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Arterial Thromboembolism: Risks,

realities and a rational first-line
approach
Virginia Luis Fuentes

Journal of Feline Medicine and Surgery

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Journal of Feline Medicine and Surgery (2012) 14, 459–470

CLINICAL REVIEW

ARTERIAL THROMBOEMBOLISM
Risks, realities and a rational
first-line approach
Virginia Luis Fuentes

Cats and ATE Practical relevance: Feline arterial

thromboembolism (ATE) is a common
Arterial thromboembolism (ATE) occurs when a thrombus formed in but devastating complication of
one part of the circulation embolises to a peripheral artery (Figure 1). myocardial disease, often necessitating
Arterial blood flow is decreased to tissues distal to the thrombus as a euthanasia. A combination of endothelial
result of mechanical obstruction and vasoconstriction of the collateral dysfunction and blood stasis in the left atrium
blood supply. In cats, the source leads to local platelet activation and thrombus
of the thrombus is generally formation. Embolisation of the thrombus results
the left auricular appendage in severe ischaemia of the affected vascular bed.
(LAA) (Figure 2). Cats are With the classic ‘saddle thrombus’ presentation
particularly prone to ATE in of thrombus in the terminal aorta, the diagnosis
comparison with other species, can usually be made by physical examination.
which is partly (but not entirely) The prognosis is poor for cats with multiple limbs
explained by their high preva- affected by severe ischaemia, but much better
lence of myocardial disease. where only one limb is affected or motor function
is present.
Associated conditions Patient group: Cats with left atrial enlargement
secondary to cardiomyopathy are typically
Most cats presenting with ATE predisposed, although cats with hyperthyroidism,
have underlying cardiac dis- pulmonary neoplasia and supravalvular mitral
ease.1,2 Males are over-repre- stenosis may also be at risk.
sented, but this probably Management: Analgesia is the main priority, and
reflects the male predisposition severe pain should be managed with methadone or
to myocardial disease.3 Hyper- a fentanyl constant rate infusion. Congestive heart
trophic cardiomyopathy (HCM) failure (CHF) requires treatment with furosemide,
is the most common under- but tachypnoea due to pain can mimic signs of
lying condition associated with CHF. Thrombolytic therapy is not recommended,
ATE (being the most common Figure 1 Thrombus (arrow) present in the but antithrombotic treatment should be started
terminal aorta in a cat presented with ATE
type of myocardial disease), as soon as possible. Aspirin and clopidogrel are
but cats with any form of well tolerated.
cardiomyopathy (other than arrhythmogenic right ventricular cardio- Evidence base: Several observational studies of
myopathy) can be presented with ATE. The risk of ATE appears to be ATE have been reported. No randomised, blinded,
greatest with more severe forms of cardiomyopathy, irrespective of the controlled studies have been reported in cats at
specific type of myocardial disease. Cats with secondary myocardial risk, for either treatment or prevention of ATE,
disease are also at risk, which includes euthyroid cats with treated although such a study comparing aspirin and
hyperthyroidism.1 Some congenital heart defects such as supravalvu- clopidogrel in cats is
currently under way.

SUPPLEMENTARY VIDEO
Virginia Luis Fuentes
Two video recordings are included
MA VetMB PhD CertVR DVC MRCVS
in the online version of this article at
DipACVIM DipECVIM-CA (Cardiology)
DOI: 10.1177/1098612X12451547
Department of Veterinary Clinical Sciences,
The Royal Veterinary College,
Hawkshead Lane, North Mymms,
Hatfield, Hertfordshire AL9 7TA, UK
Email: vluisfuentes@rvc.ac.uk

DOI: 10.1177/1098612X12451547
© ISFM and AAFP 2012 Downloaded from jfm.sagepub.com by guest on March 13, 2015 JFMS CLINICAL PRACTICE 459
R E V I E W / Feline ATE

the Veterinary Teaching Hospital of the Uni-

versity of Minnesota.1 The reported preva-
lence in cats with HCM varies from 12–21%,4,5
although these are biased population samples
that probably reflect a particularly high pro-
portion of symptomatic cats. Recent studies
of apparently healthy cats suggest that the
prevalence of subclinical HCM may be much
higher than previously thought (potentially
up to 15% of adult cats),6,7 so the prevalence
of ATE in cats with HCM is probably much
lower than 12%, as ATE is usually seen only
in cats with the most advanced cardio-
myopathies. Conversely, many cats present-
ing with ATE in first opinion practice are
euthanased, and are therefore not accounted
for in prevalence estimates based on referral
populations.

