Philip Coleridge Smith

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.

Classification and Grading of Chronic Venous Disease in the Lower Limbs-A Consensus Statement-

Classification and grading of chronic venous disease in the lower limbs : A consensus statement

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.

Neutrophil Activation and Mediators of Inflammation in Chronic Venous Insufficiency

The effect of venous hypertension on the state of activation of leucocytes has been investigated in patients with venous disease and control subjects. Leucocytes become ‘trapped’ in the circulation of the leg during periods of venous hypertension produced by sitting or standing. This is greater in the limbs of patients with chronic venous disease than controls. Studies of the plasma levels of neutrophil granule enzymes show that these are increased during periods of venous hypertension, suggesting that this causes activation of the neutrophils. Investigation of the leucocyte surface ligand CD11b shows that the more activated neutrophils and monocytes are sequestered during venous hypertension. Measurement of plasma levels of the soluble parts of the vascular (VCAM), intercellular (ICAM) and endothelial leucocyte (ELAM) adhesion molecules show that these are all elevated in patients with chronic venous disease compared to controls. Following 30 min 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. I believe that this may be the mechanism that initiates the pathological processes which lead to venous ulceration. It has recently been shown that the venotonic drug Daflon 500 mg (450 mg diosmin, 50 mg hesperidin, Servier, France) influences these processes. Surface expression of CD62L is reduced in neutrophils and monocytes, and plasma levels of soluble endothelial adhesion molecules are reduced. These observations may explain the anti-inflammatory effects of Daflon 500 mg.

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.

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.

Microangiopathy of the skin and the effect of leg compression in patients with chronic venous insufficiency

PURPOSE The reasons for the efficacy of leg compression in the treatment of chronic venous insufficiency are not clear. We have used laser Doppler fluxmetry to assess the effect of external compression on the skin microcirculation. METHODS Fifteen patients with lipodermatosclerosis caused by chronic venous insufficiency and 15 control subjects were studied in the supine and sitting positions. The laser Doppler probe, incorporated in a polyethylene chamber, was applied to the lower leg underneath a blood pressure cuff. Pressures were applied from 10 to 100 mm Hg in increments of 10 mm Hg. A computer data logging system recorded laser Doppler flux blood cell velocity, and concentration of moving blood cells. RESULTS In patients in the supine position, 20 mm Hg compression resulted in a median increase of 33% in laser Doppler flux, and a median increase of 79% in blood cell velocity, but higher pressures caused a progressive decrease in laser Doppler flux and blood cell velocity. With the patient in the sitting position, compression up to 60 mm Hg caused an increase in laser Doppler flux (median percentage increase at 20 mm Hg compression 84%) and blood cell velocity (median percentage increase at 20 mm Hg compression 22%). At 20 mm Hg compression, the concentration of moving blood cells decreased in the supine position (median percentage fall 27%) but did not change significantly in the dependent position. The effects of compression in control subjects were similar to those in patients, but to a lesser degree. CONCLUSION Our study suggests that compression treatment may achieve part of its effect by causing an increase in the microcirculatory flow velocity.

The Microcirculation in Venous Hypertension

Venous ulceration is a common problem in western countries and results in large costs to healthcare systems. A number of hypotheses of the mechanisms of development of venous ulceration have been advanced, but this question has not been fully resolved. In recent years research effort has focused on the microcirculation of the skin and many methods of investigation have been employed to study this. Some of the principal findings described in published work are reviewed in this article. It seems unlikely from the available evidence that venous ulceration is attributable solely to failure of diffusion of oxygen and other small nutritional molecules to the tissues of the skin. The microvascular changes in the skin are characterised by activated endothelium and perivascular inflammatory cells. It is much more likely that leucocytes attach themselves to the cutaneous microcirculation, become activated and produce endothelial injury. Repeated over many months or years, this chronic inflammatory process leads to be tissues changes of lipodermatosclerosis. Although there is evidence of leucocyte involvement in the pathogenesis of venous ulceration, the exact mechanisms remain to be resolved. Improved treatment for patients may be devised once a better understanding of the basic causes of this condition has been reached.

Daflon 500 mg and Venous Leg Ulcer: New Results From a Meta-Analysis

The objective of this study was to assess the effect of oral treatment with Daflon 500 mg (micronized purified flavonoid fraction [MPFF]) on leg ulcer healing. This study was conducted as a meta-analysis of randomized prospective studies using Daflon 500 mg as an adjunct to conventional treatment. Medical literature databases and the manufacturer’s records were searched for relevant clinical trials. Five prospective, randomized, controlled studies in which 723 patients with venous ulcers were treated between 1996 and 2001 were identified. Conventional treatment (compression and local care) in addition to Daflon 500 mg 2 tablets daily was compared with conventional treatment plus placebo in two studies (n=309), or with conventional treatment alone in three studies (n=414). The primary end point was complete ulcer healing at 6 months. The results are expressed as a reduction in the relative risk (RRR) of healing with 95% confidence intervals (CI). Since, in the present case, the desired treatment effect is increased ulcer healing, RRR should be positive to indicate a benefit of adjunctive Daflon 500 mg over conventional therapy alone. Type 1 error was set at 5%. At 6 months, the chance of ulcer healing was 32% better in patients treated with adjunctive Daflon 500 mg than in those managed by conventional therapy alone (RRR, 32%; 95% CI, 3% to 70%). This difference was present from month 2 (RRR, 44%; 95% CI, 7% to 94%), and was associated with a shorter time to healing (16 weeks vs 21 weeks; p=0.0034). The benefit of Daflon 500 mg was found in the subgroup of ulcers between 5 and 10 cm2 in area (RRR, 40%; 95% CI, 6% to 87%), as well as in patients with ulcers of 6 to 12 months’ duration (RRR, 44%; 95% CI, 6% to 97%). These results confirm that venous ulcer healing is accelerated by Daflon 500 mg treatment. Daflon 500 mg might be a useful adjunct to conventional therapy in large and longstanding ulcers that might be expected to heal slowly.