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Management of COVID-19 Patients

Thrombophilia in Pediatric Patients with Multisystem Inflammatory Syndrome in Children Secondary to Coronavirus Disease 2019 Supported on Extracorporeal Membrane Oxygenation

Minen, Federico*; Hands, Christopher*; Mustafa, Muhammad R; Pienaar, Alison*; Lillie, Jon*

Author Information
doi: 10.1097/MAT.0000000000001270

Abstract

The vast majority of patients requiring critical care with coronavirus disease 2019 (COVID-19) have been adults; children have predominantly been asymptomatic or had only mild symptoms. However, since a cluster of children emerged presenting with hyperinflammatory shock with features similar to Kawasaki disease, multiple case series from Europe and the US recognized that some pediatric patients present with cardiogenic shock.1–3

Materials and Methods

Evelina London Children’s Hospital pediatric intensive care unit (PICU) is the second largest PICU in the United Kingdom with more than 1,200 admissions annually, treating approximately 20 patients per year with ECMO. This center was the first to publish a case series of patients with multisystem inflammatory syndrome in children (MIS-C),1 and in total between April 14 and May 25, there have been 42 admissions that fulfil the World Health Organization criteria for MIS-C.3

We describe two patients in this cohort requiring ECMO support who had evidence of hypercoagulability and suffered thrombotic complications. ECMO was delivered using: Centrimag pump (Thoratec Corporation), 7L adult oxygenator (Eurosets), heparin bonded Maquet Bioline circuit and Bio-Medicus cannulae (multistage for access cannulae and arterial for return).

Results

Both patients presented with typical initial features of MIS-C: fever refractory to antipyretics, abdominal symptoms, skin rash, and hypotension. Initially managed as toxic shock syndrome with intravenous fluids and antibiotic therapy, they both required intubation and mechanical ventilation within 24 hours of presentation to PICU. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) samples taken from nose, throat, and bronchoalveolar lavage were negative in both patients; however, serological analysis was positive for SARS-CoV-2 IgM and IgG. Case 1 subsequently had a positive PCR postmortem throat sample.

Case 1 was the first patient presenting to our service with signs of MIS-C. He was a previously healthy 14 year old boy of Afro-Caribbean ethnicity, weighing 97 kg (body mass index [BMI] 26.8 kg/m2), admitted with acute multiorgan dysfunction (respiratory failure, myocarditis/heart failure, acute kidney injury, and liver failure). Soon after admission, he developed vasoplegic shock refractory to inotrope/vasopressor therapy with a broad complex tachyarrhythmia unresponsive to cardioversion that prompted the initiation of veno-arterial (V-A) ECMO. A 25Fr femoral access and a 15Fr right common carotid artery (RCCA) return cannula were placed as per pediatric cardiosurgical preference with cerebral near–infrared spectroscopy (NIRS) monitoring. Antifactor Xa levels targets of 0.3–0.7 IU/ml were maintained as per unit protocol. Renal replacement therapy was started; however, two filters clotted after 9 and 48 hours of hemofiltration. Antifactor Xa level was suboptimal at 0.26 IU/ml despite 30 IU/kg/hour of heparin infusion so this was increased to 35 IU/kg/hour. Ten hours after starting ECMO, fixed anisocoria and an increasing gap between the NIRS channels were noticed. Computed tomography of the head showed an acute right anterior and middle cerebral artery territory infarction (Supplemental Data File, Figure 1 http://links.lww.com/ASAIO/A535). The neurosurgical team assessed the lesion to be inoperable, and the care was redirected after 71 hours of ECMO therapy.

Case 2 was a previously healthy 12 year old girl of Afro-Caribbean ethnicity, weighing 34 kg (BMI 13.3 kg/m2), admitted with MIS-C 2 weeks after the first patient presented. She presented in vasopressor-dependent vasoplegic shock and had an episode of sudden bradycardia and hypotension leading to a pulseless electrical activity 12 hours after admission. Spontaneous circulation returned after 2 minutes of cardiopulmonary resuscitation. V-A ECMO was initiated for persistent hemodynamic instability and escalating inotropic support. Right internal jugular vein (21Fr) and RCCA (15Fr) were used as femoral vessels were deemed too small by the surgical team to rapidly place on ECMO. In view of the hypercoagulability noted in the series of patients previously admitted with MIS-C, the antifactor Xa level target was increased to 0.5–1.0 IU/ml and antithrombin-III level optimized. High-dose aspirin, methylprednisolone, and infliximab were commenced as immunomodulatory therapy as per multidisciplinary team discussion. Infliximab was preferred for its use in immunoglobulin-refractory Kawasaki disease.4 Despite antifactor Xa levels being consistently in range, 24 hours after ECMO initiation a right atrial thrombus was visualized on transthoracic echocardiography which disappeared in the following 48 hours (Supplemental Digital Content, Video1 http://links.lww.com/ASAIO/A538 and Video 2 http://links.lww.com/ASAIO/A539). Computed tomography chest excluded pulmonary embolism but demonstrated extensive parenchymal abnormality in keeping with adult COVID-19 patients (Supplemental Data File, Figure 2 http://links.lww.com/ASAIO/A536).5 It also demonstrated coronary artery dilatation. Computed tomography head was normal. Cardiac function rapidly improved but in view of poor respiratory function after 87 hours of VA-ECMO and concerns over the risk of stroke, the circuit was converted to veno-venous with the removal of the RCCA cannula and addition of an inferior vena cava access cannula via the left femoral vein (21Fr). Blood was returned to the right atrium via the in situ jugular cannula. The subsequent course was uneventful and after a total run of 136 hours, the patient was safely decannulated. She was discharged to the ward 5 days later and then home with no complications. Follow up at 3 weeks post discharge demonstrated: resolution of the coronary artery dilatation, normal cardiac function, and normal D-dimers/fibrinogen.