Clinical presentation
Figure 2 Echocardiographic image showing a thrombus (arrow) in the left auricular appendage
in a cat with HCM and left atrial enlargement. This is a right parasternal short axis view.
Ao = aortic valve, LA = left atrium Cats with ATE typically are presented with
a sudden onset of severe pain and distress.
Affected cats often vocalise, and show unam-
lar mitral stenosis have been associated with biguous signs of pain. The exact clinical signs
ATE, but this is an uncommon cause.1 There is depend on the loca-
also a risk of systemic thromboembolism with tion of the thrombus,
septic emboli in infective endocarditis, but with the most com-
this is also rare. mon presentation
The most common non-cardiac cause of being pelvic limb
ATE in cats is pulmonary neoplasia, although paralysis/paresis
this is caused by tumour emboli rather than a associated with
true thrombus.1 Rarely, no underlying condi- embolisation to the
tion is found. distal aorta (Figure
3). In some cases,
Clinical importance one pelvic limb is
more severely affect-
ATE is probably one of the most distressing ed than the other.
conditions encountered in feline practice, par- Either forelimb may
ticularly as there is often no advance warning. also be affected with
Owners experience the initial trauma of find- embolisation to the
ing their cat paralysed and in pain, only to brachial artery. The
face the subsequent devastating news of the presentation is much
poor prognosis. Owners of affected cats are Figure 3 Typical stance of a more variable with other embolisation sites
cat with a ‘saddle thrombus’,
often advised that their pet may not survive showing bilateral pelvic limb (brain, mesenteric arteries), with for example
the initial episode; or, even if it survives to paresis vomiting, abdominal pain or central nervous
discharge, may succumb to a future bout of system signs, so that the underlying throm-
thromboembolism. While both of these state- boembolic cause may not be recognised.
ments may be true, it is also true that some Most cats presenting with ATE have no
cats will regain completely normal motor known history of cardiac disease, and
function following an initial ATE episode, peracute signs of pain and paralysis may be
and ATE survivors are more likely to die of the very first indication of advanced cardiac
congestive heart failure (CHF) than ATE.1 disease.
Fortunately, only a minority of cats with car-
diomyopathy will go on to develop ATE, but
HCM is sufficiently prevalent that ATE is still
a commonly encountered problem in feline
practice. The risk of ATE appears to be greatest with more
The true prevalence of ATE is not known, as severe forms of cardiomyopathy, irrespective of
most reports originate from referral institu-
tions. Smith et al reported an overall preva- the specific type of myocardial disease.
lence of ATE of less than 0.6% of cats seen at

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 R E V I E W / Feline ATE

Physical examination
Physical findings vary according to the affect-
R e c o g n i t i o n o f AT E
ed site. With the classic ‘saddle thrombus’
lodging at the aortic trifurcation, the diagnosis History The ‘5 Ps’
can be made from physical examination alone, ✜ Sudden-onset vocalising
based on the ‘5 Ps’ of pain, paralysis, pulse- Pain
✜ Dragging of one or more limbs
lessness, poikilothermy and pallor (see box).
Motor function is usually absent or reduced Physical examination Paralysis
distal to the stifles, with skin sensation absent ✜ Lower motor neuron signs
in one or more limbs Pulselessness
distal to the tarsus.8 The combination of pelvic
limb lower motor neuron signs with absent ✜ Absent femoral pulses
femoral pulses and cold extremities is pathog- Poikilothermy
✜ Cold distal limbs
nomonic for ATE.8,9 Lower motor neuron ✜ Pale or blue pads Pallor
signs may be present in forelimbs with a
brachial thrombus, where pulselessness may ✜ Cranial tibial/gastrocnemius may be firm
be more difficult to recognise. Foot pads are
frequently pale or cyanosed in the affected
limb, which is a particularly useful finding
in forelimbs. In some cats, the ATE is only Laboratory tests
‘partial’, with some motor function in the dis-
Many cats can A wide range of biochemistry abnormalities
tal limb persisting or returning rapidly. If the be expected to may be present. Most cats will exhibit stress
embolised thrombus is small, rapidly lysed or hyperglycaemia, and azotaemia and hyper-
collateral circulation is quickly re-established, be hypotensive phosphataemia are also common. Azotaemia
motor function may be present by the time the is usually prerenal, although can also be asso-
on presentation
cat is presented. ciated with thromboembolism of a renal artery.
Rectal temperature is often reduced (see box . . . Hypertension Typically, serum creatine kinase concentra-
below), and is considered a poor prognostic tions are dramatically increased as a result
sign.1 It is important to recognise signs of rarely causes of muscle ischaemia. Hypocalcaemia and
CHF, as this confers a worse prognosis and ATE. hyponatraemia are also reported. Although
must be managed differently. Although a hyperkalaemia is an important and potentially
rapid respiratory rate is often interpreted as a fatal complication of ATE, the rise in plasma
sign of CHF in cats with heart disease, many potassium concentrations often occurs sud-
cats with ATE will be tachypnoeic due to pain, denly as perfusion is restored and some cats
whether or not they have CHF. It can be very may actually be hypokalaemic on presenta-
difficult to distinguish rapid respiratory rate tion. In older cats, thyroxine levels should be
associated with pain or stress from tachyp- measured as hyperthyroid cats may be at
noea due to pulmonary oedema, unless increased risk of ATE irrespective of any car-
crackles can be identified on auscultation. diac changes.1 Coagulation tests are frequently
Although myocardial disease is the under- normal, although D-dimers may be elevated.
lying cause of ATE in the vast majority of
cases, auscultation may be normal in up to
40% of cats presenting with ATE.1,10 Just over
half of cats will have a murmur, gallop or
It can be very difficult to distinguish rapid respiratory
arrhythmia on auscultation. rate associated with pain or stress from tachypnoea
due to pulmonary oedema, unless crackles
can be identified on auscultation.
F e l i n e AT E s t a t i s t i c s
✜ Up to 21% of cats with HCM may develop ATE5
✜ Cats presenting with ATE have a median age of 8–9 years2,12
✜ Most cats with ATE are male3
✜ Some studies report <12% of cats having any history of heart disease prior to an ATE event2
✜ Only one limb may be affected in up to 26% of cats with ATE1
✜ Up to 40% of cats with ATE may be normal on auscultation1
✜ Most cats with ATE (up to 72%) present with hypothermia3
✜ If ATE affects two limbs, around 30–40% of treated cats survive to discharge1,14
✜ If ATE affects one limb, around 70–80% of treated cats survive to discharge2,3,14
✜ Reports of mean/median survival times for cats treated for ATE range from 51–350 days2,3
✜ Reported recurrence rates for ATE range from 17–50%2,14

