Prevalence rate for inherited thrombophilia in patients with chronic and recurrent venous leg ulceration

The aim of the study was to determine the prevalence rate for inherited thrombophilia (IT) in patients with chronic (CVU) and recurrent venous leg ulceration. We also investigated and evaluated the severity of the clinical pattern of CVU in patients with and without IT. We examined 110 patients with CVU (the study group) and 110 healthy subjects (the control group). We prepared a questionnaire to be completed by each study participant. Ultrasound Doppler color imaging or/and duplex ultrasonography was performed to evaluate the efficiency of the venous system. The ankle-brachial index was calculated to determine the efficiency of the arterial system. We examined both groups for the presence of IT. IT was diagnosed in 30% of study group and in 1.8% of control group. Our diagnoses of deep vein thrombosis (DVT) were based on medical interviews, physical examinations, and an ultrasonography of the venous system and concerned 64 study group patients (58.2%), 35 of whom (31.8%) experienced recurrent DVT. Proximal and/or distal DVT was determined in an interview and/or by an ultrasonography performed for all patients with CVU and IT. In 94% of these patients, DVT was recurrent, and in 88% of patients with CVU and IT, we observed recurrent DVT and CVU. It recurred more often and persisted longer when compared to patients with CVU and no IT, despite similar management. No differences were observed in ulcer size, localization, or pain level related to ulceration between patients with CVU and IT and those with CVU and no IT.     

Mobility in patients with venous leg ulceration.

OBJECTIVES: To compare mobility in patients with venous leg ulcers to matched controls and determine the influence of mobility, age and ulcer size on ulcer healing. METHODS: 25 leg ulcer patients, and 25 matched controls wore a mobility monitor (ActivPAL, PAL Technologies Ltd, Glasgow, Scotland)) which recorded the number of steps and amount of time spent walking, standing, sitting or lying for a one-week period. A walking index was calculated. The ulcer group were treated with compression bandaging and ulcer healing recorded over 12 weeks. RESULTS: There were 13 female subjects in each group. The median age was 70.5 (range 30-89) years. There was no difference in the amount of time either group spent standing, walking and resting. There was a significant reduction in the number of steps taken and in the walking index in the ulcer group compared to controls (ulcer group, median 6,685 steps/day, range 2074-17,999; control group median 8750, range 4917-16,043, p<0.05, Mann Whitney u test). Smaller ulcers and ulcers of recent onset were most likely to heal within 12 weeks (p=0.005 and p=0.011 respectively, Chi squared test). The percentage of time spent mobilising and resting did not influence ulcer healing (r(s)=-0.125; p=0.55). CONCLUSIONS: Mobility patterns among patients with leg ulcers are not significantly different to age matched controls. Ulcer patients take fewer steps per week compared to controls indicating they have reduced calf muscle pump function. Further studies are required to determine whether therapies which increase calf muscle activity have a role in ulcer treatment.     

The causes of skin damage and leg ulceration in chronic venous disease

Chronic venous disease with skin changes of the leg is a common condition affecting up to 1 in 20 people in westernized countries. The causes of this problem are not fully understood, although research in recent years has revealed a number of important mechanisms that contribute to the disease process. Patients with chronic venous disease suffer persistently raised pressures in their deep and superficial veins in the lower limb. Leucocytes become "trapped" in the circulation of the leg during periods of venous hyper-tension produced by sitting or standing. Studies of the plasma levels of neutrophil granule enzymes shows that these are increased during periods of venous hypertension, suggesting that this causes activation of the neutrophils. Investigation of the leucocyte surface ligands CD11b and CD62L shows that the more activated neutrophils and monocytes are sequestered during venous hypertension. Measurement of plasma levels of the soluble parts of the endothelial adhesion molecules VCAM, ICAM, and ELAM show that these are all elevated in patients with chronic venous disease compared to controls. Following 30 minutes of venous hypertension produced by standing, these levels are further increased. These data suggest that venous hypertension causes neutrophil and monocyte activation, which in turn causes injury to the endothelium. Chronic injury to the endothelium leads to a chronic inflammatory condition of the skin that we know clinically as lipodermatosclerosis. This is mediated by perivascular inflammatory cells, principally macrophages, in the skin microcirculation. These stimulate fibroblasts in the skin leading to tissue remodeling and laying down of fibrous tissue. Vascular endothelial growth factor stimulates proliferation of capillaries within the skin. Skin in this state has the potential to ulcerate in response to minor injury.     

