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Journal of Veterinary Emergency and Critical Care 18(5) 2008, pp 526–531
Case Report doi:10.1111/j.1476-4431.2008.00341.x

Canine leishmaniasis with nephrotic syndrome and

aortic and caudal vena cava thromboembolism
Nuno Félix, DVM, MSc; Sofia Mouro, DVM, MSc; Cristina L. Vilela, DVM, PhD; Maria C. Peleteiro,
DVM, PhD; António J.A. Ferreira, DVM, PhD and Maria Manuela R.E. Niza, DVM, PhD

Abstract
Objective – To describe a case of leishmaniasis associated with nephrotic syndrome and aortic and caudal
vena cava thrombosis in a dog.
Case Summary – A 3-year-old male Boxer was referred to the Faculty of Veterinary Medicine, Lisbon, with
vomiting, polyuria, polydipsia, lethargy, anorexia, and weight loss. On admission, the dog was thin, quiet, and
dehydrated. Initial laboratory abnormalities were compatible with a diagnosis of leishmaniasis (confirmed by
serology and bone marrow aspirate), and nephrotic syndrome. Three days later, the animal developed lumbar
pain, paraparesis, and absent femoral pulses. Coagulation tests showed a marked reduction in antithrombin
(AT) and a mild increase in serum fibrinogen concentration. A diagnosis of thromboembolism was made. In
spite of treatment aimed at controlling the primary condition and decreasing further thrombus formation,
necrosis developed in the distal right pelvic limb and the nail beds of the left pelvic limb. Against medical
advice, medication was stopped and, 15 days later, the dog returned to the hospital, showing extensive
necrosis of both pelvic limb extremities. Euthanasia was performed at the owner’s request. Necropsy showed
a thrombus localized at the distal aorta and extending into the right iliac artery, and an additional thrombus
extending from both femoral veins onto the caudal vena cava.
New or Unique Information Provided – Thromboembolic disease is rare in dogs with leishmaniasis with
nephrotic syndrome. This case suggests that a marked decrease in AT and a mild increase in serum fibrinogen
may elicit a hypercoagulable state in these patients.
(J Vet Emerg Crit Care 2008; 18(5): 526–531) doi: 10.1111/j.1476-4431.2008.00341.x

Keywords: antithrombin, dog, fibrinogen, leishmania, thrombus

Introduction portant being antithrombin (AT).11 Dogs with nephrotic

Leishmaniasis is a zoonosis showing variable clinical
signs and is usually seen as a chronic systemic pro-
cess.1,2 Renal lesions are frequent, consisting of immune-
mediated membranoproliferative glomerulonephritis
associated with lymphoplasmacytic interstitial and tu-
bular nephritis.3 Leishmaniasis can cause nephrotic
syndrome in dogs,4 although this association is consid-
ered atypical.1 Hemostatic disorders have been de-
scribed in dogs with leishmaniasis,5 usually as bleeding
tendencies, but a hypercoagulable condition has also
been reported.6–8
Thromboembolic disease is not common in dogs.9,10
Blood clot formation is a tightly balanced process be-
tween natural pro- and anticoagulants, the most im-
From the CIISA/Faculty of Veterinary Medicine, TULisbon, Avenida da
Universidade Técnica, Lisboa, Portugal.
Address correspondence and reprint requests to
Dr. Maria Manuela R.E. Niza, Faculdade de Medicina Veterinária, Av.
Universidade Técnica, 1300-477 Lisboa, Portugal.
Email: necas@fmv.utl.pt
syndrome may develop peripheral thrombosis due to a
hypercoagulable state.12,13
This report presents a case of a dog with leishma-
niasis associated with nephrotic syndrome and aortic
and caudal vena cava thromboembolism.
Case Report
A 3-year-old male Boxer weighing 25.6 kg was referred
to the Faculty of Veterinary Medicine, Lisbon, with a
2-week history of weight loss, anorexia, and lethargy.
The animal was treated with amoxicillin/clavulanatea
(20 mg/kg, PO, q 12 h) for 1 week and, due to deteri-
oration, prednisoloneb (0.5 mg/kg, PO, q 12 h) had been
added 3 days before referral.
On admission, the dog’s history was notable for
vomiting, polydipsia, polyuria, lethargy, anorexia, and
weight loss. On physical examination, the animal was
thin and quiet. He was approximately 5% dehydrated,
with pink, dry mucous membranes, a respiratory rate

