Chapter 3 Venous Pathophysiology

Etiology and Natural History of Disease

Primary Venous Disease

Primary venous disease affects two-thirds of patients with chronic venous disease (CVD). The most accepted theory is based on increased venous hydrostatic pressure transmitted to the vein wall, causing smooth muscle relaxation, endothelial damage, and extracellular matrix degradation with subsequent vein wall weakening and wall dilatation.¹ It has also been suggested that valve damage may occur because of local inflammation.² Leukocyte migration, plasma-granulocyte activation, and increased activity of metalloproteinases causing degradation of the valve leaflets support that theory.^2,³ Figure 3-1 summarizes the pathophysiologic pathways of CVD.

Fig 3–1 Mechanisms of varicose vein formation. Increased hydrostatic pressure and wall tension in individuals with predisposing risk factors cause matrix metalloproteinase (MMPs) activation and changes in the endothelium and vascular smooth muscle function. In addition, leukocyte wall infiltration and inflammation activate MMPs and lead to extracellular matrix (ECM) degradation, venous wall weakening, and wall/valve fibrosis. Although a possible mechanism may involve primary valve insufficiency in both the axial and tributary veins, this likely represents a secondary event from primary venous wall changes and dilation. Persistent venous wall dilation and valvular dysfunction lead to increased hydrostatic pressure. MMP-mediated vein wall dilation with secondary valve dysfunction leads to chronic venous disease (CVD) and varicose vein formation. The early stages of CVD are maintained within the vasculature, leading to clinical signs of varicose veins, while more advanced CVD causes progression of chronic venous insufficiency affecting surrounding tissues and leading to skin changes and ulcer formation.

(From Raffetto JD, Khalil RA. Mechanisms of varicose vein formation: valve dysfunction and wall dilation. Phlebology 2008;23:85-98.)

Superficial veins are most commonly involved in primary CVD, followed by perforators and deep veins.⁴ It has been shown that reflux starts in superficial veins in more than 80% of the patients. In the early stages of CVD, reflux is found in the great saphenous vein (GSV) and its tributaries without almost any junctional involvement (Fig. 3-2). This is followed by reflux in the small saphenous vein (SSV) system (Fig. 3-3) and nonsaphenous veins (Fig. 3-4). Patients with competent saphenous, perforators, and deep veins may also present tributary reflux in 10%, with the GSV tributaries being affected in 65% of the cases.

Fig 3–2 Great saphenous vein (GSV) reflux from saphenofemoral junction to upper calf and the posterior accessory calf vein. The below knee segment of GSV is normal.

Fig 3–3 Severe reflux in the small saphenous vein (SSV) in a patient who presented with CEAP classes 1 through 4, itching, and pain during prolonged standing. Reflux was also found in two tributaries and two perforator veins (red dots).

Fig 3–4 Nonsaphenous vein reflux. A, Vulvar vein reflux in a female patient with a history of three pregnancies. The veins from this region are very tortuous and extend in a nonpredicted manner in the extremity. B, Sciatic nerve vein reflux giving rise to popliteal fossa varicosities that emerge in the posterolateral calf.

Isolated primary deep vein reflux is rare. It may present as either segmental or axial reflux extending from the femoral vein in the thigh to the below-knee popliteal vein. The most frequent location of primary deep vein reflux is the common femoral vein, followed by the femoral and popliteal veins ⁵ (Fig. 3-5). Because most deep venous reflux is deemed to be caused by superficial venous reflux propagation, both common femoral and femoral vein reflux are associated with GSV incompetence and popliteal vein reflux is associated with SSV and/or gastrocnemial vein incompetence⁵ (Fig. 3-6). In addition, deep vein reflux has a shorter duration compared with superficial venous reflux. Association between deep and superficial venous reflux ranges from 5% to 38%.⁵^–⁸

Fig 3–5 Examples of postthrombotic reflux from three patients. A, Severe reflux in the femoral vein in a patient who had previous extensive deep venous thrombosis from the common femoral to calf veins. B, Popliteal vein reflux in a patient who presented with swelling and pain. C, Reflux in both posterior tibial veins, which have the same color as the artery in the middle.

Fig 3–6 Imaging of the saphenofemoral junction (SFJ). A, Cephalad flow is seen in the SFJ during distal compression. The saphenous vein has a normal diameter and is competent. B, SFJ reflux rendering the common femoral vein incompetent. In such cases in patients with primary chronic venous disease, correction of the saphenous reflux abolishes the common femoral vein reflux.

