HEART TRANSPLANTATION IN A PATIENT WITH LEFT VENTRICULAR ASSIST DEVICE AFTER PUMP THROMBOSIS – THE FIRST CASE REPORT IN SERBIA TRANSPLANTACIJA SRCA KOD BOLESNIKA SA UGRAĐENIM UREĐAJEM ZA POTPORU RADA LEVE KOMORE NAKON TROMBOZE UREĐAJA-PRVI PRIKAZ

Introduction. The device thrombosis is one of the most serious complications of the left ventricle assist device implantation with a high mortality and morbidity rate. Case report. A 59-year-old male was implanted by left ventricular assist device Heart Mate II as a bridge to transplantation seventeen months before the onset of a potentially fatal complication ? the thrombosis with the complete obstruction of the device. Despite the aggressive pharmacological treatment following the initial suspicion of the pump thrombosis, the patient condition got worse with the final ?pump off? alarm that marked the discontinuance of the pump work as a result of the complete obstruction by the thrombus. An appropriate occurrence of an adequate donor resulted in a successful surgical treatment ? the heart transplantation. Conclusion. The urgent heart transplantation by the first priority rank, or the device replacement, although technically extremely demanding procedures, are successful treatment options for these patients.


Introduction
The left ventricular assist device implantation (LVAD) has emerged as a relevant option for improving quality of life and survival in patients with the end-stage heart failure.The goals of this procedure include bridge to recovery (BTR), bridge to transplant (BTT), bridge to candidacy (BTC) and destination therapy (DT).As the current generation of the continuous flow LVADs activate the coagulation system, anticoagulant therapy is recommended in order to minimize the risk of device thrombosis 1 .The device thrombosis may still occur occasionally, and systemic and local thrombolytic agents are usually applied.Surgical interventions to replace the LVAD device or urgent heart transplantation are in some cases required 2 .

