Development Of Venous Leg Ulcers Research Articles

Utility of high-frequency ultrasound in assessing cutaneous edema in venous ulcer patients.

High-frequency ultrasound (HFUS) using a 20MHz probe is a non-invasive assessment tool. Its utility in dermatology for diagnosis of disease or for monitoring of treatment response in various dermatological conditions is still being explored. Edema secondary to venous hypertension is the main pathogenic factor in the development of venous leg ulcers. However, there is no objective method for assessment of degree of edema. In this study, we explore the utility of high-frequency ultrasound in assessing cutaneous edema and for monitoring its improvement with compression therapy among patients with venous ulcer. Twenty patients with venous ulcer were enrolled in the study. Measurement of cutaneous edema was done at baseline and after 2weeks of compression therapy in all patients. The 3 levels of measurement were dorsum of foot (low site, L1), 4cm proximal to the medial malleolus (middle site, L2), and the medial aspect of the calf between the medial malleolus and the knee (upper site, L3). Baseline subepidermal low echogenic band (SLEB) measurements were 2.46±0.69mm, 2.94±0.65mm, and 2.66±0.64mm at L1, L2, and L3, respectively. There was a significant reduction in SLEB measurement after compression therapy ( p values 0.008, 0.002, and 0.003 at L1, L2, and L3, respectively). The mean percentage reduction in SLEB at level of medial malleolus (mid level - 29.61±12.24) was higher than the other 2 sites (L1-22.45±15.83 and L3 were 27.57±12.34). Cutaneous ultrasound aids in accurate assessment of level and severity of edema. Hence, it can be utilized in trials to objectively assess the adequacy of treatment for patients with venous insufficiency.

A qualitative study on the patient's narrative in the progression of chronic venous disease into a first venous leg ulcer: a series of events.

A venous leg ulcer (VLU) has a significant negative impact on quality of life. Prevention of a VLU is not yet imbedded in clinical practice because risk factors for developing a first VLU are not well known. To explore further the progression of chronic venous disease (CVD) into a first VLU from the patient's perspective. A qualitative study using semistructured interviews was conducted among male and female patients with a VLU. Patients from primary and secondary care, under and over 50 years of age, and with first and recurrent VLUs were included. The interviews were transcribed and analysed using a narrative approach to a thematic analysis. Transcripts were organized in chronological order and an iterative process was used to code the transcripts. Four key themes and the connections made between them emerged from the 11 narratives on the progression of CVD towards a first VLU: 'comorbidity', 'mobility', 'work and lifestyle' and 'acknowledgment of CVD'. Comorbidity was linked to reduced mobility and late acknowledgment of CVD. Comorbidity also affected work and lifestyle and vice versa. Work and lifestyle affected mobility and was linked to the acknowledgment of CVD. A reduction in mobility as a result of comorbidity and work and lifestyle occurred before the VLU developed. Patients did not recognize symptoms of CVD and did not acknowledge the chronicity of CVD. Healthcare professionals should be aware of reductions in mobility and the knowledge deficit in patients with CVD. What's already known about this topic? Not all patients with chronic venous disease (CVD) develop a venous leg ulcer (VLU). A patient's quality of life decreases significantly when a VLU develops. Risk factors for the development of a first VLU in patients with CVD are not well known, unlike risk factors for other chronic wounds like diabetic foot ulcer and pressure ulcers. What does this study add? The patient's narrative towards the development of a first VLU, a series of events. Insight into the events (comorbidity, mobility, work and lifestyle) that patients themselves link to the development of a VLU. Insight into the patients' acknowledgment of CVD in the progression of CVD towards a first VLU. What are the clinical implications of this work? More awareness is needed of CVD symptoms among patients and healthcare providers, as well as more awareness for prevention of a VLU in clinical practice. New insights (for further studies) are needed into the concept of mobility and the development of a VLU. Improved patient education and follow-up are needed for patients with CVD.

