Chapter 9 Coagulopathy
The hemostatic system (i.e., platelets, vascular endothelial cells, plasma coagulation factors) is a finely controlled mechanism that prevents excessive blood loss following vascular injury. Abnormalities in any part of the hemostatic system may result in bleeding. Hemostatic disorders may be classified as primary or secondary. Primary hemostasis refers to the platelet–vessel interaction; therefore primary hemostatic disorders include thrombocytopenia, thrombopathia, von Willebrand disease (vWD), and, rarely, vasculopathy. Secondary hemostasis refers to generation of thrombin and formation of a fibrin clot through a series of enzymatic reactions; therefore coagulopathies are secondary hemostatic disorders that typically result from deficiency of one or more plasma coagulation factors. In addition, enhanced fibrinolysis may result in a bleeding tendency.
Following vascular injury, platelets adhere to exposed subendothelial collagen. Under conditions of high shear forces (in arterioles and microcirculation) plasma von Willebrand factor (vWF) is also needed to support platelet adhesion. Once activated, platelets aggregate (i.e., stick to one another via crosslinking by fibrinogen) to form an unstable platelet plug. Stabilization of the platelet plug with a fibrin clot occurs through blood coagulation. The liver is the major site of synthesis for blood coagulation factors that are secreted into circulation as inactive zymogens. Plasma coagulation factors (F) II, VII, IX, and X, as well as anticoagulant protein C and protein S, require vitamin K for carboxylation of their glutamic acid residues, allowing them to bind calcium ions essential to the coagulation process. FVII (extrinsic pathway) plays a pivotal role in the initiation of coagulation, combining with membrane protein tissue factor (TF) following vessel injury. Activated FVII and TF complex (FVIIa–TF) in the presence of calcium cleaves FIX (intrinsic pathway) and FX (common pathway) to their activated forms, ultimately leading to the generation of fibrin. Platelets exert a procoagulant effect with the platelet membrane phospholipid phosphatidylserine (PS) providing a catalytic surface for enzymatic activities known as tenase and prothrombinase, resulting in activation of FX and FII (prothrombin), respectively.
The liver plays a key role in regulating fibrinolysis, synthesizing both plasminogen and the major plasma inhibitor of plasmin, α2-antiplasmin. Within the fibrinolytic system, plasminogen is converted to plasmin via tissue-type plasminogen activator (t-PA). Plasmin then degrades fibrin into soluble fibrin degradation products (FDPs). Therefore decreased production of plasminogen or α2-antiplasmin because of severe hepatic dysfunction may cause thrombosis or excessive fibrinolysis and a bleeding tendency, respectively.1 Patients with hepatic disease may have increased FDPs as a result of enhanced fibrinolysis or decreased hepatic clearance of FDPs from circulation.
Primary and secondary hemostatic disorders may be hereditary or acquired. In the context of hepatobiliary and gastrointestinal disease, there are two main considerations regarding hemostatic defects: (a) development of a hemostatic abnormality secondary to an underlying hepatobiliary or gastrointestinal disease, and (b) a hereditary or acquired hemostatic disorder causing gastrointestinal bleeding. Hepatic failure may cause coagulopathy because of impaired production of plasma coagulation factors. It has been estimated that greater than 70% of functional hepatic mass must be lost to cause clinically important decreases in clotting factors.2 Consequently, patients with massive hepatocellular necrosis and end-stage chronic hepatic disease are more likely to have a coagulopathy. Severe bleeding may exacerbate hemostatic defects (e.g., secondary to disseminated intravascular coagulation [DIC]). Depending on the cause of the hepatopathy (e.g., infectious disease, neoplasia, heat stroke), DIC may occur and contribute to an acquired hemostatic disorder. A thrombopathia associated with hepatobiliary disease has been documented in dogs with mucosal surface bleeding having normal coagulation profiles and platelet counts but impaired whole-blood platelet aggregation in response to collagen and arachidonic acid.3 Proposed mechanisms of such an acquired thrombopathia include altered arachidonic acid metabolism and prostaglandin synthesis, disruption of membrane release of calcium into the cell, and defective calcium-initiated platelet granule release.3
