J. H. Scurr

Causes of venous ulceration: a new hypothesis

Previous hypotheses about the causes of venous ulceration are inconsistent with recently published data. In patients with chronic venous insufficiency the number of functioning capillary loops visible in the skin on microscopy fell after the legs had been dependent for 30 minutes. Another study had shown that leucocytes became trapped in the circulation in dependent legs. A new hypothesis linking these two findings proposes that the trapped while cells occlude the capillaries and result in ischaemia of the skin of the leg.

Frequency and prevention of symptomless deep-vein thrombosis in long-haul flights: a randomised trial

BACKGROUND The true frequency of deep-vein thrombosis (DVT) during long-haul air travel is unknown. We sought to determine the frequency of DVT in the lower limb during long-haul economy-class air travel and the efficacy of graduated elastic compression stockings in its prevention. METHODS We recruited 89 male and 142 female passengers over 50 years of age with no history of thromboembolic problems. Passengers were randomly allocated to one of two groups: one group wore class-I below-knee graduated elastic compression stockings, the other group did not. All the passengers made journeys lasting more than 8 h per flight (median total duration 24 h), returning to the UK within 6 weeks. Duplex ultrasonography was used to assess the deep veins before and after travel. Blood samples were analysed for two specific common gene mutations, factor V Leiden (FVL) and prothrombin G20210A (PGM), which predispose to venous thromboembolism. Asensitive D-dimer assay was used to screen for the development of recent thrombosis. FINDINGS 12/116 passengers (10%; 95% CI 4.8-16.0%) developed symptomless DVT in the calf (five men, seven women). None of these passengers wore elastic compression stockings, and two were heterozygous for FVL. Four further patients who wore elastic compression stockings, had varicose veins and developed superficial thrombophlebitis. One of these passengers was heterozygous for both FVL and PGM. None of the passengers who wore class-I compression stockings developed DVT (95% CI 0-3.2%). INTERPRETATION We conclude that symptomless DVT might occur in up to 10% of long-haul airline travellers. Wearing of elastic compression stockings during long-haul air travel is associated with a reduction in symptomless DVT.

Venous ulcers and the superficial venous system

PURPOSE The purpose of this study is to identify the anatomic location of venous disease in patients with venous ulceration and chronic venous insufficiency. METHODS Both limbs of 59 consecutive patients attending the Middlesex Hospital Vascular Laboratory (London, U.K.) with venous ulceration were assessed by color duplex ultrasound scanning to determine the location of venous disease. RESULTS Isolated deep venous reflux was present in only 12 limbs (15%). A combination of deep and superficial venous reflux was found in 25 limbs (32%), and in 42 limbs (53%) there was only superficial venous reflux. CONCLUSION In just over half the patients with venous ulceration, the disease is confined to the superficial venous system. This group of patients may benefit from surgical treatment. This study emphasizes the need for vascular laboratory investigation of patients with leg ulceration.

Leukocytes: Their role in the etiopathogenesis of skin damage in venous disease

The role of leukocytes in tissue damage in the liposclerotic skin of venous disease has been investigated. Twenty-eight skin biopsy specimens were obtained from 23 patients with varicose veins of the lower limb, with a spectrum of skin injury ranging from normal to severe liposclerosis. In no patient was a venous ulcer present. Immunohistochemistry was used to determine the cell types present and provide an indication of their activity. The predominant infiltrating cell types present were T lymphocytes and macrophages. B cells and neutrophils were rarely seen. As described previously, the capillaries were greatly increased in number in the papillary dermis and exhibited grossly increased expression of factor VIII-related antigen and major histocompatibility complex class II. Surprisingly, expression of adhesion molecules endothelial leukocyte adhesion molecule-1 and vascular cell adhesion molecule were not elevated, but intercellular adhesion molecule-1 expression did increase in more severely diseased skin. Perivascular fibrin was seen occasionally, but there was no evidence of microvascular occlusion. Staining for the cytokine tumor necrosis factor-alpha was not increased in liposclerotic skin. Dermal staining for both interleukin (IL)-1 alpha and IL-1 beta was increased in severely liposclerotic skin, but this was not seen at an early stage. Epidermal staining for IL-1 alpha and IL-1 beta was not increased. All changes were confined to the subpapillary region of the skin. These findings demonstrate that accumulation of macrophages and T cells is an event associated with the development of liposclerotic skin changes that may lead to ulceration in venous disease.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Medial calf perforators in venous disease: The significance of outward flow

The role of medial calf perforators in the initiation or promotion of venous disease is incompletely understood. The purpose of this study was to define the direction of blood flow in the perforating vein of the calf in normal limbs and in those limbs of patients with venous disease under defined laboratory conditions. Both lower limbs of 57 patients, (32 women and 25 men, median age, 56 years; range, 40 to 62 years) were examined by duplex ultrasonography. In 10 patients no clinical or duplex evidence existed of venous disease. In 60 legs we found evidence of superficial venous insufficiency, complicated by lipodermatosclerosis in 29. In 15 limbs we found deep venous insufficiency. Finally, in 19 limbs no evidence existed of venous disease, but venous reflux was present in the contralateral limb. The direction of blood flow in the medial calf perforators was assessed during compression of the foot and calf, by a cuff that inflated to 60 mm Hg. Blood flow was also assessed during deflation of the cuff. We found that the direction of blood flow within medial calf perforators can be both inward or outward, even in limbs without evidence of venous disease. Outward flow could be demonstrated in 21% of perforators in normal limbs. Flow on release of distal compression occurred in 33% to 44% of perforators in limbs with evidence of venous disease but in none of the perforators in limbs without evidence of venous disease. We found that flow, during the relaxation phase, within medial calf perforators was associated with venous disease elsewhere in the limb.

