Abstract

IntroductionActivation of inflammation and coagulation was closely related and mutually interdependent in sepsis. Tissue factor (TF) and its endogenous inhibitor, tissue factor pathway inhibitor (TFPI) was the main regulators of the initiation of coagulation process. Altered plasma levels of TF and TFPI have been related to worse outcome in sepsis. The objective of this study was to investigate whether single nucleotide polymorphisms (SNPs) in the TF and TFPI genes were associated with risk and outcome for patients with severe sepsis.MethodsSeventeen SNPs in TF and TFPI were genotyped in samples of sepsis (n =577) and severe sepsis patients (n =476), and tested for association in this case–control collection. We then investigated correlation between the associated SNPs and the mRNA expression, and protein level of the corresponding gene. The mRNA levels of TF were determined using real-time quantitative reverse transcription-polymerase chain reaction and the soluble plasma levels of TF were measured using enzyme linked immunosorbent assay (ELISA) method.ResultsAssociation analysis revealed that three TF SNPs in perfect linkage disequilibrium, rs1361600, rs3917615 and rs958587, were significantly associated with outcome of severe sepsis. G allele frequency of rs1361600 in survivor patients was significantly higher than that in nonsurvivor severe sepsis patients (P =4.91 × 10-5, odds ratio (OR) =0.48, 95% confidence interval (CI) 0.33 to 0.69). The association remained significant after adjustment for covariates in multiple logistic regression analysis and for multiple comparisons. Lipopolysaccharide-induced TF-mRNA expression levels in peripheral blood mononuclear cells from subjects carrying rs1361600 AG and GG genotypes, were significantly lower than those subjects carrying AA genotype (P =0.0012). Moreover, severe sepsis patients of GG and GA genotypes showed lower serum levels of TF than patients with AA genotype (Padj =0.02). The plasma levels of TF were also associated with outcome of severe sepsis patients (Padj =0.01). However, genotype and allele analyses did not show any significant difference between sepsis and severe sepsis patients.ConclusionsOur findings indicate that common genetic variation in TF was significantly associated with outcome of severe sepsis in Chinese Han population.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-014-0631-9) contains supplementary material, which is available to authorized users.

Highlights

  • Activation of inflammation and coagulation was closely related and mutually interdependent in sepsis

  • Association analysis revealed that three Tissue factor (TF) single nucleotide polymorphism (SNP) in perfect linkage disequilibrium, rs1361600, rs3917615 and rs958587, were significantly associated with outcome of severe sepsis

  • The plasma levels of TF were associated with outcome of severe sepsis patients (Padj =0.01)

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Summary

Introduction

Activation of inflammation and coagulation was closely related and mutually interdependent in sepsis. Tissue factor (TF) and its endogenous inhibitor, tissue factor pathway inhibitor (TFPI) was the main regulators of the initiation of coagulation process. Altered plasma levels of TF and TFPI have been related to worse outcome in sepsis. The pathogenesis of severe sepsis is not Tissue factor (TF) and its endogenous inhibitor, tissue factor pathway inhibitor (TFPI), are the main regulators of the initiation of coagulation process [4,5]. Recent studies indicated that the dysfunction of TF and TFPI was closely related to the severity and outcome of sepsis [6,7]. As the main regulator in the initial step of the coagulation cascade mediated by TF, TFPI binds to coagulation factors Xa and VIIa and TF and forms an inactive complex. Experimental studies proved the benefit of the early blockade of the TF–factor VIIa activated coagulation system in reducing both systemic and pulmonary inflammation as well as coagulation, and in improving lung physiology, histological results and even survival [12,13]

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