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Feline arterial thromboembolism

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Category: Schede
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  • Disciplina: Medicina d'urgenza
  • Specie: Gatto

Arterial thromboembolism (ATE) or cardiogenic ATE (CATE) is an acute ischaemic disease resulting from the spontaneous formation of a clot in the heart chambers (usually in the left atrium) which, through the circulation, reaches the most peripheral arteries, obstructing them. Arterial thromboembolism is usually associated with heart disease and more rarely can be the consequence of trauma, hyperthyroidism, neoformations and sepsis.

 

PATHOPHYSIOLOGY

The formation of a thrombus, i.e. a large platelet aggregate and fibrin meshwork that adhere to the vascular endothelium or to the endocardium, requires the presence of one or more components of Virchow's triad:

  • injury to the endothelium;
  • stasis;
  • hypercoagulability.

Injuries to the vascular endothelium cause the exposure of collagen and activation of tissue factor, which start and amplify the coagulation process. After the propagation phase, the fibrin polymerises inside the platelet aggregate, giving rise to a thrombus that adheres to the vessel walls. As a result of the release of thromboxane A2, serotonin and other factors, the activated platelets aid propagation, vasoconstriction and new platelet aggregation.

The most common causes of vascular injuries are:

  • infections (e.g. sepsis);
  • immune-mediated phenomena (e.g. immune-mediated vasculitis, amyloidosis, phlebitis, arteritis, immune-mediated haemolytic anaemia)
  • infestations (e.g. cardiopulmonary filariasis)  
  • neoplasms (e.g. haemangiosarcomas);
  • ischaemic phenomena or phenomena resulting from tissue reperfusion (e.g. intestinal intussusception, obstructions);
  • trauma (e.g. burns, intravenous catheters).

Stasis and circulatory changes (turbulence, perfusion deficits) predispose to platelet aggregation; the most frequent causes are hypovolaemia, severe dehydration, heart diseases (e.g. valve alterations, cardiomyopathies, endocarditis) and haemodynamic imbalances (e.g. congestive heart failure, cardiac tamponade and pulmonary hypertension).

Hypercoagulability can cause the formation of clots, irrespective of their clinical manifestation. Feline platelets are markedly reactive both because of their high number and because of their greater serotonin content compared to platelets from other species.1 The hypercoagulability can be a result of disseminated intravascular coagulation, neoplasms, nephrotic syndrome and platelet disorders (e.g. autoimmune haemolytic anaemia, thrombocytosis, sepsis, Cushing’s syndrome, glomerular diseases).

The clinical manifestations of thrombosis depend on the type of vessel and on the size of the obstruction: when the thrombus obstructs an artery, ischaemia occurs; in contrast, when a vein is obstructed, blood stasis can develop. The most frequent sites of ATE in cats are:

  • aortic trifurcation (90% of cases);2
  • brachial artery;
  • renal arteries;
  • cranial mesenteric artery;
  • cerebral arteries;
  • pulmonary arteries.

 

EPIDEMIOLOGY

In the majority of cases the affected cats are of the common European breed, Abyssinians, Ragdolls and Burmese. All cats can potentially develop ATE; the predisposing factor most often detected is cardiomyopathy, which is diagnosed in 50% of cases of ATE,3 but not usually before the thrombosis. The percentages of distribution of the types of cardiomyopathy detected in cats with ATE are: 50% hypertrophic, 25% restrictive and 15% with moderator bands.4 In a study of 141 cats with cardiomyopathy, 16 had had at least one thromboembolic episode and the type of cardiomyopathy most frequently detected was hypertrophic cardiomyopathy.5 Male cats, being more predisposed to the development of hypertrophic cardiomyopathy, have a higher incidence of ATE.6

 

SIGNS

Cats with ATE are usually taken for an emergency visit because of an acute paresis, rarely involving just one leg, with a non-contributory past history.The patient is often tachypnoeic and exhibits restrictive respiratory distress characterized by fast, shallow breathing, which can be caused by pain, pulmonary oedema or a pleural effusion; some patients breathe with their mouth open and with their head extended on the neck. In rare cases the owner might report intermittent lameness. The signs of the paresis depend on the area vascularised by the artery(ies) affected by the thrombus and by the duration of the obstruction. In the majority of cases, a cat with arterial occlusion has a typical clinical picture with cold, paretic or paralytic hind or front legs (Fig. 1).

The paresis/paralysis may involve the entire leg up to the hip, or it may affect the limb more distally, from the hock or from the knee. In some cats even the tail may be affected by paresis/paralysis. The skin and the nail bed of the involved leg are painful, cold, cyanotic and do not bleed when cut. The femoral pulse does not have the same characteristics in the two limbs, or is almost entirely absent or completely absent in both limbs; the metatarsal pulse is absent. The animal may be normothermic or hypothermic and manifest signs of pain (vocalisations).

