Thromboembolism: current treatment and future directions
Initial work in the 1960s highlighted the connection between feline arterial thromboembolism and cardiac disease, whilst the association of thromboembolism with endomyocarditis and hypertrophic cardiomyopathy (HCM) from necropsy and clinical data was made in the 1970s. Since then the majority of the literature has focused on the management of the underlying cardiomyopathy, combined with therapeutic anticoagulation and/or fibrinolysis. The current understanding of the mechanisms underlying the formation of a thrombus is not complete; recent research has attempted to uncover the causes of thromboembolism in susceptible cats and the findings may improve the approach to treating this often fatal disease process.
Clinical signs and diagnosis
Acute vocalization and pain accompanied by paresis/paralysis of one or more limbs is often the first presenting sign of arterial thromboembolism. Tachypnea or open-mouthed breathing may be present from the agony or congestive heart failure. The affected limbs are cool with pale or purplish-colored digital pads (Figure 1). Arterial pulses are often absent, and the muscles of affected limbs may be firm compared to the unaffected ones. Detecting arterial occlusion by the absence of a Doppler signal or the visualization of an intraarterial thrombus via ultrasonography will confirm the diagnosis. Acute spinal cord injury could be a differential diagnosis for the above presenting signs; however, those patients are likely to have warm extremities and arterial pulses to the affected limbs. Thoracic radiographs may show cardiomegaly and biatrial enlargement as well as pleural effusion or pulmonary edema (Figures 2a and b). Uncommonly a pulmonary mass may be found, suggesting the thrombus may be secondary to neoplasia; this must be considered since neoplasia would be a likely differential diagnosis for cats with acute onset of painful, pulseless limbs and purple pads. Echocardiography should be undertaken when the patient has stable cardiopulmonary status and has been treated for pain; this may identify underlying cardiac disease (hypertrophic, dilated, restrictive, or unclassified cardiomyopathy) and may also demonstrate spontaneous echocardiographic contrast or a thrombus in the left atrium.
Treating the emergency patient
If life-threatening conditions are present (e.g. congestive heart failure: crackles, dull lung sounds), stabilizing the cardiopulmonary system takes priority. Oxygen therapy (cage, mask, or flow-by) and furosemide (1-2 mg/kg IM every 15-30 minutes) should be administered to cats with significant respiratory distress. A total furosemide dose of 5- 8 mg/kg may be necessary until the respiratory rate improves and the cat urinates. Cats seem to be more sensitive than dogs to the side effects of furosemide and determining any further doses of furosemide should be done only after assessing the effect of the previous aliquot.
Pain control is essential; the ischemic neuropathy secondary to the arterial thrombus is very painful. Pure mu agonists are often the best choice (oxymorphone 0.05-0.1 mg/kg IM, hydromorphone 0.05-0.2 mg/kg IM) to control the most severe pain. Once an intravenous catheter is placed, pain control (as well as the furosemide) can be given every 2- 4 hours IV or as a continuous infusion (e.g. fentanyl 2-5 μg/kg/hr IV). Vomiting may occur transiently due to narcotic usage. Acepromazine (0.025-0.05 mg/kg IM or IV q4-6h) can be administered to relieve anxiety and works synergistically with pure mu agonist narcotics. This dose of acepromazine is unlikely to facilitate vasodilation, but it may be antiemetic.
Fluid therapy is best tailored to the individual. Cats in congestive heart failure, as well as those receiving furosemide, should not receive IV fluids. However, some cats do not present with heart failure and may have fluid deficits (although this is unlikely since this is such an acute disease). In general, the author withhold fluids until thrombolytics are being administered, when isotonic crystalloids (0.9% NaCl) should be given IV to help prevent and treat reperfusion injury. The severe hyperkalemia that may result (serum potassium concentration > 8mM/L or bradycardia) requires treatment with dextrose (0.5 mL of 50% dextrose solution IV) and regular insulin (0.5 U/kg IV). Sodium bicarbonate (0.5 mM/L) can also be administered IV slowly over 20-30 minutes. The electrocardiographic changes seen with hyperkalemia (Figure 3) can be very subtle (e.g. prolongation of the P-R interval) or extremely severe (e.g. no P wave, tented T waves, sine wave).
