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Arterial Thromboembolism in Cats with Cardiomyopathy: Prevention & Management

Introduction

Cats with myocardial disease are at risk for developing intracardiac thrombi due to underlying mechanisms fulfilling all aspects of Virchow’s triad, including blood stasis, endothelial injury and most likely a hypercoagulable state. Impaired left ventricular filling elevates left atrial pressure resulting in dilatation and blood stasis that can be visualized as spontaneous contrast or “smoke” on echocardiographic examination. As the atrium dilates, the endothelial surface stretches and areas of separation can form exposing subendothelial collagen or result in fibrosis that allow platelet adhesion with subsequent activation and aggregation. Finally, a subset of cats with cardiac disease has been reported to have alterations in coagulation parameters which would suggest a hypercoagulable state. Such changes include increases in factor VIIIa and fibrinogen, decreases in antithrombin (III) and protein C, and altered reactivity of platelets.

The initiation of the mural thrombus begins along the dilated atrial wall and results in a sequence of platelet responses including adhesion to the subendothelial site, activation and aggregation with release of agents with pro-aggregating and vasoconstrictive properties, as well as initiating the coagulation cascade. For these reasons, the early thrombus is platelet-rich, but then becomes fibrin-rich as the thrombus further develops. As the thrombus matures, it becomes lamellated and superficial portions break off forming the emboli that travel to distant sites where their size exceeds vessel diameter and result in infarction.

Ischemic Neuromyopathy

Although cerebral, renal and splanchnic infarctions occur occasionally, terminal aortic and brachial infarction account for the vast majority of cases and result in ischemic neuromyopathy (INM) to the infarcted muscular bed. A major contributing factor of INM appears to be the release of vasoactive substances from the platelets which are activated from the embolus present in the arterial lumen, reducing collateral flow around the site of infarction. Similar factors have also been identified in humans suffering from thrombotic stroke, cardiogenic embolism (CE), cardiogenic thromboembolic stroke, and pulmonary thromboembolism. Experimental models have revealed that simple ligation of the distal feline aorta does not result in reduced blood flow to the hind limbs or the classical clinical signs of INM. Under such conditions, blood flow is maintained through an extensive collateral circulation in the vertebral system and epaxial muscles. However, when a thrombus is present or platelets are activated in association with ligation of the aorta, there is loss of this collateral circulation and clinical signs of INM are evident. There is strong evidence that serotonin plays a large role in the loss of the collateral circulation during aortic infarction. More than 98% of the circulating serotonin, a strong vasoconstrictor, is released from platelets when they become activated. There is experimental evidence that serotonin released from activated cat platelets stimulates sympathetic afferent fibers and may be at least partially responsible for the pain associated with INM. Additionally, the administration of a serotonin antagonist prior to experimental infarction maintained the collateral network and obviated the typical clinical signs of INM.

Management

The most important aspect of acute management of CE in cats is time. Owners should be strongly encouraged to give their cats 48–72 hours of in-hospital care prior to deciding upon euthanasia. Clinically, this time period allows the identification of cats that will survive acutely and can move on to more chronic at-home care. If this 48–72 hour time period is followed, then the acute mortality rate for CE should be greatly reduced.

The key points in the acute management of CE are 1) reduce continued thrombus formation associated with the embolus; 2) improve blood flow (aortic or collateral); 3) pain management; 4) treat concurrent congestive heart failure if present; and 5) supportive care.

Reducing Thrombus Formation

The most common agent chosen to reduce continued thrombus formation at the site of embolization is unfractionated heparin (UH). Unfractionated heparin inhibits the formation of the active form of factors X and II and also exhibits an antiplatelet effect in normal humans by binding to and inhibiting von Willebrand Factor (vWF). However, humans with diseases known to be associated with hypersensitive platelets, such as peripheral arterial disease (PAD), exhibit spontaneous aggregation in response to UH as well as increased responses to physiologic agonists. It is not known if cats with hyperreactive platelets exhibit a similar reaction to UH. Ideally, a coagulation panel including platelet count, PT and aPTT should be submitted prior to UH administration. This allows baseline coagulation function to be determined prior to UH therapy, as well as identifying those cats that may have a coagulopathy such as DIC. Adequate dosing of UH in cats with thromboembolic disease has been shown to be quite variable. A prudent beginning dosing regimen is 250–375 IU/kg IV initially followed by 150–250 IU/kg SQ every 6–8 hours. Injections should be given cranial to the diaphragm to assure adequate absorption. While it has been suggested that the aPTT does not correlate well with plasma UH levels, it is readily available to practitioners and should be used to adjust the UH dose to a target of 1.5–2.0 times the baseline value.

