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Coagulation Protein Disorders

By Susan M. Cotter, DVM, DACVIM (Small Animal, Oncology)


Congenital Coagulation Protein Disorders

In a severe deficiency or functional defect of coagulation proteins, clinical signs appear at an early age. Marked reductions in activity of coagulation proteins essential to hemostasis are usually fatal. Animals may be stillborn if there is <1% of normal activity or die shortly after birth owing to massive hemorrhage. Insufficient production of coagulation proteins or limited access to vitamin K by the immature neonatal liver may exacerbate a coagulation defect. If activity of any particular coagulation protein is 5%–10% of normal, the neonate may survive, but signs usually appear before 6 mo of age. It is during this time, when numerous routine procedures (eg, vaccination, declawing, tail docking, dewclaw removal, ear cropping, and castration or ovariohysterectomy) are usually done, that a bleeding tendency may become apparent.

Most of the congenital coagulation protein disorders reported in domestic animals are deficiencies or abnormalities of a single factor.

Congenital afibrinogenemia (Factor I deficiency) has been reported in a family of Saanen dairy goats but not in dogs or cats. Hypofibrinogenemia, accompanied by severe bleeding, has been reported in Saint Bernards and Vizslas and in one mixed-breed dog; the ACT, APTT, PT, and thrombin time (TT) were prolonged. Dysfibrinogenemia has been reported in an inbred family of Russian Wolfhounds (Borzois). The ACT, APTT, PT, and TT were prolonged, but fibrinogen was present by quantitative testing. Affected dogs had mild bleeding episodes with epistaxis and lameness, but trauma or surgery resulted in life-threatening bleeding. IV administration of fresh-frozen plasma or cryoprecipitate is the best treatment to stop the bleeding.

Factor II (prothrombin) disorders are rare. Boxer dogs have been reported to have abnormally functioning prothrombin but normal concentrations; the defect was inherited as an autosomal recessive trait. A disorder of Factor II has been reported in English Cocker Spaniels; clinical signs in affected puppies (epistaxis and gingival bleeding) decrease with age, and adults bruise easily or have dermatitis. In affected puppies, TT is normal, while ACT, APTT, and PT are prolonged. Treatment is by transfusion of fresh-frozen plasma or fresh whole blood if RBCs are needed.

Factor VII deficiency has been reported in Beagles, English Bulldogs, Alaskan Malamutes, Alaskan Klee Kai, Miniature Schnauzers, Boxers, and mixed-breed dogs. It is inherited in an autosomal pattern with incomplete dominance. Usually, it is not associated with spontaneous clinical bleeding, but affected dogs may have bruising or prolonged bleeding after surgery. Prolonged postpartum hemorrhaging has been reported. Factor VII deficiency is most often diagnosed coincidentally when coagulation screening tests are performed; the PT is prolonged, while APTT and other test results are normal.

Factor VIII deficiency (hemophilia A) is the most common inherited bleeding disorder in dogs and cats; it has also been reported in several breeds of horses, including Arabians, Standardbreds, Quarter horses, and Thoroughbreds. There is an X-linked pattern of inheritance, so usually females are asymptomatic carriers and males are affected. Rarely, in highly inbred families, a carrier female mated with an affected male can produce affected female offspring.

In affected puppies, prolonged bleeding is seen from the umbilical vessels after birth; from the gingiva during tooth eruption; and after surgery such as tail docking, dewclaw removal, or ear cropping. Hemarthrosis accompanied by intermittent lameness, spontaneous hematoma formation, and hemorrhagic body cavity effusions also are common clinical findings in dogs with <5% of normal Factor VIII activity. Animals with 5%–10% of normal activity often do not bleed spontaneously but exhibit prolonged bleeding after trauma or surgery. Affected cats and sometimes small dogs may show prolonged bleeding after surgery or trauma but rarely bleed spontaneously, probably because of their agility and light weight. Affected animals usually have very low concentrations of Factor VIII (<10%) and prolonged ACT and APTT. Von Willebrand factor (Factor VIII−related antigen) concentrations are normal or greater than normal. Carrier animals have intermediate concentrations of Factor VIII (40%–60%), and results of coagulation screening tests are usually normal. Care should be taken in diagnosis if animals are <6 mo old because of possible low production of coagulation factors by an immature liver. Usually, results of coagulation screening tests are normal in carrier animals.

Treatment of bleeding diatheses requires repeated transfusions of cryoprecipitate or fresh-frozen plasma (10 mL/kg) 2–3 times/day until bleeding has been controlled. Fresh-frozen plasma or cryoprecipitate is preferable to whole blood because of the possible sensitization of the animal to RBC antigens with repeated transfusions.