Heparin is traditionally used in these cases, but this is really to prevent expansion of the clot, and for thrombolysis two agents are worthy of mention.
• Streptokinase is often suggested as the drug of choice; it was evaluated retrospectively in one study (1) which looked at complications and outcomes; it sought to determine if time of streptokinase administration after onset of clinical symptoms changed the outcome, and investigated positive or negative prognostic factors. The 46 cats in this study received various dosages of streptokinase within 1-20 hours of the onset of clinical signs; all but one had heart disease, and 21 had heart failure. Streptokinase infusions lasted from 1-28 hours but there was no difference between survivors and non-survivors based on the time to, length, or dosage of streptokinase administration. Higher doses of the drug were not associated with a greater likelihood of hyperkalemia or a bleeding tendency but hyperkalemia was more likely to occur with a longer duration of streptokinase infusion. These cats were also more likely to regain arterial pulses due to a higher total dose, but not motor function. Bleeding was clinically evident in 11 cats and 3 required blood transfusions due to the severity of bleeding. Cats with a single limb affected were more likely to survive to discharge. Survival following discharge (15 cats) varied from 2 days to 23 months (mean of 51 days), which is similar to another study (2) wheremean survival was 61 days. Median time to the next thromboembolic event was 100 days. Some clinicians believe the use of streptokinase to treat cats with arterial thromboembolism cannot be justified due to its expense, risk of hemorrhage, and the lack of improvement in outcome. Whether or not this drug is likely to be of benefit, its current lack of availability requires alternatives to be researched for both prevention and treatment.
• Tissue plasminogen activator (t-PA) may be a useful alternative. One study (3) demonstrated that cats treated with t-PA had a shortened time to reperfusion and ambulation; animals that successfully completed therapy were walking within 2 days (compared to 2-6 weeks for spontaneous resolution) but 50% of cases had fatal complications (hyperkalemia, congestive heart failure and arrhythmias) whilst a prospective evaluation of t-PA (4) reported that 3 out of 11 cats treated were discharged alive, but serious adverse events in all cats (azotemia, neurologic signs, dysrhythmias, hyperkalemia, acidosis, and sudden death) forced termination of this study. The current recommended dose for t-PA is 0.25- 1.0 mg/kg/hr IV CRI for a total dose of 1-10 mg/kg (5). The cost for t-PA is significant and the clinician must balance the efficacy, cost and high complication rate if choosing to use it.
Surgical removal of arterial thromboemboli has met with mixed results. Many interventions, from balloon embolectomy to surgery, have been attempted. However, along with the high anesthetic risk due to underlying cardiac disease, most clinicians currently recommend medical therapy. For cats already affected by arterial thromboembolism, rheolytic thrombectomy (using a catheter to flush and aspirate the thrombus) can be another option, and may be an effective and useful intervention in acute cases; however access to the apparatus and the expense may be a limiting factor. One small study (6) reported successfully dissolution of the clot in 5 out of 6 cats using this method.
Three cats were discharged from hospital but all had ambulatory deficits of varying degrees consistent with a distal peripheral neuropraxia. In 2 of these cats the neurological deficits resolved within one month of discharge and the cat with the longest period of time between onset of clinical signs and the thrombectomy (192 hours) had neurological deficits persisting for 10 months after the procedure, over which time they resolved. One of the surviving cats died suddenly four months after the procedure and necropsy revealed no grossly apparent cause of death. During routine echocardiographic re-examination of another surviving cat, evidence of spontaneous contrast was seen in the left atrium three months after the procedure. This cat presented to the referring veterinarian one month later showing signs similar to the original signs of aortic thromboembolism, and was euthanized. Postmortem examination confirmed rethrombosis at the level of the aortic trifurcation. The final cat died of a combination of congestive heart and chronic renal failure two years after the procedure. In this study, the time between the onset of clinical signs and the thrombectomy procedure did not appear to be an important predictor of a successful outcome.
