The hemodynamic changes that occur in patients with acute deep vein thrombosis (DVT) are dependent on the level of thrombosis, its extent, and whether thrombus progression is slow or rapid. The severity of the hemodynamic disturbance caused by the venous obstruction will determine the development and magnitude of the presenting symptoms and signs experienced by the individual.

Localized DVT in one or two veins in the calf as shown by venography is often asymptomatic producing mild ankle edema and calf tenderness in only 50% of patients [20]. In contrast, extensive calf DVT involving the popliteal vein is often symptomatic. Significant lower extremity edema will not occur as long as the thrombus is confined to the femoral vein distal to the junction with the deep femoral or the great saphenous veins which act as collateral drainage channels. When thrombosis involves these junctions or occurs proximal to them, massive limb edema is likely to occur [21]. Furthermore, rapid progression of thrombus proximally may not allow development of a collateral circulation and may result in venous gangrene.

Plethysmographic studies of patients with lower extremity DVT have demonstrated reduced venous volume and increased outflow resistance [22–24]. The reduced venous volume is thought to be due to the reduced capacity of the lower extremity veins when they are filled with thrombus in patients with proximal obstruction. In addition, increased extravascular tissue pressure due to edema decreases the distensibility of the veins further decreasing venous volume [22–27].

Lower extremity venous pressure is increased in patients with acute DVT [28]. In patients with DVT, venous pressure was measured in the foot in patients in the horizontal position. Venous pressure was 8.5–18.4 mmHg when thrombosis was confined to the calf and/or popliteal vein, 20–51 mmHg when thrombosis involved the femoral vein, and 32–83 mmHg in patients with iliofemoral DVT [21]. Limb edema was rarely present in patients with venous pressures less than 20 mmHg and always present in patients with venous pressures greater than 50 mmHg.

Venous flow and velocity are phasic with respiration in normal limbs in the horizontal position. During inspiration, intra-abdominal pressure increases with contraction of the diaphragm. The increase in intra-abdominal pressure is transmitted to the inferior vena cava and iliac veins resulting in a decrease in the pressure gradient between the lower extremity vein and the inferior vena cava. The end result is a decrease in blood flow from the lower extremities.

During expiration, the reverse occurs as the diaphragm relaxes and intra-abdominal pressure decreases. The decrease in intra-abdominal pressure results in an increase in the venous pressure gradient between the inferior vena cava and lower extremity veins. This results in an increase in venous flow and velocity from the lower extremity veins.

In patients with acute iliofemoral DVT, the outflow resistance increases much more than the respiratory fluctuations so that this becomes the limiting factor, and flow in the deep veins distal to the obstruction loses phasicity and velocity decreases [1]. In contrast, flow and velocity in the collateral circulation increase, and higher velocities are observed. These findings explain why an ultrasonographer should look for a more proximal obstruction when performing a DVT scan in a patient with the dual finding of the absence of respiratory phasicity in the deep veins and increased velocity in the collateral veins of the lower extremity [1].

Chronic venous disease (CVD) is a term that includes all long-term morphological and functional abnormalities of the venous system, manifested either by symptoms or signs indicating a need for investigation and treatment. In patients with CVD , hemodynamic disturbances occur which result in the inability of valves, pumps, and conduits in the venous system to maintain a normal venous pressure and normal flow toward the heart. Hemodynamic disturbances are primarily caused by venous reflux, obstruction, or a combination of both [1].

Varicose veins are a common manifestation of CVD and are believed to result from the abnormal distension of connective tissue in the vein wall. Veins from patients with varicosities have different elastic properties than those from individuals without varicose veins [29, 30]. There is hypertrophy of the vein wall with increased collagen content [31], fragmentation of elastin fibers [32] with degradation, and accumulation of extracellular matrix [33].

Primary varicose veins result from venous dilatation and/or valve damage without previous DVT. Secondary varicose veins develop as a result of a prior DVT, congenital venous malformation, or arteriovenous malformation [34].

Varicose veins may also be associated with pelvic vein reflux in the absence of incompetence at the saphenofemoral junction (SFJ), thigh, or calf perforating veins. Retrograde reflux in ovarian, pelvic, vulvar, pudendal, or gluteal veins may be also associated with clinical symptoms and signs of pelvic congestion [35–38].