Factor IX deficiency (hemophilia B) is diagnosed less often than Factor VIII deficiency. It has been reported in several breeds of purebred dogs, a mixed-breed dog, Himalayan cats, a family of Siamese-cross cats, and a family of British Short-haired cats. The defect is X-linked with carrier females and affected males, although affected females can be seen in closely inbred families. Clinical presentation is similar to that of animals with Factor VIII deficiency. Animals with extremely low Factor IX activity (<1%) usually die at birth or shortly thereafter. Animals with 5%–10% of normal Factor IX activity may spontaneously form hematomas, hemarthroses, hemorrhagic body cavity effusions, or organ hemorrhage. Gingival bleeding during tooth eruption or prolonged bleeding after tail docking or dewclaw removal can occur. Some animals are asymptomatic until trauma or surgery. The ACT and APTT are prolonged. Carrier animals with 40%–60% of normal Factor IX activity are usually asymptomatic, and results of coagulation screening tests are normal. Treatment requires transfusion with fresh-frozen plasma (10 mL/kg), bid, until bleeding resolves. Often, internal hemorrhage into the abdomen, thorax, CNS, or between muscle fascial planes occurs and may be undetected until a crisis.

Factor X deficiency has been reported in a single family of American Cocker Spaniels and a mixed-breed dog. In the former, the inheritance pattern was autosomal dominant with variable penetrance. Homozygotes usually die early in life or are stillborn because of massive internal hemorrhage. Heterozygotes have mild to severe bleeding problems. The ACT, APTT, and PT are usually prolonged when animals have <30% normal activity of Factor X. Transfusions with fresh or fresh-frozen plasma are required to control hemorrhage.

Factor XI deficiency has been recognized in Kerry Blue Terriers, a female English Springer Spaniel, a Great Pyrenees dog, Weimaraners, and Holstein cattle. Mild deficiencies usually go undetected. In severe deficiencies with Factor XI at 30%–40% or less of normal activity, mild prolonged bleeding may occur after trauma or surgery. Bleeding tendencies usually are not immediate but delayed for 3–4 days. The ACT and APTT are usually prolonged. Transfusion with fresh-frozen plasma (10 mL/kg) is sufficient to stop the bleeding for up to 3 days. Inheritance is autosomal, but it has not been determined whether the gene is dominant or recessive. A single case involving an adult cat with epistaxis and diagnosed with systemic lupus erythematosus was attributed to the presence of a circulating inhibitor against Factor XI.

Factor XII (Hageman) deficiency has been reported in German Shorthaired Pointers, Standard Poodles, a family of Miniature Poodles, and in cats. Affected animals do not have clinical bleeding problems. The deficiency is usually diagnosed coincidentally when coagulation screening tests are performed and the APTT is prolonged. People with Factor XII deficiency do not have bleeding problems but are predisposed to thrombosis or infections, which is attributed to the normal role of Factor XII in fibrinolysis and complement activation. Tendencies for thrombosis or infection have not been reported in animals. Factor XII deficiency has been found to coexist with von Willebrand disease in a dog and with Factor IX deficiency in a cat, but bleeding tendencies were not exacerbated. Factor XII is not present in the plasma of birds, marine mammals, and reptiles, with no untoward effects.

Deficiency of Factors II, VII, IX, and X has been described in Devon Rex cats that experienced bleeding, most commonly after surgery. The bleeding can be controlled by vitamin K administration, and some of these cats appear to overcome the bleeding tendency as adults.

Prekallikrein deficiency has been reported in Poodles, a family of miniature horses, and a family of Belgian horses. Clinical bleeding problems are not usually apparent. One horse bled excessively after castration. The diagnosis is usually made coincidentally when coagulation screening tests are performed. The ACT and APTT are usually prolonged.

Poor clot strength in Greyhounds has been found to cause delayed postoperative bleeding. An abnormal maximum amplitude is observed on TEG in these dogs. Epsilon aminocaproic acid is effective to prevent or stop bleeding in affected dogs.

Acquired Coagulation Protein Disorders

Liver Disease:

Most coagulation proteins are produced primarily in the liver. Therefore, liver disease characterized by necrosis, inflammation, neoplasia, or cirrhosis often is associated with decreased production of coagulation proteins, anticoagulants, and fibrinolytic proteins. Because the various coagulation proteins have a relatively short half-life (4 hr to 2 days), mild to marked deficiencies can result in secondary to severe hepatopathies. The APTT and/or PT are prolonged in 50%–85% of dogs with severe liver disease, meaning that the factor activity is <30% of normal. Nevertheless, <2% actually develop hemorrhage and, when bleeding does occur, it is usually associated with concurrent disease. Coagulation tests are often performed before liver biopsy.

Severe hepatic diseases can also lead to disseminated intravascular coagulation. Fibrinogen, an acute phase reactant, and von Willebrand factor, which is produced extrahepatically, can be increased in liver disease.

