Arterial thromboembolism in cats

Introduction

Arterial thromboembolism (ATE) occurs when a thrombus embolizes within a peripheral artery and typically manifests acutely or peracutely, with severe clinical signs. The apparent propensity for cats to develop ATE (the reported prevalence is approximately 0.3-0.6% 1,2) more than other species may be due to a variety of factors, with the most notable being the higher prevalence of myocardial disease and resultant left atrial enlargement. A large proportion of ATE cats are euthanized at initial presentation owing to the severity of clinical signs, but for those that undergo therapy and survive the initial stabilization, a significant number can regain motor function in affected limbs while maintaining a good quality of life. Unfortunately, the type and severity of any concurrent or underlying conditions may limit long-term prognosis in cats experiencing ATE.

Etiology and pathophysiology

Cats appear to have an increased propensity for intracardiac thrombus formation when compared to other species 3,4, which in most cases occurs as a result of advanced cardiac disease, leading to left atrial enlargement. Hypertrophic cardiomyopathy (HCM) is the most common cardiomyopathy encountered, but any cardiomyopathy or congenital defect (e.g., mitral stenosis) affecting the left side of the heart may lead to ATE. Rarely, infective endocarditis can cause systemic embolization of septic thrombi. However, not all cases of ATE occur as a consequence of cardiac disease; pulmonary neoplasia with subsequent tumor embolism is the most common non-cardiac cause of feline ATE 2, and in a few cases the condition can occur spontaneously, with no apparent cause identified.

Virchow’s triad describes the predisposing factors for excessive thrombotic activity, namely hypercoagulability, stasis of blood flow and endothelial dysfunction (Figure 1). Alterations to one or more points of the triad can lead to ATE, and in many cats with cardiogenic ATE all factors likely play a role. One significant factor identified as contributing to hypercoagulability in cats with ATE is platelet hyperaggregation 5,6, but hypercoagulability can be difficult to determine. The gold standard for assessment of feline platelet function is platelet aggregometry, but the test is very dependent on the operator’s skill and experience 5,6. There can be significant overlap in the range of values for activated partial thromboplastin time (aPTT) and prothrombin time (PT) between hypercoagulable and normal patients and, as such, there is limited utility in identifying hypercoagulable states with these tests, which are better suited to identify hypocoagulable states. Calibrated automated thrombography is another option that has recently been shown to be more sensitive than PT, aPTT, and rotational elastography 7 and in future this may have a role in measuring hemostasis in cats. Left atrial and/or left auricular dilation can cause stasis of blood flow and endothelial damage, both of which may be exacerbated by concurrent left atrial systolic dysfunction.

As previously noted, initial thrombus formation in most ATE cats occurs in the left heart before either a fragment or the entirety of the thrombus dislodges. The thrombus then enters the systemic circulation, and eventually becomes lodged in an artery of smaller diameter than itself (Figure 2). The formation and embolism of a thrombus does not only cause direct mechanical obstruction of the affected artery; it also leads to a cascade of vasoactive events resulting in vasoconstriction of the collateral circulation. Acute ischemia of the tissues supplied by the obstructed vessel(s) results from occlusion of the systemic circulation to the affected area, and clinical signs of ATE become apparent. In most cases, the outcome is systemic hypoperfusion and shock (either maldistributive shock, cardiogenic shock, or both).

Several studies support the role of vasoactive mediators in the pathogenesis of feline ATE 8. Studies also show that collateral circulation is preserved, and paralysis is prevented by administrating cyproheptadine (a serotonin antagonist) or high-dose aspirin (which inhibits thromboxane A₂) prior to thrombus formation 9,10.

Clinical presentation

There is a higher incidence of ATE amongst male versus female cats 1,2,11,12,13, probably reflecting the higher prevalence of HCM in males 2,14. Affected cats typically present between 8-12 years of age 1,2,11,12, with over-represented breeds including the Abyssinian, Birman, and Ragdoll 2 as well as Maine Coon, Himalayan, Siamese, and Persian cats 1,2,11; however, most affected cats are domestic short- or longhair 1,2,11,12.

