Cardiogenic arterial thromboembolism causing non-ambulatory tetraparesis in a cat

Abstract

A 1-year-old oriental cat was presented with a peracute onset of tetraparesis and vocalisation. Clinical findings were suggestive of multi-site thromboembolic disease, and this was confirmed on post-mortem examination. An echocardiogram showed severe restrictive cardiomyopathy and spontaneous echogenic contrast. To the author's knowledge, this is the first reported case of tetraparesis secondary to cardiogenic arterial thromboembolic disease. Thromboembolic disease should be included as a differential diagnosis for any cat presented with a peracute onset of paresis or paralysis, even if there is no history of cardiac disease.

Arterial thromboembolism (ATE) has been reported commonly in cats secondary to cardiac disease. ¹ Most cats present with paraparesis or paraplegia, which may be more marked in one limb. Forelimb involvement is less common, but can occur in conjunction with hind limb paralysis/paresis or as an isolated event. The right forelimb is most often affected owing to the branching of the arterial supply from the heart. ² Cases involving one, two or three limbs being affected concurrently have been reported in cats, ³ but to the authors' knowledge tetraparesis has not been reported due to ATE. This report details a case of tetraparesis secondary to cardiogenic thromboembolic disease in a cat.

A 1-year-old, female spayed oriental cat presented to the clinic with an acute onset of flaccid tetraparesis and apparent pain and vocalisation. The cat had a previous episode 1-month prior of flaccid paralysis and acute lameness of the right forelimb, which resolved over the ensuing 2 weeks without veterinary intervention or treatment. There was no history of a traumatic event.

On presentation the cat was anxious, vocalising and appeared painful. Flaccid paralysis was present in all four limbs. Spinal reflexes and a deep pain response were absent in all four limbs. The cat was able to support itself in a semi-sternal position. The cat had been self-traumatising, and had a superficial excoriation on the right forelimb. Mentation was normal. All four limbs were subjectively cold on palpation and nail beds appeared cyanotic. Femoral pulses were absent bilaterally. Morphine sulfate (Morphine Sulfate Injection BP; Mayne Pharma) analgesia was administered prior to completion of the physical examination due to the extremely distressed state the cat was displaying and the difficulty in physically restraining and examining the distressed cat.

Auscultation of the thorax after sedation revealed a heart rate of 220 beats per minute and moderate tachypnoea (60 breaths per minute). A grade III/VI systolic left and right sided murmur was present. No arrhythmia was noted. Increased bronchovesicular sounds and occasional crackles were auscultated. The rectal temperature was 32.8°C. No other abnormalities were detected on physical examination.

A routine serum biochemistry profile (Table 1) revealed no significant abnormalities except for an elevated urea (suggestive of prerenal azotaemia), cholesterol, creatine kinase and total calcium. A haemogram (Table 2) showed mild neutrophilia, eosinophilia and haemoconcentration. Urinalysis showed mild haematuria, moderate glucosuria and a specific gravity of 1.025.

Table 1.

Biochemistry results.

Parameter	Value	Reference range (and unit)
Creatine kinase	725 *	0–155 IU/l
Aspartate aminotransferase	44	40–67 IU/l
Alanine aminotransferase	58	8–116 IU/l
Alkaline phosphatase	47	0–49 IU/l
Amylase	1038	495–1540 IU/l
Total bilirubin	1.0	0–17 umol/l
Total protein	78	56–85 g/l
Albumin	42	25–42 g/l
Globulin	36	24–48 g/l
Albumin/globulin ratio	1.17	0.55–1.52 (ratio)
Urea	11.5 *	7.1–10.7 mmol/l
Creatinine	88	44–134 umol/l
Phosphate	1.88	1.5–2.6 mmol/l
Calcium	2.92 *	1.6–2.53 mmol/l
Cholesterol	4.8 *	2.5–3.4 mmol/l
Sodium	158	143–158 mmol/l
Potassium	4.7	3.2–5.3 mmol/l
Sodium/potassium ratio	33.6	Ratio
Chloride	120	111–125 mmol/l
Bicarbonate	18	mmol/l
Anion gap	24.5	15–25 mmol/l

^*A value above the reference range.

