Use of low-dose thrombolytics for treatment of intracardiac thrombus and massive pulmonary embolus after aborted liver transplant leads to recovery of right ventricular function and redo liver transplantation

Abstract

This is a 61-year-old man with end-stage liver disease who experienced cardiac arrest secondary to a massive pulmonary embolus and intracardiac thrombus during cannulation for veno-venous extracorporeal membrane oxygenation (ECMO) in preparation for orthotopic liver transplantation (OLT). Surgery was aborted and the patient was taken back to the intensive care unit in cardiogenic shock on multiple vasopressors. The patient was unresponsive to heparin bolus and too high risk for systemic thrombolytics or embolectomy. He was ultimately treated with 12 mg total of alteplase through his pulmonary artery catheter over 3 hours. He had subsequent resolution of his cardiogenic shock and proceeded with successful liver transplantation 5 days after his initial event without any bleeding complications. Low-dose thrombolytic therapy in the setting of absolute contraindications to thrombolysis allowed for recovery of cardiac function and, ultimately redo OLT in a patient with otherwise little hope of survival.

Background

Massive pulmonary embolus (PE) is a catastrophic emergency, marked by haemodynamic compromise and associated with a 30-day mortality of up to 60%.¹ When acute massive PE requires cardiopulmonary resuscitation the mortality rate approaches 75%.² The current recommended treatment for massive PE is systemic thrombolysis; however, this carries a 20% risk of major bleeding and a 3%–5% risk of intracranial haemorrhage.^{3 4} Decompensated patients with cirrhosis, although coagulopathic, carry a 1% chance of developing venous thromboembolism (VTE) during hospitalisation.⁵ Prolonged hospitalisation, placement of central venous catheters, administration of blood products and use of antifibrinolytics may further increase the risk of VTE in these patients.

Treatment of massive PE in patients with cirrhosis is challenging because their coagulopathy represents a relative contraindication to therapy with thrombolytics. The therapeutic quandary becomes particularly challenging in patients with cirrhosis undergoing orthotopic liver transplantation (OLT). OLT typically involves major blood loss requiring large volume transfusions. The massive volume from transfusions and unclamping the inferior vena cava (IVC) places strain on the right heart.^{6 7}Patients with recent PE will need to demonstrate right ventricle (RV) recovery to be able to tolerate transplant.

Cases of PE and intracardiac thrombus (ICT) during OLT in the literature have been treated intraoperatively owing to their emergent nature.^6–9 This case is unique in that our patient experienced his PE and ICT prior to incision so his OLT was aborted and his cardiogenic shock was treated with low-dose thrombolytics in the intensive care unit (ICU) setting rather than in the operating room. After recovery of his right ventricular function, the patient was relisted and underwent successful liver transplant 5 days after alteplase administration. To our knowledge, this is the first case demonstrating successful treatment of massive PE and ICT with low-dose thrombolytics in a bleeding patient with cirrhosis ultimately leading to successful liver transplantation.

Case presentation

This is a 61-year-old man with a prior medical history of hepatitis C complicated by decompensated cirrhosis with a model for end-stage liver disease score of 40 admitted for orthotopic liver transplant evaluation. The patient had no prior history of PE or deep vein thrombosis (DVT). Work-up and examination revealed fluid overload and hypoxaemic respiratory distress treated with mechanical ventilation, slow continuous ultrafiltration and therapeutic thoracentesis as needed. The patient had significant coagulopathy with downtrending haemoglobin and oozing noted from his catheter puncture sites treated with transfusions of blood products, desmopressin and aminocaproic acid infusion. Consequently, no pharmacological DVT prophylaxis was given and there were no clinical signs of DVT prior to liver transplant. A transthoracic echocardiogram (TTE) done 2 days prior to transplant did not demonstrate any increased RV strain or ICT.

During veno-venous cannulation in preparation for liver transplant, the patient rapidly decompensated and experienced a cardiac arrest with pulseless electrical activity prior to being placed on systemic veno-venous bypass. Intraoperative transoesophageal echocardiogram (TEE) revealed mobile clot in the right atria and right ventricle (see online supplementary video 1). A mobile echo density was noted in the proximal pulmonary artery (PA) and attached to the PA catheter (see online supplementary video 2). The TEE also showed new, moderate right ventricular dilatation and dysfunction. PA systolic pressures were noted to be 77 mm Hg. The liver transplant was aborted and the patient was taken back to the ICU on multiple vasopressors for further management of his cardiogenic shock secondary to massive pulmonary embolism and intracardiac thrombosis.