ATE typically has an acute or peracute onset, with little to no warning. Affected cats experience significant distress, which can be harrowing for owners to witness. There is severe pain to the affected limb(s), and the cat will often vocalize and display overt signs of distress and discomfort (Figure 3). A variety of clinical signs may be observed, depending on the specific location of the thromboembolism within the peripheral circulation; this in turn is dependent on both embolus diameter and vessel diameter throughout the various levels of the arterial tree. Appendicular arteries are the most common sites for feline ATE, but non-appendicular arteries (e.g., renal, mesenteric, or cerebral vessels) can also be involved.

Distal aortic thromboembolism (saddle thrombus) at the level of the aortic trifurcation, characterized by paralysis or paresis of one or both pelvic limbs, is the most common manifestation of feline ATE. If both hind limbs are affected, one may be affected to a greater extent than the other. The next most common presentation is that of embolization within either of the brachial arteries, which results in lower motor neuron signs to the affected forelimb. Of cats diagnosed with ATE in a general practice setting, 20.8% of cats had one limb affected, 77.6% of cats had two limbs affected, and 1.2% of cats had three or more limbs affected 1. The affected limbs have overt neurologic deficits, and the cat will often drag these limbs. The degree of vascular occlusion will determine the severity of clinical signs, with partial occlusion resulting in more subtle signs. Depending on the embolism location, other signs (including central nervous system abnormalities, vomiting, or abdominal pain) may be observed 2, and diagnosis can be challenging in non-appendicular cases. Affected cats are commonly hypothermic, primarily as a result of systemic hypoperfusion and shock resulting from the vasoactive cascade following tissue ischemia; however, direct occlusion of the arterial supply to the hindquarters may also have a contributary role.

Evidence of underlying cardiac disease (e.g., murmur, gallop heart sounds, or arrhythmia) may be identified in some cats with ATE, but an absence of auscultatory abnormalities does not preclude the presence of underlying heart disease. The presence of gallop sounds in an affected cat has been associated with poor prognosis 14. Some cats may also exhibit signs of concurrent congestive heart failure (CHF), including tachypnea, dyspnea, orthopnea, lung crackles, and open-mouth breathing. 40-67% of feline ATE cases have concurrent CHF 2,12,13, but open-mouth breathing and tachypnea can also be a result of pain. The acute signs of ATE are often the first indicators of severe cardiac disease, with the majority of affected cats having no known history of heart disease prior to the ATE event.

Diagnostic findings

Stress hyperglycemia (from epinephrine and cortisol release) is commonly found, and prerenal or renal azotemia is also often noted; raised blood urea nitrogen (BUN) levels are more frequently reported, and are typically more severe, than elevations in creatinine 2,11. Prerenal azotemia results from poor systemic perfusion and shock; the BUN:creatinine ratio may be elevated. Renal azotemia occurs as a direct consequence of thromboembolism of the renal artery (although acute renal injury due to shock, or existing chronic kidney disease may also play a factor in some cases). Severe elevations in serum creatine kinase result from muscle ischemia, and hyperphosphatemia is also commonly observed. One of the most significant, and potentially life-threatening, complications in cats with ATE is hyperkalemia, which can be severe and often results from reperfusion injury once tissue perfusion is restored, although this abnormality can also be identified at presentation in some cases. Other electrolyte disturbances such as hypocalcemia and hyponatremia may also be noted. D-dimers may be elevated in affected cats, but as noted above, routine coagulation assays (such as PT and aPTT) are often within the normal reference range.

The diagnosis of appendicular ATE can typically be made on physical examination alone, with 5 cardinal signs associated with the condition, often referred to as the 5 P’s: pain, paralysis/paresis, pulselessness, pallor, and poikilothermy (Figure 4). On presentation, affected limbs are painful, often with firm muscles, and exhibit lower motor neuron signs, which may range from mild paresis to full paralysis. In one study, some motor function was retained in the affected limbs of approximately 34% of cats, and where an ATE event occurs in the forelimbs or in a single hindlimb there is a higher likelihood of motor function retention 2. In most cases, arterial pulses distal to the level of the embolism are absent or very weak, but remember that pulse quality may be difficult to determine in some cats that do not have ATE, especially forelimb pulses; detection can also be challenging in obese or uncooperative patients, especially in the face of acute pain. One method that may help in such circumstances is Doppler evaluation of the affected limb(s). The paw pads and nail beds of affected limbs should be examined; they are usually pale or even cyanotic, depending on the degree of tissue ischemia, and comparison to nonaffected limbs can be helpful (Figure 5). Poikilothermy (i.e., lower temperature in affected limbs compared to non-affected limbs) results from reduced or absent blood flow distal to the embolism. A 2.4°C (4.32°F) difference in temperature between ipsilateral affected and non-affected limbs on infrared thermography in cats has been shown to have excellent specificity (100%) and high sensitivity (80%) for ATE diagnosis 15. Further supportive evidence can be provided by differential measurements of blood glucose and serum lactate between affected and unaffected limbs. Glucose levels are lower and lactate is higher in peripheral venous samples from affected limbs distal to the embolism site when compared to that of samples from either central veins or non-affected limbs; a difference in absolute blood glucose concentration of ≥ 30 mg/dL between central and peripheral samples has been shown to have 100% sensitivity and 90% specificity in identifying feline ATE 16. Optimal cutoff values for identification of feline ATE using the serum lactate concentration difference between affected and unaffected limbs have not been determined.

