The hypercoagulable state induced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects all patients regardless of age. The incidence of venous thromboembolism in pediatric patients with SARS-CoV-2–related illnesses is not well established. Although deep vein thrombosis is rare in children in the absence of risk factors, coagulopathy and the development of thromboses have been described in pediatric patients with acute COVID-19 and multisystem inflammatory syndrome. This comprehensive review provides a detailed overview of SARS-CoV-2–associated coagulopathy as well as strategies for optimizing the evaluation, management, and prevention of thrombosis in pediatric patients.

Editor's NoteIn this issue of the Journal of Pediatric Pharmacology and Therapeutics, we conclude the 3-part series focused on COVID-19 disease, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS CoV-2). The first paper, which was published in the third issue of this year, succinctly reviewed what is known about this challenging disease with a focus on special populations. Part 2, “The Trilogy of SARS-CoV-2 in Pediatrics: Multisystem Inflammatory Syndrome in Children,” was published in the fourth issue of this year. Our primary goal with these publications is to continue to disseminate timely, comprehensive, peer-reviewed information on this disease and how this virus affects children of all ages. The information contained in these 3 publications will complement your ongoing efforts in staying contemporary with the scientifically sound, evidence-based research and clinical data for incorporation into your daily practice.

– Michael D. Reed, PharmD, Associate Editor

Introduction

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulted in a global pandemic of a severe respiratory disease known as coronavirus disease 2019 (COVID-19).1,2  COVID-19 has a heterogeneous clinical presentation from asymptomatic to critically ill with multiorgan system failure and even death.3,4  Widespread endothelial injury and coagulation activation resulting in elevated fibrinogen, D-dimer, factor VIII, and low antithrombin III has been highly associated in patients with severe COVID-19.5 

In both adult and pediatric patients, COVID-19 has been linked to the development of venous thromboembolism (VTE), including deep vein thrombosis (DVT), pulmonary emboli (PE), digital ischemia, arterial thrombosis, microvascular thrombosis, and strokes.59  The unique post–SARS-CoV-2 manifestation known as Multisystem Inflammatory Syndrome in Children (MIS-C) may pose an additional risk in the pediatric population.1013  A concerning mortality rate of 28% has been reported in a small cohort of pediatric patients with COVID-19 or MIS-C who developed thromboses.6 

The general occurrence of DVT in children without COVID-19 remains rare in the absence of risk factors. Venous thromboembolism in children exhibits a bimodal distribution where the risk is increased in neonates and infants, decreased among younger pediatric patients, and then increased again in adolescents.14  The incidence of thrombosis in children has risen from an estimated 5.3 per 10,000 pediatric hospitalizations in the 1990s to 58 per 10,000 in 2007, demonstrating an increasing rate of hospital-acquired VTE over time.14,15  Although not well established, the VTE risk specific to pediatric patients with acute COVID-19 and/or MIS-C is beginning to emerge.6,9 

Because of a paucity of evidence, recommendations outlining the optimal evaluation and management for the prevention of thrombosis within this population remain to be elucidated. Many individual institutions have developed guidelines to standardize care in this subset of patients.16,17  Expert opinion-based consensus statements have recently been published addressing the treatment and prevention of COVID-19–related and MIS-C–related thrombosis.13,18  This review, the final of the SARS-CoV-2 trilogy series, provides an overview of SARS-CoV-2–associated coagulopathy, and strategies to optimize the evaluation, pharmacologic management, and prevention considerations of thrombosis in these patients. Information in this review is current as of June 1, 2021 and is subject to change as the SARS-CoV-2 pandemic continues to evolve.