Elevated venous pressure is considered to be the main precipitating factor in the development of varicose veins. Varicose veins would not occur without hydrostatic pressure from a gravitational force [1]. The effect of dilatation is easily understood from the unrelenting radial forces against the wall of the varicose vein. What is not understood is why the dilatation of varicose veins predominantly occurs in the thigh portion of the great saphenous vein (GSV) in many patients and not in the ankle portion where the hydrostatic pressure is highest (descending theory) [1]. In addition, it is also unknown as to why superficial veins dilate and become tortuous forming varicose veins; in contrast, the GSV usually dilates and rarely becomes tortuous within the saphenous fascia.

Varicose veins have increased wall thickness and increased diameter and length [39]. This is likely due to the different elastic properties observed in varicose veins compared to normal veins [29, 30]. The ratio between collagen I and collagen III is altered as are dermal fibroblasts from the same patients suggesting a systemic disorder with a genetic basis [40]. Leukocyte activation, adhesion, and migration through the endothelium as a result of altered shear stress [41–43] contribute to the inflammation and subsequent remodeling of the venous wall and valves [44–47].

Cell culture studies have shown that smooth muscle cells have undergone phenotypic modulation from a contractile state to a proliferative and secretory state [48]. Reduction in shear stress stimulates production of transforming growth factor-β1 (TGF-β1) by activated endothelial cells and smooth muscle cells (SMCs) inducing SMC migration into the intima and subsequent proliferation as well as phenotype change. Fibroblasts proliferate and synthesize matrix metalloproteinases (MMPs) overcoming the effect of tissue inhibitors of metalloproteinases (TIMPs) . The MMP/TIMP imbalance results in degradation of elastin and collagen [42, 49, 50]. These effects may contribute to the development of hypertrophic and atrophic venous segments and valve destruction that is observed in varicose veins. Remodeling of the venous wall and abnormal venous distension prevents valve leaflets from closing properly resulting in valve failure and reflux.

Genetic factors may also play a role in the development and subsequent progression of primary varicose veins to advanced CVD. A relationship between the C282Y polymorphism in hemochromatosis (HFE gene) and venous ulceration has been described [51].

Imaging studies in patients with deep venous insufficiency have shown that approximately 30% of these patients have primary valvular incompetence rather than findings consistent with post-thrombotic injury [52, 53]. Valve agenesis or aplasia is a less likely cause of deep venous reflux [54].

Following the development of a DVT, spontaneous lysis often occurs over days or weeks, and recanalization that occurs over months or years can be found in 50–80% of patients [55–57]. Rapid thrombus resolution after DVT is associated with a higher incidence of valve competency [55, 58]. The duration of DVT recanalization and resolution depends on thrombus extent, location, local inflammation, potency of local fibrinolytic agents and proinflammatory mediators [59, 60]. Recanalization may give rise to relative obstruction and reflux in deep, superficial, and perforating veins [57]. Incomplete recanalization following DVT can lead to outflow obstruction. Less frequently, obstruction results from extramural venous compression (most commonly left common iliac vein compression by the right common iliac artery) [61, 62], from intraluminal changes [63–65], or rarely from congenital agenesis or hypoplasia [66].

Most post-thrombotic symptoms result from venous hypertension due to valvular incompetence, outflow obstruction, or a combination of both. Venous hypertension increases transmural pressure in postcapillary vessels leading to skin capillary damage with increased microvascular permeability, [67] followed by lipodermatosclerosis and, ultimately, ulceration [68]. Edema will develop when the increased lymphatic transport fails to adequately compensate for increased fluid filtration into the tissue, and thus long-standing venous hypertension is invariably associated with damaged lymphatic drainage in the skin and subfascial space in cases of post-thrombotic syndrome [69, 70]. The reported prevalence of post-thrombotic syndrome following DVT has been variable (35–69% at 3 years and 49–100% at 5–10 years) and depends on the extent and location of thrombosis and treatment [71–81].

