Activation of the Intrinsic Pathway of Coagulation in Children with Meningococcal Septic Shock

Summary

Meningococcal septic shock (MSS) is complicated by activation of coagulation, fibrinolytic, and complement systems. We studied the contact system of the intrinsic pathway of coagulation in thirteen children with MSS. Activation was assessed upon admittance to the intensive care unit and 48 h thereafter, based on the measurement of factor XII- (FXII), prekallikrein- and factor XI (FXI) antigen levels, as well as on the detection of FXIa-FXIa inhibitor, FXIIa-C1-inhibitor, and kallikrein-C1-inhibitor complexes, respectively. Levels of FXII, prekallikrein and FXI were reduced to about 50% in all patients on admission, and were significantly higher 48 h later. FXIIa-C1-inhibitor complexes were elevated in 7 patients, and kallikrein-C1-inhibitor complexes in 2 patients. FXIa-α₁-antitrypsin complexes were elevated in all patients, FXIa-C1-inhibitor complexes in nine, and FXIa-anti-thrombin III complexes in one patient. We conclude that patients with MSS have activation of the contact system, which may contribute to activation of coagulation, and thus to morbidity and mortality.

• References

• 1 McManus ML, Churchwell KB. Coagulopathy as a predictor of outcome in meningococcal sepsis and the systemic inflammatory response syndrome with purpura. Crit Care Med 1993; 21: 706-711
• 1 Østerud B, Flaegstad T. Increased tissue thromboplastin activity in monocytes of patients with meningococcal infection: related to an unfavourable prognosis. Thromb Haemost 1983; 49: 45-7
• 3 Bevilacqua MP, Pober JS, Majeau GR, Cotran RS, Gimbrone MA. Interleukin 1 (IL-1) induces biosynthesis and cell surface expression of procoagulant activity in human vascular endothelial cells. J Exp Med 1984; 160: 618-623
• 4 Moore KL, Andreoli SP, Esmon N, Esmon CT, Bang NU. Endotoxin enhances tissue factor and suppresses thrombomodulin expression of human vascular endothelium in vitro. J Clin Invest 1987; 79: 124-130
• 5 Warr TA, Mohan RV, Rapaport SI. Disseminated intravascular coagulation in rabbits induced by administration of endotoxin or tissue factor: effect of anti-tissue factor antibodies and measurement of plasma extrinsic pathway inhibitor activity. Blood 1990; 75: 1481-1489
• 6 Davie EW, Fujikawa K, Kisiel W. The coagulation cascade: Initiation, maintenance, and regulation. Biochemistry 1991; 30: 10363-10370
• 7 Kaplan AP, Silverberg M. The coagulation-kinin pathway of human plasma. Blood 1987; 70: 1-15
• 8 Levi M, ten Cate H, van der Poll T, van Deventer SJ. Pathogenesis of disseminated intravascular coagulation in sepsis. JAMA 1993; 270: 975-979
• 9 De La Cadena RA, Suffredini AF, Page JD, Pixley RA, Kaufman N, Parrillo JE, Colman RW. Activation of the kallikrein-kinin system after endotoxin administration to normal human volunteers. Blood 1993; 81: 3313-3317
• 10 Pixley RA, De La Cadena R, Page JD, Kaufman N, Wyshock EG, Colman RW, Chang A, Taylor FB. Activation of the contact system in lethal hypotensive bacteremia in a baboon model. Am J Pathol 1992; 140: 897-906
• 11 Pixley RA, De-La-Cadena R, Page JD, Kaufman N, Wyshock EG, Chang A, Taylor Jr FB, Colman RW. The contact system contributes to hypotension but not disseminated intravascular coagulation in lethal bacteremia. In vivo use of a monoclonal anti-factor XII antibody to block contact activation in baboons J Clin Invest 1993; 91: 61-68
• 12 Nuijens JH, Huijbregts CC M, Eerenberg-Belmer AJ M, Abbink JJ, Strack van Schijndel RJ M, Felt-Bersma RJ F, Thijs LG, Hack CE. Quantification of plasma factor XIIa-C1-inhibitor and kallikrein-C1-inhibitor complexes in sepsis. Blood 1988; 72: 1841-1848
• 13 Kaufman N, Page JD, Pixley RA, Schein R, Schmaier AH, Colman RW. Alpha 2-macroglobulin-kallikrein complexes detect contact system activation in hereditary angioedema and human sepsis. Blood 1991; 77: 2660-2667
