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ST-Elevation Myocardial Due to Acute in an Adolescent With COVID-19

Jessica Persson, MD, Michael Shorofsky, MD, Ryan Leahy, MD, MS, Richard Friesen, MD, Amber Khanna, MD, MS, Lyndsey Cole, MD, John S. Kim, MD, MS

DOI: 10.1542/peds.2020-049793 Journal: Pediatrics Article Type: Case Report

Citation: Persson J, Shorofsky M, Leahy R, et al. ST-elevation due to acute thrombosis in an adolescent with COVID-19. Pediatrics. 2021; doi: 10.1542/peds.2020- 049793

This is a prepublication version of an article that has undergone peer review and been accepted for publication but is not the final version of record. This paper may be cited using the DOI and date of access. This paper may contain information that has errors in facts, figures, and statements, and will be corrected in the final published version. The journal is providing an early version of this article to expedite access to this information. The American Academy of Pediatrics, the editors, and authors are not responsible for inaccurate information and data described in this version.

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ST-Elevation Myocardial Infarction Due to Acute Thrombosis in an Adolescent With COVID-19

Jessica Persson, MD1, Michael Shorofsky, MD1, Ryan Leahy, MD, MS1, Richard Friesen, MD1, Amber Khanna, MD, MS1,2, Lyndsey Cole, MD3, John S. Kim, MD, MS1

1Division of Cardiology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 2Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado 3Section of Infectious , Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado

Corresponding Author: John S. Kim, MD MS 13123 East 16th Avenue, Box 100 Aurora, Colorado 80045

Article Summary: STEMI can be the presenting diagnosis in adults with COVID-19. Presented, is a case of a 15-year-old female with coronary thrombosis-induced STEMI associated with COVID-19. Funding/Support: none Conflict of Interest Disclosures: The authors have no conflicts of interest relevant to this article to disclose Contributors’ Declaration Statements: Drs. Persson and Kim (a) provided substantial contribution to conception and design of the manuscript and (b) drafted the article and revised it critically for important intellectual content. Drs. Shorofsky, Leahy, Friesen, Khanna, and Cole (a) provided substantial contribution to conception and design, (b) revised the article critically for important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Abbreviations: ST-elevation myocardial infarction (STEMI), myocardial infarction (MI), severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), coronavirus 2019 (COVID- 19), multisystem inflammatory syndrome in children (MIS-C) Keywords: COVID-19, STEMI, thrombosis

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Abstract ST-elevation myocardial infarction (STEMI) is an identified presentation of COVID-19 in adults

but has not been reported in children. We present a case of a 15-year-old female with a coronary

thrombosis-induced STEMI in the setting of acute SARS-CoV-2 infection, not associated with

multisystem inflammatory syndrome in children (MIS-C). The patient presented with ,

ST-elevation, and myocardial dysfunction. Coronary angiography identified thrombosis treated with anticoagulation and antiplatelet therapy. Myocardial infarction must be considered in children who present with COVID-19-associated myocardial dysfunction.

Introduction

Transmural myocardial and ST-elevation myocardial infarction (STEMI) have been associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in adults. Myocardial in acute SARS-CoV-2 infection have occurred as the primary presentation1 of COVID-19, as well as a secondary thrombotic complication of the acute disease.

In children, coronary ischemia is associated with multisystem inflammatory syndrome in children (MIS-C)2,3 but there are no reports describing myocardial infarction (MI) with acute

COVID-19. Nevertheless, thrombosis is commonly associated with COVID-19 across the

lifespan.4,5

Patient Presentation

A previously healthy 15-year-old, 49-kg, female presented to the emergency department with a

one-day history of acute onset, severe chest pain with left shoulder radiation, nausea, and

vomiting. She was in her usual state of health until one week prior to presentation, when she

developed dyspnea. She developed anosmia four days prior to presentation. The patient’s sister

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had a positive SARS-CoV-2 polymerase chain reaction (PCR) on the day prior to the patient’s

presentation and another close contact had an upper respiratory infection the week prior to the

patient’s symptom onset but did not have SARS-CoV-2 testing. The patient had no significant past medical history, did not smoke, and took no medications.

