Procoagulant activity in hemostasis and thrombosis: Virchow's triad revisited

Abstract

Virchow's triad is traditionally invoked to explain pathophysiologic mechanisms leading to thrombosis, alleging concerted roles for abnormalities in blood composition, vessel wall components, and blood flow in the development of arterial and venous thrombosis. Given the tissue-specific bleeding observed in hemophilia patients, it may be instructive to consider the principles of Virchow's triad when investigating mechanisms operant in hemostatic disorders as well. Blood composition (the function of circulating blood cells and plasma proteins) is the most well studied component of the triad. For example, increased levels of plasma procoagulant proteins such as prothrombin and fibrinogen are established risk factors for thrombosis, whereas deficiencies in plasma factors VIII and IX result in bleeding (hemophilia A and B, respectively). Vessel wall (cellular) components contribute adhesion molecules that recruit circulating leukocytes and platelets to sites of vascular damage, tissue factor, which provides a procoagulant signal of vascular breach, and a surface upon which coagulation complexes are assembled. Blood flow is often characterized by 2 key variables: shear rate and shear stress. Shear rate affects several aspects of coagulation, including transport rates of platelets and plasma proteins to and from the injury site, platelet activation, and the kinetics of fibrin monomer formation and polymerization. Shear stress modulates adhesion rates of platelets and expression of adhesion molecules and procoagulant activity on endothelial cells lining the blood vessels. That no one abnormality in any component of Virchow's triad fully predicts coagulopathy a priori suggests coagulopathies are complex, multifactorial, and interactive. In this review, we focus on contributions of blood composition, vascular cells, and blood flow to hemostasis and thrombosis, and suggest that cross-talk among the 3 components of Virchow's triad is necessary for hemostasis and determines propensity for thrombosis or bleeding. Investigative models that permit interplay among these components are necessary to understand the operant pathophysiology, and effectively treat and prevent thrombotic and bleeding disorders.

Figure 1

Venn diagram illustrating the propensity of thrombosis and bleeding at the intersection of abnormalities in blood composition, vessel wall function, and blood flow/shear.

Figure 2. Schematic showing the elements of Virchow’s triad

This conceptual model describes the three components (blood flow, blood composition, vascular function) that regulate coagulation. Abbreviations: IX, factor IX; VIII, factor VIII; II, prothrombin; Fgn, fibrinogen; TM, thrombomodulin

Figure 3. Interplay between abnormalities in blood components, the vasculature, and blood flow contribute to the development of arterial thrombosis

Arterial thrombosis involves the formation of platelet-rich "white clots" that form after rupture of atherosclerotic plaques and exposure of procoagulant material such as lipid-rich macrophages (foam cells), collagen, tissue factor and/or endothelial breach, in a high shear environment. Abbreviations: TM, thrombomodulin; II, prothrombin; IIa, thrombin; Fgn, fibrinogen; TF, tissue factor

Figure 4. Interplay between abnormalities in blood components, the vasculature, and blood flow contribute to the development of venous thrombosis

Venous thrombosis involves the formation of fibrin-rich “red clots” that result from exposure of procoagulant activity on intact endothelium plus plasma hypercoagulability, in reduced or static blood flow. Venous thrombi are thought to initiate behind valve pockets, where reduced or static flow decreases wall shear stress that normally regulates endothelial cell phenotype. Abbreviations: TM, thrombomodulin; EPCR, endothelial protein C receptor; II, prothrombin; IIa, thrombin; TF, tissue factor; Fgn, fibrinogen; RBC, red blood cells

Figure 5

Circulating microparticles are derived from a variety of cell types including leukocytes, platelets, megakaryocytes, red blood cells, endothelial cells, and tumors. Microparticles (MP) carry cell-specific markers and functional properties of their parent cell.