Age-related Differences in Outcome and Severity of DIC in Children with Septic Shock and Purpura

Summary

We studied the influence of age on mortality and severity of clotting abnormalities in 79 children (median age: 3.1 years) with meningococcal sepsis. Parameters of coagulation and fibrinolysis and plasma levels of cytokines were prospectively measured on admission. The mortality rate was 27%. The age of survivors was significantly different from that of non-survivors (p = 0.013). With the exception of FVII, vWF and t-PA, parameters of coagulation and fibrinolysis, as well as plasma cytokine levels were related to outcome. Patients were divided in two groups: younger and older than median age. The mortality in children ≤3.1 years was 40% versus 13% in children >3.1 years (p = 0.006). In contrast to cytokine levels, which were not different between the two age groups, fibrinogen, prothrombin, factors V, VII, VIII, vWF, protein C, antithrombin, FDP, and the ratio PAI-l/t-PA were related to age, indicating a more severe coagulopathy in children ≤ 3.1 years despite a similar degree of inflammatory response. A relative deficiency of coagulation factors due to an immature state of the clotting system, as well as an inadequate fibrinolytic response, both related to age may have caused this more severe coagulative response in younger children, and may have contributed to the higher mortality rate.

• References

• 1 Blick RL. Disseminated intravascular coagulation. Hematology/Oncology Clinics of North America 1992; 6: 1259-1285
• 2 Hesselvik JF, Blombäck M, Brodin B, Mailer R. Coagulation, fibrinolysis, and kallikrein systems in sepsis: relation to outcome. Crit Care Med 1989; 17: 724-733
• 3 Levi M, Cate Hten, Poll TVan der, Deventer SJHvan. Pathogenesis of disseminated intravascular coagulation in sepsis. JAMA 1993; 270: 975-979
• 4 Suffredini AF, Harpel PC, Parrillo JE. Promotion and subsequent inhibition of plasminogen activation after administration of intravenous endotoxin to normal subjects. N Engl J Med 1989; 320: 1165-1172
• 5 Thijs LG, Boer JP de, Groot MCMde, Hack CE. Coagulation disorders in septic shock. Intens Care Med 1993; 19: S8-S15
• 6 Esmon NL, D’Angelo A, Vigano-D’Angelo S, Esmon CT, Comp PC. Analysis of protein C and protein S in disease states. Dev Biol Stand 1987; 67: 75-82
• 7 Esmon CT. The roles of protein C and thrombomodulin in the regulation of blood coagulation. J Biol Chem 1989; 264: 4743-4746
• 8 Fourrier F, Lestavel P, Chopin C, Marey A, Goudemand J, Rime A, Mangalaboyi J. Meningococcemia and purpura fulminans in adults: acute deficiencies of proteins C and S and early treatment with antithrombin III concentrates. Intens Care Med 1990; 16: 121-124
• 9 Fourrier F, Chopin C, Goudemand J, Hendrycx S, Caron C, Rime A, Marey A, Lestavel P. Septic shock, multiple organ failure, and disseminated intravascular coagulation. Compared patterns of antithrombin III, protein C, and protein S deficiencies. Chest 1992; 101: 816-823
• 10 Powars DR, Rogers ZR, Patch MJ, McGehee WG, Francis RB. Purpura fulminans in meningococcemia: association with acquired deficiencies of protein C and S. N Engl J Med 1987; 317: 571-572
• 11 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: 459-470
• 12 Sheth SB, Carvalho AC. Protein S and C alterations in acutely ill patients. Am J Hematol 1991; 36: 14-19
• 13 Hesselvik JF, Malm J, Dahlbäck B, Blombäck M. Protein C, protein S and C4b-binding protein in severe infection and septic shock. Thromb Haemost 1991; 65: 126-129
• 14 Leclerc F, Hazelzet JA, Jude B, Hofhuis W, Hue V, Martinot A, Voort Evan der. Protein C and S deficiency in severe infectious purpura of children: a collaborative study of 40 cases. Intens Care Med 1992; 18: 202-205
• 15 Gerson WT, Dickerman JD, Bovill EG, Golden E. Severe acquired protein C deficiency in purpura fulminans associated with disseminated intravascular coagulation: treatment with protein C concentrate. Pediatrics 1993; 91: 418-422
• 16 Powars D, Larsen R, Johnson J, Hulbert T, Sun T, Patch MJ, Francis R, Chan L. Epidemic meningococcemia and purpura fulminans with induced protein C deficiency. Clin Infect Dis 1993; 17: 254-261
