Canine Thromboembolic Disease: A Case Study and Review.

David A. Geiger
Advisor: Scott Schatzberg, DVM
Clinicians: Sharon Center, DVM, ACVIM
Scott Schatzberg, DVM

Senior Seminar Paper

Cornell University College of Veterinary Medicine
February 19, 2003
Abstract

An adult castrated male golden retriever presented with signs of acute onset, progressive,

peripheral neuromuscular disease. A complete medical work-up revealed massive thrombosis of the

caudal aorta, femoral arteries, and right femoral vein, and a diagnosis of ischemic neuromyopathy was

made. Underlying disease included hypercoagulability secondary to protein-losing nephropathy.

Canine thromboembolic disease, although relatively uncommon, is associated with a wide

range of underlying disorders and clinical presentations. Diagnosis and treatment of patients can be

challenging, and clinical decisions may be complicated by limited data regarding efficacy of various

therapeutic options. An overview of the etiology of canine thromboembolic disease, available

diagnostic methods, and various treatment modalities, including thrombolytic therapies, will be

presented.

Signalment and History

Cody, a ten-year-old castrated male golden retriever, was referred to CUHA’s Triage Service

with a chief complaint of acute hindlimb paresis and pain. He had a history of left coxofemoral

arthritis and previous left cranial cruciate ligament repair. He had been managed with Cosequin,

Rimadyl, and aspirin for his long-standing orthopedic disease. Three weeks prior to presentation, the

owner reported an acute exacerbation of his existing orthopedic lameness. This lameness remained

non-progressive and seemed only mildly painful to the owner. Ten days prior to presentation, Cody

developed a severe acute lameness in his right hind limb. He was distressed, panting, and in noticeable

pain, with visible “knuckling” of his right hind paw. He received corticosteroid, opioid, and NSAID

therapy from his local veterinarian. Although Cody’s initial pain was controlled by this therapy, his

lameness progressed in severity until he was both non-weight-bearing and hypalgesic in his right hind

limb. At this point, he was referred to Cornell for further evaluation.

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Clinical Findings

On initial exam, Cody was tachypneic and tachycardic. He was ambulatory, but retained only

minimal use of his right hind leg, which was seemingly non-painful during extensive palpation and

manipulation. He showed only mild weakness in his left hindlimb. His femoral pulses were weak but

present bilaterally. Samples of blood were submitted for complete blood count and biochemical

profile, and Cody was monitored overnight.

By the next morning, Cody’s condition had deteriorated significantly. His gait was

characterized by complete atonia of the right hindlimb with intractable pain in both hindlimbs, and an

inability to bear weight on the left hindlimb. Based on this exacerbation of signs and extreme pain, a

compressive spinal lesion involving nerve roots was suspected. The diagnostic plan included

thoracolumbar myelography followed by CT scan and/or decompressive surgery if indicated.

After Cody was induced under general anesthesia, more thorough palpation of his limbs was

possible. His right hind paw was extremely cold, and femoral pulses were absent bilaterally.

Transection of a toenail at the level of the nailbed did not yield blood, confirming absence of

peripheral perfusion. An emergency ultrasound was arranged to evaluate suspected peripheral

thromboembolism.

Ultrasound findings included evidence of massive thrombosis of the caudal aorta and both

femoral arteries. The aortic thrombus began distal to the renal arteries and extended approximately 7.6

cm caudally to include the branches of both left and right external iliac arteries. Aortic occlusion was

complete, with no Doppler blood flow visible. An unidentified vessel with laminar blood flow was

observed parallel to the aorta in the occluded region and was interpreted to be a collateral artery.

Femoral artery thrombosis was also complete, with occlusion extending distally to the level of

the stifles bilaterally. Additionally, a thrombus was visualized within the lumen of the right femoral

vein. This thrombus caused incomplete occlusion; some blood flow around its margins was visible.

Blood flow through the left femoral vein was normal.

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 Ultrasound findings also included hyperechoic renal cortices bilaterally, which were interpreted

as significant and indicative of chronic nephropathy.

