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Left Ventricular Assist Device ThrombosisAmiodarone-Induced Hyperthyroidism

Causal Link?

Rajapreyar, Indranee*; Acharya, Deepak*; Tallaj, José*; Hornbuckle, Lauren; Sharpton, Jessica; Joly, Joanna; Pamboukian, Salpy*

doi: 10.1097/MAT.0000000000000773
Case Reports

Ventricular arrhythmias occurs in 20–50% of patients supported with left ventricular assist devices (LVAD). Ventricular arrhythmias are well tolerated with LVAD support but long-term consequences include worsening right ventricular function. Management of ventricular arrhythmias in LVAD patients includes use of antiarrhythmic agents or ablation. Amiodarone has been used a first-line agent to treat ventricular arrhythmias post-LVAD implantation. Chronic treatment with amiodarone for arrhythmias can result in hyperthyroidism and hypothyroidism in 5–10% of patients. Hyperthyroidism is known to cause endothelial dysfunction, alterations in coagulation, and fibrinolytic pathways favoring hypercoagulable state. We describe two cases of left ventricular assist device (LVAD) thrombosis potentiated by amiodarone-induced hyperthyroidism (AIT) and discuss pathophysiological mechanisms for hypercoagulable state induced by hyperthyroidism.

From the *Department of Cardiology, University of Alabama at Birmingham, Birmingham, Alabama

Department of Mechanical Circulatory Support, University of Alabama at Birmingham, Birmingham, Alabama

BWH Heart and Vascular Center, Brigham and Women’s Hospital, Boston, Massachusetts.

Submitted for consideration September 2017; accepted for publication in revised form December 2017.

Disclosure: The authors have no conflicts of interest to report.

Correspondence: Indranee Rajapreyar, University of Alabama at Birmingham, 1911 University Blvd, THT 311, Birmingham, AL 35233. Email:

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Case Report

Case 1

Seventy year old male with ischemic cardiomyopathy underwent HeartWare LVAD placement in 2015. Antiplatelet therapy included aspirin (ASA) 81 mg and anticoagulation therapy consisted of warfarin with goal international normalized ratio (INR) between 1.8 and 2.2. The INR goal was lowered because of history of gastrointestinal bleeding 7 months before presentation with pump thrombosis. Patient had been on amiodarone for ventricular arrhythmias. Approximately a year after LVAD implantation, patient complained of weight loss and hot flashes. Laboratory testing revealed mildly suppressed thyroid-stimulating hormone (TSH) with free T4 at the upper limits of normal and normal free T3 (Table 1). Methimazole was initiated for treatment of subclinical hyperthyroidism. Patient presented with pump thrombosis as manifested by elevated power, high LVAD flows, dark urine, and elevated hemolysis parameters (increased lactate dehydrogenase [LDH] and plasma hemoglobin) 2 months after initial detection of abnormal thyroid function tests. Patient was hyperthyroid despite being on treatment with methimazole at time of presentation. Patient had therapeutic aspirin effect based on platelet aggregation studies. INR at the time of pump thrombosis was 2.17, and time in therapeutic range had been 87.4%. Patient underwent LVAD pump exchange. Patient was maintained on intravenous (IV) steroids perioperatively and switched to oral steroids in addition to methimazole. Postoperative course was complicated by acute renal failure requiring temporary continuous renal replacement therapy, small intracranial hemorrhage, and multiple episodes of ventricular tachycardia. He remained hyperthyroid despite being on methimazole, steroids, lithium, and cholestyramine. Thyroidectomy was considered high risk and patient had declined surgery. Patient experienced clinical deterioration with recurrent episodes of ventricular tachycardia and became more encephalopathic. Comfort care measures were instituted and LVAD therapy was discontinued as per patient and family wishes.

Table 1

Table 1

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Case 2

Thirty-two year old male with history of nonischemic cardiomyopathy underwent Heartware LVAD implantation in 2015 as a bridge to transplantation. Antiplatelet therapy included ASA 325 mg and anticoagulation consisted of warfarin with goal INR 2–3. His immediate postoperative course was complicated by ventricular arrhythmias that was well controlled with amiodarone 200 mg twice daily. Because of recurrent ventricular arrhythmias, dose of amiodarone was increased to 400 mg twice daily and mexiltene was added. His last episode of ventricular arrhythmias was 3 months before presentation with pump thrombosis. Approximately, 2 years after initial implant, patient presented to the hospital with elevated LVAD flows >10, power and laboratory parameters of hemolysis indicative of pump thrombosis.

Thyroid function tests showed decreased TSH, elevated free T4 and free T3 (Table 2). INR at presentation was 2.56 and time in therapeutic range had been 99.1%. Platelet aggregation studies performed routinely 2 months before presentation showed therapeutic effect of aspirin. The patient had experienced weight loss a month before presentation and his thyroid function tests at that time were slightly deranged with normal TSH and mildly elevated free T4.

