Underlying disease

Numerous diseases and conditions affect hemostasis. Every animal with a bleeding disorder should be evaluated for underlying disease, especially older animals with a sudden onset of symptoms and no previous history of hemorrhage. A thorough drug history should also be taken as many drugs used to treat underlying diseases affect hemostasis.

Liver disease

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 (endothelial cells in the liver, not hepatocytes) and inhibitors (protein C, protein S, antithrombin), but it is also responsible for clearance and degradation of factors, factor-inhibitor complexes and D-dimer/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 and inhibitor production, production of abnormally functioning clotting factors, increased consumption of factors by initiation of DIC, and abnormal platelet number or function. Although there is no doubt that coagulation abnormalities (mostly prolonged PT and APTT) are seen in liver disease, the clinical relevance of these defects is far from certain. Most human and animal patients with liver disease do not bleed excessively (in fact a meta-analysis suggests there is a higher risk of venous thromboembolism in human patients with liver disease, at least in those with cirrhosis [Ambrosino et al 2017]), despite abnormal coagulation assays, leading some authors to postulate as to the presence of a “rebalanced”, albeit inherently unstable and fragile, hemostatic state in liver disease (Lisman and Porte 2010). For example, decreased production of coagulation factors is offset by decreased inhibitor production and profibrinolytic forces are balanced by antifibrinolytic mediators. The revised thinking of a balanced but altered hemostatic status in liver disease has led to revised recommendations of clinical management of such patients by the International Society of Thrombosis and Haemostasis (Lisman et al 2021).

  • 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 urea nitrogen (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 count would favor the concurrent presence of DIC in synthetic liver failure). Low levels of the inhibitors, antithrombin and protein C, are also seen in hepatic failure, 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) (Toulza et al 2006). Conversely, high levels of von Willebrand factor and FVIII are seen in human patients with liver disease, since both of these are produced in endothelial cells, not hepatocytes, and increase as acute phase proteins in humans (Lisman and Porte 2010).
  • 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, IX 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 disseminated intravascular coagulation (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 and tissue factor from damaged hepatocytes would fuel the intravascular coagulative process.
  • Defects in platelet number and function: 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 (Mitchell et al 2016). 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.
  • Fibrinolysis: High levels of tissue plasminogen activator would promote fibrinolysis as would decreased concentrations of inhibitors. However, decreased plasminogen production may offset the profibrinolytic effects (Lisman and Porte 2010). As mentioned above, FDPs and D-dimer, markers of fibrin(ogen) and fibrinolysis, respectively, can be high in liver disease due to decreased clearance and do not necessarily indicate DIC or thrombosis in this setting.

Renal disease

Hemorrhage is an infrequent complication of renal disease. Thrombocytopenia may occur, but is usually mild. Mucosal bleeding, reduced platelet retention and a prolonged BMBT are features of natural and experimental uremia in dogs. These abnormalities correlate to the degree of azotemia. Platelet aggregation is either normal or mildly decreased, implicating defective platelet adhesion as the main hemostatic abnormality. The exact cause of the defect is unknown. The amount and multimeric composition of vWf in uremic dogs is normal, indicating that the adhesion defects are not due to vWf abnormalities. In contrast, dogs with acute kidney injury (AKI) had decreased aggregation with collagen and higher vWf:Ag to vWf binding to collagen ratios, similar to that seen in dogs with inherited type II vWD, where vWf is qualitatively abnormal due to decreased high molecular weight multimers (McBride et al 2019). However, the latter study did not perform multimeric analysis so the cause of the lower collagen binding in the affected dogs is unclear and there were only 10 dogs in the study with AKI. The antigen to collagen binding ratios for vWf correlated strongly to creatinine concentrations (r=0.89).

Hypercoagulability (thrombosis) is a feature of nephrotic syndrome in both man and dogs. This is mainly due to loss of antithrombin through the glomerulus, with antithrombin activities < 50% predisposing to thrombosis in dogs. Platelet hyperaggregability (from increased free arachadonic acid availability, due to decreased albumin binding from hypoalbuminemia), hyperfibrinogenemia and decreased fibrinolysis (due to urinary losses of plasminogen or increased levels of inhibitors, such as alpha2-antiplasmin) may contribute.


The incidence of clinical thrombotic or hemorrhagic complications associated with neoplasia is unknown. In one study of untreated dogs with cancer but no evidence of bleeding, abnormal coagulation results were obtained in 83% of patients, including thrombocytopenia, prolonged APTT, and hyper- and hypofibrinogenemia. One of the most common tumors associated with hemorrhagic tendencies is hemangiosarcoma in dogs. Most dogs with hemangiosarcoma have laboratory evidence of DIC. Abnormal hemostasis can be due to the maligancy itself, chemotherapy or metastatic disease (resulting in organ disease or failure) and can involve all pathways of hemostasis. Hemostatic abnormalities associated with chemotherapy are common in both human and animals, with thrombocytopenia due to myelosuppression being a frequent complication of chemotherapeutic protocols. Some antineoplastics produce thrombosis either due to direct toxic effects on the vasculature or because of effects on hemostasis, e.g. L-asparginase inhibits antithrombin production.