The influence of superficial venous surgery and compression on incompetent calf perforators in chronic venous leg ulceration.

OBJECTIVES: Previous studies have suggested that perforating vein incompetence is reduced by surgery to superficial veins. This study analysed the effect in a randomised clinical trial. DESIGN: Retrospective analysis of duplex data. METHODS: Patients in this study were part of the ESCHAR randomised controlled trial. All patients had chronic venous leg ulceration with superficial venous reflux. Patients were treated with compression bandaging alone or compression plus superficial venous surgery. Legs were assessed using colour venous duplex prior to treatment and at 3 and 12 months. RESULTS: Of 500 patients recruited to the ESCHAR trial, 261 were included in this study. One hundred and forty six of 261 legs were treated with compression alone and 115/261 underwent compression and superficial venous surgery. In the compression group, more legs had incompetent perforators at 12 months (77/131) compared to baseline (61/146, p =0.010, Wilcoxon Signed Ranks test for paired data in 131 legs). Following surgery, significantly fewer legs had incompetent calf perforators (59/115 vs 44/104 at 12 months, p =0.001, Wilcoxon Signed Ranks test for paired data in 104 legs). In addition, significantly fewer legs in the compression and surgery group developed new perforator incompetence in comparison to the group treated with compression alone (12/104 vs 36/131, p =0.003, Chi-Squared test). CONCLUSION: Surgical correction of superficial reflux may abolish incompetence in some calf perforators and offer protection against developing new perforator incompetence.     

Algorithm-based approach to management of venous leg ulceration

Management of venous ulceration has evolved tremendously during the last 2 decades. There has been considerable progress in our understanding of the pathophysiology, hemodynamics, venous imaging, and therapeutic options for venous ulcers, including endovenous ablation, iliac vein stenting, and vein-valve repair techniques. Details of these procedures are described in this issue of Seminars. With so many permutations and combinations of venous disease, including superficial and deep vein abnormalities, that produce venous ulceration, as well as a plethora of diagnostic and therapeutic tools at our disposal, it is important to have an algorithm for venous ulcer management. Also important is knowledge about risk factors that can influence poor outcomes, despite interventions for venous ulcers. In the end, authors also discuss the gray areas of venous ulcer management, which do not have common consensus and that treatment could be individualized based on patient needs.     

The prevalence of thrombophilia in patients with symptomatic peripheral vascular disease

BACKGROUND: The aim of this prospective study was to establish the prevalence of thrombophilia and hyperhomocysteinaemia using a comprehensive screen in patients with peripheral vascular disease. METHODS: A total of 150 patients with peripheral vascular disease (with an ankle brachial pressure index of less than 0.8) underwent thrombophilia screening (protein C and protein S, antithrombin, lupus anticoagulant, activated protein C resistance and factor V Leiden and prothrombin mutations). Fasting homocysteine assays were also performed. RESULTS: A thrombophilia defect was found in 41 patients (27.3 per cent). The commonest was protein S deficiency, found in 17 patients (11.3 per cent). Others included factor V Leiden mutation, found in 10 (6.7 per cent) and protein C deficiency, found in six (4.0 per cent). Lupus anticoagulant and prothrombin mutation were both found in six (4.0 per cent). One patient had an antithrombin deficiency. Only the presence of critical ischaemia was associated with a positive thrombophilia screen on single variable analysis (P = 0.03). Hyperhomocysteinaemia was present in over a third of the study group (37.3 per cent): 45 defined as moderate and 11 as intermediate. CONCLUSION: A quarter of patients with peripheral vascular disease had evidence of thrombophilia, and a third had hyperhomocysteinaemia.     

