Predictive value of the complement system for sepsis-induced disseminated intravascular coagulation in septic patients in emergency department

doi:10.1016/j.jcrc.2014.11.007

Journal of Critical Care

Volume 30, Issue 2, April 2015, Pages 290-295

https://doi.org/10.1016/j.jcrc.2014.11.007 Get rights and content

Abstract

Purpose

To investigate changes in circulating complement component C3, membrane attack complex (MAC), and mannose-binding lectin (MBL) in patients with sepsis-induced disseminated intravascular coagulation (DIC).

Materials and Methods

Adult septic patients admitted to the emergency department (ED) of Beijing Chao-Yang Hospital were enrolled. A DIC score of 5 or higher was considered sepsis-induced DIC. Circulating C3, MAC, and MBL levels were detected on ED arrival and compared between patients with and without DIC. The predictive value of C3, MAC, and MBL for sepsis-induced DIC at ED arrival and development of DIC after admission were assessed by receiver operating characteristic curve and logistic regression.

Results

We enrolled 267 septic patients between February and December 2013. Complement 3, MAC, and MBL were higher in the DIC group (P < .01). Membrane attack complex was the independent predictor of sepsis-induced DIC. The area under the curve of MAC in predicting sepsis-induced DIC was 0.793. During hospitalization, 25 patients without DIC at enrollment developed DIC. Membrane attack complex and Sequential Organ Failure Assessment independently predicted progress to DIC. The area under the curve of MAC was 0.741.

Conclusions

Complement 3, MAC, and MBL were significantly increased in septic patients with DIC. Membrane attack complex independently predicted sepsis-induced DIC and development of DIC after ED admission.

Introduction

The coagulation system is strongly activated in sepsis patients [1], with hemostatic abnormalities ranging from isolated thrombocytopenia to severe disseminated intravascular coagulation (DIC) [2], [3]. A previous study reported an incidence of 31.1% and 12.6% for overt DIC and nonovert DIC in sepsis patients, respectively [4]. Sepsis with DIC (overt and nonovert) is associated with poor outcomes, with a 28-day mortality rate of up to 50% in patients with DIC compared with 9.2% in those without DIC [4], [5]. Therefore, DIC is an indicator of adverse outcomes that needs close monitoring and progressive treatment.

Sepsis is initiated by recognition of pathogenic microorganisms by the innate immune system [6]. Inflammatory and endothelial cells are activated simultaneously by specific pathogens to produce various cytokines and inflammatory mediators and to activate the coagulation cascade. Abnormalities in this process result in pathological coagulation that can lead to conditions ranging in severity from DIC (severe cases) to multiple-organ dysfunction syndrome and significantly increased mortality [7].

The complement system is a major component of the nonspecific immune system, which has also been identified as an important activator of the coagulation cascade in sepsis. The crosstalk between the complement and coagulation cascades enhances the local coagulation function, which plays a role in limiting the spread of pathogens [8]. Complement component C5a mediates the expression of tissue factor and plasminogen activator inhibitor 1, thereby significantly enhancing procoagulant activity and inhibiting fibrinolysis [9]. Mannose-binding lectin (MBL)–associated serine protease-2 is capable of promoting fibrinogen turnover to generate thrombin, thus activating the coagulation system [10]. Subsequently, the complement system is activated by coagulation factors to generate increasing levels of C5a, leading to enhanced activation of the coagulation and complement cascades [11], [12]. The development of DIC is mainly attributed to dysfunctional crosstalk between the complement and coagulation systems in sepsis [13]. Theoretically, complement components are capable of predicting sepsis-induced DIC; however, there is a marked lack of clinical research that has tested this hypothesis.

By comparing the mean level and predictive ability of complement component C3, membrane attack complex (MAC) and MBL between septic patients with and without DIC, we aimed to determine the prognostic significance of the complement system in sepsis patients with DIC.

Section snippets

Patients

The present study was a single-center observational study conducted in the emergency department (ED) of Beijing Chao-Yang Hospital, which is the teaching hospital of Capital Medical University, with ~ 250 000 ED visitors per year. From February to December 2013, 267 consecutive adult patients fulfilling the sepsis criteria defined by the 2001 International Sepsis Definitions Conference and admitted to the high-dependency unit (HDU) of the ED in Beijing Chao-Yang Hospital were enrolled [14]. The

Characteristics of the cohort

Between February and December 2013, 267 septic patients were enrolled. The incidence of overt DIC was 18.4% at enrollment. The in-hospital mortality was 38.6%. The median MEDS score was 13 (10-16). The mean APACHE II and SOFA scores were 14.2 ± 4.4 and 8.8 ± 6.2, respectively.

Characteristics of the study cohort are shown in Table 1. There were no significant differences in age, sex, comorbidity, and infection site between the DIC and non-DIC groups. Mortality in Emergency Department Sepsis, APACHE

Discussion

The present study indicated that complement levels significantly increased in sepsis patients with DIC. Membrane attack complex predicted overt DIC at ED arrival and predisposition to DIC during hospitalization.