The low molecular-weight heparins (LMWH) are an alternative to UH. These agents are smaller in size than standard heparin but maintain a critical peptide sequence that prevents the activation of factor X. They have less activity towards factor II, therefore monitoring of the aPTT is not required. Similar to UH, they exhibit mild antiplatelet effects in normal humans but less pro-aggregating effects in humans with hypersensitive platelets. Dalteparin (Fragmin®) and enoxaparin (Lovenox®) have been used in cats at 100 IU/kg SQ q 24–12 hours and 1.0–1.5 mg/kg SQ q 24–12 hours, respectively.

Improve Arterial Blood Flow

Aortic Flow

Re-establishing arterial flow to the infarcted organs would appear to be a primary therapeutic goal. This could be accomplished by removal of the aortic embolus either through embolectomy or dissolution by using thrombolytic drugs. There are many limitations to embolectomy in the cat and surgical intervention has generally been contraindicated given the operative risks. Thrombolytic drugs such as streptokinase and tissue-plasminogen activator (t-PA) have been used in cats to dissolve emboli and re-establish aortic flow. The sudden resumption of arterial flow to infarcted organs, especially the pelvic limbs, results in the mobilization of metabolic products such as potassium and organic acids from ischemic/necrotic tissues into the systemic circulation and is termed “reperfusion injury”. Given that approximately 50% of cats will regain motor function over a 4–6 week period following the CE event with conservative treatment, the benefit to risk ratio for thrombolytic therapy must be determined for each individual cat. While it would appear that cats with more complete infarction should not receive thrombolytic therapy due to higher risk for reperfusion injury, these cats are probably less likely to regain motor function than a unilateral infarction and therefore possibly a greater clinical benefit.

Streptokinase combines with plasminogen to form an activator complex that converts plasminogen to the proteolytic enzyme plasmin which degrades fibrin, fibrinogen, plasminogen, coagulation factors and streptokinase. The streptokinase- plasminogen complex converts circulating and fibrin-bound plasminogen and is therefore considered a non-specific activator of plasmin. Streptokinase is typically administered by giving 90,000 IU IV over 1 hour followed by an infusion of 45,000 IU/hour for up to 8 hours. Streptokinase is potentially antigenic but allergic reactions have not been reported in cats. Currently the smallest amount of streptokinase that can be purchased is 750,000 IU (estimated cost of $300) which would provide over 15 hours of infusion time.

Unlike streptokinase, t-PA does not readily bind circulating plasminogen and therefore does not induce a systemic proteolytic state. The recommended dosing protocol for t-PA is 0.25 to 1 mg/kg/h IV for a total dose of 1 to 10 mg/kg. Activase® is supplied in 50 mg and 100 mg bottles with an estimated cost of $1500 and $3000 respectively. The average cat will not require more than 50 mg and smaller amounts of t-PA can be purchased (Cathflo® Activase®, Genentech, San Francisco, CA, USA) for approximately $100 per 2 mg.

Improve Collateral Flow

If dissolution of the embolus is unsuccessful or not attempted, then increasing perfusion to the pelvic limbs can be attempted by increasing flow through the collateral network. Platelet release products have been implicated as the agents responsible for the loss of collateral flow associated with cardioembolic infarction. Therefore, antiplatelet agents may help improve collateral flow by reducing the amount of vasoactive substances released from platelets. For these agents to be most helpful, they should be given as soon after the CE event as possible.

Aspirin has been shown to reduce the amount of released thromboxane A2 from activated cat platelets and improve collateral flow in an experimental cat model of aortic infarction. 650 mg (approximately 150 mg/kg) of aspirin resulted in plasma salicylate levels of 200–300 µg/ml although salicylate toxicity in cats has been documented at 300 µg/ml. Given that antiplatelet effects can be seen at 20–50 µg/ml and this can be accomplished with a dose of 10.5 mg/kg in the cat, it would seem prudent to administer no more than the standard dose of 25 mg/kg of aspirin to avoid potential toxicity.

Clopidogrel (Plavix®) has been shown to reduce serotonin release from activated platelets in cats, as well as help maintain the collateral network in an experimental model of feline aortic infarction. Additionally, there is evidence that clopidogrel acts as vasomodulating agent, reducing the vasoconstrictive response to multiple agents. The administration of 75 mg of clopidogrel orally upon presentation may be helpful in improving collateral flow and should not be associated with adverse effects or toxicity.

