**3. Pathophysiology of CDV**

Near 60% of blood volume flows is in the venous system, the majority of it in the lower limbs and in the cutaneous circulation, and near 20-25% occupies the splanchnic circulation [55]. The venous system returns the blood to the heart and is a low-pressure, slow-velocity, largevolume and low-resistance vascular system [1]. Venous return results from the interaction of diverse mechanisms, like a central pump (respiratory cycle and heart), a pressure gradient, a peripheral venous pump, and veins valvular system [43]. The venous volume in the lower limb is the result of the interaction between these mechanisms and reflects the balance between blood inflow and outflow [1].

CVD is caused by venous hypertension, valvular insufficiency, and/or blood reflux [56–58]. Venous hypertension might be accompanied by outflow obstruction [57] and can affect the superficial, perforator, and deep veins [3, 58]. Insufficient lymphatic drainage or a dysfunction of calf muscle pump are very often associated with this disease [59]. Venous hypertension is related to structural (veins and valves), hemodynamic (obstruction, reflux, stasis), biomechanical (calf muscle pump strength and ankle range of motion) and biochemical factors (leucocyte-endothelial process inflammation) [57, 58].

The exact mechanisms behind the development of CVD are not clear yet [57, 60]. The major hypothetical sequence of events places venous hypertension as the trigger, causing inflammation of the veins' wall and of vein valves, with inflammation, as the condition aggravates, spreading to the skin and the muscles, causing dermal changes, like hyperpigmentation, subcutaneous tissue fibrosis (lipodermatosclerosis), and tissue necrosis and ulceration [20, 51, 57, 59] in the most severe cases [60].

Venous obstruction occurs because of the triad: blood stasis, changes in the vessel wall, and hypercoagulability [61]. This may occur as a phlebitis (obstructions of superficial venous system) or as deep venous thrombosis (obstructions of deep venous system), and can be diagnosed as acute or chronic [12]. The acute deep venous thrombosis may cause nociceptive pain, swelling and tenderness, and both phlebitis and deep venous thrombosis must be confirmed by venous ultrasonography [57]. The ensuing venous hypertension then opposes venous return, leading to luminal hypoxemia and vein wall distension, which impairs perfusion and causes endothelial hypoxia and leukocyte invasion of the vein's media [61]. A progressive remodeling process is then triggered consisting of hypoxemia-related venous/capillary wall injury, leukocytes accumulation and adhesion, progressive blockage of capillary blood flow, and ongoing damage of subcutaneous tissues and skin (lipodermosclerosis and skin ulceration) [62].

Usually, venous reflux and obstruction occur together [57]. Following obstruction, venous recanalization occurs and blood flow through the vein is restored [61]. However, lysis of the clot or thrombus is usually only partial and the residual thrombus might undergo fibrosis that may completely obstruct the lumen of the vein, for example involving leaflets [61]. Collateral blood circulation may develop in these cases and obstruction may be overcome [57]. Sometimes, calf perforating veins may be an important collateral venous path when the popliteal vein is involved, causing CVD of a secondary etiology [57].

The initial hypertension in CVD may also be caused by valvular incompetence alone [60]. Varicose veins may result from endothelial changes (reduced elastin and smooth muscle content, together with increased collagen) associated with hypoxia, causing weakened venous tone [60]. Other changes include downregulated apoptosis [63], decrease energy for cell metabolism and increased lysossomal activity [64].

#### **3.1. Etiology and anatomical location of CVD**

[42, 52]. There are several risk factors associated with CVD that patients should be informed of by the health professionals, like the use of hormonal contraceptives by women, daily routines (sitting or standing), pregnancy, age, obesity and heredity factors (i.e., family history) [1, 37, 42, 49, 53]. Also important, advice regarding behavioral changes, engaging in so-called venous exercises and the proper use of the health care services, should be offered to CVD patients [42]. Getting the right advice from health care professionals is an important measure

Because of the wide spectrum of factors that cause functional impairment in these patients and the high costs of treatment [2, 3, 8], the prevention of CVD by educational and prophylactic interventions has been shown to be clinically cost-effective, by avoiding disease progres-

Near 60% of blood volume flows is in the venous system, the majority of it in the lower limbs and in the cutaneous circulation, and near 20-25% occupies the splanchnic circulation [55]. The venous system returns the blood to the heart and is a low-pressure, slow-velocity, largevolume and low-resistance vascular system [1]. Venous return results from the interaction of diverse mechanisms, like a central pump (respiratory cycle and heart), a pressure gradient, a peripheral venous pump, and veins valvular system [43]. The venous volume in the lower limb is the result of the interaction between these mechanisms and reflects the balance

