The term arterial thromboembolism (ATE) identifies the embolisation of a clot in an artery in the systemic circulation. In cats, the initial blood clot tends to form inside the cavities of the left heart, particularly in the left atrium and left auricle. The clot, or a fragment of it, can subsequently flow to an anatomical location in the systemic circulation, normally represented by a “saddle” location at the aortic trifurcation, and subsequently compromise the blood flow in both external iliac arteries. Occasionally, emboli may travel into more distal arteries, compromising the blood flow to a single limb. The compromise in blood flow results in ischaemic neuromyopathy. The majority of cats presenting with ATE have underlying severe heart disease, although neoplasia and thyroid disease can also be associated with ATE.
Most cats experiencing a significant episode of ATE display signs of acute pain and paresis/paralysis of the affected limbs. The paws of the affected limb can appear pale or cyanotic (Figure 1), depending on the severity of the local ischaemia, and the limb extremity feels generally colder than non-affected limbs. In most cases, the “saddle” thrombus obstructs the external iliac arteries and consequently femoral pulses are weak or absent. However, if the thrombus lodges across the internal iliac arteries, femoral pulses may still be palpable despite the presence of pain and hindlimb paralysis/paresis. Conversely, femoral pulsation may be difficult to be detected in some cats and the use of a Doppler transducer can facilitate the identification of arterial pulsation in the affected limb.
Diagnosis can be challenging and is usually based on history and clinical signs. Free-roaming cats experiencing an episode of ATE can be found recumbent on the ground and in pain, leading their owners to think about a road traffic accident. Indeed, neurological disorders and musculoskeletal injuries should always be considered as differential diagnoses.
The ischaemic damage to the skeletal muscles secondary to ATE causes marked elevations of aspartate aminotransferase (AST) and creatine kinase (CK), which should be considered important, albeit non-specific, biomarkers of ATE in cats. The CK values, in particular, are so significantly elevated in feline ATE that measured values are often “off-scale”, requiring serial dilutions to allow a correct measurement. It should be noted, however, that both AST and CK have short half-lives in cats and their values peak at 6 to 12 hours, returning to baseline concentrations within 24 to 48 hours after the acute ischaemic event. Therefore, it is vital to measure these enzymes shortly after the onset of paresis/paralysis in order to rule out or confirm feline ATE. Hyperglycaemia, azotaemia, hypocalcaemia, hyperphosphataemia, hyperkalaemia and hypernatraemia can also be observed in feline ATE as non-specific signs of stress, cardiovascular shock, dehydration, rhabdomyolysis and reperfusion injury.
Another simple test that can be used in support of a diagnosis of ATE is the measurement of blood glucose obtained from the paretic or paralytic limb using a pinprick on the patient’s paw. It has been demonstrated that this is significantly lower than glucose concentration from the jugular vein or a large vein in an unaffected limb, whereas no significant differences are observed in other non-ambulatory subjects whose clinical signs are due to non-ischaemic lesions. A similar finding can be observed when measuring blood lactate from affected and unaffected limbs. Finally, elevated feline NT-proBNP can direct the attending clinician towards a diagnosis of underlying cardiac disease.
Thoracic radiographs may reveal cardiomegaly and signs of congestive heart failure (CHF). With sufficient training, clinicians can confirm the presence of concomitant heart disease, pleural effusion and pulmonary oedema via point-of-care ultrasonography. Sometimes, ultrasonography also allows identification of a thrombus (Figure 2) or spontaneous echo-contrast (“smoke”) within the heart chambers. More experienced ultrasonographers can visualise the point of obstruction using colour Doppler ultrasound examination of the abdominal aorta.
There is little scientific evidence and no consensus among clinicians regarding the ideal treatment of cats affected by ATE since any therapeutic approach aimed at relieving the vascular obstruction poses an increased risk of ischaemia-reperfusion (IR) injury. Indeed, rapid reperfusion can paradoxically induce and exacerbate tissue injury and necrosis. The mechanisms underlying IR injury are complex, multifactorial and involve generation of reactive oxygen species (ROS) that is fuelled by reintroduction of molecular oxygen when the blood flow is re-established, calcium overload, opening of the mitochondrial membrane (MPT) pores, endothelial dysfunction and pronounced inflammatory responses that can lead to cell death.
