Thromboembolism

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Radiogrpahic appearance of a dog with pulmonary thromboembolism, showing right heart enlargement, enlargement of the pulmonary arteries, and blunting of the left caudal lobar artery[1]
Large pulmonary thromboembolism in a dog due to Dirofilaria immitis infection

Thromboembolism is a cardiovascular disease characterized by formation of intravascular embolism (clot).

Thromboembolism is a state in which the hemostatic balance shifts toward excessive platelet activation and fibrin deposition, leading to thrombosis[2]. During thrombotic episodes, dogs can have normo- or hyper-coagulable states[3].

Initiation of fibrin formation by contact activation requires proteolytic conversion of plasma factor XII to the protease factor XIIa on an endothelial surface. Factor XIIa activates the next zymogen in the coagulation cascade, factor XI, to factor XIa, which in turn converts factor IX to factor IXaβ. This series of reactions, referred to as the intrinsic pathway of coagulation, drives thrombin generation and fibrin formation. However, the importance of the intrinsic pathway, as a whole, to clot formation and stability at a site of injury is probably limited, as factor XII deficiency is not associated with abnormal bleeding[4].

Predisposing conditions causing hypercoagulability, blood flow stasis, or endothelial injury (e.g. orthopedic surgery, Dirofilaria spp infection) are likely triggers, as well as other mediators, such as neurohumoral factors[5].

In dogs, thrombus formation is also associated with increased matrix metalloproteinase activities.

Unlike cats, canine thromboembolism is nearly always a secondary phenomenon[6].

Although thromboembolism may occur anywhere within the cardiovascular system, common predilection sites include the aorta, kidneys and lungs.

Aortic thrombosis in dogs is more likely to involve local thrombosis in the distal aorta with embolization to the arteries of the pelvic limb resulting in chronic progressive ambulatory dysfunction[7].

A number of underlying disease processes are responsible for this condition including:

Depending on location of the thrombus, affected dogs present with acute fever, auscultatable murmur, lethargy, hindlimb paresis, dyspnea (due to pulmonary edema and pneumothorax[15]) or lumbar pain (acute nephritis).

Hematological findings with this condition include elevated BUN, creatinine, creatine kinase, cardiac troponin[16], D-dimer concentration and NT-proBNP levels[17].

Urinalysis usually reveals varying degrees of proteinuria with a urine protein-to-creatinine concentration ratio > 0.5[18].

A definitive diagnosis usually requires echocardiographic or postmortem examination.

Options for thromboprophylaxis available for clinical use in small animal patients are very limited, with heparin, aspirin and clopidogrel predominating[19]. Chronic warfarin administration is also well-tolerated and appears to be an effective, though costly, short-term and long-term alternative.

New orally-bioavailable anti-factor Xa products such as apixaban, have recently emerged as safe long-term preventatives of thromboembolism in human medicine and may eventually reach the veterinary markets[20].

Inhibition of matrix metalloproteinases, with drugs such as doxycycline (a nonspecific matrix metalloproteinase inhibitor), may also be an effective therapeutic intervention in the management of acute pulmonary thromboembolism[21].

The prognosis depends upon degree of cardiopulmonary compromise and patient response to therapy.

References

  1. Mitchell CW (2009) The imaging diagnosis of pulmonary thromboembolism. Can Vet J 50(2):199-202
  2. Kitrell D & Berkwitt L (2012) Hypercoagulability in dogs: treatment. Compend Contin Educ Vet 34(5):E1-E5
  3. Bauer N & Moritz A (2013) Characterisation of changes in the haemostasis system in dogs with thrombosis. J Small Anim Pract 54(3):129-136
  4. Cheng Q et al (2010) A role for factor XIIa-mediated factor XI activation in thrombus formation in vivo. Blood 116(19):3981-3989
  5. Han L et al (2010) Effects of thrombolytic drugs and a selective endothelin-1 receptor antagonist on acute pulmonary thromboembolism in dogs. Chin Med J (Engl) 123(4):395-400
  6. Neel JA et al (2012) Thrombocytosis: a retrospective study of 165 dogs. Vet Clin Pathol 41(2):216-222
  7. Winter RL et al (2012) Aortic thrombosis in dogs: presentation, therapy, and outcome in 26 cases. J Vet Cardiol 14(2):333-342
  8. Usechak PJ et al (2012) Thrombotic complications associated with atrial fibrillation in three dogs. J Vet Cardiol 14(3):453-458
  9. Boston SE et al (2011) Transtumoral plating as a novel method for palliative limb spare and thromboembolism in a dog with a distal radial primary bone tumor. Can Vet J 52(6):650-655
  10. O'Marra SK et al (2012) Investigating hypercoagulability during treatment for immune-mediated thrombocytopenia: a pilot study. J Vet Emerg Crit Care (San Antonio) 22(1):126-130
  11. Ridyard AE et al (2010) Evaluation of platelet activation in canine immune-mediated haemolytic anaemia. J Small Anim Pract 51(6):296-304
  12. Goodwin LV et al (2011) Hypercoagulability in dogs with protein-losing enteropathy. J Vet Intern Med 25(2):273-277
  13. Carretón E et al (2013) D-dimer deposits in lungs and kidneys suggest its use as a marker in the clinical workup of dogs with heartworm (Dirofilaria immitis) disease. Vet Parasitol Jan 16
  14. Kramer L et al (2011) Evaluation of lung pathology in Dirofilaria immitis-experimentally infected dogs treated with doxycycline or a combination of doxycycline and ivermectin before administration of melarsomine dihydrochloride. Vet Parasitol 176(4):357-360
  15. Sobel KE & Williams JE (2009) Pneumothorax secondary to pulmonary thromboembolism in a dog. J Vet Emerg Crit Care (San Antonio) 19(1):120-126
  16. Carretón E et al (2011) Dirofilaria immitis infection in dogs: cardiopulmonary biomarker levels. Vet Parasitol 176(4):313-316
  17. Haßdenteufel E et al (2012) NT-proBNP as a diagnostic marker in dogs with dyspnea and in asymptomatic dogs with heart murmur. Tierarztl Prax Ausg K Kleintiere Heimtiere 40(3):171-179
  18. Lake-Bakaar GA et al (2012) Aortic thrombosis in dogs: 31 cases (2000-2010). J Am Vet Med Assoc 241(7):910-915
  19. Smith SA (2012) Antithrombotic therapy. Top Companion Anim Med 27(2):88-94
  20. Wong PC et al (2011) Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor. J Thromb Thrombolysis 31(4):478-492
  21. Neto-Neves EM et al (2011) Metalloproteinase inhibition protects against cardiomyocyte injury during experimental acute pulmonary thromboembolism. Crit Care Med 39(2):349-356