Oxygen diffusion in chronic venous ulceration

A diffusion barrier to oxygen caused by fibrin deposition around dilated, proliferating capillaries in patients with venous hypertension may contribute to the development of venous ulceration. This diffusion barrier was studied in 18 patients with venous ulcers using the transcutaneous oxygen (TcPO2) monitor (TCM204 Radiometer, America). TcPO2 sensors were placed adjacent to venous ulcers on lower limbs and on the chest and foot of each patient. Readings were taken after a sensor temperature of 44 degrees C was reached (10-15 minutes). TcPO2 values were markedly decreased in skin adjacent to the ulcers (10 +/- 2 mmHg) compared with those of the chest (64 +/- 2 mmHg) and foot (43 +/- 2 mmHg). Inhalation of 100% oxygen for 10 minutes increased chest TcPO2 in all patients (145 +/- 8 mmHg) and increased TcPO2 in skin around the ulcers in 17 of 18 patients (61 +/- 13 mmHg). This study supports the existence of a local pathologic barrier to oxygen diffusion in patients with venous ulcers.     

Clinician's perspectives on the treatment of venous leg ulceration

Treatment of venous leg ulcers (VLU) represents a considerable challenge to the health care professional and to the patient alike. Much of the current literature regarding VLU focuses on either wound pathophysiology and treatment of chronic venous insufficiency or the patients' experience of the condition. We present two studies that examine more closely the clinicians' experience of treating VLU and reflect upon how that understanding may further enhance better outcomes for patients in the future. The first of these studies is a qualitative investigation of 49 clinicians treating VLU in the UK and USA. The second is a quantitative, online survey of 304 clinicians' beliefs, attitudes and practices in the UK, Germany and USA. Findings show that the clinicians' experience of treating VLU is often accompanied by frustration and dissatisfaction with treatment challenges and uncertain outcomes. Practices and treatment choices were found to vary widely and differ by countries. We conclude that a key aspect in improving VLU treatment is in listening to the frustrations of the clinician when considering new approaches to therapy.     

Current concepts in chronic venous ulceration.

OBJECTIVES: despite numerous reports on the distribution of reflux in patients with venous ulceration, there is no consensus on the contribution of each venous system. This study was performed to evaluate the distribution of reflux in this group of patients. METHODS: a literature search from 1980 to 1998 was performed. Because duplex scanning is the best method for detecting venous reflux, we only included reports that used this diagnostic modality. All studies with less than 30 ulcerated limbs were excluded. Since most reports did not give detailed data on perforator veins, reflux in these veins was combined with the superficial and deep veins. Documented episodes of superficial or deep vein thrombosis were noted. RESULTS: thirteen studies that included 1249 ulcerated limbs fulfilled the inclusion criteria. The mean age of patients was 59 years (95% CI: 54-63, range: 14-93). Reflux was detected in 1153 (92%) of limbs. Reflux confined to the superficial veins alone was seen in 45% of limbs, in the deep veins alone in 12% and in both the superficial and deep veins in 43% of limbs. The overall involvement of the superficial veins was 88% and of the deep veins 56% (p <0. 0001). A documented episode of deep vein thrombosis was reported in only six of the 13 studies and the incidence was found to be 32%. CONCLUSIONS: reflux in the superficial veins is seen in 88% of limbs with venous ulcers (CEAP classes 5 and 6). Isolated superficial vein incompetence is detected in 45%, while reflux in the deep venous system alone is seen in only 12%. These data have significant clinical implications, since reflux in the superficial system can be easily eliminated by excision of the affected veins.     

Understanding the underlying causes of chronic leg ulceration

Leg ulcers are debilitating and have a significant negative impact on patients' quality of life. It is particularly important to understand the underlying causes of leg ulcers that are described as 'slow to heal' to ensure they are managed effectively.     

Recent insights into the causes of chronic leg ulceration in venous diseases and implications on other types of chronic wounds

Venous ulceration represents the most prevalent form of difficult-to-heal wounds and these problematic wounds require a significant amount of healthcare resources for their treatment. In order to develop effective treatment regimens a clearer understanding of the underlying pathological processes that lead to skin breakdown is required. However, to date, most of these studies have tended to focus on describing the pathology of already-established ulcers. By bringing together relevant aspects of diverse disciplines such as inflammation, cardiovascular, and connective tissue biology, we aim to provide an insight into how circulatory abnormalities that are caused by the underlying disease etiology can induce local tissue inflammation resulting in tissue breakdown. Initially this results in internal tissue damage but if the underlying disease is not treated, the internal tissue damage can worsen and lead to open ulceration. This article discusses the cause-and-effect relationships between chronic venous insufficiency and venous ulceration, focusing particularly on the biological processes that lead from the underlying disease condition to overt ulceration. Available evidence also suggests that formation of pressure, diabetic foot and arterial ulcers, and ulcers as results of blood disorders, is also likely to share some of the same biological processes as venous ulcers.     

