Pulmonary artery stent thrombosis and symptomatic pulmonary hypertension following COVID-19 infection in Alagille patient: A case report

Abstract

BACKGROUND

Alagille syndrome is a multisystem disease that results in various vascular anomalies, commonly involving the cardiac and pulmonary systems. To the best of our knowledge, there is no literature regarding the cardiovascular outcomes of these patients in association with coronavirus disease 2019 (COVID-19).

CASE SUMMARY

A 34-year-old woman with a history of Alagille syndrome who underwent successful atrial septal defect with partial anomalous pulmonary veins and patent ductus arteriosus repair, as well as left pulmonary artery catheterization and stenting in childhood due to pulmonary stenosis. The patient was without any respiratory symptoms and was a dancer prior to contracting COVID-19. Several weeks after her COVID-19 infection, she developed left pulmonary artery stent thrombosis and subsequent symptomatic pulmonary hypertension. A treatment strategy of anticoagulation alongside pharmacological agents for pulmonary hypertension for 3 months followed by balloon pulmonary artery angioplasty to reopen the stenosis was unsuccessful.

CONCLUSION

In the era of COVID-19, patients with pulmonary vascular malformations and endovascular stents are at an increased risk for chronic thromboembolic disease. Patients may benefit from prophylactic antiplatelet or anticoagulation therapy. Stent thrombosis is a devastating phenomenon and should be treated urgently and aggressively with balloon pulmonary angioplasty, and/or a thrombolytic agent.

Key Words: Alagille syndrome; Pulmonary artery stent; Stent thrombosis; COVID-19; Chronic thromboembolic pulmonary hypertension; Pulmonary hypertension; Case report

Core Tip: We suggest that in this era of coronavirus disease 2019, patients with endovascular stents and known pulmonary vessel malformations be considered for preventive anticoagulation or antiplatelet therapy, since a thrombotic event in such patients may result in secondary pulmonary hypertension and devastating, irreversible damage. Furthermore, patients with thrombosed stents should be treated aggressively and quickly once a clot is diagnosed.

INTRODUCTION

Alagille syndrome is an autosomal dominant disease characterized by cardiac, pulmonary, skeletal, liver, kidney, and eye anomalies, as well as a characteristic facial dysmorphism. It is thought to result from a defective Notch signaling pathway. Mutations in JAG1 are implicated in approximately 90% of cases, with mutations in NOTCH2 and JAG1 deletions accounting for the rest[1]. It is also known by the name of arteriohepatic dysplasia, consistent with the various vascular malformations associated with the syndrome, such as patent ductus arteriosus (PDA), atrial septal defects (ASD), and anomalous pulmonary veins[2]. Treatment for Alagille syndrome is often complex and is focused on the medical and/or surgical management of individual anomalies[3]. Management by a team that is intimately familiar with the Alagille syndrome’s typical course is of utmost importance.

CASE PRESENTATION

Chief complaints

In February of 2022, a 34-year-old woman was evaluated in our hospital for shortness of breath of 5 days’ onset.

History of present illness

The patient experienced a cough in January 2022 and was diagnosed with coronavirus disease 2019 (COVID-19) infection. Her disease course was mild with no dyspnea and required no medical treatment or oxygen supplementation. Her symptoms improved and she returned to her daily routine for several weeks. One month after her COVID-19 diagnosis she presented to our emergency department with acute dyspnea and chest pain. On evaluation she had an oxygen saturation of 93% on room air and had respirations of 18/minute. Chest X-ray showed no lung infiltrates. Laboratory values were remarkable for a D-Dimer of 995 ng/mL (normal range < 500 ng/mL) and negative for troponins. A CT angiogram showed thrombosis of a stent in the left pulmonary artery (LPA) (Figure 1A and B) with impaired flow to the distal arteries and mosaicism of lung parenchyma (Figure 1C). She was hospitalized for a few days, initially treated with enoxaparin subcutaneously, and subsequently discharged on apixaban 5 mg PO bid.

