Thromboembolic Medication Review

Thromboembolic Medication Review

Andrew Waxman, DVM, DACVIM (Cardiology)

Anticoagulants are useful in a range of conditions, from pulmonary/aortic thromboembolism to disseminated intravascular coagulation (DIC). The appropriate selection of medication will depend on whether the goal is the dissolution of a thrombus or the prevention of potential thrombosis (thromboprophylaxis). Only thrombolytics can break down a thrombus, while anticoagulants can indirectly support thrombus breakdown.

Antiplatelet Medications:

  • Aspirin is an irreversible inhibitor of cyclooxygenase 1 and 2 (COX-1, COX-2). In platelets, this enzyme catabolizes arachidonic acid into prostaglandins. These prostaglandins are a requirement for the production of thromboxane A2 (TXA2). TXA2 in platelets promotes platelet aggregation and vasoconstriction. Because platelets lack a nucleus, they cannot produce new active COX enzymes, thus rendering the platelet incapable of producing TXA2.1,2
  • Thienopyridines (clopidogrel) selectively inhibit ADP dependent platelet aggregation. They work independently of COX pathways. This category of drug does not work in vitro, indicating a likely hepatic metabolism to reach the active form.2,3
    • Pros:
      • Cheap, available over the counter (aspirin).
      • Many studies have set dosing recommendations and shown benefit.4
      • Well tolerated.
    • Cons:
      • Side effects include hematemesis, vomiting, and anorexia.1,2,4
      • Oral medications may be hard to administer to some cats. Clopidogrel is bitter.

Heparin:

  • Unfractionated heparin is a mixture of glycosaminoglycan molecules with variable anticoagulant properties. Heparin complexes with antithrombin, and this complex inhibits a variety of coagulation factors. One of the main activities is the inhibition of thrombin, which in turn stops the formation of fibrin as well as thrombin induced platelet activation. Metabolism of unfractionated heparin is variable as the larger molecules are cleared quickly and the smaller molecules undergo renal clearance.1,2,5
  • Low molecular weight heparin (LMWH) is produced from enzymatic processing of unfractionated heparin. LMWH has less activity against thrombin, but is suitable to block factor Xa. The smaller molecules have a more predictable half-life and undergo renal clearance.1,2,5
    • Pros:
      • Well tolerated and easily administered in one study.6
      • Few reported side effects.6
    • Cons:
      • Injectable formulations only.
      • Expensive (recently less expensive with coupons).
      • Requires monitoring of anti-factor Xa with levels extrapolated from humans. Levels may not correlate to clinical efficacy.7
      • Unproven dosing frequency.7
      • Study outcomes are conflicting.

Factor Xa Inhibitor:

  • Rivaroxaban (Xarelto) interrupts coagulation at the intersection of the intrinsic and extrinsic pathways and prevents thrombin generation.
    • Pros:
      • Oral medication
      • Predictable anticoagulant effect
      • Canine and feline studies show it is considered safe
      • Safe as dual therapy (clopidogrel/rivaroxaban)
    • Cons:
      • Expensive compared to Clopidogrel
      • Bitter, similar to clopidogrel10

Vitamin K Antagonists:

  • Warfarin or Coumadin are the most commonly used vitamin k antagonist anticoagulants. It functions by interfering with hepatic production of vitamin K dependent coagulation factors II, VII, IX, and X.1,2,8
    • Pros:
      • Drug is relatively inexpensive
    • Cons:
      • Requires frequent measurement of PT for monitoring.1,2,8
      • Diet, concurrent medications, and disease states can affect warfarin activity.2,8
      • Complication can include life-threatening hemorrhage.
      • Patients can become initially hypercoagulable when starting this medication as warfarin also inactivates the anticoagulants protein C and S that have shorter half lives than the coagulation factors.8

Thrombolytic Agents:

  • Include urokinase, streptokinase, and recombinant tissue plasminogen activators (rt-PA). These agents all share a mechanism to stimulate an endogenous pathway for thrombus degradation. 9
  • TPA is released by endothelial cells and will convert free plasminogen to plasmin, which digests fibrin.
    • Pros:
      • Facilitates degradation of in-situ thrombus
    • Cons:
      • Plasmin can degrade other proteins in the coagulation pathway leading to increased risk of hemorrhage. Can lead to catheter site hemorrhage or worrisome if recent trauma or surgery.
      • Have not provided strong evidence for increased survival. 9

-Andrew Waxman, DVM, DACVIM (Cardiology)

References:

  1. Smith SA, Tobia AH. Feline arterial thromboembolism: an update. Vet Clin Small Anim 2004; 34:1245-71.
  2. Lunsford KV, Mackin AJ. Thromboembolic therapies in dogs and cats: an evidence-based approach. Vet Clin Small Anim. 2007; 37:579-609.
  3. Hogan DF, Andrews DA, Green HW, et al. Antiplatelet effects and pharmacodynamics of clopidogrel in cats. J Am Vet Med Assoc. 2004; 225:1406-11.
  4. Smith SA, Tobias AH, Jacob KA, et al. Arterial thromboembolism in cats: acute crisis in 127 cases (1992020010) and long-term management with low-dose aspirin in 24 cases. J Vet Intern Med. 2003; 17:73-83.
  5. Hirsh J, Raschke R. Heparin and low-molecular weight heparin, the seventh ACCP conference on antithrombotic and thrombolytic therapy. CHEST 126:188S-203S.
  6. Smith CE, Rozanski EA, Freeman LM, et al. Use of low molecular weight heparin in cats: 57 cases (1999-2003). J Am Vet Med Assoc 2004; 225:1237-41.
  7. Van De Wiele CM, Hogan DF, Green HW, Sederquist KD. Antithrombotic effect of enoxaparin in clinically healthy cats: a venous stasis model. J Vet Intern Med. 2010; 24:185-91.
  8. Ansell J, Hirsch J, Poller L, et al. The pharmacology and management of vitamin K antagonists: the seventh ACCP conference on antithrombotic and thrombolytic therapy. CHEST 126:204S-233S.
  9. Maxwell, LK. Anticoagulants: Beyond heparin (Proceedings). DVM 360 Aug 1, 2009.
  10. Guillaumin, J. What is new regarding treatment and prognosis of FATE (Proceedings). IVECCS 2023.