Thrombophilia and chronic venous ulceration.

It is known that thrombophilia (TP) is a risk factor for deep venous thrombosis (DVT), and that DVT predisposes to chronic venous ulceration (CVU). However, the relationship between TP and CVU has not been well studied. Review of the literature reveals that the prevalence of TP in CVU patients is high--similar to the prevalence found in patients with a history of DVT. This is despite many patients with CVU having no clear history, or duplex evidence of previous DVT. TP may predispose to CVU by leading to macro- or micro-vascular thrombosis. This association raises several issues regarding the investigation, prevention and management of patients with venous disease.     

Hemodynamic effects of supervised calf muscle exercise in patients with venous leg ulceration: a prospective controlled study

HYPOTHESIS: Because more than two thirds of patients with venous ulcer have an impaired calf muscle pump, enhancement of its ejecting ability with physical training may generate an improved hemodynamic milieu sufficient to promoting ulcer healing. This study evaluated the effects of short-term supervised calf exercise on calf muscle pump function and venous hemodynamics in limbs with venous ulceration. DESIGN: Prospective controlled study. SETTINGS: University-associated tertiary care hospital. PATIENTS: The study consisted of 2 groups. An exercise group comprised 10 patients (median age, 72 years) receiving supervised isotonic calf muscle exercise for 7 consecutive days. A control group comprised 11 patients matched with those in the exercise group for age, sex, ulcer size, and ulcer duration (all, P>.09). Patients in both groups had perimalleolar venous leg ulcers, impaired calf muscle function (ejection fraction, <60%), and full ankle joint movement. INTERVENTIONS: After providing a complete clinical history, both groups underwent a physical examination, venous duplex scanning, and air plethysmography. The venous filling index, venous volume, residual venous volume, and residual volume fraction of the calf on standing were measured plethysmographically at baseline and on day 8, in addition to calf muscle endurance as determined by the maximal number of plantar flexions performed against a fixed 4-kg resistance during 6 minutes (1 flexion/s). Operators were blinded to the subject's group. Exercise in the first group entailed consecutive active plantar flexions using a standardized 4-kg resistance pedal ergometer. Subjects daily completed 3 sets of flexions of 6 minutes each. All patients had short-stretched compression bandaging. MAIN OUTCOME MEASURES: The ejected venous volume and ejection fraction were evaluated in both groups at baseline and on day 8. RESULTS: Both groups had a similar hemodynamic performance at baseline for all the variables evaluated (P>.10). After 7 days of exercise, patients in the exercise group improved their ejected venous volume by 67.5%, ejection fraction by 62.5%, residual venous volume by 25% (all 3, P =.006), and their residual volume fraction by 28.6% (P =.008). Changes in the control group within the same period were small (all, P>.10). By day 8, the exercise group had a significantly better ejected venous volume (P<.001) and ejection fraction (P<.001) than the control group. The venous filling index and the venous volume did not change (P>.50) in either study group. Calf muscular endurance in the exercise group increased 135%, from a median 153 plantar flexions at baseline to 360 on day 7 (P<.001). CONCLUSIONS: By increasing the muscular endurance, efficacy, and power of the calf muscle, isotonic exercise improves its ejecting ability and the global hemodynamic status in limbs with venous ulceration. Prospective evaluations of the clinical effects of calf muscle pump strengthening for the treatment of venous leg ulceration are indicated by the results of this study.     