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R E V I E W / Feline ATE

As many as 70–80% of cats with a single limb affected will survive to discharge,
with up to 90% survival rates in cats presenting with some motor function.

Radiography Natural history and prognosis

In the absence of
audible crackles,
thoracic radiogra-
phy may be the most
reliable way to con-
firm the presence of
CHF, but should not
be undertaken in
cats with severe
respiratory distress.
Thoracic radio-
graphs are also help-
ful for identifying
pulmonary mass lesions in those cats with an
underlying neoplastic cause (Figure 4).
Echocardiography
As the type of cardiomyopathy is not particular- in
ly relevant, it is not usually necessary to per-
form immediate echocardiography. Most cats
have a dilated left atrium (LA), and some will
have left ventricular systolic dysfunction.1–3,11,12
Spontaneous echo contrast (‘smoke’) is also
frequently present, and is believed to be a
marker of increased risk of ATE.13 In contrast
with most other scenarios, one cannot
assume that CHF is the cause of respiratory
distress simply because the LA is enlarged
on echocardiography, as LA enlargement
will be present in most cats with ATE.
In cats with a recent onset of signs, it may be
possible to identify the thrombus in the termi-
nal aorta using ultrasound imaging, but the
diagnosis of ATE in cats with pelvic limb pare-
sis is usually based on the distinctive clinical Figure 5 ATE affecting the
findings rather than imaging. Lack of a visible left pelvic limb of a Sphynx
thrombus in the terminal aorta does not rule region of ischaemia is
out ATE, particularly if signs are of greater evident as darker skin (a).
than 24 h duration. Where no underlying car- Two
diac disease is identified, further local imag- is evident over the
ing of the occluded artery is more justifiable.
Figure 4 Lateral thoracic
radiograph from a cat with
ATE, showing a mass lesion
in the caudodorsal thorax.
Tumour emboli are probably
responsible for the
thromboembolic signs
cats with pulmonary
neoplasia
SUPPLEMENTARY VIDEO
An echocardiographic video showing
spontaneous echo contrast (swirling
‘smoke’) in the left atrium is included
in the online version of this article at
DOI: 10.1177/1098612X12451547
cat. A well demarcated
days later, progression
of ischaemic skin damage
lateral aspect of the
tarsometatarsal area (b)
Many cats are immediately euthanased on
diagnosis. However, although ATE is widely
perceived to be inevitably disastrous, some
subpopulations of cats do much better than
others. As many as 70–80% of cats with a sin-
gle limb affected will survive to discharge,
with up to 90% survival rates in cats present-
ing with some motor function.14 This contrasts
sharply with rates of survival of <40% in treat-
ed cats overall.1,14 However, in the study by
Smith et al, rates of survival to discharge
improved over the 10-year period evaluated,
with 73% of cats surviving to discharge in the
last year of study. Hypothermia appeared to
be one of the most reliable markers of reduced
initial survival in this study, with <50%
chance of survival to discharge in cats with a
rectal temperature <37.2°C on presentation.1
The main mortality risks over the first 2–3
days are from CHF or hyperkalaemia from
reperfusion syndrome. Pain is severe in the ini-
tial 24 h, but decreases substantially after the
first 48 h. The cranial tibial and gastrocne-
mius muscles may become firm with severe
ischaemic muscle damage, and ischaemic
nerve damage may result in ‘dropped
hocks’ as well as loss of distal sensation.
Femoral pulses frequently return within 3–5
days. Where tissue ischaemia has been severe,
there is a risk of skin and muscle necrosis,
which usually manifests within the first 2 weeks
(Figure 5). In severe cases, this may lead to loss
of toes or distal limbs. Sometimes skin may
necrose more proximally, sparing the extremi-
ties. Ischaemic nerve damage may be reversible,
although this can take 8 weeks or longer.
Reports of average long-term survival vary
between 51 and 350 days. The most common
cause of death is CHF, although ATE may
recur in up to 50% of cats.2

Blood pressure measurement a b

A Doppler blood pressure measuring system
can be used to identify the presence or absence
of distal limb flow based on an audible Doppler
signal when the crystal is positioned over the
artery in question. Although the prevalence of
systemic hypotension in feline ATE has not
been reported, many cats can be expected to
be hypotensive on presentation. Conversely,
it should not be assumed that supranormal
systolic pressures indicate primary systemic
hypertension. Hypertension rarely causes ATE,
and increased blood pressure is more likely to
be caused by pain-induced stress.