Table 2.

Haematology results.

Parameter	Value	Reference range (and unit)
Red blood cell count	9.78 *	4.8–9×109/l
Haemoglobin	153 *	80–140 g/l
Haematocrit	0.46 *	0.24–0.45 l/l
Mean corpuscular volume	47	39–56 fl
Mean corpuscular haemoglobin	16	13–18 pg
Mean corpuscular haemoglobin concentration	336	290–340 g/l
White blood cell count	19.4	7–20×109/l
Neutrophils %	68	%
Neutrophils absolute	13.2 *	2.5–12.5×109/l
Lymphocyte %	21	%
Lymphocyte absolute	4.1	1.5–7×109/l
Monocytes %	1	%
Monocytes absolute	0.2	0–0.85×109/l
Eosinophils %	8	%
Eosinophils absolute	1.6 *	0–1.5×109/l
Basophils %	2	%
Basophils absolute	0.4	<0.14×109/l

^*A value above the reference range.

An echocardiogram was performed. Marked left atrial enlargement was noted on B-mode right parasternal short axis view (Fig 1). The left atrial to aortic ratio was 3.7:1 (reference range 1.25±0.18) ⁴ with the left atrium measured at 2.2 cm and the aorta at 0.6 cm. Spontaneous echocardiographic contrast was seen in the left atrium. Severe hyperechoic thickening of the left ventricular endomyocardium and increased diastolic left ventricular free wall (0.7 cm, under 0.6 cm considered normal) ⁵ and interventricular septal thickness (0.8 cm, under 0.6 cm considered normal) ⁵ were noted on B and M-mode right parasternal short axis views (Figs 2 and 3). Systolic anterior motion of the mitral valve was present. A regurgitant jet through the mitral valve had a peak velocity of 2.3 m/s, correlating with an increased left atrial pressure (between 21 and 26 mmHg; normal 0–5 mmHg in diastole). ⁶ These findings were consistent with restrictive cardiomyopathy (RCM) due to either endomyocardial fibrosis or endomyocardial fibroelastosis.

Fig 1.

B-mode right parasternal short axis echocardiogram view showing the marked enlargement of the left atrium. The left atria are 2.2 cm in diameter and the aortic root is 0.6 cm diameter. Image courtesy of Dr Chris Warman, Veterinary Radiology Ltd, Veterinary Specialist Group, Auckland, New Zealand.

Fig 2.

B-mode right parasterial short axis echocardiogram view of the thickened left ventricular free wall and IVS. Hyperechoic changes are noted on the endomyocardium. Image courtesy of Dr Chris Warman, Veterinary Radiology Ltd, Veterinary Specialist Group, Auckland, New Zealand.

Fig 3.

M-mode right parasternal short axis echocardiogram view of the thickened left ventricule. Left ventricular posterior wall (LVPW) 0.7 cm diameter. IVS 0.8 cm diameter.

A grave prognosis was given. Euthanasia was discussed and was declined by the owners. Supportive therapy was initiated with buprenorphine analgesia (Temgesic, Reckitt and Colman) 0.02 mg/kg SC q6–8 h, dalteparin (Fragmin; Pfizer) 100 U/kg SC once daily and benazepril (Fortekor; Pfizer Animal Health) 0.5 mg/kg PO once daily. Although the decision to treat with furosemide (Salix; Intervet) ideally would have been made based on evidence of cardiogenic pulmonary oedema on thoracic radiographs rather than clinical dyspnoea and tachypnoea, a trial treatment (2 mg/kg) was given subcutaneously and the cat's respiratory rate and effort were monitored. The cat's demeanour and breathing improved after the initiation of treatment, therefore, furosemide 2 mg/kg was scheduled for every 6 h SC. The cat remained stable for the next 12 h then became peracutely obtunded, dyspnoeic and unresponsive and died 24 h after presentation.

