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Physiologic hemostasis is a complex interplay between procoagulant and anticoagulant forces combining cellular and humoral factors so that neither excess hemorrhage nor clotting occurs. Surgery, cardiopulmonary bypass (CPB), trauma, and the associated resuscitation frequently alter this finely tuned equilibrium, resulting in pathological hypercoagulable or hemorrhagic states.
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One of the critical components of physiologic coagulation is the generation of fibrin. Normally, very little circulating fibrin exists as it is produced de novo at the site of injury from its widely distributed precursor, fibrinogen. As the final product of the common coagulation pathway, the insoluble form of fibrin serves as the structural framework on which a dynamic hemostatic plug is created. In addition to its role as a template for coagulation, a highly concentrated fibrin network acts as a governor to limit the spread of thrombin and the proliferation of abnormal systemic coagulation. Fibrin production is tightly conserved and dependent not only on fibrinogen levels, but requires the presence of active thrombin, platelets, and Factor XIII (FXIII).
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In the fluid phase of coagulation, fibrinogen is cleaved at N-terminal peptides by thrombin. This leads to the formation of soluble fibrin monomers, which rapidly polymerize with neighboring molecules into an insoluble fibrin matrix. The presence of thrombin indirectly contributes to the stability of the resultant fibrin network through tissue expression of the antifibrinolytic protease, plasmin activator inhibitor 1 (PAI-1). Thrombin is also required to activate FXIII, which is integral to the constitution of stable, crosslinked fibrin and in the incorporation of endogenous antifibrinolytics alpha-2-antiplasmin (α2-AP) and activated thrombin-activatable fibrinolysis inhibitor (TAFIa) into the matrix.
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Additionally, the fibrin complex facilitates platelet aggregation and activation via glycoprotein IIa/IIIb receptors, thereby augmenting and further stabilizing the hemostatic plug in the cellular phase of coagulation. The role of the fibrin complex transcends that of primary hemostasis in that it is also involved in complex immunologic and inflammatory interactions enabling fibroblast proliferation, endothelial cell spreading, angiogenesis, and leukocyte signaling.
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While fibrin generation is essential to enabling physiologic hemostasis, equally important is its modulation by a complementary series of lytic proteases (Figure 58-1). In its circulating form, plasminogen is functionally inert and demonstrates little intrinsic fibrinolytic activity. However, when combined with fibrin and tissue plasminogen activator (tPA), active plasmin is produced. In vivo, tPA binds to αC domains on the fibrin matrix along with plasminogen to form a ternary complex. This conformation causes plasminogen to convert into the active protease, plasmin. Subsequently, active plasmin cleaves the fibrin and exposes additional sites for plasminogen binding, thereby driving further fibrinolysis. Highly crosslinked fibrin, which is typically encountered proximate to sites of vascular injury, is resistant to plasmin-mediated fibrinolysis due to the presence of the anti-fibrinolytics α2-AP and TAFIa. Moreover, plasmin production is inhibited in these areas by PAI-1 suppression of tPA release. Consequently, physiologic fibrinolysis is maintained towards the periphery of the hemostatic plug, away from the site ...