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Pathophysiology
Thrombus formation is a complex process, but
it is generally accepted that platelet activation,
blood stasis and endothelial dysfunction all
contribute in varying degrees to ATE in cats
(Figure 6). Thrombogenesis involves multiple
signalling pathways coordinating the interac-
tions between platelets, coagulation factors
and the endothelium, so that haemostasis can
be safely achieved without risk of inappropri-
ate thrombosis in the healthy individual.15,16
Resting platelets have surface glycoproteins
which allow adhesion to the vessel wall where
the endothelial layer is damaged or lost. Von
Willebrand factor (vWF) is necessary for this
adhesion, triggering platelet activation and
production of adenosine diphosphate (ADP)
and thromboxane A2 (TXA2). Local release of
ADP and TXA2 activates additional platelets,
leading to further recruitment. Tissue factor in
the vessel wall results in thrombin produc-
tion, which activates platelets via a different
pathway. The growing platelet plug includes
increasing numbers of platelets bridged
together by fibrinogen, linking platelet inte-
grin αIIbβ3 receptor sites.
The endothelium normally produces factors
that help maintain ‘thromboresistance’. These
antithrombotic factors include antithrombin,
thrombomodulin, tissue-type plasminogen
activator (tPA), prostacyclin (PGI2) and nitric
oxide. Fast rates of blood flow are associated
with nitric oxide production mediated by
shear stress, whereas blood stasis may reduce
this antithrombotic effect.
Cats appear to be much more prone to
intracardiac thrombus formation than dogs,
and even humans. Human intracardiac
thrombosis is associated particularly with
heart failure and atrial fibrillation, and can
lead to embolic stroke. Spontaneous echo
contrast indicates increased risk of embolic
stroke in human patients, and is believed to
be associated with increased risk of ATE in
cats.
Platelet function
Assessing platelet function in cats is particu-
larly difficult as their platelets appear espe-
cially reactive compared with other species.
The gold standard test for assessing platelet
function (platelet aggregometry) requires
operator skill and experience, and results will
vary depending on the precise technique and
agonist used.17,18 Problems are exacerbated
in cats, as even venepuncture technique can
affect the results. Evidence of a hypercoagula-
ble state can be obtained by measuring circu-
lating markers of thrombin generation such as
thrombin–antithrombin complex concentra-
tions.19
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R E V I E W / Feline ATE
Some of the factors involved in thrombus formation
Figure 6 The left panel of the diagram shows the normal state, where a healthy
endothelium contributes to a microenvironment that inhibits thrombosis within a blood
vessel (‘thromboresistant’). Endothelial production of nitric oxide (NO), antithrombin
(AT) and prostacyclin (PGI2), and endothelial expression of thrombomodulin inhibit
attachment and activation of platelets. The right panel represents an environment
that promotes thrombogenesis, where the endothelium is damaged or missing, and
collagen is exposed. Platelets attach to collagen-bound von Willebrand factor (vWF),
resulting in platelet activation. Activated platelets release adenosine diphosphate (ADP)
and thromboxane A2 (TXA2), which activate additional platelets. Tissue factor results in
thrombin generation, which amplifies the effects of platelet activation and leads to
further thrombin production, as coagulation factors such as Xa become involved.
Platelet–platelet affinity is enhanced as attachments form with fibrinogen and vWF,
leading to a more stable thrombus. The sites of action of aspirin, clopidogrel and
heparin are shown
It is generally Blood stasis
accepted Spontaneous echo contrast is believed to be a
marker of blood flow stasis and, as mentioned,
that platelet is a known risk factor for human thromboem-
bolism. Spontaneous echo contrast is common-
activation, ly encountered in cats presenting with ATE,
blood stasis and this has been linked with low velocities of
blood flow in the LAA.13 A direct association
and endothelial between low LAA blood flow velocities and
ATE has not been demonstrated in cats,
dysfunction however.
all contribute to
Endothelial function
ATE in cats. The endothelial contribution to thrombo-
regulation is difficult to test. Studies in
rats have shown that an increase in atrial pres-
sure reduces endocardial expression of throm-
bomodulin, leading to an increase in local
generation of thrombin and risk of thrombus
formation.20 This suggests that LA stretch may
itself be responsible for increasing thrombo-
genicity. LA enlargement is well documented
as a risk factor for feline ATE.1,2,11,12,14 In human
HCM patients, the degree of LA enlargement
correlates well with plasma concentrations of
thrombin–antithrombin complexes.21
Cats appear to be much more prone to intracardiac
thrombus formation than dogs, and even humans.
JFMS CLINICAL PRACTICE 463
R E V I E W / Feline ATE
Risk factors
History
✜ Previous ATE, even if mild transient signs
Echocardiography
✜ Spontaneous echo contrast/
visible thrombus
✜ Left atrial enlargement
✜ Systolic dysfunction of the left atrium
✜ Systolic dysfunction of the left ventricle
How to identify cats at risk
Our ability to identify cats at risk of ATE has
greatly improved, but relies on access to
echocardiography (see box above). Many cats
at risk of ATE do not even have auscultatory
abnormalities, and as these apparently
healthy cats are not likely to be selected for
screening by echocardiography, most cats
presenting with ATE will have no known
history of heart disease.1,14 Cats with a history
of ATE are clearly at risk, as are cats with a
visible atrial thrombus or spontaneous echo
contrast. Any cat with myocardial disease and
LA enlargement has an increased risk, partic-
ularly if LA systolic function is impaired. The
risk is also increased in cats with left ventricu-
lar systolic dysfunction.11 The short-term risk
of ATE for asymptomatic cats with HCM and
normal LA size is probably low.
Therapy for ATE
The range of drugs used in the treatment of
ATE is summarised in Table 1.
Thrombolytic therapies
Although it seems logical to attempt to remove
or lyse the thrombus in cats with ATE, this
approach is not recommended. Surgery is not
advocated because of the high mortality rates,
and catheter removal of a thrombus is tech-
nically very challenging. More importantly,
thrombolytic therapy with tPA or streptokinase
results in mortality rates that are at best no
lower than without thrombolytic treat-
ment.3,22,23 This is because any method that
results in sudden reperfusion of ischaemic tis-
sue will risk the life-threatening complications
of reperfusion injury. This occurs when
ischaemic metabolites such as potassium and
free oxygen species are flushed into the
systemic circulation, causing arrhythmias,
acid–base disturbances, renal dysfunction and
death.
464 JFMS CLINICAL PRACTICE
Anticoagulant/antiplatelet therapies
In general, anticoagulant therapy with vita-
Many cats at min K antagonists appears to be more effec-
risk of ATE tive than antiplatelet therapy in preventing
stroke or peripheral arterial embolism in
do not even have human patients, including those with HCM
auscultatory and atrial fibrillation.24–26 The preference for
warfarin is less clear-cut in patients without
abnormalities. atrial fibrillation, and trials are currently
under way comparing aspirin versus warfarin
As these in patients with dilated cardiomyopathy and
apparently sinus rhythm.27
healthy cats are Warfarin
Despite the many difficulties associated with
not likely to be its use, the principal anticoagulant recom-
selected for mended to prevent human stroke is still war-
farin. Warfarin blocks the effects of vitamin K
screening by necessary for coagulation factors II, VII, IX
and X to be activated. Warfarin is highly
echocardiography, protein-bound with unpredictable pharmaco-
most cats kinetics and pharmacodynamics, making it a
difficult drug to use safely and effectively,
presenting with even in human patients. Warfarin’s effects can
ATE will have no be monitored by measuring the prothrombin
time, and standardising the value for each
known history of batch of reagent to derive an international
normalised ratio (INR).
heart disease. Use of warfarin has been reported in cats
with a history of ATE.2,3,28 The target INR for
cats of 2.0–3.0 has been extrapolated from
human guidelines,28 but there are so many
factors that can influence the effects of
warfarin, both thrombus formation and
haemorrhage are still possible. The intensive
monitoring necessary with warfarin also com-
promises feline quality of life in terms of fre-
quent clinic visits for blood sampling and an
indoor lifestyle.
Unfractionated heparin
Unfractionated heparin is a mixture of
sulfated glycosaminoglycans, requiring anti-
thrombin for its anticoagulant effect. The
heparin–antithrombin complex inactivates
several coagulation factors, but particularly
thrombin and Xa. The onset of effect is more
rapid with high doses compared with low
doses.29
Heparin is often used early in the course of
feline ATE to reduce extension of the existing
thrombus, although its efficacy for this pur-
pose has not been established.1,3,14,30 The risk
of haemorrhage appears to be small, but the
benefit is unknown.
Low molecular weight heparins
In prevention of human deep vein thrombo-
sis, unfractionated heparin has been largely
superseded by low molecular weight heparin
(LMWH) because of its longer half-life and
more predictable dose response. This allows
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 R E V I E W / Feline ATE

