Obviously, severe endothelial injury may trigger thrombosis by exposing VWF and tissue factor. However, inflammation and other noxious stimuli also promote thrombosis by shifting the pattern of gene expression in endothelium to one that is “prothrombotic.” This change is sometimes referred to as endothelial activation or dysfunction and can be produced by diverse exposures, including physical injury, infectious agents, abnormal blood flow, inflammatory mediators, metabolic abnormalities, such as hypercholesterolemia or homocystinemia, and toxins absorbed from cigarette smoke. Endothelial activation is believed to have an important role in triggering arterial thrombotic events.
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The role of endothelial cell activation and dysfunction in arterial thrombosis is also discussed in Chapters 10 and 11. Here it suffices to mention several of the major pro-thrombotic alterations:
Procoagulant changes. Endothelial cells activated by cytokines downregulate the expression of thrombomodulin, already described as a key modulator of thrombin activity. This may result in sustained activation of thrombin, which can in turn stimulate platelets and augment inflammation through PARs expressed on platelets and inflammatory cells. In addition, inflamed endothelium also downregulates the expression of other anticoagulants, such as protein C and tissue factor protein inhibitor, changes that further promote a procoagulant state.
Anti-fibrinolytic effects. Activated endothelial cells secrete Plasminogen activator inhibitors (PAI), which limit fibrinolysis and downregulate the expression of t-PA, alterations that also favor the development of thrombi.
Turbulence (chaotic blood flow) contributes to arterial and cardiac thrombosis by causing endothelial injury or dysfunction, as well as by forming countercurrents and local pockets of stasis. Stasis is a major factor in the development of venous thrombi. Under conditions of normal laminar blood flow, platelets (and other blood cells) are found mainly in the center of the vessel lumen, separated from the endothelium by a slower-moving layer of plasma. By contrast, stasis and turbulence have the following deleterious effects:
Both promote endothelial cell activation and enhanced procoagulant activity, in part through flow-induced changes in endothelial gene expression.
Stasis allows platelets and leukocytes to come into contact with the endothelium when the flow is sluggish.
Stasis also slows the washout of activated clotting factors and impedes the inflow of clotting factor inhibitors.
Turbulent and static blood flow contributes to thrombosis in a number of clinical settings. Ulcerated atherosclerotic plaques not only expose subendothelial ECM but also cause turbulence. Abnormal aortic and arterial dilations called aneurysms create local stasis and consequently are fertile sites for thrombosis (Chapter 9). Acute myocardial infarction results in focally noncontractile myocardium. Ventricular remodeling after more remote infarction can lead to aneurysm formation. In both cases, cardiac mural thrombi are more easily formed because of the local blood stasis (Chapter 11). Mitral valve stenosis (e.g., after rheumatic heart disease) results in left atrial dilation. In conjunction with atrial fibrillation, a dilated atrium also produces stasis and is a prime location for the development of thrombi. Hyperviscosity syndromes (such as polycythemia vera, Chapter 12) increase resistance to flow and cause small vessel stasis; the deformed red cells in sickle cell anemia (Chapter 12) cause vascular occlusions, and the resultant stasis also predisposes to thrombosis.