Case report
A 59 year-old male with the sudden recurrence of the shortness of breath was admitted to our hospital.Seventeen months before he has been implanted LVAD Heart Mate II as a bridge to transplantation due to the end stage heart failure (Figure1).After the initial uneventful recovery after LVAD implantation, he suffered two episodes of gastrointestinal hemorrhage in the fourth and the seventh month postoperatively, which were successfully treated conservatively.His outpatient anti-coagulation regimen was Warfarin with a goal INR of 2-3 as well as Acetylsalicylic acid 100 mg daily.His other medications (from last check up four weeks ago) included Ramipril 5mg daily, Amlodipine Besylate 5 mg daily, Spironolacton 25 mg daily, Furosemide 20 mg twice daily ,Pantoprazole 40 mg twice daily, Amiodarone 200mg daily, Levothyroxine 50 mcg daily, Atorvastatin 20 mg daily.
At the admission the patient was dyspneic and anxious.The physical examination showed blood pressure of 85/60 mmHg and a heart rate of 80 beats/min.Laboratory tests were consistent with hemolysis.LDH was elevated at 2300 IU/L (a rise from 400 at the previous check up four weeks ago), plasma free hemoglobin (pfHGB) 18 mg/dl and reticulocytes 2,2%.The INR value was 2,1.The LVAD parameters were as following: the pump speed (PS) was initially 8600 rpm but spontaneously dropped down to 8000 rpm, pump flow (PF) +++ (---), pump power (PP) 15,1-21w and pulsatily index (PI) 1,3.Before the onset of symptoms the LVAD parameters were: PS 8600 rpm; PF 5,2 l/min; PP 4,6 w; PI 7,1.The controller device showed a number of "low flow" alarms.The first echocardiogram revealed the increase in the dimensions of the left ventricle (both the left ventricular end diastolic diameter (LVEDD) and left ventricular end systolic diameter (LVESD) from 6,0 /5,0 cm to 7,3/6,7 cm, respectively.The left ventricle ejection fraction (LVEF) was 15% -Simpson`s method.Aortic valve was opening with every beat compared with every third or fourth beat on his last clinic visit.On the color doppler examination there was no flow through both inflow and outflow cannulas.
The patient was treated by heparin infusion, followed by the infusion of alteplase through the central venous line (started with bolus of 10 mg alteplase during 10 min period, followed by the infusion of 10 mg per hour).During the application of the second dose of alteplase on the day 2 after the admission, the patient complained of the acute severe pain on the left side of his chest.At that moment the "pump off" alarm occurred on the monitor display, marking the spontaneous discontinuance of the pump.The patient's LVAD controller was turned off and double drug support with norepinephrine and milrinone was started.
Echocardiogram performed after the pump stopped and the inotrope support started showed the mild decrease in the left ventricle dimensions (LVEDD 5,9, LVESD 4,7 cm) with the LVEF in the basal part of 22%.There was a trace of mitral regurgitation.Aortic valve was normaly opening with every beat.There was no flow through both inflow and outflow cannulas as well as through the outflow graft.The chest CT scan showed the competent outflow graft anastomosis on the ascending aorta as well as the free inflow cannula in the left ventricle.The outflow graft was of substantially narrow lumen with no signs of kinking.The inflow cannula was in the correct position placed in the direction of the posterior leaflet of the mitral valve.There were no signs of infection around the pump and the drive line.(Figure 2) The haemodynamic inotrope support was continued for the next nine days.The vital sings in that time were: temperature 36.5 C, heart rate of 90 beats/minute, mean respiratory rate 24 breaths/ minute, mean arterial pressure of 70 mmHg and oxygen saturation of 95%.Despite the risks presented the patient refused suggested pump replacement surgery.He was then en listed on the priority waiting list for heart transplantation.At the day 11 upon admission the favorable occurrence of the adequate donor resulted in the succesfull surgical treatmentheart transplantation.The operation was carried out as usual under the extracorporeal circulation with the arterial cannulation of the left femoral artery and separate venous cannulation of both caval veins performed after chest reentry.Following resternotomy it was proceded with the extensive adhesiolysis of the very tough pericardial adhesions.The heart was explanted "en block" with the device.After the preparation of the donor heart, the transplantation was performed by biatrial technique.(Figure 3)Later inspection of the explanted device confirmed the thrombotic masses in both the inflow and the outflow cannulas and the completely clogged pump rotor.The operation was completed without complications and the uneventful recovery followed.During the postoperative period the patient was hemodynamically stable, anicteric, eupneic, with good tolerance of physical stress.The regular myocardial biopsy was performed two weeks and one month after the operation.There were no signs of cell or humoral rejection of a transplanted heart.Echocardiography showed normal width of the aorta of 3.1 cm, the normal dimensions of the left ventricle (EDDLV 4.7 cm, ESDLV 2.9 cm), excellent systolic function, EFLV 75% by Teicholc, 80% by Simpson.The left atrium size was 3.2 cm.The right ventricle was 2.5 cm with normal tricuspid valve function and morphology.On the hospitalization day 36 (25 days after transplantation) he was transfered from the isolated care unit to the general care unit and on the day 44 he was discharged home in good general condition.In the regular monthly check-ups he did well.All clinical, histological and laboratory parameters were in the therapeutic range 14 months after the transplantation.

