Clinical Disorders Frequently Associated With Thromboembolic Disease

By | 2013-07-19

Hypercoagulable States

Many systemic and metabolic diseases are associated with an increased risk of arterial or venous thrombosis andTE. Primary hypercoagulable states refer to congenital abnormalities increasing the risk for thrombosis. Primary hypercoagulable states remain poorly characterized and are infrequently recognized in animals.

Secondary hypercoagulable states refer to risk factors that promote the development of thrombosis. Table Causes and Predisposing Factors of Thrombosis and Thromboembolism lists causes and predisposing factors of thrombus and TE. Secondary hypercoagulable states resulting in thromboembolism have been described in a variety of systemic and metabolic diseases.

Causes and Predisposing Factors of Thrombosis and Thromboembolism

Vascular Endothelial Damage Hypercoagulability Abnormal Blood Flow
Arteriosclerosis Infection/sepsis/abscess Neoplasia
Atherosclerosis Neoplasia Cardiomyopathy
Vasculitis Hyperadrenocorticism Congestive heart failure (CHF)
Heartworm disease Protein losing nephropathy (PLN) Endocarditis
Catheterization Protein losing enteropathy (PLE) Hypovolemia
Injection of irritating substances Disseminated intravascular coagulation (DIC) Shock
Neoplasia Thrombocytosis Anemia
Vascular incarceration/compression Platelet hyperreactivity Polycythemia
Hyperhomocysteinemia Immune-mediated hemolytic anemia (IHA) Dehydration
Feline ischemic encephalopathy (FIE) Parvovirus infection Hyperviscosity
Fibrocortilaginous embolism    

Disseminated Intravascular Coagulation

DIC is a specific pathologic process that involves the development of thrombi in the microvasculature and the generalized consumption of platelets and coagulation factors. This results in simultaneous hemorrhage and thrombosis, ischemia, and multiorgan failure. disseminated intravascular coagulation is characterized by overwhelming thrombin and plasmin activation. Various unrelated diseases associated with disseminated intravascular coagulation are unified by unregulated activation of mononuclear cell cytokines initiating simultaneous coagulation and fibrinolysis. Multiple cytokines are believed to be responsible for the initiation of disseminated intravascular coagulation through induction of tissue factor expression on monocytes and endothelial cells. Tumor necrosis factor (TNF)-alpha and interleukin-6 (IL-6) are two of many cytokines involved in the pathogenesis of DIC. Cytokines also inhibit natural anticoagulants including protein C and S complex, tissue factor pathway inhibitor, and antithrombin III. Cytokines affect endothelial integrity, promoting platelet adhesion and resulting in increased levels of plasminogen activator inhibitor-1 (PAI-1) and promote fibrin deposition.

DIC occurs in patients with a wide variety of clinical disorders. Heatstoke, sepsis, pancreatitis, neoplasia, immune-mediated disease, trauma, and toxin exposure are common inciting causes of DIC. The trigger causing disseminated intravascular coagulation in these seemingly unrelated syndromes may be systemic inflammatory response syndrome and the production of proinflammatory cytokines including but not limited to TNF, IL-1, and IL-8. The most important step in treating disseminated intravascular coagulation is elimination of the underlying pathologic condition or triggering mechanisms and the conditions that promote this hypercoagulable state. Anticoagulants have been advocated, although clinical data regarding efficacy are lacking.

Protein-Losing Nephropathy

Protein-losing nephropathy (PLN) results in loss of plasma proteins into the urine through injured glomeruli. The small molecular weight of antithrombin III (65,000 daltons) allows it to pass through the glomerulus similarly to albumin. The resulting hypercoagulable state is most often associated with venous thrombosis and can result in pulmonary TE. Arterial (aortic) thromboembolism has also been reported in dogs with PLN.

Hyperadrenocorticism

Both spontaneous hyperadrenocorticism and exogenous administration of glucocorticoids have been associated with the development of thromboemboli. The hypercoagulable state in spontaneous hyperadrenocorticism is characterized by an increase in coagulation factors II, V, VII, IX, X, XII, and fib-rinogen, coupled with a decrease in the natural anticoagulant antithrombin III. Thrombin-antithrombin complexes are also increased in dogs with hyperadrenocorticism but with no clinical signs of thrombosis, suggesting subclinical thrombosis. Long-term exogenous administration of glucocorticoids is associated with proteinuria and glomerular changes. Whether or not this ultimately results in loss of antithrombin III and hyper-coagulability is unknown. Both arterial and venous thromboembolism have been diagnosed in dogs receiving exogenous glucocorticoids.

Feline Cardiomyopathy

The cause of feline thromboembolism is multifactorial and principally accompanies myocardial disease with associated injury to left ventricular or left at rial endothelium. Some affected cats with aortic thromboembolism have elevated blood levels of homocysteine when compared with cardiomyopathic cats without TE, and homocysteine metabolism may be abnormal in some felines. Several coagulation abnormalities leading to hypercoagulabil-ity have been identified in cats with aortic TE. Platelets from some cardiomyopathic cats have also been shown to be hyper-aggregable in response to adenosine phosphate (ADP) in vitro.

Immune-Mediated Hemolytic Anemia

Pulmonary thromboembolism is a major complicating factor to the high rate of mortality in IMHA. Because of the difficulties in antemortem diagnosis of PTE, most estimates of the number of dogs with IMHA and thromboembolism are based on necropsy results and range from 15% to 80%. Use of intravenous catheters, elevated bilirubin concentration, elevated alkaline phosphatase concentration, and decreased albumin have all been associated with development of pulmonary TE. Severe leukocytosis, left shift, and neutrophil toxic change may serve as laboratory markers of systemic thrombosis in some cases. Derangements in routine coagulation tests, prothrombin time (PT), partial thromboplastin time (PPT), and fibrinogen concentration are common in IMHA patients. Thrornbocytopenia is also common and severe thrombocytope-nia (platelets <50,000/uL) occurs in approximately 25% of IMHA patients. Fibrin (or fibrinogen) degradation products and D dimer are increased in greater than 50% affected of dogs. disseminated intravascular coagulation is also commonly diagnosed in IMHA.