Endothelial Activation in Patients With Chronic Venous Disease

OBJECTIVES Leukocyte trapping due to leukocyte-endothelial activation has been implicated as the cause of lipodermatosclerosis and ulceration in patients with chronic venous disease. We investigated endothelial activity in normal controls and patients subjected to short-term venous hypertension. METHODS Twenty-five normal volunteers and 30 patients with chronic venous disease divided into two groups: varicose veins with skin changes (LDS, n = 15); and varicose veins without skin changes (VVs, n = 15) were studied. Blood samples were taken from a foot vein before and after experimental venous hypertension. Plasma levels of ELAM-1 (endothelial leukocyte adhesion molecule-1), ICAM-1 (intercellular adhesion molecule-1), VCAM-1 (vascular cell adhesion molecule-1), and von Willebrand factor (vWf) was measured by an ELISA. RESULTS There was a significant rise in the plasma concentration of ELAM-1, ICAM-1 and VCAM-1 in patients and normal controls in response to venous hypertension. Basal levels of plasma VCAM-1 and vWf were higher in patients with LDS compared to patients with VVs. The magnitude of rise of VCAM-1 was greater in patients with LDS compared to patients with VVs (p = 0.01, Mann-Whitney U-test). There was no difference in the basal levels or in the magnitude of change in plasma ICAM-1 and ELAM-1 between the two patient groups. CONCLUSION Venous hypertension results in endothelial activation which may aid endothelial-leukocyte adhesion. Patients with LDS exhibit increased VCAM-1, which is a counterligand for receptors expressed by monocytes and lymphocytes signifying that these cells may be more important in the development of skin changes.

Consensus Paper on Venous Leg Ulcers

No justification is needed for a group of specialists trying to summarize current knowledge about the pathophysiology. investigation and management of venous leg ulcers. It is a very common and still largely neglected condition where ignorance is sometimes matched by dogmatic opinions. This paper is the outcome of the deliberations of 20 specialists in various aspects of venous ulcer disease from the United States and several European countries. The Alexander House Group met initially in May 1990 and again in October 1991 to identify those aspects of venous ulceration where consensus exists between leading experts from Europe and the United States. The participants in these meetings have tried to confine their statements to those areas where there is widespread agreement but, at the same time. they have sought to identify areas where much further research is required. Statements made in this document are supported by an extensive bibliography.

Increased plasma vascular endothelial growth factor among patients with chronic venous disease

Skin damage in the presence of chronic venous disease is partially mediated through leukocytes. The endothelium is activated and exhibits proliferation in the skin. Up-regulation of vascular endothelial growth factor (VEGF) expression in the skin of patients with chronic venous disease has been demonstrated with immunohistologic techniques. Abnormal VEGF expression can have local deleterious effects. The aim of this study was to determine whether patients with chronic venous disease have elevated plasma levels of VEGF. We conducted a prospective study with 30 patients with varicose veins of clinical, etiologic, anatomic, and pathologic class C3 (normal skin, n = 15) and C4 (trophic skin changes, n = 15) and 25 control subjects with no clinical evidence of venous or arterial disease of the lower limb. Blood samples were collected from a foot vein of each subject before and after a period of experimental venous hypertension produced by means of standing. Assay of VEGF protein was performed with a sandwich enzyme-linked immunosorbent assay. Plasma VEGF level was elevated in both groups of patients with venous disease compared with the control group. The median VEGF levels among patients were 81 pg/mL (interquartile range [IQR] 56 to 122) supine and 98 pg/mL (IQR 63 to 153) after standing for 30 minutes. Median VEGF levels among control subjects were 52 pg/mL (IQR 35 to 71) lying supine and 60 pg/mL (IQR 39 to 105) after standing for 30 minutes. Experimental venous hypertension caused a small rise in VEGF levels among the patients but not the control subjects. Further studies are required to determine whether increased VEGF expression contributes to tissue injury in chronic venous disease.

Effect of leg elevation on the skin microcirculation in chronic venous insufficiency

PURPOSE Leg elevation is advised in the treatment of venous disease associated with edema. We have used laser Doppler fluxmetry to assess the effects of leg elevation on the skin microcirculation. METHODS Fifteen patients with lipodermatosclerosis caused by chronic venous insufficiency and 15 control subjects were studied. Measurements were made from the liposclerotic skin of patients and 8 cm above the medial malleolus in control subjects. Laser Doppler flux, blood cell velocity, and concentration of moving blood cells were recorded with the subject lying in the supine position and after elevating the foot 30 cm above the heart level. RESULTS In subjects in the horizontal position, the resting laser Doppler flux was significantly higher in patients with lipodermatosclerosis than in control subjects (median difference 63 arbitrary units; 95% confidence interval: 36, 108). This difference was due to a higher concentration of moving blood cells in the patient group (median difference 6.5 arbitrary units; 95% confidence interval: 3.4, 9). The blood cell velocity was not statistically significant between the two groups. On leg elevation, there was a substantial increase in the laser Doppler flux in the patient group; the median percentage increase in flux was 45% (p < 0.01). This was due to an increase in blood cell velocity; the median percentage increase was 41% (p < 0.01). There was no corresponding change in the concentration of moving blood cells. The results in the control group showed a similar trend but have not reached statistical significance. CONCLUSION We conclude that limb elevation enhanced the microcirculatory flow velocity in liposclerotic skin of patients with chronic venous insufficiency.