Thrombosis (clot formation within a cardiac chamber or vascular lumen) and embolization (occurring when a clot fragment or other foreign material lodges within a vessel) commonly accompany feline myocardial diseases. The site of cardiogenic embolism is variable. Most commonly, the distal aorta is affected ("saddle" embolization). Various other organs (particularly the kidney) may become affected during embolic "showers."

PATHOGENESIS

One or more of three essential conditions must be present for thrombosis to occur: 1) local vessel or tissue injury; 2) circulatory stasis; and 3) altered blood coagulability. Collateral circulation plays a critical role in progression and resolution of clinical thromboembolic disease, and is modulated by vasoactive substances (e.g., serotonin and others) released by the clot and other substrates.

CLINICAL FINDINGS

Consequences of arterial thromboembolism depend upon: 1) site of embolization, 2) the severity and duration of occlusion, 3) degree of functional collateral circulation, and 4) development of serious complications. If thromboembolism is suspected, a minimum data base should include thoracic radiographs, ECG, echocardiogram, biochemical profile, urinalysis, FeLV/FIV test. Distal arterial embolism usually results in peracute clinical signs of lateralizing paresis, vocalization, and pain. Occasionally, intermittent claudication or right front paresis is reported. Signs of CHF (dyspnea, tachypnea, anorexia) or syncope may be present concurrently. Clinical signs are attributable to CHF and specific tissues or organs that are embolized (e.g., azotemia from renal infarction, bloody diarrhea from mesenteric infarction, posterior paresis from saddle embolus). More than 90% of affected cats present with a lateralizing posterior paresis caused by a saddle clot at the distal aortic trifurcation. Clinical signs are characterized by: Paralysis; Pain; Pulselessness (lack of palpable femoral arterial pulses); and Polar (cold distal limbs and pads) extremities. Anterior tibial and gastrocnemius muscles are often firm or become so from ischemic myopathy by 10 to 12 hours post embolization. In most cases they become softer 24 to 72 hours later. Acutely affected cats can move their back legs by virtue of flexing and extending the hip in a "dragging" manner, but they can not flex and extend the hock. Invariably, one leg is more severely affected than the other is. Nail beds are cyanotic and distal limbs are commonly swollen. Occasionally, a single brachial artery is embolized, causing monoparesis (usually right front leg). Intermittent claudication may be observed. In such cases arterial pulses may be palpated, foot pads feel warm (normal), and nail beds are not cyanotic. This frequently precedes subsequent, severe thromboembolic events. Less common sites of embolization include renal, mesenteric, pulmonary, coronary, and cerebral arteries. Most affected cats are clinically dehydrated and hypothermic.

Common clinical pathology abnormalities include elevated BUN and creatinine at presentation; elevated serum alanine aminotransferase and aspartate aminotransferase (SGOT) by about 12 hours and peak by 36 hours post embolization, indicating hepatic and skeletal muscle inflammation and necrosis; increased lactate dehydrogenase and creatine phosphokinase enzymes shortly after embolization indicating widespread cellular injury. Hyperglycemia, mature leukocytosis, lymphopenia, and hypocalcemia may be present. Acute hyperkalemia can result from reperfusion injury of skeletal muscles downstream from the embolus. Hypokalemia is a common consequence of anorexia and diuretic therapy. Coagulation abnormalities may be detected.

Echocardiography provides rapid, noninvasive assessment of cardiac structure and function, detects intracardiac thrombi when present, and assists in formulating appropriate therapy and prognosis. Multiple imaging planes are required to detect small mural thrombi. Spontaneous echo contrast ("smoke") may be present in the LA or LV, is associated with blood stasis, and is a harbinger for increased thromboembolic risk.

TREATMENT GOALS

1) Manage concomitant CHF or serious arrhythmias; 2) general patient support (nutritional supplementation, correction of hypothermia, prevent self mutilation); 3) adjunctive therapies--limit thrombus growth/ formation; and 4) prevent repeated events.

Thrombolytic Therapy

Streptokinase (90,000IU over 20 minutes followed by 45,000 IU CRI for 2-24h) and urokinase act by generating the nonspecific proteolytic enzyme plasmin through conversion of the proenzyme plasminogen. This causes a generalized lytic state with the incipient hazard of bleeding complications.