Surgical embolectomy appears the most logical approach; however, this is difficult due to the size of the affected vessels and the anaesthetic risks encountered in cardiac patients with cardiovascular shock. It is also an extremely unrewarding technique due to the high mortality associated with rapid reperfusion (IR injury). Physical thrombolytic therapy may also appear as a rational intervention. This can be performed with pressurised saline jets to physically dissolve the thrombus with clinical outcome comparable (if not inferior) to conservative management. Medical thrombolytic therapy (urokinase, streptokinase and tissue plasma activator) has shown mixed results, especially because of complications due to rapid reperfusion. In analogy with myocardial infarction in people, these expensive drugs are only effective if administered within hours of the occurrence of ischaemia, which is rarely possible in veterinary patients.
Conservative management is commonly recognised as an acceptable management for feline ATE cases, as long as pain is optimally controlled and patients undergoing treatment are properly selected. The rationale of this conservative approach is to support the patient until the development of collateral circulation to provide sufficient blood supply to the ischaemic areas. The time necessary for a satisfactory clinical improvement may range from days to months.
Euthanasia should be considered in cases of nonresponsive patients (lack of clinical improvement after two to three days or unsatisfactory pain control) or for those exhibiting signs highly associated with a negative prognosis (severe hypothermia, multiple limbs affected with complete loss of motor function, concurrent CHF). The fact that feline ATE is a devastating clinical manifestation is undisputable. However, if euthanasia with no attempt to treat is excluded from survival analyses, the number of cats that can survive to discharge can increase up to approximately 70 percent.
Parameters that should be evaluated to select potential survivors include having a rectal temperature above 37.2°C (98.9°F), the presence of limb motor function as evidenced by voluntary movement of limbs or positive withdrawal reflex, the absence of congestive heart failure (CHF) (ie pulmonary oedema, pleural effusion), having just a single limb affected (rather than two or more) and the absence of hyperkalaemia (ie potassium below 5mmol/l).
Of all the above parameters, rectal temperature is the strongest survival predictor, indicating that hypothermia is most likely a reflection of compromised systemic haemodynamic status rather than just local hypoperfusion.
Short-term, in-hospital, conservative management
The goal of conservative treatment of ATE is to guarantee adequate rest, comfort and pain relief, reduce the risk of further thrombus formation, improve systemic perfusion and preserve the function of the affected limbs, control effusions in cardiac cases complicated by CHF and provide additional support where needed.
The ideal analgesic for cats affected by ATE probably depends on different patient responses, individual clinician’s experience and drug availability. However, a variety of successful analgesic drugs have been reported, including butorphanol, buprenorphine, morphine, methadone and fentanyl.
During the acute phase (hospitalisation period), anticoagulative therapy should be considered to inhibit the coagulation cascade by interfering with the formation of one or more active coagulation factors. Intravenous or subcutaneous unfractionated heparin (UFH, 250 IU/kg SC q8h) can represent a good choice due to the rapid onset of its anticoagulation properties. Conversely, intramuscular administration of heparin should be avoided due to the risk of injection-site haematomas. Despite the popular use in veterinary practice, low-molecular weight heparin (LMWH; 80 to 150 IU/kg SC q8h) does not seem to offer any practical advantage over UFH for short-term treatment. Cats absorb and eliminate LMWH very rapidly and therefore require higher doses and more frequent injections of the LMWH to achieve the therapeutic effects observed in human patients. It is also considerably more expensive than UFH.
Correcting systemic perfusion is a challenging task, especially in cats with signs of CHF who should never receive aggressive fluid therapy. However, if patients are not in CHF and appear dehydrated, cautious fluid therapy would certainly be indicated. Acepromazine (ACP) has been advocated for many years as a suitable drug to improve systemic perfusion in cats with ATE. However, its hypotensive effect can also exacerbate the signs of shock and many clinicians consider the use of ACP inappropriate for cats with ATE. Similarly, external physical warming should only be performed very cautiously to avoid the risk of peripheral vasodilation and reduction of core perfusion. Little is known about the benefits of physiotherapy. Deep tissue massage of the affected areas and gentle forced movements of the affected limbs may be beneficial, as long as the manoeuvre does not evoke pain or discomfort. Soft beds and gentle turning of the patient may also improve the cat’s discomfort. Management of congestion in CHF cases is mostly based on administration of loop diuretics (ie furosemide or torasemide).