A systematic review on risk factors in developing a first-time Venous Leg Ulcer.

Venous Leg Ulcers (VLU) occur in about 1% of the Western population. A VLU takes 3-12months to heal, it recurs often, and it has a negative impact on the quality of life. The risk factors for the development of a first VLU are not well-understood and prevention of a first VLU therefore remains underappreciated. The aim of this study was to identify risk factors for developing a first VLU in adults (aged>18years) by searching the literature. We searched the Cochrane Library, Pubmed, Cinalh and Narcisto identify studies that investigated risk factors in developing a VLU. The last search was performed in January 2018. Two reviewers independently reviewed the abstracts and full-text articles, and assessed the methodological quality of the included studies. Results of studies using duplex scanning, and comparing participants with and without VLUs were included in the qualitative analysis. Where possible a quantitative meta-analysis was conducted. We found five studies that investigated the relation of several risk factors with VLU development. The methodological differences of the studies made it impossible to perform a quantitative analysis. The risk factors higher age (four studies), higher body mass index (four studies), low physical activity (four studies), arterial hypertension (four studies), deep vein reflux (three studies), deep venous thrombosis (three studies) and family history of VLU (three studies) were significantly associated with a VLU in the majority of the studies. To what extent they influence the development of a VLU remains unclear because of the limited number of studies that investigated the association of these risk factors with VLU development, and the heterogeneity of these studies. Further studies are needed to confirm the association of these risk factors with the development of a VLU and to explore overweight and low physical activity in more detail.

Compression for Primary Prevention, Treatment, and Prevention of Recurrence of Venous Leg Ulcers: An Evidence-and Consensus-Based Algorithm for Care Across the Continuum.

Chronic venous insufficiency is a prevalent disease that frequently leads to development of venous leg ulcers. While a number of evidence-based clinical practice guidelines have been developed that provide guidance for clinicians when caring for patients with chronic venous insufficiency, they lack adequate detail concerning selection and application of compression for prevention and management of venous leg ulcers. In order to address this need, the WOCN Society appointed a task force to develop an algorithm for compression for primary prevention, treatment, and prevention of recurrent venous leg ulcers in persons with chronic venous insufficiency. The task force used findings from a scoping literature review to identify current best evidence needed to support decision points and pathways within the algorithm. In addition, the task force convened a panel of 20 clinicians and researchers with expertise in lower extremity venous disorders in order to establish consensus around pathways and decision points within the algorithm lacking robust evidence. Following initial construction of the algorithm, a second interdisciplinary group of expert clinicians established content validity and provided additional qualitative feedback used to complete final revisions of the algorithm. This article reviews the process used to create this landmark algorithm, including generation of the evidence- and consensus-based statements used in its construction, the various pathways, and rich supplemental materials embedded within the algorithm, and the process used to establish content validity.

Oral aspirin for treating venous leg ulcers.

Oral aspirin for treating venous leg ulcers.

HFE p.C282Y gene variant is associated with varicose veins in Russian population.

Recently, the association of polymorphism rs1800562 (p.C282Y) in the hemochromatosis (HFE) gene with the increased risk of venous ulceration was shown. We hypothesized that HFE gene polymorphism might be involved not only in ulceration process, but also in susceptibility to primary varicose veins. We genotyped HFE p.C282Y (rs1800562) and p.H63D (rs1799945) variants in patients with primary varicose veins (n=463) and in the control group (n=754). In our study, p.282Y variant (rs1800562 A allele) was significantly associated with the risk of varicose veins (OR 1.79, 95% CI=1.11-2.89, P=0.02). A borderline significant reverse association of p.63D variant (rs1799945 G allele) with venous leg ulcer development was revealed in Russians (OR 0.25, 95% CI=0.06-1.00, P=0.05), but not in the meta-analysis (P=0.56). We conclude that the HFE gene polymorphism can affect the risk of developing primary varicose veins.

