Activation of the coagulation cascade also sets into motion a fibrinolytic cascade that limits the size of the clot and contributes to its later dissolution (
Fig. 4.10 ). Fibrinolysis is largely accomplished through the enzymatic activity of plasmin, which breaks down fibrin and interferes with its polymerization. An elevated level of breakdown products of fibrinogen (often called fibrin split products), most notably fibrin-derived D-dimers, are a useful clinical markers of several thrombotic states (described later). Plasmin is generated by enzymatic catabolism of the inactive circulating precursor plasminogen, either by a factor XII–dependent pathway (possibly explaining the association of factor XII deficiency and thrombosis) or by plasminogen activators. The most important plasminogen activator is t-PA; it is synthesized principally by endothelium and is most active when bound to fibrin. This characteristic makes t-PA a useful therapeutic agent, since its fibrinolytic activity is largely confined to sites of recent thrombosis. Once activated, plasmin is in turn tightly controlled by counterregulatory factors such as α2-plasmin inhibitor, a plasma protein that binds and rapidly inhibits free plasmin.
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Fig. 4.10 Thefibrinolyticsystem,illustratingvariousplasminogenactivatorsandinhibitors(seetext).
Coagulationoccursviathesequentialenzymaticconversionofacascadeofcirculatingandlocallysynthesizedproteins.
Tissuefactorelaboratedatsitesofinjuryisthemostimportantinitiatorofthecoagulationcascadeinvivo.
Atthefinalstageofcoagulation,thrombinconvertsfibrinogenintoinsolublefibrinthatcontributestoformationofthedefinitivehemostaticplug.
Coagulationnormallyisrestrictedtositesofvascularinjuryby: limitingenzymaticactivationtophospholipidsurfacesprovidedbyactivatedplateletsorendothelium, circulatinginhibitorsofcoagulationfactors,suchasantithrombinIII,whoseactivityisaugmentedbyheparin-likemoleculesexpressedonendothelialcells expressionofthrombomodulinonnormalendothelialcells,whichbindthrombinandconvertitintoananti-coagulant, activationoffibrinolyticpathways(e.g.,byassociationoftissueplasminogenactivatorwithfibrin).
The balance between the anticoagulant and procoagulant activities of endothelium often determines whether clot formation, propagation, or dissolution occurs (
Fig. 4.11 ). Normal endothelial cells express a multitude of factors that inhibit the procoagulant activities of platelets and coagulation factors and that augment fibrinolysis. These factors act in concert to prevent thrombosis and to limit clotting to sites of vascular damage. However, if injured or exposed to proinflammatory factors, endothelial cells lose many of their antithrombotic properties. Here, we complete the discussion of hemostasis by focusing on the antithrombotic activities of normal endothelium; we return to the “dark side” of endothelial cells later when discussing thrombosis.
The antithrombotic properties of endothelium can be divided into activities directed at platelets, coagulation factors, and fibrinolysis.
Platelet inhibitory effects. An obvious effect of intact endothelium is to serve as a barrier that shields platelets from subendothelial vWF and collagen. However, normal endothelium also releases a number of factors that inhibit platelet activation and aggregation. Among the most important are prostacyclin (PGI2), nitric oxide (NO), and adenosine diphosphatase; the latter degrades ADP, already discussed as a potent activator of platelet aggregation. Finally, endothelial cells bind and alter the activity of thrombin, which is one of the most potent activators of platelets.