Patients with both chronic obstruction and reflux have the highest incidence of clinical C of CEAP 4–6 disease [71]. The risk of ipsilateral post-thrombotic syndrome is highest in patients with recurrent thrombosis and is often associated with congenital or acquired thrombophilia [82–85]. More recent studies suggest that skin changes and/or ulceration are less frequent (4–8% in 5 years) in patients with thrombosis proximal to the knee if they have been treated with adequate anticoagulation, early mobilization, and long-term compression therapy [86, 87]. Mechanical dysfunction of the calf muscle pump may enhance development of leg ulceration suggesting the importance of the range of ankle motion [88] and patient activity [89] in relation to progression of disease. Obesity is another risk factor for severe venous disease and may be related to its association with decreased fibrinolytic activity in blood and tissues [90].

Incompetent perforating veins (IPVs) can be defined as those that penetrate the deep fascia and allow blood flow from the deep to the superficial system. The flow in IPVs in the calf is usually bidirectional, outward during muscular contraction and inward during relaxation. In normal legs and in the majority of patients with primary uncomplicated varicose veins, the net flow is inward from superficial to deep (reentry perforating veins) [91, 92]. The net flow is also inward in patients with femoral vein reflux, provided the popliteal valves are competent. However, flow is predominantly outward in the presence of popliteal valve incompetence (axial reflux) and especially when there is associated deep venous obstruction [92, 93]. The IPVs are associated with superficial and/or deep venous reflux but are rarely found in the absence of reflux [94–96]. In the majority of IPVs, their diameter, volume flow, and velocity increase with clinical severity of CVD whether or not there is coexisting deep venous incompetence [92, 97–102]. Up to 10% of patients, often women, presenting with clinical C of CEAP 1–3 disease , have non-saphenous superficial reflux in association with unusually located IPVs [103].

The valves and walls of superficial veins are more prone to structural failure than deep veins because they are surrounded by connective tissue and subcutaneous fat. In contrast, deep veins are surrounded by rigid structures such as muscle and fascia. Therefore, the walls and valves of the superficial veins are more vulnerable to the changes in shear stress and hydrostatic pressure [104–106].

The concept of retrograde flow in the GSV and the presence of a “private recirculation” were first demonstrated by Trendelenburg in 1891 [91] by placing a tourniquet at mid-thigh and asking the patient to tiptoe repeatedly when it was observed that veins emptied with refilling from above when the tourniquet was released. We now know that the circuit consists usually of a reflux source feeding a saphenous trunk, conduction of reflux, down toward the foot, and reentry points back into deep veins via perforating veins. The presence of this phenomenon has been demonstrated using two simultaneous duplex probes, above and below the knee [107]. In this study, reflux was demonstrated to start and stop simultaneously, even when the probes were swapped around. In another study, volume displacements in patients were quantified within saphenous trunks using duplex ultrasound in response to calf compression [108]. The findings of bidirectional flow in the GSV and perforating veins by Bjordal [109, 110] were confirmed in the same year by Folse [111] who used the CW Doppler which had just become available and by duplex ultrasound scanning in later years. The conclusion was that in the presence of competent deep veins, despite inward and outward flow in perforating veins during walking, the net effect is inward. However, when deep venous valves were incompetent and valves in the GSV were competent, Bjordal found that calf contraction caused upward flow in the saphenous vein and that in limbs with both deep and superficial venous reflux, walking produced bidirectional flow in IPVs with the net effect being outwards [109, 110]. It is now recognized that in the majority of patients, the origin of the downward flow in the superficial system of veins is through the SFJ, thigh IPVs, the SPJ, or a combination of two or even all three and that calf IPVs are reentry points. This is the basic rationale for the CHIVA technique [1]. However, two RCTs have shown that following ablation of superficial incompetence, only 35–40% of IPVs function normally and that new IPVs appear over time [112, 113]. Furthermore, some 6–8% of ulcer patients show only isolated IPVs as a possible cause for their ulcers [114].