Venous leg ulcers: Summary of new clinical practice guidelines published August 2014 in the Journal of Vascular Surgery

The Society for Vascular Surgery (SVS) and the American Venous Forum (AVF) published guidelines for the management of venous leg ulcers in August 2014. The goal of this article (Part 2) is to summarize the guidelines that address diagnosis and treatment recommendations published jointly by the SVS and AVF that may affect the nursing practice of vascular nurses. Specific sections include wound evaluation, therapies used on the wound bed itself, compression, and operative or endovascular management. Part 1, published elsewhere in this issue, addressed the epidemiology and financial impact of ulcers, venous anatomy, pathophysiology of venous leg ulcer development, clinical manifestations, and prevention of venous leg ulcers. These 2 parts together provide a comprehensive summary of the joint SVS and AVF guidelines for care of venous leg ulcers.

Chronic Nonhealing Wounds: Could Leg Ulcers Be Hereditary?

Background. A number of well-known acquired and putative inherited etiological factors contribute to the development of venous leg ulcer (VLU). Aim. In this study we set out to perform a meta-analysis of putative genetic and acquired factors predisposing to VLU development. Methods. VLU patients (n=157) were divided into three subgroups in accordance with their acquired etiological factors. The frequencies of four genetic factors were determined: the R506Q (Leiden) mutation of the F5 gene, the G20210A mutation of the F2 (prothrombin) gene, the 2451 A/G SNP of the fibroblast growth factor receptor 2 (FGFR2) 3′ UTR, and the −308 G/A SNP of the tumor necrosis factor α (TNFA) promoter. Results. The −308 TNFA SNP exhibited a higher frequency among VLU patients without known acquired predisposing factor in their history, than among patients with thrombosis or soft tissue infection in their history (Fisher P=0.0173). Conclusions. This study has demonstrated that the group of VLU patients is heterogeneous in their genetic predisposing factors. Further large-scale studies are needed to delineate the associations among genetic and acquired etiological factors with regard to VLU development and to integrate the consequences of the already known genetic factors to the management of VLU.

The effect of a cryotherapy gel wrap on the microcirculation of skin affected by chronic venous disorders

The aim of this randomized clinical trial was to investigate a cryotherapy (cooling) gel wrap applied to lower leg skin affected by chronic venous disorders to determine whether therapeutic cooling improves skin microcirculation. Chronic venous disorders are under-recognized vascular health problems that result in severe skin damage and ulcerations of the lower legs. Impaired skin microcirculation contributes to venous leg ulcer development, thus new prevention therapies should address the microcirculation to prevent venous leg ulcers. Sixty participants (n = 30 per group) were randomized to receive one of two daily 30-minute interventions for four weeks. The treatment group applied the cryotherapy gel wrap around the affected lower leg skin, or compression and elevated the legs on a special pillow each evening at bedtime. The standard care group wore compression and elevated the legs only. Laboratory pre- and post-measures included microcirculation measures of skin temperature with a thermistor, blood flow with a laser Doppler flowmeter, and venous refill time with a photoplethysmograph. Data were collected between 2008 2009 and analysed using descriptive statistics, paired t-tests or Wilcoxon signed ranks tests, logistic regression analyses, and mixed model analyses. Fifty-seven participants (treatment = 28; standard care = 29) completed the study. The mean age was 62 years, 70% female, 50% African American. In the final adjusted model, there was a statistically significant decrease in blood flow between the two groups (-6.2[-11.8; -0.6], P = 0.03). No statistically significant differences were noted in temperature or venous refill time. Study findings suggest that cryotherapy improves blood flow by slowing movement within the microcirculation and thus might potentially provide a therapeutic benefit to prevent leg ulcers.

