Pathophysiology of Varicose Veins
Primary Mechanism: Valvular Incompetence and Vein Wall Weakening
Varicose veins develop when genetic predisposition causes loss of elasticity in the vein wall, leading to valve leaflet failure, which allows backward blood flow (reflux) and creates increased venous pressure that progressively dilates and elongates the veins. 1, 2
The Cascade of Venous Dysfunction
Initial structural failure: The valvular dysfunction is presumed to result from loss of elasticity in the vein wall, with subsequent failure of the valve leaflets to fit together properly, creating incompetent valves that allow blood to flow in the reverse direction rather than the normal distal-to-proximal and superficial-to-deep flow pattern. 1, 2
Progressive vein dilation: With increased pressure on the affected venous system from reflux, the larger veins become elongated and tortuous, creating the characteristic appearance of varicose veins. 1, 2
Hemodynamic consequences: Rather than blood flowing from distal to proximal and superficial to deep, failed or incompetent valves allow blood to flow in the reverse direction, establishing a vicious circle between structural changes in valves and venous wall and hemodynamic forces leading to reflux and venous hypertension. 1, 3
How Venous Hypertension Develops
Venous hypertension—the signature pathophysiologic feature of varicose veins—results from the combination of gravitational forces, valvular incompetence, and increased intravenous pressure. 4
Mechanisms of Increased Venous Pressure
Gravitational pooling: Prolonged standing increases venous pressure in the lower extremities, which explains why symptoms typically worsen at the end of the day after prolonged standing and improve with leg elevation. 1, 2, 5
Valvular reflux: Incompetent valves allow retrograde blood flow, creating sustained elevated pressure in the superficial venous system with reflux duration ≥500 milliseconds considered pathologic. 6, 4
Increased intra-abdominal pressure: Chronically increased intra-abdominal pressure due to obesity, pregnancy, chronic constipation, or tumors contributes to elevated venous pressure by impeding venous return. 1, 5
Deep venous obstruction: Deep venous thrombosis causing damage to valves and secondary revascularization can lead to increased pressure in the superficial system. 1
Calf muscle pump dysfunction: Ineffective function of the calf muscle pump fails to adequately propel blood proximally, contributing to venous stasis and hypertension. 7
Molecular and Cellular Consequences of Venous Hypertension
Endothelial Dysfunction and Inflammation
Shear stress activation: Shear stress on venous endothelial cells due to reversed or turbulent blood flow activates inflammatory pathways, with the endothelium and glycocalyx sensing changes in shear stress via specialized receptors. 1, 4
Leukocyte activation: Expression of adhesion molecules allows the activation of leukocytes leading to endothelial attachment, diapedesis, and transmigration into the venous wall/valves, resulting in venous wall injury and inflammatory cells in the interstitial tissues. 4
Inflammatory cascade: A complex of cytokines, chemokines, growth factors, proteases and proteinases, produced by activated leukocytes, creates an environment of persistent inflammation with progressive clinical changes from varicose veins to more advanced presentations of skin changes and venous ulceration. 4
Structural Alterations
Extracellular matrix abnormalities: The structural integrity of protein and the extracellular matrix is altered, with biochemical and structural alterations of the vessel wall enhancing the progressive events of chronic venous disease. 7, 4
Impaired balance of growth factors: Imbalanced growth factors and cytokines contribute to progressive vein wall weakening and dilation. 7
Genetic alterations: Genetic susceptibility provides a basis for fascial weakness of the vein wall or supporting fascia, with family history representing a predominant risk factor. 7, 8
Risk Factors Contributing to Pathophysiology
Established Risk Factors
Non-modifiable factors: Family history of venous disease, female sex, and older age are established risk factors that increase likelihood of developing varicosities, with prevalence estimated at 25-33% in women and 10-20% in men. 1, 2, 5, 7
Modifiable factors: Prolonged standing exacerbates the condition by increasing venous pressure, while obesity increases intra-abdominal pressure impeding venous return. 1, 2, 5
Hormonal influences: Circulating estrogens increase venous distensibility, leading to secondary valvular incompetence, which explains higher prevalence in women and during pregnancy. 8
Prior thrombotic events: Deep venous thrombosis causes damage to valves through thrombophlebitis or venous obstruction, creating primary valvular incompetence. 1, 7, 8
Clinical Manifestations of Venous Hypertension
Symptom Progression
Early symptoms: Localized symptoms include pain, burning, itching, and tingling at the site of varicose veins, while generalized symptoms consist of aching, heaviness, cramping, throbbing, restlessness, and swelling in the legs. 1
Advanced manifestations: Signs of more serious underlying vascular insufficiency include changes in skin pigmentation, eczema, infection, superficial thrombophlebitis, venous ulceration, loss of subcutaneous tissue, and lipodermatosclerosis. 1
Temporal pattern: Symptoms are often worse at the end of the day, especially after prolonged standing, and usually resolve when patients sit and elevate their legs, reflecting the gravitational component of venous hypertension. 1, 2
Common Pitfalls in Understanding Pathophysiology
Chicken-or-egg debate: While the exact sequence is debated, there exists a vicious circle between structural changes in valves and venous wall and hemodynamic forces—both contribute to progressive disease rather than one being purely primary. 1, 3
Not just cosmetic: Although varicose veins may cause varying degrees of discomfort or cosmetic concern, they represent true pathophysiologic dysfunction with potential for progression to serious complications including ulceration. 1
Mechanotransduction complexity: The molecular pathogenesis involves complex mechanotransduction of venous hypertension through mechanosensors and mechanotransducers in the vein wall, with downstream signaling pathways that remain incompletely understood. 9