The Tissue Factor and Plasminogen Activator Inhibitor Type-1 Response in Pediatric Sepsis-induced Multiple Organ Failure^[*]

Summary

Study Objective

Cytokines increase endothelial tissue factor (TF) and tissue plasminogen activator inhibitor type -1 (PAI-1) expression in vitro. Tissue factor interacts with factor VII to facilitate thrombosis and PAI-1 inhibits fibrinolysis by endogenous plasminogen activators.

Because cytokine release is increased in children with sepsisinduced multiple organ failure (MOF), we hypothesized a cytokine associated increase in circulating TF and PAI-1 antigen release, and systemic activity in these patients.

Study Design

One hundred and seven consecutive children, who met the criteria for sepsis, and 10 critically ill children without sepsis, were enrolled in the study. Plasma TF and PAI-1 antigen and activity levels, Interleukin-6 antigen levels (IL-6), nitrite + nitrate levels (marker of nitric oxide production) and number of organs failing were measured on days 1-3 of sepsis.

Results

Increased TF and PAI-1 antigen, and PAI-1 activity levels were associated with increasing IL-6 and nitrite + nitrate levels (p <0.05), the development of MOF (p <0.05), and mortality (p <0.05). Increased systemic PAI-1 activity was associated with cardiovascular, renal, and hepatic failure (p <0.05). Increased systemic TF activity was associated with the development of coagulopathy (p <0.05) and tended to be associated with mortality (p =0.06, power .77)

Conclusions

A shift to an anti-fibrinolytic endothelium phenotype characterizes children who develop sepsis-induced MOF and mortality. Children with coagulopathy have a shift to a pro-coagulant phenotype. These findings support potential therapeutic roles for PAI-1 and TF pathway inhibitors in reversal of this devastating pathophysiologic process.