Conclusions

Complement 3, MAC, and MBL were significantly increased in sepsis patients with DIC. Membrane attack complex was helpful in predicting sepsis-induced DIC.

Conflict of interest

The authors declare that they have no conflict of interest.

Acknowledgments

The authors sincerely thank Gui-Juan Dong, Qian Zhang, and Miao-Miao Wang for their excellent assistance. The authors also thank both the ED and Biochemistry Laboratory staff for their helpful contributions to the study.

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Disseminated Intravascular Coagulation Is an Independent Predictor of Adverse Outcomes in Children in the Emergency Department with Suspected Sepsis
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Pediatric studies also report high rates of DIC in sepsis and high mortality rates in patients with DIC, up to 50% in 1 PICU study.18 Adult studies have shown significantly increased mortality in patients with overt DIC in the ED based on the ISTH criteria.7,31,32 These data suggest that the DIC score can be a valuable objective tool that should be incorporated into the emergency care setting.
To evaluate the impact of early disseminated intravascular coagulation (DIC) on illness severity in children using a database of emergency department ED encounters for children with suspected sepsis, in view of similar associations in adults.
Laboratory and clinical data were extracted from a registry of emergency department encounters of children with suspected sepsis between April 1, 2012, and June 26, 2017. International Society of Thrombosis and Hemostasis DIC scores were calculated from laboratory values obtained within 24 hours of emergency department admission. Univariate logistic regression, multivariable logistic regression, and Cox regression were used to assess the influence of DIC scores on vasopressor use (primary outcome), mortality, ventilator requirement, pediatric intensive care unit admission, and hospital duration (secondary outcomes). The optimal DIC score cutoff for outcome prediction was determined.
Of 1653 eligible patients, 284 had DIC scores within 24 hours, including 92 who required vasopressors and 23 who died within 1 year. An initial DIC score of ≥3 was the most sensitive and specific DIC score for predicting adverse outcomes. Those with a DIC score of ≥3 vs <3 had increased odds of vasopressor use in both univariate (OR, 4.48; 95% CI, 2.63-7.62; P < .001) and multivariable (OR, 3.78; 95% CI, 1.82-7.85; P < .001) analyses. Additionally, those with a DIC score of ≥3 vs <3 had increased 1-year mortality with a hazard ratio of 3.55 (95% CI, 1.46-8.64; P = .005).
A DIC score of ≥3 was an independent predictor for both vasopressor use and mortality in this pediatric cohort, distinct from the adult overt DIC score cutoff of ≥5.
Sepsis roadmap: What we know, what we learned, and where we are going
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For example, C5a blockade protects to the cecal ligation and puncture (CLP)-induced septic rats via increasing their survival in the 10-day model [77,78]. Thus it becomes very challenging to target C5a in sepsis because, in one way it controls the function of T cells and on the other hand, it promotes the pro-inflammatory function, coagulation events, and MODS-associated with sepsis [79,80]. On the other hand, the decrease in circulating C3 and C4 components of the CS in septic patients accounts for the high risk of DISC and poor prognosis [81,82].
Sepsis is a life-threatening condition originating as a result of systemic blood infection causing, one or more organ damage due to the dysregulation of the immune response. In 2017, the world health organization (WHO) declared sepsis as a disease of global health priority, needing special attention due to its high prevalence and mortality around the world. Most of the therapeutics targeting sepsis have failed in the clinics. The present review highlights the history of the sepsis, its immunopathogenesis, and lessons learned after the failure of previously used immune-based therapies. The subsequent section, where to go describes in details the importance of the complement system (CS), autophagy, inflammasomes, and microbiota along with their targeting to manage sepsis. These systems are interconnected to each other, thus targeting one may affect the other. We are in an urgent need for a multi-targeting therapeutic approach for sepsis.
Components of the lectin pathway of complement activation in paediatric patients of intensive care units
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Recently, Zhao et al. (2015a) found MBL (as well as C3 and the membrane attack complex) to be increased with sepsis, severe sepsis and shock. Furthermore, higher MBL, C3 and MAC were associated with disseminated intravascular coagulation and a fatal outcome (Zhao et al., 2015a,b). That, to some extent, is in agreement with our data showing changes in serum concentrations of complement-related PRMs and MASP-2.
Infections are a major cause of childhood mortality. We investigated components of the lectin pathway of complement activation in the context of sepsis at both genetic and protein levels in neonates, infants and older children. Major components of the lectin pathway and two genes for Toll-like receptors were studied in 87 neonates with confirmed sepsis and compared with 40 babies with infections who did not develop sepsis (disease controls) and 273 infection-free neonatal controls. A second cohort comprised 47 older children with sepsis and 87 controls. Low MBL-conferring genotypes (LXA/O + O/O) were more frequent in sepsis patients than in healthy controls but no significant differences in the frequency of SNPs of other lectin pathway genes (FCN1, FCN2, FCN3, MASP1/3, MASP2) or TLR receptor genes (TLR2, TLR4) were found. One case of primary MASP-2 deficiency was found among healthy pre-terms and one neonate suffering from SIRS was heterozygous for the rare FCN1 gene mutation, +6658 G > A. Generally, sepsis was associated with low serum MBL and low ficolin-2 concentrations on admission. Among neonates, ficolin-1 and MASP-2 levels were elevated in sepsis relative to healthy, but not disease, controls. Unlike neonates, ficolin-3 and MASP-2 levels were lower in older patients than in healthy controls while no difference was found for ficolin-1. With the possible exception of MBL, inherited lectin pathway insufficiencies do not seem to predispose to sepsis, rather changes in protein concentrations reflect alterations in disease course.
Defining immunological dysfunction in sepsis: A requisite tool for precision medicine
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C3 fragments released during septic shock may contribute to the development of fatal complications such as profound hypotension and disseminated intravascular coagulation.80,81 Levels of membrane attack complex in serum independently predict sepsis-induced disseminated intravascular coagulation.82 Excessive complement consumption in sepsis could result from the inability of the other elements of the innate and adaptive immune response to resolve infection.
Immunological dysregulation is now recognised as a major pathogenic event in sepsis. Stimulation of immune response and immuno-modulation are emerging approaches for the treatment of this disease. Defining the underlying immunological alterations in sepsis is important for the design of future therapies with immuno-modulatory drugs.
Clinical studies evaluating the immunological response in adult patients with Sepsis and published in PubMed were reviewed to identify features of immunological dysfunction. For this study we used key words related with innate and adaptive immunity.
Ten major features of immunological dysfunction (FID) were identified involving quantitative and qualitative alterations of [antigen presentation](FID1), [T and B lymphocytes] (FID2), [natural killer cells] (FID3), [relative increase in T regulatory cells] (FID4), [increased expression of PD-1 and PD-ligand1](FID5), [low levels of immunoglobulins](FID6), [low circulating counts of neutrophils and/or increased immature forms in non survivors](FID7), [hyper-cytokinemia] (FID8), [complement consumption] (FID9), [defective bacterial killing by neutrophil extracellular traps](FID10).
This review article identified ten major features associated with immunosuppression and immunological dysregulation in sepsis. Assessment of these features could help in utilizing precision medicine for the treatment of sepsis with immuno-modulatory drugs.
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This would signify higher degree of complement activation in DIC patients. Increased MAC levels on arrival to the hospital has been proposed to indicate a tendency to develop DIC during hospitalization in septic patients too [76]. In addition, since plasma VWF multimers behave as a cofactor for factor I-mediated cleavage of complement C3b to iC3b (a step necessary to inhibit complement activation by the alternate pathway), the persistence of ultra-large VWF multimers in DIC may not be able to perform this inhibitory function [77].
Disseminated intravascular coagulation (DIC) is an acquired thrombo-haemorrhagic disorder which arises in clinical scenarios like sepsis, trauma and malignancies. The clinic-laboratory diagnosis of DIC is made in a patient who develops the combination of laboratory abnormalities in the appropriate clinical scenario. The most common laboratory parameters in this setting have been the clotting profile, platelet count, serum fibrinogen and fibrin degradation markers. These tests had the advantage that they could be performed easily and in most laboratories. However, with the better understanding of the pathophysiology of DIC, in recent years, more specific tests have been suggested to be useful in this setting. The newer tests can also prove to be useful in prognostication in DIC. In addition, they may provide assistance in the selection and monitoring of patients diagnosed with DIC.
Value of complement component 3 in predicting the prognosis of children with sepsis
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^☆: The study was performed in emergency department of Beijing Chao-Yang Hospital Affiliated to Capital Medical University.