Cody’s clinical pathology data revealed a number of significant abnormalities. Serum

chemistry findings included hypoalbuminemia (2.5 g/dL), markedly increased creatine kinase (22,110

U/L) and AST (1543 U/L), and hypercholesterolemia (622 mg/dL). CBC revealed a stress leukogram.

Urinalysis findings included marked proteinuria (1105 mg/dL), a component of which was measured

as hemoprotein, and an elevated protein:creatinine ratio (9). Coagulation panel revealed significantly

decreased serum antithrombin III activity (48%), increased fibrinogen (1203 mg/dL), and mildly

shortened prothrombin time (13 sec).

Other ancillary studies included a heartworm test and Leptospira titers, both of which were

negative, and a thyroid panel, which was within normal limits.

Problems

Our problem list consisted a bilateral huindlimb neuromyopathy, peripheral

thrombosis/thromboembolism, proteinuria, hypoalbuminemia, increased serum CK and AST,

hypercholesterolemia, decreased serum ATIII levels, and increased fibrinogen. These problems are

best addressed in groups and as they relate to the laboratory data.

Differential Diagnoses

The discovery of Cody’s peripheral thrombosis confirmed ischemic degeneration as the cause

of his neuromyopathy. In cases of intravascular thrombosis/thromboembolism, the severity of

ischemic injury to tissues is due to both primary loss of blood flow as well as secondary effects of

vasoactive substances released by the thrombus. Thromboxane A2, serotonin, prostaglandins, and 5-

hydroxytryptamine are thought to induce massive peripheral vasoconstriction, impairing collateral

circulation. This mechanism is supported by studies demonstrating that surgical ligation of the caudal
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aorta fails to produce signs comparable to those observed in aortic thromboembolism. Additionally,

pre-treatment with antagonists to thromboxane A2 and serotonin provide some protection against

ischemic tissue necrosis in animals with experimentally induced aortic thromboembolism (Kittleson).

Proteinuria carries a relatively long list of differentials based on three categories of origin: pre-

renal, renal, or post-renal. When concurrent hypoalbuminemia, is present, renal (glomerular) disease is

typically implicated. An increased urinary protein:creatinine ratio, indicating clinically significant

renal proteinuria, supports this conclusion. The two main causes of glomerular disease are

glomerulonephritis and amyloidosis.

Glomerulonephritis is an inflammatory disease of the glomerular capsule which leads to

inappropriate proteinuria. This disease process is characterized by the accumulation of antigen-

antibody complexes in the glomerular capsule. Immune complexes may be formed remotely and

deposited at the filtration barrier, or circulating antibodies may bind to antigenic moieties located on or

intrinsic to glomerular cells. Chronic glomerular inflammation leads to degeneration of the filtration

barrier, ultimately resulting in inappropriate filtration of serum proteins. Nearly any disease process

which provokes a robust circulating antibody response has the potential to induce glomerulonephritis.

In Cody’s case, initial and ancillary diagnostics ruled out several potential underlying diseases,

including dirofilariasis, sepsis, leptospirosis, and pancreatitis. Several major disease categories

remained uninvestigated, however, including immune-mediated disorders, rickettsial disease,

neoplasia, and idiopathic disease.

Amyloidosis is a manifestation of systemic inflammatory disease in which amyloid fragments

are deposited in multiple organs, including the kidneys. Amyloid is an acute-phase reactant protein

produced in response to tissue damage. Accumulation in the kidney occurs in the glomerular capsule,

and inflammatory destruction of the filtration barrier results in proteinuria. Although amyloidosis is a

differential for glomerular disease, it is relatively rare. Additionally, Cody did not show overt signs of

systemic inflammatory disease or multi-organ dysfunction. Amyloidosis was therefore considered less
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likely as a cause of his renal disease. The only way to differentiate amyloidosis from

glomerulonephritis definitively is via renal biopsy, which was not performed.