Various diagnostic imaging modalities such as ultrasonography, angiography, computed tomography or magnetic resonance imaging of the implicated artery can be employed to confirm the diagnosis or investigate the presence of underlying causes, but these are rarely necessary.

Treatment and outcome

Acute stabilization and short-term management

Since the majority of cats with ATE present in severe pain and distress, a priority for initial therapy is prompt and effective analgesia, ideally with full mu opioid agonists (e.g., methadone, fentanyl, oxymorphone, or hydromorphone). Oxygen therapy is recommended for any cat in respiratory distress (Figure 6). However, a frank discussion should take place with the owners, explaining the various prognostic factors to consider when deciding to proceed with treatment versus euthanasia. Rectal temperature lower than 37°C (98.6°F) 1,2, bradycardia 2,11, absent motor function 2, having more than one limb affected 2 and confirmed concurrent CHF are all associated with reduced survival.

Following initial stabilization with analgesia and oxygen therapy, and without sacrificing patient stability, the cat should be assessed for evidence of CHF. Pulmonary edema may be identified on radiography, while the presence of pleural effusion may be determined using focused point-of-care ultrasound. Thoracocentesis should be performed in cats with significant pleural effusion. In cats with confirmed CHF (or when CHF is highly suspected) diuretic therapy (furosemide at 1-2 mg/kg IV or IM) should be administered and repeated at appropriate intervals until an effect is reached. The dosing interval may then be adjusted as necessary.

Signs of poor systemic perfusion and shock, which are present in most ATE cases, should be promptly addressed. Patients with severe decompensated cardiac disease may have cardiogenic shock, while tissue ischemia and release of vasoactive substances can lead to maldistributive shock; the specific approach to address the hypoperfusion will vary based on the nature of the shock, but this can be difficult to distinguish on presentation. Fluid therapy may be considered in dehydrated cats without evidence of CHF, but caution is emphasized with administering IV fluids to any animal with concurrent cardiac disease. Positive inotropes such as pimobendan (0.15 mg/kg IV or 0.3 mg/kg PO) may therefore be a more useful option for cats with decompensated cardiac disease and CHF, especially those with signs of systolic myocardial dysfunction; however, evidence of a definitive survival benefit with such agents is lacking. Poor systemic perfusion and shock results in low rectal temperatures and even generalized hypothermia in many cases, but active warming should be avoided until systemic perfusion is corrected, since it will only serve to worsen core perfusion and the clinical effects of shock as a result of peripheral vasodilation, which leads to more diversion of blood from essential organs.

Antithrombotic therapy should be started once the patient is stabilized in order to prevent propagation of existing thrombi and prevent new thrombi developing, but note these drugs do not cause lysis of existing thrombi. Either low-molecular weight heparin such as dalteparin (75-150 U/kg SC q6h) 17, or unfractionated heparin (250-300 U/kg q6h) 17,18 is recommended and is then typically discontinued 2-3 days after stabilization and the patient has been transitioned to oral antithrombotic medication.

Clopidogrel should be started as soon as the patient can tolerate oral medication. This drug antagonizes adenosine diphosphate, leading to reversible inhibition of platelet aggregation. An initial loading dose of 75 mg PO q24h per cat is recommended, followed by a maintenance dose of 18.75 mg PO per cat q24h 19. Many cats become aversive to clopidogrel owing to its apparent bitterness, and options to increase compliance such as formulations within gelatin capsules or flavored liquid should be considered. Clopidogrel is typically well-tolerated otherwise, although signs of excessive bleeding (e.g., bruising) may be seen at the higher dosage. Peripheral veins should be used for blood sampling in patients receiving this therapy, and appropriate compression bandages used to ensure hemostasis following venipuncture.

