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Compendium May 2012 (Vol 34, No 5)

Hypercoagulability in Dogs: Treatment

by Dianne Kittrell, DVM, DACVIM, Larry Berkwitt, DVM, DACVIM

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    Hypercoagulability is a state in which the hemostatic balance shifts toward excessive platelet activationand fibrin deposition, leading to thrombosis. Although a definitive diagnosis is often difficult to make, identifying patients at risk for thromboembolism is critical. By identifying these patients and understanding mechanisms that contribute to hypercoagulability, clinicians can select protocols that aid in thrombus prevention. Several therapeutic options exist, including antiplatelet, anticoagulant, and fibrinolytic drugs.

    Hypercoagulable states include various acquired clinical disorders characterized by an increased risk for thromboembolism. Thrombosis is the formation of a clot or thrombus inside a blood vessel that obstructs the flow of blood through the circulatory system. Thromboembolism is the obstruction of a blood vessel by a thrombus carried by the blood from the site of origin to a distal site.

    Thrombosis is one of the leading causes of death in critically ill people despite the use of prophylactic anticoagulant therapy.1 Additionally, canine thromboembolic disease is an important clinical disorder of veterinary medicine that requires a treatment plan to address the acute ischemic crisis as well as the underlying disease. As the understanding of hemostasis evolves, the ability to identify patients at risk for thrombosis becomes increasingly important so that preventive measures and appropriate therapy can be instituted. This article reviews available therapies for hypercoagulability. A companion article reviews the pathophysiology of hypercoagulability and the major acquired abnormalities that are associated with thromboembolism in dogs.


    When hypercoagulability is diagnosed or suspected, therapy to prevent clot extension and recurrence is indicated. In experimental conditions, thromboemboli begin to dissolve without treatment within hours of formation.2 However, in naturally occurring disease, a prothrombotic tendency may persist. Medical treatment of thromboembolic diseases consists of inhibition of new thrombus formation by use of antiplatelet drugs, anticoagulants, and vitamin K antagonists and dissolution of existing thrombi with thrombolytic drugs (FIGURE 1).

    Key Facts

    • A definitive diagnosis of hypercoagulability is often impossible to make, and empirical therapy may be necessary to reduce the risk of recurrent thrombosis.
    • The risk for thromboembolism appears cumulative. Multiple conditions associated with hypercoagulability as well as factors leading to blood stasis or endothelial damage may occur in the same patient.
    • Identification of at-risk patients is important to instituting appropriate therapies to prevent thrombus formation, propagation, and recurrence.

    Information regarding blood flow and thrombus consistency is important in making appropriate therapeutic decisions. Thrombosis may occur in arteries or veins. The mechanisms of thrombus formation and risk factors involved vary between these two locations. Because of the high blood pressure and blood flow in arteries, blood stasis and patient immobilization do not significantly affect the risk for thrombus formation in these vessels, and hypercoagulability of blood has a relatively minor role. Instead, the high shear conditions present in most arteries result in a greater proportion of platelets in arterial thrombi.3 Strategies to inhibit arterial thrombogenesis therefore focus mainly on antiplatelet drugs.3 In venous thrombosis, on the other hand, blood stasis and patient immobilization are important risk factors, as are prothrombotic abnormalities. Venous thrombi form under low shear forces and tend to contain lower numbers of platelets.3 Early venous thrombi are platelet rich, but as they mature, they extrude platelets.3 Strategies to limit venous thrombogenesis focus mainly on anticoagulants, although antiplatelet drugs also are employed.

    Antiplatelet Drugs

    Antiplatelet drugs function to inhibit platelet aggregation and adhesion. There are three classes: cyclo-oxygenase inhibitors, adenosine diphosphate (ADP) receptor antagonists, and glycoprotein IIb/IIIa (GPIIb/IIIa) receptor antagonists.

    Aspirin, a cyclo-oxygenase inhibitor, is a standard antiplatelet drug. It irreversibly inactivates platelet cyclo-oxygenase, thereby inhibiting metabolism of arachidonic acid and subsequent generation of thromboxane A2. Thromboxane is a potent platelet agonist and acts as an amplification signal in platelet activation.

    Clopidogrel, an antiplatelet agent, is an ADP receptor antagonist. It is a thienopyridine derivative. Its active metabolite binds specifically to theplatelet ADP receptor, thereby inhibiting platelet recruitment and ADP-mediated activation of the platelet fibrinogen receptor (GPIIb/IIIa).

    GPIIb/IIIa receptor antagonists are potent antiplatelet drugs that block platelet–fibrinogen binding, which is the final common pathway for platelet aggregation.4 Abciximab, tirofiban, and eptifibatide are examples of GPIIb/IIIa antagonists.


    In veterinary patients, anticoagulant therapy should be instituted when a condition associated with hypercoagulability is diagnosed (TABLE 1) and the risk for thromboembolism is considered to be high. Anticoagulants do not lyse existing thrombi but inhibit their propagation and recurrence. Standard available heparin products include unfractionated heparin and low-molecular-weight heparins (LMWH). Warfarin is also used as an anticoagulant.

