Pathophysiology of chronic venous disease Authors Patrick C Alguire, MD, FACP Barbara M Mathes, MD, FACP, FAAD Section

Editors John F Eidt, MD Joseph L Mills, Sr, MD Deputy Editor Kathryn A Collins, MD, PhD, FACS Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2013. | This topic last updated: may 1, 2013. INTRODUCTION Chronic venous disease is a common medical problem that can result in significant morbidity and mortality. The clinical presentation of this disorder spans a spectrum from asymptomatic but cosmetically troublesome small blue ectatic veins and varicosities, to severe fibrosing panniculitis, dermatitis, edema, and ulceration. (See "Clinical manifestations of lower extremity chronic venous disease".) The final common pathway that leads to chronic venous insufficiency is the development of venous hypertension. In most cases, venous hypertension results from obstruction to venous flow, dysfunction of venous valves, and/or failure of the "venous pump." In these situations, flow is directed abnormally from the deep to the superficial system, producing local tissue inflammation fibrosis, and occasionally ulceration. This topic will review normal venous anatomy and physiology, and the pathophysiology of venous hypertension with its clinical consequences. Other aspects of chronic venous insufficiency are discussed separately. NORMAL VENOUS ANATOMY AND PHYSIOLOGY Three major vascular pathways are responsible for draining blood away from the superficial vessels of the skin and subcutaneous fat and include: (See "Classification of lower extremity chronic venous disorders", section on 'Anatomy'.)

Superficial veins The superficial veins are a network of subcutaneous veins that are superficial to the deep muscular fascia and include the great saphenous and small saphenous veins. (figure 1 and figure 2). Deep veins The deep veins are located deep to the muscle fascia (figure 3). Deep veins are either within the muscle (ie, intramuscular, such as the gastrocnemius and soleus) or between the muscles (ie, intermuscular); the latter are more important in the development of chronic venous insufficiency [1]. The intermuscular veins, which accompany the lower extremity arteries, include the anterior tibial, posterior tibial, peroneal (fibular), popliteal, and femoral veins. The lower leg intermuscular veins are exposed to high subfascial pressures during calf muscle contraction. Perforating veins The perforating veins communicate between the deep and superficial venous systems. One very important group of perforating veins,

Cocketts perforators, connect the posterior tibial veins to the posterior accessory great saphenous vein (ie, vein of Leonardo), indirectly draining into the deep venous system. Determinants of venous flow The venous valves and "venous pump" are the two major determinants of venous flow.

Venous valves are typically bicuspid. Venous valves direct flow from distal to proximal and from the superficial system to the deep system except in the foot, where flow is directed from the deep system to the superficial system. Venous valves increase in number in direct relation to the hydrostatic pressure; in the distal deep veins, for example, they may occur every 2 centimeters [1]. The venous pump refers to the pumping effect of leg muscles on venous flow. As blood is directed proximally in the deep venous system by muscular contraction, it enters the deep venous system from the superficial system, draining the skin and subcutaneous tissues.

The effectiveness of the pump is dependent upon the presence of competent venous valves. Competent valves serve two main functions: they prevent the transmission of sudden rises in venous pressure in the superficial veins and capillaries during muscular contraction; and, at the end of muscle contraction, the valves prevent retrograde flow back into the superficial system. When this system is functioning appropriately, the ambulatory venous pressure in the superficial system is maintained between 20 and 30 mmHg. GENESIS AND CONSEQUENCES OF CHRONIC VENOUS HYPERTENSION In the presence of venous obstruction, incompetent venous valves, or inadequate muscle contraction, ambulatory venous pressures can reach 60 to 90 mmHg. This level of venous pressure constitutes venous hypertension, and is capable of initiating the anatomic, physiologic, and histologic changes associated with chronic venous insufficiency (table 1) [2-5]. Anatomic changes Valvular incompetence is the primary anatomic abnormality associated with venous hypertension. Deep vein thrombosis is an example of a disorder that causes venous hypertension (because of diminished proximal flow of venous blood) and chronic venous insufficiency via this mechanism. The increase in pressure is transmitted backward into the superficial venous system; thrombosis also destroys the valves, resulting in persistence of venous hypertension even if the thrombosed veins are recanalized. Chronic venous insufficiency is also associated with fewer valves per unit length which contributes to higher venous pressures [6]. This process becomes a vicious cycle. As deep and superficial veins become distended with excess volume, anatomic distortion of the vessel wall produces further valvular incompetence. The actual volume of refluxed blood in patients with venous insufficiency may be relatively small. However, when the superficial veins are already maximally distended, small increases in volume produce large increases in pressure [7]. It is the transmission of this

excess pressure that is responsible for most of the skin changes characteristic of chronic venous insufficiency. (See 'Lipodermatosclerosis' below and "Clinical manifestations of lower extremity chronic venous disease".). Physiologic changes Standing is normally associated with reflex constriction of the precapillary arterioles; by diminishing the transmission of arterial pressure to the capillary bed, this response protects the capillary bed from surges in venous hydrostatic pressure when assuming an upright posture. Patients with venous hypertension may lose this reflex; as a result, large increases in venous pressure are transmitted directly to the superficial capillary system [8-10]. Histologic changes Sustained venous hypertension is associated with characteristic histological and ultrastructural changes that underlie the cutaneous manifestations of chronic venous insufficiency. Venous hypertension is associated with changes in the venous wall, including variation in wall thickness, increases in type 1 collagen, decreases in type III collagen, degradation of extracellular matrix, and reductions in the number of smooth muscle cells [11-13]. These changes weaken the vessel wall and may lead to abnormal venous dilation [14]. The chronic release of inflammatory mediators is a fundamental cause for the trophic skin changes associated with venous insufficiency.