Investigations

Initial TEE revealed a large mobile echodensity in the right atrium and right ventricle. The echodensity appeared to be partially attached to the catheter traversing the tricuspid valve. A mobile echodensity was also seen in the right atrial appendage and in the proximal PA. The right ventricle was moderately dilated with moderately depressed systolic function (see online supplementary videos 1 and 2).

Initial platelet count of 21 000/µL

Initial haemoglobin of 8.7 g/dL

Initial haematocrit of 26.8%

Initial international normalised ratio (INR) of 11.7

Treatment

After TEE verification of PE and ICT, a bolus of 8000 units of heparin was given in the operating room and the patient was placed on a heparin infusion at 250 units/hour. The aminocaproic acid infusion was discontinued. Dobutamine, norepinephrine and epinephrine infusions were started and titrated to maintain a mean arterial pressure above 60 mm Hg. The patient was given a 300 mg bolus of amiodarone and started on an amiodarone drip for recurrent episodes of supraventricular tachycardia after recovery of spontaneous circulation. His ventilatory requirements were relatively minimal despite his large clot burden, requiring only a positive end expiratory pressure of 5 cmH2O and a fraction of inspired oxygen level of 60%. Six units of fresh frozen plasma was given due to an INR of 11.7.

Despite initiation of anticoagulation, vasopressor requirements continued to increase throughout the course of the day. Surgical embolectomy was too high risk secondary to advanced liver disease and profound shock. Venoarterial ECMO was also not an option given bleeding risk and because it would disqualify him from a liver transplant, the only option for long-term survival. A traditional dose of 100 mg of intravenous alteplase, or even half dose given his INR of 11.7 and recent bleeding were felt likely to cause fatal haemorrhage.^{10 11} Approximately 17 hours after cardiac arrest, a 4 mg/hour infusion of alteplase was given through the PA catheter over 3 hours for a total of dose of 12 mg of alteplase. Due to his haemodynamic instability from PE and ICT, his heparin infusion was continued during alteplase administration. The patient was monitored extremely closely but there was no evidence of bleeding.

Over the next 72 hours, the patient was completely weaned off his vasopressor infusions. A CT pulmonary angiogram (CT-PA) showed no residual intracardiac clot or clot in the pulmonary arteries. A repeat transthoracic echo at 48 hours postcardiac arrest demonstrated a PA pressure of 38 mm Hg normal right ventricular systolic function and a mildly dilated right ventricle (see online supplementary video 3). These echocardiogram findings represented significant improvement in function and size compared with the intraoperative TEE.

Patient experienced mild oozing from catheter sites but his haemoglobin remained stable requiring only 1 unit of cryoprecipitate and 2 units of packed red blood cells over the course of 5 days. His mental status remained intact and a non-contrast head CT showed no evidence of bleeding.

On day 5 after his aborted liver transplant, patient was taken back to the operating room for orthotopic liver transplant, which was completed without incident. His heparin infusion was held during his surgery. The patient did not require transfusions postoperatively and was started on prophylactic doses of subcutaneous heparin on postoperative day 3.

Outcome and follow-up

The patient’s postoperative course was complicated by hepatic stricture requiring stent placement, vancomycin-resistant enterococcus bacteraemia and multidrug-resistant pseudomonas pneumonia. Despite antibiotic therapy and supportive care, the patient regrettably passed away secondary to septic shock 61 days after his liver transplant.

Discussion

There are a variety of factors that place patients at risk for developing PE and ICT during OLT. Microthrombi are more prevalent in patients with cirrhosis and the delicate balance between anticoagulation factors and procoagulant proteins is disturbed.⁸ Venous stasis during clamping of the portal and hepatic veins and excess activation of clotting factors due to injury to large capillary beds during hepatectomy further activates Virchow’s triad.⁸ Other risk factors include placement of angiocatheters, veno-venous ECMO and prolonged hospitalisation with immobilisation. While antifibrinolytics such as aminocaproic acid and tranexamic acid have been postulated to increase risk of thrombosis, recent studies have not shown any evidence to suggest increased risk of VTE in OLT patients who receive antifibrinolytic therapy.^{5 12}

