Circadian Variation of Plasminogen-Activator-Inhibitor-1 Levels in Children with Meningococcal Sepsis

Navin P Boeddha,Marjon H Cnossen,Jan A Hazelzet,Marieke Emonts,Gertjan J Driessen,Pablo Garcia De Frutos

doi:10.1371/journal.pone.0167004

Abstract

ObjectiveTo study whether the circadian variation of plasminogen-activator-inhibitor-1 (PAI-1) levels, with high morning levels, is associated with poor outcome of children with meningococcal sepsis presenting in the morning hours.DesignRetrospective analysis of prospectively collected clinical and laboratory data.SettingSingle center study at Erasmus MC-Sophia Children’s Hospital, Rotterdam, the Netherlands.Subjects184 patients aged 3 weeks to 18 years with meningococcal sepsis. In 36 of these children, PAI-1 levels at admission to the PICU were measured in plasma by ELISA.InterventionsNone.Measurements and main resultsCircadian variation was studied by dividing one day in blocks of 6 hours. Patients admitted between 6:00 am and 12:00 am had increased illness severity scores and higher PAI-1 levels (n = 9, median 6912 ng/mL, IQR 5808–15600) compared to patients admitted at night (P = 0.019, n = 9, median 3546 ng/mL, IQR 1668–6118) or in the afternoon (P = 0.007, n = 7, median 4224 ng/mL, IQR 1804–5790). In 184 patients, analysis of circadian variation in relation to outcome showed more deaths, amputations and need for skin grafts in patients admitted to the PICU between 6:00 am and 12:00 am than patients admitted during the rest of the day (P = 0.009).ConclusionsCircadian variation of PAI-1 levels is present in children with meningococcal sepsis and is associated with illness severity, with a peak level in the morning. Whether circadian variation is an independent risk factor for morbidity and mortality in meningococcal sepsis needs to be explored in future studies.

Highlights

Meningococcal endotoxins and the subsequent inflammatory host response induce excessive coagulation and downregulation of fibrinolysis in meningococcal sepsis
Circadian variation of PAI-1 levels is present in children with meningococcal sepsis and is associated with illness severity, with a peak level in the morning
Plasminogen-activator-inhibitor-1 (PAI-1) levels are increased and result in inhibited fibrinolysis and impaired anticoagulant mechanism, since PAI-1 neutralizes activated protein C [2], leading to severe disseminated intravascular coagulation (DIC). [3, 4] The PAI1 4G/5G polymorphism is associated with PAI-1 levels and with outcome

Summary

Introduction

Meningococcal endotoxins and the subsequent inflammatory host response induce excessive coagulation and downregulation of fibrinolysis in meningococcal sepsis. [5, 6] In meningococcal sepsis, clustering of fatal cases in the morning hours has been reported repeatedly. These findings are generally interpreted as the result of delayed detection of symptoms and subsequent health care seeking behavior, as signs of severe illness may be overlooked in the night or early morning hours. [7, 8] We hypothesize that the circadian variation of PAI-1, with high morning levels, is associated with excess mortality of cases presenting in the morning hours, possibly due to aggravation of multiple organ failure secondary to more severe DIC. These findings are generally interpreted as the result of delayed detection of symptoms and subsequent health care seeking behavior, as signs of severe illness may be overlooked in the night or early morning hours. [7, 8] We hypothesize that the circadian variation of PAI-1, with high morning levels, is associated with excess mortality of cases presenting in the morning hours, possibly due to aggravation of multiple organ failure secondary to more severe DIC.

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