526 & Veterinary Emergency and Critical Care Society 2008

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Canine leishmaniasis and thromboembolism

of 40/minute, and a heart rate of 130/minute. His rectal The animal lived in an area where leishmaniasis was
temperature was 39.3 1C (102.7 1F), and he demon- endemic. Leishmaniasis is frequently associated with
strated discomfort on abdominal palpation. kidney and liver disease. Dirofilariasis is also endemic
Differential diagnoses at this stage included liver and in this area, although it does not frequently cause renal
kidney disease, endocrine disorders such as Addison’s or hepatic disease.
disease, diabetes mellitus, and diabetes insipidus, and The dog was admitted to the faculty’s hospital and
electrolyte disorders such as hypokalemia and hyper- supportive therapy was initiated with 0.9% salinec
calcemia. Initial tests consisted of a complete blood (4 mL/kg/h, IV) and cimetidined (5 mg/kg, IV, q 8 h).
count, serum biochemistry, and urinalysis. Abdominal Amoxicillin/clavulanatea and prednisoloneb adminis-
and thoracic radiographs were also performed. tration were continued, with the objective of reducing
The initial laboratory results are described in Table 1. the risk of kidney damage by immune complex depo-
Urine sediment examination was unremarkable. Ab- sition, the major path for leishmaniasis-induced kidney
dominal and thoracic radiographs did not reveal any failure.
abnormalities. Blood and bone marrow samples were obtained for
Increased serum concentrations of BUN, phosphorus, diagnosis of leishmaniasis. The presence of dirofilaria-
potassium, and creatinine, combined with low urine sis was evaluated by ELISA.e Further laboratory tests
specific gravity in the face of dehydration and protein- were performed to better assess liver function and the
uria, were consistent with renal failure. Increased levels severity of proteinuria. An abdominal ultrasound was
of liver enzymes could be attributed to primary hepatic also performed.
disease or, in the case of ALP, be related to prior steroid Leishmaniasis serology was positive (IF 1/160; refer-
administration. Increased globulin levels were probably ence value o1/80), and bone marrow aspirate revealed
related to increased globulin synthesis by hepatocytes Leishmania spp. parasites. Dirofilariasis testing was neg-
and immunoglobulin synthesis by B-lymphocytes, trig- ative. Fasting and postprandial serum bile acid con-
gered by immunomediators released during inflamma- centrations were consistent with normal liver function.
tory and infectious states. Hypoalbuminemia could be Urine protein-creatinine ratio was increased (Table 1).
explained by increased loss through the kidneys or de- Abdominal ultrasonography did not reveal any abnor-
creased liver synthesis, a normal acute-phase response. malities. Leishmaniasis treatment with allopurinolf
(30 mg/kg, PO, q 24 h) was then initiated and am-
Table 1: Relevant initial laboratory data oxicillin/clavulanatea was discontinued.
On the night of the third day of hospitalization, the
Reference animal displayed lumbar pain and paraparesis, and
Parameter Patient value interval was tachypneic and tachycardic, with a normal CRT
Blood count and mucous membrane color. Neither femoral pulse
Leukocytes (cells/mL) 26,000 6000–17,000 could be palpated. The differential diagnoses for the
Neutrophils (cells/mL) 24,220 3000–11,500 absence of femoral pulses were thromboembolic dis-
Lymphocytes (cells/mL) 780 1000–4800
ease (which could be caused by nephrotic syndrome,
Platelets (cells/mL) 204,000 200,000–500,000
Blood biochemistry parasitic-induced vasculitis, and cardiogenic thrombo-
Albumin (g/L) [g/dL] 23.5 [2.35] 27–38 [2.7–3.8] embolism) and hypotension. Blood samples were taken
Globulin (g/L) [g/dL] 62.0 [6.20] 25–45 [2.5–4.5] for coagulation testing, and abdominal and cardiac ul-
Total protein (g/L) [g/dL] 85.5 [8.55] 52–82 [5.2–8.2] trasound examinations were performed. Butorphanolg
ALT (U/L) 414 1.2–44.2
(0.2 mg/kg, IV, q 6 h) was administered for analgesia,
AST (U/L) 180 6.4–23.5
ALP (U/L) 228 15–127 and dalteparinh (100 IU/kg, SQ, q 24 h) was initiated to
BUN (mmol/L) [mg/dL] 46.8 [131] 7.1–17.9 [20–50] prevent formation of additional thrombi. On the fol-
Creatinine (mmol/L) [mg/dL] 133.5 [1.51] 68.1–106.1 [0.77–1.2] lowing morning, the dog’s clinical condition had dete-
Cholesterol (mmol/L) [mg/dL] 9.9 [385] 2.8–7.7 [110–300] riorated. Right pelvic limb nail beds were cyanotic and
Phosphorus (mmol/L) [mg/dL] 2.75 [0.89] 0.97–2.00 [0.31–0.65]
distal portions of both pelvic limbs were cold and
Chloride (mmol/L) 110.9 109–122
Sodium (mmol/L) 147.1 144–160 painful on palpation. As these observations reinforced
Potassium (mmol/L) 6.9 3.5–5.8 the clinical suspicion of arterial thromboembolism, both
Urinalysis pelvic limbs were gently massaged every 2 hours and
Urine specific gravity 1.015 41.030 warm compresses were applied every 4 hours to pro-
Protein (g/L) [mg/dL] 3 [300] Absent
mote circulation.
Urine protein-creatinine ratio 3.5 o1
Coagulation tests showed a marked reduction of AT
ALT, alanine aminotransferase; AST, apartate aminotransferase; ALP, (50%; reference interval 80–120%), a mild increase in
alkaline phosphatase; BUN, blood urea nitrogen. serum fibrinogen concentration (5.21 g/L [521 mg/dL];