Prevention of further thrombus formation
The largest retrospective report to date studied 127 cats with a first episode of arterial thromboembolism (7). The goals of this study were to determine which aspects of presentation provide useful prognostic information, to provide accurate survival curves for cats surviving the initial episode, and to compare low and standard dose aspirin therapy in the cats that survived the initial episode. Most (76.4%) of these cats had no known prior medical condition and males were over-represented 2:1. The majority of cats had both pelvic limbs affected by thromboembolism; in 16 cats, only one pelvic leg was affected (8 right and 8 left). One thoracic limb was affected in 15 cats and 3 cats had both rear and one thoracic limb affected. There was also one cat each with a mesenteric and cerebral thrombosis. Thrombi were found in the left atrium of 6 cats during echocardiography and another 3 cats had thrombi (2 left atrium and 1 left ventricle) found on necropsy. Neoplastic emboli accounted for only 5% of the population.
Heart failure was present in 55 of the 127 cats and 32 cats were euthanized without therapy. Treatments provided varied according to clinician preferences but included fluids, analgesics, oxygen supplementation, and streptokinase. Variable doses of unfractionated heparin were used more commonly than aspirin for anticoagulant therapy. Any combination of the above treatments was possible. Overall survival rate was 35% (not dissimilar to the survival rate in other studies (1,8) whilst survival rate for the treated cats was 45%, with a trend towards better survival in the later years of the study. This study found that cats with higher rectal temperatures and higher heart rates on initial presentation were more likely to survive. 44 of the 87 cats that survived the initial thromboembolic event were medicated at home with either high dose aspirin, low dose aspirin, or nothing, plus other cardiac medications as necessary. Eleven of the 44 cats experienced 16 additional thromboembolic events, of which 9 were fatal. Time to first recurrence was 191 +/- 152 days. Nine of the 44 cats were alive at the end of the study with a mean survival time of 117 days. Cats with heart failure during the initial episode survived a significantly shorter time compared to cats without heart failure (77 vs. 223 days). There was no significant difference in survival for the cats on high versus low dose aspirin.
A retrospective report reviewed 100 cases of feline aortic thromboembolism and found similar characteristics to the other studies mentioned here (8). The 37% of cats that survived the initial episode and were discharged were most commonly managed with warfarin, which has a reported superiority over aspirin therapy for the prevention of recurrent thromboembolism (9). The average overall survival time for these cats was 11.5 months. Precise follow-up information was available on 22 cats; of these 6 were euthanized due to recurrent episodes of thromboembolism. Note that warfarin-treated cats not only may have recurrent thromboembolic episodes but also significant to fatal bleeding complications, so use of this drug requires careful monitoring and frequent assessments of coagulation parameters.
Low molecular weight heparins
Low molecular weight heparins (LMWH) such as dalteparin and enoxaparin have recently been used as preventative agents. One study retrospectively studied dalteparin (10) to document the ease and duration of administration, complications, and frequency of aortic thromboembolism. Of 57 cats, 43 had cardiomyopathy and received on-going therapy with dalteparin (47-220 U/kg q12-24h SC). None received coagulation testing. About half of these cats had thromboemboli prior to initiating dalteparin. Eight cats had documented or suspected aortic thromboemboli while on therapy. Cats with thromboemboli prior to dalteparin therapy were more likely to have a reoccurrence. There was no difference in the survival times with or without the use of concurrent aspirin. More cats in this study died because of congestive heart failure or heart failure-related euthanasia than because of thromboembolism-related euthanasia. It is not possible to draw conclusions from this study whether dalteparin played any role in the reduction of episodes of aortic thromboembolism.
