Basic mechanisms and pathogenesis of venous thrombosis

Abstract

In 1856 Virchow proposed a triad of causes for venous thrombosis, postulating that stasis, changes in the vessel wall or changes in the blood could lead to thrombosis. We now know that abnormally high levels of some coagulation factors and defects in the natural anticoagulants contribute to thrombotic risk. Among these, factor V Leiden, which renders factor Va resistant to activated protein C, is the most prevalent with approximately 5% of the Caucasian population having this genetic alteration. These genetically controlled variants in coagulation factors work in concert with other risk factors, such as oral contraceptive use, to dramatically increase thrombotic risk. While these abnormalities in the blood coagulation proteins are associated with thrombotic disease propensity, they are less frequent contributors to thrombosis than age or cancer. Cancer increases thrombotic risk by producing tissue factor to initiate coagulation, by shedding procoagulant lipid microparticles or by impairing blood flow. Age is the strongest risk factor for thrombosis. Among possible reasons are fragility of the vessels potentially contributing to stasis, increased coagulation factor levels, impaired function of the venous valves, decreases in the efficacy of natural anticoagulants associated with the vessel wall, increased risk of immobilization and increased risk of severe infection.

Figure 1

A modified version of Virchow's triad focusing on the findings that chronic low level inflammation has little impact on venous thrombosis (unlike arterial thrombosis), but that acute inflammation does increase venous thrombosis.

Figure 2. A model venous valve involvment in the initiation of thrombosis

The region just downstream of the valve is prone to hypoxia leading to endothelial cell activation. This upregulates adhesion molecules like P-selectin, which in turn can bind to leukocytes or leukocyte microparticles. Since the microparticles contain tissue factor, the interaction with the activated endothelium results in concentrating tissue factor to trigger coagulation that is rapid enough to result in thrombus formation.

Figure 3. The relationship between age and venous thrombotic risk

Figure 3 a: The risk of deep vein thrombosis (DVT) rises markedy with increasing age in both men and women. Figure 3b: The risk of pulmonary embolism (PE) also rises with increasing age. (Reproduced by kind permission of American Medical Association from Silverstein et al: Trends in the incidence of deep vein thrombosis and pulmonary embolism. A 25-year population-based study. Arch Intern Med, Mar 23, 158:585-593, copyright © (1998) American Medical Association. All rights reserved.)