Angiology

Venous disease in the legs occurs very commonly in the general population in Western countries. Around one third of women have trunk varices. A lower prevalence has been observed in men but some recent surveys have suggested that the occurrence in men may be comparable to that in women. The prevalence increases with age but the incidence of new cases appears to be constant throughout adult life. Open venous ulcers occur in about 0.3% of the adult population and a history of open or healed ulceration occurs in around 1%. The etiology of chronic venous disease in the legs is unknown. A genetic predisposition may be present but evidence for this and for a mode of inheritance is lacking. There is some suggestion that prolonged standing may be a risk factor but studies are open to considerable bias. In women, obesity and previous pregnancy has been associated with the presence of varicose veins but the evidence is inconsistent. There have been few well-conducted studies examining diet and bowel habit as a risk factor. The risk of ulceration is related to the severity of varicosities and venous insufficiency, and is increased following deep vein thrombosis. Much further research is required to investigate the cause of this common condition in the general population.

Chronic venous insufficiency (CVI) is a very variable and complex entity that has stimulated different attempts at classification. Several proposals have been made in recent years, based on objective and anatomical criteria, most of them incomplete and unsatisfactory. Finally the CEAP classification was presented in 1994. This certainly is the most nearly complete classi fication, since it takes into consideration not only the main aspects of CVI: Clinical, Etiological, Anatomical, and Pathophysiological, but also the degrees of severity, reported in the form of scores. It is now accepted internationally although it still has some flaws (such as the absence of the corona phlebectactica sign) and inaccuracies (above all in the clinical part and the scoring). Recently, some members of the Promoting Committee proposed a substantial modi fication of the part on scores, coming closest to the clinical reality, instrumental diagnosis, and current therapies. The characteristics of CEAP enable us to affirm that this represents the most original and useful classification, not only for clinical studies, but also in the assessment of therapeutic results and in patient follow-up. Like all classifications, CEAP also needs to be validated by means of clinical studies in order to demonstrate its applicability. For this purpose, a European Working Group was set up in 1997. The first interesting results of 872 dossiers collected by means of a computerized program (European Phlebological File) were presented at several international congresses and concentrated on the consistency and reproducibility of the clinical part of the CEAP classification in different clinical settings.

Chronic venous insufficiency (CVI) is inseparably linked to elevated venous pressure and is accompanied by vascular, dermal, and subcutaneous tissue damage and restructuring. Abundant evidence exists both in humans and in experimental models to suggest that the tissue damage may be initiated by generation of an inflammatory reaction. inflammatory indi cators include elevation of endothelial permeability; attachment of circulating leukocytes to the endothelium; infiltration of monocytes, lymphocytes, and mast cells into the connective tissue; and development of fibrotic tissue infiltrates and several molecular markers, such as growth factor or membrane adhesion molecule generation. Indicators of an inflammatory reaction are already detectable at early stages of CVI and may be involved in the development of primary venous valve dysfunction. One of the important questions is to identify trigger mechanisms for the inflammatory reaction in CVI. Current evidence suggests that, among several possible mechanisms (hypoxia, humoral stimulation), a shift in fluid shear stress from normal physio logical levels and endothelial distension under the influence of elevated venous pressure may serve as trigger mechanisms for inflammation.

The causes of venous ulceration remain unclear. Twentieth-century hypotheses concentrated on the possibility that this problem was caused by failure of oxygen delivery to the skin. However, it has been difficult to substantiate these predictions in practice. Although the presence of tissue hypoxia has been suggested by studies in which transcutaneous oxygen tension has been assessed with transducers heated to unphysiological temperatures, when oxygen measurements are made at room temperature there is little evidence of tissue hypoxia. This has led to the assessment of alternative mechanisms of ulcer development. There has been considerable interest in recent years in the inflammatory processes that surround venous ulceration. A complex sequence of events appears to surround the develop ment of leg ulceration.