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N. Félix et al.

reference interval 1–5 g/L [100–500 mg/dL]), and nor-

mal values for prothrombin, activated partial throm-
boplastin (aPTT), and thrombin times. A second blood
count revealed an ongoing leukocytosis with mature
neutrophilia and lymphopenia, with a normal platelet
count. Echocardiographic examination showed no ab-
normalities. B-mode ultrasonography revealed an image
compatible with a thrombus in the aortic bifurcation,
leading to the diagnosis of aortic thromboembolism as-
sociated with nephrotic syndrome secondary to leish-
maniasis. Because of the progression of clinical signs
consistent with lack of perfusion to the pelvic limbs,
thrombolytic therapy with tissue plasminogen activator
or streptokinase was recommended. However, the use
of thrombolytic drugs was declined by the owner due to
financial constraints. The animal remained on daltep- Figure 2: Extensive necrosis of the skin in both hind limbs. The
arin, butorphanol, allopurinol, intravenous fluids, and poor elasticity of the necrotic tissue resulted in the postmortem
cimetidine. Steroid administration was discontinued to artefact skin splitting that may be seen in the middle of the right
leg.
avoid possible prothrombotic effects.
In spite of treatment, the animal’s condition wors-
ened and, 4 days later, necrosis developed in the distal served from nail beds up to the right thigh mid-femoral
extremity of the right pelvic limb (Figure 1) and the left region and, in the left thigh, up to the adductor and
pelvic limb nail beds. Against medical advice, the own- semimembranous muscles.
ers elected to take the dog home, discontinuing all Histologic examination revealed degenerative and
medication. Fifteen days later, the dog returned, show- necrotic tubular changes in both kidneys. Other lesions
ing extensive necrosis of both pelvic limb extremities consisted of membranoproliferative glomerulonephri-
(Figure 2). Euthanasia was performed at the owner’s tis, with occasional adherences to the Bowman capsule.
request. Interstitial fibrosis of variable severity was also present
Necropsy showed an extensive, well-organized, yel- throughout both kidneys. These findings were in agree-
lowish thrombus localized at the distal aorta and ex- ment with the clinical and laboratory signs of renal
tending onto the right iliac artery (Figure 3). Another failure. No gross lesions were seen in the heart.
thrombus extended from both femoral veins onto the
caudal vena cava. The skin of both pelvic limbs was
necrotic, extending from the nail beds proximally to up Discussion
to the mid-tibia. Extensive muscular necrosis was ob-
This report presents a case of leishmaniasis with ne-
phrotic syndrome and thromboembolism in a dog.
Dogs with leishmaniasis-associated nephrotic syn-
drome usually show clinical signs of renal failure.2 In
the case reported here, histopathologic changes in the
kidneys were consistent with canine visceral leishma-
niasis.14 In this species, only a small number of animals
with glomerulonephritis develop all the abnormalities

Figure 3: Red-yellowish thrombus extending from the distal

Figure 1: Necrosis of the right hind limb distal extremity, aorta into the right iliac artery through the iliac bifurcation
including hind limb nail beds. (white arrow).