An investigation into the pharmacokinetics of LMWH in normal cats studied the dosage and dosing frequency required to maintain anti-Xa activity within the range of 0.5-1.0 IU/mL (11), efficacy being gauged by the degree of Factor Xa inhibition. They found that LMWH can be administered effectively to healthy cats, but requires frequent subcutaneous administration to maintain anti-Xa activity. This may demonstrate why dalteparin in the aforementioned study (10) (dosing was q12- 24h) may not have proven efficacious.
Recent interest has centered around the use of thienopyridines which have an anti-platelet effect. The theory is that by impairing platelets from becoming activated and forming clots the fatal thromboembolic sequelae of HCM can be prevented. Ticlopidine was first studied (12) but consistently caused vomiting and anorexia, suggesting that the drug is not clinically useful due to its side effects despite having an in vitro anti-platelet effect. Clopidogrel, on the other hand, is reported to have a significant antiplatelet effect at multiple dosages in cats without any significant adverse effects (13) and has many promising characteristics that make its clinical use appealing. Once daily oral administration may promote client compliance, its anti-platelet effect lasted 3-7 days after the last dosage, and serotonin secretion was also lower in treated cats (higher serotonin levels have been associated with more severe signs of arterial thromboboembolism). The minimum effective dose was not determined in this study, but the lowest dose used which had anti-platelet efficacy was 18.75 mg PO q24h, whilst a dose of 75 mg PO q24h was also found to be effective with no adverse effects. The next step is to prove if clopidogrel is the drug of choice to prevent thromboembolism in cats with HCM via a prospective, randomized, double-blinded controlled trial of its use compared to a placebo. Hopefully, this drug will be proven to prevent episodes of arterial thromboembolism in the future.
Current research into abnormal coagulation
Virchow’s triad suggests that hypercoagulability is caused by the interplay of 3 parameters: endothelial damage, alterations in blood flow, and coagulation factor and/or platelet hyper-aggregability. Alterations in blood flow, especially flow stasis, have been the long-held tenet of thrombus formation in the cat. One study (14) reported low-flowvelocities in the left atrial appendage of cats and identified a subgroup at increased risk of spontaneous echocardiographic contrast and possible thromboembolism. There is recent interest in measuring hemostatic markers in cats with HCM. Two recent studies (15, 16) suggest that molecules such as thrombinantithrombin (TAT) complexes and D-dimers may be elevated in cats with critical illness or heart disease, but the correlation to HCM is weak and an individual cat may have normal measures despite the presence of severe HCM. Another group demonstrated hypercoagulability (defined as having 2 or more of the following: increased fibrinogen, Factor VIII:C activity, low antithrombin activity, TAT, or D-dimer elevations) in 43 cats with cardiomyopathy (17) and found such hypercoagulability criteria in cats with spontaneous echocardiographic contrast or arterial thromboembolism, not left atrial enlargement alone. This is the second study to show that left atrial enlargement by itself does not correlate with hypercoagulability. Most recently, the author’s laboratory used a commercial analyzer (18) to assess platelet function in both normal cats and cats with HCM but concluded that this did not distinguish between affected and normal animals and is not currently the best test to study hypercoagulability. In fact there is as yet no simple analytical tool available for the evaluation of the hyper-coagulable state in cats but thromboelastography (TEG) is becoming more widely available and can assess all phases of coagulation from instigation of coagulation through to fibrinolysis. One group used TEG to assess for hypercoagulability in cats with HCM (19) and found that although individual cats may be hypercoagulable there is significant overlap in data between healthy cats and those with HCM.
If treated quickly and effectively, some cats may improve and have functional mobility to the previously affected limb. The cost of therapy, both for drugs and hospitalization, is high and comes with risk for adverse events. However, the possible improvements and survival may indicate that the cat can have a good quality of life until the next arterial thromboembolism event occurs.
