressed. This complex therapy was applied in 112 severe cases of venous failure; in 96% the result was excellent, in 3% adequate and in 1% poor. The guiding principles for the successful solution of chronic venous failure are a correct diagnosis and a correctly performed operation. Only proper care can guarantee good results.     

Layered shaving of venous leg ulcers

A method for the quick preparation of refractory venous ulcer beds for autografting is described. Irrespective of their clinical or bacteriological state, ulcer granulations and other products of frustrated healing are shaved in layers down to an even and surgically clean base using an ordinary skin grafting knife. Our experience with 32 consecutive patients (58 ulcers) is reported. The mean duration of hospital stay, the patient being completely healed on discharge, was 18.3 days. This represents a decrease of more than 3 weeks when compared to a previously used standard method. No investigation into the question of recurrence was carried out as available evidence, which is critically reviewed, indicates no significant relation between the method of grafting and the incidence of recurrence.     

Oxidative stress in chronic venous leg ulcers

Venous leg ulcers are common and cause considerable morbidity in the population. As healing may be slow or may never be achieved, ulcers create persistent and substantial demands on clinical resources. Great efforts have been made to accelerate tissue repair in chronic venous leg ulcers with limited success. This may at least be partly due to the limited knowledge on the microenvironment of chronic wounds. In fact, the tremendous impact of the microenvironmental conditions on the outcome of wound healing has increasingly become apparent. Oxidative stress as a consequence of an imbalance in the prooxidant-antioxidant homeostasis in chronic wounds is thought to drive a deleterious sequence of events finally resulting in the nonhealing state. The majority of reactive oxygen species are most likely released by neutrophils and macrophages and to an unknown extent from resident fibroblasts and endothelial cells. As the inflammatory phase does not resolve in chronic wounds, the load of reactive oxygen species persists over a long period of time with subsequent continuous damage and perpetuation of the inflammation. In this article, we will critically discuss recent findings that support the role of oxidative stress in the pathophysiology of nonhealing chronic venous leg ulcers.     

Analysis of therapy-resistant venous leg ulcers

Chronic leg ulcers represent a major health-care problem with considerable socioeconomic impact. Patients with seemingly therapy-resistant leg ulcers are common to all clinics. The purpose of the present study was to (1) examine a group of patients with nonhealing venous leg ulcers treated with a double-layer bandage and (2) evaluate whether the addition of an interactive hydrocolloid wound dressing could initiate healing in these patients. Twenty-two patients with ulcers caused by venous insufficiency were included. The patients had a mean ulcer duration of 27.6 years. Duration of the present ulcer was at least 1 year (mean >/= 4.1 years). Twenty of the 22 patients showed massive lipodermatosclerosis. Before inclusion, all patients had used double-layer bandage consisting of a zinc-impregnated bandage or stocking and a self-adhesive compression bandage for 1 year or longer without improvement. The new regimen was a triple-layer treatment with the hydrocolloid water applied over the ulcer and the traditional double-layer bandage unchanged. Three patients were dropped from the study. Nineteen patients were followed until healing or for 10 months. Nine of the 19 patients who completed the study healed. Ulcer area was reduced by 70% or greater in 7 patients and by 30% to 40% in two patients. One ulcer did not respond to the treatment and worsened slightly. The results of this study were encouraging and indicate that the triple-layer treatment with the hydrocolloid dressing applied to the ulcer should be evaluated in a randomized, controlled study in patients with less pessimistic prognoses.     

Biochemical analysis of wound fluid from nonhealing and healing chronic leg ulcers

The purpose of this study was to determine the biochemical composition of fluid taken from chronic wounds, to compare these values with that of serum, and therefore to assess whether the wound fluid is representative of the extracellular environment of the wound. Paired wound fluid and blood samples were collected from eight patients with chronic leg ulcers in a nonhealing and healing phase. Wound fluid and serum samples were screened for a profile of general biochemical analyses, including electrolytes, lactate, glucose, and protein analyses. Electrolyte levels were essentially identical in wound fluid and serum samples. Lactate and lactate dehydrogenase levels were significantly greater and glucose and bicarbonate levels were significantly lower in wound fluid when compared with the paired serum samples. Albumin and total protein levels in wound fluid were on average half those of serum levels. In this small sample of eight patients, wound fluid collected from chronic leg ulcers is an exudate with the biochemical composition expected in extracellular fluid. In addition, bicarbonate and glucose levels increase and C-reactive protein levels decrease in wound fluid, but remain unchanged in serum, during healing. These results suggest changes in the state of hypoxia and the inflammatory process in the healing wound.     

Free tissue transfer provides durable treatment for large nonhealing venous ulcers

BACKGROUND: Most venous ulcers (VUs) will heal with conventional treatment, which focuses on improving regional venous hemodynamics. This treatment, however, often fails to heal large, recurrent VUs that are associated with severe lipodermatosclerosis (LDS). These complicated ulcers may require correction of local venous hemodynamics and replacement of the surrounding LDS with healthy tissue. We report our experience managing 24 especially difficult VUs with debridement and free flap coverage. PATIENTS AND METHODS: Between 1987 and 1997, 25 free flap procedures were performed in 22 patients for 24 recalcitrant VUs. Ulcers had been present for a mean of 5.24 years and had failed to heal with conservative therapy and split-thickness skin grafts (STSGs) (mean, 2.2). Eleven patients (46%) had exposed bone, tendon, or joint. At operation the area of LDS was excised, and all perforating veins were ablated. The defects after excision ranged from 100 to 600 cm(2) (mean, 237 cm(2)). The free flap was inset within the defect and covered with an STSG. RESULTS: We healed all 24 ulcers with free tissue transfer (one patient required a second flap after the first failed). There were no deaths. Local complications that required repeat STSG occurred in three (13%) of the 24 successful flap transfers. Four other flaps had minor local complications that healed with local wound care. Follow-up was available for 21 of the 24 successful flap transfers. No recurrent ulcers were identified in the territory of the flap after a mean of 58 months, but three patients had new ulcers in the same leg after 6 to 77 months. Patients with severe complications were hospitalized longer than those with minor or no complications (45.7 vs 12.8 days, P <.01), and their hospital charges were greater ($76,681 vs $30,428, P <.01). CONCLUSION: Free tissue transfer can provide rapid healing and long-term relief from severe VUs that are unable to be treated with conventional therapy. This technique improves venous hemodynamics, removes all liposclerotic tissue, provides an abundant blood supply, and resolves the tissue-related components of chronic ulceration. Although further work is needed to determine the optimal indications, this technique provides a durable treatment for especially recalcitrant ulcers.     