Recombinant tissue-type plasminogen activator (p-ta) has a lower affinity for circulating plasminogen and does not induce a systemic fibrinolytic state. It binds to fibrin in within the thrombus and converts the entrapped plasminogen to plasmin. This initiates a local fibrinolysis with limited systemic proteolysis. Tissue plasminogen has been evaluated in cats with spontaneous thromboembolism by Pion (0.25 to 1.0 mg/kg/hr IV [total IV dose, 1-10 mg/kg); 43% of treated cats survived the therapy and walked within 48h of administration, but 50% of the treated cats died during therapy.

Anticoagulant Therapy

Heparin. Heparin binds to lysine sites on plasma antithrombin III, enhancing its ability to neutralize thrombin and activated factors XII, XI, X, IX; this prevents activation of the coagulation process. Efficacy has never been established and its use for this indication remains controversial. Unfractionated heparins have been traditionally used, although low molecular weight heparins (LMWH) are now available and provide greater potential for efficacy and safety. LMWH has greater bioavailability and longer plasma half life than standard unfractionated heparins, and can be given as a fixed, subcutaneous dose once daily. Currently, dosage and efficacy of LMWH are under investigation. With unfractionated heparin, reported dosages vary widely; it may be administered at the time of admission as an initial IV doses (100-200 IU/kg), then 50-100 IU/kg subcutaneously q6 to 8 hours. The dose is then adjusted to prolong PT 1.5-2 times pretreatment values. Bleeding is a major complication.

Coumarin. The coumadin drug warfarin impairs hepatic vitamin K metabolism, a vitamin necessary for synthesis of procoagulants factors II or prothrombin, VII, IX, and X). The initial oral daily dosage (0.25 to 0.5 mg/cat) is adjusted to prolong the prothrombin time to twice the normal value; alternatively, it is adjusted by the international normalization ratio (INR) to maintain a value of 2.0 to 3.0. as follows: INR=[Cat Prothrombin Time) Control Prothrombin Time] ^ISI By this monitoring technique, evaluation of anticoagulant therapy with the PT is adjusted for variations in thromboplastin reagent and laboratory technique. The laboratory should provide an index of sensitivity of the thromboplastin reagent called an international sensitivity index (ISI). Warfarin and heparin therapies are overlapped for several days in humans because when coumarin treatment is initiated, the level of protein C (a naturally occurring antithrombotic protein) is decreased, creating a thrombogenic potential. Overlapping heparin therapy theoretically counteracts this transient procoagulant effect before other vitamin K-dependant factors (factors II, IX, and X) are affected by warfarin. However the author does not routinely overlap these therapies and has not noticed untoward effects.

Unsubstantiated Therapies

Acutely affected cats are high anesthetic risks for thrombelectomy due to coexisting CHF, arrhythmias, and DIC. Various medical therapies have been proposed to promote vasodilation (acepromazine, hydralazine), but their hypotensive side effects, non uniform arterial dilation, and poor response to innate vasoconstrictive chemicals (serotonin) limit their usefulness.

Critical Monitoring

Hyperkalemia can occur acutely as a result of re-perfusion injury. Thus, continuous ECG monitoring is valuable during the first 3 days of hospitalization. Periodic evaluation of BUN and electrolytes are important.

Supportive Measures

Relief of muscle pain is an important consideration during the first 48 hours after thromboembolism. Aspirin is administered for myalgia associated with ischemic myopathy, in addition to its antiplatelet effects. Epidural analgesia with morphine (0.05-0.1mg/kg) can be safe and effective when administered within the first 12-18 hours after embolization. It is important to maintain hydration, electrolyte balance, and nutritional support. If CHF has been resolved and anorexia persists, placement of a nasoesophageal feeding tube is advocated for alimentation, particularly during the first week of therapy. Self mutilation of distal limbs devitalized by an occlusive saddle embolus is common during convalescence and is characterized by excessive licking or chewing of the toes or lateral hock. Application of a loose-fitting bandage, stockinet, or other barrier is usually effective. Avoid placement of indwelling venous catheters into veins of legs devitalized by occlusive embolus.

Prevention of Arterial Thromboembolism

Effective strategies for preventing arterial thromboembolism have not been identified. Acquired cardiovascular disease coupled with complex interaction between platelets, blood components and other factors make it unlikely for simple remedies to have great efficacy. Strategies include anti-platelet drugs, anticoagulation drugs, and measures to limit hypercoagulability.