Extrahepatic biliary obstruction (EHBO) may cause vitamin K–dependent coagulopathy because of impaired absorption of this fat-soluble vitamin from the intestines. Intrahepatic cholestasis has been postulated to decreased vitamin K absorption in some cats with hepatic disease (e.g., cholangiohepatitis, hepatic lipidosis), with a correlation existing between increased serum alkaline phosphatase and coagulation abnormalities.4 Other rare potential causes of a vitamin K-dependent coagulopathy include severe intestinal disease leading to impaired absorption of vitamin K and oral antibiotic therapy resulting in decreased synthesis of vitamin K by intestinal flora. One study of experimentally induced cholestasis (via ligation of the common bile duct) in dogs resulted in inhibition of adenosine diphosphate (ADP) and collagen-induced platelet aggregation in vitro, with impaired platelet function attributed to elevated serum bile acids rather than bilirubin.5
Hemostatic disorders in patients with underlying hepatobiliary disease may be noted initially when performing a coagulation screen in preparation for hepatic biopsy or surgery. Alternatively, such patients may be presented for a bleeding, either spontaneous or following surgery or trauma, due to their underlying hepatobiliary disease. In patients presented for gastrointestinal hemorrhage, it may be challenging to determine if a hemostatic disorder has exacerbated mucosal bleeding caused by underlying gastrointestinal disease rather than either condition occurring alone.
Because severe hepatic dysfunction is required to impair production of blood coagulation factors, acute massive hepatocellular necrosis and cirrhosis are more likely than other hepatopathies to cause clinically significant hemostatic disorders. Toxin ingestion appears to be the most common cause of massive hepatocellular necrosis and subsequent coagulopathy. Chapter 61 discusses hepatotoxins that cause hemostatic disorders.
Coagulation abnormalities in dogs and cats with hepatic disease are common. Sixty-six percent to 93% of dogs6–8 and 82% of cats4 have at least one coagulation test abnormality, the most common being prolongation of the activated partial thromboplastin time (aPTT) in 75% of dogs and prothrombin time (PT) in 77% of cats evaluated. Histopathologic diagnoses reported in dogs with coagulation abnormalities include acute hepatitis with necrosis, chronic active hepatitis, cirrhosis, and diffuse hepatocellular carcinoma,8 whereas diagnoses reported in cats include hepatic lipidosis, cholangiohepatitis, and lymphoma.4 Approximately 45% of cats with severe hepatic lipidosis have abnormal coagulation profiles.9 Despite the high prevalence of coagulation test abnormalities in dogs and cats with hepatobiliary disease, few have clinically evident bleeding tendencies.4,7–9
Vitamin K–dependent coagulopathies may develop in patients with EHBO, particularly if the obstruction is complete and of several days’ duration. The most common causes of EHBO in dogs include necrotizing cholecystitis secondary to cholelithiasis, pancreatitis, and neoplasia.10–12 The most common causes of feline EHBO fall into two groups: neoplasia of either biliary or pancreatic origin, and inflammatory diseases including pancreatitis, cholangiohepatitis, cholecystitis, and cholelithiasis.13 The prevalence of coagulation test abnormalities in dogs and cats with extrahepatic biliary disease varies, potentially as a consequence of some patients having EHBOs that are partial or acute. In one retrospective study of cats with EHBO, eight of 18 (44%) cats had a prolonged PT whereas 10 of 18 (56%) had a prolonged aPTT; all cats with prolonged PT also had an aPTT prolongation.13 However, in a retrospective study of cats with obstructive cholelithiasis, a normal coagulation profile was noted in all eight cats tested.14 Similar differences have been noted in dogs with EHBO. Nine dogs undergoing choledochal tube stenting had normal PT and aPTT,11 whereas prolongation of aPTT was associated with mortality among 57 dogs undergoing extrahepatic biliary surgery.10 In this latter study, the retrospective nature precluded determination of the cause of prolonged aPTT, but DIC and systemic inflammatory response syndrome (SIRS) secondary to septic bile peritonitis and vitamin K malabsorption may have contributed to the coagulopathy.10 Although coagulation profile results are variable amongst both dogs and cats with EHBO, bleeding is uncommonly observed in such patients with abnormal hemostatic profiles. However, there is a case report of excessive bleeding associated with vitamin K deficiency in a dog with an EHBO.15