CVD is caused by venous hypertension, valvular insufficiency, and/or blood reflux [56–58]. Venous hypertension might be accompanied by outflow obstruction [57] and can affect the superficial, perforator, and deep veins [3, 58]. Insufficient lymphatic drainage or a dysfunction of calf muscle pump are very often associated with this disease [59]. Venous hypertension is related to structural (veins and valves), hemodynamic (obstruction, reflux, stasis), biomechanical (calf muscle pump strength and ankle range of motion) and biochemical factors (leu-

The exact mechanisms behind the development of CVD are not clear yet [57, 60]. The major hypothetical sequence of events places venous hypertension as the trigger, causing inflammation of the veins' wall and of vein valves, with inflammation, as the condition aggravates, spreading to the skin and the muscles, causing dermal changes, like hyperpigmentation, subcutaneous tissue fibrosis (lipodermatosclerosis), and tissue necrosis and ulceration [20, 51, 57,

Venous obstruction occurs because of the triad: blood stasis, changes in the vessel wall, and hypercoagulability [61]. This may occur as a phlebitis (obstructions of superficial venous system) or as deep venous thrombosis (obstructions of deep venous system), and can be diagnosed as acute or chronic [12]. The acute deep venous thrombosis may cause nociceptive pain, swelling and tenderness, and both phlebitis and deep venous thrombosis must be confirmed by

for preventing and managing CVD [42].

sion to the last stages [49, 54].

148 Clinical Physical Therapy

**3. Pathophysiology of CDV**

between blood inflow and outflow [1].

59] in the most severe cases [60].

cocyte-endothelial process inflammation) [57, 58].

The etiology of CVD can be described as primary, secondary (post-thrombosis) or congenital [13]. Although reflux is the major hemodynamic alteration in CVD, in secondary venous disease most of the cases present a mix of reflux and obstruction [58]. It seems that 80% of cases of CVD have a secondary etiology of post-thrombotic pathology, and 20% are of primary cause, as a result of valvular incompetence [57].

In the superficial system, the insufficiency is most often the result of a primary preexisting weakness in the vessel wall or valve, as a consequence of a direct injury, excessive venous distention caused by hormonal effects or high hydrostatic pressure, or secondary to venous obstruction (i.e., phlebitis) [33, 59, 65, 66]. Failure in valve functioning (superficial veins) may increase superficial venous pressure, resulting in venous dilatation and varicose veins [59]. Although the primary mechanism of valvular incompetence in superficial veins is not fully known [57], it appears that first changes in the mechanical properties of the vein wall caused by increased collagen content and decreased amount of elastin and smooth muscle, leading to vessel enlargement occur and next, valvular insufficiency develops [57].

The perforating veins can also become insufficient by primary incompetence of vein valves or secondary to venous obstruction [67]. In these cases, there is reflux from deep to superficial venous system: with valve incompetence the reflux to saphenous veins may allow the re-entry of venous blood to the deep venous system [67]. In the case of secondary incompetence, the high intravascular pressures are transmitted to superficial veins, causing the enlargement of dermal capillaries and increasing filtration to the interstitial space [57, 67].

Deep veins insufficiency has been suggested to be the consequence of deep veins thrombosis in the majority of cases, i.e., from secondary etiology [59]. However, primary deep venous incompetence is also common (8-22% of the cases [12]) but is usually compensated by a strong muscle [12, 57]. It seems that outflow obstruction and reflux caused by valve damage may cause deep vein thrombosis and these two alterations together increase the probability of the development of post-thrombotic syndrome [12, 61].

Deep venous thrombosis may also occur because of an intrinsic venous process, such as a previous deep venous thrombosis episode with inadequate recanalization or venous stenosis, or because of extrinsic compression, as in May-Thurner syndrome [66]. Also, it can be caused by venous agenesis, such as in the Klippel-Trenaunay syndrome, trauma, surgical mishap, and tumors [57].

Congenital CVD, in which case the condition is already present at birth, also exist. However, this might be recognized only later in life, such as in the cases of the Klippel-Trenaunay (varicosities and venous malformations, capillary malformation, and limb hypertrophy) [33] and Parkes-Weber (venous and lymphatic malformations, capillary malformations, and arteriovenous fistulas) syndromes [66].
