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A Closer Look at Tissue Plasminogen Activator in Small Animals

By Megan Whelan, DVM, DACVECC, CVA
angell.org/emergency
emergency@angell.org
617-522-7282

Arterial thromboembolism (ATE) in cats can be a devastating disease with a poor outcome, often in seemingly “healthy,” young cats. One study showed of 250 cats that presented to general practices, there was a 61.2% euthanasia rate at presentation.1 Cats are typically treated conservatively with supportive care including pain medication, nursing care, and treating the underlying cause. The pictures below show one ATE cat that was medically managed and the end-stage damage of ischemic necrosis that can occur to the hindlimbs:

There are other interventions that are being used in ATE cats including human recombinant Tissue Plasminogen Activator (TPA) or Alteplase, which is a sterile lyophilized powder that should be kept refrigerated. This product is readily available and is a powder that contains an enzyme that has the property of fibrin-enhanced conversion of plasminogen to plasmin.2 This conversion results in local fibrinolysis or clot breakdown. There have been multiple studies in cats and dogs dating back decades including one study in 1992, describing the use of TPA for intraocular fibrinolysis in dogs.3 The last prospective study of TPA use was in 11 cats with ATE. There were different dosing protocols; Group A: received CRI of 5 mg IV of TPA over 4 hours, or an accelerated administration protocol; Group B: received 1 mg TPA bolused IV, then 2.5 g IV over 30 min, then 1.5 mg IV over 1 hour. The investigator could also administer another 5 mg dose of TPA if no side effects were noted and there was no clinical improvement. The study was terminated due to the high complication rates after administration of the drug. Adverse effects were seen in all 11 cats, and included azotemia (n=5), neurological signs (n=5), cardiac arrhythmias (n=5), hyperkalemia (n=4), acidosis (n=2) and sudden death (n=1). In this study ATE cats were included if the thromboembolic event was within 12 hours.4

Since the prior 2010 study, Altepase had been used in dogs and cats in various ways including to improve catheter function in patients receiving extracorporeal renal replacement therapy.5 There is also a case report using Alteplase intravesically in a dog to dissolve a urinary bladder clot.6

Each small vial of Altepase is reconstituted with 2.2 mL of sterile water and gently swirled, not shaken, until complete dissolution of the powder occurs. The cost per vial is about $150.00 and the concentration is 1 mg/mL. This “clot-buster” drug has been used in people with central venous access devices to help restore catheter function and in cases of myocardial infarction within 6 hours of clinical signs. The reconstituted TPA is good for 8 hours, and has been frozen and then used for up to 6 months duration. The solution has no preservatives so sterility cannot be guaranteed post the 8 hour time frame.7

Currently, Angell Animal Medical Center is participating in an international, multi-institutional, randomized, double-blinded clinical study evaluating the use of TPA in 40 cats with ATE. The primary investigator of the Bilateral Lysis of Aortic Saddle Thrombus with Early TPA (BLASTT) study is Dr. Julien Guillaumin from the Ohio State University College of Veterinary Medicine. There are specific exclusion criteria, but the main inclusion criteria is that 2-3 limbs need to be affected and the event must have occurred within 6 hours so that treatment can be initiated within 6 hours of the event. Then, either TPA or placebo (0.9% NaCl) is administered at 1 mg/kg with a maximum dose of 6 mg. 10% percent of the dose is given as a small bolus over a minute, followed by a 60-minute CRI. There is a limb scoring scheme that is then used, every 12 hours, to determine any notable changes to the pulses and motor in the limbs. The study is still being conducted, but the interim analysis of the 33 cats and the accompanying initial data is indicating that the earlier the intervention, the better.

The use of TPA remains controversial and should be determined on an individual case basis after discussion with the owner of the potential benefits and possible adverse side effects in his/her cat. For those clients, wanting to be more aggressive in treatment, TPA may be the drug to help cats. It is clear that more studies need to be conducted to elucidate the ideal timing and dose.

 

1 .Borgeat et al. Arterial Thromboembolism in 250 Cats in General Practice: 2004-2012. J Vet Intern Med 28:102-108; 2014.

  1. Cathflo Activase (Atleplase) Drug Insert, Genentech, Inc. South San Francisco, CA 94080-4900.
  2. Gerding et al. Use of Tissue Plasminogen Activator for Intraocular Fibrinolysis in Dogs. Am J Vet Res 54: 894-896, 1992.
  3. Welch et al. Prospective Evaluation of Tissue Plasminogen Activator in 11 cats with Arterial Thromboembolism. J of Fel Med Surg 12: 122-128, 2010.
  4. Langston et al. Use of Tissue Plasminogen Activator in Catheters Used for Extracorporeal Renal Replacement Therapy. J Vet Intern Med 28: 270-276, 2014.
  5. Pineda et al. Dissolution of Urinary Bladder Clots in a Dog with Alteplase. J Vet Intern Med 29: 1627-1628, 2015.
  6. Hogan, DF: Thrombolytic agents. In Small Animal Critical Care Medicine, Second Edition. Canada, 2015, Saunders.

Photos courtesy of Dr. Therese O’Toole

 

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