Venous Disease

The aetiology and pathophysiology of chronic venous insufficiency and leg ulcers

Summary

Chronic venous insufficiency (CVI) affects up to 2% of the population in western countries, a prevalence similar to that of diabetes. One in five affected patients suffers leg ulceration at any one time, and patients endure recurrent episodes of ulceration. The cost to healthcare systems is massive: in the United Kingdom it has been estimated that £600 millions per year (US $1000 millions) is spent on the management of legs ulcers.

The pathophysiology of chronic venous insufficiency (CVI) in large veins is well established. Deep or superficial veins become incompetent, permitting reverse flow and resulting in raised pressure in the superficial veins during ambulation.

The reasons why this results in leg ulceration have been discussed for many years. Initially it was suggested that arterio-venous anastomoses deprived the skin of nutrition. Later it was proposed that pericapillary fibrin cuffs prevent oxygen diffusion to the tissues. These suggestions do not provide a complete answer and more recently it has been shown that leucocytes which are trapped in the leg during venous hypertension become activated and cause damage to the endothelium of the lower limb. This probably results in the chronic inflammatory condition of the skin called lipodermatosclerosis. The capillary circulation in this skin is abnormal and susceptible to catastrophic breakdown resulting in leg ulcers.

Our understanding of these processes is incomplete, but further research may lead to identification of factors which could be changed by the use of drugs. Whilst the use of compression bandaging and hosiery will remain the main treatment in patients with CVI, the availability of more active drugs will be of great use.

The aetiology and pathophysiology of chronic venous insufficiency and leg ulcers

Introduction

CVI continues to cost the healthcare systems of western countries large sums every year. This disease becomes more prevalent with advancing age so it is likely that more patients will be treated as the average age of populations increases. The prevalence of CVI is 1 – 2% in western countries and leg ulceration is present in 0.2% in of the population1. In the UK venous ulcers are treated in the community by General Practitioners and Community Nurses. Between 10% and 30% of nursing time may be occupied with dressing leg ulcers 2. The cost of this is massive, amounting to £2000 – £4000 per year for each of the 150 000 – 200 000 patients with leg ulcers. In the UK it is estimated that £600 millions (US$ 1 billion) is spent on this diagnosis per annum, 2% of the healthcare budget.

1 Callam MJ, Ruckley CV, Harper DR, Dale JJ. Chronic ulceration of the leg: extent of the problem and provision of care. Br Med J 1985; 290:1855-6

2 Bosanquet N. Costs of venous ulcers: from maintenance therapy to investment programmes. Phlebology Suppl 1, 1992, 44-46.

The aetiology and pathophysiology of chronic venous insufficiency and leg ulcers

Large vein pathophysiology

CVI results from failure of the valves in deep or superficial veins. Deep vein valves may becoming incompetent following a deep vein thrombosis or may become ‘floppy’ and loose competence due to primary valve failure. Varicosities of the superficial veins may result in CVI if the volume of reverse flow is large enough. Venous valvular incompetence results in raised venous pressure in the superficial veins of the leg during ambulation. This was first studied by Pollack and Wood, in 1949, who examined normal subjects, patients with varicose veins and others with a history of deep vein thrombosis. They confirmed that pressure in the ankle vein decreased on walking and showed that the decrease in pressure in subjects with varicose veins was less than in normal subjects. Subjects with a history of deep vein thrombosis had a minimal fall in pressure.1,2.

1 Pollack A.A. Wood E.H. Venous pressure in the saphenous vein at the ankle in man during exercise and during changes of posture. J Appl Physiol 1949 1:649-662.

2 Pollack A.A. Taylor B.E. Myers T.T. Wood E.H. The effect of exercise and body position on the venous pressure at the ankle in patients having venous valvular defects. J Clin Invest 1949 28:559-563.

The aetiology and pathophysiology of chronic venous insufficiency and leg ulcers

The Microcirculation in CVI

A number of authors have discussed evidence for the presence of arterio-venous shunts which they suggested prevented nutrition reaching the skin. These have never been shown objectively and quantitative measurement has not shown increased arterio-venous shunting in patients with venous disease.

Increasing interest in the cutaneous microcirculation lead Browse and Burnand to propose a theory suggesting that fibrin cuffs, which they had demonstrated histologically surrounding capillaries in the region of the liposclerotic skin of patients with CVI, might act as a barrier to diffusion of oxygen and other small molecules.1 Subsequently a number of authors have studied oxygen delivery to skin by transcutaneous oxygen tension measurements. 2,3,4 These have shown reduced transcutaneous oxygen tension in the skin in areas of lipodermatosclerosis. change. The skin is heated to 43oC in making these measurements and it is now known that the vasodilatory response of liposclerotic skin is reduced compared with normal skin. The reduced transcutaneous oxygen measurements may be due to poor hyperaemic response to heating. 5 Objective assessments of gas transfer using either xenon clearance 6 or oxygen return time following a period of ischaemia 7 show no evidence of a diffusion problem. Calculations based on a theoretical model of gas diffusion undertaken by Michel suggest that the composition of the fibrin cuff (99% water) would be unlikely to impair the transfer of small molecules 8.

