Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is associated with thrombotic complications in adults, but the incidence of COVID-19 related thrombosis in children and adolescents is unclear. Most children with acute COVID-19 have mild disease, but coagulopathy has been associated with multisystem inflammatory syndrome in children (MIS-C), a post-infectious complication. We conducted a multicenter retrospective cohort study to determine the incidence of thrombosis in children hospitalized with COVID-19 or MIS-C and to evaluate associated risk factors. We classified patients into one of three groups for analysis: COVID-19, MIS-C, or asymptomatic SARS-CoV-2. Among a total of 853 admissions (426 COVID-19, 138 MIS-C, and 289 asymptomatic SARS-CoV-2) in 814 patients, there were 20 patients with thrombotic events (TE) (including 1 stroke). Patients with MIS-C had the highest incidence (6.5%, 9/138) versus COVID-19 (2.1%, 9/426) or asymptomatic SARS-CoV-2 (0.7%, 2/289). In patients with COVID-19 or MIS-C, the majority of thrombotic events (89%) occurred in patients ≥12 years. Patients > 12 years with MIS-C had the highest rate of thrombosis at 19% (9/48). Notably, 71% of TE that were not present on admission occurred despite thromboprophylaxis. Multivariable analysis identified the following as significantly associated with thrombosis: age ≥12 years, cancer, presence of a central venous catheter, and MIS-C. In patients with COVID-19 or MIS-C, hospital mortality was 2.3% (13/564), but was 28% (5/18) in patients with thrombotic events. Our findings may help inform pediatric thromboprophylaxis strategies.
Human endothelial cells (ECs) synthesize, store, and secrete von Willebrand factor multimeric strings and coagulation factor (f) Viii. it is not currently known if ecs produce other coagulation factors for active participation in coagulation. We found that 3 different types of human ECs in primary culture produce clotting factors necessary for fX activation via the intrinsic (fViii-fiX) and extrinsic (tissue factor [TF]-FVII) coagulation pathways, as well as prothrombin. Human dermal fibroblasts were used as comparator cells. TF, FVII, FIX, FX, and prothrombin were detected in ECs, and TF, FVII, FIX, and FX were detected in fibroblasts. In addition, FVII, FIX, FX, and prothrombin were detected by fluorescent microscopy in ec cytoplasm (associated with endoplasmic reticulum and Golgi proteins). fX activation occurred on human umbilical vein EC surfaces without the addition of external coagulation proteins, proteolytic enzymes, or phospholipids. tumour necrosis factor, which suppresses the generation of activated protein C and increases TF, augmented FX activation. Fibroblasts also produced TF, but (in contrast to ECs) were incapable of activating FX without the exogenous addition of FX and had a marked increase in FX activation following the addition of both FX and FVII. We conclude that human ecs produce their own coagulation factors that can activate cell surface fX without the addition of exogenous proteins or phospholipids. Human endothelial cells (ECs) help maintain blood flow and prevent extra-vascular blood loss. The precise molecular contributions of ECs to haemostasis are unknown. We conducted experiments to determine if human ECs can produce coagulation proteins. Comparative experiments were performed with human fibroblasts, sub-EC vascular wall components that are exposed to blood upon vascular wall injury. For many years hepatocytes were considered the predominant (or exclusive) site of coagulation factor production 1-9. In recent murine and human studies, however, liver sinusoidal ECs (LSECs), rather than hepatocytes, were demonstrated to be the primary cellular source of factor (F) VIII 10-13. Other extra-hepatic vascular ECs, including human umbilical vein ECs (HUVECs) and human glomerular microvascular ECs (GMVECs), have also been shown to produce FVIII 14-18. FVIII is stored in EC Weibel-Palade bodies (WPBs), and secreted along with ultra-large (UL) von Willebrand factor (VWF) multimers 18. The FVIII data suggest that ECs may have a more active role in coagulation factor production than previously appreciated. ECs produce surface regulatory proteins that prevent excessive coagulation. These include thrombomodulin (TM), endothelial protein C receptor (EPCR), tissue factor pathway inhibitor (TFPI), and protein C (PC) 19-22. TM-bound thrombin converts PC that is bound to EPCR into activated protein C (APC). APC (and protein S [PS]) inactivates activated FVIII and FV 23-25 and, therefore, limits the functions of FVIII-FIX (intrinsic tenase complex) and FX-FV (prothrombinase complexes). TFPI inhibits t...
Objectives Patients with febrile neutropenia are at high risk of morbidity and mortality from infectious causes. Decreasing time to antibiotic (TTA) administration is associated with improved patient outcomes. We sought to reduce TTA for children presenting to the Emergency Department (ED) with fever and neutropenia. Methods In a prospective cohort study with historical comparison, TTA administration was evaluated in patients with neutropenia presenting to the Children’s of Alabama ED. A protocol was established to reduce delays in antibiotic administration and increase the percentage of patients who receive treatment within 60 minutes of presentation. One hundred pre-protocol patient visits between August 2010 and December 2011 were evaluated and 153 post-protocol visits were evaluated between August 2012 and September 2013. We reviewed individual cases to determine barriers to rapid antibiotic administration. Results Antibiotics were administered in 96.9 ± 57.8 minutes in the pre-protocol patient group and only 35% of patients received antibiotics within 60 minutes of presentation and 70% received antibiotics within 120 minutes. After implementation of the protocol, TTA for neutropenic patients was decreased to 64.3 ± 28.4 minutes (p < 0.0001) with 51.4% receiving antibiotics within 60 minutes and 93.2% within 120 minutes. Conclusion Implementing a standard approach to patients at risk for neutropenia decreased TTA. There are numerous challenges in providing timely antibiotics to children with febrile neutropenia. Identified delays included venous access (time to effect of topical anesthetics, and difficulty obtaining access), physicians waiting on laboratory results, and antibiotic availability.
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