1. 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.
2. Atkin CE, Gallo AM, Kurzman ID, et al. Risk factors, clinical signs and survival in cats with a clinical diagnosis of idiopathic hypertrophic cardiomyopathy: 74 cases (1985-1989). J Am Vet Med Assoc 1992;201:613-618.
3. Pion PD. Feline aortic thromboemboli and the potential utility of thrombolytic therapy with tissue plasminogen activator. Vet Clin North Am Small Anim Pract 1988;18:79-86.
4. Welch KM, Rozanski EA, Freeman LM, et al. Prospective evaluation of tissue plasminogen activator in 11 cats with arterial thromboembolism. J Fel Med Surg 2010;12:122-128.
5. Pion PD, Kittleson MD. Therapy for feline aortic thromboembolism. In: Kirk RW, editor. Current Veterinary Therapy. Philadelphia: WB Saunders Co. 1989;295-302.
6. Reimer S, Kittleson MD, Kyles AE, et al. Use of rheolytic thrombectomy in the treatment of feline distal aortic thromboembolism. J Vet Intern Med 2006;20:290-296.
7. Smith SA, Tobias AH, Jacob KA, et al. Arterial thromboembolism in cats: Acute crisis in 127 cases (1992-2001) and long-term management with lowdose aspirin in 24 cases. J Vet Intern Med 2003;17:73-83.
8. Laste N, Harpster NK. A retrospective study of 100 cases of feline distal aortic thromboembolism: 1977-1993. J Am Anim Hosp Assoc 1995;31:492-500.
9. Baty CJ. Feline hypertrophic cardiomyopathy: an update. Vet Clin North Am Small Anim Pract 2004;34:1227-1234.
10. Smith CE, Rozanski EA, Freeman LJ, et al. Use of low molecular weight heparin in cats: 57 cases (1999-2003). J Am Vet Med Assoc 2004;225:1237-1241.
11. Alwood AJ, Downend AB, Brooks MB, et al. Anticoagulant effects of low-molecular weight heparins in healthy cats. J Vet Intern Med 2007; 21:378-387.
12. Hogan DF, Andrews DA, Talbott KK, et al. Evaluation of antiplatelet effects of ticlopidine in cats. Am J Vet Res 2004;65:327-332.
13. Hogan DF, Andrews DA, Green HW, et al. Antiplatelet effects and pharmacodynamics of clopidogrel in cats. J Am Vet Med Assoc 2004;225:1406-1411.
14. Schober KE, Maerz I. Assessment of left atrial appendage flow velocity and its relation to spontaneous echocardiographic contrast in 89 cats with myocardial disease. J Vet Intern Med 2006;20:120-130.
15. Bédard C, Lanevschi-Pietersma A, Dunn M. Evaluation of coagulation markers in the plasma of healthy cats and cats with asymptomatic hypertrophic cardiomyopathy. Vet Clin Pathol 2007;36:167-172.
16. Brazzell JL, Borjesson DL. Evaluation of plasma antithrombin activity and D-dimer concentration in populations of healthy cats, clinically ill cats, and cats with cardiomyopathy. Vet Clin Pathol 2007;36:79-84.
17. Stokol T, Brooks MB, Rush JE, et al. Hypercoagulability in cats with hypertrophic cardiomyopathy. J Vet Intern Med 2008;22:546-552.
18. Jandrey KE, Norris JW, MacDonald KA, et al. Platelet function in clinical healthy cats and cats with hypertrophic cardiomyopathy: analysis using the Platelet Function Analyzer-100. Vet Clin Pathol 2008;37:385- 388.
19. Jandrey KE, Norris JW, Kittleson MD, et al. Thromboelastographic (TEG) analysis of cats with hypertrophic cardiomyopathy. In: Proceedings. 8th European Emergency and Critical Care Society Congress, Berlin, 2009;99.