Discussion
Thromboembolic events in patients who recived LVAD are common despite the anticoagulant therapy.The most frequent presentations are: cerebrovascular accident, transient ischaemic attack, arterial non-central nervous system embolism, or pump thrombosis (PT).The device thrombosis of a certain degree was reported in 4% of patients with LVAD implanted as a destination therapy and in 1.5% of patients with LVAD implanted as a bridge to transplantation. 3There are two main categories of risk factors that predispose to the LVAD thrombosis: device-related and non-device-related. 4In the screening for and the diagnosis of LVAD thrombosis laboratory tests are crucial.LVAD thrombosis cause haemolysis and in the early stages it can be identified by elevated lactate LDH, plasma-free haemoglobin, and indirect bilirubin levels.Non-invasive diagnostic tests alone are of limited accuracy.Under the certain circumstances echocardiography can give some indirect evidence like the reduction in diastolic flow velocity trough the cannula and/or increased systolic to diastolic flow ratio.Rarely, the direct presentation of LVAD thrombus can be seen.But, the ultrasound "ramp study" is highly sensitive and specific in the detection of axial PT when used in conjunction with LDH levels. 5The exact role of routine computed tomography angiography is unclear.MSCT is helpful in patients with an unexplained elevated LDH, in order to rule out other causes that may increase this marker and in order to assess patients with a suspected malposition of one of the pump parts.Furthermore, the routine use of MSCT may require a skillful cardiovascular imager with LVAD experience for interpretation. 6LVAD pump parameters will demonstrate increased pump power or intermittent power spikes.The pump flow rate will be overestimated with a concomitant decrease in the pulsatility index resulting from the reduction of the flow through the LVAD. 7Ideal strategy for the treatment of LVAD thrombosis is yet to be defined.Medical therapy usually includes the unfractionated heparin infusion, thrombolysis, glycoprotein IIb/IIIa inhibitors, and thrombin inhibitors.These medications are associated with many side effects, mostly bleeding.Most centres weigh the risks associated with the pump replacement versus thrombolytic therapy in an individualised manner, because it is unclear which patients will have good reponse to medical therapy.If a patient is haemodynamically unstable the recommended treatment is the pump replacement.On the other hand, if the patient can be hemodynamically stabilized the other option is the priority heart transplantation. 8oldstain et al. formed the algoritam for the diagnosis and therapy of thrombosed LVAD.Patients with LDH elevations or de novo power elevations that appear late in the clinical course should be promptly evaluated for frank hemolysis.In the case of the appropriate left ventricle unloading detected by the echocardiography and rump study, the other causes for hemolysis and heart failure symptoms should be searched for.If adequate LV unloading is not confirmed, a MSCT angiogram to evaluate the position of the inflow cannula and outflow graft is indicated.Furthermore, the evidence of unimpeded flow of the contrast from the LV cavity through the outflow graft and into the aorta should be obtained.In the presence of inflow cannula malposition or kinking of the outflow graft, surgical correction should follow.In the absence of pump inflow or outflow abnormalities the inability to unload the LV on the rump study points to the pump thrombosis.In that case patient should be transferred to the ICU for close monitoring and initiation of intravenous heparin and inotropic/diuretic therapy as needed depending on heart failure symptoms.Persistent hemolysis, heart failure symptoms, and/or power spikes may be addressed with more aggressive anti-thrombotic therapy with direct thrombin inhibitors.If the hemolysis persists despite aggressive anti-thrombotic therapy, then LVAD replacement should be considered.Patient could be put on the urgent listing for heart transplantation if the estimated waiting time is no more than a few days and heart failure symptoms can be readily controlled.If the low output state persists and the heart failure progresses, the urgent LVAD replacement is mandatory.If the patient is not potential surgical candidate, in the presence of end-organ dysfunction or hemodynamic compromise the systemic thrombolytic therapy may be attempted but the prognosis is poor.Some authors advise that patients with PT with red alarms-pump stoppage, and in shock unresponsive to battery and controller exchanges require urgent LVAD replacement. 9n our clinic, the preffered first line treatment in hemodynamically stable patients with PT is thrombolytic therapy with Actylisis.In the patient reported above the initial aggressive medical treatment was not successful.On the day 2 following admission there was a total thrombotic occlusion of the LVAD.After the pump stopped it was disconnected from the controller and the inotropic support initiated.As he was hemodynamically stable and not motivated for the pump replacement, despite the risks presented, he was put on the priority list for the heart transplantation.Nine days later the adequate donor appeared and the patient underwent heart transplantation.The operation was completed successfully.

Conclusion
The LVAD thrombosis with total occlusion is one of the most serious complications with a high morbidity and mortality and the treatment must be started immediately.The urgent heart transplantation by the first priority rank or the replacement of the device, although technically extremely demanding are for the present the successful treatment options for these patients.While our patient had an excellent outcome considering his grave presentation, it again brings up the issue of the optimal management of the LVAD thrombosis.Received on July 1, 2018.Revised on October 14, 2018.Accepted on November 13, 2018.