Table 1 ATE therapy

Drug Dose Advantages Disadvantages Comments

Methadone 0.6 mg/kg slow Potent analgesia mu agonist, titrate to effect
IV q4–6h Vomiting is rare
Analgesics

Fentanyl 3–5 µg/kg slow Potent mu agonist, titrate to effect

IV, followed by analgesia
2–5 µg/kg/h CRI
Buprenorphine 0.02 mg/kg IV Widely available Not sufficiently Partial opioid agonist
or IM q6h potent for severe
pain
Furosemide 1–2 mg/kg q1–8h Rapid diuresis May cause Confirm tachypnoea is due
IV azotaemia and to pulmonary oedema
treatment

hypokalaemia
CHF

Pimobendan 0.625–1.25 May improve Oral medications May worsen outflow tract
mg/cat q12h PO hypotension difficult with obstruction, so do not use
severe respiratory if loud murmur is present
distress
Unfractionated 100–250 U/kg IV, Inexpensive Effective dose Do not use IM – risk of
heparin 50–200 U/kg SC May reduce and dosing bleeding
q6h expansion or interval unknown
extension of May increase risk
thrombus of haemorrhage
Effect can be
monitored with
prothrombin time
Anticoagulants

Enoxaparin 1 mg/kg q8–12h ?Reduced risk of Expensive

SC haemorrhage Effective dose
and dosing
interval unknown
Dalteparin 100 IU/kg q12h ?Reduced risk of Expensive
SC haemorrhage Effective dose
and dosing
interval unknown
Warfarin 0.5 mg/cat q24h Inexpensive Unpredictable DO NOT USE
PO Effect can be pharmacokinetics
monitored with INR High risk of
haemorrhage
Requires frequent
blood sampling to
monitor effects
Aspirin 75 mg/cat q72h Inexpensive Efficacy unknown Low dose may also be given
PO (high dose) Mostly well q48h
Antiplatelet drugs