Post-mortem examination revealed an enlarged heart with a thickened left ventricular free wall (8 mm) and interventricular septum (IVS) (5 mm), and a thickened white left ventricular endocardium (Fig 4). Organising thromboemboli were seen in the distal aorta at the level of the external iliac arteries (Fig 5), and the left and right subclavian arteries (Fig 6). The heart weighed 20 g (6.19 g/kg, normal 3–4 g/kg). ⁷ The left atrium was dilated to four times the size of the right atrium. Organising thrombo-emboli were noted in the pulmonary arteries.

Fig 4.

Longitudinal section of the heart at necropsy. The left ventricular endocardium is white and thickened (arrow). The left ventricular free wall is 8 mm thick.

Fig 5.

Aortic bifurcation with thromboembolus (arrow).

Fig 6.

Thromboembolus in the right subclavian artery, elevated by forceps. Right subclavian artery with thromboembolus (at tip of forceps).

Significant histological findings included thickening (1–2 mm) of the endomyocardium of the left ventricular free wall, IVS and atrial wall by well organised fibrosis and multifocal areas of chrondroid metaplasia (Fig 7). Mild hypertrophy of the pulmonary arteriolar and bronchiolar smooth muscle was noted (Fig 8). Mild pulmonary interstitial pneumonia and oedema were noted. Peracute myofibre necrosis was seen in the right and left sartorius skeletal muscle. These findings were consistent with RCM with left ventricular endocardial fibrosis, with resultant thromboembolic disease affecting the left and right subclavian arteries, distal aortic trifurcation and pulmonary arteries. Congestive heart failure may have also been present given the finding of pulmonary alveolar oedema.

Fig 7.

Heart endocardial fibrosis and chrondroid metaplasia. Bar=100 μm.

Fig 8.

Lung pulmonary smooth muscle hypertrophy. Bar=50 μm.

ATE is a common complication in feline patients with cardiomyopathy. ⁸ In one study thromboembolic disease was the initial presenting sign of cardiac disease in 97/127 cats, as in the case reported here. ³ ATE is also a common cause of death in patients with cardiac disease. One study reported ATE to be the most common cause of death in a population of 250 cats with hypertrophic cardiomyopathy (HCM). ⁹ Thromboembolism prevalence seen during post-mortem evaluations has been as high as 48% of patients with HCM, 29% of patients with RCM and 25% of patients with dilated cardiomyopathy (DCM) and 14% of cats with excessive left ventricular moderator bands. ² One study showed an increased prevalence in the neutered male accounting for 63% of the study population. The same study showed HCM was the most frequent underlying cardiac disease, and most cases showed a significantly increased left atrial size, as measured by the left atrial to aortic ratio. ¹⁰ Average age of presentation is 7.7 years, although ATE has been reported in cats from 1 to 20 years old. Purebred cats are overrepresented. ³ Differential diagnosis for an acute onset of tetraparesis in a cat include fibrocartilagenous embolism, intervertebral disc disease, spinal neoplasia, cervical spinal trauma, metabolic changes, polyradiculoneuritis and toxic events. ^2,3,11

For ATE to occur, thrombus formation must occur in any of the left atrium, left atrial appendage or left ventricle. Risk factors include altered blood coagulability, local tissue or vessel injury and altered blood flow or circulatory stasis. ² Underlying altered platelet aggregation physiology has been shown in cats with cardiac disease leading to enhanced platelet activation. ¹² Many of the risk factors are present in cats with cardiomyopathy. Endomyocardial damage is common in all forms of feline cardiomyopathy, and chamber enlargement and/or reduced contractility result in increased chamber volumes and blood stasis. Impaired blood flow reduces the clearance of clotting factors. ² Once a thrombus forms it can embolise and lodge in a down stream artery with the anatomical site affected depending on the size of the embolus. ¹ Endomyocardial damage and severe enlargement of the left atrium were both seen during the post-mortem examination of this patient and organising thrombi were seen in both the left and right subclavian arteries and at the distal aortic trifurcation.

