Anticoagulants

Chapter 187 Anticoagulants



Elizabeth Rozanski, DVM, DACVIM (Internal Medicine), DACVECC, Daniel L. Chan, DVM, DACVECC, DACVN, MRCVS



KEY POINTS



• Thromboembolic complications may be a significant contributor to morbidity and mortality in critically ill patients.

• Anticoagulant therapy has its effect by altering only one aspect (blood factors) of the hypercoagulability (Virchow’s) triad.

• Anticoagulants affect either platelets or clotting factors.

• There are significant risks associated with anticoagulant therapy, so it should be undertaken with care.

• The choice of anticoagulant employed in a particular patient depends on the nature of the hemostatic disturbance, clinician preference, and the ability to monitor therapy.


INTRODUCTION


Anticoagulants impair the body’s ability to form clots. Pathologic blood clots may be formed at the site of a vascular injury, which is termed a thrombus, or may be formed elsewhere in the body (such as within the large leg veins) and detach and lodge in a distal location. Movement of a thrombus is termed an embolic event. The term thromboembolism is used to encompass either type of clot. Clots may also form in the venous or the arterial circulation and in the portal vein. Clinical signs associated with clot formation vary from absent or mild to acutely devastating. The resultant clinical picture may be of severe cardiovascular collapse, which is associated most commonly with massive pulmonary thromboembolism (PTE) or portal vein thrombosis with subsequent severe portal hypertension.


Thromboembolic complications are being recognized increasingly as an important contributor to patient morbidity and mortality in critically ill veterinary patients.1-3 Prevention of clot formation is therefore warranted for a wide variety of reasons, including cardiac disease, immune-mediated disease, protein-losing conditions, sepsis, and disseminated intravascular coagulation. The most appropriate dosage and appropriate anticoagulant for each condition and species has not been established in veterinary medicine but may depend on several factors such as the nature of hemostatic disturbance (arterial versus venous thrombosis), clinician preference, familiarity with the agents, and ability to monitor therapy. The goals of this chapter are to provide a review of the various anticoagulants and to describe their use in animals.


The normal procoagulant and anticoagulant systems act in balance to provide appropriate hemostasis associated with vascular injury and to limit excessive thrombosis that may be associated with decreased tissue perfusion or other end-organ damage. A hypercoagulable state develops when there are alterations in one or more of the following: blood characteristics (e.g., true hypercoagulability), vascular stasis, and endothelial damage or disruption. The relationship of these three components and thrombus formation is referred to as Virchow’s triad. In most critically ill animals, abnormalities likely exist in two or even all three of the components of Virchow’s triad. An important distinction is that arterial thrombi tend to be composed primarily of platelets and are formed in areas of rapid blood flow. In venous thrombosis, the clot tends to be composed of fibrin and red blood cells and usually is formed in areas of venous stasis or in patients with antithrombin (AT) deficiency.


In people, deep vein thrombosis and PTE are major manifestations of thromboembolic disease. In cats, the most common thromboembolic problem is aortic thromboembolism associated with cardiac disease. Thromboembolic conditions described in dogs include aortic thromboembolism, PTE, and portal vein thrombosis. To date, deep vein thrombosis has not been described in veterinary patients.


In light of differences in the pathogenesis of thrombi, anticoagulant strategies include altering platelet function or affecting clotting factor activity. For ease of classification, anticoagulant medications are commonly divided into (1) antiplatelet drugs, (2) oral anticoagulants, and (3) parenteral anticoagulants. Recommended dosages of these agents are listed in Table 187-1.