ATE is characterized by the “4 Ps”: Pain, Pulseless (absence of femoral pulse), Paralysis (paralysis, paresis) andPolar (hypothermiain the affected regions). Heart murmurs and/or a gallop rhythm are often detected through auscultation. In the case of intermittent lameness, the pulse may be detected, the foot pads have a normal temperature, the nail bed is not cyanotic and bleeds when cut. Thromboembolism of the renal, mesenteric or pulmonary artery can lead to organ dysfunction that can be diagnosed by biochemical tests and diagnostic imaging. Thrombi in the arteries of the central nervous system may produce signs ascribable to epilepsy or neurological deficits.

 

DIAGNOSIS

The absence of the femoral pulse, combined with the presence of pain, paralysis/paresis, cardiac auscultation positive for diseases and X-ray examination are generally sufficient to make a suspected diagnosis of ATE. Coagulation tests, vascular Doppler and ultrasonography confirm the suspected diagnosis. Angiography, magnetic resonance imaging, computed tomography and scintigraphy can be useful in some doubtful cases.

Blood tests:

The haematological and blood chemistry alerations that can be detected in the course of ATE are:

  • hyperuraemia (associated with high blood creatinine levels when the thrombus also involves the renal arteries: if both renal arteries are involved, the animal develops acute renal failure);
  • increases in alanine transaminase and aspartate transaminase levels (related to liver damage); the increases are detectable by 12 hours after the thromboembolic event and peak values are reached after 36 hours;7
  • an increase in lactate dehydrogenase;
  • an increase in creatine kinase;
  • hyperglycaemia;
  • lymphocytopenia;
  • hypocalcaemia;
  • hypercholesterolaemia;
  • higher levels of lactate in the ischaemic leg;
  • changes in coagulation parameters (hypercoagulation).

X-ray examination of the chest is always necessary as it can show signs of congestive heart failure (e.g. pulmonary oedema, pleural effusion and cardiomegaly), as well as possible spinal problems useful for excluding other diseases. Rarely,  radiographic signs may be absent. The electrocardiographic trace may highlight changes attributable to enlargement of the heart chambers and to conduction problems. In many cats it is possible to detect a pattern of left atrial and ventricular enlargement, ventricular tachyarrhythmias or a left bundle block, commonly found in the course of hypertrophic cardiomyopathy.

Echocardiography can be used to determine the presence of cardiomyopathy and to visualise thrombi (especially those in the left ventricle); initially the thrombotic formation appears as “cigarette smoke” inside the left ventricle. When thrombi are detected in the left ventricle through echocardiography, the left auricle must also be investigated carefully. Angiography is used to pinpoint the thrombus, to assess its extent, the type of obstruction and the collateral vascularisation. The contrast medium is not detected distal to the clot (sign of blockage). Non-selectiveangiocardiography makes it possible to define the nature of the heart disease, locate the embolus and determine its size.8 Before performing this examination, the animal must be stabilised.

The differential diagnosis includes:

  • trauma;
  • primary or metastatic spinal tumours (e.g.lymphoma);
  • inflammation;
  • intervertebral disc protrusion;
  • fibrocartilaginous infarcts;9
  • diabetic neuropathy;
  • myasthenia gravis.

 

TREATMENT

Treatment can be surgical or medical. Surgery is performed by removing the clot through embolectomy. This procedure can be direct (the clot is removed surgically from the abdominal aorta) or by means of a Fogarty catheter, balloon angioplasty or vascular stent.10Vascular catheters are used more frequently in human medicine, but not much in veterinary medicine, in part because of the small size of blood vessels in the cat. The surgical procedures require general anaesthesia, which can only be performed when the patient has been stabilised. Since patients with ATE often have heart disease, they are at high anaesthesiological risk; furthermore, the complications responsible for the high mortality rate (reperfusion injury and hyperkalaemia) discourage systematic use of surgery. The survival rate of patients treated surgically is of around 50%.11

Medical treatment consists of:

  • oxygen therapy in patients that have respiratory distress;
  • analgesia;
  • treatment of congestive heart failure and arrhythmias;
  • preventing the formation of new thrombi, thrombolysis;
  • rapidly restoring effective circulation and promoting collateral blood flow;
  • support therapy (nutrition, fluid therapy, prevention and treatment of hypothermia, prevention of self-mutilation).

Oxygen therapy during critical care can initially be performed using a “flow by” technique (oxygen tube near the nasal cavities 100-200 ml/kg/min) or an oxygen tent; nasal cannulae can be applied later for continuous administration of oxygen.