Perforator vein (PV) reflux in primary CVD always occurs in association with superficial vein reflux.⁹ Essentially, PVs become incompetent secondary to either ascending extension of superficial vein reflux or descending propagation of the reflux in a reentry fashion (Fig. 3-7). Most often, PV reflux originates from the GSV system and renders the deep veins incompetent in 13% of the cases.⁹ Deep vein reflux secondary to PV reflux is usually segmental and has a short duration.⁹

Fig 3–7 Schematic drawing of the different patterns of perforator reflux development. A and B, Reflux developed in descending manner in a reentry perforator at the lower medial calf. N, Normal; R, reflux. Schematic drawing of the different patterns of perforator reflux development. A and B, Reflux developed in descending manner in a reentry perforator at the lower medial calf. N, Normal; R, reflux.C, Baseline ultrasound examination in a 53-year-old female patient with a long-standing history of chronic venous disease. On the right limb, she had great saphenous vein (GSV) reflux from the lower thigh to the upper calf and in the posterior calf accessory vein. On the left limb, she had reflux in the GSV from the saphenofemoral junction to the upper calf and the posterior accessory calf vein. There was no perforator vein reflux at this time. D and E, During the second examination at 38 months on the right limb, the patient developed ascending reflux in the GSV, a perforator vein at the thigh, a new reflux site in a posterior calf tributary, and a midcalf perforator. On the left limb, she developed a reentry type of reflux in a medial perforator vein from the posterior calf accessory vein. She had worsening of her disease from CEAP class 2 to 3 in the right limb and from class 3 to 4A in the left limb. She also became symptomatic in the left limb, with aching and itching along the varicosities of medial calf. N, Normal; R, reflux. The red dot indicates reflux in a perforator vein. The red letters and lines indicate the new sites of reflux in the second examination.For legend see opposite page.

Secondary Venous Disease

Secondary venous disease is caused by a thrombotic event or is secondary to trauma. The incidence of arteriovenous fistula (AVFs) as cause of secondary CVD is reduced compared with postthrombotic CVD (Fig. 3-8).

Fig 3–8 Arteriovenous fistula causing significant venous hypertension (swelling of the entire limb, pain, and discoloration) in a male patient after a gunshot wound in the left groin. A, Fistula between the deep femoral artery and the common femoral vein. There are high velocities with a low resistance pattern. B, Waveform with turbulent flow in the common femoral vein proximal to the fistula. C, The common femoral vein is dilated (2.8 cm) due to the local high pressure. D, Dilatation of the saphenofemoral junction and the great saphenous vein with continuous reflux (not shown).

Most frequently, AVFs are created when both common femoral vessels are inadvertently punctured during endovascular procedures or secondary to penetrating or blunt traumatic injuries. Animal models based on AVF creation have been used to explain the findings of chronic venous disease.¹⁰ Initially, lower resistance in the distal portion of the artery and pulsatile flow in the vein are noted. Venous hypertension supervenes, distending the veins and causing some degree of edema in the limb but no reflux. Subsequently, the valves are unable to appose what portends the reflux. Continuous venous hypertension and reflux entail valve atrophy and “arterialization” of the venous wall in the long term. In humans, the occurrence of CVD secondary to AVFs is rare and requires a long course to generate clinical impairment that frequently is devastating.

Deep venous thrombosis (DVT) is a result of stasis, endothelial damage, and/or hypercoagulable state. The predisposing factors for DVT and therefore secondary CVD are well established, including pregnancy, operations, immobilization, malignancy, trauma, and obesity. Patients who sustain inherited disorders (i.e., active protein C resistance, protein S and antithrombin III deficiency) are also prone to develop thromboembolic events.

Regardless of the initial thrombi formation, the majority of the limbs evolve with thrombus resolution. Notably, only one-third of the patients with secondary CVD develop postthrombotic syndrome (PTS), which consists of signs and symptoms such as pain, edema, heaviness, and intolerance to efforts that may progress to skin changes and ulcers (Fig. 3-9). Often, patients with PTS have a combination of reflux and obstruction (Fig. 3-10). PTS represents the most severe manifestation of secondary CVD, carrying significant socioeconomic impact, and is discussed in Chapter 15.