On initial presentation, the patient was afebrile but ill-appearing with mild tachypnea, normal

rate, pressure, and saturation in room air. Physical examination revealed no

dyspnea, murmur, gallop, conjunctivitis, rash, or calf tenderness. Chest radiography was normal.

Electrocardiography demonstrated ST-elevation in anterolateral leads (V3-V6, I, and aVL), ST

depression in leads V1 and V2, and T wave inversion in lead III (Figure 1). She was given

aspirin 325 mg.

Initial laboratory evaluation was notable for elevated troponin (0.579 ng/mL; upper limit of

normal (ULN) 0.119 ng/mL) and D-dimer (0.92 mg/L; ULN 0.5 mg/L). SARS-CoV-2 PCR on

nasopharyngeal swab was positive. There was neutrophilic leukocytosis (15,000/mcL) with

lymphopenia (absolute lymphocyte count 790/mcL). C-reactive protein, procalcitonin,

erythrocyte sedimentation rate, count, and ferritin were all normal. Urine pregnancy test

was negative.

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Given the concern for cardiac chest pain, with the differential diagnosis including STEMI,

myocarditis, and MIS-C, the patient was transferred to a pediatric quaternary care center for

further evaluation and management. Repeat laboratory evaluation upon arrival at the pediatric

referral center (four hours after initial presentation) demonstrated rising troponin (13.7 ng/mL)

and D-dimer (1.23 mg/L) and elevated serum NT-pro BNP (676 pg/mL; ULN 125 pg/mL). She received one dose of intravenous immunoglobulin (IVIG) 2 g/kg given concern for myocarditis and/or MIS-C. Transthoracic echocardiogram demonstrated akinesis of the left ventricular (LV) apex with normal function of the basal and mid-wall segments and a resultant ejection fraction of

54% (Supplemental Video 1 and 2). Right ventricular function was normal and coronary were normal in origin and size. For the diagnosis of STEMI, she was taken emergently to the cardiac catheterization laboratory for coronary angiography under general anesthesia.

In the catherization laboratory, LV end diastolic pressure was elevated (11 mmHg). Coronary angiography demonstrated a in the distal ramus branch of the left coronary with abrupt cessation of flow in the distal left anterior descending coronary artery, consistent with complete occlusion near the LV apex (Figure 2 and Supplemental Video 3). The right were patent. Given the time to catheterization, distal nature of the thrombosis, and small coronary artery size, percutaneous coronary intervention (PCI) and/or thrombectomy were not performed. A bolus of unfractionated heparin (100 units/kg) was given, followed by a continuous infusion (goal anti-Factor Xa level 0.5 -0.7 units/mL). For antiplatelet therapy, two boluses and

24-hour continuous infusion of eptifibatide (glycoprotein IIb/IIIa inhibitor) were administered, followed by dual antiplatelet therapy (DAPT) with clopidogrel and aspirin.

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She was admitted to the pediatric cardiac intensive care unit and treated for acute COVID-19 with five-day course of remdesivir. Corticosteroids were not prescribed given lack of hypoxemia.

No additional IVIG nor other immunomodulatory medications were prescribed, as her clinical picture was not consistent with MIS-C.

Ultrasonography revealed no deep thromboses. Agitated saline echocardiography revealed no patent foramen ovale. She had no personal history of thrombosis. Family history revealed miscarriages in the patient’s mother and sister, but no family history of or myocardial infarction at a young age. Standard coagulation tests were normal. Targeted

thrombophilia testing demonstrated normal protein C, protein S, antithrombin III levels, with

negative prothrombin mutation and lupus anticoagulant. Beta-2 glycoprotein and anti-cardiolipin

antibodies were negative, aside from an elevated anti-cardiolipin IgG of 56.4 CU (ULN < 20.0

CU). profile revealed a low HDL at 27.7 mg/dL.

After peak to 20 ng/dL, serum troponin declined after initiation of antithrombotic therapy. D-

dimer declined at 24 hours. At discharge, DAPT, apixaban, atorvastatin, and metoprolol

succinate were prescribed.

Upon discharge, the patient established coordinated care with an adult cardiologist in her

hometown and a pediatric cardiologist at the pediatric hospital from which she was discharged.

She developed small LV thrombi in the setting of apical akinesis and anticoagulation non-

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compliance. The patient’s medications were resumed and close outpatient follow-up with her cardiologist planned.

