Importance of hemostatic gene polymorphisms for susceptibility to and outcome of severe sepsis

Texereau, J.; Pène, Frédéric; Chiche, Jean‐Daniel; Rousseau, C.; Mira, Jean‐Paul

doi:10.1097/01.ccm.0000126363.46191.dc

Cited by 88 publications

(49 citation statements)

References 50 publications

(80 reference statements)

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“…Ahrens and associates reported that the homozygous IL-6-174 G polymorphism was predictive for the development of sepsis (37). FVL mutation did not affect the outcome of sepsis in our patient as seen in the literature (32).…”

Section: Discussionsupporting

confidence: 71%

“…Most positive association studies examine genes for important inflammatory molecules such as IL-1 family, IL-6, IL-10, IL-18, TNF-α, in the complement pathway the mannose binding lectin, properdin, factor D, C3, late complement deficiency (LCCD); in coagulation and fibrinolytic system such as tissue-plasminogen activator, PAI-1, FVL, protein C and thrombomodulin; molecules for recognition of antigens such as toll-like receptors and CD-14 (27)(28)(29)(30)(31)(32).…”

Section: Discussionmentioning

confidence: 99%

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Effect of Various Genetic Polymorphisms on the Incidence and Outcome of Severe Sepsis

Sipahi

Pocan

Akar

2006

Clin Appl Thromb Hemost

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Sepsis is systemic response to infection with bacteria, viruses, fungi, protozoa, or rickettsiae. If not recognized and treated early, the progression from sepsis to severe sepsis, septic shock, and multiple organ dysfunction syndrome (MODS) are seen (1).Although pharmacologic, laboratory, and surgical advances have improved the outcomes of many infections, the mortality of sepsis and septic shock is high. The incidence of sepsis is more than 500,000 cases each year in the United States. The mortality rate is between 30% and 80% (2). Severe sepsis is a primary cause of death, especially in intensive care units.The systemic inflammatory response to infection (systemic inflammatory response syndrome-SIRS) is a complex situation (3). At the beginning of infection, pathogen-associated microbial patterns (PAMPs) are recognized by pattern recognition receptors (PRRs-cellular receptors expressed on extracellular membranes) and NF-kappa B (NF-KB) release. NF-KB is an important intracellular protein and translocated to the nucleus then the gene transcription of proinflammatory (tumor necrosis factor-α [TNF-α], interleukin [IL]-1, interleukin-6 [IL-6] and anti-inflammatory [IL-10] cytokines) (4). They trigger many physiologic responses such as stimulation of polymorphonuclear neutrophils, stimulation of the kallikrein-kinin system, activation of factor XII and extrinsic pathway, production of tissue factor (TF), and the activation of coagulation cascade and the complement system (5).Why do some children show mild clinical symptoms against infectious agents and others die within a few hours?Genetic epidemiologic studies suggest that variations in host genetic factors influence the outcome of sepsis (3,6-9). Several genetic polymorphisms have been identified in patients with sepsis and septic shock, including the TNF-α and TNF-β genes, the IL-1 family, the IL-6, the IL-10, the CD-14, the angiotensin-converting enzyme, Summary: Several genetic polymorphisms have been identified in patients with sepsis and severe sepsis, such as the tumor necrosis factor-α (TNF-α) and TNF-β genes, the interleukin-1 (IL-1) family, the IL-6, the IL-10, the CD-14, the Toll-like receptors, plasminogen activator inhibitor type 1, and the factor V 1691G-A mutations. In this study, the relationship between the TNF-α 308G/A, the IL-6-174 G/C, the PAI-1, the FVL, the EPCR, and the Cathepsin G (Ars 125Ser) polymorphisms and the development and outcome of sepsis in pediatric patients was studied. TNF-α 308 G/A, PAI-1 4G/4G, and EPCR mutations influence the risk of severe sepsis in children. IL-6 174 G/C, FVL, and Cathepsin G (Ars 125 Ser) did not influence the incidence and mortality of severe sepsis.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Effect of Various Genetic Polymorphisms on the Incidence and Outcome of Severe Sepsis

Sipahi

Pocan

Akar

2006

Clin Appl Thromb Hemost

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“…In fact, many publications focused their attention on using the plasma levels of certain factors, such as protein C (PC), procalcitonin, TNF-, and plasminogen activator inhibitor-1 (PAI-1), as prognostic markers [14][15][16]. Other publications have investigated specific genetic polymorphisms in candidate genes [7,10,[17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

“…Specific genetic factors might predict the risk not only for developing severe infection, but also for developing organ dysfunction leading to death [18][19][20]. Among TNF-α variants, a polymorphism that affects TNF-α expression has been located at nucleotide position -308 (TNF-α rs1800629 G/A) and has been associated with morbidity and mortality in severe forms of fulminant purpura, mucocutaneous leishmaniasis and sepsis [28].…”

