Anticoagulant effects. Normal endothelium shields coagulation factors from tissue factor in vessel walls and expresses multiple factors that actively oppose coagulation, most notably thrombomodulin, endothelial protein C receptor, heparin-like molecules, and tissue factor pathway inhibitor. Thrombomodulin and endothelial protein C receptor bind thrombin and protein C, respectively, in a complex on the endothelial cell surface. When bound in this complex, thrombin loses its ability to activate coagulation factors and platelets, and instead cleaves and activates protein C, a vitamin K–dependent protease that requires a cofactor, protein S. Activated protein C/protein S complex is a potent inhibitor of coagulation factors Va and VIIIa. Heparin-like molecules on the surface of endothelium bind and activate antithrombin III, which then inhibits thrombin and factors IXa, Xa, XIa, and XIIa. The clinical utility of heparin and related drugs is based on their ability to stimulate antithrombin III activity. Tissue factor pathway inhibitor (TFPI), like protein C, requires protein S as a cofactor and, as the name implies, binds and inhibits tissue factor/factor VIIa complexes.
Fibrinolytic effects. Normal endothelial cells synthesize t-PA, already discussed, as a key component of the fibrinolytic pathway.
The primary abnormalities that lead to intravascular thrombosis are (1) endothelial injury, (2) stasis or turbulent blood flow, and (3) hypercoagulability of the blood (the so-called “Virchow triad”) (
Fig. 4.12 ). Thrombosis is http://ebooksmedicine.net
THROMBOSISInactivates tissue factor-VIIa complexes molecule Anti-thrombin III Thrombin Thrombin t-PA Inactivates thrombin (also factors IXa and Xa) Inhibits platelet aggregation Activates fibrinolysis Endothelial effects PGI2, NO, and adenosine diphosphatase Inactivates factors Va and VIIIa Active protein CProtein C (requires protein S) receptorpathway inhibitor
THROMBOSISVWF Extrinsic coagulation sequence Exposure of membrane-bound tissue factor Platelet adhesion (held together by fibrinogen)
Fig. 4.11 Anti-coagulantpropertiesofnormalendothelium(top)andprocoagulantpropertiesofinjuredoractivatedendothelium(bottom).NO, Nitricoxide;PGI2, prostaglandinI2(prostacyclin);t-PA, tissueplasminogenactivator;VWF, vonWillebrandfactor.Thrombinreceptorsarealsocalledprotease-activatedreceptors(PARs).
Fig. 4.12 Virchow’striadinthrombosis.Endothelialintegrityisthemostimportantfactor.Abnormalitiesofprocoagulantsoranti-coagulantscantipthebalanceinfavorofthrombosis.Abnormalbloodflow(stasisorturbulence)canleadtohypercoagulabilitydirectlyandalsoindirectlythroughendothelialdysfunction.
one of the scourges of modern man, because it underlies the most serious and common forms of cardiovascular disease. Here, the focus is on its causes and consequences; its role in cardiovascular disorders is discussed in detail in Chapters 10 and 11.
Endothelial injury leading to platelet activation almost inevitably underlies thrombus formation in the heart and the arterial circulation, where the high rates of blood flow impede clot formation. Notably, cardiac and arterial clots are typically rich in platelets, and it is believed that platelet adherence and activation is a necessary prerequisite for thrombus formation under high shear stress, such as exists in arteries. This insight provides part of the reasoning behind the use of aspirin and other platelet inhibitors in coronary artery disease and acute myocardial infarction.