Exocrine pancreatic insufficiency (EPI) may result in a vitamin K–dependent coagulopathy as a result of lipase deficiency preventing breakdown of dietary triglycerides into monoglycerides and fatty acids, a step in lipid digestion that is needed for adequate solubilization and absorption of fat soluble vitamins.16
Primary hemostatic disorders are more likely than coagulopathies to cause gastrointestinal bleeding. Severe thrombocytopenia (platelet count <30,000/µL) is the most common primary hemostatic disorder causing mucosal surface bleeding. Differential diagnoses for severe thrombocytopenia include idiopathic thrombocytopenic purpura (ITP), secondary immune-mediated thrombocytopenia (associated with drugs, neoplasia, or infectious diseases), bone marrow suppression, or various infectious diseases (especially tick-borne diseases). ITP is the most common cause of severe thrombocytopenia in dogs but is rare in cats. vWD and thrombopathia are other primary hemostatic disorders that may cause gastrointestinal bleeding, either spontaneous or associated with underlying gastrointestinal disorders. Dogs and cats with hereditary thrombopathies may present with petechiae, ecchymoses, excessive bleeding following surgery or trauma, or bleeding from various mucosal surfaces including the gastrointestinal tract. Well-characterized canine hereditary thrombopathies include thrombasthenic thrombopathia (also referred to as Glanzmann thrombasthenia), an absence or deficiency of the platelet glycoprotein (GP) IIb/IIIa receptor for fibrinogen (documented in Otterhounds and Great Pyrenees17), Basset Hound thrombopathia (a platelet signal transduction defect resulting in abnormal cyclic adenosine monophosphate [cAMP] metabolism18), platelet δ-storage pool deficiency (caused by decreased dense granule ADP content, reported in the American Cocker Spaniel19), and platelet procoagulant deficiency (also referred to as Scott syndrome, which is a result of abnormal membrane PS exposure and described in the German Shepherd20). A thrombopathia caused by a platelet δ-storage pool deficiency has also been documented in blue smoke Persian cats with Chediak-Higashi syndrome.21 Acquired platelet function defects may occur following ingestion of nonsteroidal antiinflammatory drugs (NSAIDs) or in association with uremia, cholestatic hepatic disease, and dysproteinemias. In gastrointestinal bleeding following NSAID administration, the cause is more likely gastrointestinal ulceration than an acquired thrombopathia, although concurrent platelet dysfunction could exacerbate bleeding.
Coagulopathies are more often associated with cavity bleeding than mucosal surface bleeding, but secondary hemostatic defects should be considered in patients with gastrointestinal bleeding. Mild to moderate thrombocytopenia has been documented in dogs with anticoagulant rodenticide poisoning, but marked thrombocytopenia (<30,000/µL) has also been reported.22 Melena, hematochezia, and other surface bleeding (e.g., epistaxis, hematuria, gingival bleeding) have been noted in dogs with anticoagulant rodenticide poisoning and normal platelet counts.23 A hereditary vitamin K–dependent coagulopathy attributable to defective γ-glutamylcarboxylase has been reported in Devon Rex cats with spontaneous hemorrhage into the thoracic cavity, joint, and urinary bladder.24,25 Hereditary FVII deficiency is typically considered an asymptomatic defect or a cause of minor bleeding, although severe bleeding has been reported, most often after surgery or trauma.26 Hematochezia has been noted in FVII-deficient Beagles without other signs of colonic inflammation.26 Of the intrinsic coagulopathies, hemophilia A (FVIII deficiency) or hemophilia B (FIX deficiency) may be more likely than others to cause bleeding within the gastrointestinal tract; severe gastrointestinal hemorrhage, potentially in association with coccidiosis, has been reported in hemophilic puppies.27