528 & Veterinary Emergency and Critical Care Society 2008, doi: 10.1111/j.1476-4431.2008.00341.x

that characterize the nephrotic syndrome. Dogs present
more commonly with incomplete nephrotic syndrome,15
as in the case described here, where edema and ascites
were absent.
Thromboembolism may develop both in humans and
in dogs with protein-losing nephropathies and nephro-
tic syndrome.16,17 Although early reports led to the as-
sumption that arterial thrombus formation was a rare
consequence of these diseases in dogs,11 a review of
clinical and pathological features of 137 dogs with pro-
tein-losing nephropathies and nephrotic syndrome re-
ported arterial thromboembolism as the second most
common cause of death, being present in 25.7% of all
cases that underwent necropsy examination.18 How-
ever, thromboembolic signs in a dog with nephrotic
syndrome secondary to leishmaniasis have only been
reported once in the scientific literature.6
The three main predisposing factors for thrombus
formation, known as Virchow’s triad, are endothelial
injury, abnormal blood flow (or stasis), and hyper-
coagulability.19 In this case, coagulation tests showed a
marked reduction in AT and a mild increase in serum
fibrinogen concentration, which is compatible with a
hypercoagulable state. In addition, the dog’s immobi-
lization during hospitalization could have impaired
normal blood flow, causing stasis.20
AT production is part of the body’s natural antico-
agulant system and its deficiency due to urinary loss
plays a major role in the pathophysiology of thrombi
formation in nephrotic syndrome.3,11 The highest risk of
thrombosis is correlated to an AT activity below 50%.11
In dogs, subnormal AT activity has been suggested as a
useful indicator for thrombotic tendency,18 which sup-
ports our findings. Another possible cause for dimin-
ished AT levels is increased consumption through clot
formation and enlargement. In the case described, AT
consumption probably occurred concomitantly with its
urinary loss.
The possibility of disseminated intravascular coagu-
lation (DIC) was also considered, as it has been de-
scribed in dogs with leishmaniasis.7 The diagnosis of
DIC remains a challenge due to the lack of specific
markers of hypercoagulability.21 The fibrinogen frag-
ment D/E assay had been advocated for DIC screen-
ing;22,23 however, this test has a low specificity for
DIC21 and critically ill dogs screened for hemostatic
dysfunction may show normal fragment D/E levels.24
A D-dimer assay or thrombelastography may be help-
ful for diagnosing and characterizing hypercoagulabil-
ity associated with DIC and other conditions.25–28
Considering the normal platelet counts in this case,
the hypothesis of an acute or an advanced DIC state
was unlikely. In patients with DIC, low platelet num-
bers have been correlated with the decrease of AT
& Veterinary Emergency and Critical Care Society 2008, doi: 10.1111/j.1476-4431.2008.00341.x
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Canine leishmaniasis and thromboembolism
activity.29 Furthermore, late-stage DIC is associated
with prolonged coagulation times and hypo-
fibrinogenemia, while our patient had normal pro-
thrombin time and activated partial thromboplastin
time values with hyperfibrinogenemia.30
Increased fibrinogen levels may have contributed to
thrombus formation, as fibrinogen is a precursor of fibrin,
increases blood viscosity, and stimulates platelet aggrega-
tion.17 Nephrotic syndrome triggers hyperfibrinogenemia
via increased liver fibrinogen synthesis and selective kid-
ney retention.17 Hypoalbuminemia and corticosteroid
treatment may also have contributed to the hypercoagu-
lable state in this patient.17
Font et al. described the only reported case of leish-
maniasis-induced nephrotic syndrome complicated by
aortic thromboembolism.6 In that case, the dog had a
2-month history of progressive weight loss, anorexia,
and diarrhea. The reason for referring the animal was a
sudden onset of weakness and proprioceptive deficits
of the left pelvic limb.
Font et al.6 described decreased AT levels (65%) and
hypofibrinogenemia, while we found lower AT activity
(50%) and hyperfibrinogenemia. The duration of dis-
ease may have accounted for these differences as, at the
time of clinical signs referable to thromboembolic signs,
disease was present for 18 days in our case and 54 days
in the former. Changes in hemostatic profile with time
and disease stage have been recognized in human pa-
tients with nephrotic syndrome.16 At earlier stages, AT
levels are diminished, while fibrinogen levels are in-
creased,31 similar to our clinical findings.
When the clinical signs suggestive of thromboembo-
lism appeared, specific diagnostic tests such as ultra-
sound were not available. The low-molecular-weight
heparin (LMWH) dalteparin was selected because this
type of heparin may have better bioavailability and
may achieve a higher peak plasma concentration than
unfractionated heparins of higher molecular weight.32
LMWH may also lower the risk of bleeding side-effects
because it shows more specific activity against coagu-
lation factor Xa.33 Several dosing regimes for LMWH
administration in dogs have been suggested, from
100 IU/kg once a day to 150 IU/kg 2 or 3 times a day,
depending on the LMWH used, the therapeutic goal,
and the patient’s clinical status.10,34–36 Reduced LMWH
doses and routine monitoring are advised in human
renal failure patients, because the anti-factor Xa activity
of LMWH is strongly correlated with creatinine clear-
ance.33 Although the safety of LMWH in renal failure
veterinary patients has not yet been thoroughly eval-
uated, we adopted the more conservative dose of
100 IU/kg once daily to avoid potential side-effects,
because monitoring of anti-factor Xa activity and
thrombelastography were unavailable.
529