In studies involving human patients with cardiomyopathy, increased risk of cardiogenic ATE is seen in patients with enlarged left atria or left atrial appendages and in patients with ‘smoke’ or spontaneous echogenic contrast (SEC), as seen on echocardiography. SEC denotes an increase in blood echogenicity due to red blood cell aggregation. ¹³ The patient presented here had both an enlarged left atrium and SEC present during the echocardiographic study.

The most common place for embolus lodgement is the distal aortic trifurcation, ^1,14 with up to 90% of reported cats being affected by a ‘saddle thrombus’. ² Other reported anatomical sites to be occluded include the right brachial artery and less commonly, the left brachial, renal, mesenteric, pulmonary, coronary and cerebral arteries. ^2,3 This case reported here demonstrates embolism of both the left and right subclavian arteries can be seen concurrently with a ‘saddle thrombus’. Although it is impossible to prove these embolic events occurred at the same time, the peracute onset of tetraparesis in this patient suggests this is likely.

Clinical signs vary depending on the blood vessel embolised, the degree of collateral circulation and the severity and duration of the occlusion. Clinical signs are peracute in onset and are due to ischaemic neuromyopathy from loss of arterial blood supply, congestive heart failure or both. ¹ They include paresis or paralysis, pain, vocalisation, dyspnoea or tachypnoea. Physical findings commonly include paresis, paralysis, loss of arterial pulses, cold extremities, cyanotic nail beds, swollen or firm distal muscles, crackles, a gallop rhythm or cardiac murmur. ^1,15 Hypothermia can be seen in patients with distal aortic ATE and has been shown to be an important negative prognostic indicator in a number of studies. ^2,3

Elevated creatine kinase and azotaemia are both commonly seen on routine biochemistry in patients with ATE. ³ Creatine kinase increases shortly after an embolic event, therefore, it was unusual that this patient had such a modest creatine level. The blood sample was taken within 1 h of the onset of clinical signs and it may be that a greater elevation would have been noted on a subsequent blood analysis. Hyperglycaemia is commonly seen in cats with ATE associated with stress, as was seen in this patient. ³ Cardiomegaly is often noted on thoracic radiographs although 11% of cats have been reported to have normal cardiac silhouettes. ² Thoracic radiographs were not performed in this patient. SEC or a thrombus may be seen during echocardiography. This is associated with blood stasis and is considered a marker of a prothrombotic state. In human cardiology it is used in patients as a determinant of risk for a thromboembolic event, ¹³ and in cats is also considered a marker for increased thromboembolic risk. ³ In humans, however, the relationship between SEC and thrombus development is not fully understood. The presence of SEC has been shown to be platelet independent in vitro. ¹³ Nevertheless, clinically SEC is a reliable precursor of cardiogenic ATE events. ¹⁶ This patient had both SEC and thromboembolism.

This patient presented with tetraparesis and all four limb cyanosis and cold extremities, suggestive of thromboembolic disease. The acute onset of dyspnoea and tachypnoea noted by the owner and noted on physical examination at presentation could be related to congestive heart failure (44% of cats presented with concurrent congestive heart failure in one study), ³ pain or due to the presence of a pulmonary thromboembolism (PTE). PTE was noted on post-mortem examination in this cat. Financial constraints did not allow for thoracic radiographs to be performed. There was no indirect evidence on echocardiography to suggest a PTE as a cause for the presenting dyspnoea. The dyspnoea did not resolve with the administration of aggressive analgesia even though the patient's general demeanour did improve. However, it did improve with the administration of furosemide suggesting that this patient presented with congestive heart failure as well as ATE. A SC route of administration was chosen as IV access was not possible in this patient and the volume of furosemide precluded intramuscular administration. Analgesia and sedation prior to a full physical examination were also performed due to the high degree of distress and pain the patient was displaying. Ideally, a full physical examination would be performed prior to administering an analgesic with sedative effects, however, delaying this was not considered to be ethical for this patient.