    Table 1. Known Etiologic Factors for Thrombotic Eventsa,b

    Disease Category



    • Hypercortisolism (hyperadrenocorticism and iatrogenic corticosteroid administration)
    • Diabetes mellitus


    • Immune-mediated hemolytic anemia
    • Lymphocytic enteritis (protein-losing enteropathy)


    Protein-losing nephropathy


    • Pancreatitis
    • Sepsis
    • Parvoviral enteritis
    • Dirofilariasis


    • Acute leukemias
    • Solid tumors


    • Infective endocarditis
    • Heartworm disease

    aCommon diseases selected for review of proposed or known mechanisms of hypercoagulability.

    bHackner SG, Schaer BD. Thrombotic disorders. In: Weiss DJ, Wardrop KJ. Schalm’s Veterinary Hematology. 6th ed. Ames, IA: Wiley-Blackwell; 2010:668-678.

    Unfractionated Heparin

    The anticoagulant activity of unfractionated heparin is due to its high affinity for antithrombin. Once bound with unfractionated heparin, antithrombin undergoes a conformational change that potentiates the inhibition of thrombin and activated factor X (Xa).5 Heparin anticoagulation is monitored using the activated partial thromboplastin time (aPTT), which evaluates the intrinsic and common coagulation pathways. The goal of anticoagulant therapy is to maintain a therapeutic range of 1.5 to 2.5 times either the patient’s baseline aPTT (if available) or the upper limit of the reference interval for aPTT.

    The primary limitation of unfractionated heparin is its molecular heterogeneity (molecular weight: 3000 to 35,000 daltons), which results in an anticoagulant response that varies widely among patients. Binding of unfractionated heparin to plasma proteins, platelets, and endothelial cells and the variability of plasma concentrations of heparin-binding proteins in patients with thromboembolic disease contribute to the unpredictable anticoagulant response. Antithrombin levels are reduced with unfractionatedheparin use, and to avoid rebound hypercoagulability with cessation of therapy, it is important to taper therapy over several days.6 Concurrent anticoagulation via platelet function inhibition (e.g., aspirin administration) has been demonstrated to reduce the risk of rebound hypercoagulability in people.7

    Low-Molecular-Weight Heparins

    LMWH are manufactured from unfractionated heparin with a uniform molecular weight of approximately 5000 daltons. Although LMWH also exert anticoagulant effects by binding with and catalyzing the activity of antithrombin, their molecular weight allows binding with antithrombin exclusively.8 By not binding with thrombin, LMWH have less influence on the common coagulation pathway than unfractionated heparin; this explains the lack of increase in aPTT in patients treated with LMWH.9 In people, treatment with LMWH elicits a more predictable anticoagulant response than does treatment with unfractionated heparin because of the better bioavailability, a longer half-life, and dose-independent clearance of LMWH.8 Alteration of platelet aggregation is a concern with the use of LMWH in people; however, it has not been found to be a problem in dogs.9


    Warfarin prevents the activation of the vitamin K–dependent coagulation factors II, VII, IX, and X and proteins C and S. Warfarin inhibits vitamin K epoxide reductase activity in the liver, thereby preventing the regeneration of vitamin K from the epoxide.10 The onset of action is 2 to 3 days. Rapid inhibition of proteins C and S results in a transient period of hypercoagulability; therefore, heparin should be started concurrently with warfarin for 3 to 5 days to prevent thrombosis.11 Warfarin therapy is adjusted based on the International Normalized Ratio (INR), which is considered to be superior to the prothrombin time. The INR was developed by the World Health Organization to address wide variations in the thromboplastins used for various prothrombin time (PT) tests between laboratories. It can be calculated by the formula (Patient PT/Control PT)ISI, with ISI being a value specific to the thromboplastin in each PT test.12 Maintenance of the INR between 2.0 and 3.0 minimizes the risk of hemorrhage without limiting the effectiveness of warfarin therapy.13 Close monitoring is necessary with warfarin therapy because the anticoagulant effect varies between patients and the most common complication is life-threatening hemorrhage.