Association Between Venous Leg Ulcers and Sex Chromosome Anomalies in Men

We report here two cases of men, aged 46 and 23 years, with refractory chronic venous leg ulcers in association with sex chromosome aberrations: one with a 47,XXY/48,XXXY karyotype (Klinefelter syndrome) and the other with a 47,XYY karyotype (Jacob syndrome). In both patients, the occurrence of leg ulcers was the reason for seeking medical care; their medical history was other-wise unremarkable. Chromosomal analyses were performed due to the unusually young age for development of venous leg ulcers. The pathophysiology behind the occurrence of venous leg ulcers in patients with numerical aberrations of the sex chromosomes is incompletely understood. Involvement of elevated plasminogen activator inhibitor-1 levels in the pathogenesis of venous leg ulcers has been reported in patients with Klinefelter syndrome. Notably, our patient with 47,XXY/48,XXXY presented with androgen deficiency but normal plasminogen activator inhibitor-1 activity.

Genetic Background of Venous Leg Ulcer Development

Fibroblast growth factor receptor 2 gene codes for IIIb and IIIc transcript variants, which play pivotal roles in normal wound healing. Tumor necrosis factor α mediates several biological processes including wound healing. We aimed to characterise the expression pattern of IIIb expressed by in vitro cultured keratinocytes and in skin biopsy samples of venous leg ulcer patients, and to identify polymorphisms which may play a role in the pathomechanism of prolonged wound healing in venous leg ulcer patients. Real-time reverse transcription polymerase chain reaction and Western blotting methods were used for expression studies, polymerase chain reaction with TaqMan probes and with restriction fragment length polymorphism method were performed for polymorphism studies. We demonstrated that the expression of IIIb is related to the proliferation states of HaCaT keratinocytes and its expression is down-regulated in the uninvolved epidermis of venous leg ulcer patients ( n = 15) compared to the epidermis of controls ( n = 15). We identified a polymorphism in the 3’ untranslated region (2451A/G) of the fibroblast growth factor receptor 2 gene, which displayed a significant difference in the allelic distribution between leg ulcer patients ( n = 82) and controls ( n = 82; p = 0.0103). We hypothesize that this polymorphism may be a susceptibility factor for venous leg ulcer. In another set of experiment we demonstrated that the A allele of the –308 tumor necrosis factor α polymorphism might be a potential factor for venous leg ulcer susceptibility; however, our data suggest that this association is secondary and the primary association probably exists with obesity.

The altered expression of syndecan 4 in the uninvolved skin of venous leg ulcer patients may predispose to venous leg ulcer

Syndecan 4 (SDC4), a heparan sulfate proteoglycan, and neuropilin 1 (NRP1), a transmembrane receptor, are both involved in normal wound healing, but little is known about their possible role in venous leg ulcer pathogenesis. We aimed to investigate whether there are any expression abnormalities and/or gene polymorphisms of SDC4 and NRP1 associated with venous leg ulcer. SDC4 showed significantly lower mRNA and protein expression in the uninvolved dermis of venous leg ulcer patients (n=15) compared with controls (n=15; p=0.0136), while NRP1 showed no expression abnormalities. None of the examined SDC4 and NRP1 polymorphisms showed a difference in their allelic distribution between leg ulcer patients (n=92) and controls (n=92). We hypothesize that SDC4 may play an essential role not only in the inflammation and tissue formation phases of normal wound healing, but its expression abnormalities observed in the uninvolved dermis of venous leg ulcer patients may contribute to venous leg ulcer development.

Hypothetical molecular mechanisms by which local iron overload facilitates the development of venous leg ulcers and multiple sclerosis lesions