Clopidogrel has been shown to be more efficacious than aspirin for the secondary prevention of ATE 20, but since the mechanisms of action of the two drugs differ, dual therapy may be a consideration in some patients, although studies on the efficacy of this combination are lacking. Aspirin inhibits platelet aggregation by irreversible inhibition of thromboxane A₂ production on the platelet, and is usually administered at a dose of 20.25-81 mg per cat PO q72h. It should only be administered once the patient has resumed eating to reduce the risk of gastrointestinal ulceration.

Thrombolytic therapies, including tissue plasminogen activator 21,22, streptokinase 11, and urokinase 23 are not recommended in ATE cats; no survival benefit has been shown with these drugs when compared with standard-of-care antithrombotic therapies, and moreover significant complications have been observed with thrombolytic agents, in particular life-threatening hyperkalemia, most likely a manifestation of reperfusion injury.

The patient’s pain levels should be routinely assessed, with effective analgesia continued for a minimum of 24-48 hours. After this point the need for full mu opioid agonist analgesics greatly diminishes, and buprenorphine (a partial mu opioid agonist) may be sufficient. In addition, further diagnostics to investigate possible underlying causes should be performed once the patient is stabilized. These may include a hemogram, serum biochemistry, echocardiography or ultrasonography of any implicated arteries as indicated based on the patient’s initial assessment.

Reperfusion injury to ischemic tissues may lead to severe, life-threatening hyperkalemia and acidosis, and is one of the most significant complications encountered during therapy. All cases should be closely monitored for biochemical derangements, especially in the initial 48-72 hours following presentation. Reperfusion injury should be promptly addressed with appropriate therapies (e.g., administration of dextrose, insulin and dextrose, calcium gluconate, or sodium bicarbonate) as necessary. Manipulation of affected limbs (including physiotherapy) should be avoided for at least 72 hours, as it may cause an acute influx of potassium and lactate into the circulation, increasing the risk of reperfusion injury.

Long-term management

Clopidogrel (18.75 mg/cat) should be continued long term and has been shown to be superior to aspirin for the secondary prevention of ATE 20. Oral factor Xa inhibitors (e.g., rivaroxaban at 0.5-1 mg/kg/day) have been suggested as alternative antithrombotic agents for both short- and long-term management of ATE, but prospective data on their efficacy is limited. However, clinical studies of rivaroxaban are ongoing, and retrospective analysis of dual therapy using clopidogrel and rivaroxaban showed this combination was well tolerated with few adverse effects 24. It is currently recommended that such drugs should be administered in combination with, and not as a replacement for, standard clopidogrel therapy 19.

Low-molecular weight heparin or unfractionated heparin therapy can be continued at home long term in cats that have experienced severe ATE or those with recurrent ATE events, but these options are not routinely used for long-term management, and outcome data regarding this approach are limited.

Appropriate clinical therapy of cardiac disease is necessary in most cases of ATE due to the high prevalence of underlying heart disease. Cats with concurrent CHF require ongoing diuretic therapy with furosemide (0.5-2 mg/kg PO q8-12h). Renal function and electrolytes should be evaluated and, if normal, angiotensin-converting enzyme (ACE) inhibitors (either benazepril at 0.5-1 mg/kg or enalapril at 0.25-0.5 mg/kg, both PO q12-24h) should be considered, followed by close monitoring of renal function. Caution is required in cats with azotemia or known existing renal disease. Pimobendan (0.3 mg/kg PO q12h) may be used off-label in cats with evidence of systolic dysfunction. Antiarrhythmic therapies should be governed by the type and severity of any concurrent arrhythmias, and readers are directed to other resources for an in-depth review of long-term management of such cases 19.

Physiotherapy, including passive mobility exercises on affected limbs, is recommended as soon as the patient is stabilized, pain is well controlled and the risk for reperfusion injury has subsided. Owners should be educated on how to perform the exercises, and passive manipulation of the affected limbs should continue at home for at least several weeks until motor function improves and the risk for muscle contracture has reduced.

