Aortic thromboembolism in cats (Proceedings)

*These proceedings previously published for the 2007 AVMA Convention; Washington, DC.

Introduction:

Distal aortic thromboembolism (ATE) is most commonly recognized as a devastating sequel to underlying cardiac disease in the cat. The purpose of the following pages is to present the reader with a review of the veterinary literature as it pertains to pathophysiology, diagnosis, treatment, and prognosis for cats with ATE as well as to provide some comparisons between different treatment and prophylactic measures.

Incidence and Pathophysiology:

ATE most commonly affects middle-aged (5-7year) male domestic variety cats. (male:female ratio 2:1 – 3:1). Most affected cats are spayed or neutered, however, analysis has not identified sterilization or lack thereof as a significant risk factor.1-2 The vast majority of cats with ATE have clinical evidence of underlying cardiac disease, however, neoplasia, aortic surgery, infectious disease, sepsis, and foreign body have all been associated with this condition. On rare occasion, a predisposing condition is not identified. ATE is seen in approximately 10-20% of cats with underlying cardiac diseases and is associated with concurrent evidence of congestive heart failure (CHF) in greater than 50% of cases.1-3

In 1856, Virchow proposed that blood stasis, a hypercoagulable state, local vascular injury or a combination thereof may predispose to thrombosis (Virchow's Triad). Most, if not all, of the underlying conditions in cats with ATE can be explained by one more aspects of Virchow's Triad. Cats with underlying cardiac disease and left atrial enlargement will have stasis of blood in the left atrium and/or left atrial appendage, In addition, endocardial changes are common on histopathologic examination of the heart in these cats. Recently, some risk factors for thromboembolic disease in humans have also been investigated in cats with ATE.4-5 Hyperhomocysteinemia was not identified as an independent risk factor for ATE, however, it is quite possible that other factors predisposing to hypercoagulable states may be identified in cats with ATE in the future.4-5

ATE is an embolic event. We believe that the thrombus forms within the enlarged left atrium and is then ejected into the systemic circulation, most commonly lodging in the terminal aorta. Mere obstruction of the lumen of the aorta is not the only factor contributing to decreased perfusion to the hind-limbs as it has been well documented that even after ligation of the terminal aorta, collateral circulation will maintain oxygen delivery to the hind-limbs. It is strongly believed that the interplay of the activated platelets within the ATE results in the elaboration of numerous vasoactive mediators including but not limited to Thromboxane A2 (TXA2) and serotonin. These mediators cause vasoconstriction and limit flow through the collateral circulation. A well-established model of ATE in cats is characterized by ligation of the terminal aorta, 6th lumbar, and deep circumflex iliac arteries and aortic injection of bovine thromboplastin.6

Diagnosis:

Distal ATE is most often a clinical / physical examination diagnosis that is later confirmed through ancillary diagnostic testing such as angiography, aortic ultrasound, differential blood flow as detected by Doppler between the fore and hind-limbs, or differential hind-limb: fore-limb glucose (significantly decreased in hind-limbs) and lactate concentrations (significantly increased in hind-limbs).7

Physical examination findings consistent with distal ATE include absent or weak hind-limb pulses, hind-limb pain, hyporeflexia / areflexia, cool extremities, cyanotic nail beds, firm gastrocnemius muscles, and paresis or paralysis. In cases where distal ATE extends more proximally, additional clinical signs referable to acute renal failure or ischemic gastrointestinal disease may be present.

When ultrasonographically imaging the distal aorta, the clinician must recognize that immature emboli tend to be relatively hypoechoic and difficult to identify when compared to more mature emboli. In these instances, angiography or non-selective CT aided angiography can help identify the extent of the ATE.

Acute Management of Cats with ATE:

Much debate exists as to the appropriate therapeutic strategy for the initial management of cats with ATE. Therapy may be directed towards preventing progression and recurrence of ATE through anticoagulation and supportive care (conservative approach) or towards clot lysis and prevention of recurrence through anticoagulation. The following summarizes the current veterinary literature on options for the management of ATE.

