Knowledge of the thromboembolic diseases has advanced significantly in veterinary medicine. Hypercoagulability is important to recognise since the development of thrombi can increase morbidity and duration and cost of hospitalisation, and in some cases lead to death. This will be a brief review of some of the common oral thromboprophylactic drugs used in veterinary medicine.
Types of thrombi
Before getting to the use of medications available to reduce the risk of thromboembolism in our patients, we’ll just spend some time on the two general types of thrombi and the causes of hypercoagulability in clinical practice. The current classification of thromboemboli is dependent on location.
Thrombi that form in the arterial circulation are composed primarily of platelets and fibrin while thrombi that form in the venous circulation are composed primarily of fibrin and entrapped erythrocytes. It is, therefore, reasoned that the platelet-rich thrombi in the arterial circulation are more likely to be initiated by platelet activation and thus, prevention of these thrombi is best provided by antiplatelet therapy such as aspirin and clopidogrel.
By the same reasoning, fibrin-rich thrombi in the venous circulation would be best prevented by anticoagulant drugs such as the heparins or rivaroxaban. For example in canine immune-mediated haemolytic anaemia (IMHA), most available evidence pertaining to thromboembolic complications is focused on pulmonary thromboembolism (PTE). The typical human model of PTE consists of pulmonary emboli broken from thrombi that have formed in the deep leg veins, or deep vein thrombosis. Dogs, of course, do not typically form thrombi in leg veins. The origin of the pulmonary embolus is often unclear and likely varies from patient to patient. The origin may, in fact, be the pulmonary circulation itself. As the thrombus initiating factors are difficult to predict in the dog, and canine IMHA patients have been found to have circulating activated platelets, prophylactic therapy that includes antiplatelet drugs is likely beneficial.
Risk factors for thromboemboli
What are the risk factors for our patients to develop emboli? Virchow’s triad describes the main factors which can predispose patients to thromboembolic events and includes endothelial dysfunction, hypercoagulability of blood and blood stasis/altered blood flow. The following table includes some examples of factors in clinical practice that may predispose to thromboembolic events.
The main 2 drugs evaluated in veterinary medicine are aspirin and clopidogrel (Plavix®).
Aspirin is a cyclooxygenase (COX) inhibitor. Thromboxane-A2 is produced by platelets via the COX enzyme and is a potent platelet agonist.
A dose of 0.5 mg/kg/day in a dog can inhibit normal platelet aggregation in an in-vitro setting. However, 30% of dogs can exhibit aspirin resistance and thus will not experience any antiplatelet effect following aspirin administration. It is believed that platelets cannot manufacture additional copies of COX so the blockade induced by aspirin is likely for the life of that platelet (6 days +/- 1.1 in dogs and cats). This is how ultra-low dose aspirin protocols work, a small amount of aspirin given daily will result in a blockade of all platelet COX in the body. Studies in dogs have evaluated ultra-low dose aspirin (0.5 mg/kg PO q 24h) with TEG and showed that aspirin failed to mitigate hypercoagulability consistently.
Things can get more complicated when considering cats and there is little consistent evidence that aspirin is an effective antiplatelet agent in cats. This is likely because feline platelets undergo aggregation via several substances and the role of thromboxane is minimal. High dose aspirin in cats (15 mg/kg PO q 48hr) can decrease platelet aggregation but again these effects are not consistent and adverse effects may occur at this dose so it is not recommended.
Clopidogrel is an antagonist of the P2Y12 receptor which is an ADP receptor found on the surface of the platelet. ADP is needed for platelet aggregation.
A dose of 1 mg/kg in dogs resulted in effective decrease in ADP-induced platelet aggregation as early as 3 hours post-oral administration. There are reports of human patients exhibiting resistance to the effects of clopidogrel but none such effects documented in veterinary patients. The biggest study in veterinary medicine evaluating aspirin vs. clopidogrel for thromboprophylaxis was for feline arterial thromboembolism (ATE). All the cats in the study had previously experienced an ATE 1-3 months prior and survived. Of the 72 cats evaluated, the median survival time of cats in the aspirin group was 190 days vs. over 400 days in the clopidogrel group.
Rivaroxaban is a newer anticoagulant drug. Unlike the other anticoagulants (warfarin, heparin), it comes in an oral form, requires less frequent dosage (typically q 12-24 h) and has a lower risk of haemorrhage. It is a factor Xa inhibitor which due to its specificity decreases the risk of bleeding.
A study evaluating its use in dogs with IMHA showed it to be well-tolerated but there is not enough evidence currently to know if it is superior to clopidogrel or aspirin for these dogs. Due to its specificity for factor Xa, normal coagulation panels (PT, PTT) cannot be used to monitor the drug’s effects and anti-fXa panels have to be performed. Few places aside from a few academic institutions have this capability. This medication is also more expensive than clopidogrel or aspirin which further limits its use at this time.
In conclusion, while there have been significant advances made in antiplatelet and anticoagulant therapy for dogs and cats further research is still needed. At this time clopidogrel is likely the most efficacious thromboprophylactic medication currently available for small animal patients.
Hogan, D.F., Fox, P.R., Jacob, K., Keene, B., Laste, N.J., Rosenthal, S., Sederquist, K. and Weng, H.Y., 2015. Secondary prevention of cardiogenic arterial thromboembolism in the cat: the double-blind, randomized, positive-controlled feline arterial thromboembolism; clopidogrel vs. aspirin trial (FAT CAT). Journal of Veterinary Cardiology, 17, pp.S306-S317.
Kidd, L. and Mackman, N., 2013. Prothrombotic mechanisms and anticoagulant therapy in dogs with immune‐mediated hemolytic anemia. Journal of Veterinary Emergency and Critical Care, 23(1), pp.3-13.
Mellett, A.M., Nakamura, R.K. and Bianco, D., 2011. A Prospective Study of Clopidogrel Therapy in Dogs with Primary Immune‐Mediated Hemolytic Anemia. Journal of veterinary internal medicine, 25(1), pp.71-75.
Morassi, A., Bianco, D., Park, E., Nakamura, R.K. and White, G.A., 2016. Evaluation of the safety and tolerability of rivaroxaban in dogs with presumed primary immune‐mediated hemolytic anemia. Journal of Veterinary Emergency and Critical Care, 26(4), pp.488-494.
Rackear, D., Feldman, B., Farver, T. and Lelong, L., 1988. The effect of three different dosages of acetylsalicylic acid on canine platelet aggregation. Journal of the American Animal Hospital Association, 24(1), pp.23-26.
Weinkle, T.K., Center, S.A., Randolph, J.F., Warner, K.L., Barr, S.C. and Erb, H.N., 2005. Evaluation of prognostic factors, survival rates, and treatment protocols for immune-mediated hemolytic anemia in dogs: 151 cases (1993–2002). Journal of the American Veterinary Medical Association, 226(11), pp.1869-1880.
Yang, V.K., Cunningham, S.M., Rush, J.E. and Laforcade, A., 2016. The use of rivaroxaban for the treatment of thrombotic complications in four dogs. Journal of Veterinary Emergency and Critical Care, 26(5), pp.729-736.