When sufficient protein is excreted in the urine, nephrotic syndrome may develop. By

definition, nephrotic syndrome is a compilation of four clinical abnormalities: proteinuria,

hypoalbuminemia, generalized edema, and hypercholesterolemia. Cody did not exhibit peripheral

edema; his nephropathy was characterized as early nephrotic syndrome.

Creatine kinase and AST, both muscle-specific enzymes, are liberated via any type of myocyte

damage. The combined findings of significantly increased creatinine kinase and AST indicate severe

muscle insult, which, in Cody’s case, was due to ischemia.

Cody’s most significant coagulation abnormality was decreased antithrombin III (ATIII).

Antithrombin III is the primary inhibitor of the common coagulation pathway. It acts to inhibit the

conversion of prothrombin to thrombin, and subsequently decreases the rate of fibrin production.

Antithrombin III is lost early in protein-losing disorders due to its low molecular weight. Decreased

serum ATIII, secondary to renal disease, is a common cause of a hypercoagulable state in dogs (Fox).

Increased fibrinogen activity may simply reflect underlying inflammatory disease, or it may be

a result of increased thrombin production and activity. The finding of a shortened PT was equivocal;

alone, it would not reflect a primary problem. It is, however, consistent with the other findings

suggesting a hypercoagulable state.

Intravascular thrombosis occurs via one of three mechanisms: significant alterations in laminar

blood flow, damage to vascular endothelium, or presence of a hypercoagulable state (Fox). Sluggish

or static blood flow promotes coagulation due to erythrocyte and platelet clumping. It remains the

primary etiology of peripheral thromboembolism secondary to cardiac disease in cats, but is rare in

dogs (Kittleson).

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 When vascular endothelial cells are damaged, liberated intracellular pro-adhesion molecules

and inflammatory cytokines stimulate the coagulation cascade. Any disease which causes

inflammatory or traumatic injury to blood vessels can initiate this process (Fox).

Persistence of a hypercoagulable state is recognized as a common cause of peripheral

thromboembolism in dogs. While primary hemostatic abnormalities causing hypercoagulability are

extremely rare, there are a number of disease processes which induce secondary coagulopathies. As

mentioned previously, decreased levels of anticoagulant factors, primarily ATIII, secondary to protein-

losing nephropathy are a common cause of hypercoagulability in dogs. Other disorders which may

induce hypercoagulable states include hyperadrenocorticism, IMHA, hypothyroidism, and neoplasia.

Increased levels of pro-coagulant factors, or altered factor activity, may also lead to inappropriate

coagulation (Van Winkle).

In Cody’s case, altered blood flow was considered unlikely as a primary cause of intravascular

thrombosis. After initial arterial thrombosis, however, we believe that blood stasis on the venous side

was a likely cause of the right femoral vein thrombosis.

Although direct evidence of vascular damage was not found, a contributing component of

diffuse vasculitis was considered possible. Many of the potential underlying causes of Cody’s

glomerular disease have the potential to induce vascular inflammation.

Persistence of a hypercoagulable state was the most clearly documented cause of thrombosis in

this case, supported directly by evidence of chronic renal disease and decreased serum ATIII.

Diagnosis

Presumptive diagnosis was ischemic neuromyopathy secondary to aortic

thrombosis/thromboembolism. The suspected underlying etiology was hypercoagulability due to

protein losing nephropathy and diffuse vasculitis. While we were able to determine the mechanism of

disease responsible for Cody’s clinical presentation, the underlying cause remains unknown.
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Treatment

In all cases of peripheral thromboembolic disease, treatment must address both the acute

ischemic crisis as well as the underlying disease process. Ideally, treatment would include

anticoagulant therapy and extensive supportive care with sequential monitoring of coagulation

parameters. Treatment to address the underlying disease should be tailored to its specific cause, and

should minimize the potential for future thrombosis.

Due to financial constraints, our treatment was restricted to conservative supportive care in the

short term. Empirical therapy was initiated to address Cody’s underlying disease without a definitive

diagnosis.