Pathophysiology of SARS-CoV-2 Inflammation and Coagulopathy

SARS-CoV-2–associated coagulopathy, although not fully understood, appears to involve a complex set of interconnected networks encompassing all 3 elements of Virchow's triad (activation of coagulation, endothelial damage, and cytokine storm).19,20  The pathogenesis of COVID-19 has been described as dynamic interactions between 4 chained vicious feedback loops: the viral loop, the hyperinflammatory loop, the noncanonical renin-angiotensin system axis loop, and the hypercoagulation loop.21  Initiation of the cycle is triggered once SARS-CoV-2 gains cellular entry via the angiotensin-converting enzyme-2 (ACE2) receptor.22  Upon binding, ACE2 is downregulated, resulting in a surplus of angiotensin II (AT-II), which evokes systemic inflammation, endothelial dysfunction, and a procoagulant state.23  Once endothelial cells are damaged, plasminogen activator inhibitor 1 is released and tissue factor (TF) is activated (aTF) within endothelial cells, monocytes, and neutrophils.24,25  The activation of aTF induces a systemic thrombotic and hyperinflammatory state with the release of intracellular procoagulant microvesicles.19,24  This cyclical process further promotes ongoing endothelial damage with decreased prostacyclin and nitric oxide production, thereby triggering uninhibited platelet activation.25  Additional contributing factors include the activation of T cells, neutrophils, monocytes, macrophages, the release of procoagulants (e.g., von Willebrand factor and factor VIII), and activation of neutrophil extracellular traps.2426  The pathogenesis of MIS-C–associated thrombosis mirrors that of acute COVID-19. A more detailed description outlining the pathophysiology of acute COVID-19 and MIS-C in pediatrics can be found in parts 1 and 2, respectively, of our trilogy.27,28 

Progressive endothelial damage, platelet activation, and coagulation factor release amplifies inflammatory cytokine secretion, resulting in a cytokine storm.22  Seemingly specific to COVID-19, associations involving interleukin-6 (IL-6), IL-8, IL-10, IL-1β, and tumor necrosis factor α are most commonly detailed in the literature (Figure).7,24,26  Although much still remains unknown, current data suggest a collaboration of endothelial damage, hyperinflammation, platelet hyperactivation, and thrombin generation that ultimately results in COVID-19–related thromboses.22,24  A call to action for further research on the pathophysiology and mechanisms of the prothrombotic state in children with COVID-19 or MIS-C has been suggested.18 

Figure.

Proposed pathophysiology of thrombus formation in patients with SARS-CoV-2.

Figure.

Proposed pathophysiology of thrombus formation in patients with SARS-CoV-2.

Acute COVID-19 Coagulopathy. Although the true incidence of VTE in pediatric patients with COVID-19 remains unknown, COVID-19 has been associated with both venous and arterial thrombotic complications in adult patients regardless of the use of therapeutic or prophylactic anticoagulation.29,30  In 2 recent meta-analyses of mostly adult patients with acute COVID-19, arterial thrombosis rates were 2% and venous thrombosis rates were 21%, with nearly 1 in 4 of patients in the intensive care unit developing a VTE.31,32 

There is some emerging data with regard to children with acute COVID-19 and thrombosis. A retrospective case series of pediatric patients with COVID-19 (n = 8; mean age, 12.9 years; range, 2–20 years) varying in illness severity, reported similar clinical and laboratory observations compared with what has been reported in adults.33  The authors found that all patients had elevated fibrinogen, D-dimer, C-reactive protein, lymphopenia, and prolonged prothrombin time (PT) during the early stages of infection, suggestive of a hyperinflammatory state. Interestingly, despite comparable laboratory features indicative of an altered or hypercoagulable state, this pediatric cohort did not develop symptomatic thromboembolic events or an associated increased mortality.