Leukocytes accumulate and adhere to the endothelium of small vessels and become activated [15,16]. This microvascular leukocyte-trapping hypothesis is supported by histological findings of increased numbers of macrophages, T lymphocytes, and mast cells in the tissue of patients with chronic venous hypertension [17,18]. Increased expression of matrix metalloproteinases and other proteinases by the vessel cells breaks down the vascular extracellular matrix and leads to abnormal vascular permeability and edema. The presence of proteolytic enzymes in subcutaneous tissues leads to the formation cutaneous ulcers, which heal poorly and can become chronic [19]. Migration of erythrocytes from the vascular space into tissue, and their subsequent degradation, results in the characteristic brown hyperpigmentation in the gaiter area. The release of ferritin and ferric oxide from the erythrocytes may result in oxidative stress and additional metalloproteinase activation, promoting tissue damage, ulcer formation, and delayed ulcer healing [20].

Lipodermatosclerosis Patients with significant venous insufficiency can develop a severe fibrosing panniculitis of the subcutaneous tissue; the clinical representation of the panniculitis is known as lipodermatosclerosis. (See "Clinical manifestations of lower extremity chronic venous disease".) Lipodermatosclerosis presents as an area of indurated inflammatory tissue that binds the skin down to the subcutaneous tissue (picture 1A-C). Lipodermatosclerosis is associated with abnormal, elongated, glomerular-like capillaries with increased vascular permeability [21]. Dermal fibrosis may be the result of TGF-1 fibrogenic cytokine release from activated leukocytes that have migrated out of the abnormally permeable vessels into

the tissues. TGT-1 cytokine increases the production of collagen and subcutaneous fibrosis [18]. Capillaries are virtually absent in areas of fibrotic scars, leading to a condition known as atrophie blanche or livedoid vasculopathy (picture 2) [22]. The lack of blood flow may explain the proclivity for these areas to develop ulcers. (See "Livedoid vasculopathy".) As with valvular incompetence, worsening lipodermatosclerosis may become part of a vicious cycle. As the fibrosis increases, it may become so extensive and constrictive as to girdle and strangle the lower leg, further impeding lymphatic and venous flow. Low shear stress Shear stress is inversely related to venous pressure. Thus, venous hypertension is associated with low shear stress. Leukocytes aggregate and activate when subjected to low shear stress, promoting inflammatory and thrombotic reactions [23-25]. It is not known how low shear stress promotes inflammatory events in the venous system; however, this process seems important in causing the pathological changes in veins and valves. SUMMARY AND RECOMMENDATIONS

Chronic venous disease is a common medical problem that can result in significant morbidity and mortality. The final common pathway that leads to chronic venous insufficiency is the development of venous hypertension, particularly within the deep venous system. (See 'Introduction' above.) Deep veins are classified as within the muscles (ie, intramuscular) or between the muscles (ie, intermuscular). Abnormalities of the intermuscular veins (anterior tibial, posterior tibial, peroneal [fibular], popliteal, and femoral veins) play a more significant role in the development of chronic venous insufficiency. The intermuscular veins of the lower leg veins are exposed to high subfascial pressures during calf muscle contraction. (See 'Normal venous anatomy and physiology' above.) Venous valves direct flow from distal to proximal and from the superficial system to the deep system except in the foot, where flow is directed from the deep system to the superficial system. Blood is directed proximally within the deep venous system by muscular contraction (ie, the venous pump). The effectiveness of this pumping action is dependent upon the presence of competent vein valves to prevent transmission of sudden increases in venous pressure, and prevent retrograde flow. When this system is functioning, the ambulatory venous pressure in the superficial system is maintained between 20 and 30 mmHg. (See 'Determinants of venous flow' above.) Valvular incompetence is the primary anatomic abnormality associated with venous hypertension, but obstruction (eg, deep vein thrombosis) and failure of the venous pump may contribute. Anatomic distortion of the vessel wall from excess venous pressure exacerbates valvular incompetence. (See 'Anatomic changes' above.) Sustained venous hypertension is associated with histologic and ultrastructural changes that lead to increased vascular permeability (edema) and the chronic release of inflammatory mediators that are the fundamental cause of cutaneous

hyperpigmentation, trophic skin changes, and ulceration. (See 'Physiologic changes' above and 'Histologic changes' above.) Lipodermatosclerosis refers to areas of indurated inflammatory tissue that bind the skin to the underlying subcutaneous tissue. The severity of lymphatic destruction is directly correlated to the degree of venous hypertension. (See 'Lipodermatosclerosis' above.)