Anticoagulant therapy consisted of aspirin, an NSAID, and coumadin, a vitamin K antagonist.

While aspirin, an inhibitor of platelet function, is a relatively benign drug, coumadin has the potential

to cause uncontrollable bleeding, and coagulation parameters should be monitored carefully during its

use.

It is important to stress that anticoagulant therapy only acts to prevent further thrombus

formation. Our treatment plan relied on normal mechanisms of recannulation and formation of

collateral circulation to resolve the existing thrombosis.

Empirical medical therapy was intended to address a wide range of potential underlying

diseases responsible for Cody’s renal disease and his presumptive vasculitis. We chose doxycyline

based on its activity against the typical infectious agents that might lead to glomerulonephritis,

enalapril for its ability to reduce hydrostatic pressure in the glomerulus and moderate proteinuria,

piroxicam and fentanyl for control of inflammation and pain, and omega-3 fatty acids for their

potential anti-inflammatory effects. Supportive care included frequent limb massage, range-of motion

exercises, and assisted walks.

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Outcome

Treatment was continued for approximately one week. A coagulation panel drawn two days

after initiation of coumadin therapy revealed excessively prolonged clotting times, and the coumadin

dose was reduced accordingly. Further coagulation tests were not conducted due to financial

constraints. Serum lactate and pH were measured from samples obtained from venous circulation in

both hindpaws. Excessively high lactate and low pH were measured in the right hindpaw as compared

with the left, which correlated with the relative severity of ischemic injury between limbs.

Following initiation of our treatment, significant improvement was noted. Cody’s left hindlimb

function improved to near normal with minor motor deficits, and he exhibited some voluntary

movement of his right hindlimb. Femoral pulses became consistently strong on his left side, and

intermittently palpable on the right. Despite this improvement, his prognosis for long-term health was

extremely guarded without identification of his underlying disease. For this reason, Cody’s owner

decided that euthanasia was the most humane option for him.

Discussion

Canine thromboembolic disease is a relatively rare but important clinical disorder of veterinary

medicine. While peripheral thrombosis in dogs is related to the analogous and more common disease

in cats, the underlying disease processes differ greatly. Furthermore, diagnosis of this disorder in dogs

is complicated by inconsistency of signs as compared to a typical feline presentation. Retrospective

studies suggest that as many as half of all dogs affected with peripheral thromboembolic disease

present with recurrent or progressive signs. This is in stark contrast to the typical acute presentation of

feline peripheral thromboembolic disease, and may delay prompt diagnosis and treatment. As

discussed, canine thromboembolic disease is a secondary manifestation of an underlying disease

process, and all cases require a treatment plan which addresses both the acute ischemic crisis as well as

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the underlying disease. A definitive diagnosis is often impossible to make, and empirical therapy may

be necessary to reduce the risk of recurrent thrombosis.

Although not used in this case, several types of thrombolytic therapies exist which may be of

clinical use in veterinary medicine. All of these treatment modalities, including surgical embolectomy

and chemical thrombolysis, have been adapted from their original applications in human medicine.

Several important fundamental discrepancies between thromboembolic disease in humans and in dogs

must be considered when evaluating the potential benefit of these therapies.

The most significant manifestations of thromboembolic disease in humans are pulmonary,

cerebral, and cardiac emboli – all acutely life-threatening conditions requiring immediate resolution.

These events are generally dramatic, and immediate medical attention is frequently sought. As a

result, doctors treating human thromboembolic disease often have the opportunity, and the need, to

administer therapy within hours of an acute event. Conversely, the clinical manifestations of canine

thromboembolic disease are generally limited to pulmonary and distal aortic emboli and, less

frequently, cerebrovascular accident. Due to limited accessibility to veterinary care and widely

variable clinical presentations of disease, diagnosis of peripheral thromboembolism in dogs is often

delayed significantly. This lowers the potential efficacy of therapies which are designed for immediate

use (Fox). Furthermore, there is significant evidence to show that dogs are able to recover more

rapidly than humans from pulmonary thromboembolism, a human disease modeled extensively in

dogs. Specifically, experimental data shows that dogs typically recover from massive pulmonary

embolism within six weeks, while resolution in humans may take up to a year. The mechanism of clot

lysis in dogs is thought to be significantly more effective than in humans, and may be a result of

increased activity of endogenous plasminogen activators in dogs (Lang). These findings suggest that

immediate, aggressive thrombolytic therapy for peripheral thromboembolic disease in dogs may not be

necessary in many cases.

