Chronic Venous Insufficiency: Pathophysiology and Treatment

  Although peripheral vascular problems are encountered throughout many healthcare arenas, venous insufficiency with resultant venous stasis dermatitis and ulceration remains a challenging clinical scenario. New therapies are emerging as the understanding of the pathophysiologic mechanisms causing venous disease are clarified. As more is known about the underlying causation of venous insufficiency, the more directed the therapy has become. This article will outline the pathophysiology as well as effective treatment modalities for the patient population affected with peripheral vascular disorders.

Venous Insufficiency Features

  Chronic venous disease, a common problem in both sexes, has an estimated prevalence of 17% in men and 40% in women.1 The presence of varicose veins, a common finding linked to venous insufficiency, is even more prevalent in female patients. Estimates of varicose veins are as high as 56% in men and 60% in women. (Estimations vary widely due to variations in age, race, and definitions and measurements of the disease.)^1,2   Chronic venous insufficiency (CVI) occurs when venous hypertension exists due to incompetent valves, a finding most commonly occurring in the lower extremities, with recognized risk factors including prolonged standing, pregnancy, female gender, trauma, surgery, and genetics — risk factors that are associated with development of varicose veins and venous thrombosis. Resultant inflammation from the disruption in normal blood flow plays a pivotal role in the development of stasis dermatitis and ulceration. Ulceration, once present, may be further complicated by bacterial colonization, which contributes to poor wound healing.   Understanding the venous anatomy and physiology of the lower extremities under normal conditions is important to comprehension of the causative pathology of CVI. Systems of deep and superficial veins connected by perforator veins exist in the lower extremities. Bicuspid valves are located in the superficial and deep veins that help to ensure that blood is pumped toward the heart and prevent reflux of blood toward the feet while the patient is standing in an upright position. The valves of the perforating veins function to prevent reflux of blood from the deep veins into the superficial veins.³ Under normal conditions when patients are standing erect, venous return is pulsatile and the valves open and close approximately 20 times per minute.⁴ The valves close when the pressure on the luminal side of the valve from the proximally directed jet is less than the pressure caused by the recirculation eddy below the valve leaflets.⁴ The valves open and close based on pressure rather than flowing through the veins, allowing for prevention of reflux through complete closure of the valve.   Venous valves themselves have features that make them vulnerable to initiation and formation of thrombus and subsequent further damage that leads to CVI. The endothelial cells lining the wall of the valve pocket are subject to disturbed flow and stasis at times during the valve opening-and-closing cycle. This stasis in the valve sinus may change the expression of thrombotic factors from endothelial cells and prevent influx of clotting factor inhibitors, creating a microenvironment of hypercoaguability.⁵ The stasis or flow recirculation in the valve cusps also promotes white blood cells (WBCs) and platelets to be trapped. In multiple studies, infiltration of valvular leaflets and surrounding vascular walls with WBCs was demonstrated in all valve specimens from patients with chronic vascular disease, but not found in specimens from controls.^6,7 Furthermore, the valves and walls in the superficial veins are more prone to structural failure than deep veins. Superficial veins are surrounded by connective tissue and fat, whereas deep veins are surrounded by muscle and fascia.³   Changes in shear stress or pressure can rapidly induce inflammation; may require remodeling of the wall and valves that underlie chronic venous pathology, including varicose veins, reticular veins, and venous stasis dermatitis; and, eventually lead to ulceration.^8-9 In a study with direct angioscopic observation with veins under increased pressure, the walls and valves of the lower extremity venous system undergo physical changes that include thickening and thinning of the wall, dilatation of the valve annulus, and stretching of the leaflets, as well as complete destruction of the valve. An imbalance between matrix metalloproteases (MMPs), including MMP-2 and MMP-9, and their tissue inhibitors (TIMPs), along with elevated levels of cytokines and growth factors, favor alterations in the extracellular matrix.^8,10 When Chiu et al compared the results of in vivo animal studies with disrupted venous flow to those of findings in patients with chronic venous disease, they found the results comparable. Overall findings confirmed that there was: 1) increased WBC infiltration in the valves and walls of veins; 2) elevated ICAM-1 (intercellular adhesion molecule) in the walls and valves; 3) increased ICAM-1, VCAM-1 (vascular cellular adhesion molecule), and E-selectin (an endothelial leukocyte adhesion molecule) in plasma, which suggest endothelial activation; 4) elevated levels of activated WBCs and reactive oxygen species in plasma; 5) increased macrophages, lymphocytes, and mast cells in skin biopsies; 6) increased mast cell infiltration; 7) increased ratios of TIMP-1/MMP-2 and TIMP-2/MMP-2, as well as increased levels of TGF-b1 (transforming growth factor) and basic fibroblast growth factor in the walls of varicose veins; 8) elevated levels of vascular endothelial growth factor and platelet-derived growth factor; and 9) increased levels of MMP-9.³   Venous endothelial cells form a monolayer that is directly exposed to the blood in the veins. Endothelial cells play a large role in the pathophysiology of chronic venous stasis, as they can influence vascular remodeling, modulate hemostasis and thrombosis, mediate inflammatory responses, and can regulate vascular smooth muscle cell contraction. With prolonged stasis and reflux, there is increased interaction between venous endothelial cells and WBCs. This increased interaction leads to activation of endothelial cells and upregulation of proinflammatory genes that underlie the pathology of all chronic venous disease.⁴ Endothelial cells exposed to disturbed flow exhibit different responses in structure, function, signaling, and gene expression than endothelial cells exposed to normal flow.³

