Based on the effects of various factor deficiencies in humans, it is believed that, in vivo, factor VIIa/tissue factor complex is the most important activator of factor IX and that factor IXa/factor VIIIa complex is the most important activator of factor X (Fig. 4.7B ). The mild bleeding tendency seen in patients with factor XI deficiency is likely explained by the ability of thrombin to activate factor XI (as well as factors V and VIII), a feedback mechanism that amplifies the coagulation cascade.
Among the coagulation factors, thrombin is the most important, because its various enzymatic activities control diverse aspects of hemostasis and link clotting to inflammation and repair. Among thrombin’s most important activities are the following:
Conversion of fibrinogen into crosslinked fibrin. Thrombin directly converts soluble fibrinogen into fibrin monomers that polymerize into an insoluble fibril, and also amplifies the coagulation process, not only by activating factor XI, but also by activating two critical cofactors: factors V and VIII. It also stabilizes the secondary hemostatic plug by activating factor XIII, which covalently crosslinks fibrin.
Platelet activation. Thrombin is a potent inducer of platelet activation and aggregation through its ability to activate PARs, thereby linking platelet function to coagulation.
Proinflammatory effects. PARs also are expressed on inflammatory cells, endothelium, and other cell types (
Fig. 4.9 ), and activation of these receptors by thrombin is believed to mediate proinflammatory effects that contribute to tissue repair and angiogenesis.
Anti-coagulant effects. Remarkably, through mechanisms described later, on encountering normal endothelium, thrombin changes from a procoagulant to an anticoagulant; this reversal in function prevents clots from extending beyond the site of the vascular injury.
Factors That Limit Coagulation. Once initiated, coagulation must be restricted to the site of vascular injury to prevent deleterious consequences. One limiting factor is simple dilution; blood flowing past the site of injury washes out activated coagulation factors, which are rapidly removed by the liver. A second is the requirement for negatively charged phospholipids, which, as mentioned, are mainly provided by platelets that have been
Fig. 4.9 Roleofthrombininhemostasisandcellularactivation.Thrombingeneratesfibrinbycleavingfibrinogen,activatesfactorXIII(whichisresponsibleforcrosslinkingfibrinintoaninsolubleclot),andalsoactivatesseveralothercoagulationfactors,therebyamplifyingthecoagulationcascade(
Fig.
4.7 ).Throughprotease-activatedreceptors(PARs),thrombinactivates(1)plateletaggregationandTxA2secretion;(2)endothelium,whichrespondsbygeneratingleukocyteadhesionmoleculesandavarietyoffibrinolytic(t-PA),vasoactive(NO,PGI2),orcytokine(PDGF)mediators;and(3)leukocytes,increasingtheiradhesiontoactivatedendothelium.ECM, Extracellularmatrix;NO, nitricoxide;PDGF, platelet-derivedgrowthfactor;PGI2, prostaglandinI2(prostacyclin);TXA2, thromboxaneA2;t-PA,tissue-typeplasminogenactivator.See
Fig.4.11 foranticoagulantactivitiesmediatedbythrombinviathrombomodulin.(Courtesy of Shaun Coughlin, MD, PhD, Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California.) activated by contact with subendothelial matrix at sites of vascular injury. However, the most important counter-regulatory mechanisms involve factors that are expressed by intact endothelium adjacent to the site of injury (described later).