Table 2

Table 2

Treatment with IV hydrocortisone was initiated for AIT before LVAD pump exchange. The patient underwent successful pump exchange with normalization of hemolysis labs and normal VAD parameters. The patient was treated with steroids and methimazole with no improvement in thyroid function tests. Propylthiouracil (PTU) was substituted for methimazole and cholestyramine was added with mild decrease in free T4 and increase in TSH. He was discharged home on ASA 325 mg and warfarin with target INR range 2.5–3. The patient underwent thyroidectomy because of failure of medical management and thyroid replacement therapy was initiated.

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Ventricular arrhythmias occurs in 20–50% of patients supported with left ventricular assist devices.1 Chronic treatment with amiodarone for arrhythmias can result in hyperthyroidism and hypothyroidism in 5–10% of patients.2

In the combined analysis of patients enrolled in the bridge to transplant trial and continued access protocol heartware ventricular assist device (HVAD) trial, 8.1 % of patients experienced pump thrombosis and the risk factors included elevated mean arterial pressure >90 mm Hg, INR < 2 and ASA < 81 mg.3 There were no identifiable risk factors other than hyperthyroid status that could have contributed to LVAD pump thrombosis in both cases. Blood pressure was well controlled in both cases. Both patients had therapeutic antiplatelet effect with aspirin as determined by platelet aggregation studies. Thromboelastography (TEG) was performed for both cases at the time of clinical presentation (Tables 1 and 2). Because of lack of standardization of TEG in patients supported with LVAD, no conclusions were drawn regarding effectiveness of anticoagulant and antiplatelet therapy. Routine TEG testing was not performed at our center hence comparison data were not available. Despite lower INR goal of 1.8–2.2 for patient 1, INR was above two except two INR values that were below therapeutic range and patient was bridged with heparin with therapeutic anti-Xa levels. There was no clinical suspicion for pump thrombosis preceding the hospitalization and ventricular arrhythmias at time of presentation.

Hyperthyroidism in both cases was difficult to treat: first-line treatment with methimazole and steroids was not successful, and PTU and cholestyramine had to be added. In resistant cases of hyperthyroidism, thyroidectomy is recommended. The first patient was frail, and declined further surgeries. The second patient was still hyperthyroid despite medical management and underwent thyroidectomy successfully.

Endothelial activation and dysfunction is known to occur with hyperthyroid state.4 Elevated plasma-free T4 levels were associated with increased risk of venous thrombosis independent of TSH levels.5 Hyperthyroidism leads to an increase in vWF:Ag levels which can result in increased platelet activation and platelet plug formation.6 Studies have also shown increase in factor VIII antigen levels and increased factor VIII–related coagulant activity in hyperthyroidism and normalization of levels with restoration of euthyroid status.7 In patients with hyperthyroidism, fibrinogen levels, thrombin-activable fibrinolysis inhibitor, factor X activity are increased and levels of protein C, protein S, tissue factor pathway inhibitor are decreased favoring hypercoagulable state.8,9 There is imbalance in the fibrinolytic system with decreased release of tissue plasminogen activator and increased plasminogen activator inhibitor levels thereby decreased fibrinolytic activity.10,11 Endothelial dysfunction, platelet activation, and decreased fibrinolytic activity increases susceptibility to thrombotic state in hyperthyroidism.

Fifty percent of patients on amiodarone have normal thyroid function tests preceding the development of overt clinical thyroid dysfunction.12 Medical management of hyperthyroidism poses several challenges which include higher than normal doses of thionamides which can potentiate toxicity and delayed time to remission because of prolonged elimination half-life of amiodarone.13 Plasmapheresis can be temporarily effective in reducing thyroid hormone levels, iodine and to a lesser extent amiodarone.14 Thyroidectomy should be considered if there is failure to respond to medical management, recurrence of hyperthyroidism, antithyroid drug toxicity, and need for amiodarone to prevent ventricular arrhythmias.15 Mortality and morbidity of thyroidectomy in patients supported with left ventricular assist devices are unknown.

Lack of hypercoagulable workup in both patients is one of the limitations of this case report. However, both patients did not have any history of venous or arterial thromboembolism and hypercoagulable workup was not done in the past. Individual factor levels, protein C and S levels were not performed at the time of presentation because of unreliable test results while experiencing a thrombotic event and anticoagulation with warfarin.

Patients supported with LVAD who develop hyperthyroidism should be closely monitored for manifestations of pump thrombosis which can occur despite therapeutic anticoagulation. Surveillance monitoring should include hemolysis labs at frequent intervals, reporting of changes in urine color and notification of any alterations in pump parameters such as increased pump powers. Amiodarone discontinuation or substitution with alternative antiarrhythmic agent should be considered when there is laboratory evidence of rising free T4 levels despite normal TSH.

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left ventricular assist device thrombosis; amiodarone; hyperthyroidism

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