• 17 Fijnvandraat K, Derkx B, Peters M, Bijlmer R, Sturk A, Prins MH, Deventer SJH van, Cate JWten. Coagulation activation and tissue necrosis in meningococcal septic shock: severely reduced protein C levels predict a high mortality. Thromb Haemost 1995; 73: 15-20
• 18 Pollack MM, Ruttimann UE, Getson PR. Pediatric risk of mortality (PRISM) score. Crit Care Med 1988; 16: 1110-1116
• 19 Sternberg JC. A rate nephelometer for measuring specific proteins by immunoprecipitation reaction. Clin Chem 1977; 23: 1456-1464
• 20 Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 237-246
• 21 Boer JPde, Abbink J, Brouwer M, Meijer C, Roem D, Voom G, Lambers J, Mourik Jvan, Hack CE. PAI-1 synthesis in the human hepatoma cell line Hep G2 is increased by cytokines. Evidence that the liver contributes to acute phase behaviour of PAI-1. Thromb Haemost 1991; 65: 181-185
• 22 Boermeester MA, Leeuwen PAM, Coyle SM, Wolbink GJ, Hack CE, Lowry SF. IL-1 blockade attenuates mediator release and dysregulation of the hemostatic mechanism during human sepsis. Arch Surg 1995; 130: 739-748
• 23 Marlar RA, Endres-Brooks J, Miller C. Serial studies of protein C and its plasma inhibitor in patients with disseminated intravascular coagulation. Blood 1985; 66: 59-63
• 24 Taylor FB, Chang A, Esmon CT, D’Angelo A, Vigano-D’Angelo S, Blick KE. Protein C prevens the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest 1987; 79: 918-925
• 25 Clouse LH, Comp PC. The regulation of hemostasis: the protein C system. N Engl J Med 1986; 314: 1298-1304
• 26 Boer JPde, Creasy AA, Chang AK, Roem D, Brouwer MC, Eerenberg AJM, Hack CE, Taylor FB. Activation patterns of coagulation and fibrinolysis in baboons following infusion with lethal or sublethal dose of Escherichia coli. Circ Shock 1993; 39: 59-67
• 27 Philippe J, Offner F, Declerck PJ, Leroux-Roels G, Vogelaers D, Baele G, Collen D. Fibrinolysis and coagulation in patients with infectious disease and sepsis. Thromb Haemost 1991; 65: 291-295
• 28 Voss R, Matthias FR, Borkowski G, Reitz D. Activation and inhibition of fibrinolysis in septic patients in an internal intensive care unit. Br J Haematol 1990; 75: 99-105
• 29 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: 271-278
• 30 Engebretsen LF, Kierulf P, Brandtzaeg P. Extreme plasminogen activator inhibitor and endotoxin values in patients with meningococcal disease. Thromb Res 1986; 42: 713-716
• 31 Pralong G, Calandra T, Glauser MP, Schellekens J, Verhoef J, Bachmann F, Kruithof EK. Plasminogen activator inhibitor 1: a new prognostic marker in septic shock. Thromb Haemost 1989; 61: 459-462
• 32 Poll Tvan der, Levi M, Büller HR, Deventer SJHvan, Boer JPde, Hack CE, Cate JWten. Fibrinolytic response to tumor necrosis factor in healthy subjects. J Exp Med 1991; 174: 729-732
• 33 Komelisse RF, Hazelzet JA, Savelkoul HFJ, Hop WCJ, Suur MH, Borsboom ANJ, Risseeuw-Appel IM, Voort Evan der, Groot Rde. The relationship between plasminogen activator inhibitor-1 and proinflamma-tory and counterinflammatory mediators in children with meningococcal septic shock. J Infect Dis 1996; 173: 1148-1156
• 34 Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, Powers P. Development of the human coagulation system in the full-term infant. Blood 1987; 70: 165-172
• 35 Nardi M, Karpatkin M. Prothrombin and protein C in early childhood: normal adult levels are not achieved until the fourth year of life. J Pediatr 1986; 109: 843-845
• 36 Pixley R, Cadena RDL, Page J, Kaufman N, Wyshock E, Chang A, Taylor F, Colman R. The contact system contributes to hypotension but not disseminated intravascular coagulation in lethal bacteremia. J Clin Invest 1993; 91: 61-68
• 37 Carr C, Bild GS, Chang ACK, Peer GT, Palmier MO, Frazier RB, Gustafson ME, Wun T-C, Creasy AA, Hinshaw LB, Taylor FB, Galluppi GR. Recombinant E. coli-derived tissue factor pathway inhibitor reduces coagulopathic and lethal effects in the baboon gram negative model of septic shock. Circ Shock 1995; 44: 126-137