Pain Management

Cardiogenic embolism can result in severe pain and controlling this pain is a critically important aspect of acute CE treatment. While some cats may demonstrate clear and dramatic signs such as vocalization and self-mutilation, others may be more stoic and only exhibit anorexia, elevated heart rate or mild anxiety. It should be assumed that all cats are experiencing clinically relevant pain and analgesics should be considered. Butorphanol (0.2–0.4 mg/kg SQ, IM, IV q 1–4 hours), hydromorphone (0.08–0.3 mg/kg SQ, IM, IV q 2–6 hours), buprenorphine (0.005–0.01 mg/kg SQ, IM, IV q 6–12 hours), and oxymorphone (0.05–0.1 mg/kg SQ, IM, IV q 1–3 hours) have been widely used in cats and appear to provide good analgesia with little adverse effects. In severe or refractory cases, fentanyl (4–10 µg/kg IV bolus followed by 4–10 µg/kg/h infusion) can be used.

Treatment of Concurrent Congestive Heart Failure

Decompensated congestive heart failure is a common comorbid condition associated with CE and reported in 44 to 66% of cases. Acute management utilizing diuretics, oxygen and nitroglycerin is important and will frequently result in resolution of the congestive state.

Supportive Care

Nutritional support is a critically important aspect that is often overlooked. If the cat is not eating or the caloric intake is inadequate, nasoesophageal feeding should be considered. Fluid therapy may be necessary in hypotensive cats and may assist in the removal of metabolic toxins, such as potassium and organic acids released from infarcted tissues, as well as vasoactive substances released from activated platelets. On the other hand, many cats are in congestive heart failure when they present and many more are likely to decompensate if fluid therapy is too aggressive. Therefore, it is recommended to cautiously use parenteral fluid therapy only in cases that would benefit from its use. Physical therapy to maintain flexibility of joints and encourage collateral flow is encouraged but may have to be postponed until the initial painful period has subsided.

Prevention

Primary prevention is focused on preventing the first CE event in a cat with an apparent increased risk such as underlying cardiac disease. Secondary prevention is focused on preventing a subsequent or recurrent CE event.

While there is some variability, primary prevention is generally recommended in cats that have 1 or more of the following: LA/Ao (left atrium to aortic ratio from cross-sectional 2-D echocardiographic examination) ratio of ≥ 1.7 or LADs (left atrial diameter during systole) of ≥ 2.0 cm from M-mode echocardiographic examination, or the presence of spontaneous contrast “smoke” within the left atrium from 2-D echocardiographic examination. Secondary prevention is recommended in all cats that have already had a CE event regardless of echocardiographic findings.

Concurrent Cardiac Therapy

Ideally, the substrate for thrombus formation should be removed. Unfortunately, this is rarely achievable (i.e., taurine-deficient DCM). However, judicious use of diuretics, angiotensin-converting enzyme inhibitors, β-blockers, calcium- channel blockers or digoxin may allow for improved cardiac function and resolution of cardiac chamber dilatation. Therefore, adequate concurrent therapy for the underlying cardiac disease is an important aspect of CE prevention.

Antithrombotic Therapy

The unproven and unguided use of antithrombotic agents for the prevention of CE in the cat is widespread. The studies that exist in veterinary medicine are retrospective with very small numbers of cats which preclude any statistically significant conclusions from being made. With that in mind, the following discussion highlights individual drug classes and what is known about their effects and possible efficacy in cats at risk for CE.

1. Antiplatelet agents

Aspirin

Aspirin is an indirect antiplatelet agent inhibiting secondary platelet aggregation. Platelets are irreversibly inhibited through the acetylation of their cyclo-oxygenase preventing the formation of thromboxane A2. Recurrent CE in cats receiving aspirin varies from 25–75%. However, aspirin does appear to be safe in cats. There is a growing body of evidence that aspirin, when administered at sub-toxic doses, has minimal to no antiplatelet effects in the cat.

 Standard dose: 25 mg/kg PO q 72–48 h (2–3 days)

 Low-dose: 5 mg/cat PO q 72–48 h (2–3 days)

The thought with the low-dose is that the platelet inhibition is maintained while the inhibition of endothelial production of prostacyclin (PGI), an antagonist to platelet aggregation and vasoconstriction, is not affected. It has not been proven that this lower dose of aspirin is more effective than the standard dose and it is generally accepted that the standard dose of aspirin results in a clinically antithrombotic effect in humans. The lower dose has been reported to have less GI adverse effects in cats.

Clopidogrel (Plavix®)

Clopidogrel is an ADP antagonist that prevents primary and secondary platelet aggregation to multiple agonists and is a more potent agent than aspirin. Clopidogrel also prevents the conformational change of the GPIIb/IIIa receptor complex, reduces the release of platelet secretory products such as serotonin, and exhibits vasomodulating effects.

 Clopidogrel : 18.75 mg PO q 24 h (1/4 of a 75 mg tablet)

While no clinical data are currently available on clopidogrel, the Feline Arterial Thromboembolism; Clopidogrel vs. Aspirin Trial (FAT CAT) study is currently ongoing to assess clinical efficacy. Additionally, the drug appears to be safe in cats.