This paper presents a hypothetical model of role for iron in the development of venous leg ulcers and multiple sclerosis. Elevated concentrations of iron were found in the skin affected by venous hypertension and also in the areas of brain with multiple sclerosis lesions. Individuals with hemochromatosis gene (HFE) mutations: C282Y and H63D, which result in a less efficient transport of iron by macrophages, are characterized by an increased risk for venous leg ulcer and multiple sclerosis. Multiple sclerosis is a T cell-mediated disease, and T cells probably participate in the development of venous ulcers. This deleterious role of ferric ions could be related to the regulation of T cell proliferation and apoptosis. Under normal conditions excessive accumulation of T cells cannot take place, because nitric oxide and interferon-gamma drive these cells toward apoptosis. However, in tissues with a high concentration of iron, T lymphocytes proliferate instead of undergoing apoptosis. This is possible due to the internalization of the INF-gammaR2 chain of the interferon-gamma receptor, the downregulation of inducible nitric oxide synthase expression in macrophages and the inactivation of the active site of caspases. Yet, it should be emphasized that this hypothesis does not claim for the increased concentration of iron as a direct causal factor for the development of venous ulcerations or multiple sclerosis, but rather, iron is a factor that modulates and exaggerates the autoimmune process. Iron chelators, administered systemically or locally, should potentially exhibit therapeutic and prophylactic activity against venous leg ulcers and multiple sclerosis.

Association Between the Use of β-Adrenergic Receptor Agents and the Development of Venous Leg Ulcers

To explore an association between the use of beta-adrenergic receptor agonists or antagonists and the onset of venous leg ulcers (VLUs). Retrospective cohort study. Ambulatory setting of general practice in the United Kingdom. Patients Patients followed by participating physicians. Onset of VLU. A total of 414 887 patients registered in the General Practice Research Database met our study criteria for eligibility. Of these individuals, 62 886 were exposed to a beta-adrenergic receptor agonist and 54 861 were exposed to a beta-adrenergic receptor antagonist (6620 used both beta-adrenergic receptor antagonists and agonists). Of those exposed to a beta-adrenergic receptor agonist, 15.5% developed a VLU, whereas 18.4% of those who were not exposed developed a VLU. Of those exposed to a beta-adrenergic receptor antagonist, 18.2% developed a VLU, whereas 19.9% of those not exposed developed a VLU. The odds ratio (OR) of association between beta-adrenergic receptor antagonist and VLUs was 1.02 (95% confidence interval [CI], 0.99-1.04); for the association between beta-adrenergic receptor agonist and VLUs, 0.84 (95% CI, 0.82-0.86). The fully adjusted ORs were 1.04 (95% CI, 0.98-1.11) and 0.44 (95% CI, 0.42-0.45), respectively. Furthermore, using propensity score models, we were able to confirm the association for beta-adrenergic receptor agonist users. In addition, beta-adrenergic receptor antagonist users in many of the propensity score quintiles were also protected from developing VLUs. A protective association between beta-adrenergic receptor agonists and perhaps beta-adrenergic receptor antagonists and VLUs exists. There is strong laboratory evidence to support these epidemiologic findings. The evidence in this study should not be used as a rationale for treatment of VLUs with beta-adrenergic receptor agents but should be compelling for the consideration of a randomized clinical trial.

A potential role of interferon-γ in the pathogenesis of venous leg ulcers

Venous leg ulcer is the most severe expression of chronic venous insufficiency. Venous ulcerations are always associated with venous ambulatory hypertension, but the exact mechanism leading from pathological hemodynamics in venous circulation to the necrotic lesions in the skin still remains undiscovered. It has been shown that tissue injury in venous ulcer patients was induced by leukocytes. However, though infiltrating leukocytes have at their disposal a powerfully cytotoxic arsenal, it has not been discovered which molecular mechanisms may contribute to the skin damage. The search for this hypothetical factor responsible for the development of ulceration should be focused on mechanisms leading to apoptosis of keratinocytes, on pathogenesis of related dermatological pathologies, on other pathologies associated with epithelial lesions, and on mechanisms responsible for the expression of adhesion molecules. A thorough review of the literature, with special regard to cytokines, has revealed that proinflammatory cytokine--interferon-gamma (INFgamma)--could be a pivotal cytokine in the pathogenesis of venous ulceration. This cytokine, however, has not been investigated in venous leg ulcer patients before. INFgamma is a glycoprotein with numerous immunological and antiproliferative activities. The most important message from recent investigations is the fact that INFgamma seems to be the main mediator of keratinocyte apoptosis. INFgamma mediates also leukocyte chemotaxis, and enhances the expression of adhesion molecules involved in the pathophysiology of chronic venous insufficiency. Therapeutic injections of interferons can result in skin necrosis. If it were proven that INFgamma was responsible for the development of venous leg ulcers, this fact would have important clinical consequences. In such a case, anti-INFgamma agent could be used, either in the management of active ulceration, or in the prevention of recurrent ulcer.