N. Félix et al.
Dalteparin was initiated before the AT level was de-
termined. After laboratory data became available,
dalteparin was continued, as thrombolytic therapy us-
ing streptokinase or a tissue plasminogen activator10,37
was declined by the owner due to financial constraints.
The efficacy of LMWH in reducing further clot forma-
tion cannot be assessed due to the short duration of
treatment and the absence of data on anti-factor Xa ac-
tivity. Furthermore, the caudal vena cava thrombus, not
originally present, was only detected postmortem,
when the dog was off medication for 2 weeks.
Glucocorticoids are recommended for canine leish-
maniasis to decrease clinical signs caused by formation
and deposition of immunocomplexes. However, an as-
sociation of excess glucocorticoid administration and
thromboembolism occurrence in dogs has been sug-
gested.38,39 Therefore, glucocorticoids were discontin-
ued as soon as thromboembolic-related clinical signs
became apparent in our patient.
Prophylactic anticoagulation is prescribed for hu-
mans with nephrotic syndrome at a high risk of throm-
bosis to improve morbidity and mortality.40 A similar
approach could be advantageous for dogs with leish-
maniasis with nephrotic syndrome. Low-dose aspirin is
an attractive choice for thromboprophylaxis. Platelet
aggregation and thromboxane synthetase activation are
currently considered major pathophysiologic events for
the development of glomerular disease of several eti-
ologies.15 Low-dose aspirin (0.5 mg/kg, PO, q 24 h)
prevents coagulation by inactivating platelet cycloox-
ygenase, inhibiting platelet aggregation, while preserv-
ing endothelial prostacyclin formation and its beneficial
effects (vasodilatation, inhibition of platelet aggrega-
tion).39 Aspirin was not administered in this case due to
the risk of gastric ulceration in a patient with renal
failure receiving steroid therapy.
Specific thromboxane synthetase inhibitors have been
shown to decrease glomerular cell proliferation, poly-
morphonuclear leukocyte infiltration, and fibrin deposi-
tion in dogs with dirofilariasis-induced immune complex
glomerulonephritis.41 Other drugs that could be of
benefit to improve glomerular disease are angiotensin-
converting enzyme inhibitors and o-3 essential fatty
acids.38,39,42
Leishmaniasis-associated nephrotic syndrome can be
complicated by thromboembolic events, with signifi-
cant costs in terms of morbidity and mortality. The
similar outcome of the case described here and the 1
reported previously6 suggests that the presence of
thromboembolic events in dogs with leishmaniasis car-
ries a poor prognosis. Recent advances in the diagnosis
and understanding of procoagulant states in compan-
ion animals have increased the awareness of the vet-
erinary community for these challenging diseases. They
530 & Veterinary Emergency and Critical Care Society 2008, doi: 10.1111/j.1476-4431.2008.00341.x
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also provide new opportunities for early medical inter-
vention, possibly leading to better outcomes. We be-
lieve that a regular measurement of AT, fibrinogen, and
other coagulation parameters, performed early in the
course of leishmaniasis-associated protein-losing ne-
phropathy, should be considered for identification of
high-risk animals. For these dogs, the clinical benefit of
thromboprophylaxis with adequate anticoagulant re-
gimes should also be critically evaluated through ap-
propriate studies.
Footnotes
a
Clavamox 500, Laboratórios Bial-Portela & Ca, S.A., S. Mamede do
Coronado, Portugal.
b
Lepicortinolo, Decomed Farmacêutica S.A., Vila Nova de Gaia, Portugal.
c
d
0.9% saline, B Braun Medical Lda, Queluz de Baixo, Portugal.
Tagamet, Smith Kline, Algés, Portugal.
e
Witness Dirofilaria, Synbiotics Europe, Lyon, France.
f
Zyloric, GlaxoSmithKline, Algés, Portugal.
g
Torbugesic Fort Dodge Laboratory, Veterinaria SA, Girona, Spain.
h
Fragmin, Pfizer, Porto Salvo, Portugal.
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