Figure 1 Imaging examinations of the patient. A: Axial view; B: Sagittal view of a chest computerized tomography (CT) with contrast, mediastinal window, showing lack of propagation of contrast material in the left lower lobe branch of the left pulmonary artery; C: Axial view of a chest CT with contrast, lung window, lower lobe view, demonstrating a widened blood vessel in the right lower lung and ground glass opacities throughout; D: Axial view of a chest CT with contrast, lung window, upper lobe view, demonstrating a widened blood vessel in the right lower lung and mosaicism of lung parenchyma; E: Right heart catheterization (October 2022) showing contrast propagation through 3 arteries distal to the left pulmonary artery stent; F: Right heart catheterization (February 2023) showing complete occlusion of the arteries distal to the fractured and thrombosed stent in the left pulmonary artery; G and H: Axial view of a high-resolution chest CT, November 2022, ground-glass opacities and mosaicism bilaterally.

Four months later she continued to suffer from dyspnea on exertion and was still requiring supplemental oxygen for exertion and during sleep. A 6-minute walk test demonstrated a desaturation from 97% at the start to 79% after 445 meters on room air. An echocardiogram demonstrated an ejection fraction of 65%, no leak around the ASD site, systolic pulmonary pressure of 34 mmHg, and normal size and respiratory collapse of the inferior vena cava. There was flattening of the interventricular septum, suggesting right ventricular overload. A right heart catheterization (RHC) was done in October 2022, which confirmed significant precapillary pulmonary hypertension (PHTN) with a mean pulmonary artery pressure (MPAP) of 62 mmHg (normal range < 20 mmHg), a normal pulmonary capillary wedge pressure of 14 mmHg (normal range < 15 mmHg), and pulmonary vascular resistance (PVR) of 20 Wood units (normal range < 2 Wood units). Pulmonary artery angiography showed a thrombosed and fractured stent in the LPA. No collateral vasculature was observed, suggesting a recent occlusion. Balloon dilation to just 2.5 mm was performed due to concerns of pulmonary congestion. After contrast material was injected, three intact vessels were visualized distal to the stent (Figure 1E).

History of past illness

This patient’s childhood history includes an ASD with partial anomalous pulmonary veins (PAPVR), PDA, and LPA stenosis. She underwent surgical repair of her ASD, PAPVR and PDA at 2 years old. At age 9 she underwent balloon dilation and stent placement in the LPA, followed by re-stenting at age 15. During her RHC at age 15, her MPAP was 30 mmHg. She is also known to have chronically elevated GGT of 73 IU/L (normal range 0-30 IU/L) at baseline, and chronic kidney disease with a baseline creatinine of 1.45 mg/dL (normal range 0.6-1.1 mg/dL). Alagille syndrome diagnosis was confirmed after a JAG1 mutation was noted on genetic testing in 2023. Prior to her COVID-19 infection, she led an active life, was a dancer and worked full time as a kindergarten teacher.

Personal and family history

No Alagille syndrome in the family, parents and siblings are healthy.

Physical examination

The patient presented to the emergency department in February 2022. Physical examination showed an oxygen saturation of 93% on room air, 18 breaths per minute. Lungs were clear bilaterally on auscultation with no crackles or wheezing. No central pallor or cyanosis were noted. The abdomen was soft and non-tender to palpation. No erythema or edema concerning for deep vein thrombosis (DVT) were noted in the lower extremities.

During her last outpatient follow up in March 2023, her physical examination was not significantly changed. Oxygen saturation was 94% on room air at rest, respirations were 16 per minute. Lungs were clear bilaterally on auscultation. Abdomen was soft and non-tender to palpation. No signs of DVT. She uses 2 L of oxygen via nasal cannula while ambulating.

Laboratory examinations

During her initial evaluation at the emergency department in January 2022, the complete blood count was significant for mild leukocytosis with a white blood cell count of 11.6 K/micl (normal range 4.5-11 K/micl), and a neutrophil count of 9.4 K/micl (normal range 1.8-7.7 K/micl). A complete metabolic panel demonstrated no electrolyte abnormalities and was consistent with her baseline labs. Coagulation studies were remarkable for a D-Dimer of 995 ng/mL (normal range < 500 ng/mL) and was cause to perform a CT angiogram.

During outpatient follow-up, her pulmonary function test (PFT) in April 2022 showed moderate restrictive lung disease (FEV₁ = 56%, FVC = 59%, FEV₁/FVC = 0.82%, TLC = 72%) with a moderately lower diffusion capacity (DLCO = 56%). There has been no significant change in her PFTs throughout her follow-up with the outpatient lung clinic over the past 16 months. There are no baseline PFTs to compare to from before her COVID-19 infection.