Aspirin. Aspirin is administered during and after a thromboembolic episode for its theoretical effect to limit further events. Aspirin induces a functional defect in platelets by irreversibly inactivating (through acetylation) cyclo-oxygenase. In the platelet, cyclo-oxygenase converts arachidonic acid to thromboxane A2 which induces platelet activation (through release of platelet adenosine diphosphate), and which stimulates vasoconstriction [in the vascular wall cyclo-oxygenase converts arachidonic acid to prostacycline which inhibits platelet aggregation and induces vasodilation]. The aspirin-induced acetylation of the cyclo-oxygenase enzyme is irreversible and persists for the life of the platelet which is 7 to 10 days, as does platelet aggregation and release response to various agonists. In cats aspirin (25 mg/kg, or 1/4 of a 5-grain tablet q48 -72h PO) effectively inhibits platelet function for 3 to 5 days and is relatively safe. Investigators have failed to demonstrate a survival difference between high dogs (>40mg/cat) versus low dose (5mg/cat) aspirin, although morbidity was reduced using the low dose. Gastrointestinal side effects and can be severe with over dosage. There is no evidence that aspirin is efficacious to prevent first time or recurrent thromboembolism.

Coumarin (see above). Warfarin can be considered for management of advanced myocardial disease. Because of potential bleeding side effects, however, most extol caution or reserve coumadins for attentive owners with indoor cats recovering from arterial embolism, and whose cat has high risk for thromboembolism.

Modulation of Hypercoagulability. Hyperhomocysteinemia is a risk factor for thromboembolism in people. Preliminary data suggests that a similar relationship may occur in some cats. Folic acid and B12 supplementation might be beneficial in cats with hyperhomocysteinemia or in cats recovering from thromboembolism.

Indicators of a Relatively Favorable Prognosis

 Resolution of CHF and/or control of serious arrhythmias,

 Lack of LA/LV thrombi or spontaneous echo contrast,

 Reestablishment of appetite,

 Maintenance of relatively normal BUN/creatinine and electrolytes,

 Return of limb viability/function (e.g., loss of swelling; return of normal limb temperature; return of motor ability),

 Return of femoral arterial pulses and pink nail beds,

 Lack of self mutilation, and

 Committed owner.

Indicators of a Grave Prognosis

 Refractory CHF or development of malignant arrhythmias,

 Acute hyperkalemia (from reperfusion of injured muscles),

 Declining limb viability (e.g., progressive hardening of the gastrocnemius and anterior tibial muscle group; failure of these muscles to become soft 48-72 hours after presentation; development of distal limb necrosis),

 Multi organ/multisystemic embolization (neurologic signs, bloody diarrhea, acute renal failure),

 History of previous embolic episodes,

 Presence or development of LA/LV thrombus or spontaneous echo contrast,

 Rising BUN/creatinine,

 Disseminated intravascular coagulation,

 Unresponsive hypothermia,

 Severe LA enlargement with arrhythmia and myocardial failure, and

 Uncommitted owner with limited financial resources.

REFERENCES

1.  Moore KE, Morris N, Dhupa N, et al. Retrospective study of streptokinase administration in 46 cats with arterial thromboembolism. J Vet Emerg Crit Care 10;245-257, 2001

2.  Fox PR. Feline myocardial diseases. In Fox PR, Sisson DD, Moise NS (eds): Textbook of Canine and Feline Cardiology Principles and Practice. 2nd Ed, Philadelphia, WB Saunders, 1999

3.  Laste NJ, Harpster NK. A retrospective study of 100 cases of feline distal aortic thromboembolism: 1977-1993. J Am Anim Hosp Assoc 31:492,1995

4.  Pion PD, Kittleson MD, Peterson SL, et al. Thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) in feline aortic thromboembolism: Clinical and experimental data. (Abstract). In: Proc 5th Am Col Vet Int Med Forum, 1987, p 925.

5.  Greene CE. Aspirin and feline platelet aggregation. J Am Vet Med Assoc 188, 1820, 1985

6.  Smith SA, Tobias AH, Jacob KA, et al. Arterial thromboembolism in cats: Acute crisis in 127 cases (1992-2001) and long-term management with low-dose aspirin in 24 cases. J Am Vet Int Med 17:73-83; 2003