Prognosis

One study noted that only 12% of cats diagnosed with ATE in general practice survived at least 7 days after presentation 1; 61.2% of cats were euthanized at presentation, 8.8% were euthanized and 2.8% died within 24 hours of starting treatment, and overall only 27.2% survived beyond 24 hours 1. In contrast, survival rates of approximately 30-40% (and even up to 73%) have been reported in referral settings 2,11,12,13 although the influence of referral bias cannot be excluded as an explanation for these figures. The low overall survival rates in general practice may, conversely, reflect a perception of a hopeless prognosis and an inherent bias toward euthanizing affected cats on presentation. Moreover, survival rates in cats with only a single affected limb can be up to 70-80% 11,13 and can even be 90% if some motor function is retained at presentation 12. The clinical signs resulting from ATE often significantly improve after the first 24-48 hours of therapy, and many of the patients that survive longer than 48-72 hours will regain some or even all motor function within 1-2 months. Such outcomes suggest that consideration of therapy for at least the initial 72 hours is justified and could potentially result in increased survival rates overall. However, having two or more limbs affected 1,2, a history of previous ATE events 14, bradycardia 2,11, presence of gallop heart sounds 14, and rectal temperature lower than 37°C (98.6°F) 1,2 are all significant negative prognostic indicators, with rectal temperature lower than 37.2°C (98.96°F) at presentation associated with a survival rate of less than 50% 2.

Long-term complications may also be observed in cats that survive an ATE event. The incidence of muscle contracture can be mitigated by performing physiotherapy during hospitalization and continuing it at home following discharge. Necrosis and skin sloughing may occur on affected limbs secondary to ATE-induced ischemia, and can take several days to become apparent. Such lesions may be localized to individual digits or may affect larger areas of skin, and surgical management may be necessary. Amputation of the affected limb may be necessary if perfusion is so poor as to result in entire limb necrosis 2. Paw excoriations due to dragging of limbs, and self-trauma of affected limbs due to neuropathic pain, are complications that may be encountered in cases with persistent neurologic deficits. Gabapentin therapy may be considered for managing neuropathic pain in these cats, but its utility in cats with ATE has not been investigated. The risks and warning signs of these complications should be clearly communicated to owners, ideally prior to any decision on treatment versus euthanasia.

Preventative measures

As with many diseases, prevention is better than cure, but despite this, studies evaluating the efficacy of any therapy for the primary prevention (i.e., preventing a first ATE event in an at-risk patient) are lacking. Clopidogrel is currently recommended in at-risk cats for prevention of ATE 19 and is shown to have superior efficacy over aspirin in increasing time to ATE recurrence or cardiac death in cats following an initial ATE event 20. Identification of at-risk cats is probably the most significant barrier to prevention, since there is a high prevalence of underlying subclinical cardiac disease, which owners may be oblivious to, and investigation for an underlying heart disease should be prompted whenever a murmur, gallop sound, or arrhythmia is detected in asymptomatic cats. Various echocardiographic parameters have been associated with increased risk for ATE in cats with known cardiac disease. These include the presence of spontaneous echo contrast (smoke) (Figure 7), moderate-to-severe left atrial enlargement, reduced left auricular appendage velocities, reduced atrial fractional shortening, reduced left atrial ejection fraction, and increased left ventricular wall thickness, and are all considered indications for starting clopidogrel therapy in asymptomatic cats. Recently developed guidelines state that cats classified as having stage B2 cardiomyopathy (asymptomatic with moderate-to-severe left atrial enlargement) are considered at increased risk for the development of CHF or ATE, and recommend clopidogrel for all cats at this stage or beyond 19. The benefit of dual therapy with clopidogrel and either aspirin or a factor Xa inhibitor for prevention of ATE relative to therapy with clopidogrel alone is currently unknown. Recommendations are currently limited for cats with non-cardiogenic causes of ATE or patients with no identifiable underlying cause, since most prevention strategies are directed towards factors associated with cardiogenic ATE.

Conclusion

Whilst arterial thromboembolism (ATE) can be a peracute and dramatic presentation, with a typically guarded to poor long-term outlook, by no means is it a death sentence for all cats. With rapid intervention, careful clinical decisions and intensive care, the overall prognosis is variable and is dependent on the cause and the severity of presenting signs. Given that many clinical signs will resolve within the first 72 hours after the onset of ATE, consideration of therapy for at least this initial period is justified for many cases.