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 Surgical embolectomy has been evaluated experimentally in cats, but is associated with a high

rate of morbidity/mortality and is not generally considered a viable therapy for peripheral

thromboembolism (Kittleson). Similarly, very little clinical data has demonstrated efficacy for this

approach in dogs. Complications of embolectomy include re-thrombosis and reperfusion injury. It

may be possible to reduce the risk of reperfusion injury and other complications of embolectomy via

intensive monitoring and supportive care, but this therapy remains to be proven clinically efficacious

(Kittleson).

Thrombolytic drugs, which actively dissolve existing thrombi, have been used extensively in

human medicine to treat thromboembolic disease. The advantages of this type of therapy include

potentially rapid resolution of acute disease and shorter recovery times. The disadvantages, which are

extensive, include risk of hemorrhage, little to no clinical data regarding efficacy or safety in domestic

animals, and potentially prohibitive costs. The two main thrombolytic drugs available for use in

veterinary medicine are streptokinase and recombinant tissue plasminogen activator.

Streptokinase is a plasminogen activator derived from β-hemolytic Streptococcus spp. It

catalyzes the conversion of plasminogen to plasmin, which is the primary protein responsible for

fibrinolysis. Unfortunately, streptokinase is active in vivo against all circulating plasminogen, and

causes fibrinolysis systemically. This creates a risk of hemorrhage. Because it is of bacterial origin,

anaphylactic reactions are also a risk. Only one study exists reporting the effects of streptokinase in

dogs with peripheral thromboembolism. Ramsey, et al, treated four dogs suffering from

thromboembolic disease with streptokinase. One dog had a right atrial thrombus with no signs of

peripheral thromboembolism. The remaining three dogs were each treated with streptokinase infusions

and achieved clinical improvement (ambulation) in 2-4 weeks. Two dogs died suddenly at 6 weeks

and 10 months post-recovery; the third was not followed beyond 6 months. Control animals were not

used. The results presented do not suggest that streptokinase provides shorter recovery than

anticoagulant therapy alone, but further studies are warranted.

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 Another experimental study using streptokinase in cats with artificially thrombosed caudal

aortas suggested low morbidity with tested doses, but no significant clinical improvement was noted

post-therapy (Kittleson).

A recombinant form of endogenous tissue plasminogen activator (TPA) was created for human

medicine to address some of the disadvantages of streptokinase, most notably its lack of clot

specificity. TPA’s mechanism of action is the same as streptokinase; it is released from vascular

endothelial cells and acts to balance coagulation with fibrinolysis in vivo. In circulation, however,

TPA is bound to an inhibitory protein, plasminogen activator inhibitor (PA-i), until it comes in contact

with a fibrin clot, at which point TPA is cleaved, becoming active. This relative fibrin specificity

allows use of TPA therapy with a significantly reduced risk of systemic hemorrhage. The extremely

short half-life of TPA in vivo (2-3 minutes) also reduces the risk of unintended hemorrhage. However,

this risk is still present due to residual anticoagulant effects, and may increase with higher doses, such

as those needed to break up large thrombi (Clare). In humans, TPA is used often for cerebral, cardiac,

and pulmonary embolisms, which are typically smaller than those seen in aortic thromboembolism.

This raises the possibility of decreased clot specificity at clinically useful doses for canine peripheral

thromboembolism. Finally, TPA is extremely expensive; the cost of the drug alone for a large-breed

dog exceeds $1000.

