The liver plays an important role in hemostasis. Not only is it the site of production of many of the coagulation factors, including the vitamin K-dependent factors, fibrinogen and factor VIII, but it is also responsible for clearance and degradation of factors, factor-inhibitor complexes and FDPs. Although coagulation abnormalities are common in naturally occurring liver disease (93% of dogs in one study and 82% of cats in another study had at least one abnormal coagulation test), clinical signs of hemorrhage are not commonly seen, except in severe fulminant liver disease (which initiates DIC or induces synthetic failure). Liver disease can be associated with impaired coagulation factor production, production of abnormally functioning clotting factors, increased consumption of factors by initiation of DIC, and abnormal platelet number or function.

• Decreased production: Severe liver disease resulting in synthetic liver failure can produce coagulation abnormalities from decreased production of coagulation factors. In these situations, there will be other clinical and laboratory evidence of severe liver failure, e.g. hypoalbuminemia, hypocholesterolemia, low UN (note that not all of these abnormalities may be present in individual patients), in conjunction with a long PT, APTT, and ACT due to hypofibrinogenemia (that is often very severe). Some animals may also have concurrent DIC, which can be difficult to distinguish from synthetic liver failure (erythrocyte fragments, high thrombin-antithrombin [TAT] complexes and low or progressively decreasing platelet counts would favor the concurrent presence of DIC in synthetic liver failure). Low levels of the inhibitors, antithrombin and protein C, are also seen in synthetic liver disease, but are not specific for this hepatic condition. For instance, some dogs with chronic hepatitis and portosystemic shunts have low AT and protein C (indeed, Protein C appears to be consistently low in dogs with acquired or congenital portosystemic shunts compared to dogs with microvascular dysplasia).
  
  
• Decreased activation of vitamin K-dependent enzymes: Vitamin K is a fat-soluble enzyme requiring bile secretion (for fat emulsification in the intestine) for absorption. Cholestatic liver disease can result in a lack of vitamin K, with decreased production of vitamin K-dependent enzymes (factors II, FVII, X and X) and a vitamin K-responsive coagulopathy. Remember also that important inhibitors of the coagulation cascade, Protein C and protein S, are also vitamin-K dependent. In human patients, abnormal carboxylation of vitamin K-dependent enzymes (resulting in decreased enzyme activity) has been documented in patients without evidence of cholestasis.
  
  
• Production of abnormal factors: Abnormal fibrinogen molecules (dysfibrinogenemia) is a feature of some liver diseases, such as hepatomas and acute and chronic liver disease, in human patients. The abnormal fibrinogen cannot form fibrin or cannot polymerize, resulting in inadequate clot formation and hemorrhage, with a prolonged TCT.
  
  
• Initiation of DIC: DIC can be initiated by a variety of hepatic diseases, such as neoplasia and acute fulminant hepatic failure. Although decreased clearance of activated clotting factors, inhibitors and D-dimer/FDPs occurs in some of these diseases, elevated plasmin-antiplasmin and (TAT) complexes support the presence of DIC. DIC is thought to be initiated through cytokine-mediated tissue factor exposure on Kupffer cells and/or circulating monocytes. The release of procoagulant phospholipids from damaged hepatocytes would fuel the intravascular coagulative process.
  
  
• Platelets: Many human patients with cirrhosis have a mild to moderate thrombocytopenia. The exact mechanism is unknown, but it may be due to sequestration in the spleen, immune-mediated destruction of platelets, decreased production of thrombopoietin, or combinations thereof. In human patients with acute fulminant liver disease and some with cirrhosis, thrombocytopenia can be due to concurrent DIC. In contrast, thrombocytosis has been documented in some animals with hepatic disease (especially if early or mild). Dogs with various types of hepatic disease have defective whole blood platelet aggregation. This has been attributed to the antiplatelet effects of circulating FDPs and increased bile acids, altered platelet phospholipids, and increased proportions of older, less active platelets.