WSAVA Nov 2021 Proceedings - Flipbook - Page 25
likely to resolve in days to weeks.
Antithrombotics are not recommended in the treatment of hyperadrenocorticism in dogs, and a variety of diseases in cats (IMHA, PLN, exogenous use of corticosteroids, and hyperadrenocorticism).
Anticoagulation - When?
Antithrombotic drugs are recommended in patients at high risk of
thrombosis, or those that have already experienced thrombosis/thromboembolism. In patients with thrombosis, treatment involves antithrombotic
medications, treating the underlying disease, and supportive care.
Anticoagulation – What and How?
Antithrombotics diminish/inhibit the formation of new clots, but do not degrade existing clots. Amongst the antithrombotics, are antiplatelet drugs
and drugs that inhibit clotting factor activity (eg. Anticoagulants).
Platelet antagonists
Aspirin and clopidogrel are the most commonly used antiplatelet drugs.
Aspirin (acetylsalicylic acid) is widely availability (over the counter), easy
to dose (oral SID), and low cost. However, aspirin is less effective in dogs
and cats than in people. Aspirin inhibits COX-1, which prevents thromboxane A2 (TXA2) production leading to diminished platelet aggregation.
However, TXA-2 induced aggregation is not the only physiologic route to
activating platelets, and it is varying degrees of reliance on this mechanism may explain the different antithrombotic efficacy of aspirin across
species. Disadvantages of aspirin include lack of platelet specificity,
systemic side effects (such as GI bleeding), and potential for aspirin resistance. Aspirin can also be difficult to dose due to the large tablet size and
a low anti-platelet dose (0.5-1.0mg/kg PO q 24 hours in dogs). That being
said, the ideal dose of aspirin for thromboprophylaxis in dogs or cats is
not known. Reported doses in cats vary from 5-81mg/cat every 48-72
hours. Decreased dosing frequency is indicated in cats due to their relative deficiency of hepatic glucuronidation resulting in a longer elimination
half-life. Based on the FATCat study,3 clopidogrel is now recommended in
preference to aspirin for cats at risk of thromboembolism.
The primary mechanism of action of clopidogrel is inhibition of P2Y12, the thrombocyte ADP receptor. Like aspirin, clopidogrel is an oral
medication and undergoes hepatic metabolism, but unlike aspirin requires
metabolism to an active metabolite. This need for hepatic activation and
elimination results in a delayed onset of antiplatelet effects and significant variability in efficacy in people. Advantages of clopidogrel include
potential for greater anti-platelet efficacy (vs. aspirin) and more convenient dosing (2mg/kg/day dosing, 75mg and 300mg tablets). Potential
adverse effects, although uncommon, include hepatotoxicity, bleeding,
and gastrointestinal signs. The recommended clopidogrel dose is 1-3mg/
kg/day in dogs (may consider a 4-10mg/kg loading dose on day 1), and
18.75mg/cat/day for cats (ie. ¼ of a 75mg tablet, may consider a 37.5mg
loading dose).4
Anticoagulants
Anticoagulants include warfarin, heparins, FXa inhibitors (eg. rivaroxaban), and direct thrombin inhibitors. The CURATIVE guidelines suggest
that warfarin should not be used in dogs and cats because of a narrow
therapeutic index and lack of evidence of improved outcomes. Heparins
and rivaroxaban are used most commonly in veterinary medicine.
Unfractionated heparin (UFH)
Heparin and its derivatives disrupt secondary hemostasis by activating
antithrombin (AT), resulting in inactivation of thrombin and factor Xa. UFH
exists as many polymers of variable size and molecular weight. Potential
advantages of UFH include proven efficacy, easy monitoring (in-hospital
with ACT, or aPTT), lower cost than LMWH, availability of an antidote
(protamine), and rapid onset of action. UFH is most commonly used as a
CRI in veterinary patients undergoing extracorporeal therapy.5 Potential
disadvantages of UFH include the need for parenteral administration,
short half-life (necessitating IV CRI or frequent SQ dosing), unpredictable
response (in large part due to non-specific protein binding) and risk of
bleeding complications. As such, when UFH is used, therapeutic monitoring is recommended.6
Low molecular weight heparin (LMWH)
Heparin can also be processed to produce LMWH, which, owing to its
standardized size has more predictable biologic effects. By definition,
LMWHs have a lower average molecular weight than UFH preparations.
Unlike UFH which can bind to both AT and thrombin, most of heparin molecules in LMWH are only able to interact with AT alone (or AT and FXa),
such that the anti-Xa activity of LMWH is much greater than the anti-IIa
activity. Like UFH, LMWHs are very efficacious anticoagulants. In humans,
LMWHs have a long half-life facilitating once or twice-daily dosing, and a
more predictable response negating the need for laboratory monitoring.
Ideally however, monitoring is performed in the hospital, which requires
measurement of anti-Xa activity. Potential disadvantages include a longer
onset of action, higher cost, the need for SQ injection (not given IV), and
difficulty in reversing the effects (protamine less effective than for UFH).
Different LMWHs are available (eg. dalteparin, enoxaparin). The CURATIVE
guidelines suggest an initial dalteparin dose of 100-175 U/kg SC q8h in
dogs, and 75U/kg SC q6h in cats.4 Although limited data is available in
veterinary medicine to guide LMWH dosing, we aim for a target anti-Xa
activity of 0.5-1.0 U/mL 2h post-dose.7
Factor Xa inhibitors
Rivaroxaban was the first orally active direct factor Xa inhibitor available
on the market and is the most widely studied of the class in dogs and
cats. The CURATIVE guidelines suggest that the use of either direct
Xa inhibitors or LMWH in dogs and cats is reasonable for anticoagulation.8 Based on preliminary data the recommended dose is 1-2mg/kg/day
in dogs, and 0.5-1 mg/kg/day in cats.4
Duration of therapy with antiplatelet or anticoagulant drugs, depends on
many factors. Antithrombotic therapy should be life-long for incurable
diseases (eg. PLN, cardiomyopathy). In contrast diseases which are
expected to be controlled with medication (eg. IMHA) may just require
antithrombotic therapy for the high-risk period of their disease. Curative
Domain 5 provides information about how do adjust anticoagulant medication in patients that require surgery.9
References:
1. Goggs, R., et al. ACVECC CURATIVE guidelines: Small animal. J Vet
Emerg Crit Care 29, 12-36 (2019).
2. deLaforcade, A., et al. CURATIVE: Domain 1-Defining populations at
risk. J Vet Emerg Crit Care 29, 37-48 (2019).
3. Hogan, D.F., et al. Secondary prevention of cardiogenic arterial thromboembolism in the cat: The double-blind, randomized, positive-controlled
feline arterial thromboembolism; clopidogrel vs. aspirin trial (FAT CAT). J
Vet Cardiol 17 Suppl 1, S306-317 (2015).
4. Blais, M.C., et al. CURATIVE: Domain 3-Defining antithrombotic protocols. J Vet Emerg Crit Care 29, 60-74 (2019).
5. Ross, S. Anticoagulation in intermittent hemodialysis: pathways, protocols, and pitfalls. Vet Clin North Am Small Anim Pract 41, 163-175 (2011).
6. Sharp, C.R., et al. CURATIVE: Domain 4-Refining and monitoring antithrombotic therapies. J Vet Emerg Crit Care 29, 75-87 (2019).
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