    Thrombolytic therapy is aimed at lysis of existing thromboemboli. The potential benefits must be balanced against the risk of hemorrhage, which, in people, has been reported to be three times higher in patients treated with fibrinolytics than in patients managed with heparin alone.14 Traditional fibrinolytics include streptokinase, urokinase, and recombinant tissue plasminogen activator (r-tPA). Streptokinase is produced by β-hemolytic streptococci. Urokinase is a protease that is produced by the kidneys and is naturally found in urine. Streptokinase and urokinase exert fibrinolytic effects by forming complexes with plasminogen, which promotes the formation of plasmin and results in a lytic state. The r-tPA products activate plasminogen to form plasmin, which degrades fibrin and results in clot lysis. The r-tPA products activate bound plasminogen more rapidly than they activate freely circulating plasminogen; thus, they are described as clot-specific agents. Researchers in a 1996 canine study15 described the successful use of streptokinase in four patients with naturally occurring aortic thromboembolism (ATE). A 1998 case report described the successful use of r-tPA for dissolution of a distal aortic thrombus in a dog.16 Despite successful clot lysis, one major complication of thrombolytic therapy is life-threatening hemorrhage.2

    Although much of the documentation of reperfusion injury is from studies of feline ATE, the significance of this complication must not be overlooked. The authors of a 1988 review of r-tPA use in cats with naturally occurring ATE reported mortality rates as high as 50% and attributed these deaths to reperfusion hyperkalemia during clot lysis.17


    Hypercoagulability describes an imbalance of normal mechanisms involving clot formation or clot lysis that results in a tendency to favor clot formation. In recent years, increased attention has been given to thromboembolism associated with naturally occurring disease. Much of what is understood in animals is extrapolated from human literature. Treatment is typically reserved for patients with documented emboli. Prophylactic therapy also should be considered in patients with risk factors for thromboembolic disease. Aspirin, heparin, and warfarin have been the mainstays of antithrombotic therapy in veterinary medicine. Pharmacologic thrombolysis also may be a therapeutic option, although it is not as widely used in animals. Anticoagulant and fibrinolytic therapy must be tailored to maximize anticoagulant intensity while minimizing hemorrhagic risks.

    Downloadable PDF


    1.Williams MT, Aravindan N, Wallace MJ, et al. Venous thrombosis in the intensive care unit. Crit Care Clin 2003;19(2):185-207. 

    2. Dennis JS. Clinical features of canine pulmonary thromboembolism. Compend Contin Educ Pract Vet 1993;15(12):1595-1603.

    3. Hackner S. Antiplatelet drugs: what, when and how? ACVIM Forum 2006. http://www.vin.com/acvim/2006/. Accessed February 2008.

    4. Smith SA. Beyond heparin and aspirin: new anticoagulant drugs on the horizon. ACVIM Forum 2006. http://www.vin.com/acvim/2006/. Accessed February 2008.

    5. Lindahl U, Backstrom G, Hook M, et al. Structure of the antithrombin-binding site of heparin. Proc Natl Acad Sci U S A 1979;76(7):3198-3202.

    6. Darien BJ. Acquired coagulopathy V: thrombosis. In: Feldman BF, Zinkl JG, Jain NC, eds. Schalm’s Veterinary Hematology. 5th ed. Hoboken, NJ: Wiley-Blackwell; 2000:574-580.

    7. Laur MA, Houghtaling PL, Peterson JG, et al. Attenuation of rebound ischemia after discontinuation of heparin therapy by glycoprotein IIb/IIIa inhibition with eptifibatide in patients with acute coronary syndromes: observations from the platelet IIb/IIIa in unstable angina: receptor suppression using integrilin therapy (PURSUIT) trial. Circulation 2001;104(23):2772-2777.  

    8. Weitz JI. Low-molecular weight heparins. N Engl J Med 1997;337(10):688-698.

    9. Harnett BE, Kerl ME. Unfractionated and low-molecular-weight heparin for hypercoagulability in dogs and cats. Vet Med 2007;102(3):187-200.

    10. Brooks MB, de Laforcade A. Acquired coagulopathies. In: Weiss Dj, Wardrop KJ, eds. Schalm’s Veterinary Hematology. 6th ed. Ames, IA: Blackwell Publishing; 2010:654-660.

    11. Monnet E, Morgan MR. Effect of three loading doses of warfarin on the international normalized ratio for dogs. Am J Vet Res 2000;61(1):48-50.

    12. Fox PR, Petrie JP, Hohenhaus A. Peripheral vascular disease. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. 6th ed. Philadelphia, PA: Saunders; 2004:1145-1165.

    13. Hull R, Hirsh J, Jay R, et al. Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis. N Engl J Med 1982;307(27):1676-1681.  

    14. Goldhaber SZ, Buring JE, Lipnick RJ, Hennekens CH. Pooled analyses of randomized trials of streptokinase and heparin in phlebographically documented acute deep venous thrombosis. Am J Med 1984;76(3):393-397.

    15. Ramsey CC, Burney DP, Macintire DK, et al. Use of streptokinase in four dogs with thrombosis. JAVMA 1996;209(4):780-785.

    16. Clare AC, Kraje BJ. Use of recombinant tissue plasminogen activator for aortic thrombolysis in a hypoproteinemic dog. J Am Vet Med Assoc 1998;212(4):539-543.

    17. Pion PD. Feline aortic thromboemboli and the potential utility of thrombolytic therapy with tissue plasminogen activator. Vet Clin North Am Small Anim Pract 1988;18(1):79-86.

    References »

    NEXT: Minimally Invasive Abdominal and Thoracic Surgery: Principles and Instrumentation

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