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Normal or increased numbers of megakaryocytes in thrombocytopenic patients are indicative of increased platelet destruction, consumption or sequestration. Some of the more common causes of platelet consumption and sequestration include: DIC, sepsis, vasculitis and splenic torsion. These can usually be excluded on the basis of clinical findings. Immune-mediated thrombocytopenia (ITP) is a common cause of thrombocytopenia in the dog. As previously discussed, definitive diagnosis can be unrewarding, so nonimmune causes should be excluded. Rickettsial disease (Ehrlichiosis, Rocky Mountain spotted fever) may induce a nonimmune thrombocytopenia with megakaryocytic hyperplasia. These are diagnosed serologically. Negative titers, however, do not exclude tick-borne disease, and should be repeated in 10 to 14 days. ITP may be idiopathic or may occur together with other autoimmune processes, such as IMHA or SLE. In addition, it may develop secondary to drug administration (most notably, sulphonamides), live-virus vaccination, neoplasia (especially lymphoid) and infection. Suspicion of ITP, therefore, should prompt a thorough search for underlying causes or systemic immune-mediated disease. Together with a complete blood count, chemistries, and urinalysis, the following diagnostic tests are indicated: radiology or ultrasound, a direct Coombs' test, and antinuclear antibody test (ANA). In addition, serology for tick-borne diseases and occult dirofilariasis should be considered in the dog, and viral serology in the cat.

Thrombopathia

Vascular disorders are a relatively uncommon cause of bleeding. In the patient with a primary hemostatic disorder and normal platelet numbers, a platelet function defect is likely. A prolonged BMBT in a patient with adequate platelet numbers confirms thrombopathia. The drug history should be carefully appraised, because numerous drugs can cause or contribute to thrombopathia. Diseases known to precipitate platelet dysfunction should be excluded. If no obvious cause of acquired thrombopathia can be found, a hereditary disorder is suspected.

Von Willebrand‟s disease (vWD) is the most common canine hereditary bleeding disorder. Von Willebrand‟s factor (vWf) is produced and stored in canine endothelial cells and plays a central role in platelet adhesion. In plasma, vWF forms a complex with coagulation factor VIII and appears to stabilize the functional half-life of this factor. High-molecular-weight vWf multimers are most effective in platelet adhesion. Deficiency of vWf, or preferential loss of high-molecular-weight forms, results in impaired adhesion.

There are three types of vWD. Type I is most common. It is associated with a partial, quantitative deficiency of vWF, with normal multimer distribution. Type I vWD has been described in numerous dog breeds, including the Doberman, Rottweiler, and German Shepherd. Isolated cases have been reported in cats. Clinical severity is variable and correlates with reduction in vWF concentration. Severely affected dogs (<20% vWF) can bleed spontaneously. Mildly affected dogs undergo bleeding only if subjected to surgery or trauma, or if the condition is exacerbated by another bleeding tendency. Type II vWD is characterized by low vWF concentration and a disproportionate loss of high-molecular-weight multimers. It has been described in German Shorthaired Pointers and Wirehaired Pointers. Type III vWD is a severe quantitative deficiency of vWF. Familial forms have been reported in Chesapeake Bay Retrievers, Shetland Sheepdogs, and Scottish Terriers. Sporadic cases have been reported in other breeds. Types II and III vWD cause a severe bleeding tendency, typically with episodes of hemorrhage occurring within the first year of life.

Diagnosis is generally achieved via ELISA testing, with results reported as a percentage of the laboratory's standard plasma. Values less than 50% are considered vWf deficient. Differentiation between types I and II vWD requires determination of multimer distribution via immunoelectrophoresis. Animals with systemic stress or critical illness may have abnormal vWf. Therefore, decreased vWF titers in such patients should not be over-interpreted.

Diagnosis of other thrombopathies requires specific platelet function testing, performed by specialized laboratories.

Disorders of Secondary Hemostasis

Causes of disorders of secondary hemostasis are listed in Figure 3. An algorithm outlining the approach to secondary hemostatic disorders is presented in Figure 4.

Hereditary coagulopathies are quantitative disorders of specific coagulation factors, usually noted in purebred dogs. Acquired disorders include vitamin K deficiency or antagonism, hepatic disease, DIC, and the presence of anticoagulants (e.g., heparin). These acquired conditions tend to affect multiple factors in both the intrinsic and extrinsic pathways. Factor VII has the shortest half-life (4 to 6 hours), so prolongation of the PT may precede PTT prolongation in early vitamin K deficiency or early acute hepatic failure. Conversely, the PTT alone may be prolonged with chronic hepatic disease, DIC, heparin therapy, or with dilution (e.g., colloid therapy or massive crystalloid fluid administration).