Increased leukocyte activation has been shown in patients with venous disease as well as increased expression of soluble endothelial adhesion molecules. Histologic studies of the skin in patients with chronic venous disease show a perivascular infiltration of the capillaries of the papillary plexus (the most superficial part of the dermis) with monocytes, macrophages, and connective tissue proteins including fibrin. Fibrosis of the skin and subcutaneous tissues may be initiated by increased gene expression and production of transforming growth factor-β 1. Vascular endothelial growth factor may be involved in the capillary proliferation that has been reported in the skin by a number of authors. Increased expression of several tissue metallo proteinases has been reported both in liposclerotic skin and periulcer skin. The tissue inhibitors of metalloproteinases are also increased and the net result is unclear. Treatment of venous disease using micronized purified flavonoid fraction moderates some of the inflammatory markers, including leukocyte ligand expression and endothelial adhesion molecule shedding. These compounds have also been shown to reduce leukocyte-endothelial adhesion in animal models of ischemia-reperfusion injury. Many inflammatory processes have now been shown to be involved in the development of the skin changes in patients with chronic venous disease. However, the precise sequence of events that leads to leg ulceration is still unclear. Pharmacologic treatments aimed at moderating some of these inflammatory processes are now under investigation as potential ways of treating patients with the more advanced stages of venous disease.

Early manifestations of chronic venous insufficiency (CVI) are edema, hyperpigmentation, and lipodermatosclerosis. Late complications are cutaneous ulceration and delayed healing. The specific hallmarks of this inflammation include CD68-positive infiltration into the dermal tissue, monocytes, and lymphocytes and enhanced endothelial permeability. This may lead to "fibrin cuff" formation. In addition, membrane adhesion molecules are present and cytokine expression is seen.

In one experimental model of mesenteric venous hypertension, the inflammatory process was detected in its earliest stages. This was evident in the form of neutrophilic leukocyte adhesion to venular endothelium as well as migration of cells across the endothelium and basement membrane into the interstitial space. Simultaneously, parenchymal cell death was detected. This suggests that the mechanism that triggers the inflammatory reaction is venous hypertension. This may cause venous distension and a shift in fluid shear stress. Our obser vations suggest that patients with venous insufficiency demonstrate circulatory humoral stim ulators for leukocyte activation. Otherwise, there is evidence that the inflammatory reaction is limited to the region of the venous ulceration or at least to the skin areas with severe microangiopathy. It may be that activated leukocytes traverse perivascular cuffs and release active transforming growth factor-β1 (TGF-β1) which has been found to be elevated exclu sively in areas of clinically active CVI. Surgical intervention markedly decreases the number of dysfunctional vein segments and allows pharmacologic agents to protect normal structures from continuing damage.

Daflon® 500 mg, the purified micronized flavonoid fraction containing 90% diosmin and 10% hesperidin, acts favorably in venous ulcer treatment by inhibiting the synthesis of prostaglandins and free radicals. It decreases bradykinin-induced microvascular leakage and may act favorably to inhibit leukocyte activation, trapping, and migration. Clinically, edema is reduced, ulcer healing is accelerated, and leukocyte trapping diminished. The action of micronized purified flavonoid fraction is beginning to be better understood, and as further knowledge is gained, better pharmacologic control of CVI is a tantalizing promise.

Chronic venous insufficiency (CVI) affects a large number of people in Western countries, and is responsible for considerable inconvenience, discomfort, suffering, and costs.

Micronized purified flavonoid fraction (MPFF, 450 mg diosmin plus 50 mg hesperidin- Daflon 500 mg) is a potent venotropic drug used in the treatment of venous insufficiency. Pharmacological and clinical studies demonstrated the comprehensive mode of action of Daflon 500 mg: it increases venous tone, it improves lymph drainage, and it protects the microcircu lation. Clinical international, prospective, multicenter, randomized, controlled studies versus placebo studies documenting the effects of Daflon 500 mg in CVI at advanced stages with edema, skin changes, and venous leg ulcer are reviewed. In edema, one of the most frequent complaints of patients, Daflon 500 mg brings about a significant reduction in leg circumference, thanks to its capacity to inhibit inflammatory reactions and to decrease capillary hyperper meability. The rationale for the use of Daflon 500 mg for treatment of skin disorders and venous leg ulcer is its action on the microcirculation-damaging processes. Regarding skin changes, Daflon 500 mg has been shown to improve venous trophic disorders, like gravitational (stasis) dermatitis, and dermatofibrosclerosis. In venous leg ulcer, Daflon 500 mg's clinical efficacy has been demonstrated in addition to standard treatment or versus standard treatment alone.

Daflon 500 mg, thanks to its comprehensive mode of action on the veins, lymphatics, and microcirculation, is the method of choice not only in the early stages of CVI treatment, but also in the severe stages of this condition, in combination with compression treatment, scle rotherapy, and surgery if appropriate.