Some clinical data exists regarding the use of TPA in cats with aortic thromboembolism. In

one study, 43% of cats treated with TPA regained limb function within two days. Unfortunately, 50%

of the cats treated died during therapy, primarily from reperfusion injury. Furthermore, 90% of the

recovered cats rethrombosed within three months despite anticoagulant therapy (Kittleson). These

results suggest that TPA is potentially useful if its effects can be moderated to reduce reperfusion

injury. Nonetheless, even successful resolution of acute disease must be viewed in light of the variable

ability to prevent recurrent episodes.

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 In dogs, clinical data documenting TPA’s effects is limited to a single published case. Clare

and Kraje report the use of TPA in a dog with aortic thrombosis secondary to protein-losing

enteropathy. In this case, multiple boluses of TPA were administered, after which circulation rapidly

improved. Rethrombosis several days later necessitated repeat administration of TPA. Clinical

improvement was noted after two weeks, and normal function had returned by seven weeks. The dog’s

status was not reported beyond five months (Clare). While the initial rapid improvement in this case is

notable, lasting recovery did not begin until two weeks post-therapy. Again, we do not believe this

demonstrates a significant decrease in recovery time compared with our own case. Because data

regarding TPA use in dogs is so limited, reliable conclusions regarding its efficacy cannot be drawn at

this time. However, TPA’s extensive success as a thrombolytic therapy in humans and its

demonstrable superiority over urokinase (an endogenous streptokinase analogue) regarding speed of

thrombolysis (Prewitt, Hoy) warrant further clinical investigation in dogs.

Veterinarians face substantial obstacles in the diagnosis and treatment of disorders as complex

as canine thromboembolic disease. The difficulty in making prompt, definitive diagnoses, along with

the extensive resources needed to appropriately manage such a disease creates a significant challenge.

Lack of conclusive data regarding available therapies further complicates this process. While disorders

do exist that can be managed effectively with conservative treatment, thromboembolic disease is not

one of them. Effective resolution of clinical signs requires aggressive medical therapy with continued

monitoring of effects. The costs of therapy may be prohibitive, and the risk of recurrence is

significant. Refinement of emerging therapies may prove beneficial, but the unique demands of the

veterinary patient -both physiological and practical- must be considered.

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 References

DeLahunta, Alexander. Veterinary Neuroanatomy and Clinical Neurology. Philadelphia: Saunders,

1983.

Kittleson, Mark; Kienle, Richard. Thromboembolic Disease. In Small Animal Cardiovascular

Medicine. St. Louis: Mosby, 1998.

Fox, Philip, et al: Peripheral Vascular Disease. In Ettinger’s Textbook of Veterinary Internal
Medicine. Saunders, 2000.

Van Winkle TJ, et al. Clinical and pathological features of aortic thromboembolism in 36 dogs. J Vet
Emerg Crit Care 3:13, 1993.

Lang IM, et al: Factors contributing to increased vascular fibrinolytic activity in mongrel dogs.
Circulation 87:1990, 1993.

Ramsey CC, et al. Use of streptokinase in four dogs with thrombosis. JAVMA 209:780, 1996.

Clare AC, et al. Use of recombinant tissue-plasminogen activator for aortic thrombolysis in a
hypoproteinemic dog. JAVMA 212:539, 1998.

Prewitt RM, Hoy C, et al. Thrombolytic therapy in canine pulmonary embolism. Comparative effects
of urokinase and r-TPA. Am Rev Respir Dis. 1990 Feb;141(2):290-5.

Prewitt RM. Principles of thrombolysis in pulmonary embolism. Chest. 1991 Apr;99(4 Suppl):157S-
164S.

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Boswood A, Lamb CR, White RN. Aortic and iliac thrombosis in six dogs. J Small Anim Pract. 2000
Mar;41(3):109-14.

Ariani M, Fishbein MC, et al. Dissolution of peripheral arterial thrombi by ultrasound. Circulation.
1991 Oct; 84(4):1680-8.

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