Massive PE and ICT complicating OLT are frequently catastrophic events. Although rare, there are nearly 80 documented cases published as case reports or case series with a mortality rate of 91% for isolated massive PE and 50% for those with PE and ICT.^{7 9} Haemodynamic instability and massive PE may occur at any time during OLT.^7–9 Jackson et al reported thromboembolic events occurred 37% during the reperfusion phase, 30% during the preanhepatic phase and 33% during the anhepatic phase of the procedure.⁶ This case, however, represents the first documented case of a thromboembolic event during anaesthesia induction and cannulation for veno-venous haemofiltration treated successfully with catheter-directed thrombolytics (CDT).⁸

Previously described therapies for massive PE and ICT include anticoagulation alone with inotropic support, low-dose thrombolytics, systemic thrombolytics and embolectomy.^{6 7} There is no consensus regarding treatment for massive PE and ICT complicating OLT due to its rarity. However, recent large, multicentre trials evaluating catheter-directed low-dose thrombolytics for submassive and massive PE have demonstrated resolution of shock and improvement in RV strain with reduced risk of major bleeding compared with systemic thrombolytics.^{3 13 14} The PERFECT registry notably included a small number of patients with absolute contraindications to thrombolytic therapy and none experienced major bleeding episodes.¹⁴ The Seattle II and Ultima studies, which are the largest studies to date using CDT therapy, did not have any incidence of intracranial bleeding and only one combined instance of major bleeding from the groin compared with a 3%–5% rate of intracranial haemorrhage for systemic thrombolysis.^{13 15} These trials certainly suggest a role for local infusion of low-dose thrombolysis over systemic thrombolytics in the setting of a patient with massive PE and high bleeding risk due to their greater safety profile. Surgical embolectomy is another option; however, the risk of in-hospital mortality from embolectomy has been shown to be close to 25% in meta-analyses. In comparison, 1-year survival following OLT has recently been quoted to be above 80%.¹⁶ The current American College of Chest Physicians guidelines recommendation is to proceed with surgical embolectomy only in patients who are likely to die of shock prior to administration of thrombolytics.¹⁷ In addition, surgical embolectomy requires a cardiothoracic surgeon who is willing to operate on an extremely high-risk patient. The least aggressive approach of anticoagulation and inotropic support alone mitigates the bleeding risk associated with thrombolysis but has only demonstrated a survival rate of 38%.¹⁰ While heparin alone can lead to resolution of PE, our patient did not demonstrate any improvement in his haemodynamics when he was on heparin and did remarkably better once the alteplase infusion was given. In our opinion, the present evidence favours using low-dose thrombolytics in the setting of massive PE and ICT in OLT patients, and in any patient with massive PE and high bleeding risk if anticoagulation alone is not sufficient to resolve shock.

After our patient had recovery of right ventricular function, the decision regarding timing of relisting for OLT was based on multidisciplinary discussion between our liver transplant surgeons, anaesthesiologist and pulmonary consultants. The risk of bleeding and infection in a decompensated patient with cirrhosis certainly informed our decision to relist the patient in an expedited manner.

Based on the results of our case report and other similar reports, we suggest consideration of local infusion of low-dose thrombolytics when encountering massive PE and ICT during OLT if the patient is unresponsive to anticoagulation alone or develops worsening haemodynamics despite anticoagulation therapy. If a PA catheter is in place, consider infusion through the catheter. If not, catheter-directed thrombolysis is another option. There are not enough data to suggest optimal dosing, but we used recent trials on low-dose thrombolytics and centre experience to guide our therapy.^{3 13–15} If thrombolytics are given in an operating room setting during OLT, patients are at even higher bleed risk and should be given a lower dose of thrombolytics than the dosing used in our case. Previous case reports have demonstrated successful treatment with as little as 0.5–4 mg of alteplase intraoperatively.^{7 9}

We hope this case report will add to the rapidly growing body of literature regarding the treatment of massive and submassive PE in the setting of high bleeding risk.

Learning points.

• Massive pulmonary embolus (PE) and intracardiac thrombus during orthotopic liver transplantation (OLT) are relatively rare but frequently fatal therefore carry great clinical significance.

• Low-dose thrombolytic therapy should be considered in patients undergoing OLT with massive PE who are initially unresponsive to anticoagulation alone.

• This is the first case of successful catheter-directed alteplase infusion in setting of massive PE occurring during the veno-venous cannulation phase of OLT.

• While recent studies on low-dose thrombolytics have shown a great efficacy and safety profile, ideal thrombolytic dosing for patients with massive PE and absolute contraindications to thrombolysis remains to be determined.

• Submassive and massive PE represent a complex spectrum of disease that requires a multidisciplinary approach base taking into account patient-specific factors and centre expertise.