Another single-institution retrospective review of pediatric patients admitted with symptomatic COVID-19 during a 3-month period found 26% of patients (n = 7) developed VTE, divided almost evenly between DVT and PE, with the youngest pediatric patient 2 months of age.9  Slightly more than half of the patients who developed VTE (57%) were on pharmacologic prophylaxis with either low molecular weight heparin (LMWH) (n = 3) or apixaban (n = 1). One patient with pneumonia at the time of diagnosis was readmitted with PE after discharge, prompting their team to begin post-discharge thromboprophylaxis in patients with respiratory symptoms. Obesity (BMI >95th percentile) was reported in 19% (5 of 27), and 19% (5 of 27) had sickle cell disease. However, these comorbidities were not associated with an increase in VTE development. Half of the entire cohort of patients required respiratory support of ≥5 L of nasal cannula supplemental oxygen. Increased ventilatory support was found to be significantly associated with VTE (p = 0.006). Coagulation parameters were abnormal in most patients, including elevated D-dimer (mean, 6.41 mg/L; normal, 0.27–0.5 mg/L), prolonged PT (mean, 17.8 seconds; upper limit of normal [ULN], 14.8 seconds), prolonged partial thrombin time (PTT) (mean, 65.6 seconds; ULN, 44.8 seconds), and elevated fibrinogen (mean, 642 mg/dL; ULN, 283 mg/dL). Platelet counts were variable, ranging from normal to high in most patients (183–789 k/μL), with 41% of patients developing platelet counts less than the institutional lower limit of normal (<150 k/μL) and 26% with significant thrombocytopenia (<50 k/μL).

The largest pediatric multicenter retrospective study to date, including 853 admissions for 814 patients, reported an incidence of VTE in hospitalized children of 2.1% in COVID-19 (9 of 426) compared with 0.7% in asymptomatic SARS-CoV-2 (2 of 289).6  Thrombotic events were noted in 9 patients with COVID-19 consisting of DVT (4 of 9), PE (3 of 9), intracardiac thrombus (2 of 9), and cerebral sinus venous thrombosis (1 of 9). The mortality for patients with COVID-19 with reported thrombosis was 33% and related to cardiac arrest, acute myelogenous leukemia, or multiorgan failure. With the variety of COVID-19–associated thromboses that have been reported in pediatric patients, it is imperative to consider the role of prophylactic or therapeutic anticoagulants in patients perceived to be at the highest risk for thromboses.6,34,35 

MIS-C Coagulopathy. Like Kawasaki disease (KD), MIS-C is an acute systemic vasculitis associated with widespread hyperinflammation and a procoagulant state.18,36  The risk of thrombosis is increased in patients with MIS-C and especially in those with or who develop severe ventricular dysfunction or coronary artery aneurysms (CAAs).37  Whitworth et al6  reported thrombotic events in 6.5% of patients (n = 9) hospitalized with MIS-C, including DVT (n = 7), stroke (n = 1), and intracardiac thrombus (n = 1). Most of those who developed thrombosis (n = 7) were receiving thromboprophylaxis, although all had at least 1 additional thrombotic risk factor, including central venous catheter, cancer, and obesity.6 

Assessing Risk Factors for SARS-CoV-2–Related Thrombosis

Outside the context of SARS-CoV-2–associated infections, risk stratification for the development of thrombosis has been suggested when evaluating hospitalized pediatric patients. Branchford et al38  identified thrombotic risk factors, including mechanical ventilation, presence of a central venous catheter, active infection, recent surgery, malignancy, obesity, dehydration, inflammatory disease, hospitalization >4 days, and prior hospitalization within 30 days. Loi et al39  formulated recommendations for the evaluation and management of pediatric patients with regard to thrombosis for those hospitalized with COVID-19 at their institution. These recommendations were extrapolated from literature in adult patients with COVID-19 and what is known about pediatric thrombosis without SARS-CoV-2 infection. Until further data are available, we recommend using known thrombotic risk factors when assessing for the risk of thrombosis in pediatric patients with SARS-CoV-2–related illness (Table 1).

Table 1.

Risk Factors for Venous Thromboembolism18,3840,45,58,78 

Risk Factors for Venous Thromboembolism18,38–40,45,58,78
Risk Factors for Venous Thromboembolism18,38–40,45,58,78

After assessing for thrombosis risk factors, the unanswered question remains as to the threshold for initiating pharmacologic prophylaxis in the setting of acute COVID-19. In pediatric patients without SARS-CoV-2, the initiation of various thrombosis prevention measures is dependent on the patient's bleeding risk and specific risk factors. Pediatric patients are considered low risk for VTE if they have 1 or fewer risk factors, medium risk with 2 risk factors, and high risk with 3 or more risk factors, with early ambulation, and mechanical and pharmacologic prophylaxis recommended based on number of risk factors and the patient's bleeding risk.40  However, because thrombotic risk factors are disproportionately weighted, institution-specific guidelines have been developed to guide practitioners in initiating pharmacologic prophylaxis for their hospitalized pediatric patients.16,17  Pediatric patients admitted with acute COVID-19–related illness should be evaluated frequently for thrombotic risk with implementation of prophylaxis when deemed clinically indicated by the treating medical team.