The role of the fibrin cuff in the development of venous leg ulcers

The prevalence of venous ulcers has been quoted as between 0.15% and 1% in Europe and between 600,000 and 2.5 million in the US. The relative frequency of venous leg ulcers is thought to be decreasing due to improvements in community care, prevention and diagnosis, although the ageing population means there is a potential for numbers to increase. Despite these reductions, the economic and social impact is far-reaching — venous leg ulcers cost around £200 million per year in the UK and $1 billion in the US.

Comparative Study of NonInvasive Vascular Imaging Techniques in the Evaluation of Chronic Venous Leg Ulcers

Aim: To compare noninvasive vascular imaging techniques in the evaluation of chronic venous leg ulcers, and to detect the discriminating parameters between primary valvular incompetence (PVI) and postthrombotic syndrome (PTS).Methods: A total of 61 limbs with chronic venous ulcers were included in this study. Of 61 limbs, 31 had PVI and remaining 30 had documented PTS. The distribution of venous reflux including superficial, deep, and perforating vein was determined by duplex ultrasound. The venous functions including venous volume (VV: ml), venous filling index (VFI: ml/sec), ejection fraction (EF: %), and residual volume fraction (RVF: %) were evaluated by air plethysmography (APG). The near–infrared spectroscopy (NIRS) was used to measure calf muscle total hemoglobin (tHb), oxygenated hemoglobin (O2Hb), and deoxygenated hemoglobin (HHb) levels using APG exercise protocol, and the changes in these parameters were divided into three patterns; Type I: The HHb does not increase beyond the O2Hb during the total procedure. Type II: The HHb increases beyond the O2Hb during the excise. Type III: The HHb increases beyond the O2Hb during the total procedure. Patients with Type III were considered to have most significant calf muscle dysfunction.Results: Superficial venous incompetence was significantly predominant in the PVI (p = 0.031). The proportion of deep vein incompetence was significantly higher in the PTS (p = 0.023). Of these, patients with PTS had significantly higher proportion of femoral vein (FV) and popliteal vein (POPV) incompetence compared to these with PVI (p = 0.0006, 0.0015, respectively). There was no statistically significant difference in the proportion of perforator incompetence between the groups (p = 0.611). There were no significant differences in VV (94.8 ± 43.7, 84.7 ± 48.8, p > 0.999), VFI (5.04 ± 2.49, 5.19 ± 3.15, p = 0.236), EF (51.9 ± 19.2, 47.2 ± 25.3, p = 0.903), and RVF (54.8 ± 22.3, 66.1 ± 29.8, p = 0.378). In the NIRS examinations, Type I was found in 20 limbs (64.5%) in the PVI and 3 (10%) in the PTS, and this was a statistically significant (p < 0.0001). On the contrary, Type III was seen in 1 limb (3.2%) in the PVI and 19 (63.3%) in the PTS. The proportion of Type III was significantly higher in the PTS (p < 0.0001).Conclusions: These data suggest that reflux in the FV and POPV might play more important role in the development of venous leg ulcers in patients with PTS. The APG–derived parameters did not improve the discrimination power between the two groups. The increased NIRS–derived HHb in the exercising calf muscle is profound in patients with PTS, suggestive of a promising parameter both in the discrimination of the patients with chronic venous leg ulcers and in the follow–up of the patients with deep vein thrombosis.