Vitamin K Deficiency:

Vitamin K is solubilized in mixed micelles before passive diffusion across the brush border. Fat malabsorption associated with inadequate amounts of bile salts (eg, biliary obstruction), lymphangiectasia, or severe villous atrophy may result in vitamin deficiency and coagulopathy owing to the lack of production of the functional vitamin K−dependent Factors II, VII, IX, and X.

Ingestion of Anticoagulant Rodenticides:

Ingestion of certain rodenticides by dogs and cats causes a coagulopathy owing to the lack of production of functional vitamin K−dependent factors (see Rodenticide Poisoning). Inactive precursor coagulation Factors II, VII, IX, and X are still produced by the liver, but γ-carboxylation of the inactive precursors does not occur, because the rodenticide inhibits the epoxide-reductase enzyme required for recycling of active vitamin K. There are two general classes of anticoagulant rodenticides: the coumarin compounds (warfarin, coumafuryl, brodifacoum, and bromadiolone) and the indanedione compounds (diphacinone, pindone, valone, and chlorophacinone). The anticoagulant rodenticides are further divided into first- and second-generation based on their toxicity and half-life. In general, the half-life of the coumarins (up to 55 hr) is much shorter than that of the indanedione compounds (15–20 days). Various concurrently administered drugs and coexisting disease may exacerbate the toxicity of the ingested anticoagulant.

Affected animals may have hematoma formation (especially over pressure points) and bruising of superficial and deep tissues. Often, the animals do not bleed within the first 24 hr after ingestion of the toxin. The APTT, PT, and ACT are usually prolonged. Factor VII has the shortest half-life of the vitamin K−dependent coagulation proteins; therefore, the PT is often abnormal before other tests and can be used to monitor response to treatment. With acute ingestion, emetics, absorbents, and cathartics are used to minimize absorption. Vitamin K therapy is often initiated even in asymptomatic animals. Vitamin K1, 2.5–5 mg/kg SC, divided between several injection sites, is recommended for initial treatment of coumarin toxicity, followed by 1.25–2.5 mg/kg, PO, bid for 4–6 days if the ingestion is thought to be minimal. PT should be measured 48 hr after termination of treatment, and if prolonged, treatment should be continued for another 14 days. If the initial PT is normal, another PT should be performed in 48 hr. If that test is normal, treatment can be discontinued. Dosages of vitamin K1 as high as 5 mg/kg, PO, for 3–6 wk may be required for treatment of indanedione toxicity; however, these high dosages should be administered cautiously, because Heinz body anemia has been reported in dogs given 4 mg/kg for 5 days. IV administration of vitamin K1 is not recommended, because anaphylactic reactions can result. Administration of vitamin K3 is not useful.

Disseminated Intravascular Coagulation (DIC):

DIC is not a primary disease but occurs secondary to numerous underlying diseases, such as bacterial, viral, rickettsial, protozoal, or parasitic diseases; heat stroke; burns; neoplasia; or severe trauma. The underlying disease causes an uncontrolled systemic inflammatory response characterized by massive activation and consumption of coagulation proteins, endogenous inhibitors, fibrinolytic proteins, and platelets.

In the initial stage of DIC, the animal is hypercoagulable because of circulating inflammatory mediators that cause activation of hemostasis through increased exposure of TF and inhibitor consumption. With time, consumption of coagulation factors, if not compensated by increased production, may lead to a hypocoagulable state with overt clinical symptoms. Because of the progressive nature of DIC, the clinical findings vary considerably and range from no overt signs of disease, accompanied by no or perhaps only subtle changes in traditional hemostasis parameters (APTT, PT, d-dimer, fibrinogen, and platelet count), to clinical signs of organ failure, associated with microvascular thrombosis in vital organs, finally culminating in overt bleeding symptoms. The latter presentation is traditionally thought of as the characteristic DIC patient, in which there are also pronounced alterations in hemostasis parameters and a drop in the platelet count.

Thromboelastography can differentiate the stage of DIC in dogs. Dogs diagnosed in the hypercoagulable stage have a much better chance of survival than dogs diagnosed in the hypocoagulable stage. This is likely because of early and aggressive intervention through supportive and/or antithrombotic therapy while the underlying disease is treated. Aggressive treatment likely minimizes thromboembolic complications and delays or even prevents progression to overt signs.

In veterinary medicine, the laboratory diagnosis of DIC is not standardized and the hemostatic function tests used are not consistent, but DIC is often diagnosed based on three or more abnormal hemostatic parameters such as APTT, PT, fibrinogen, d-dimer, platelet count, and RBC morphology, along with predisposing disease, which is a sensitive but unspecific approach. Postmortem fibrinolysis makes necropsy an insensitive diagnostic criterion.

Therapy is often empirically directed at correcting the imbalance in the hemostatic system while treating the underlying disease aggressively. Administration of balanced electrolyte solutions and plasma expanders to maintain effective circulating volume is imperative. The response to treatment with fresh-frozen plasma and heparin is unpredictable, and their use is controversial.