Cats affected by ATE are usually inappetent and nutritional support can be achieved with appetite stimulants (eg mirtazapine), naso-oesophageal tubing or oesophagostomy.
Long-term, conservative management at home
When the patient appears sufficiently comfortable and is regaining appetite, discharge should be discussed. Owners should be informed of the guarded prognosis and be prepared to support their cat at home. Cats with underlying cardiac disease should receive appropriate diuretic treatment.
Prophylactic anticoagulation therapy has been debated for several years. However, at present, there is limited scientific evidence to support a specific medication or protocol. Heparin (UFH or LMWH) treatment requires frequent parenteral administrations to achieve consistent anticoagulation and is not generally suitable for home treatment. Therefore, oral antiplatelet aggregation treatment may represent a more practical option.
Aspirin has been used for decades in the management of feline ATE due to its analgesic and antiplatelet effects at the standard dose of 25mg/kg PO q48 to 72h which equates to one paediatric aspirin tablet (75mg tablets in the United Kingdom) for an average sized cat. However, a lower dose (5mg/cat/PO q48 to 72h) seems associated with fewer side effects and similar recurrence rates of ATE when compared to the traditional dose, although a compounding pharmacy is necessary to obtain accurate low dosing. Nevertheless, very little is known about pharmacokinetics and clinical efficacy of aspirin in preventing ATE.
Clopidogrel (18.75mg/cat [a quarter of a 75mg tablet] PO q24h) is another inhibitor of platelet aggregation that seems to have fewer adverse effects in cats. It is commonly used in veterinary practice as a daily medication to prevent recurrence of ATE, often in association with aspirin. The clinical efficacy of clopidogrel for ATE prevention has been reported in cats without previous history of ATE in a recent study (Hogan et al., 2015), which demonstrated that cats receiving clopidogrel after their first episode of ATE are significantly less likely to develop a recurrent event compared to aspirin and had a longer median time to recurrence (443 days vs 192 days, respectively). In the same study, clopidogrel was also associated with a significantly reduced likelihood of the composite endpoint of recurrent ATE or cardiac death, with a longer median time to event (346 days vs 128 days). Therefore, clopidogrel administration has been shown to significantly reduce the likelihood of recurrent ATE compared with aspirin in cats. Although clopidogrel is well tolerated, one of the challenges of this therapy can be difficulty in administration since the medication has a bitter taste, which some cats intensely dislike (even those who take other medications without protest).
Novel oral anticoagulants (NOACs), which are also referred to as “non-vitamin K oral anticoagulants” (unlike warfarin), currently represent an alternative therapeutic approach. These drugs inhibit factor Xa (rivaroxaban and apixaban) or thrombin formation (dabigatran), ultimately reducing thrombus formation with fewer side effects compared to warfarin. An ongoing study (SUPERCAT Study) at the University of Georgia (USA) comparing rivaroxaban to clopidogrel in cats may help in determining if a direct Xa inhibitor can be, or should be, used in place of clopidogrel for ATE prevention in cats.
Long-term survival is negatively affected by the concomitant presence of CHF or other significant concomitant disease (eg neoplasia, renal failure, etc). Many survivors can experience a full recovery. However, a degree of neurologic or muscular dysfunction of affected limbs may persist in some patients. Recurrence rate of ATE is relatively low (approximately 30 percent), although recurrent episodes are often fatal or require prompt euthanasia. Congestive heart failure represents the most common cause of death (or euthanasia) in cats surviving initial acute episodes of thromboembolism (median survival time of 77 days, compared to 223 days in cats with ATE without concurrent CHF, in one study). Clear and effective communication with the carers of a cat affected by ATE is pivotal in the clinical management of this severe condition since the delivery of correct information on the available evidence of therapeutic options, as well as prognostic indicators, represents invaluable support in allowing informed decisions to be reached.