1 Browse NL and Burnand KG. The cause of venous ulceration. Lancet 1982 ii 243-5.

2 Stacey MC, Burnand KG, Layer GT and Pattison M. Transcutaneous oxygen tensions as a prognostic indicator and measure of treatment of recurrent ulceration. Br J Surg 1987 74: 545.

3 Clyne CAC, Ramsden WH, Chant ADB and Wenster JHH. Oxygen tension in the skin of the gaiter area of limbs with venous ulceration. Br J Surg 1985 72: 644-7.

4 Moosa HH, Falanga V, Steed-DL, Makaroun MS, Peitzman AB, Eaglstein WH, Webster MW. Oxygen diffusion in chronic venous ulceration. J Cardiovasc Surg Torino. 1987 28: 464-7.

5 Cheatle TR, Stibe ECL, Shami SK, Scurr JH, Coleridge Smith PD. Vasodilatory capacity of the skin in venous disease and its relationship to transcutaneous oxygen tension. Br J Surg 1990; 78:607-10.

6 Cheatle TR, McMullin GM, Farrah J, Coleridge Smith PD, Scurr JH. Three tests of microcirculatory function in the evaluation of treatment for chronic venous insufficiency. Phlebology 1990; 5:165-72.

7 Stibe E, Cheatle TR, Coleridge Smith PD, Scurr JH. Liposclerotic skin: a diffusion block or a perfusion problem? Phlebology 1990; 5:231-6.

8 Michel CC. Oxygen diffusion in oedematous tissue and through pericapillary cuffs. Phlebology 1990; 5:223-30.

The aetiology and pathophysiology of chronic venous insufficiency and leg ulcers

The role of leucocytes in chronic venous insufficiency

In 1987 Moyses et al 1 noticed that leucocyte sequestration occurred in normal subjects when the lower limb was subjected to venous hypertension for a 40 minute period. He made his volunteers to sit without moving on a bicycle saddle and took blood samples from the long saphenous vein at the ankle. The venous pressure in the superficial veins of the lower limb was 80 – 100 mm Hg.

Thomas et al 2 repeated this experiment, comparing patients with CVI to control subjects with normal lower limb veins. He observed a difference in white cell trapping between the two groups. Patients trapped 30% of white cells after 60 minutes of sitting, whilst control subjects trapped only 7% (fig. 1). After return to the lying position white cells began to leave the limb.

Capillary microscopy studies which suggested that following ambulatory venous hypertension fewer capillaries were visible in the skin of patients with venous disease than before ambulatory venous hypertension. A hypothesis was published suggesting that the ‘trapped’ white cells were responsible for endothelial injury which over many months or years resulted in damage to the microcirculation and leg ulceration (fig. 2) 3. This proposal included many of the mechanisms known to be responsible for critical ischaemia. The hypothesis suggested that with standing the rise in venous pressure and fall in blood flow to the lower limb favours adhesion of leucocytes to the microcirculatory endothelium. The fall in lower limb blood flow is attributable to a number of mechanisms. Cardiac output falls by about 40% on rising to the standing position, due to diminished cardiac return. Measurement of femoral artery blood flow shows a decline of 60% in response to rising to the standing position from the supine position. Measurement of skin perfusion using laser Doppler fluxmetry shows a similar decrease in the cutaneous blood flow on standing.

Observation of capillaries during ambulatory venous hypertension shows that they dilate and that there is a considerable reduction in their flow velocity. These factors combine to reduce the shear rate in the microcirculation, an important factor influencing leucocyte adhesion. 4 A reduction in shear rate favours neutrophil adhesion which probably occurs in the post-capillary venule. The leucocyte adhesion detected by Moyses in control subjects is probably a physiological phenomenon that does not normally persist for any length of time. Usually venous pressure in the lower limb falls rapidly on walking and even with small muscular contractions of the leg. In patients with CVI sustained venous hypertension occurs, even during walking, so the leucocyte trapping may be more persistent. The trapped leucocytes become activated releasing free radicals and proteolytic enzymes resulting in endothelial injury (fig. 3, 4). Over a long period this damages the microcirculation.

This initial suggestion has now been studied in greater detail. Work in the Middlesex Hospital Vascular Laboratory has shown that in control subjects exposed to venous hypertension produced by standing for 30 minutes, neutrophil degranulation can be demonstrated by measurement of plasma elastase and lactoferrin, enzymes which are usually stored in neutrophil granules 5. Measurements have also been made in patients with venous disease. Blood was taken from the arm veins of patients (not the lower limb veins) of patients with varicose veins, liposclerotic skin change and active venous ulceration 6,7. In all samples, the levels of lactoferrin and elastase were higher in the patient than the age and sex-matched control groups. More recent measurements (unpublished observations) have shown evidence that endothelial adhesion of leucocytes during venous hypertension results in damage to the endothelium, as assessed by release of soluble adhesion molecules into the blood.