There is little debate that stabilization of major body systems and appropriate management of the underlying condition (cardiac disease in 45/46 cases in one series) should be a priority in cats with ATE.8 CHF (if present) is most often brought under control through oxygen therapy, diuretic administration, sedation, vasodilation, and appropriate cardiac medications for the specific type of underlying cardiac condition.

Uniformly, cats that present with acute ATE have significant discomfort and stress. It is reasonable to assume that pain and stress associated activation of the sympathetic nervous system would be less that ideal for cats with significant underlying cardiac disease. Aggressive strategies for providing analgesia and sedation for cats with ATE are indicated. The author prefers to use a combination of Fentanyl (Abbott Laboratories, N. Chicago, IL) administered by constant rate infusion (CRI) at 2(g/Kg bolus then 2-5(g/Kg/hr for analgesia and Midazolam (Abbott laboratories, N. Chicago, IL) (0.1-0.22mg/Kg IV) for sedation. Sedation administered early in the course of management of patients with ATE will also facilitate completion of phlebotomy, acquisition of vascular access, placement of a feeding tube, and diagnostic procedures with minimal stress to the patient. Early placement of a feeding tube will allow early nutritional support (most cats with ATE are anorexic) and the administration of free water so as to help maintain hydration while keeping solute load to a minimum.

Heparin exerts its anticoagulant effect through activation of ATIII with subsequent inhibition of activated factors XII/XI/X/IX/II. Heparin is used extensively in the initial management of cats with ATE, however, its efficacy in preventing progression of the clot or improving survival when compared to aspirin or warfarin has not been substantiated. The author prefers to administer heparin by a loading dose 100u/Kg IV followed by a CRI at 10-30u/Kg/hr. Endpoints or efficacious values for aPTT prolongation (1.5-2.5x control) have been "borrowed" from the human literature largely based on efficacy in a different disease process (deep venous thrombosis). Presently, know neither the efficacy nor what is an appropriate level of anticoagulation for preventing thrombus extension or recurrence in cats. Contrary to the thought that bleeding is a "major" complication of heparin therapy9 , the author has only experienced one minor bleeding complication in a cat managed initially with unfractionated heparin. Preliminary work investigating Low Molecular Weight Heparin (LMWH) (Fragmin; Pharmacia Inc., Peapack, NJ) has shown efficacy in increasing anti-Xa activity in cats.10 Further investigation is warranted to determine the potential efficacy of LMWH for use in cats with ATE.

Aspirin exerts its anti-thrombotic effects through inhibition of the production of TXA2 and thus platelet activation via inhibition of cyclooxygenase. Optimal dosage of aspirin and its efficacy for the management of ATE is currently unknown. However, aspirin administered at 25mg/Kg PO every 48-72hrs is a generally safe and commonly used medication for the initial and long term management of cats with ATE. One of the limitations of aspirin is that it may only inhibit platelet activation in response to TXA2, and not in response to numerous other stimulators of activation such as thrombin and subendothelial collagen. In the future, other agents such as GPIIa/IIIb antagonists may prove to be of greater benefit for prevention of platelet activation in cats with ATE.

Because of the local elaboration of vasoactive substances, one area of treatment has focused on vasodilator therapy to help "open up" collateral circulation and improve hind-limb perfusion. Acepromazine is probably the most widely used of these medications. Acepromazine has not been shown to counteract the vasodilation induced by local vasoactive mediators, nor has it been shown to improve perfusion to the hind-limbs of cats with ATE. In addition, acepromazine has a long half-life and may cause hypotension. Acepromazine should be used with caution in cats with ATE.

A medication that has been used to theoretically counteract local serotonin associated vasoconstriction is cyproheptadine. This therapy is also not proven successful in the clinic, however, it is quite safe and there is some evidence that pretreatment with serotonin antagonists in experimentally induced ATE does improve hind-limb perfusion.11 Cyproheptadine may also improve appetite. In one series of cats with ATE, of the 19 survivors, 5 had received cyproheptadine.1 In addition, 63% of cats that received cyproheptadine survived. Statistical analysis reveals that survival in cats that received cyproheptadine was not significantly different than survival in those that had not received cyproheptadine although this finding could be a result of Type II error.

