Dr. Kramer On: Arterial Thromboembolism In Cats
...cardiogenic thromboembolic disease.
Clinical Presentation
The clinical presentation of ATE depends on the anatomical site of embolization. The most common clinical presentation of ATE in cats is the classic "saddle thrombus" where the thrombus embolizes to the distal abdominal aorta leading to occlusion of various combinations of the internal and external iliac and sacral arteries. The next most common site of embolization is to the right brachial artery leading to signs affecting the right forelimb. Other sites include the renal, mesenteric, cerebral, and left brachial arteries. In particularly grave cases, multiple sites of embolization ("embolic shower") can occur.
Most of these cats present with an acute history of vocalization, pain, tachypnea, and varying degrees of paralysis. Many cats (44% in one study) will also be in congestive heart failure and have associated signs. It is important early on in the clinical workup to determine if the tachypnea is pain-related or a symptom of CHF and treat appropriately. Occasionally, cats may present with an intermittent history of claudication where the owner may notice the cat shaking a limb due to pain. This is usually associated with smaller thrombi embolizing to the affected limb.
Pathophysiology
For a thrombus to form, one or more predisposing prothrombotic conditions need to exist: (1) stasis of blood, (2) vascular or endothelial damage, (3) hypercoagulable state. All three of these conditions can be seen in cats with cardiogenic ATE.
Stasis. Both left atrial enlargement and decreased atrial function can lead to stasis of blood within the LA. One manifestation of the stasis is the appearance of spontaneous contrast ("smoke") within the LA. In one study, moderate to marked left atrial dilation was present in 71% of cats with ATE. There was mild LA dilation in 22% of the cases and 7% had no evidence of atrial enlargement. In addition, left atrial function is also altered which results in decreased blood flow within the left auricular appendage (LAA). Doppler blood flow studies show a decreased maximal LAA blood flow velocity in cats with cardiomyopathy. In that study, flow of <0.20 m/s was linked to the presence of spontaneous contrast within the LA.
Endothelial damage. In all forms of cardiomyopathy in cats, there is endothelial damage of the endocardium in the LA and LV cavities. Pathologic findings include patchy or diffuse areas of fibrosis, small areas of infarction, and disruption of the endothelial surface. These changes can lead platelet activation and aggregation with subsequent activation of the intrinsic clotting cascade.
Hypercoagulability. Measuring hypercoagulability in cats is difficult in the clinical setting. In one coagulopathy study, cats with cardiomyopathy demonstrated criteria of hypercoagulability in 50% of cats with spontaneous echocardiographic contrast and 57% of cats with ATE. The ATE cats also had significant elevations of vFW which was attributed to downstream endothelial damage. Recently, a thromboelastography (TEG) study demonstrated a significant increase in clot strength in cats with cardiogenic ATE. Other factors that may affect hypercoagulability in cats include alterations in AT III, Factor VIII, protein C and Lp(a). More work in this area needs to be done.
When these conditions exist, thrombus formation usually occurs within the LA, most commonly at the LAA. Frequently, the presence of spontaneous contrast will be seen prior to thrombus formation. A thrombus may be adhered to the wall (mural thrombus) or may be freely mobile within the LA or LV cavities (ball thrombus). Embolization is the process where the thrombus or a piece of it travels out of the heart into the aorta and eventually lodges at one of the sites previously discussed. Once the thrombus embolizes, vasoactive substances (e.g. serotonin and thromboxane A2) are released from platelets within the thrombus which causes further vasoconstriction and leads to decreased collateral blood flow. It is the release of these vasoactive substances that seems to result in the clinical signs associated with ATE. This can be demonstrated by experimental ligation of the terminal abdominal aorta which does not cause either paralysis of the rear legs or the pain demonstrated in ATE cats.
Treatment
Once a diagnosis of ATE is made, treatment consists of treating the underlying heart disease and, if present, CHF, anticoagulation therapy to prevent the formation of other thrombi and to prevent the embolized thrombus from getting larger, and analgesia to control the pain in the acute phase. Additional therapies may include vasodilator therapy and judicious use of fluid therapy in an attempt to improve collateral circulation.
Thrombolytic therapy is controversial and rarely recommended due to concerns about reperfusion injuries and hyperkalemia. In the author's opinion, gradual thrombolysis utilizing the body's normal thrombolytic system is preferable to streptokinase or t-PA (tissue-plasminogen activator). In the only clinical study using t-PA for thrombolysis in ATE cats, there was a 50% mortality rate associated with the rapid reperfusion that occurred. Similarly, rheolytic throbectomy using an AngioJet catheter to remove the thrombus resulted in a 50% mortality rate in a recent small study.
Future treatments may include anti-serotonin drugs and thromboxane A2 inhibitors which may help mitigate the effects of serotonin and thromboxane A2 on the collateral circulation. Sarpogrelate is a 5-HT2A receptor antagonist (i.e. anti-serotonin drug) that has been shown to inhibit serotonin-mediated restenosis in coronary arteries and to improve exercise capacity in patients with angina pectoris. There are no published studies of the use of this drug in cats but it warrants investigation. The use of cyproheptadine or mirtazapine as appetite stimulants in ATE cats may yield additional anti-serotonin benefits on the collateral circulation.