Prevention and Treatment of COVID-19–Related Thrombosis

Various hematology societies, including the American Society of Hematology and the International Society on Thrombosis and Haemostasis, have published anticoagulation recommendations for hospitalized and symptomatic adults with COVID-19.4143  Evidence-based guidance for thrombotic management in pediatric patients with COVID-19 is lacking across inpatient and outpatient settings.18  Suggested laboratory monitoring in adults which may be extrapolated to pediatric patients until more data are available include: complete blood count with platelet count, fibrinogen, PT/PTT, and D-dimer.41  Changes in clinical and laboratory features, such as extremity swelling, worsening respiratory exam, declining platelet count, or a rising D-dimer, may be indicative of worsening disease severity which would warrant further monitoring, evaluation, and potential modifications to medical management. However, because of insufficient evidence, it remains unclear whether parameters such as the D-dimer have the same prognostic value in children as seen in adult patients.39 

A recent consensus-based recommendation for the use of anticoagulation in pediatric patients was published based on an international survey of pediatric hematologists and critical care physicians with expertise in thrombosis.18  Based on a 90% (18 of 20) survey response rate, routine use of pharmacologic thromboprophylaxis in (hospitalized or outpatient) children with asymptomatic SARS-CoV-2 in the absence of an indwelling central venous catheter or other VTE risk factors (Table 1) is not recommended. Mechanical thromboprophylaxis with sequential compression devices and pharmacologic prophylaxis is recommend in children with COVID-19–related illnesses with additional preexisting or hospital-acquired VTE risk factors or when the D-dimer is significantly elevated (>5 times ULN) in the absence of contraindications. Whitworth et al6  noted that significantly elevated D-dimer (>5 times ULN) was associated with the development of thrombosis in children, with the caveat that these laboratory data were missing in one third of their patient population. In another report of 27 pediatric patients with acute COVID-19, there was a trend toward higher D-dimer (>5 mg/L) in those who had VTE, although this was not significant, possibly because of the small sample size.9  Elevated and rising D-dimer may be reflective of coagulation activation from infection or sepsis, cytokine storm, and impending organ failure.41  Perhaps more information on this laboratory parameter as it relates to pediatric patients with acute COVID-19 will become available with future publications. A multidisciplinary expert report characterizing thrombosis risk and considerations for thromboprophylaxis in pediatric patients with MIS-C–related and COVID-19–related illness (with the use of clinical vignettes) is available for additional guidance in the management of these patients.44 

Prophylactic anticoagulation should be considered in postpubertal patients with multiple risk factors and/or at the discretion of the clinical care team (Table 1).18,40,45,46  For prepubertal patients, thromboprophylaxis with LMWH should be considered in critically ill children admitted with severe COVID-19, those with thrombophilic conditions, a strong family history of thrombophilia in a first-degree relative, a prior history of VTE, and/or increased BMI for age. The decision to use pharmacologic prophylaxis may be considered with the use of a guideline or as a multidisciplinary approach involving the primary medical team (e.g., pediatric intensivists, pediatric hospitalists) and pediatric hematology, particularly if multiple thrombotic risk factors are present. When pharmacologic prophylaxis is being considered in pediatric patients with COVID-19, LMWH or unfractionated heparin (UFH) is recommended based on more extensive pediatric experience with these agents.18,39  The use of direct oral anticoagulants is not routinely recommended in this setting secondary to a lack of data supporting their use in pediatric patients with COVID-19, although they have been used in some patients for continuing prophylaxis after hospital discharge.6 

