In addition to inflammation-associated increased thrombin activity, down-regulation of coagulation and fibrinolysis inhibitors
occur.3,16 Initially, total tissue and urokinase plasminogen activator activities increase at a normal ratio to TNF-alpha concentrations.16 This converts plasminogen to plasmin and increases circulating plasmin–alpha2-antiplasmin activities. However, fibrinolytic activity subsequently decreases because of increased plasminogen activator
inhibitor activity. This inhibition of plasminogen activation may be the most important factor in inflammation-associated
DIC.16,24 It is not clear how, why, and where plasminogen activator inhibitor increases.16 In addition, TNF-alpha causes down-regulation of thrombomodulin,3,16 resulting in the inactivation of the protein C-protein S anticoagulant pathway, which controls microvascular thrombosis.16 The increase in plasminogen activator inhibitor and down-regulation of thrombomodulin in systemic inflammation predispose
patients to microvascular thrombosis.3,16
Systemic neoplasia
The mechanism of malignancy-induced DIC is poorly understood. DIC is thought to be a result of malignant cell invasion of
the endothelium, the production of tissue factor by neoplastic cells, or the production of proteins by neoplastic cells that
directly activate factor X.3,8
Hepatic disease
A severely decreased functional hepatic mass results in decreased production of coagulation and fibrinolysis factors and inhibitors
and decreased Kupffer cell activity.3,6,23,25 The Kupffer cells of the liver remove activated clotting factors, FDPs, and absorbed endotoxin (from the gastrointestinal
tract) from circulation.3,25,26 So severe hepatic disease can cause imbalance between coagulation and fibrinolysis because of increased circulating activated
clotting factors, FDPs, and endotoxin. Increased circulating FDPs contribute to DIC in three ways: making fibrin dysfunctional,
altering normal thrombin activity, and binding to platelets to create a thrombocytopathy.1-4
Direct activation of factor X
Snake envenomation, increased circulating trypsin secondary to pancreatitis, and certain neoplasms directly activate factor
X.3 This activation increases systemic circulating activity of thrombin (Figure 1).
Common endpoint
Regardless of the cause of DIC, these underlying disorders all increase systemic circulating thrombin and plasmin. The increased
thrombin causes excessive fibrin clot deposition and systemic microvascular thrombosis. The microvascular thrombosis contributes
to poor organ perfusion with possible ischemia-associated cell death or organ failure. The microvascular thrombosis also excessively
entraps platelets and exceeds the thrombopoietic capacity of the bone marrow.2-4,7,8,12,21 Therefore, consumptive thrombocytopenia is commonly associated with DIC. The excessive fibrin generated from thrombin deposits
on the endothelium, resulting in endothelial damage and red blood cell shearing (schistocytosis).3 The damaged vascular endothelium and red blood cell stroma amplify coagulation by expressing and releasing tissue factor.
The damaged endothelium, damaged extravascular tissues, and activated factor XII convert plasminogen to plasmin through tissue
plasminogen activator and urokinase plasminogen activator. Excessive plasmin generation causes rapid dissolution of fibrin
clots and the degradation of activated factors V, VIII, IX, and XI. This contributes to the hemorrhagic tendencies of patients
with the acute form of DIC.3 Excessive plasmin has also been shown to activate complement, allowing lysis of red blood cells and platelets.3,13
Many of the coagulation and fibrinolysis inhibitors (e.g. antithrombin, alpha2-antiplasmin, activated protein C) that localize coagulation and maintain a balance between coagulation and fibrinolysis are
consumed during the process of excessive thrombin and plasmin generation.
CONCLUSION
Understanding the hemostatic process and how it can be compromised is critical in managing patients with DIC. The next article
shows you how to diagnose and treat this common, life-threatening disorder in pets.
Justin D. Thomason, DVM
Clay A. Calvert, DVM, DACVIM
Craig E. Greene, DVM, MS, DACVIM
Department of Small Animal Medicine and Surgery
College of Veterinary Medicine
University of Georgia
Athens, GA 30602
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