Pathomechanism of chronic venous insufficiency and leg ulcer.

Uniform view of chronic venous diseases has been formed in the last 3 decades. Chronic venous insufficiency (CVI) is a functional disorder of the venous system of the lower limb. The basis of the pathology is always the venous hypertension caused by valvular insufficiency and reflux with or without venous outflow obstruction. Epifascial, subfascial and transfascial forms of CVI can be distinguished. In the practice these forms are almost always combined. The consistent venous hypertension is the initiating factor in alterations in the microcirculation which leads to skin changes and venous ulceration. The precise mechanism of the development of venous leg ulcer is still uncertain. A recent hypothesis suggests that leukocytes are trapped in the capillaries and attaching to the endothel they become activated and release proteolytic enzymes, free radicals which have destructive effects on lipid membranes, proteins as well as on many connective tissue compounds. The endothelium plays active role in the complex mechanism. Increased expression of tissue metalloproteinases has been observed in the periulcer skin. The presence of perivascular leukocyte infiltration and fibrin cuff is a reflexion of an inflammatory process. The clinical stages of CVI are likely to be the results of a systemic inflammatory response to a period of venous hypertension.

Lupus anticoagulant and venous leg ulceration.

Most leg ulcers occur in patients with venous insufficiency. However, not all patients with venous insufficiency develop leg ulcers. Recent studies have found that factors causing clotting abnormalities, e.g. anticardiolipin antibody (ACA), are associated with leg ulcers. Although lupus anticoagulant, like ACA, belongs to the group of antiphospholipid antibodies, its presence in patients with venous leg ulceration has not been previously reported. To determine the presence of lupus anticoagulant in patients with venous leg ulceration. We investigated the presence of lupus anticoagulant in 27 patients with venous leg ulcers and compared these data with controls. Lupus anticoagulant was evaluated in all subjects by the Russell's viper venom test. Of 27 patients with venous leg ulceration, 16 (59%) were shown to have lupus anticoagulant, while only one of 32 controls (3%) was found to have lupus anticoagulant. Thus, lupus anticoagulant was significantly more frequent in patients with venous leg ulcers than in controls (P < 0.001). We suggest that lupus anticoagulant could be a hitherto unknown factor contributing to the development of venous leg ulcers.

Modulation of urokinase-type and tissue-type plasminogen activator occurs at an early stage of progressing stages of chronic venous insufficiency.

Chronic venous insufficiency (CVI) progresses through a series of clinical stages, from healthy skin to poorly healing leg ulcers. The aim of this study was to analyse the distribution pattern and activity level of urokinase-type (uPA) and tissue-type plasminogen activators (tPA) in normal skin and in tissue biopsies of progressing stages of CVI, prior to and including venous ulceration. Biopsies 6 mm thick were taken from 14 healthy volunteers and 37 patients with 5 different stages of CVI: telangiectases; stasis dermatitis; hyperpigmentation; lipodermatosclerosis; and leg ulcer. Changes in the enzymatic activity and spatial localization of uPA and tPA during the progression of CVI were examined using in situ histological zymography. Normal skin and skin with telangiectases showed a punctate PA activity, consisting of both uPA and tPA activity. As CVI progressed, an increase in the distribution of uPA and a decrease in tPA activity was observed. The spatial localization of uPA was widespread within the dermis of biopsies from stasis dermatitis and lipodermatosclerosis and was associated in particular with the dermoepidermal junction. Hyperpigmented skin revealed a pattern of PA expression similar to that of healthy skin. However, leg ulcer specimens exhibited peak levels of uPA with little tPA. Furthermore, a plasminogen-independent protease activity that was not present in any of the earlier stages of CVI appeared. Our results indicate that there are profound changes in PA activity during the progression of CVI and that these changes begin early in CVI, for example, in stasis dermatitis. We hypothesize that the balance or imbalance of the PA activity in the later stages of CVI is an important pathogenic factor for the development of venous leg ulcer.