LMWH has been shown to be safe and effective in children and is preferred to UFH given its better bioavailability and longer duration of action.47  Special consideration should be extended to patients with impaired renal function and those at extremes of weight (Table 2).4850  The American College of Chest Physicians Evidence-Based Clinical Practice Guidelines for VTE prophylaxis recommends initial enoxaparin 0.5 mg/kg/dose administered subcutaneously every 12 hours (maximum: 30 mg subcutaneously every 12 hours or 40 mg subcutaneously daily) to achieve an LMWH–anti-factor Xa (anti-Xa) range of 0.1 to 0.3 IU/mL (Table 2).51  To assess LMWH efficacy and avoid toxicity, blood should be drawn for anti-Xa levels 4 hours after the second or subsequent dose and adjusted to achieve desired levels according to the medication nomogram (Table 3).51  The rationale for anti-Xa level monitoring in children is that there is a lack of data for bleeding risk in hospitalized pediatric patients with COVID-19 and limited data regarding LMWH prophylactic dosing in this population.51  In a single-institution report described earlier of 10 pediatric patients with acute COVID-19 receiving prophylactic LMWH, those who had anti-Xa levels monitored (n = 6) did not develop thrombosis, whereas 3 of the 4 treated with fixed-dosing LMWH developed thrombosis.9  As when considering the use of any anticoagulant, caution is advised in those who may be at increased risk of bleeding, such as patients with marked thrombocytopenia (platelets ≤50 k/μL), hypofibrinogenemia (<100 mg/dL by Clauss method), International Society on Thrombosis and Haemostasis–defined major bleeding, and concomitant ASA at doses >5 mg/kg/day.

Table 2.

Initial Dosing of Enoxaparin for Pediatric Patients48,58,7985 

Initial Dosing of Enoxaparin for Pediatric Patients48,58,79–85
Initial Dosing of Enoxaparin for Pediatric Patients48,58,79–85
Table 3.

Enoxaparin Dosage Titration (modified from Monagle et al.)59 

Enoxaparin Dosage Titration (modified from Monagle et al.)59
Enoxaparin Dosage Titration (modified from Monagle et al.)59

Although not evaluated in those with COVID-19, IV enoxaparin infusions given during 30 minutes have been demonstrated to be similar to SQ administration with regard to dosing, efficacy, and safety in pediatric patients.52  Scenarios where IV administration may be advantageous to SQ administration include changes related to the patient's underlying condition where drug absorption may be altered.53  Physiologic SQ or skin changes related to edema, peripheral vasoconstriction in patients receiving vasopressor support, and reduced regional blood flow in the area of injection (e.g., burns) may all contribute to this variability in drug levels.53,54  Similar to SQ administration, LMWH–anti-Xa levels may be obtained 4 hours after the second or third IV infusion with no consensus regarding when to obtain levels relative to the beginning or end of the 30-minute infusion.5254  Peaks are ideally timed from the end of infusion; however, the 30-minute difference is unlikely to be clinically significant when evaluating LWMW–anti-Xa administered intravenously.

In patients with an increased bleeding risk, in those who are clinically unstable (e.g., extracorporeal membrane oxygenation), those with severe renal impairment, or those with heightened potential to require emergency procedures or surgical intervention, UFH is recommended as the anticoagulation of choice, secondary to the shorter half-life (about 1 hour) compared with LMWH (about 6 hours) and rapid neutralization with protamine sulfate compared with only neutralizing up to 60% of the anti-Xa activity in LMWH.55,56  Prophylactic and therapeutic dosing of UFH can be found in Table 4. For most patients, especially those with an inflammatory state (e.g., COVID-19, MIS-C), UFH monitoring with anti-Xa is preferred compared with activated partial thrombin time (aPTT). Monitoring via aPTT is more vulnerable to biologic interference and increased factor VIII levels related to the hyperinflammatory state, all of which may result in underestimating the anticoagulant effect, leading to excessive and inappropriate UFH dosing and risks.47 

Table 4.

