Abnormal clot formation is an important cause of morbidity and death in veterinary medicine that, broadly speaking, is due to aberrations in one or more factors of the Virchow triad: blood flow stasis, endothelial dysfunction, and hypercoagulability. Abnormal clot formation can lead to thrombosis, clot extension, and thromboembolism.
Clinically, abnormal clot formation can go unnoticed; however, thromboembolic disease of substantial size or major sites (eg, brain, lungs, aorta) can cause profound clinical signs, organ damage, and death. Thromboembolic disease complicates many common diseases in veterinary medicine.
Congenital Anticoagulant Disorders in Animals
Congenital deficiency of any anticoagulant protein has not been recognized in domestic animals. If such a condition exists in animals, it is probably incompatible with life.
Acquired Procoagulant Disorders in Animals
The presence of hypercoagulability is difficult to assess clinically in dogs and cats.
The importance of hypercoagulability and thromboembolic disease was not well defined in veterinary medicine until the advent of viscoelastic testing, which enables global assessment of hemostatic function in whole blood. Advantages of viscoelastic testing include evaluation of the viscoelastic properties of developing blood clots (including clot formation, kinetics, strength, stability, and resolution) and immediate detection of hyper- and hypocoagulable states.
Certain diseases in animals have been associated with increased risk of thrombosis. Cats with cardiomyopathy, especially those with an enlarged left atrium, can develop large thromboemboli in the aorta or brachial artery. Heartworm disease can also be associated with thrombosis in cats. Thrombosis has been reported in dogs with protein-losing nephropathies, hyperadrenocorticism, protein-losing enteropathy, neoplasia, heat stroke, sepsis, heartworm disease, and immune-mediated hemolytic anemia. Dogs with pancreatitis have been found to have evidence of hypercoagulability, and in some dogs the presence of multiple comorbid processes listed here increases the risk of thrombosis. Thrombi and thromboemboli have been reported in horses with systemic inflammatory diseases (eg, colic, laminitis, or equine ehrlichial colitis) and in instances of prolonged jugular catheter placement and infusion of drugs that irritate the vasculature.
Neoplasia is also a risk factor for hypercoagulability and likely associated complications, such as thromboembolic disease. Many cells and proteins involved in maintaining hemostasis are also involved in cancer growth, invasion, metastasis, and angiogenesis. Deep vein thrombosis is an important clinical complication in human cancer patients; however, whether the same is true in dogs with cancer is unknown.
In protein-losing nephropathies (eg, glomerulopathies, nephrotic syndrome, renal amyloidosis), a deficiency of antithrombin has been well documented. With a molecular weight of 57,000 kilodaltons (kD), antithrombin is similar in size to albumin (60,000 kD); therefore, glomerular lesions sufficient to result in albumin loss also result in antithrombin loss. Other abnormalities identified in renal disease include increased responsiveness of platelets to agonists, increased procoagulant activities, and decreased antiplasmin activity.
Hypercholesterolemia has been associated with increased risk of thromboembolism. It is hypothesized that endothelial and platelet membrane phospholipid concentrations are altered, leading to damaged vasculature and increased platelet responsiveness to agonists, respectively. Increased production of thromboxane via the cyclooxygenase pathway in platelets has been observed. Diseases characterized by hypercholesterolemia include hyperadrenocorticism, diabetes mellitus, nephrotic syndrome, hypothyroidism, and pancreatitis. All have been associated with increased risk of thrombus formation, often pulmonary thrombosis.
In cats with cardiomyopathy, endomyocardial lesions and turbulent blood flow through the heart chambers and valves secondary to altered myocardial functioning are thought to initiate thrombus formation. Specific deficiencies of anticoagulant or fibrinolytic proteins have not been reported. Although antithrombin is markedly increased in these cats, it does not provide protective benefits. Cats with cardiac disease secondary to hyperthyroidism are often treated not only with drugs to alter thyroid function, but also with drugs (eg, propranolol, atenolol, or diltiazem) that abate clinical signs of cardiac dysfunction.
Horses that have colic associated with endotoxemia have decreased plasminogen activity and protein C antigen concentration. Their mortality rate and risk of thrombus formation are increased. Laminitis is thought to be the end result of several diverse systemic disorders. Microthrombi in the vasculature of the hoof lamina have been identified in the early stages of laminitis. One theory is that endotoxin has direct effects on the vasculature and activates contact factors in the coagulation cascade. Ischemia of the lamina secondary to edema, vascular compression, and possible blood shunting at the level of the coronet also damage endothelium. When circulation is reestablished, reperfusion injury results, and the exposed subendothelial collagen promotes thrombosis.
