Feline Thromboembolic Disease

Thromboembolic disease (TED) is an important and relatively frequent complication of feline myocardial disease. Thrombosis represents clot formation within a cardiac chamber or vessel, and embolization occurs when a clot fragment lodges in a distal vessel. In the case of feline TED, the clot fragment usually arises from atrial thrombi or from atrial lesions and most commonly embolizes to the distal aortic trifurcation. Other less frequent sites of embolization include brachial, renal, celiac, and cerebral arteries. TED is frequently the first sign of underlying cardiomyopathy.

In a recent retrospective study of 127 cats with arterial thromboembolism (ATE), it was the first sign of cardiac disease in 76% of affected cats.

Physical occlusion of the aorta alone will not cause this syndrome. Vasoactive substances released by the thrombus/endothelium are believed to cause vasoconstriction of collateral vessels. Serotonin and prostaglandins are the likely vasoactive agents. This causes ischemic damage to peripheral nerves, muscle and sometimes skin.

The presence of a thromboembolic event usually indicates the existence of underlying cardiac pathology. Typically cardiomyopathy and left atrial enlargement are present. However, we and others have observed cats without obvious cardiomyopathy and without left atrial enlargement experience a thrombotic event. Neoplasia and hyperthyroidism (even in the absence of cardiac changes) are disorders with which TED has also been associated.

1. History:

• Acute onset of posterior paresis with:
  • Extreme pain
  • Hard/firm muscle groups in the affected legs
  • It is not uncommon for this to be the only clue to the presence of cardiomyopathy
  • Other signs of feline cardiomyopathy (dilated or hypertrophic) may be present

2. Physical Examination:

• Lower motor neuron paralysis of the affected limb with
  • Lower motor neuron sensorimotor neuropathy
  • Extreme pain
  • Firm muscle groups
  • Cyanotic nail beds
  • Weak to absent arterial pulse in limb
  • Cool to palpation
  • Failure of nail beds to bleed with short clipping
• May have signs of feline cardiomyopathy (dilated or hypertrophic) as per above
• Gallop cardiac rhythms and murmurs of AV valve insufficiency are frequently encountered, however it is reported that as many as 40% of cats with ATE may not have auscultable abnormalities.

3. Other diagnostic aids:

• As for feline cardiomyopathy depending on type
• Blood work indicates muscle necrosis (elevated CK and AST)
• Acute renal failure, metabolic acidosis, DIC, or hyperkalemia
• Blood work may indicate reduced GFR
• Blood work may indicate hyperthyroidism

4. Therapy:

• Surgery is not a real consideration.
  • Removal of the clot will not reverse the collateral circulatory “shut down” and anesthesia is very risky in these patients
• Medical therapy
  • Inhibit clot formation
    • Aspirin to prevent further thromboembolic events. As a cyclooxygenase inhibitor, it prevents formation of thromboxane thus preventing platelet aggregation.
      • Low dose ASA (5 mg/cat q 3 days) vs high dose ASA (81 mg/cat q 3 days)
      • There is some evidence to suggest that the low dose may be preferred to the traditional high dose.
    • Clopidogrel – 18.75 mg/cat SID (PO). Clopidogrel is a platelet function inhibitor that appears, in a limited study, to be safe and effective in cats.
      • Clopidogrel is safer and more effective than ASA in people
      • Results of a trial investigating the use of aspirin vs clopidogrel in cats with TED will be forthcoming (FATCAT trial).
    • Heparin may be useful (to prevent further thromboembolic events) – 200 units/kg IV as a loading dose followed 4 hours later by 150-200 units/kg SQ after obtaining ACT or PTT, May repeat again at 8 hours after obtaining ACT or PTT. Goal is 1.5-2 times increase in the pre-heparin ACT or PTT result. Once this is achieved, reduce to 100-150 units/kg Q 8 hours. Must monitor closely for hemorrhage. Heparin will not lyse the existing clot, but will prevent further clot formation via its anticoagulant effects. By enhancing antithrombin III activity, it inhibits coagulation factors II, IX, X, XI, and XII.
    • Low molecular weight heparin (LMWH) is an alternative to regular unfractionated heparin (UH). LMWH has higher bioavailability, longer half-life, less protein binding, and more predictable effects than UH. As such, LMWH is potentially easier and safer to use than UH. Because of its’ different structure, LMWH selectively inhibits factor X and does not prolong coagulation times. It is administered subcutaneously once to twice daily (see formulary for doses).
  • Pain management is a very important part of therapy. Opioids such as morphine, butorphanol, or fentanyl patches are typically used.
  • Supportive care: nutrition, warming, physical therapy, prevention of self-mutilation
  • Thrombolytic therapy with enzymes such as streptokinase and tissue plasminogen activator (TPA) has been used with some success to dissolve thromboembolic episodes. These agents can be quite expensive. Since many cases recover spontaneously due to recanalization or collateralization, studies are lacking to demonstrate an improvement with these agents over placebo. Use of TPA has demonstrated a 50% resolution of thrombi with ambulation in 48 hours of treatment. However, 50% died during therapy (due to hyperkalemia and metabolic acidosis [reperfusion syndrome] in 70%).
  • Treatment of concurrent CHF and/or malignant arrhythmias may also be necessary.
  • It is important to monitor respiratory status, heart rhythm (ECG), renal function, electrolytes (especially potassium), temperature, and mobility.