Dosing of Unfractionated Heparin56,58 

Dosing of Unfractionated Heparin56,58
Dosing of Unfractionated Heparin56,58

It is unclear how effective pharmacologic thromboprophylaxis is in preventing VTE events in pediatric patients with COVID-19, and optimal dosing is yet to be determined. Whitworth et al6  reported one third (3 of 9) of pediatric patients with COVID-19 and VTE developed their thrombotic event while receiving thromboprophylaxis. One additional patient who had an upper extremity DVT at the time of clinical presentation with COVID-19 developed a second upper extremity DVT while on therapeutic enoxaparin. It is noteworthy that all of these patients had additional comorbid conditions known to be risk factors for the development of VTE. Major bleeding was reported in 2% (7 of 426) of the patients with COVID-19, and 2 of these 7 were receiving anticoagulation at the time of the event.6  A pediatric clinical trial, COVID-19 Anticoagulation in Children–Thromboprophylaxis (COVAC-TP) Trial (NLM, NCT04354155), is active and recruiting at the time of this publication. COVAC-TP is an open-label, multi-center trial evaluating the safety, dose requirements, and exploratory efficacy of twice-daily subcutaneous enoxaparin for VTE prophylaxis in hospitalized symptomatic children testing positive for SARS-CoV-2.57 

Recommendations for therapeutic management are derived from established guidelines prior to the SARS-CoV-2 pandemic.58,59  Patients receiving anticoagulation therapy prior to a COVID-19–related admission should continue the current regimen unless contraindicated. Initiation of therapeutic anticoagulation is recommended in patients who meet one of the following conditions: 1) objectively confirmed thrombosis documented via imaging; 2) clinical, laboratory, or imaging finding highly consistent with PE; or 3) physical findings consistent with thrombosis, such as superficial thrombophlebitis, peripheral ischemia or cyanosis, or thrombosis of dialysis filters, tubing, or catheters. Either SQ LMWH or a continuous infusion of UFH may be used for treatment of DVT (Tables 2 and 4) to achieve an LMWH–anti-Xa level of 0.5 to 1 IU/mL and a UFH–anti-Xa level of 0.35 to 0.7 IU/mL, respectively.58,59  Achieving desired therapeutic LMWH–anti-Xa levels in pediatric patients may be challenging because dosing depends on multiple factors, including age, weight, and pharmacokinetic factors (e.g., renal function, altered plasma binding) compared with adult patients.6064  We recommend all pediatric patients with COVID-19 who are initiated on therapeutic LMWH have their anti-Xa levels monitored frequently and adjusted as necessary (Table 3). Again, use of anticoagulation should be balanced with the patient's risk of bleeding.

Thrombolytic therapy may be considered in the setting of thrombosis with risk to life or limb as part of a multidisciplinary decision including interventional radiology, hematology, and intensivists as clinically indicated.39  Unless contraindicated, systemic alteplase or formulary equivalent may be preferred compared with local mechanical thrombolysis to reduce the risk of health care provider exposure to SARS-CoV-2.

In terms of duration of thrombotic risk, adult patients hospitalized for acute medical illness were found to be at increased risk of VTE for up to 90 days after discharge.41  Observational studies in adult COVID-19 patients reported symptomatic VTE incidence between 0.6% and 2.6% at 30 to 42 days after COVID-19 discharge.65,66  Extrapolating this incidence to pediatric patients in the absence of supporting evidence is not appropriate. However, Goldenberg et al18  recommended considering the use of postdischarge pharmacologic thromboprophylaxis in children with COVID-19 or MIS-C only if D-dimer remains elevated at the time of discharge and other identifiable risk factors for VTE exist (Table 1). Consultation with hematology is strongly recommended where anticoagulation may be indicated after discharge, especially in those with morbid obesity (BMI ≥40 kg/m2), immobility, recent trauma/surgery, known thrombophilia, or family history of DVT/PE in a first-degree relative. Prophylactic anticoagulation may be considered for a 1-month duration after discharge in these patients. The lack of pediatric data has limited the development of an evidence-based practice guideline.