Discussion

We present the first reported case of an adolescent with STEMI in the setting of acute SARS-

CoV-2 infection. Hypercoagulability6 and thrombotic disease7 in COVID-19 is thought to be

related to microcirculatory inflammation and platelet activation resulting in vascular

thromboses.5 Inflammatory platelet activation is thought to play a role in MI due to COVID-19 in adults5,6 and STEMI may be the first presenting clinical manifestation,1 as it was in this

pediatric case. Additionally, with the COVID-19 pandemic, multisystem inflammatory syndrome in children (MIS-C) has emerged.2 Coronary artery ectasia in MIS-C is quite common and

coronary similar to that seen in is associated with myocardial

ischemia and infarction.3,8,9 The association between MI and COVID-19 in children has been

anticipated but not yet reported.

There is risk of thromboembolic events in patients with COVID-19. The pathogenesis, while

incompletely understood, is likely related to Virchow’s triad of endothelial ,

hypercoagulable state, and blood flow stasis.10 Endothelial dysfunction is thought to be caused by direct invasion of the endothelial cells by SARS-CoV-2.11 COVID-19 has been associated

with a hypercoagulable state induced by increased prothrombotic factors.5,12 Interestingly, our

patient exhibited no elevated inflammatory markers. Though pre-existing prothrombotic

conditions and family history of thrombosis may pose additional thrombosis risk associated with

SARS-CoV-2 infection, the evidence for thrombophilia testing in adults varies widely. Some

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literature surmises that COVID-19 disease, itself, suffices as a primary cause of thrombosis and

recommends no additional testing, while others suggest extensive testing.13,14 It is unknown how

to apply this range of recommendations to a child with MI. In this case, the patient’s only finding

on thrombophilia testing was elevated anti-cardiolipin IgG. The patient may have developed

antiphospholipid syndrome as a result of COVID-19, however, follow up testing at 12 weeks will

be needed to confirm this diagnosis.15,16 Finally, the patient was not overweight and lipid panel

revealed merely a low HDL; this was not thought to be a strong risk factor in a healthy 15-year-

old. Nevertheless, the patient was prescribed atorvastatin for post-MI management for the

hypothesized beneficial pleotropic effects, including decreased inflammation, inhibition of

platelet aggregation, improved endothelial function, stimulation of endothelial progenitor cells,

and increased plaque stability.17,18

Left ventricular dysfunction by echocardiography should prompt consideration of COVID-19- associated myocarditis. In this case, an empiric dose of IVIG was given for the potential of myocarditis and MIS-C. When ST-segment elevation is noted in a child presenting with COVID-

19, myopericarditis should also be considered. Further, the differential diagnosis of ST-elevation is broad and can be divided into ischemic and non-ischemic etiologies. Non-ischemic etiologies include pericarditis, early repolarization, bundle-branch blocks, and LV hypertrophy with strain.17 Although the majority of adults who present with acute chest pain, ST-elevation, and

ischemia have had atherosclerotic plaque rupture, it is important to consider alternative causes of

ischemia, particularly in young people.18,19

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The standard of care for adults is door-to-PCI time within 90 minutes.16,20 This standard has been

reinforced during the COVID-19 pandemic.21 Additionally, if PCI is not feasible, transfer to a

primary PCI center with intervention within 120 minutes is recommended.17,20

Treatment strategies for adolescents with STEMI will need to be extrapolated from the adult

recommendations.17,20 Primary stenting, balloon angioplasty, and manual aspiration

thrombectomy were considered in this patient. However, intervention was not attempted due to

the small vessel size, evidence of flow around the thrombus, and risk of dissection. Rather,

systemic anti-thrombotic therapies were employed. Alternatively, intra-coronary or systemic

fibrinolytic therapy, both described in coronary thrombosis due to Kawasaki disease, might be

considered in COVID-19-associated STEMI in children.8

This case presents an adolescent requiring emergent PCI for COVID-19-associated STEMI.