Keywords

Thrombosis - fibrinolysis - nitric oxide - cytokines - sepsis - interleukin-6

^* This study was supported in part by NIHRO1GM41734-04A1 and 3M01RR0056GCRC

• References

• 1 Proulx F, Gauthier M, Nadeau D. Timing and predictors of death in pediatric patients with multiple organ system failure. Crit Care Med 1994; 22: 1025-31.
• 2 Moore KL, Andreoli SP, Esmon NL, Esmon CT, Bang NU. Endotoxin enhances tissue factor and suppresses thrombomodulin expression of human vascular endothelium in vitro. J Clin Invest 1987; 79 (01) 124-30.
• 3 Schorer AE, Rick PD, Swaim WR, Moldow CF. Structural features of endotoxin required for stimulation of endothelial cell tissue factor production; exposure of preformed tissue factor after oxidant mediated endothelial cell injury. J Lab Clin Med 1985; 106 (01) 38-42.
• 4 Sandset PM, Abildgaard U. Extrinsic pathway inhibitor – the key to feedback control for blood coagulation initiated by tissue thromboplastin. Haemostasis 1991; 21 (04) 219-39.
• 5 Grau GE, de Moerloose P, Bulla O, Lou J, Lei Z, Reber G, Mili N. et al. Haemostatic properties of human pulmonary and cerebral microvascular endothelial cells. Thromb Haemost 1997; 77 (03) 585-90.
• 6 Doughty LA, Kaplan SS, Carcillo JA. Inflammatory cytokine and nitric oxide responses in pediatric sepsis and organ failure. Crit Care Med 1996; 24: 1137-43.
• 7 Bernard GR, Vincent JL, Laterre PF, LaRosa JP, Dhainaut JF, Lopez-Rodriguez A, Steingrad JS. et al. Safety and efficacy trial of activated protein C in severe sepsis. N Engl J Med 2001; 344 (10) 699-709.
• 8 Fareed J, Callas DD, Hoppensteadt D, Bermes Jr EW. Tissue factor antigen levels in various biological fluids. Blood Coagul Fibrinolysis 1995; 6 Suppl 1: S32-6.
• 9 Asakura H, Kamikubo Y, Goto A, Shiratori Y, Yamazaki M, Jokaji H, Saitto M. et al. Role of tissue factor in disseminated intravascular coagulation. Thromb Res 1995; 90 (03) 217-24.
• 10 Gando S, Nanzaki S, Sasaki S, Kemmotsu A. Significant correlations between tissue factor and thrombin markers in trauma and septic patients with disseminated intravascular coagulation. Thromb Haemost 1998; 79 (06) 1111-5.
• 11 Gando S, Nanzaki S, Sasaki S, Aoi K. Kemmotsu. Activation of the extrinsic coagulation pathway in patients with severe sepsis and septic shock. Crit Care Med 1998; 26 (12) 2005-9.
• 12 Wada H, Sakuragawa N, Mori Y, Takai M, Nakasaki T, Shimura M, Hiroyama K. et al. Hemostatic molecular markers before the onset of disseminated intravascular coagulation. Am J Hematol 1999; 60 (04) 273-8.
• 13 Warr L. Human plasma extrinsic pathway inhibitor activity: II. Plasma levels in disseminated intravascular coagulation and hepatocellular disease. Blood 1989; 74 (03) 994-8.
• 14 Sabharwal AK, Bajaj SP, Ameri A, Tricomi SM, Hyers TM, Dahms TE, Tayor Jr. FB. et al. Tissue factor pathway inhibitor and von Willebrand factor antigen levels in adult respiratory distress syndrome and in a primate model of sepsis. Am J Respir Crit Care Med 1995; 151 (3 Pt 1): 758-67.
• 15 Brandtzaeg P, Sandset PM, Joo GB, Ovstebo R, Abildgaard U, Kierulf P. The quantitative association of plasma endotoxin, antithrombin, protein C, extrinsic pathway inhibitor and fibrinopeptide A in systemic meningococcal disease. Thromb Res 1989; 55 (04) 459-70.
• 16 Cremer R, Leclerc F, Jude B, Sadik A, Leteurtre S, Fourier C, Martinot A. et al. Are there specific hemostatic abnormalities in children surviving septic shock with purpura and having skin necrosis or limb ischemia that need skin grafts or limb amputation?. European J Pediatr 1999; 159 (02) 127-32.
• 17 Nurnberger W, Michelmann I, Burdach S, Gobel U. Endothelial dysfunction after bone marrow transplantation: increase of soluble thrombomodulin and PAI-1 in patients with multiple transplant related complications. Ann Hematol 1998; 76 (02) 61-5.
• 18 Gardlund B, Sjolin J, Nilsson A, Roll M, Wickerts CJ, Wretlund B. Plasma levels of cytokines in primary septic shock in humans: correlation with disease severity. J Infect Dis 1995; 172 (01) 296-301.
• 19 Brandtzaeg P, Joo GB, Brusletto B, Kierulf P. Plasminogen activator inhibitor 1 and 2, alpha-2-antiplasmin, plasminogen, and endotoxin levels in systemic meningococcal disease. Thromb Res 1990; 57 (02) 271-8.
• 20 Haj MA, Robbie LA, Croll A, Adley GD, Bennett B. Fibrinolytic changes in a patient with toxic shock syndrome; release of active u-PA. Intensive Care Med 1998; 24 (03) 258-61.
• 21 Kidokoro A, Iba T, Fukunaga M, Yagi Y. Alterations in coagulation and fibrinolysis during sepsis. Shock 1996; 05 (03) 233-8.
• 22 Kornelisse RF, Hazelzet JA, Savelkoul HF, Hop WC, Suur MH, Borsboom AN, Risseuw-Appel IM. et al. The relationship between plasminogen activator inhibitor-1 and pro-inflammatory and counter-inflammatory mediators in children with meningococcal septic shock. J Infect Dis 1996; 173 (05) 1148-56.
• 23 Hermans PW, Hillerd ML, Booy R, Daramola O, Hazelzet JA, deGroot R, Levin M. 4G/5G promoter polymorphism in the plasminogen activator inhibitor 1 gene and outcome of meningococcal disease. Meningococcal Disease Group. Lancet 1999; 354 (9178): 556-60.