5. Prognosis:

• With complete aortic occlusion: 35% survive initial episode
• With suprarenal aortic thrombosis: grave prognosis due to acute renal failure, GI ischemia, spinal cord dysfunction and degeneration
• Partial embolization: 70% survive initial episode
• Spontaneous resolution occurs in over 50% of cases within 2 to 6 weeks.
• The recurrence rate of re-embolization appears to be high, usually within 6 months (with ASA).
• In one study of 100 cases (Laste et al. JAAHA 1995):
  • 63% died or were euthanized during hospitalization
  • 37% survived to live a median of 10 months, ave = 11.5 months
  • Re-embolization occurred in 50% of survivors
• In another more recent study of 127 cases (Smith et al. JVIM 2003):
  • 65% died or were euthanized during initial hospitalization
  • 35% survived (discharged) to live a median of 117 days (about 4 months)
  • Re-embolization occurred in 25% of survivors
• Persistence of low rectal temperature is associated with a poor short-term prognosis.
• Others report that survival is related to presence of co-morbid factors:
  • If there is no concurrent CHF – median survival time = 225 days
  • If CHF is also present – median survival time was
    • 77 days in one study
    • 184 days in another

6. Prophylaxis:

• Aspirin (81 mg/cat q 3 days or twice weekly) has been recommended for all cats with an enlarged left atrium, however there is no data to indicate if aspirin is any better than placebo. There is some evidence to suggest that low dose aspirin (5 mg/cat Q 3 days) is equally as efficacious with fewer side effects. Clearly many cats have recurrent bouts of thrombosis while on aspirin.
• Clopidogrel 18.75 mg/cat Q 24 hours has recently been advocated for thromboprophylaxis in cats. The results of a trial (FATCAT) comparing aspirin vs clopidogrel in cats with ATE should be forthcoming.
• Heparin enhances antithrombin III activity. Close monitoring for severe hemorrhage is necessary. Seek a 1.5 to 2 times increase in PTT above preheparin levels. Hemorrhage can be reversed with protamine sulfate.
• Coumarin (warfarin) inhibits synthesis of Vitamin K dependent clotting factors (II, VII, IX, & X). It will take about 3 days for coumarin to be effective (the delay needed for existing clotting factors to decline). Dose: 0.06 – 0.1 mg/kg q 24 hours PO. Monitor response via PT on day 0, 1, 2, 3, 5, 7, 10, 14, 21, 35, q 4wks. Vitamin K1 will reverse coumarin overdose. During the first three days of therapy patients may be in a “hypercoagulable state”. Some recommend concurrent use of heparin during this time. There is no clinical evidence to support that warfarin is superior to aspirin in the prophylaxis of ATE.
• As mentioned above, low molecular weight heparin (LMWH) may prove to be a safer alternative than heparin or coumarin in ATE prophylaxis. Dosage and efficacy are currently being evaluated.