Imaging examinations

During the initial evaluation in February 2022, a CT angiogram showed a thrombus at the site of a stent in the left lower lobe pulmonary artery (Figure 1A and B) with impaired flow to the distal arteries and mosaicism of lung parenchyma (Figure 1C).

Three blood vessels were visualized distal to the stent during her first RHC in October 2022 (Figure 1E), but none were visualized after contrast injection during her second RHC in February 2023 (Figure 1F).

FINAL DIAGNOSIS

The final diagnosis was pulmonary artery stent thrombosis with consequent worsening PHTN following COVID-19 infection in a patient with Alagille syndrome.

TREATMENT

Following the RHC in October of 2022, a multidisciplinary discussion was held with PHTN specialists, interventional cardiologists, and cardiothoracic surgeons. A treatment strategy was formulated that included lowering her PHTN using pharmacological agents for 3 months, followed by another RHC to attempt reopening the occluded stent, all while maintaining anticoagulation using apixaban. She was started on sildenafil 20 mg PO tid and macitentan 10 mg PO daily. Approximately one month into treatment, the patient reported worsening dyspnea both at rest and during exertion. A 6-minute walk test demonstrated worsening hypoxemia and distance, with desaturations from 91% at the start to 72% on room air at the end of 240 meters. Sildenafil and macitentan were discontinued.

During a follow-up multidisciplinary meeting, the possibility of post-COVID pneumonitis was considered as a contributor to her dyspnea. This was supported by the mosaic pattern on CT (Figure 1D, G and H), but challenged by the lack of characteristic infiltrates on chest X-ray, no worsening PFTs, and no other clinical signs of infection. A decision was reached to treat her for this possibility using prednisone 20 mg PO daily for 2 months, followed by a taper period. The prednisone did not improve her dyspnea, 6-minute walk test, or PFTs.

OUTCOME AND FOLLOW-UP

A follow-up RHC 3 months later showed a complete occlusion of the endovascular stent with no distal arteries visualized after contrast injection (Figure 1F). All attempts to recanalize the LPA with microcatheters failed. However, there was an improvement of the MPAP to 45 mmHg, PVR to 14 mmHg, and a stable PCWP of 15 mmHg. Following the heart catheterization, she was started on riociguat 5 mg PO bid but experienced urticaria and rash that did not improve on antihistamines, leading to its discontinuation. Since then, she has demonstrated a stable state, with her 6-min walk test in April 2023 showing desaturations from 92 to 73% over 510 meters on room air. She requires oxygen supplementation on exertion and during sleep and is far from her baseline level of functioning. She is being followed at the lung clinic and lung transplant center at our institution.

DISCUSSION

Alagille syndrome is a multisystem disease with potentially devastating manifestations, particularly of the cardiovascular, pulmonary and renal systems. To the best of our knowledge, this is the first documented case of an Alagille patient who presented with a fractured and thrombosed stent and consequent worsening of PHTN following a COVID-19 infection. Although our patient had extensive surgical repairs as a child, she has lived and functioned normally for the past 20 years. We suspect that a combination of a hypercoagulable state due to COVID-19[4], the thrombogenic effect of a stent[5], and narrowed and obstructed pulmonary vessels contributed to her disease process. Since her endovascular stent thrombosis was confirmed, she has failed multiple treatment modalities, including pharmacological therapy and invasive balloon angioplasty. She is a high-risk surgical candidate for endarterectomy due to the relatively distal location of the thrombosed stent and the narrowed, spindly vessels distal to the stent[6]. Based on our experience with this case, we suggest that in this era of COVID-19, patients with endovascular stents and known pulmonary vessel malformations be considered for preventive antiplatelet or anticoagulation therapy, since a thrombotic event in such patients may result in secondary PHTN and devastating, irreversible damage. Furthermore, patients with thrombosed stents should be treated aggressively and quickly once a clot is diagnosed. Catheter-directed thrombolysis or systemic tissue-type plasminogen activator use may be appropriate considering the chance of poor recovery following conservative treatment[7]. Further reports are necessary to determine the treatment regime with the highest efficacy.

CONCLUSION

Based on our experience treating this patient, we suggest that COVID-19 infection places patients with endovascular stents and known pulmonary vessel malformations at high risk for stent thrombosis and secondary pulmonary hypertension. Hence, we suggest these patients be considered for preventive antiplatelet or anticoagulation therapy. Once a thrombosed stent is diagnosed, prompt and aggressive treatment should be pursued to prevent an adverse disease course.