Leukocyte activity in the microcirculation of the leg in patients with chronic venous disease

Purpose: It has been suggested that leukocyte trapping and activation in the microcirculation of the leg skin causes lipodermatosclerosis and ulceration in patients with chronic venous disease. Ambulatory venous hypertension is accepted as the physiologic factor that leads to ulceration. We investigated leukocyte endothelial adhesion in patients who were subjected to short-term venous hypertension.Methods: Two groups of patients with venous disease were studied: group 1, varicose veins with skin changes (n = 15); and group 2, varicose veins without skin changes (n = 15). Blood samples were taken from a foot vein before and after standing for 30 minutes to raise the venous pressure in the lower limb, and after lying supine again for 10 minutes. The samples were analyzed for leukocyte surface CD11b and L-selectin (CD62L) expression using a flow cytometer. Plasma-soluble L-selectin was also measured using an enzyme-linked immunosorbent assay.Results: In patients with skin changes, median neutrophil CD11b levels fell from 4.66 to 3.83 arbitrary units (p = 0.005, Wilcoxon) after 30 minutes of venous hypertension. Median monocyte CD11b levels fell from 7.65 to 5.8 arbitrary units (p = NS, Wilcoxon) after venous hypertension and then fell further to 5.43 arbitrary units (p = 0.02 vs baseline; Wilcoxon) when the venous hypertension was removed. Neutrophil and monocyte L-selectin levels also fell in response to venous hypertension, remaining low even after venous hypertension was removed. A similar pattern was seen in patients with uncomplicated varicose veins. There was a rise in soluble L-selectin in the plasma of both groups of patients after venous hypertension, reflecting leukocyte adhesion to endothelium. In the group of patients with skin changes the level of soluble L-selectin rose from 695 ng/ml to 836 ng/ml (p = 0.02, Wilcoxon), and in the group without skin changes the rise was from 700 ng/ml to 801 ng/ml (p = 0.02, Wilcoxon).Conclusion: Venous hypertension results in sequestration of the more activated population of neutrophils and monocytes in the microcirculation of the leg in patients with venous disease. These cells bind to the endothelium, releasing L-selectin, and do not emerge from the limb when venous hypertension is reversed. These findings do not differ between patients with varicose veins and those with skin changes. (J Vasc Surg 1997 26:265-73.)     

The healing of chronic venous leg ulcers with prepared human amnion

Forty chronic venous leg ulcers were treated, before split skin grafting, with human amnion prepared in one of the four following ways: tissue-culture-maintained, frozen, fresh or lyophilised. Although there was no significant statistical difference in the results obtained with the different preparations of amnion, we found that lyophilised amnion was at least as good as the other preparations in promoting a good take of the skin grafts and was the simplest to store and use. It also produced the shortest healing times. Frozen and fresh amnion were easier to prepare than lyophilised amnion but gave a lower graft take and a longer healing time. Tissue-culture-maintained amnion was the most difficult to prepare and gave the poorest results. Its use was abandoned during the trial because of technical difficulties and a high infection rate.     

Longer-term changes in quality of life in chronic leg ulceration

Studies that have examined patients' health-related quality of life have consistently shown improvements following intensive and effective treatments over relatively short follow-ups. However, little is known of the longer-term effects of treatment on patients. As part of a study in southwest London, United Kingdom, all patients having a current leg ulcer were examined (n = 113) and those who were able completed the Nottingham Health Profile (n = 95) and were then followed up at 24 and 48 weeks. The patients had a mean age of 76 +/- 13 (SD) years, with 60 (63.2%) being women. Before the study, the ulcer had been present for a median of 8 months (range 0.5-144), and a median area of ulceration of 4.0 cm2 (range 0.5-171.5 cm2). After 24 weeks, there was a significant improvement in pain (mean difference [d] = 9.6, p = 0.002), which was true for both the 41 patients with ulcers present (d=10.07, p = 0.013) and the 43 patients whose ulcers had healed (d = 11.46, p = 0.047). However, after 48 weeks, these improvements had been reduced in both groups (healed ulceration d = 5.76, unhealed patients d = 6.41). Energy, which had improved after 24 weeks in the patients whose ulcers, had healed (d = 11.46), deteriorated in both patient groups after 48 weeks (healed = -5.67, unhealed = -13.43). Mobility status was maintained with healed ulceration (d = 1.05) but deteriorated with unhealed ulceration (d = -13.19). The positive effects of treatment on health-related quality of life may not be sustained over time. This may be a consequence of the general deterioration in the health status of these elderly patients as they age.