Analgesia is necessary since ATE, especially in the first 12-24 hours, causes an ischaemic neuropathy responsible for severe pain; handling a paretic leg can exacerbate the pain. Possible analgesics are morphine at a dose of 0.2-0.5 mg/kg i.v. or i.m. every 2-6 hours or as a constant rate infusion at 3 mg/kg/min, fentanyl administered as an initial bolus of 5-10 mg/kg followed by a constant rate infusion of 5-10 mg/kg/hour, or hydromorphone at a dose of 0.05-0.1 mg/kg i.m. or i.v. every 2-6 hours.

The main side effects of treatment with opioids in patients with ATE are respiratory depression (which can make the respiratory distress worse) and reduced gastrointestinal motility.  Acepromazine at a dose of 25-50 mg/kg i.v. every 8-12 hours can be used to reduce the state of anxiety and, thanks to the vasodilatation that it induces, to facilitate collateral blood flow. It should be remembered that acepromazine, because of its property of lowering blood pressure, can worsen already compromised perfusion.

Congestive heart failure, when present, can be treated during the emergency with oxygen therapy and furosemide at a dose of 1-2 mg/kg i.v. or i.m. every 8-12 hours. The specific treatment for heart diseases and arrhythmias must be instituted after specialist consultation.

Prophylactic antithrombotic therapy consists of heparin, warfarin or platelet antagonists. The drug most widely used for this purpose is heparin which, binding to antithrombin III, inactivates factors II and Xa, preventing activation of coagulation. Heparin does not dissolve already formed clots, but prevents existing clots from getting bigger and prevents the formation of new clots. Unfractionated heparin can be administered at a dose of 250 IU/kg s.c. every 6 hours. The dose administered must be capable of increasing the activated partial thromboplastin time (aPTT) 1.5- to 2-fold; the aPTT must be measured every 12-24 hours and before beginning heparin treatment. In an attempt to limit the spontaneous haemorrhages that can occur in patients receiving heparin, protamine (which neutralises anti-factor II activity) can be administered: the dose is 1 mg every 100 IU of unfractionated heparin if administered within 1 hour of the onset of bleeding, 0.5 mg protamine/100 IU of unfractionated heparin if administered within 2 hours and 0.25 mg/100 IU if used beyond 2 hours.12Enoxaparin is a low molecular weight heparin  with a longer half-life than dalteparin and is administered at a dose of 1.25 mg/kg s.c. every 6 hours. Its efficacy should be monitored by measuring anti-Xa factor. Dalteparin – which is another low molecular weight heparin - is administered at a dose of 150 IU/kg s.c. every 4-6 hours (the kinetics are different in cats and humans). The monitoring of dalteparin treatment should also be performed by measuring anti-Xa factor, but at least 48-72 hours after the start of therapy (the time required to reach stable values in the blood). Low molecular weight heparins are more expensive than sodium heparin and their monitoring is more complex. Protamine is not effective when low molecular weight heparins are administered since these latter inhibit the activity of factor Xa; the treatment for bleeding during the use of low molecular weight heparins is fresh plasma.

When using warfarin (a coumarin), which acts by inhibiting both the formation of the vitamin K-dependent clotting factors (factors II, VII, IX and X) and the production of protein C and S, coagulation must be monitored closely by measuring the prothrombin time (PT) or International Normalised Ratio (INR) before and after treatment; the INR is useful for avoiding problems related to the different measurement methodologies present on the market. If the PT or the INR have increased excessively, the warfarin therapy must be suspended and vitamin K1 administered at a dose of 1-2 mg/kg per os or s.c. On the third day after beginning treatment with vitamin K1, the PT or the INR is re-evaluated: if the values are still high, the vitamin K1 therapy should be continued; if instead the coagulation tests have normalised, warfarin can be administered again, halving the dose and combining it with heparin. Because of the high risk of systemic haemorrhages, the dose used is 0.06-0.09 mg/kg per os every 24 hours.

Aspirin (acetylsalicylic acid) is the most widely used platelet antagonist; it is administered per os at a dose of 0.5-1 mg/kg or 5 mg/cat every 72 hours.13 Acetylsalicylic acid blocks the production of the enzyme cyclo-oxygenase in platelets and in the endothelium; the action on platelet cyclo-oxygenase is irreversible (thus its effect lasts for the entire life of the platelets in circulation, which is around 7-10 days) and blocks the production of thromboxane A2 which is responsible for vasoconstriction and platelet aggregation. Aspirin’s action on endothelial cyclo-oxygenase is instead reversible (it lasts around 24 hours) and allows the conversion of arachidonic acid into endoperoxidase, which is converted into prostacyclin, a powerful inhibitor of platelet aggregation. The side effects of aspirin are vomiting, anorexia and, rarely, death, due to cats’ poor ability to metabolise the drug in the liver; the use of aspirin does not preclude the formation of new thrombi. Some authors recommend prophylactic administration of aspirin in cats with left ventricular dilatation, even if they have not yet had ATE.14