5 mg/kg q72h PO tolerated

(low dose) Risk of
haemorrhage low
Clopidogrel 18.75 mg/cat Expensive Efficacy unknown
q24h PO Mostly well
tolerated
May have additive
effect with aspirin
Risk of
haemorrhage low

CRI = constant rate infusion, CHF = congestive heart failure, INR = international normalised ratio

dosing according to body weight in human an uncontrolled retrospective study of cats

patients, without a need to monitor the coag- that included 43 cats with cardiomyopathy.32
ulation effects. In cats, the optimal dosing
schedule for the LMWHs enoxaparin and Aspirin
dalteparin is not known. In a study comparing Aspirin is well tolerated, and is associated
enoxaparin, dalteparin and unfractionated with a 20% reduction in stroke in high-risk
heparin in healthy cats, only unfractionated human patients.33 Aspirin irreversibly inhibits
heparin showed adequate anti-Xa activity.30 platelet cyclo-oxygenase (COX)-1, a key step
Anti-Xa activity does not always correlate in converting arachidonic acid (AA) to TXA2.
with clinical antithrombotic effects, how- This inhibition lasts for the lifetime of the
ever.31 Use of dalteparin has been reported in platelet, and is achieved at low doses. Aspirin

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R E V I E W / Feline ATE
also inhibits endothelial COX-1 at higher
doses, which converts AA to (antithrombotic)
prostacyclin. The association in human
patients between aspirin dose and antithrom-
botic effect is therefore not linear. Treatment
failure with aspirin may variously reflect poor
patient compliance; platelet activation via
ADP or collagen; increased production of
new platelets unaffected by aspirin; genetic
polymorphisms; or the presence of TXA2-
independent mechanisms of thrombogenesis.
We know that pre-treating cats with very
high doses of aspirin (650 mg) can prevent
vasoconstriction of the collateral circulation
that accompanies thromboembolism.34 We
also know that cats at risk can still develop
ATE despite aspirin therapy, and we do not
even know whether aspirin reduces ATE
incidence in cats, as no placebo-controlled
study has ever been undertaken. The inci-
dence of ATE with low-dose aspirin (5 mg/cat
q72h) was not different from high-dose
aspirin (40 mg/cat q72h) in Smith et al’s
study, although the incidence of side effects
was lower.1
In the absence of reliable outcome data, the
only other means of assessing aspirin in cats
is by resorting to measuring platelet function,
which is often unsatisfactory in cats. A recent
platelet aggregation study in healthy cats
showed that aspirin had no effect on whole
blood aggregation using ADP and collagen
agonists, although plasma concentrations of
TXB2 (a stable metabolite of TXA2) were
decreased.35 An older study had shown a sim-
ilar lack of effect of aspirin on whole blood
platelet aggregation in healthy cats with ADP
and collagen, but marked inhibition of aggre-
gation when AA was used as the agonist (AA
is the more relevant agonist for testing the effi-
cacy of aspirin).36 Both studies suggest that
aspirin is effective at inhibiting platelet COX-
1 in healthy treated cats, but other TXA2-inde-
pendent pathways may still result in platelet
aggregation. Aspirin also appears to inhibit
serum TXB2 production in cats with myocar-
dial disease.37
Clopidogrel
Clopidogrel is an irreversible ADP antagonist
that further reduces the risk of vascular events
in human patients when added to aspirin, at
the cost of a slightly increased risk of haemor-
rhage.38 ADP is a weak platelet agonist on its
own, but is important in potentiating platelet
activation in response to collagen, vWF and
thrombin.16 ADP also amplifies the effect of
TXA2. Studies in normal cats showed that
clopidogrel decreased platelet aggregation in
response to ADP and collagen, and decreased
platelet serotonin release.39 Clopidogrel
appears to be well tolerated in cats.39
466 JFMS CLINICAL PRACTICE Downloaded from jfm.sagepub.com by guest on March 13, 2015
Approach to the cat with
acute ATE
Initial presentation
Most cats presented with ATE in extreme
distress and pain are euthanased. Unless ade-
quate doses of suitable opiates can be provid-
ed (ie, methadone, oxymorphone or fentanyl),
then euthanasia should certainly be discussed
frankly with the owner. With partial ATE
(ie, only one limb affected or some motor
function persisting), the pain is less severe
and the prognosis much better. This should
also be discussed frankly with the owner.
Physical examination provides useful prog-
nostic information: cats with a rectal tempera-
ture <37°C are less likely to be survivors.
Confirmed CHF may also worsen the prog-
nosis. The first 24 h are the most painful and
distressing for the cat, so if euthanasia is the
likely outcome, it is better to euthanase as
soon as possible after the onset of signs.
First 60 minutes
It may be necessary to manage pain even
before a decision is made to treat (see box at top
of page 467). Cats presenting with the severe
Cats with pain associated with bilateral pelvic limb ATE
a rectal must be treated with potent analgesics titrated
to effect, such as intravenous methadone or a
temperature constant rate infusion of fentanyl (fentanyl
patches will take too long to take effect). For
<37°C are less cats with partial ATE, buprenorphine may be
likely to be adequate.
The next priority is to determine whether
survivors. CHF is present. Oxygen should be adminis-
tered to cats with respiratory distress.
Inspiratory crackles on auscultation are high-
ly suggestive of pulmonary oedema. Sig-
nificant pleural effusion is less likely to
develop acutely with ATE, although this can
also be identified using physical examination
when breath sounds are absent ventrally.
For tachypnoeic cats with normal breath
sounds, thoracic radiographs should be
obtained. If pulmonary oedema is suspected,
then intravenous furosemide should be
administered at 1–2 mg/kg. Furosemide
should be repeated to effect, at hourly inter-
vals or more frequently depending on the
severity of respiratory distress.
Once pain is addressed and CHF signs con-
trolled, antithrombotic treatment can be start-
ed. The goal of antithrombotic therapy is to
prevent extension of existing thrombus, and to
prevent new thrombus formation, not to lyse
existing thrombus. The value of unfractionat-
ed heparin or LMWHs for this use has not
been established in cats. An alternative
approach is to use oral agents such as aspirin
or clopidogrel from the start, and not include
heparin at all. The author uses both aspirin
and clopidogrel together as early as possible.
 R E V I E W / Feline ATE