Table 187-1 Anticoagulants Used in Veterinary Medicine

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ANTIPLATELET DRUGS


Platelet aggregation at the site of endothelial damage or areas of blood stasis is often the first step in the development of a thrombus. Platelets initially adhere to the site of injury by reacting with exposed submembrane collagen and microfibrils on the damaged wall. Platelet adherence to the damaged endothelium is mediated by collagen and von Willebrand factor and results in the activation of the platelets. Activated platelets then change their discoid shape, becoming small spheres with many projections called pseudopods. Platelets stick to one another and form aggregates. This aggregation is mediated primarily by von Willebrand factor and fibrinogen. Certain substances further initiate and maintain platelet aggregation and activation. These substances include the exposed collagen fibers, adenosine diphosphate, serotonin, thrombin, and arachidonic acid metabolites (e.g., thromboxane A2).4 Antiplatelet drugs include aspirin, thienopyridine derivatives, and glycoprotein IIb/IIIa antagonists.



Aspirin


Aspirin is the most widely known and used antiplatelet drug. Aspirin acts to permanently inhibit cyclooxygenase (COX) which, in turn, inhibits the synthesis of thromboxane A2. Thus aspirin is a potent inhibitor of platelet aggregation in response to arachidonic acid, but much less so when stimulated by thrombin. Aspirin is most effective as an antithrombotic agent when administered in low dosages (0.5 to 2 mg/kg q24h) rather than at higher dosages.5 At high dosages, aspirin will also inhibit the production of prostacyclin and increase the likelihood of clinically significant gastrointestinal ulceration. Additionally, higher dosages may actually result in a hypercoagulable state in dogs.6 In humans it has also been recognized that some individuals may become “aspirin resistant,” which is inconsistently defined but reflects a failure to develop platelet inhibition at the standard dosages.7 Aspirin resistance may be induced by the co-administration of aspirin with other nonsteroidal antiinflammatory agents (e.g., ibuprofen). This acquired aspirin resistance has not been observed in patients treated concurrently with COX-2–specific agents.8


In vitro and in vivo studies have confirmed that aspirin is effective at inhibiting platelet function in dogs when used in low dosages.8-10 One randomized control trial evaluating dogs with glomerulonephritis treated all dogs with low-dose aspirin, leading some nephrologists to consider low-dose aspirin therapy to be a standard of care for affected dogs.11 Another retrospective study of dogs with immune-mediated hemolytic anemia included the addition of low-dose aspirin to the standard immunosuppressive therapy, and this report suggested increased short-term and long-term survival in these dogs compared with those that received conventional therapy.12 Neither of these studies specifically evaluated the effects or benefits of aspirin in these disease processes. The optimal use and dosage of aspirin as an antiplatelet drug in dogs remains to be determined. However, in low dosages, it is a safe, readily available, and inexpensive drug and should likely be considered if antiplatelet activity is deemed necessary.


As an analgesic, aspirin has been used widely in dogs at a dosage of 25 mg/kg PO q12h. At this dosage however, aspirin will decrease the total thyroxine level and may lead to severe gastrointestinal hemorrhage in some dogs.13,14 It is important to realize that the effects of aspirin therapy may be dosage specific, such that at analgesic levels the drug may lose its antiplatelet properties.


Aspirin has also been used in cats with cardiomyopathy judged to be at high risk of thromboembolic disease at the relatively high dosage of 81 mg/cat 3 times a week. Studies have established that aspirin at higher dosages is effective at inhibiting some stimuli to platelet activation in vitro.15,16 However, as long as 15 years ago, the rationale of treating all cats with aspirin to prevent thromboembolic disease was being questioned because of lack of efficacy and the potential for side effects.17 More recently, a single retrospective study advocated low-dose (5 mg/cat q72 h) aspirin as a long-term approach to preventing recurrence of arterial thromboembolism in cats with a prior episode.18 Thus, in cats, although aspirin effectively alters platelet function, actual clinical efficacy in preventing the devastating complication of arterial thromboembolism is lacking. Further controlled prospective studies are warranted to demonstrate protective benefits associated with aspirin therapy. Nevertheless, a low-dosage approach to aspirin therapy is at the very least unlikely to be harmful in cats affected with cardiomyopathy.

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Sep 10, 2016 | Posted by in SMALL ANIMAL | Comments Off on Anticoagulants

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