Section: Introductionmentioning

confidence: 99%

Biomarkers in sepsis at time zero: intensive care unit scores, plasma measurements and polymorphisms in Argentina

Wingeyer

Cunto

Nogueras

et al. 2011

J Infect Dev Ctries

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Introduction: A patient's response to sepsis is influenced by their genetic background. Our objective was to use plasma markers, such as protein C (PC), D-dimer, Plasminogen Activator Inhibitor-1 (PAI-1) levels, and the PAI-1 rs1799889 4G/5G and Tumor Necrosis Factor-α rs1800629 G/A polymorphisms to improve classical intensive care unit (ICU) scores. Methodology: We studied 380 subjects, 166 with sepsis. We performed coagulation tests: plasma PAI-1 and PC levels were evaluated by chromogenic methods; and D-dimer was evaluated by immunoturbidimetric assay. Polymorphisms were performed using for polymerase chain reactions followed by digest with specific restriction enzyme. We acquired the APACHE and SOFA scores (time zero), sex, age, body mass index, associated co-morbidities, length of ICU stay (days), the severity of sepsis (sepsis, severe sepsis or septic shock), the HIV status and the ICU outcome (survival or death). Results: We found significant differences between patients who died (n=80) and those who survived (n=86) in terms of the ICU length of stay (6 vs. 10 days), septic shock (64 versus 24%), age (51 versus 38 years old), HIV+ condition (34 versus 16%), SOFA (7 versus 4), APACHE (19 versus 13), D-dimer (4.32 versus 2.88 g/ml), PC (46.0 versus 63.5 %) and PAI-1 (33.0 versus 16.5 UA/l). When we used a regression analysis with dichotomized variables, only the SOFA 4 , PAI-1 16 , HIV status and the PAI-1 4G allele proved to be predictors of death at time zero. Conclusions: In the future, ICU scores may be further improved by adding certain genomic or plasma data.

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“…Severe protein C (PC) or protein S (PS) deficiencies, antiphospholipid antibodies (APA) and factor V G1691A (FV G1691A), prothrombin G20210A (PT G20210A), and the plasminogen activator inhibitor were also shown to be participants in the development of PF [1][2][3][4][5][6][7][8]. It is possible that methylene tetrahydrofolate reductase C677T (MTHFR C677T) mutation, homocysteine, lipoprotein (a), or antiphospholipid antibody may play a role in development of PF.…”

Section: Introductionmentioning

confidence: 99%

Outcome in children with purpura fulminans: Report on 16 patients

et al. 2005

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Purpura fulminans (PF) is a severe disorder of acute onset with high morbidity and mortality. In children, this rapidly progressive illness is usually associated with severe bacterial or viral infections. However, some other conditions may participate in the development of PF. Our objective was to investigate the underlying and associated disorders and the outcomes of the disease in 16 children, 7 males and 9 females ranging in age from 3.5 months to 12 years (median age, 2 years). Thirteen of the 16 children (81%) were 4 years of age or younger. The remaining 3 patients were 9, 10, and 12 years of age. Among these 13 infants and small children, 7 (43%) had infection, 2 infants had congenital cardiac disorders necessitating minor or major surgical intervention, and 1 infant and 3 children had different miscellaneous disorders. The factor V G1691A mutation was present in six of the 13 small children (46%). None of the 3 older children carried the mutation. Six (37.5%) of the 16 patients had protein C deficiencies, and 9 (56%) had protein S deficiencies. These deficiencies, except one for protein S, were acquired. Ten patients except two who were diagnosed at this center were treated with fresh frozen plasma. They were also given heparin. Nine (69%) of the 13 children 4 years of age or younger and one of the older children (33%) required amputation. Five of the six patients (83%) who had factor V G1691A mutation, and who also exhibited severe infection, required amputation. This study suggests that an age of 4 years or less is a risk factor for the development of PF during severe infections, especially in the presence of factor V G1691A mutation and congenital heart disease, necessitating major or minor surgical interventions. This study also shows that the amputation rate in 10 patients, after excluding the patients who had been referred to our center after development of sequelae, was 60%. The survival rate among these 10 patients may indicate that, with the treatment protocol, PF need not be regarded as a lethal disease any more. It is also suggested that effective immunization programs and better health care have probably resulted in some changes in the etiological profile of PF. Am. J. Hematol. 80:20–25, 2005. © 2005 Wiley‐Liss, Inc.

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Importance of hemostatic gene polymorphisms for susceptibility to and outcome of severe sepsis

Cited by 88 publications

References 50 publications

Effect of Various Genetic Polymorphisms on the Incidence and Outcome of Severe Sepsis

Effect of Various Genetic Polymorphisms on the Incidence and Outcome of Severe Sepsis

Biomarkers in sepsis at time zero: intensive care unit scores, plasma measurements and polymorphisms in Argentina

Outcome in children with purpura fulminans: Report on 16 patients

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