A p p r o a c h t o t h e c a t w i t h AT E
FIRST HOUR
Two limbs affected
No motor function
Severe pain Euthanasia?
Hypothermia K
IV furosemide
Physical
examination, CHF Oxygen
Initial place IV line
assessment
Crackles
Tachypnoea Pulmonary infiltrates
One limb affected
Some motor function
Mild pain No crackles
Normothermia No pulmonary infiltrates
Chest
Normal respiration Normal respiration radiographs

Methadone, Aspirin +
or fentanyl infusion clopidogrel

First 24 hours possible in cats with CHF. As there is no point

Further investigations/monitoring
Once pain and CHF have been addressed
and antithrombotic treatment started, further
investigations may be undertaken (see box
below). Apart from monitoring vital signs, gen-
eral demeanour and mobility, renal function
and electrolytes should be monitored. Echo-
cardiography will help determine whether the
underlying cause of ATE is cardiac disease.
Management
Intravenous fluid therapy may be needed in
azotaemic cats, but should be avoided where
in giving diuretics and intravenous fluids con-
currently, the first approach with azotaemic
cats with CHF should be to reduce diuretic
dose and try other approaches to improve
cardiac function. Although not authorised for
use in cats, pimobendan (1.25 mg per cat
q12h) may be helpful for cats with systolic
dysfunction, and can be tried as long as there
is no murmur present. Nursing care is
extremely important to ensure that cats are
kept comfortable and to watch for early warn-
ing signs of complications. Cats should be
kept warm to promote circulation, with warm

A p p r o a c h t o t h e c a t w i t h AT E
FIRST 24 HOURS
(after initial management)

Oral furosemide IV fluids

to effect (if CHF, reduce or stop
furosemide instead)
Pimobendan

↑ Creatinine

Current or previous CHF

Hypotension
No evidence of CHF

↑ [K+]
Aspirin +
clopidogrel Echocardiography
(if available)
IV fluids + Ca gluconate
Methadone,
or fentanyl infusion

Downloaded from jfm.sagepub.com by guest on March 13, 2015 JFMS CLINICAL PRACTICE 467
R E V I E W / Feline ATE

ambient temperatures preferred to direct consequences of ischaemic tissue necrosis. As

heating pads. Physiotherapy may be helpful. pulses return, reperfusion of ischaemic tissue
Passive manipulation may help to prevent can cause sudden life-threatening fluctuations
muscle contracture, although no studies have in serum potassium concentrations and reac-
evaluated the effects. tive oxygen species, as well as acid–base bal-
ance. Cats that are apparently making good
24–48 hours post-ATE progress can suddenly and dramatically
Further investigations/monitoring deteriorate. This makes monitoring for such
Improvement is generally easy to identify. Pain changes very difficult. Even with serum bio-
usually decreases over the first 24–36 h. An chemistry testing q8h, critical electrolyte
improvement in warmth, pulse quality and changes may develop between blood sam-
motor function of the affected limb(s) is an pling periods. Fortunately, cats with partial
indication that limb perfusion is improving. ATE appear to be less vulnerable to sudden
Pulse strength will often improve within 4–5 reperfusion syndrome.
days, reflecting improved circulation, even
without specific thrombolytic measures. Where Management
there is evidence of severe ischaemic nerve Therapy with aspirin and clopidogrel is con-
damage, this may take weeks to improve.8 tinued. Analgesia is generally continued, but
Identifying the warning signs of adverse most cats will be more comfortable after 24 h.
effects or complications is much more chal- Pelvic limbs may still be hard, cold and
lenging. The main complications are CHF, paretic, and may benefit from gentle rewarm-
reperfusion injury, azotaemia and the local ing and passive manipulation.