We compared the fibrinogen levels and heparin dosing of these patients with all 38 children supported with ECMO in our institution in 2018 and 2019. Fibrinogen levels before and during the ECMO therapy were persistently higher in our series compared with 2018–2019 patients (Figure 1A). They also received higher doses of heparin infusion (Figure 1B). MIS-C patients had significantly elevated D-dimers, but this could not be compared as they were not routinely performed in our institution in pre-COVID-19 era. Neither patient had evidence of significant hemolysis on reviewing their blood films and plasma-free hemoglobin; lactate dehydrogenase was slightly raised in both with peak values of 739 U/L in case 1 and 710 in case 2 (120–300 U/L normal range), but these are reported to be elevated in MIS-C.

Figure 1.
Figure 1.:
Graphs for fibrinogen level and heparin infusion hourly dose for both multisystem inflammatory syndrome in children (MIS-C) patients are compared with median and interquartile ranges for 38 patients receiving extracorporeal membrane oxygenation (ECMO) before them in 2018–2019. Time thrombosis was recognized is indicated for each patient: *Time of thrombotic event case 1, #time of thrombotic event case 2. Q1, first quartile, Q3, third quartile. A, Fibrinogen level and trends. B, Heparin infusion dose.

Discussion

We report two pediatric patients affected by MIS-C progressing to refractory shock needing ECMO support. Thrombosis developed despite heparin doses that were higher than the average for our ECMO population. Fibrinogen levels were markedly higher than in patients without MIS-C undergoing ECMO.

COVID-19 is associated with large vessel vasculitis and a generalized prothrombotic state with increased levels of fibrinogen and D-dimers in adult critically ill patients.6 This state is associated with ischemic events and higher mortality.7 The incidence of venous thromboembolic events (VTE) in critically ill patients admitted to ICU with SARS-CoV-2 have been reported to be as high as 27%, and arterial vascular events up to 3.7% despite standard weight-based VTE prophylaxis with low molecular weight heparin.6 Up to 96% of patients receiving continuous renal replacement therapy experienced circuit clotting.7,8 Adult patients affected by SARS-CoV-2 admitted to ICU for acute respiratory distress syndrome (ARDS) receiving an increased prophylactic dose of nadroparin had a significant decrease in D-dimer levels and reduced hypercoagulability in viscoelastic tests.9

Among 42 children admitted in our ICU from April 2020 with MIS-C, the patients presenting with a severe clinical picture demonstrated hyperinflammation and hypercoagulability with raised fibrinogen and D-dimers.

This is, to our knowledge, the first description of thrombotic complications in pediatric population with MIS-C undergoing ECMO.

When case 1 presented, our experience in treating patients with MIS-C was limited and reports about COVID-19 in the pediatric population were of a mostly benign picture with 0.6% progression to ARDS or multiorgan system dysfunction.10 PCR from nose and throat samples were repeatedly negative for SARS-CoV-2 so he was managed as a case of toxic shock syndrome. We followed our standard anticoagulation approach for patients on ECMO (Supplemental Data File, File 1 http://links.lww.com/ASAIO/A537), aiming for antifactor Xa levels of 0.3–0.7 IU/ml, based on the observation that an antifactor Xa range of 0.35–0.7 IU/ml is associated with a high thrombus resolution rate and no thrombus progression.11 Initial antifactor Xa and activated partial thromboplastin time ratio (APTT) ratio were low (0.26 IU/ml and 1.6, respectively) so as ECMO flows were stable and the heparin infusion rate was increased to 35 IU/kg/hour which is higher than average for our ECMO patients. Unilateral pupillary dilatation change was noticed ten hours after ECMO commencement and the subsequent levels of antifactor Xa and APTT few hours after this were in range (0.35 IU/ml and 2.2, respectively).