Thromboprophylaxis (clot prevention) is standard treatment in some diseases of small animals, including protein-losing nephropathy and immune-mediated hemolytic anemia (1). In addition, clot prevention may be considered in small animals with multiple hypercoagulable diseases.
In an animal with thrombi or thromboemboli, it is imperative to diagnose and manage any underlying disease processes, and to provide good supportive care, including pain management.Maintenance of adequate tissue perfusion is critical.
Pearls & Pitfalls
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Dissolution of clots and prevention of clot extension by administration of anticoagulants (eg, heparin, direct factor Xa inhibitors) and antiplatelet drugs (eg, aspirin, clopidogrel) has had mixed success, in part because of a lack of evidence regarding effective dosing of these drugs for clot prevention.
Unfractionated heparin is most commonly used as initial treatment. Low-molecular-weight heparins have been evaluated in cats with aortic thromboembolism; however, the cost is appreciably higher, and no clear benefit has been shown when compared with unfractionated heparin.
Heparin facilitates the action of antithrombin, but to be effective, adequate antithrombin must be present. In dogs with protein-losing nephropathies or in horses with endotoxemia, plasma transfusion could be necessary before heparin therapy is effective. For clot prevention in dogs with immune-mediated hemolytic anemia, individually adjusting heparin doses according to anti-Xa activity has been found to improve outcomes, compared with nonindividualized (standardized) dosing (2).
Drugs that inhibit factor Xa (eg, rivaroxaban and apixaban) can be administered orally and do not require frequent monitoring. Their use is being studied in dogs and cats; however, expense is an issue. Currently, the only treatment shown to increase survival time after the initial thrombotic event in cats is clopidogrel (18.75 mg/cat, PO, every 24 hours longterm), which inhibits platelet function.
Use of fibrinolytic compounds to enhance dissolution of clots has shown promise in animals.
Tissue plasminogen activator (TPA), also known as alteplase, has more fibrin specificity than does streptokinase or urokinase and, therefore, provides more localized fibrinolytic effects. The main deterrent to the use of TPA is its high cost. A study of cats with aortic thrombosis that were treated with TPA found a risk for reperfusion injury and hyperkalemia after the clot dissolved (3).
Streptokinase is more available and less expensive; however, the therapeutic dose is difficult to determine. In addition, many animals have naturally occurring antibodies to streptokinase as a result of previous streptococcal infections.
Key Points
Many of the underlying diseases that cause DIC can also cause localized thromboembolism.
Aortic thromboembolism in cats with cardiomyopathy has a guarded prognosis, as well as risk of recurrence.
Thromboprophylaxis (clot prevention) is recommended for a number of diseases in small animals including protein-losing nephropathy and immune-mediated hemolytic anemia.
For More Information
Goggs R, Blais M-C, Brainard BM, et al. American College of Veterinary Emergency and Critical Care (ACVECC) Consensus on the Rational Use of Antithrombotics in Veterinary Critical Care (CURATIVE) guidelines: small animal. J Vet Emerg Crit Care (San Antonio). 2019;29(1):12-36.
deLaforcade A, Bacek L, Blais M-C, et al. 2022 update of the Consensus on the Rational Use of Antithrombotics and Thrombolytics in Veterinary Critical Care (CURATIVE) domain 1- defining populations at risk. 2022;32(3):289-314.
Also see pet owner content regarding blood-clotting disorders of dogs, cats, and horses.
References
Goggs R, Blais M-C, Brainard BM, et al. American College of Veterinary Emergency and Critical Care (ACVECC) Consensus on the Rational Use of Antithrombotics in Veterinary Critical Care (CURATIVE) guidelines: small animal. J Vet Emerg Crit Care (San Antonio). 2019;29(1):12-36. doi:10.1111/vec.12801
Helmond SE, Polzin DJ, Armstrong PJ, Finke M, Smith SA. Treatment of immune-mediated hemolytic anemia with individually adjusted heparin dosing in dogs. J Vet Intern Med. 2010;24(3):597-605. doi:10.1111/j.1939-1676.2010.0505.x
Guillaumin J, Gibson RM, Goy-Thollot I, Bonagura JD. Thrombolysis with tissue plasminogen activator (TPA) in feline acute aortic thromboembolism: a retrospective study of 16 cases. J Feline Med Surg. 2019;21(4):340-346. doi:10.1177/1098612X18778157