CVI Management

  Treatment of CVI starts with prevention. Patients with known risk factors of obesity, female gender, prolonged standing, or recent trauma or surgery should be counseled on preventative measures such as weight loss, compression stockings, and lower extremity exercises throughout the day that focus on foot movement. Exercise may increase the velocity of the main jet of returning blood and reduce pressure on the luminal side of the valve leaflets, allowing for closure of the valves and minimizing reflux and preventing endothelial cell exposure to reverse or disturbed blood flow.^3,4 When CVI already exists, treatment focuses on restoration of normal blood return and minimization of reflux and venous hypertension. Compression stockings are a mainstay of treatment, as they help to prevent blood from pooling in the lower extremities and to reduce edema. Other common therapies include external laser therapy, sclerotherapy, endovenous obliteration of the saphenous vein, and surgery.¹¹   Pharmacological therapy, generally used as adjunct to more definitive therapy, thus far has been with medications aimed at preventing interaction of leukocytes with the endothelium, therefore preventing an inflammatory cascade. Examples of pharmacological therapies include: coumarin, an alpha-benzopyrone that is limited by its hepatotoxicity; diosmin with micronized purified flavonoid fraction (MPFF), which inhibit leukocyte activation, adhesion, and migration; rutin and rutosides, which increase venous tone by blocking inactivation of noradrenaline; horse chestnut seed extract, which has similar mechanism of action as MPFF but has failed to demonstrate clinical benefit; and other plant extracts such as ruscus extracts, ginkgo biloba, proanthocyanidines (which have been investigated, but only with limited clinical benefit and small sample sizes).¹² Other less-studied treatment modalities include water-filtered infrared A radiation, oral doxycycline in combination with topical tacrolimus, and portable sequential compression devices.^13-15   Disturbed blood flow in the venous system with resultant endothelial cell-mediated inflammation are the underlying factors in all chronic venous disease. Prevention in patients with known risk factors is the most effective means to reduce the incidence of chronic venous disease. Many treatments are available, but further studies need to be done to bridge the gap between evidenced-based medicine and current clinical practice. Kathryn C. Durham is a clinical research fellow in the department of dermatology at the University of Texas Medical School at Houston. Adelaide A. Hebert is professor and director of pediatric dermatology at University of Texas Medical School at Houston; is board certified in dermatology, pediatric dermatology, and wound healing; and has served as the consultant dermatologist for the Hermann Center for Wound Healing in Houston for the past 23 years.

References

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