Clopidogrel, another platelet inhibitor, belonging to the thienopyridines (ADP receptor antagonists, together with ticlopidine), prevents the binding of ADP to its platelet receptor (ADP2Y12), making the bond between the GP IIb-IIIa receptor and fibrinogen impossible, with a consequent reduction in platelet aggregation. Clopidogrel can be administered at a dose of 19 mg/cat per os every 24 hours. It is difficult to monitor both of these drugs (aspirin and clopidogrel) because this requires an evaluation of platelet function. In cats, ticlopidine has been demonstrated to be able to decrease platelet aggregation at doses of 18.74 mg/cat per os every 24 hours; it can, however, cause vomiting and anorexia.5 Cats tolerate clopidrogrel better.16

GPIIb-IIIa inhibitors such as eptifibatide, are being evaluated in veterinary medicine. Eptifibatide inhibits GP IIb-IIIa (a platelet receptor) and its action is, therefore, limited to these cells. It acquires high affinity for fibrinogen and von Willebrand factor when platelet activation occurs, limiting the formation of platelet aggregates and coronary thrombi.16

When a clot forms in the bloodstream, natural thrombolysis can occur through the effects of plasminogen and plasminogen activators. Activating enzymes such as urokinase and tissue plasminogen activator (t-PA), breaks down a peptide bond in plasminogen which forms plasmin. Plasmin degrades fibrin and fibrinogen, giving rise to soluble degradation products. Streptokinase can also be used to dissolve thrombi. This enzyme, produced by some bacteria (e.g. Streptococcus pyogenes), is capable of inducing the formation of plasmin from plasminogen. It is administered at a dose of 90,000 IU/cat i.v. in 30 minutes and then 45,000 IU i.v. every hour for 3 hours.17 Streptokinase can cause systemic fibrinolysis, coagulopathies and a bleeding diathesis. When thrombolysis is effective in removing the vascular embolism, hyperkalaemia, reperfusion injury and metabolic acidosis can develop; these changes may cause the death of the patient. Reperfusion injuries are the result of accumulation of lactic acid, potassium and cytokines in the extra- and intravascular compartments of the regions distal to the thrombus.

When, as a result of the thrombolysis, blood flow is restored in the areas downstream of the thrombus, the accumulated substances are transported in the general circulation giving rise to systemic effects that can compromise already altered cardiac function. Streptokinase treatment should not be used in cats that have already been treated with heparin (because of the high risk of haemorrhages), in anuric patients, or in patients in which it is not possible to perform coagulation tests and monitor potassium concentration. t-PA has a greater specificity of action than streptokinase towards fibrin in a clot and has poor affinity for circulating plasminogen. The dose required to achieve clot lysis is not capable of activating circulating plasminogen or of inducing a state of systemic proteolysis. The recommended dose of t-PA is 0.25-1 mg/kg/hour up to a total of 1-10 mg/kg i.v.18 In a study19 aimed at evaluating t-PA in ATE, a mortality rate of 50% was observed during treatment, with the deaths caused by reperfusion injuries and hyperkalaemia. The subjects that survived showed an improvement in neuromuscular function and walking ability within 48 hours after the start of treatment (in cats with spontaneous resolution there can be a remission of signs in 1-6 weeks). Treatment with streptokinase and t-PA is rarely used because of the high mortality rate.

Besides specific treatment for ATE, it is essential to provide support therapy, which consists of supplying the animal with suitable nutrition (e.g. introducing a tube for enteral nutrition), administering fluids to restore effective blood flow and rehydrating dehydrated patients; self-mutilation should be prevented by fitting the animal with a ruff and administering effective analgesics.

 

PROGNOSIS

The average survival rate in cats treated with different therapeutic approaches is around 25 - 35%.20 The average survival is between 117 and 345 days,13 although it is shorter in cats with congestive heart failure. The prognosis depends on the type of thromboembolism, the time elapsed, the presence or not of areas of infarction in the organs and tissues distal to the thrombus and on the severity of the underlying heart disease. In spite of treatment and prevention, patients with ATE can develop a new thromboembolic event in the days and months after the first episode. Body temperature is considered one of the most important prognostic factors; in one study it was observed that patients with a temperature above 37.2°C had a 50% possibility of survival, while in patients with a temperature below 35.6°C during hospitalisation, the survival rate was below 25%.21 Patients that respond favourably to treatment require 7-14 days to obtain a gradual return of functions, while 6-8 weeks are necessary for full recovery.

 

References

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  2. Baty CJ et al: Natural History of Hypertrophic cardiomyopathy and aortic thromboembolism in a family of domestic shorthair cats. J Vet Intern Med 2001;15:595..
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  16. Bright JM, Downers K, Hellyer P.In vitro anti-aggregatory effects of the GP IIb/IIIa antagonist eptifibatide on feline platelets. J Vet Intern Med. 2002 Nov-Dec;16(6).
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