Coronavirus disease (COVID-19), caused by a novel Coronavirus (SARS-CoV-2), is expanding in the pediatric population with an ever-growing array of clinical presentations. As of March 16, 2021, globally, there were 1119,960,700 confirmed cases of COVID-19, including 2,656,822 deaths, reported to WHO [1]. During the initial wave of the pandemic, children were thought to be relatively spared by this virus. A review of 72,314 cases by the Chinese Center for Disease Control and Prevention showed that only 1% of the cases (416 cases) were in children younger than 10 years of age [2]. In a report by the US-CDC, only 1.7% (2572 cases) occurred in children aged < 18 years and 98% (146,510) occurred in adults aged ≥ 18 years [3].
Similar to adults, there were children who present with mild symptoms or no symptoms at all. However, with growing number of pediatric cases, a unique hyper-inflammatory syndrome, linked to SARS-CoV-2 infection, has emerged in children referred to as multisystem inflammatory syndrome in children (MIS-C). This Kawasaki Disease (KD)-like illness associated with COVID-19 in children was first described in April 2020 in the United Kingdom in 8 pediatric patients [4]. Since then, clusters of children with MIS-C have been described across Europe and the USA [5,6,7,8]. This syndrome shares features of KD, toxic shock syndrome, and macrophage activation syndrome and is associated with significantly elevated inflammatory markers [9, 10].
As cases increased, criteria for MIS-C were defined by New York State Department of Health and Centers for Disease Control and Prevention [11, 12]. Systolic myocardial dysfunction in the mild-to-moderate range has been reported most commonly, though severely diminished ventricular function has been reported [13]. Acute COVID-19 patients have been shown to be at a heightened risk of thrombotic complications secondary to pro-inflammatory state, multi-organ vasculitis, and immobilization [14]. While the burden of thrombotic complications is yet to be fully understood in children with ether acute COVID-19 or MIS-C, we hypothesize that the acquired thrombophilia seen in acute COVID-19 infections may also be seen in children with MIS-C.
Children with MIS-C have laboratory findings suggesting that a pro-coagulable state exists in these patients similar to COVID-19 infection. However, the actual reports of thrombotic events in MIS-C patients have been rare. The use of antiplatelet and/or anticoagulation therapies has been reported frequently. Some studies have discussed their practices of anticoagulation, most commonly prophylactic dosing rather than therapeutic dosing with very few providing indications for prophylactic anticoagulation [12]. In a survey study by the International Kawasaki Disease Registry, acetylsalicylic acid (ASA) was felt to be indicated by 91% of respondents and therapeutic anticoagulation dosing would be used for patients with giant coronary artery aneurysms (61%) and those with a severe clinical presentation (33%) [12]. The registry advises consideration of prophylactic dosing of anticoagulation, such as enoxaparin, in patients at higher baseline risk of venous thromboembolism (ex: patients ≥ 12 years old with altered mobility, obesity, known thrombophilia or history of thrombus, critical presentation, etc.), along with pneumatic sequential compression devices [12]. In addition, they recommend consideration of therapeutic dosing of anticoagulation in patients with giant coronary aneurysms, at least moderately diminished ventricular systolic function and other thrombosis concerns [12]. The knowledge regarding this new disease is still scarce. The management of these patients has large variability across centers and depends on local expertise and extrapolation from adult and pediatric data for COVID-19 disease [12, 15]. Guidelines regarding the thrombotic evaluation and anticoagulation management of hospitalized children with MIS-C remains lacking.
The Advanced Cardiac Therapies Improving Outcomes Network (ACTION) is a collaborative network designed to improve the outcomes of pediatric patients with end-stage heart failure and involves centers from across North America [16]. The ACTION learning network’s anticoagulation committee is a multi-institutional, multidisciplinary collective that includes providers with expertise in antithrombosis management at tertiary care pediatric centers around the world. The committee gathered information concerning COVID-19 anticoagulation practices at various centers and harmonized the data to formulate a set of recommendations. Given the rapid evolution of data, the ACTION network leveraged their expertise in development of collaborative learning pathways to create a consensus document as a shared baseline for clinical care. Consistent with established network practices, this will enable reassessment of guidance over time and across centers, with the ability to recognize and respond to changes in real time as dictated by incoming clinical experience. These are consensus-based recommendations on the use of anticoagulation therapy and thromboprophylaxis in children hospitalized with MIS-C. These guidelines are for patients who are admitted with MIS-C and not for outpatients with suspected MIS-C. Outpatient management should be determined by the primary physician caring for the patient. In addition, these are recommendations and final decision should be individualized by the primary physician according to the patient’s complete clinical picture (Fig. 1).