Centers without pediatric interventional cardiology expertise should consider whether the age

and/or weight threshold should be lowered to include the care of a child requiring PCI for

STEMI. The unusual presentation of STEMI in an adolescent, as well as the potential reluctance

of adult centers to care for a child requiring PCI, contributed to the delay in this patient’s

evaluation. Systemic fibrinolytic therapy might be considered if a delay to PCI is projected.17,20

Transfer from an adult PCI center to a pediatric center poses challenges. Most pediatric centers are not staffed for emergent PCI. Adult STEMI evaluations can often be done without general anesthesia; however, this may not be feasible in a child. SARS-CoV-2 infection posed an additional issue in this patient who received general anesthesia with endotracheal intubation.

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In summary, this case describes a 15-year-old with acute coronary artery thrombosis-induced

STEMI secondary to COVID-19. Coronary artery thrombosis was not a consequence of MIS-C.

This patient was treated with systemic anticoagulation and DAPT. Though pediatric MI is exceedingly rare, the hyperinflammatory and hypercoagulable state caused by COVID-19 may be a novel cause of pediatric MI. In addition to myopericarditis, the potential for acute coronary artery thrombosis must be considered in children with COVID-19 presenting with chest pain.

PCI centers should reconsider age and weight thresholds for intervention in children. Pediatric centers should consider the need for emergent PCI in a child presenting with MI. Nevertheless, further study of this disease entity is needed and its distinction from MIS-C must be made.

Acknowledgments:

The authors would like to thank Drs. Aken Desai, James Gaensbauer, Nicholas Houska, Katja

Gist, and Michele Loi for their contributions to the care of this patient, participation in reviewing this manuscript, and for the care they provide for children with heart disease, COVID-19, and thrombosis.

References:

1. Stefanini GG, Montorfano M, Trabattoni D, et al. ST-Elevation Myocardial Infarction in Patients with COVID-19: Clinical and Angiographic Outcomes. Circulation. 2020;141(25):2113-2116. doi:10.1161/circulationaha.120.047525

2. Belhadjer Z, Méot M, Bajolle F, et al. Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic. Circulation. 2020;142(5):429-436. doi:10.1161/circulationaha.120.048360

3. Ma W, Li C, Zhang W, Ji Z, Li Y. Anterior wall myocardial infarction in a 16-year-old man caused by coronary artery aneurysm during the outbreak of COVID-19. Bmc Cardiovasc Disor. 2020;20(1):314. doi:10.1186/s12872-020-01593-z

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4. Loi M, Branchford B, Kim J, Self C, Nuss R. COVID‐19 anticoagulation recommendations in children. Pediatr Blood Cancer. 2020;67(9):e28485. doi:10.1002/pbc.28485

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8. JC, El-Said H, Tremoulet AH, Friedman K, Gordon JB, Newburger JW. Management of Myocardial Infarction in Children with Giant Coronary Artery Aneurysms after Kawasaki Disease. The Journal of Pediatrics. 2020;221:230-234. doi:10.1016/j.jpeds.2020.02.033

9. Ishii M, Ueno T, Akagi T, et al. Guidelines for catheter intervention in coronary artery in Kawasaki disease. Published online October 2001.

10. Mehta JL, Calcaterra G, Bassareo PP. COVID‐19, thromboembolic risk, and Virchow’s triad: Lesson from the past. Clin Cardiol. 2020;43(12):1362-1367. doi:10.1002/clc.23460

11. Lowenstein CJ, Solomon SD. Severe COVID-19 is a Microvascular Disease. Circulation. 2020;142(17):1609-1611. doi:10.1161/circulationaha.120.050354

12. Ranucci M, Ballotta A, Dedda UD, et al. The procoagulant pattern of patients with COVID‐ 19 acute respiratory distress syndrome. J Thromb Haemost. 2020;18(7):1747-1751. doi:10.1111/jth.14854

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Figure 1: Initial electrocardiogram: There is ST-elevation in the anterolateral leads (V3-V6, I, and aVL) with ST depression in leads

V1-V2 and T wave inversion in lead III. An ectopic atrial rhythm is also noted.

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Figure 2: Left coronary artery angiogram: The left main coronary artery and branching pattern is normal. There is a well-organized filling defect in the distal ramus branch of the left coronary artery, where the vessel measures approximately 1.3 mm. There is flow visualized around the filling defect. Additionally, the distal left anterior descending coronary artery terminates abruptly suggesting distal occlusive thrombus.

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