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REFERENCES
1. Tretbar LL. Deep veins. Dermatol Surg 1995; 21:47. 2. Franzeck UK, Haselbach P, Speiser D, Bollinger A. Microangiopathy of cutaneous blood and lymphatic capillaries in chronic venous insufficiency (CVI). Yale J Biol Med 1993; 66:37. 3. Takase S, Pascarella L, Lerond L, et al. Venous hypertension, inflammation and valve remodeling. Eur J Vasc Endovasc Surg 2004; 28:484. 4. Takase S, Pascarella L, Bergan JJ, Schmid-Schnbein GW. Hypertension-induced venous valve remodeling. J Vasc Surg 2004; 39:1329. 5. Pascarella L, Penn A, Schmid-Schnbein GW. Venous hypertension and the inflammatory cascade: major manifestations and trigger mechanisms. Angiology 2005; 56 Suppl 1:S3. 6. Sales CM, Rosenthal D, Petrillo KA, et al. The valvular apparatus in venous insufficiency: a problem of quantity? Ann Vasc Surg 1998; 12:153. 7. Browse NL. The etiology of venous ulceration. World J Surg 1986; 10:938. 8. Stcker M, Schbe MC, Hoffmann K, Schultz-Ehrenburg U. Cutaneous microcirculation in skin lesions associated with chronic venous insufficiency. Dermatol Surg 1995; 21:877. 9. Jnger M, Klyscz T, Hahn M, Rassner G. Disturbed blood flow regulation in venous leg ulcers. Int J Microcirc Clin Exp 1996; 16:259. 10. Christopoulos DC, Belcaro G, Nicolaides AN. The hemodynamic effect of venous hypertension in the microcirculation of the lower limb. J Cardiovasc Surg (Torino) 1995; 36:403. 11. Sansilvestri-Morel P, Rupin A, Badier-Commander C, et al. Imbalance in the synthesis of collagen type I and collagen type III in smooth muscle cells derived from human varicose veins. J Vasc Res 2001; 38:560. 12. Travers JP, Brookes CE, Evans J, et al. Assessment of wall structure and composition of varicose veins with reference to collagen, elastin and smooth muscle content. Eur J Vasc Endovasc Surg 1996; 11:230. 13. Jacob MP, Badier-Commander C, Fontaine V, et al. Extracellular matrix remodeling in the vascular wall. Pathol Biol (Paris) 2001; 49:326. 14. Bergan JJ, Schmid-Schnbein GW, Smith PD, et al. Chronic venous disease. N Engl J Med 2006; 355:488. 15. Thomas PR, Nash GB, Dormandy JA. White cell accumulation in dependent legs of patients with venous hypertension: a possible mechanism for trophic changes in the skin. Br Med J (Clin Res Ed) 1988; 296:1693.

16. Moyses C, Cederholm-Williams SA, Michel CC. Haemoconcentration and accumulation of white cells in the feet during venous stasis. Int J Microcirc Clin Exp 1987; 5:311. 17. Wilkinson LS, Bunker C, Edwards JC, et al. Leukocytes: their role in the etiopathogenesis of skin damage in venous disease. J Vasc Surg 1993; 17:669. 18. Pappas PJ, DeFouw DO, Venezio LM, et al. Morphometric assessment of the dermal microcirculation in patients with chronic venous insufficiency. J Vasc Surg 1997; 26:784. 19. Herouy Y, May AE, Pornschlegel G, et al. Lipodermatosclerosis is characterized by elevated expression and activation of matrix metalloproteinases: implications for venous ulcer formation. J Invest Dermatol 1998; 111:822. 20. Wenk J, Foitzik A, Achterberg V, et al. Selective pick-up of increased iron by deferoxamine-coupled cellulose abrogates the iron-driven induction of matrixdegrading metalloproteinase 1 and lipid peroxidation in human dermal fibroblasts in vitro: a new dressing concept. J Invest Dermatol 2001; 116:833. 21. Bates DO, Curry FE. Vascular endothelial growth factor increases hydraulic conductivity of isolated perfused microvessels. Am J Physiol 1996; 271:H2520. 22. Franzeck UK, Bollinger A, Huch R, Huch A. Transcutaneous oxygen tension and capillary morphologic characteristics and density in patients with chronic venous incompetence. Circulation 1984; 70:806. 23. Traub O, Berk BC. Laminar shear stress: mechanisms by which endothelial cells transduce an atheroprotective force. Arterioscler Thromb Vasc Biol 1998; 18:677. 24. Yoshizumi M, Abe J, Tsuchiya K, et al. Stress and vascular responses: atheroprotective effect of laminar fluid shear stress in endothelial cells: possible role of mitogen-activated protein kinases. J Pharmacol Sci 2003; 91:172. 25. Ohura N, Yamamoto K, Ichioka S, et al. Global analysis of shear stress-responsive genes in vascular endothelial cells. J Atheroscler Thromb 2003; 10:304.