2. Anticoagulants

The anticoagulants have been shown to be superior to antiplatelet drugs in the prevention of CE in humans and this is related to the differing underlying pathophysiologic mechanisms. Such data currently do not exist in veterinary medicine.

Warfarin

Warfarin is a vitamin K antagonist and prevents the formation of coagulation factors II, VII, IX and X as well as the formation of the anticoagulant proteins C and S. The plasma levels of protein C fall prior to the coagulation factors, so a potential transient hypercoagulable state is induced for the first 4–6 days of warfarin therapy. For this reason, it is recommended to concurrently administer heparin during this time. There can be tremendous intra- and inter-individual variation of clinical response in cats. There are many drug interactions with warfarin, so any concurrent medications should be evaluated for potential interactions. Warfarin therapy requires diligent clinical monitoring and adjustments to life style. Therapeutic monitoring is done by measuring the changes to the prothrombin time (PT). The PT should be repeated daily during the first week of therapy, then twice weekly for 2–4 weeks. If stable, the PT is repeated weekly for 1–2 months followed by once every 1–3 months. The target range is 1.3–1.6 times baseline value. A more sensitive monitoring tool that can be used is the international normalization ratio (INR). The target INR range is 2.0–3.0. The recurrence rate for cats receiving warfarin has been reported to be from 43 to 50%. Bleeding complications, both minor and major, are reported in approximately 20% of cats. While warfarin is currently considered the standard of care for prevention of cardioembolic disease in humans, the variability in clinical response and requirement of frequent monitoring have dramatically curtailed its use in cats.

  • Warfarin: 0.25–0.5 mg/cat PO q 24 h (1 mg tablets)

Heparin

  • 150–250 IU/kg SQ q 8 h (1,000 or 10,000 IU/ml); administer this concurrently during the first 4–6 days of warfarin therapy

Low-molecular weight heparins

The LMWH reduce the activation of factor X (Xa) through antithrombin, but unlike UH they inhibit the activation of thrombin to a much smaller degree so the risk for bleeding is reduced and therapeutic monitoring is ineffective and unnecessary. These agents have proven effective in the acute treatment of myocardial infarction and venous thrombosis/thromboembolism in humans. The major limitations of these agents are cost and compliance as these agents must be given subcutaneously. There are a number of reports in the veterinary literature suggesting treatment protocols for the LMWH based on anti-Xa levels. However, there is a known dissociation between the pharmacokinetics and pharmacodynamics of the LMWH in vivo, which is a major reason that therapeutic monitoring of anti-Xa in humans is not recommended. A recent study demonstrated that there was a dramatic antithrombotic effect with enoxaparin when administered every 12 hours even though there was no measurable anti-Xa activity, suggesting that enoxaparin does not need to be administered more frequently than twice a day.

The CE recurrence rate from one retrospective study using dalteparin in cats was reported to be 43%.

 Dalteparin (Fragmin®): 100 IU/kg SQ q 24–12 h (10,000 IU/ml)

 Enoxaparin (Lovenox®): 1.0–1.5 mg/kg SQ q 24–12 h (100 mg/ml)

Synthetic Xa inhibitors

A relatively new class of anticoagulant drugs is the synthetic Xa inhibitors. These drugs are a homogenous formulation of the pentasaccharide sequence that is the specific inhibitor of factor Xa with no effect on factor IIa (thrombin) or platelet function. Fondaparinux (Arixtra®) is a novel antithrombotic drug used in the prevention and treatment of thromboembolic events in humans. Fondaparinux is administered subcutaneously, has a bioavailability of 100%, is excreted unchanged in the urine, and increases the affinity of AT(III) for factor Xa (300-fold). The high bioavailability, infrequent dosing and lack of requirement for drug monitoring may make fondaparinux an attractive alternative to UH and LMWH.

 Fondaparinux (Arixtra®): 0.06 mg/kg SC q 12 h

Idraparinux is a second generation Xa inhibitor that has an even longer drug effect than fondaparinux allowing once a week administration in humans. However, clinical trials in humans have identified an increased risk of bleeding compared to warfarin making the future of this drug unknown. Rivaroxiban is an orally available Xa inhibitor that will get FDA approval in the very near future. This drug has demonstrated antithrombotic effects in cats and may play an important role in the prevention of CE in cats.

Direct Thrombin Inhibitors

This class of drugs inhibits factor IIa and is on the leading edge of prevention of cardioembolic disease in humans. Dabigatran is approved for the prevention of CE secondary to atrial fibrillation in humans and is the first drug to be shown to be superior to warfarin in this regard. This drug or related direct thrombin inhibitors (DTI) may play a large role in the future of CE prevention in cats.

Daniel F. Hogan, DVM, DACVIM (Cardiology)

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