Changes in the hemodynamics of veins that result in venous hypertension are transmitted into the microcirculation resulting in an increase in the hydrostatic pressure in capillaries. This results in transcapillary filtration that exceeds lymphatic drainage and contributes to interstitial edema formation. Venous hypertension slows blood flow in the capillaries allowing leukocyte adhesion to capillary endothelium and initiating an inflammatory reaction [115]. One theory contends that inflammation opens gaps between endothelial cells through a mechanism involving vascular endothelial growth factor (VEGF) , nitric oxide synthase (NOS) , and contraction of actin and myosin filaments present in endothelial cells [116]. If the gaps continue to enlarge, this results in increased capillary permeability to fluid and macromolecules, allowing extravasation of red and white blood cells into the interstitial space with edema formation. Swollen endothelial cells with enlarged intercellular spaces make the capillary lumen irregular. The subsequent increase in macromolecular permeability causing plasma, fibrinogen, and red blood cell leakage impairs nutrient exchange [117, 118].

The skin is the final target of chronic venous hypertension and the hemodynamic changes in veins. Clinical manifestations caused by alteration in skin capillaries are hyperpigmentation, venous eczema, lipodermatosclerosis, atrophie blanche, and eventually venous ulceration (Fig. 2.2). Several mechanisms for the development of venous ulcers have been postulated of which the theory of “leukocyte trapping ” is the most likely [119]. It is hypothesized that the primary injury to the skin is extravasation of macromolecules such as fibrinogen and alpha-2-macroglobulin as well as red blood cells causing pigmentation into the dermal interstitium [120, 121]. Red blood cell degradation products and extravasation of interstitial proteins are potent chemoattractants and presumably generate an initial inflammatory signal that results in leukocyte recruitment and migration into the dermis [115]. Pathologic events occur during leukocyte migration into the dermis, and the end product is dermal fibrosis. An increase in transforming growth factor beta-1 (TGF-β1) , released by macrophages and mast cells or auto-induced by dermal fibroblasts, causes an imbalance in tissue remodeling which results in increased collagen synthesis and affects matrix metalloproteases (MMPs) as well as their tissue inhibitors (TIMPs). It is hypothesized that an imbalance in MMPs and their regulation may cause or contribute to venous ulcer formation. A cascade of inflammatory events results in cutaneous changes which include skin hyperpigmentation caused by hemosiderin deposition and eczematous dermatitis. Fibrosis may develop in the dermis and subcutaneous tissue lipodermatosclerosis . There is an increased risk of cellulitis and leg ulceration [118, 120, 121].

The function of the lymphatic vessels is very important. They are involved in the recirculation of lymphocytes and proteins, transport of microorganisms by lymph, and drainage of interstitial fluid to blood. The average human body weighing 65 kg contains 3 L of blood plasma and 12 L of interstitial fluid. Up to 8–12 L of afferent lymph are produced each day of which 4–8 L of ultrafiltrate are reabsorbed into the bloodstream. The concentration of proteins in plasma, interstitial fluid, afferent lymph, and efferent lymph is 70 g/L, 20–30 g/L, 20–30 g/L, and 60 g/L, respectively. The fluid turnover reaches up to two thirds of the total volume of interstitial fluid daily [122]. The skin on the lower extremities contains a denser and more extensive network of lymphatic capillaries than the skin of the upper extremities [123]. Due to orthostatism, lower extremities have higher filtration pressure and influx of fluids, and it is thought that the capacity for lymph transport in the lower extremities is greater in order to compensate for the higher influx of interstitial fluid caused by the effects of orthostatism and gravity. Spontaneous contractility of lymphatic vessels contributes to lymph transport. Regular contractions of lymph vessels at a frequency of 2–4 per minute were observed in vitro, and spontaneous contractions of prenodal lymphatic vessels that drive lymph have been observed in human legs [124]. Internal extensions of lymphatic endothelial cells act as valves and guarantee a one-way lymph flow [122]. In a steady state, extravasation of fluids and proteins from blood vessels is balanced by lymphatic drainage and return into the bloodstream. If microvascular filtration in blood capillaries and venules as occurs in advanced CVD exceeds the capacity for lymphatic drainage for sufficiently long periods, edema develops in afflicted areas by accumulation of tissue fluid in the interstitium. In addition, lymphatic dysfunction and structural damages to the lymphatic network are associated with varicose veins, and subsequent lymph stasis and reduced lymph transportation lead to inflammation [125]. This is associated with lipid accumulation in the media of the diseased veins. Such accumulation of inflammatory lipids in the vein wall might further damage adventitial lymphatic vessels .