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. 2013 Mar 5;10(1):7.
doi: 10.1186/1476-9255-10-7.

Novel biomarkers for early prediction of sepsis-induced disseminated intravascular coagulation in a mouse cecal ligation and puncture model

Jingchun Song  1 , Dunzhong Hu, Chao He, Tao Wang, Xuefeng Liu, Linhao Ma, Zhaofen Lin, Zili Chen
Affiliations

Novel biomarkers for early prediction of sepsis-induced disseminated intravascular coagulation in a mouse cecal ligation and puncture model

Jingchun Song et al. J Inflamm (Lond). .

Abstract

Introduction: The objective of this study was to identify biomarkers of sepsis-induced disseminated intravascular coagulation (DIC) among platelet-derived factors using biotin label-based custom protein microarray technology in a mouse cecal ligation and puncture (CLP) model.

Methods: KM mice were randomized into sham-operated and CLP groups. Blood samples were obtained immediately and at 1 h, 2 h, 6 h, 12 h, 24 h, 48 h and 72 h after establishment of the CLP for platelet count, coagulation assay and blood chemistry. Lung and mesentery tissues were examined histologically at all corresponding time points, looking for microthrombus formation. Serial protein microarray analysis was performed to detect platelet-derived factors.

Results: The survival rate 72 h post-CLP was 15%, but there was no mortality among the sham-operated mice. Compared with the sham group, the platelet count (n = 5, p < 0.05), fibrinogen concentration (n = 5, p < 0.05) and alanine aminotransferase level of the CLP group began to decrease significantly at 6 h post-CLP. Significant prolongation of prothrombin time (n = 5, p < 0.05) and activated partial thromboplastin time (n = 5, p < 0.05) and elevation of D-dimer (n = 5, p < 0.05) occurred after 6 h post-CLP. On histology, microthrombus formation in lung and mesentery tissue was observed in the CLP groups 6 h post-CLP and had become significant and extensive 12 h post-CLP (n = 5, p < 0.05). On protein microarray analysis and ELISA, thrombospondin (TSP), tissue inhibitor of metalloproteinase 1 (TIMP-1) and thymus chemokine-1 (TCK-1) all increased during the first 2 h post-CLP, then remained at a higher level than in the sham group for 72 h post-CLP (n = 5, p < 0.05).

Conclusions: TSP, TIMP-1 and TCK-1 are elevated in the early stage of sepsis-induced DIC in a mouse CLP model and may be considered early markers for sepsis-induced DIC.

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Figures

Figure 1
Figure 1
Survival rate after cecal ligation and puncture (CLP). The CLP procedure resulted in significantly greater mortality than a sham operation. CLP group, n = 20; sham group, n = 10. p < 0.01 vs. sham group (Wilcoxon’s test).
Figure 2
Figure 2
Blood markers of disseminated intravascular coagulation in cecal ligation and puncture (CLP) group and sham groups. *Significant difference compared with sham group (n = 5, p < 0 .05).
Figure 3
Figure 3
Blood chemistry in cecal ligation and puncture (CLP) group and sham group. *Significant difference compared with sham group (n = 5, p < 0 .05).
Figure 4
Figure 4
Histological changes in mouse lung and mesentery tissue. Samples were obtained 6 h post-cecal ligation and puncture (CLP) (hematoxylin and eosin; ×400). A: Mixed thrombus in lung tissue 6 h post-CLP. B: Fibrin thrombus in mesentery tissue 6 h post-CLP. C: Multiple thrombi in lung tissue 12 h post-CLP.
Figure 5
Figure 5
The percentage platelet surface expression of CD62P and CD63 by flow cytometry in CLP group and sham group. *Significant difference compared with sham group (n = 5, p < 0 .05).
Figure 6
Figure 6
Custom protein microarray analysis in cecal ligation and puncture (CLP) group and sham group. A: Sham group. B: 1 h post-CLP group. C: 2 h post-CLP group. D: 6 h post-CLP group. E: 12 h post-CLP group. F: 24 h post-CLP group. G: 48 h post-CLP group. H: 72 h post-CLP group.
Figure 7
Figure 7
Protein microarray signal intensities of TSP, PF4, TIMP-1 and TCK-1 in cecal ligation and puncture (CLP) group and sham group. *Significant difference compared with sham group (n = 5, p < 0.05).
Figure 8
Figure 8
Serum concentrations of TSP, TIMP-1 and TCK-1 in cecal ligation and puncture (CLP) group and sham group by ELISA. *Significant difference compared with sham group (n = 5, p < 0.05).
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