The microcirculation of the skin has been studied by histological methods 8 and by capillary microscopy 9. Both techniques show capillary proliferation – vastly more capillaries are visible by both techniques. However, capillary microscopy shows that these probably arise from a single capillary loop and appear like a glomerulus, rather than an increase in the numbers of capillaries. Recent immunohistochemical investigations have studied the pericapillary cuff, which contains collagen IV, laminin, fibronectin and tenascin as well as fibrin. The endothelium is perturbed, expressing increased amounts of factor VIII related antigen 10, 11 and adhesion molecules, especially inter cellular adhesion molecule-1 (ICAM-1). Endothelial-leucocyte adhesion molecule-1 (ELAM-1) may be slightly upregulated but vascular cell adhesion molecule (VCAM) appears to be normal in patients without venous ulceration. Endothelium damaged in this way is more likely to attract the adhesion of leucocytes. Around the outside of the capillaries the presence of the fibrin cuff is substantiated, but it additionally12. A strong leucocyte infiltration has been measured in patients with venous disease 13 and these cells are macrophages and T-lymphocytes.

Many factors remain to be fully explained. The progress from the chronic inflammatory state to actual ulceration is difficult to investigate and there is no animal model. A possible answer is that an initiating stimulus causes massive activation of the peri-vascular macrophages resulting in extensive tissue and blood vessel destruction. This may be a spontaneous event such as thrombosis of one of the capillary loops, which has been observed using capillary microscopy14. Alternatively minor trauma to the region may set in motion the series of events which leads to ulcer formation.

Conclusions

A better understanding of the mechanisms discussed above may help in identifying factors that might be modified by drug treatment. Compression bandaging and hosiery will remain the main method of treating CVI, but in the future the use of appropriate drugs may be helpful in the management of many patients.

1 Moyses C, Cederholm-Williams SA, Michel CC. Haemoconcentration and the accumulation of white cells in the feet during venous stasis. Int J Microcirc: Clin Exp 1987; 5: 311-320.

2 Thomas PRS, Nash GB and Dormandy JA. White cell accumulation in the dependent legs of patients with ambulatory venous hypertension: a possible mechanism for trophic changes in the skin. Br Med J 1988; 296: 1693-5.

3 Coleridge Smith PD, Thomas P, Scurr JH, Dormandy JA. Causes of venous ulceration: a new hypothesis. Br Med J 1988; 296: 1726 – 8.

4 Schmid-Schoenbein GW, Fung YC, Zweifach BW. Vascular endothelium-leukocyte interaction; sticking shear force in venules. Circ Res. 1975; 36: 173-84.

5 Shields DA, Andaz S, Abeysinghe RD, Porter JB, Scurr JH and Coleridge Smith PD. Neutrophil activation in experimental ambulatory venous hypertension. Phlebology 1994; 9:119-124.

6 Shields DA, Andaz S, Abeysinghe RD, Porter JB, Scurr JH, Coleridge Smith PD. Plasma Lactoferrin as a Marker of White Cell Degranulation in Venous Disease. Phlebology 1994; 9:55-58.

7 Shields DA, Andaz SK, Sarin S, Scurr JH, and Coleridge Smith PD. Plasma elastase in venous disease. Br J Surg 1994; 81:1496-1499.

8 Burnand KG, Whimster I, Naidoo A, Browse NL. Pericapillary fibrin in the ulcer-bearing skin of the leg: the cause of lipodermatosclerosis and venous ulceration. Br Med J 1982; 285: 1071 – 2.

9 Haselbach P, Vollenweider U, Moneta G, Bollinger A. Microangiopathy in severe chronic venous insufficiency evaluated by fluorescence video-microscopy. Phlebology 1986; 1: 159 – 69.

10 Wilkinson LS, Bunker C, Edwards JC, Scurr JH; Coleridge Smith PD. Leukocytes: their role in the etiopathogenesis of skin damage in venous disease. J Vasc Surg. 1993; 17: 669-75.

11 Veraart JC, Verhaegh ME, Neumann HA, Hulsmans RF, Arends JW. Adhesion molecule expression in venous leg ulcers. Vasa 1993; 22: 213-8.

12 Herrick SE, Sloan P, McGurk M, Freak L, McCollum CN, Ferguson MW. Sequential changes in histologic pattern and extracellular matrix deposition during the healing of chronic venous ulcers. Am J Pathol. 1992 141:1085-95.

13 Scott HJ, McMullin GM, Coleridge Smith PD, Scurr JH. A histological study into white blood cells and their association with lipodermatosclerosis and ulceration. Br J Surg 78: 210-1, 1990.

14 Franzeck UK, Speiser D, Haselbach P and Bollinger A. Morphologic and dynamic microvascular abnormalities in chronic venous incompetence (CVI). Phlebologie 1989; eds. Davy A, Stemmer R. John Libbey Eurotext Ltd, Montrouge, France 1989, pp104-7.