Anticoagulant Rodenticide Toxicity

The most common cause of vitamin K deficiency in dogs is the ingestion of anticoagulant rodenticides. Synthesis of vitamin K–dependent factors (II, VII, IX, and X) occurs in the liver. Vitamin K is an essential cofactor for carboxylation of these proteins, rendering them functional. Anticoagulant rodenticides interfere with recycling of vitamin K, resulting in rapid depletion.

Clinical signs of a secondary hemostatic disorder generally occur 2 to 3 days post-ingestion. Prolongation of the PT occurs first but, by the time hemorrhage is evident, the PT, PTT, and ACT are usually all prolonged. FSP, d-dimer, and fibrinogen concentrations are generally normal. The platelet count is usually normal, but it may be decreased by consumption during bleeding. Toxicologic testing is not usually helpful in the emergency situation, but it may serve to confirm an uncertain diagnosis.

Hepatic Disease

Severe hepatocellular damage or biliary obstruction results in variable factor deficiencies or abnormalities in vitamin K metabolism, or both. Both quantitative and qualitative platelet disorders may occur. PT and PTT can be prolonged. FSP and d-dimer concentrations may be elevated. Excessive fibrinolysis can result from the reduced clearance of plasminogen activators and reduced synthesis of fibrinolytic inhibitors. Differentiation from DIC is sometimes impossible based on coagulation testing alone, and depends on clinical findings, serum chemistry results, and liver function testing. Bleeding tendencies must be corrected before pursuing hepatic biopsy or other invasive procedures. Transfusion of fresh frozen plasma can temporarily offset factor deficiencies. Stored whole blood and packed red blood cells should be avoided due to the increased ammonia concentrations. Vitamin K1 may be beneficial in some patients; efficacy should be ascertained by repeat coagulation testing at least 12 hours after initiating therapy.

Disseminated Intravascular Coagulation (DIC)

Disseminated intravascular coagulation (DIC) refers to the intravascular activation of hemostasis with resultant microcirculatory thrombosis. Ultimately, exaggerated consumption of platelets and coagulation factors may result in defective hemostasis and a bleeding tendency. Fibrinolysis of microthrombi generates FSPs, further exacerbating the disorder.

DIC occurs secondary to a wide variety of underlying disease processes. These include: sepsis, the systemic inflammatory response syndrome (SIRS), severe infections (viral, bacterial, and protozoal), neoplasia, shock, heat stroke, hemolysis, pancreatitis, severe hepatic disease, trauma, and tissue necrosis. The pathophysiology and manifestations of DIC have been extensively reviewed elsewhere.

The diagnosis of acute, fulminant DIC usually is made easily, but diagnosing chronic or subclinical DIC may prove more difficult. There is always an underlying disease causing DIC that should be identified rapidly, if possible. Laboratory findings are extremely variable. Thrombocytopenia is almost invariably present, but relative changes may be undetected unless a recent count is available for comparison. The PT, and more often the PTT, may be prolonged, but both may be normal if compensatory factor production is adequate.

Significant elevations of FSP or d-dimer levels are highly suggestive of DIC, but are nonspecific. Schizocytes on blood smear examination are significant, but they are not always present and may occur with other conditions. Diagnosis of DIC, therefore, requires careful consideration of both the clinical and the laboratory findings, with no single finding being pathognomonic. Any suspicion of DIC should prompt a thorough search for an underlying cause, as successful management depends on its correction.

Inherited Coagulopathies

The clinical severity of the various inherited coagulopathies depends on the magnitude of the factor deficiency and the exposure of the animal to trauma that may precipitate bleeding. Most develop bleeding within the first year of life. Mildly affected animals may not bleed until later in life, particularly if they do not undergo surgery or trauma. Similarly, factor VII deficiency tends to produce milder disease, with later onset bleeding.

Inherited coagulopathies should be suspected in younger animals, in breeds associated with factor deficiencies, if there is a history of recurrent bleeding, and if acquired causes are ruled out or deemed unlikely. A deficiency of factor VII prolongs only the PT, whereas factor VIII and IX deficiencies (hemophilia A and B) cause prolongation of the PTT. Both parameters are prolonged with deficiencies of factors I, II, and X. Diagnosis requires specific factor assays performed by specialized laboratories.

Table 1. Clinical features helpful in differentiating between primary and secondary hemostatic abnormalities.

Table 2. Screening tests for the evaluation of hemostasis.

Table 3. Normal values for screening coagulation tests.

* Normal values are laboratory and technique dependent.