^☆☆: Source of Funding: None.

¹: These authors contributed to the work equally and should be regarded as co-first authors.

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SepsisPredictive value of the complement system for sepsis-induced disseminated intravascular coagulation in septic patients in emergency department☆,☆☆

Abstract

Purpose

Materials and Methods

Results

Conclusions

Introduction

Section snippets

Patients

Characteristics of the cohort

Discussion

Conclusions

Conflict of interest

Acknowledgments

Thromb Res

Dev Comp Immunol

Trends Immunol

Coagulation system and platelets are fully activated in uncomplicated sepsis

Crit Care Med

Disseminated intravascular coagulation in infectious disease

Semin Thromb Hemost

Sepsis-associated disseminated intravascular coagulation and thromboembolic disease

Mediterr J Hematol Infect Dis

Clinical course and outcome of disseminated intravascular coagulation diagnosed by Japanese Association for Acute Medicine criteria

Thromb Haemost

Complement: a key system for immune surveillance and homeostasis

Nat Immunol

A novel C5a receptor-tissue factor cross-talk in neutrophils links innate immunity to coagulation pathways

J Immunol

Simultaneous activation of complement and coagulation by MBL-associated serine protease 2

PLoS One

Activation of the classical pathway of complement by Hageman factor fragment

J Exp Med

Sepsis
Predictive value of the complement system for sepsis-induced disseminated intravascular coagulation in septic patients in emergency department☆,☆☆