Case notes
Sparky, a 10-year-old male neutered domestic
shorthair, was presented for veterinary attention
having disappeared 4 days earlier. On the day of
presentation, he had reappeared in the owner’s
garden with paralysis of the
right pelvic limb and paresis Vital signs
of the left pelvic limb.
Rectal temperature 36·9°C
Physical examination Sparky
was bright and alert, and was not Heart rate 204/min
showing any obvious signs of pain. Respiratory rate 36/min
In contrast with the left pelvic limb Sparky at presentation

the right was cold, but the pads of Auscultation Normal

both limbs were pink. The right mildly increased urea and normal creatinine,
Femoral pulses Absent on
tarsus was unstable. right, weak on and mild hypokalaemia. As Sparky was comfortable
left and haemodynamically stable, echocardiography
Assessment and initial was carried out, and showed left ventricular
approach Sparky’s signs were consistent with ATE affecting hypertrophy with LA enlargement and spontaneous echo
the terminal aorta (saddle thrombus). He had some motor contrast (HCM).
function in the left pelvic limb, and had no signs of CHF,
suggesting a better prognosis. He was hypothermic, Treatment and outcome Sparky was discharged on
suggesting a worse prognosis. He was comfortable at the a treatment regimen of low-dose aspirin, clopidogrel,
time and so it was considered that there was little to lose benazepril and pimobendan, and instructions to keep him
by treating him. His tarsal laxity was a concern, confined for the next 4 weeks. Three months later,
but his mobility would be restricted for the his gait was close to normal with no tarsal
immediate future anyway. Sparky was given instability (see accompanying supplementary
buprenorphine (0.2 mg/kg IM) as a first-line video). Thereafter he had no further
treatment. thromboembolic episodes, but 18 months
SUPPLEMENTARY VIDEO
A video recording showing Sparky
later he developed pleural effusion
Further investigations Biochemistry at reassessment 3 months after the associated with CHF. His CHF signs were
and blood pressure measurement were thromboembolic episode is included in initially controlled with the addition of
the online version of this article at furosemide to the previous therapy, but he
performed. Sparky’s systolic blood pressure
DOI: 10.1177/1098612X12451547
was normal (120 mmHg systolic using subsequently developed atrial fibrillation and
Doppler sphygmomanometry). His refractory ascites, at which point euthanasia
biochemistry was largely unremarkable, with was performed.

468 JFMS CLINICAL PRACTICE Downloaded from jfm.sagepub.com by guest on March 13, 2015

>48 hours post-ATE
Affected cats will probably be happier and
more comfortable at home after the initial 72 h
post-ATE. If there is still any discomfort, oral
buprenorphine can be administered by the
owner. The owner should be warned that
acute deterioration is still possible. The
aspirin and clopidogrel can be continued for
longer term prophylaxis. Cats with affected
pelvic limbs tend to move with the distal
limbs extended behind them; there is thus a
risk of excoriation of the dorsal aspect of the
limbs, which may require dressings to protect
them. The owner should be instructed on how
to administer physiotherapy at home, and
how to identify early signs of distal limb
necrosis. This occurs in a minority of patients,
and is usually restricted to cats with very
severe ischaemic damage.
Cats should be rechecked every 3–4 days for
the first 2 weeks, initially to reassess limb
function and the need for continued analgesia,
presence of pulses, control of CHF signs, and
renal function. In the second week, cats
should be monitored to ensure there are no
necrotic changes in the skin or digits second-
ary to ischaemic damage.
Prevention
Prevention of ATE is clearly preferable to
attempting to treat it. The lack of controlled,
prospective studies in cats makes it difficult to
choose therapies on anything other than an
empirical basis. A large multi-centre study is
currently under way evaluating the relative
risk of ATE recurrence in cats treated with
aspirin versus clopidogrel. Dual antiplatelet
therapy with aspirin and clopidogrel has
become a standard antiplatelet combination in
human patients, and is the preferred choice
for therapy of ATE in cats in the author’s
clinic, but has not been studied in a controlled,
prospective manner. Warfarin and the
LMWHs are associated with too many phar-
macokinetic problems to be currently recom-
mended in cats. Pimobendan is occasionally
used off-label in cats with advanced cardio-
myopathy, and may have some effect in
reducing platelet aggregation.40
Although there are a number of newer
antithrombotic treatments available for
thromboprophylaxis in human patients at
high risk of ATE, there is no consensus as to
whether these agents are superior to war-
farin.41–43 Some of the newer alternatives
to warfarin may ultimately prove useful in
cats.
Sadly, even if an effective preventive
therapy were to be identified, ATE will still
continue to be a major problem until we can
improve our ability to identify cats at risk.
Downloaded from jfm.sagepub.com by guest on March 13, 2015
R E V I E W / Feline ATE
KEY POINTS
✜ ATE occurs most commonly in cats with advanced myocardial
disease; such cats may be clinically silent.
✜ Diagnosis of ATE can usually be based on physical examination
findings.
✜ Survival to discharge following ATE is more likely in normothermic
cats with only one limb affected or some motor function present.
✜ Prognosis is worse in cats with CHF, but some cats can be
tachypnoeic due to pain in the absence of CHF.
✜ Effective analgesia is essential for the first 24–48 h and is best
provided by methadone or a fentanyl infusion.
✜ Antithrombotic treatment need not be complicated – clopidogrel
and aspirin can be used in the treatment of cats with ATE,
as well as for prevention.
Funding
The author received no specific grant from any funding agency in the public,
commercial or not-for-profit sectors for the preparation of this article.
Conflict of interest
The author does not have any potential conflicts of interest to declare.
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