Poor prognostic indicators include refractory congestive heart failure, malignant arrhythmias, acute hyperkalaemia, loss of limb viability, multi-organ or multi-systemic embolism, a left atria diameter of >2 cm, the presence of smoke or cardiac chamber thrombus, increasing azotaemia, hypothermia on presentation and an uncommitted owner or limited financial resources. ^1,2 The case reported here demonstrated many of these poor prognostic factors including severe left atrial enlargement, smoke, hypothermia on presentation, multiple concurrent thrombosed sites, limited financial resources and possibly, congestive heart failure. A decision to attempt treatment despite the grave prognosis was made by the owner.

RCM accounted for 20.7% of feline patients with cardiomyopathy in one study. ⁵ It is a primary myocardial disorder which is characterised by diastolic dysfunction and increased myocardial stiffness. ¹⁷ The aetiopathophysiology of this condition is not fully known, however, endomyocarditis of indeterminate cause and subsequent development of endomyocardial fibrosis is an hypothesised cause. ^17,18 As was seen in the case reported here, severe and extensive endocardial scarring including fibrous tissue deposition and chondroid metaplasia is seen on histopathological examination of the heart. Heart weight to body weight ratios are generally mildly to moderately increased. ^17,18

Treatment of ATE is multifactorial and can involve symptomatic supportive care (nutrition, analgesia, prevention of self trauma, wound management) thrombolysis, anticoagulant therapy and treatment for concurrent cardiomyopathy and congestive heart failure. The use of thrombolytic therapy is contentious as it is expensive and the survival to discharge rates are as good, or better in patients that do not receive thrombolytic therapy. ^1,3,14 There have been no prospective studies published to date to determine the safest and most effective anticoagulant for thromboprophylaxis in cats, and it is still unknown if using any anticoagulant improves morbidity and mortality rates. ¹ Low dose aspirin (81 mg every 72 h) and ultra low dose aspirin (0.5 mg/kg every 72 h), ³ warfarin, ² unfractionated or low molecular weight heparin (LMWH) ¹⁹ and the theienoyridine platelet antagonists such as clopidogrel ^8,12,20 have all been used. Clopidogrel has been shown to result in anti-platelet effects in healthy cats, however, the survival benefit in patients with ATE has not been demonstrated to date. ⁸ Recently studies involving the use of LMWH in cats showed a questionable anticoagulant effect which may not be uniform across individuals. ²¹ LMWH was chosen in this patient given its ease of administration, availability and the lack of necessity for regular monitoring of coagulation parameters. It is unlikely that administration of an alternative or additional antithrombotic medication would have improved this patient's survival outcome given the multiple concurrent poor prognostic indicators.

The patient died after a peracute onset of obtundation and respiratory distress. It may be that that patient died from a pulmonary artery thromboembolism as this was seen on the post-mortem examination. It is possible that the patient died from a fatal arrhythmia. ATE patients are often hypokalaemic and can present with cardiac arrhythmias. ² As per the owner's wishes, the patient was given a ‘do not resuscitate’ status while in hospital. An electrocardiographic evaluation was not performed when the patient died.

The patient in this case study had had a previous episode of flaccid paralysis in the right forelimb. This episode most likely represented an arterial thromboembolic event. An echocardiographic examination at this time would have undoubtedly shown this patient's underlying cardiac disease. There is a question as to whether the presenting tetraparesis may have been avoided if the patient had been diagnosed at the time of the first paretic event. It is unknown at this stage if instituting prophylactic anticoagulant therapy has a survival or morbidity benefit. ^1,3,14 A study is underway evaluating the use of clopidogrel and aspirin in patients with ATE. ¹² The results of this study may give clinicians a scientific basis for their recommendations regarding prophylactic antithrombotic treatment in asymptomatic patients or in patients that present with ATE secondary to underlying cardiomyopathy.

Arterial thromboembolic disease as a consequence to cardiomyopathies in cats carries a poor to guarded prognosis. ² As was seen in this report multiple concurrent emboli, hypothermia and clinical signs of congestive heart failure on presentation are poor prognostic indicators. This report indicates that cardiogenic arterial thromboembolic disease should be considered as a differential diagnosis for any feline patient presenting with a peracute onset of multiple limb paresis or paralysis, especially if arterial pulses are weak or absent or if there are indications of cardiac disease on physical examination.