Thrombolytics and Thrombectomy:

Streptokinase (Astra USA Inc., Westborough, MA) is an exogenous activator of plasminogen derived from streptococcus species with activity in the dog, cat, rabbit, and primate.12 Streptokinase was initially investigated as a potential thrombolytic for cats with experimentally induced ATE in 1986. Results identified a dose range that was well tolerated in normal cats and caused laboratory evidence of fibrinolysis, but only illustrated very marginal efficacy towards restoring blood flow to the hindlimbs.6 However, it must be recognized that multiple factors including the model, duration of therapy, and dose of streptokinase administered may not have been appropriate for the naturally occurring disease in cats. The conclusion was made that streptokinase warranted further investigation for use as a thrombolytic in cats with ATE.

Streptokinase moved into the clinical arena in the 1990s with two series of studies to evaluate efficacy in naturally occurring ATE. One series identified 6 cats with ATE in which 90,000u was administered IV as a loading dose over 30min and was followed with 45,000u/hr for various dosing intervals. All 6 cats died during SK infusion.13 Electrolyte abnormalities (hyperkalemia) thought to result from rapid reperfusion were identified in three cats just prior to death.13

A second series of cats (n=46) received streptokinase at various doses and over various durations.8 In this series, 25/44 regained femoral pulses within 24 hours and 14 regained motor function (11 in the first 24 hours).8 However, overall, 18 cats died while hospitalized and 13 additional cats were euthanized due to poor response to treatment or complications. In this series, 15 cats were discharged from the hospital. ATE recurred in 7 of those 15 cats discharged from the hospital.8

Overall survival to discharge was comparable between the two large scale retrospective studies in which cats with ATE were treated without thrombolytics and that in which 46 cats were treated with streptokinase (there was not a statistically significant difference).1,2,8 Additional investigation to compare the duration of time to return to function, cost of hospitalization, and numerous other factors between different treatment groups would be very interesting.

Tissue Plasminogen Activator (TPA) is a serine protease that preferentially activates plasminogen in the presence of fibrin. TPA has seen very limited use in ATE in cats most likely due to its high price. One case series demonstrated acute thrombolysis and rapid return to ambulation in 43% of cats treated with TPA, however, a mortality rate of 50% was demonstrated concurrently.14

Rheolytic thrombectomy has recently been described as an alternative for management of cats with ATE.15 Rheolytic thrombectomy involves catheterization of the carotid artery and passage of the thrombectomy catheter down the aorta using fluoroscopic guidance. Although only 6 cats were treated in this prospective pilot study, only 3 cats survived to discharge (comparable to thrombolytics and conservative therapy strategies).

Prevention and Prognosis:

Survival to discharge from the hospital has been reported to be from 33-39% in the three large retrospective evaluations of cats with ATE.1,2,8 If one pools and evaluates each of the survivors from these studies, survival in cats that received aspirin (n=18) was 6.8 ± 10.5months; median 2.9months and in those that received warfarin (n=24), was 11.4 ± 11.3months; median 9mo. Statistically, there was no difference in duration of survival between these two groups of cats (p>.05). There was a 37% incidence of re-embolization in the aspirin group and a 50% incidence in the warfarin group. There was not a significant difference in the incidence of re-embolization or the time to re-embolization between cats that received aspirin and those that received warfarin. One must take extreme caution in interpreting these results because dose / degree of anticoagulation induced by warfarin and dose of aspirin as well as numerous other factors such as type of underlying cardiac disease and concurrent treatment measures are not accounted for. Of some concern was that 12.5% (3/24) of cats treated with warfarin died or were euthanized due to warfarin associated hemorrhage.

