Fibrinolysis
Fibrinolysis begins simultaneously with coagulation cascade activation. Endothelial and extravascular tissue damage facilitate
the conversion of plasminogen to plasmin through the release of tissue plasminogen activator from the endothelium and urokinase
plasminogen activator from the kidneys. Factor XII can facilitate the conversion as well.3,15 Plasmin degrades fibrin and fibrinogen into fibrin degradation products (FDPs) (Figure 1) and degrades activated factors V, VIII, IX, and XI.3 The liver removes FDPS from circulation.12
Physiologic inhibitors of coagulation
Numerous physiologic inhibitors in plasma localize coagulation activity to the injury site and maintain balance between coagulation
and fibrinolysis to minimize bleeding and ensure continuous organ perfusion. The most important inhibitor is antithrombin
III (antithrombin). Antithrombin is a physiologic inhibitor of blood coagulation in normal animals. Heparin accelerates antithrombin
complex formation with thrombin. These antithrombin-thrombin complexes are removed by the liver, which decreases circulating
thrombin. It has been suggested that antithrombin also inactivates factors IX, X, XI, and XII and kallikrein and plasmin.3,14,18
In addition, circulating thrombin loses its coagulation activity by binding to an endothelial receptor, thrombomodulin. The
thrombin-thrombomodulin complexes activate protein C to activated protein C. Activated protein C, with the assistance of cofactor
protein S, inactivates factors V and VIII.5,14,16,17,19,20
The fibrinolytic system is primarily opposed by alpha2-antiplasmin and by plasminogen activator inhibitor. Alpha2-antiplasmin binds and inactivates plasmin. Plasminogen activator inhibitor inactivates tissue plasminogen activator and urokinase
plasminogen activator, which regulates the conversion of plasminogen to plasmin.5,16,17
DIC ETIOLOGY AND PATHOPHYSIOLOGY
DIC is a common syndrome, especially in critically ill dogs, and is always secondary to an underlying disorder.1-9 Many clinically diverse disorders can initiate DIC, but they share certain disease mechanisms that result in a common endpoint:
excessive systemic circulating activities of thrombin and plasmin. These excessive thrombin and plasmin activities are the
primary contributors in the development of DIC.3,5 In addition, many secondary events such as thrombocytopenia or thrombocytopathy, excessive consumption of coagulation or
fibrinolysis inhibitors, and complement activation contribute to the DIC syndrome.1-5,12,21
Underlying disorders
Table 1. Conditions Associated with DIC*
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The most common diseases or conditions that initiate DIC are systemic inflammation, systemic neoplasia, hepatic disease, and
direct factor X activation (Table 1).2,21
Systemic inflammation
Systemic inflammation produces numerous cytokines; those most important in DIC are interleukin-1 and TNF-alpha.5,15 These cytokines promote the production and expression of tissue factor from monocytes and endothelial cells, which are the
primary events that initiate DIC in patients with systemic inflammation.3,5,15-17,22,23 Factor VII binds to tissue factor, serving to activate factor X, which converts prothrombin to thrombin (Figure 1).
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