  • Primary hemostasis: Thrombocytopenia is a common finding in animals with neoplasia. This may be due to decreased production (myelophthisis, tumor release of suppressive cytokines or chemotherapy-related), immune-mediated destruction, blood loss, sequestration and increased consumption in DIC. As mentioned under the section on monoclonal gammopathies, animals with paraproteinemias have evidence of decreased platelet function. Acquired von Willebrand disease has been reported in human patients with multiple myeloma, lymphoma, Wilm’s tumor and myeloproliferative disease. A similar phenomenon has not been reported in animals. In a recent study in dogs with lymphoma, platelets were shown to be hyperaggregable.
  • Secondary hemostasis: Isolated factor deficiencies have rarely been reported in animals with neoplasia, most factor deficiencies are due to DIC. Coagulation can be initiated by a variety of tumors, due to activation of factors directly (e.g. mucinous adenocarcinomas can activate factor X), tissue factor expression (e.g. hemangiosarcoma), and production of inhibitors (e.g. mast cell tumors, which release heparin).
  • Fibrinolysis: Excessive fibrinolysis is a feature of certain tumors in human patients, such as promyelocytic leukemia. This syndrome has not been recognized in animals.

Monoclonal gammopathy

Animals with paraproteinemias due to B or plasma cell neoplasia (e.g. multiple myeloma) commonly exhibit clinical signs of bleeding, including epistaxis, petechiae, gingival bleeding and bleeding into the gastrointestinal tract. Monoclonal gamma globulins (especially IgM and IgA) coat platelets, interfering with platelet aggregation, adhesion and phospholipid exposure. Some also interact directly with coagulation factors, inhibiting secondary hemostasis. They also interfere with fibrin polymerization, resulting in defective fibrin production.

Infectious disease

Many infectious agents can affect hemostasis, either by affecting bone marrow production of platelets, affecting platelet function, inducing vasculitis or initiating DIC.

  • Bacteria: Acute endothelial injury can result in DIC in animals with leptospirosis. Gram-negative bacteria release endotoxins, which initiates DIC. DIC can also be seen with other bacterial infections, including gram positive bacteria, particularly when infection is severe and induces a systemic inflammatory response which triggers DIC (e.g. cytokines upregulate tissue factor). Rocky Mountain Spotted Fever induces a coagulopathy mainly due to endothelial cell injury from invasion of endothelial cells (see acquired vessel wall defects for more information). Ehrlichia canis and platys can produce thrombocytopenia (partly by immune-mediated mechanisms) and decreased platelet function.
  • Parasites: Dogs with severe heartworm infection can develop DIC, which can be mimicked by experimental injection of heartworm extract. There is also platelet hyperaggregability in canine heartworm disease, rationalizing the use of aspirin as one of the components of treatment for this disorder. Angiostrongylus vasorum, a nematode that lives in the heart and pulmonary vessels, is associated with severe bleeding disorders in dogs, particularly in endemic areas in Europe and the United Kingdom. Direct damage to vessels can cause severe hemorrhage, but abnormalities in hemostatic test results consistent with DIC are also seen in some dogs.
  • Snake envenomation: Many snake venoms contain enzymes which can activate coagulation factors, initiate DIC or break down fibrinogen. In fact, the snake venom from Bothrops atrox (Reptilase) is incorporated into serum FDP collection tubes to cause clotting of intact fibrinogen.
  • Viruses: Disseminated intravascular coagulation is a complication of feline infectious peritonitis virus and feline panleukopenia virus infections. Feline leukemia virus can produce thrombocytopenia or thrombocytosis. In one study, cats with feline immunodeficiency virus had thrombocytopenia, prolonged APTTs (which was shortened by dilution with pooled cat plasma) and high fibrinogen concentrations. The reasons for the prolonged APTTs were not found.

Lupus anticoagulants

Lupus anticoagulants (or antiphospholipid antibodies) are specific antibodies with affinity for anionic phospholipids. The most common targets are beta2-glycoprotein I, prothrombin, protein C and protein S. In human patients, lupus anticoagulants or antiphospholipid antibodies occur in patients with SLE, other immune-mediated diseases, drug-induced disorders and certain infectious diseases. The syndrome is associated with arterial and venous thrombosis, recurrent fetal loss and thrombocytopenia. The exact mechanism how these antibodies induce thrombosis is not known, and mechanisms may differ depending on the antibody specificity.

Antiphospholipid antibodies were detected in a 2 year-old Chesapeake Bay Retriever with hemolytic anemia, nephrotic syndrome, polyarthropathy, thrombocytopenia and pulmonary thromboembolism. The dog had a normal PT, negative FDPs, a high fibrinogen, a mildly prolonged ACT, and a persistently long APTT which did not correct when mixed with normal dog plasma in vitro or after prolonged incubation. The dog also had a prolonged Russell viper venom time (RVVT) and kaolin clot time (KCT), confirming the presence of the antibodies, because assays sensitive to deficiencies in phospholipid (APTT, RVVT, KCT) will be prolonged in animals with antiphospholipid antibodies.

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