Prevention and Treatment of MIS-C Thrombosis

Reported cases of thrombotic events including DVT (1%–5%), stroke (<1%), intracardiac thrombus (<1%), and PE (7%) in patients with MIS-C suggest an increased risk of thrombosis in this population.6,13,6769  The thrombosis risk in this patient population is also applicable to those with or who develop severe ventricular dysfunction or CAAs.37  Antiplatelet therapy with low-dose ASA should be considered for all patients who meet KD criteria, have coronary artery changes, or have other risk factors for thrombosis (Table 5).13,37  Aspirin is commonly used in KD to attenuate vasculitis, thus preventing thromboembolism, making it a logical choice for use in MIS-C.36  Because of the presence of platelet activation, thrombocytosis, altered flow dynamics in affected coronary arteries, and endothelial damage mirroring characteristics seen in KD, the American College of Rheumatology guidelines13  recommend initiating low-dose ASA (3–5 mg/kg/day; maximum, 81 mg/day) in all patients with MISC with KD features, CAAs, and thrombocytosis.70  Doses exceeding low-dose ASA for the treatment of MIS-C are not recommended given the lack of evidence supporting ASA's role in reducing the frequency of CAA.28  Low-dose ASA should be continued until the platelet count has normalized and normal coronary arteries are confirmed upon reevaluation at least 4 weeks after diagnosis of MIS-C (Table 5).13  Aspirin therapy is contraindicated in patients with active bleeding and/or thrombocytopenia (defined as platelet count ≤80,000/μL).13 

Table 5.

Multisystem Inflammatory Syndrome in Children (MIS-C) Antiplatelet and Anticoagulation13 

Multisystem Inflammatory Syndrome in Children (MIS-C) Antiplatelet and Anticoagulation13
Multisystem Inflammatory Syndrome in Children (MIS-C) Antiplatelet and Anticoagulation13

Clinical features of MIS-C are similar to those of KD where there is a role for ASA in treatment as described above. Low-dose ASA therapy encompasses the smallest possible dose required to induce antiplatelet effects without the development of Reye syndrome.70  In patients with KD and concurrent influenza, alternative antiplatelet agents are recommended to minimize this risk. As such, in children with MIS-C also found to have influenza or other viral pathogens, the clinical team may consider use of an alternative antiplatelet agent for a minimum of 2 weeks. Alternative antiplatelet agents include oral clopidogrel 0.2 mg/kg/day (maximum, 75 mg/dose) once daily or dipyridamole 2 to 6 mg/kg/day given in 3 divided doses (maximum, 100 mg/dose).71,72  Avoiding concomitant use of NSAIDs in pediatric patients with CAA is recommended because NSAIDS can antagonize the irreversible platelet inhibition induced by ASA.70 

MIS-C patients with CAAs and a maximal z score of 2.5 to 10.0 should be treated with low-dose ASA alone, whereas those with a maximal z score of ≥10 should be treated with low-dose ASA and therapeutic anticoagulation (e.g., enoxaparin or warfarin; Table 5).13  Therapeutic anticoagulation is strongly recommended for all patients with severe left ventricular dysfunction or large CAA.13  Patients with MIS-C and a documented thrombus or an ejection fraction of less than 35% should receive therapeutic anticoagulation with enoxaparin for at least 2 weeks after discharge.13  For all patients not described in Table 5, antithrombotic therapies should be individually tailored based on a risk and benefit assessment.13,37  The use of pharmacologic thromboprophylaxis with heparins in patients with MIS-C receiving concomitant ASA therapy, at a dose of 5 mg/kg/day or less, has not been associated with a significantly increased risk of bleeding.18  Consideration for the use of pharmacologic thromboprophylaxis should also be considered in patients with additional VTE risk factors or persistent elevation in D-dimer at the time of discharge as detailed above.

Certain patients with MIS-C may be at a higher risk, warranting longer duration of therapeutic anticoagulation or in those with documented thrombosis. Patients with MIS-C with CAA and a z score >10 will require prolonged treatment.13  Those patients with ongoing moderate to severe left ventricular dysfunction will likely require longer durations of enoxaparin directed by cardiology and hematology specialty providers.

