Case 1
A 26-year-old female with a past medical history of pulmonary atresia and ventricular septal defect status-post fenestrated extracardiac Fontan procedure (bidirectional Glenn anastomosis), complicated by protein-losing enteropathy, liver cirrhosis, right ventricular failure, pulmonary vein stenosis, atrial fibrillation and flutter, as well as epicardial pacemaker placement, presented to clinic with one week of progressive left upper extremity swelling, abdominal distension, and dyspnoea. Warfarin had been switched to aspirin 81 mg daily two years prior to presentation following a gastrointestinal haemorrhage. Aspirin was discontinued two weeks prior to presentation due to progressive anaemia. Esophagogastroduodenoscopy with video capsule endoscopy and colonoscopy at that time had revealed duodenitis and small bowel arterial venous malformations with active bleeding.
The patient presented to the emergency department with worsening anemia. She was normotensive, tachycardic (heart rate (HR) 110–120), and oxygenating well (SpO2 > 95%) breathing ambient air. Despite haemodynamic stability, considering the high inherent risk of thrombosis in Fontan patients, CT with delayed-phase contrast imaging was obtained, revealing a pulmonary embolus extending from the left subclavian vein into the superior vena cava and an intrahepatic thrombus extending into the inferior vena cava (Figure 1). Multiple lung opacities, likely representing infarcts, were also identified. Anticoagulation was initiated with an unfractionated heparin infusion; however, serum anti-Xa levels were persistently sub-therapeutic. With haematology input, subcutaneous enoxaparin twice daily was chosen as an alternative regimen. The course was complicated by acute blood loss anaemia secondary to recurrent gastrointestinal haemorrhage, likely from known small bowel arterial venous malformations. Given low concern for active upper gastrointestinal bleeding, repeat esophagogastroduodenoscopy was deferred. Ongoing haematology recommendations were appreciated, and the frequency of enoxaparin was decreased to once daily with resolution of haemorrhage and stabilisation of haemoglobin.
Serial parasagittal contrast CT images of Fontan thrombosis in Case 1. F, Fontan conduit; T, thrombus.
Ten months after discharge, imaging revealed complete resolution of the pulmonary, innominate, and brachiocephalic venous thrombi (Figure 1). The hepatic venous thrombus had decreased in size, with resolution at twenty months. In agreement with haematologist recommendation, anticoagulation was transitioned from subcutaneous enoxaparin to oral rivaroxaban 20 mg daily. Malabsorption due to protein-losing enteropathy was a concern; therefore, rivaroxaban activity (blood level) was monitored every eight weeks for dose titration. Rivaroxaban activity increased steadily over time and dose was ultimately decreased to 5 mg daily.
Case 2
A 12-year-old male with a past medical history of congenital single ventricle (double outlet right ventricle) and pulmonary stenosis status-post fenestrated extracardiac Fontan procedure (17 mm conduit, bidirectional Glenn anastomosis) as well as percutaneous device closure of the pulmonary valve due to elevated circuit pressures and symptomatic protein-losing enteropathy presented with progressive dyspnoea. He was tachycardic (HR 110s), normotensive, and hypoxemic (SpO2 near 60%). His saturations improved to the low 80s on a nonrebreather mask. CT with delayed-phase contrast imaging demonstrated extensive bilateral pulmonary emboli and another large thrombus in the junction of the left brachiocephalic and internal jugular veins (Figure 2).
Serial coronal contrast CT images of Fontan thrombosis in Case 2. S, superior vena cava; T, right pulmonary artery thrombus.
The patient reported compliance with aspirin 81 mg daily prior to presentation. Upon admission, anticoagulation was initiated with a heparin infusion, then switched to enoxaparin in agreement with haematologist recommendation. Thrombolysis was considered in the setting of hypoxia, but risk was deemed to outweigh benefit. Given a family history of thrombosis, cardiolipin and beta-2-glycoprotein antibodies were measured and found to be absent. Due to concerns with compliance, anticoagulation therapy was transitioned to rivaroxaban 20 mg daily prior to discharge with continuation in the outpatient setting. Rivaroxaban activity (blood level) was measured periodically for monitoring in the setting of protein-losing enteropathy. Two years after discharge, the patient remained without further thromboembolic complications associated with the Fontan circulation.
Discussion
Prior to this report, successful medical management of extensive thromboembolic events in Fontan patients has not been described. Surgical intervention with thrombectomy or removal of the Fontan conversion remains the classic approach to management. Reference Agarwal, Firdouse and Brar 1 , Reference Driesen, Voskuil and Grotenhuis 2 , Reference Panthee, Murakami, Ando, Takaoka and Ono 3 Here we report successful medical management of Fontan thrombosis.
Since it was first described in 1971, the Fontan procedure has been increasingly utilised as a palliative intervention for patients with CHD. Reference Fontan and Baudet4 In 2018, there were an estimated 50,000 patients living with Fontan circulation around the world. While the Fontan procedure certainly provides an increased life expectancy for patients with complex CHD, the intervention is associated with a unique set of potentially life-threatening complications. Thrombosis is one of the most common sequelae, with an estimated 11% incidence and 25% prevalence of systemic and pulmonary thromboembolic events, according to some studies. Reference Egbe, Connolly and Niaz5
Blood flow in the Fontan circuit is passive, producing a static environment conducive to clot formation. Chronic venous congestion and low cardiac output also lead to poor perfusion of gastrointestinal mucosa and enterocyte dysfunction, resulting in protein-losing enteropathy. Subsequent loss of antithrombotic proteins such as antithrombin 3, protein S, and protein C results in haemodynamic imbalance and thrombophilia. Furthermore, loss of heparin sulphate and syndecan-1 proteoglycans increases inflammation and perpetuates central venous pressure elevation. Coagulopathy may develop from the loss of both pro- and anti-clotting factors, precipitating thrombosis or bleeding. The size of Fontan conduit is also likely a factor in hemostasis. In case 2, the 17 mm conduit is considered undersized, possibly increasing the risk of thrombosis.
The best therapeutic approach for prevention of thrombosis in Fontan circulations has yet to be established. Generally, all patients are maintained on either aspirin 81 mg daily or full anticoagulation after Fontan procedure. Both aspirin and warfarin are thought to reduce thrombosis risk compared to no anticoagulation (over 50% risk reduction and 9% failure compared to no anticoagulation). When rivaroxaban and aspirin are compared, there is a similar thrombotic event risk, but a lower risk of bleeding when rivaroxaban is used. Reference Agarwal, Firdouse and Brar1 Of note, there is a paucity of data regarding thrombosis prevention in Fontan patients with protein-losing enteropathy.
When considering anticoagulation options in this patient population, decreased gastrointestinal absorption secondary to gut oedema must also be considered. Protein-losing enteropathy almost certainly contributed to thrombosis in these cases, but protein-losing enteropathy also would have increased their surgical risk from an invasive thrombectomy. Thrombolytics would have been contraindicated in the first case due to active gastrointestinal bleeding. Medical management was acceptable since both patients were haemodynamically stable, but they both required close monitoring for the development of haemodynamic instability and for resolution of their thrombi. Given the issues with malabsorption secondary to protein-losing enteropathy, monitoring of anticoagulant activity was essential to the success of these cases.
Financial support
This research received no specific grant from any funding agency, commercial, or not-for-profit sectors.
Competing interests
None.
Ethical standards
The patients discussed here have provided permission to publish the report.
