Aortic thromboembolism in cats (Proceedings)

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. 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.

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 or 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.4 Investigations of cats with cardiac disease and those with ATE suggest that a hypercoagulable state may play a role in the development of ATE in some individuals. Future studies utilizing thromboelastography may aid in the further evaluation of hypercoagulable states in cats with ATE in helping elucidate whether the problem is one of primary hemostasis, hypercoaglability, impaired fibrinolysis, or a combination thereof.

ATE is an embolic event. It is believed 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.

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: central glucose (significantly decreased in hind-limbs) and lactate concentrations (significantly increased in hind-limbs).

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. Color doppler ultrasound techniques may aid in better imaging the area in question. Alternatives including 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/removal and prevention of recurrence through anticoagulation. The following summarizes the current options for the management of ATE.

General Treatment Considerations: 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. 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 than 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 administered by constant rate infusion (CRI) at 2g/Kg bolus then 2-5g/Kg/hr for analgesia and Midazolam (0.1-0.22mg/Kg IV) for sedation. Sedation and analgesia 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 (sodium) load to a minimum.

Conservative Treatment Considerations: Heparin exerts its anticoagulant effect through activation of Antithrombin (AT) 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. After routine assessments of hemostasis (platelet count, PT, aPTT, fibrinogen, AT, D-dimer) to ensure than an underlying hypocoaglable state is not present, the author prefers to administer heparin by a loading dose 100u/Kg IV followed by a CRI at 10-30u/Kg/hr. Heparin therapy should be initiated as quickly as possible. 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, we know neither the efficacy nor the appropriate level of anticoagulation for preventing thrombus extension/propagation or recurrence in cats. Contrary to the thought that bleeding is a "major" complication of heparin therapy, the author has only experienced one minor bleeding complication in a cat managed initially with unfractionated heparin. Work investigating low molecular weight heparins (LMWH) has shown efficacy in increasing anti-Xa activity in cats.10-12 However, results to date bring into question the practicality of their use in the acute management of 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 anti-platelet agents may prove to be of greater benefit for prevention of platelet activation in cats with ATE. Please see Prevention and Prognosis below.

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 extreme 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 clinical setting, however, it is quite safe and there is some evidence that pretreatment with serotonin antagonists in experimentally induced ATE does improve hind-limb perfusion while mitigating the clinical signs.13-14 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.

Conservative therapy (excluding thrombolytic therapy and thrombectomy) of cats with ATE results in approximately 37-39% survival.

Thrombolytic Therapy: Streptokinase is an exogenous activator of plasminogen derived from streptococcus species with activity in the dog, cat, rabbit, and primate.15 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.7 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.16 Electrolyte abnormalities (hyperkalemia) thought to result from rapid reperfusion were identified in three cats just prior to death.16

A second series of cats (n=46) received streptokinase at various doses and over various durations.9 In this series, 25/44 regained femoral pulses within 24 hours and 14 regained motor function (11 in the first 24 hours).9 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 (33%) as is similar to cats treated conservatively. ATE recurred in 7 of those 15 cats discharged from the hospital.9

Urokinase is another plasminogen activator that is produced in the kidney. In one case series, infusion of urokinase to cats with ATE resulted in a 41% rate of survival to discharge (comparable to other conservative and thrombolytic strategies).17

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.18 A second study investigating the use of TPA, 11 cats were administered TPA a median of 4 hours (range 2-12) after the onset of clinical signs.19 In that study, some cats received 5mg TPA over 4 hours while others received a 1mg bolus followed by 2.5mg over 30min, and 1.5mg over an hour. If clinical signs persisted after 4 hours, 5mg TPA via CRI over another 4 hours was added to either protocol. Survival to discharge was 27%.19

Thrombectomy: Rheolytic thrombectomy has recently been described as an alternative for management of cats with ATE.20 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). Cats in this study were treated a mean of approximately 45 hours after the onset of clinical signs.20

Overall survival to discharge appears comparable between conservatively treated animals and those treated with thrombolytics and thrombectomy. However, many of these trials are very small in scale, and the population of cats with ATE is variable in many aspects, including the time between onset of clinical signs and initiation of therapy, a factor that the author believes is critical.

Humans that develop acute limb ischemia secondary to embolic disease that present with a loss of sensory and motor function are at risk for irreversible ischemia and major tissue loss.21 These individuals represent the most severe category of limb ischemia. Even with treatment, the prognosis is guarded in these patients and immediate <2hrs re-establishment of blood flow is critical. Surgical and endovascular treatments are considered in these patients.21 Future investigations in veterinary medicine utilizing surgical embolectomy or endovascular thrombectomy in addition to the local delivery of thrombolytics are warranted. Local delivery of thrombolytics would allow for adminsitration of low doses and might also minimize systemic side effects of thrombolytic administration.

     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. 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>0.05). 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 interpret these results with extreme caution 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, a thienopyridine has been investigated in cats. Thienopyridines inhibit the binding of ADP to its receptors which indirectly reduces aggregation. A prospective study comparing the thromboprophylactic efficacy of clopidogrel and aspirin is 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, prospective clinical trials 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 indicate and that with aggressive initial treatment and diligent supportive care, meaningful periods of survival are possible.

Portions of these proceedings have been previously published for various veterinary CE Conferences.

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