Recently, the antiplatelet effects of clopidogrel (Plavix; Bristol-Meyers-Squibb-Sanofi; New York, NY) a thienopyridine have been investigated in the laboratory setting. Clinical studies are ongoing.

The Future:

In the future, we must strive to better understand the pathophysiology of ATE in cats and to objectively determine optimal methods for treatment and prevention of ATE. Stimulation of angiogenesis with agents such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (BFGF) may prove to be an interesting area of future investigation for the management of ATE in cats. These agents have shown some promise for inducing angiogenesis in canine and rabbit models of hind-limb ischemia. In addition, a prospective clinical trial evaluating aspirin, heparin, LMWH, warfarin, and alternative inhibitors of platelet function may help elucidate the optimal agents for prophylaxis against re-embolization.

Finally, the veterinary community must recognize that the prognosis for cats with ATE is not as poor as current opinion may believe and that with aggressive initial treatment and diligent supportive care, meaningful periods of survival are possible.

References:

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Laste NJ, Harpster NK. A retrospective study of 100 cases of feline distal aortic thromboembolism: 1977-1993. J Amer Anim Hosp Assoc 1995;31: 492-500

Fox PR. Feline Cardiomyopathies. In: Fox PR, Sisson D, Moise NS eds. Textbook of Canine and Feline Cardiology Principles and Clinical Practice; 2nd ed. Philadelphia: WB Saunders Co; 1999. Pp. 658-678

Hohenhaus AE, Fimantov R, Fox PR et al. Evaluation of plasma homocysteine concentrations in cardiomyopathic cats with congestive heart failure and arterial thromboembolism. Proceedings of the 17th Annual ACVIM Forum. Chicago, IL 1999. P. 715

McMichael MA, Freeman LM, Selhub J et al. Plasma homocysteine, B vitamins, and amino acid concentrations in cats with cardiomyopathy and arterial thromboembolism. J Vet Int Med 2000;15: 507-512

Killingsworth CR, Eyster GE, Adams T et al. Streptokinase treatment of cats with experimentally induced aortic thrombosis. Am J Vet Res 1986;47: 1351-1359

McMichael M, Rozanski EA, Rush JE. Low blood glucose levels as a marker of arterial thromboembolism in dogs and cats. Proceedings of the 6th International Veterinary Emergency and Critical Care Symposium. San Antonio, TX 1998. P. 836

Moore KE, Morris N, Dhupa N et al. Retrospective study of streptokinase administration in 46 cats with arterial thromboembolism. J Vet Emerg Crit Care 2000;10: 245-257

Fox PR. Feline Cardiomyopathies. In: Ettinger SJ, Feldman EC eds. Textbook of Veterinary Internal Medicine; Diseases of the Dog and Cat; 5th ed. Philadelphia: WB Saunders Co; 2000. Pp. 914-923

Goodman JS, Rozanski EA, Brown D et al. The effects of low molecular weight heparin on hematologic and coagulation paramateres in normal cats. Proceedings of the 17th Annual ACVIM Forum. Chicago, IL 1999. P. 733

Nevelsteen A, De Clerck F, De Gryse A. Restoration of post-thrombotic peripheral collateral circulation in the cat by ketanserin, a selective 5-HT2 receptor antagonist. Arch Int Pharmacodyn Ther 1984;270: 268-279

Wulf R, Mertz E. Studies on plasminogen VIII. Species specificity of streptokinase. Can J Biochem 1969;47:927-931

Ramsey CC, Riepe RD, Macintire DK et al. Streptokinase: a practical clot-buster? Proceedings of the 5th International Veterinary Emergency and Critical Care Society Symposium. San Antonio, TX 1996. Pp. 225-228

Pion PD. Feline aortic thromboemboli and the potential utility of thrombolytic therapy with tissue plasminogen activator. Vet Clin North Am Sm Anim Pract 1988;18: 79-86

Reimer SB, Kittleson MD, Kyles AE. Use of rheolytic thrombectomy in the treatment of feline distal aortic thromboembolism. J Vet Intern Med. 2006;20: 290-6