By the time case 2 was admitted, we had seen multiple MIS-C cases so antifactor Xa levels were deliberately titrated higher (levels 0.5–1.0 IU/ml). The antithrombin-III level was optimized and immunomodulatory therapy rapidly started. Despite that, an intracardiac thrombus was first noticed 36 hours after initiating ECMO (Supplemental Video File, Video1 http://links.lww.com/ASAIO/A538 and Video 2 http://links.lww.com/ASAIO/A539). At that moment, antifactor Xa levels, APTT, ratio and antithrombin-III level were in range (0.59 IU/ml, 2.7, and 83.1 IU/dl, respectively). Echocardiography at the time of cannulation and 12 hours later did not show any thrombus.

Acute thrombotic events are a recognized complication associated with ECMO; we suggest, however, that hypercoagulability demonstrated by high fibrinogen and D-dimer levels in MIS-C increase the likelihood of thrombotic complications despite high doses of heparin. RCCA access may have increased the risk of stroke; however, the association of carotid artery cannulation and neurologic injury in pediatric population is inconclusive.12,13 Additionally, in the early phase of ECMO support hemorrhagic lesions are more likely, whereas the incidence of ischemic lesions increases with a longer ECMO run time.14 As only two patients from our cohort of MIS-C received ECMO, it is not possible to make specific recommendations on anticoagulation policies.

Belhadjer et al.2 reported 35 children with acute heart failure in the settings of MIS-C of whom 10 (28%) needed V-A ECMO support and all survived. This study focused on cardiac findings and did not highlight thrombophilia or anticoagulation issues. Before this report, myocardial injury related to SARS-CoV-2 was only described in the adult population.15 It is vital that all patients with MIS-C are reported to the international registry, extracorporeal life support organization, so further evidence can be obtained on the risk of thrombosis in this group of patients.

Conclusions

Patients with MIS-C needing ECMO support demonstrated markedly higher fibrinogen levels compared with the non-MIS-C population on ECMO and a high incidence of thrombosis in this retrospective review of cases. This increased risk of thrombosis should be considered when optimizing the anticoagulation strategy for this group on ECMO.

Table 1. - Biomarkers Regarding Inflammation, Coagulation, and Cardiac
Patient 1 Patient 2
Local Hospital Admission Pre ECMO ECMO Prethrombosis Peak/Nadir* Value (day) Local Hospital Admission Pre ECMO ECMO Prethrombosis Peak/Nadir* Value (day)
WCC (×109) 7.2 14.0 30.1 38.9 (5) 15.0 20.0 32.0 32.0 (3)
Lymphocytes (×109) 0.3 1.0 0.9 0.3 (3) 0.2 0.2 0.3 0.2 (2)
Hemoglobin (g/L) 97 77 108 77 (1) 96 88 98 88 (1)
Platelets (×109) 202 190 206 123 (5) 112 103 111 73 (2)
Fibrinogen (g/L) N/A 9.5 N/A 10.8 (2) 5.7 5.8 6.8 6.8 (3)
D-dimers (mg/L FEU) N/A 6.44 N/A 13.5 (4) >8 69.4 47.1 69.8 (1)
INR (ratio) 1.3 1.2 1.2 1.2 (1) 1.5 1.7 1.5 2.3 (1)
APTT (ratio) 1.0 1.5 1.6 2.5 (3) 1.4 1.3 2.7 5.3 (5)
Antifactor Xa (IU/ml) N/A N/A 0.26 0.45 N/A N/A 0.59 1.3 (5)
Antithrombin III (87–125 IU/dl) N/A N/A N/A N/A N/A N/A 101 37
Ferritin (μg/L) N/A 2,185 N/A 4,220 (3) 3,891 4,815 3,088 4,815 (1)
Pro-BNP (ng/L) N/A 22,717 N/A >35,000 (2) N/A 14,017 >35,000 >35,000 (1)
Troponin T (ng/L) N/A 249 N/A 675 (2) 56 43 84 110 (2)
CRP (mg/L) 332 463 483 556 (2) 340 306 321 343 (3)
Procalcitonin (μg/L) N/A >100 N/A >100 (1–2) N/A >100 >100 >100 (1–4)
Values shown at the time of: admission to hospital, admission to pediatric intensive care unit, and sample taken before thrombosis being recognized. Note: 1,500 U of antithrombin III was given to increase value to 101.
*Nadir for lymphocytes, hemoglobin, platelets, antithrombin III.
APTT, activated partial thromboplastin time ratio; CRP, C-reactive protein; INR, international normalized ratio; N/A, not available; Pro-BNP, B-type natriuretic peptide; WCC, white cell count.

Acknowledgment

The authors would like to acknowledge the whole Evelina ECMO team including Paul James, Andrew Nyman, Jo Perkins, Ben Griffiths, Miriam Fine-Goulden, Ariane Annicq, Jenny Budd, Xabier Freire-Gomez, Simone Speggiorin, Caner Salih, Conal Austin; Guy’s, King’s and St Thomas’ Medical School Students Danny Johnson and Sung Jin Park; Evelina Cardiology team including Paraskevi Theocharis, James Wong, Kuberan Pushparajah, Owen Miller and Ariana Spanaki.

References

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Keywords:

COVID19; SARS-2-CoV; ECMO; fibrinogen; thrombophilia; shock

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