Venous Pathophysiology

Endothelium and Hemostasis

The endothelium forms the inner cell lining of all blood vessels in the body and is a spatially distributed tissue. In an average individual, the endothelium weighs approximately 1 kg and covers a total surface area of 4000 to 7000 square meters. The endothelium has been described as a primary determinant of pathophysiology or as a target for collateral damage in most, if not all, disease processes. ^, Endothelial cells play a critical role in the balance between procoagulant and anticoagulant mechanisms in healthy individuals. Most of the thrombosis–thrombolysis processes occur in juxtaposition to the endothelium, and hence the endothelium is one of the pivotal regulators of homeostasis.

Under normal conditions, endothelial cells maintain a vasodilatory and local fibrinolytic state in which coagulation, platelet adhesion, and activation are suppressed. A non-thrombogenic endothelial surface is maintained by a number of mechanisms, including: (1) endothelial production of thrombomodulin and subsequent activation of protein C; (2) endothelial expression of heparan sulfate and dermatan sulfate, which accelerate anti-thrombin and heparin cofactor II activity; (3) constitutive expression of tissue factor pathway inhibitor (TFPI); and (4) local production of tissue plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). In addition, the production of nitric oxide (NO) and prostacyclin by the endothelium inhibits the adhesion and activation of leukocytes and produces vasodilation. Tissue factor (TF) production is also inhibited by NO.

Veins and arteries may differentially express homeostatic mediators. For example, von Willebrand factor (vWF) is expressed to a greater extent on the endothelium of veins compared to arterial endothelium, and tPA is less commonly expressed in venous endothelium. Systemic inflammatory insults such as conferred by tumor necrosis factor-α (TNF-α) may cause endothelial activation and result in increased surface expression of cell adhesion molecules (CAMs), such as P-selectin, E-selectin, and intracellular CAM (ICAM), thereby promoting the adhesion and activation of leukocytes as well as platelets, and can lead to pathological thrombosis. Clinically, soluble P-selectin, in combination with Wells’ score and D-dimer, has a high sensitivity and specificity for the diagnosis of DVT. ^,

Venous Biomechanics

Veins allow a very large volume capacitance and tonal regulation to rapidly redistribute overall blood volume. Approximately 60% to 80% of circulating blood is stored in the venules and systemic veins at any given time. The function of the blood capacitance system via vasoregulation is to maintain the filling of the heart as well as to compensate for orthostatic changes. The physiology of venous blood flow in the limb related to the calf muscle pump and other actions is detailed in Chapter 24 (Vascular Laboratory: Venous Physiologic Assessment).

Everyday activities and changes in body position cause large changes in venous pressure. The average venous pressure at the foot is approximately 100 mm Hg in a person 5 feet 10 inches (1.78 m) tall weighing 75 kg. This pressure drops significantly with ambulation and during recumbence. The venous valves are endothelium-lined folds of tunica intima that allow unidirectional flow, contribute to this pressure reduction, and maintain prograde blood flow. To accommodate pressure and volume changes, veins undergo complex alterations in shape, depending on the blood volume, resistance, and the amount of blood flow within the system. Less vascular resistance occurs with a circular shape than an elliptical shape, and thus as venous volume increases, resistance to flow lessens.

Unlike arteries, large veins lack an extensive elastic lamella (composed of elastin) but exhibit marked distensible properties. Veins have a much smaller ratio of wall thickness to radius and higher incremental distensibility in the low-pressure range than arteries, thus indicating that the elastic modulus of veins can greatly exceed the stress modulus of arteries. As a result, veins have a high breaking pressure, nearly four atmospheres. Much of the stress-bearing function of the vein wall may depend on its smooth muscle cell and elastin content, in contrast to the abundance of collagen in the arterial wall. Indeed, vein wall compliance is decreased after experimental venous thrombosis (VT) injury, which correlates with its increased collagen content, and disrupted elastin, as measured histologically.

Venous Thrombosis Pathways

Coagulation Cascade

Hemostasis is typically initiated by damage to the vessel wall and disruption of the endothelium, although it may be initiated in the absence of vessel wall damage, particularly in VT. Vessel wall damage simultaneously results in release of TF, a cell membrane protein, from injured cells and circulating blood, with subsequent activation of the extrinsic pathway of the coagulation cascade. These two events are critical to the activation and acceleration of thrombosis ( Fig. 9.1 ). Differences in local organ mechanisms may cause region-specific susceptibility to thrombosis. For example, hemostasis in cardiac muscle may be more dependent on the extrinsic pathway for thrombosis, whereas skeletal muscle may be more dependent on the intrinsic pathway for thrombosis.

Coagulation can be activated through the intrinsic pathway with activation of factor XI to XIa, which subsequently converts factor IX to IXa and promotes formation of the Xase complex and ultimately thrombin. Another mechanism by which this occurs in vitro is through the contact activation system, whereby factor XII (Hageman factor) is activated to XIIa when complexed to prekallikrein and high-molecular-weight kininogen (HMWK) on a negatively charged surface; factor XIIa then activates factor XI to XIa. Both thrombin and factor XIa are also capable of activating factor XI.

Thrombin (factor II) is central to coagulation through its action of cleavage and release of fibrinopeptide A (FPA) from the α chain of fibrinogen and fibrinopeptide B (FPB) from the β chain of fibrinogen. This causes fibrin monomer polymerization and cross-linking, which stabilizes the thrombus and the initial platelet plug. Thrombin also activates factor XIII to XIIIa, which catalyzes the cross-linking of fibrin as well as that of other plasma proteins, such as fibronectin and α ₂ -antitrypsin, resulting in their incorporation into the thrombus and increasing resistance to thrombolysis. In addition, factor XIIIa activates platelets as well as factors V and VIII, further amplifying thrombin production.