下肢慢性静脉溃疡的综合治疗

目的探讨下肢慢性静脉溃疡的综合治疗方法。方法回顾性分析2012年7月~2013年1月我科收治的10例下肢慢性静脉溃疡患者（10条患肢）的临床资料,均采用大隐静脉高位结扎加抽剥并联合应用透光曲张静脉刨吸术、泡沫硬化剂注射、腔镜深筋膜下交通静脉结扎术等方法处理小腿病灶。分别在术前及术后3个月对临床症状的改善情况采集数据,按临床严重程度评分（VCSS）方法进行评估。结果患者均成功实施联合手术治疗方案,在术后的VCSS评分项目中得到改善[（12.3±2.06）v s （9.6±1.71）]。随访（6.70±1.45）个月,疼痛较前均有缓解,未发现患肢有曲张浅静脉残余或复发,8例溃疡基本愈合,仅有2例还有残余溃疡,但都控制在2 cm内,已愈合的溃疡未见复发。结论下肢慢性静脉溃疡经正确选择联合治疗方案进行处理后的效果是理想且安全的,而且其短期效果稳定。     

Effect of sharp debridement using curette on recalcitrant nonhealing venous leg ulcers: A concurrently controlled, prospective cohort study

The objective of this study was to evaluate the effect of sharp debridement on the progression of recalcitrant chronic venous leg ulcers (CVLU) and to assess the feasibility of performing this procedure in an outpatient setting. We performed a prospective study of 55 CVLU (53 patients) over a 12-month period. The study group, which underwent debridement, contained 28 CVLU whose wound beds had slough, nonviable tissue, and no granulation tissue. The control group was 27 CVLU with minimal (15-20%) granulation tissue, but no slough or nonviable tissue. Treatments were otherwise similar. Age, body mass index, mean ulcer surface area (MSA) and mean ulcer duration were comparable in both groups. Ulcer measurements were taken at 4 weeks before debridement, at the time of debridement, and 4 and 20 weeks post-debridement. There was no change in the MSA from 4 weeks before to the time of debridement in either group. At 4 weeks post-debridement, the study ulcers showed a 6 cm(2) reduction in the MSA vs. a 1 cm(2) reduction in controls (P = 0.02). By week 20 post-debridement, the study ulcers achieved a 7.4 cm(2) reduction in the MSA vs. an increase of 1.3 cm(2) in controls (P = 0.008). Between weeks 8 and 20 post-debridement, 16% of study ulcers vs. 4.3% of control ulcers achieved complete healing. Infection rates and antimicrobial usage were similar. We conclude that sharp debridement is effective in stimulating healing of recalcitrant CVLU. It is safe, well tolerated, and can be performed in an outpatient setting.     

Compression treatment of venous and venous/arterial leg ulcers

The French National Authority for Health has recalled recommendations for the use of compression in the treatment of venous or venous/arterial leg ulcers. Different types of bandages and compression stockings must be used. The pressure to be achieved is between 30 and 40 mm Hg at the ankle (and below 30 mm Hg in case of mixed ulcers). In daily practice, beyond these recommendations, the choice of type of compression must also take into account the size of the ulcer, the appearance of the wound, the existence of leg dysmorphia, the volume of the oedema and also the general condition of the patient.     

Management of mixed arterial and venous leg ulcers

BACKGROUND: The aim was to assess healing in patients with mixed arterial and venous leg ulcers after protocol-driven treatment in a specialist leg ulcer clinic. METHODS: The study included consecutive patients referred with leg ulceration and venous reflux over 6 years. Legs without arterial disease (ankle : brachial pressure index (ABPI) above 0.85) were treated with multilayer compression bandaging and patients with severe disease (ABPI 0.5 or less) were considered for immediate revascularization. Those with moderate arterial compromise (ABPI above 0.5 up to 0.85) were initially managed with supervised modified compression and considered for revascularization if their ulcer did not heal. Healing rates were determined using life-table analysis. RESULTS: Of 2011 ulcerated legs, 1416 (70.4 per cent) had venous reflux. Of these 1416, 193 (13.6 per cent) had moderate and 31 (2.2 per cent) had severe arterial disease. Healing rates by 36 weeks were 87, 68 and 53 per cent for legs with insignificant, moderate and severe arterial disease respectively (P < 0.001). Seventeen legs with moderate and 15 with severe arterial disease were revascularized. Of these, ulcers healed in four legs with moderate and seven with severe disease within 36 weeks of revascularization (P = 0.270). Combined 30-day mortality for revascularization was 6.5 per cent. CONCLUSION: A protocol including supervised modified compression and selective revascularization achieved good healing rates for mixed arterial and venous leg ulceration.