Prevention of SARS-CoV-2 Infection

The best way to prevent SARS-CoV-2–related complications, including thrombosis, is to prevent infection. Caregivers and patients should continue to take all precautions in order to prevent children from contracting SARS-CoV-2. These measures include hand hygiene using hand sanitizer or soap and water, social distancing, and appropriate face covering to include nose and mouth.73  All eligible individuals, including pediatric patients and caregivers, should receive the SARS-CoV-2 vaccine when approved in those populations provided there are no contraindications. The FDA and the CDC issued a statement recommending a pause in the administration of the AD26.COV2.S Johnson & Johnson vaccine to investigate the 6 adult reported US cases of a very rare but severe thrombocytopenia syndrome, “vaccine-induced immune thrombotic thrombocytopenia (VITT)” (note VITT was renamed as “thrombosis with thrombocytopenia syndrome (TTS)” by the FDA and the CDC), occurring 6 to 13 days after vaccination.74,75  A risk-to-benefit analysis found the benefits of vaccination substantially outweighed the potential risks, and FDA Emergency Use Authorization for vaccination in patients 18 years and older was resumed after a 10-day pause. As of this writing, both the Pfizer-BioNTech and Moderna COVID-19 vaccines are now FDA approved under Emergency Use Authorization for children ages ≥12 years.76,77 

Conclusion

Until more data focusing on pediatric patients become available, we recommend using a combination of clinical judgment, institutional guidelines, and expert opinion consensus statements while carefully considering the risk of bleeding and thrombosis in children with SARS-CoV-2–related illness in whom thromboprophylaxis is being considered. Pediatric patients should be evaluated based on clinical signs and symptoms, VTE risk factors, and laboratory findings encompassing all potential thrombosis risk factors. A multidisciplinary approach and frequent review of the literature is critical to promote optimizing clinical outcomes as the landscape of data is frequently changing for SARS-CoV-2 in patients of all ages. Treatment decisions should always be tailored to the individual patient using the best available evidence as a guide.

ABBREVIATIONS

     
  • ACE2

    angiotensin-converting enzyme 2;

  •  
  • anti-Xa

    anti–factor Xa;

  •  
  • aPTT

    activated partial thromboplastin time;

  •  
  • ASA

    aspirin;

  •  
  • AT-I

    angiotensin-I;

  •  
  • AT-II

    angiotensin-II;

  •  
  • BMI

    body mass index;

  •  
  • CAA

    coronary artery aneurysm;

  •  
  • CDC

    Centers for Disease Control and Prevention;

  •  
  • COVID-19

    coronavirus disease 2019;

  •  
  • DVT

    deep vein thrombosis;

  •  
  • FDA

    US Food and Drug Administration;

  •  
  • IL

    interleukin;

  •  
  • IV

    intravenous;

  •  
  • KD

    Kawasaki disease;

  •  
  • LMWH

    low molecular weight heparin;

  •  
  • MIS-C

    multisystem inflammatory syndrome in children;

  •  
  • NSAID

    nonsteroidal anti-inflammatory agents;

  •  
  • PE

    pulmonary embolism;

  •  
  • PT

    prothrombin time;

  •  
  • PTT

    partial thromboplastin time;

  •  
  • SARS-CoV-2

    severe acute respiratory syndrome coronavirus 2;

  •  
  • SQ

    subcutaneous;

  •  
  • TF

    tissue factor;

  •  
  • UFH

    unfractionated heparin;

  •  
  • ULN

    upper limit of normal;

  •  
  • VTE

    venous thromboembolism

Disclosures. The authors declare no conflict or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria.

Ethical Approval and Informed Consent. Given the nature of this paper, institution board/ethics committee review was not required.

Acknowledgments

The authors are grateful for the review by Leslie Raffini, MD, including her thoughtful suggestions and expertise, and Michael Reed, PharmD, for his guidance.

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Author notes

Department of Pharmacy (VLT), Inova L.J. Murphy Children's Hospital, Falls Church, VA; Department of Pharmacy (SP), Children's Hospital of The King's Daughters, Norfolk, VA; Pediatric Specialists of Virginia (CRV), Fairfax, VA; Inova Fairfax Hospital, Children's National Hospital, and George Washington University School of Medicine (CRV), Fairfax, VA.