Immunothrombosis and plasma fibrinolytic function for pediatric COVID-19: a secondary analysis from the COVAC-TP trial

Abstract

The relationship between fibrinolysis, inflammation, and prothrombotic risk among children hospitalized for coronavirus disease 2019 (COVID-19)–related illness is ill defined. To investigate the association between plasma fibrinolytic capacity and proinflammatory cytokine concentrations among children hospitalized for primary COVID-19 infection and multisystem inflammatory syndrome in children (MIS-C), we hypothesized that cytokine concentrations differ by clinical phenotype and are associated with hypofibrinolysis. We analyzed banked plasma specimens serially collected from children aged <18 years admitted for primary COVID-19 or MIS-C and enrolled in the COVID-19 Anticoagulation in Children–Thromboprophylaxis multicenter trial, an open-label, multicenter, phase 2 clinical trial conducted between July 2020 and May 2021. Plasma coagulative and fibrinolytic function were measured via the clot formation and lysis (CloFAL) assay and modified mini-euglobulin clot lysis assay (ECLA). Interleukin-1β (IL-1β), IL-6, and IL-8, and tumor necrosis factor α were measured by the Meso Scale Discovery assay. Correlations were evaluated using Spearman rank testing. A total of 132 banked plasma specimens from 38 participants (COVID-19: n = 18; MIS-C: n = 20) were analyzed. Overall, increased coagulative function (ie, elevated CloFAL area under the curve) and impaired fibrinolytic function (ie, reduced CloFAL fibrinolytic index [FI] and elevated modified mini-ECLA clot lysis time ratio [CLTR]) were observed but most notably among those with MIS-C. Plasma cytokine concentrations correlated with assay indices of hypofibrinolysis (ie, modified mini-ECLA CLTR and CloFAL FI). In summary, among children hospitalized for COVID-19–related illness, hypercoagulability and hypofibrinolysis are mediated, in part, by inflammation that may contribute to prothrombotic risk. This trial was registered at www.ClinicalTrials.gov as #NCT04354155.