Thromboembolic complications in children with COVID-19 and MIS-C: A narrative review

Abstract

COVID-19 and multisystem inflammatory syndrome in children (MIS-C) have been associated with a higher incidence of hypercoagulability and thromboembolic events (TEs), even in children, leading to relevant morbidity, and mortality. However, our understanding of such complications in childhood is limited. To better understand the incidence, clinical manifestations, risk factors, and management of COVID-19 and MIS-C-related TEs in children, a review of the current literature and a brief update on pathophysiology are given. Sixty-two studies, describing 138 patients with TEs associated with COVID-19 or MIS-C, were included. The overall number of TEs was 157, as 16 patients developed multiple TEs: venous TEs represented the majority (54%), followed by arterial thrombosis (38%, mainly represented by arterial ischemic stroke-AIS), and intracardiac thrombosis (ICT) (8%). Within the venous TEs group, pulmonary embolism (PE) was the most frequent, followed by deep venous thrombosis, central venous sinus thrombosis, and splanchnic venous thrombosis. Notably, 10 patients had multiple types of venous TEs, and four had both venous and arterial thrombosis including a newborn. Most of them (79 cases,57%) had at least one predisposing condition, being obesity the most frequent (21%), especially in patients with PE, followed by malignancy (9%). In 35% of cases, no data about the outcome were available About one-third of cases recovered, 12% improved at discharge or follow-up, and 6% had persistent neurological sequelae. The mortality rate was 12%, with death due to comorbidities in most cases. Most fatalities occurred in patients with arterial thrombosis. Pediatricians should be aware of this life-threatening possibility facing children with SARS-CoV-2 infection or its multisystemic inflammatory complication, who abruptly develop neurological or respiratory impairment. A prompt intensive care is essential to avoid severe sequelae or even exitus.

Keywords: COVID-19; MIS-C; children; embolism; stroke; thrombosis.

FIGURE 1

Distribution of thrombotic events by age and sex.

FIGURE 2

Distribution of thrombotic events by localization. N (%), expressed on the total of 157. AIS, arterial ischemic stroke; CVST, central venous sinus thrombosis; DVT, deep venous thrombosis; ICT, intracardiac thrombosis; PE, pulmonary embolism; SVT, splanchnic venous thrombosis.

FIGURE 3

Localization of Venous, arterial, and intracardiac TEs. ACA, anterior cerebral artery; CVS, cerebral venous sinus; L, left, MCA middle cerebral artery; PE, pulmonary embolism; PCA, posterior cerebral artery; R, right.

FIGURE 4

Distribution of thrombotic events by localization in patients with COVID-19 and MIS-C. * excluding AIS. AIS, arterial ischemic stroke; COVID-19, coronavirus disease 2019; CVST, central venous sinus thrombosis; DVT, deep venous thrombosis; ICT, intracardiac thrombosis; MIS-C, multisystem inflammatory syndrome in children; PE, pulmonary embolism; SVT, splanchnic venous thrombosis.

FIGURE 5

Pathomechanisms involved in SARS-CoV-2-induced thrombosis. Different SARS-CoV-2-induced pathways converge and result in a prothrombotic state. SARS-CoV-2 binding with the ACE2 receptor reduces its activity, increasing Ang2 levels and resulting in increased proinflammatory and prothrombotic signals. These signals mediate endothelial dysfunction and platelet hyperactivation, which is also directly induced by SARS-CoV-2 infection. Contemporary, the hyperinflammatory state induced by SARS-CoV-2 infection contributes to endothelial dysfunction following the reduction of antithrombotic factors and the degradation of glycocalyx. Moreover, SARS-CoV-2 induces complement hyperactivation, resulting in endothelial damage, platelet hyperactivation, and thrombosis. ACE2, angiotensin-converting enzyme 2; Ang, angiotensin; APC, activated protein C; ATIII, antithrombin III; EPCR, endothelial protein C receptor; FVIII, factor VIII; IL-1, interleukin 1; IL-6, interleukin 6; MASP-2, mannose-binding lectin-associated serine protease; NO, nitric oxide; PGI₂, prostacyclin; TFPI, tissue factor pathway inhibitor; TM, thrombomodulin; TNF, tumor necrosis factor; vWF, von Willebrand factor.