Anti-thrombotic therapies
Aspirin. Results in deceased platelet aggregation by irreversibly inactivating cyclooxygenase and inhibiting thromboxane A2 production. The dose typically used in cats is 81 mg (or 25mg/kg) q72hrs. GI side effects are rarely seen at this dose but should be watched for. There are authors who recommend a micro dose of aspirin (5mg/kg) but it is unclear whether this dose causes fewer GI side effects or is as effective at decreasing platelet aggregation as the higher dose.
Coumadin (warfarin). Inhibits vitamin K metabolism in the liver which leads to decreased production of factors II, VII, IX, and X. The initial dosage is 0.25 to 0.5 mg/day. When using this drug, regular monitoring of coagulation profiles should be undertaken to maintain the prothrombin time at twice the normal value. The patient should be monitored for bleeding complications.
Clopidogrel (Plavix).. Inhibits platelet aggregation by selectively inhibiting the binding of ADP to its platelet receptor and the subsequent ADP-mediated activation of the GPIIb/IIIa complex. There is currently an ongoing clinical trial, (FAT CAT) that was designed to compare effectiveness of clopidogrel to aspirin at preventing ATE. The dosage in cats is ¼ of a 75-mg tablet per day. In some cases in people it has been used in conjunction with aspirin to decrease platelet aggregation. For more information concerning FATCAT (Feline Aortic Thromboembolism Clopidogrel vs. Aspirin Trial), or to enroll a case in the clinical trial, visit the trial web site at www.vin.com/FATCAT.
Heparin. Unfractionated heparin (UFH) binds to antithrombin III which causes a conformational change that enhances the enzyme's ability to neutralize thrombin and factor Xa. Heparin can enhance ATIII activity up to 1000 times baseline activity. Dosages in cats vary. We typically start with an initial IV dose of 2000 IU, and then continue the cat on 250 IU/kg SC QID. Ideally, the dose should be adjusted to maintain the activated partial thromboplastin time at a level 50% above normal. The patient should be monitored for bleeding complications.
Low molecular weight heparin (LMWH). As opposed to unfractionated heparin, LMWH consists of polymers within a narrow range of molecular weights (mean wt 5000 Daltons). There are reportedly less bleeding complications seen with LMWH compared to UFH which makes it safer for long-term outpatient use. LMWH has a greater affinity for inactivating factor Xa than does unfractionated heparin. In people, LMWH preparations have a longer plasma half-life and better bioavailability at low doses than UFH, and a more predictable dose response. Cats have been shown to require higher dosing and shorter intervals than people to achieve the same level of anti-factor Xa activity. Lovenox (enoxaparin) and Fragmin (dalteparin) are two LMWH that have been used in cats with ATE. The recommended dose of Lovenox is 1mg/kg BID and for Fragmin 100 U/kg BID. The different LMWHs vary in potency and bioavailability. Consequently, one drug is not interchangeable for another. As a group, LMWHs all enhance AT inhibition of FXa more so than AT inhibition of thrombin. Enoxaparin has an anti-Xa/anti-thrombin ratio of 3.3 and dalteparin has a ratio of 2.0.
Synthetic heparin-like compounds. Fondaparinux and idraparinux are new synthetic heparin analogs that have similar or better efficacy profiles compared to various LMWHs. Fondaparinux is commercially available but very expensive, and idraparinux is currently in phase III clinical trials in humans. The primary potential advantage of idraparinux over other LMWHs is the favorable pharmacokinetic profile. It has an extremely long plasma half-life in humans, rats, dogs, and rabbits allowing the use of a once-weekly dosing protocol in humans. Neither drug has been tested in cats as of this date.
In our practice, we typically maintain ATE cats at home on enoxaparin (1mg/kg SC BID) and clopidogrel (18.75mg PO SID) along with concurrent cardiac medications. If we feel the cat is at extremely high risk of repeat embolization, we will add aspirin in along with the LMWH and clopidogrel.
Prognostic indicators
Patients that are markedly hypothermic and bradycardic at presentation have a worse prognosis compared to the rest of the ATE population. The presence of a ball thrombus in the LA or LV is another negative indicator. Single limb paresis cats have a better prognosis compared to multi-limb paresis cases.
In the author's experience, if euthanasia is recommended in only the most severe cases (i.e. extremely poor myocardial function, refractory CHF, severe hypothermia and/or bradycardia, presence of a large ball thrombus) between 50% and 75% of the cases can survive to discharge. Most of the cats will have significant return of motor function within two weeks of the embolic event to the point of resuming normal activity at home. In a small number of cases, there may be ischemic necrosis of a distal portion of the affected limb that will need to be treated with conservative treatment (e.g. wet to dry bandage changes, debridement, and antibiotics). Surgical amputation is rarely required.
Repeated embolic episodes occur in between 25% and 50% of the cats that are discharged, but the majority of those cats will survive the episode. Over the long-term, most of the cats die of CHF rather than directly from a thromboembolic event. Very close monitoring of these cats, including repeat echocardiograms, is required to monitor response to treatment and make adjustments as needed. It is also very important to educate the client on what to expect. With proper client education and aggressive treatment, many more ATE cats than previously reported can survive the initial episode and return home for a significant period of time with a decent quality of life. It is important to also remember that this is a treatable but not curable condition. The long-term prognosis is still poor with approximately 25% of the patients alive one year after the initial ATE episode.