• 14 Pixley RA, Zellis S, Bankes P, DeLa Cadena RA, Page JD, Scott CF, Kappelmayer J, Wyshock EG, Kelly JJ, Colman RW. Prognostic value of assessing contact system activation and factor V in systemic inflammatory response syndrome. Crit Care Med 1995; 23: 41-51
• 15 Fijnvandraat K, Derkx B, Peters M, Bijlmer R, Sturk A, Prins MH, van Deventer SJ H, ten Cate JW. Coagulation activation and tissue necrosis in meningococcal septic shock: severely reduced protein C levels predict a high mortality. Thromb Haemost 1995; 73: 15-20
• 16 Sinclair JF, Skeoch CH, Hallworh D. Prognosis of meningococcal septicaemia. Lancet 1987; 2: 38
• 17 Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L. Maturation of the hemostatic system during childhood. Blood 1992; 80: 1998-2005
• 18 Wuillemin WA, Minnema M, Meijers JC M, Roem D, Eerenberg AJ M, Nuijens JH, ten Cate H, Hack CE. Inactivation of factor XIa in human plasma assessed by measuring factor XIa-protease inhibitor complexes: major role for C1-inhibitor. Blood 1995; 85: 1517-1526
• 19 Boermeester MA, van Leeuwen PA M, Coyle SM, Houdijk AJ P, Eerenberg AM, Wolbink GJ, Pribble JP, Stiles DM, Wesdorp RI C, Hack CE, Lowry SF. Interleukin-1 receptor blockade in patients with sepsis syndrome: evidence that interleukin-1 contributes to the release of interleukin-6, elastase and phospholipase A2, and to activation of the complement, coagulation and fibrinolytic system. 1995. Doctoral Thesis University of Amsterdam; The Netherlands: pp 169-194
• 20 Brandtzaeg P, Mollnes TE, Kierulf P. Complement activation and endotoxin levels in systemic meningococcal disease. J Infect Dis 1989; 160: 58-65
• 21 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
• 22 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. Throm Res 1990; 57: 271-278
• 23 Fijnvandraat K, Peters M, Derkx B, van Deventer S, ten Cate JW. Endotoxin induced coagulation activation and protein C reduction in meningococcal septic shock. Prog Clin Biol Res 1994; 388: 247-254
• 24 Roman J, Velasco F, Fernandez F, Fernandez M, Villalba R, Rubio V, Vicente A, Torres A. Coagulation, fibrinolytic and kallikrein systems in neonates with uncomplicated sepsis and septic shock. Haemostasis 1993; 23: 142-148
• 25 Colman RW. Disseminated intravascular coagulation due to sepsis. Sem Hematol 1994; 31: 10-17
• 26 de Smet BJ, de Boer JP, Agterberg J, Rigter G, Bleeker WK, Hack CE. Clearance of human native, proteinase-complexed, and proteolytically inactivated C1-inhibitor in rats. Blood 1993; 81: 56-61
• 27 Schapira M. Major inhibitors of the contact phase coagulation factors. Semin Thromb Haemost 1987; 13: 69-78
• 28 Morrison DC, Cochrane CG. Direct evidence for Hageman factor (factor XII) activation by bacterial lipopolysacharides (endotoxins). J Exp Med 1974; 140: 797-811
• 29 Kalter ES, Dijk WC, Timmerman A. Activation of purified human plasma prekallikrein triggered by cell wall fractions of Escherica coli and Staphylococcus aureus. J Infect Dis 1983; 4: 682-691
• 30 Roise O, Bouma BN, Stadaas JO. Studies on interactions of endotoxin with factors of the contact system in plasma. Prog Clin Biol Res 1080; 308: 401-405
• 31 Girffin JH. Role of surface-dependent activation of hageman factor (blood coagulation factor XII). Proc Natl Acad Sci USA 1978; 75: 1998-2002
• 32 Ragni MV, Sinha D, Seaman F, Lewis JH, Spero JA, Walsh PN. Comparison of bleeding tendency, factor XI coagulant activity, and factor XI antigen in 25 factor Xl-defieient kindreds. Blood 1985; 65: 719-724
• 33 Saito II. Contact factors in health and disease. Semin Tliromb Haemost 1987; 13: 36-49
• 34 Lämmle B, Wuillemin WA, Huber I, Krauskopf M, Zurcher C, Pflugshaupt R, Furlan M. Thromboembolism and bleeding tendency in congenital factor XII deficiency – a study on 74 subjects from 14 Swiss families. Thromb Haemost 1991; 65: 117-121
• 35 Gailani D, Broze Jr GJ. Factor XI activation in a revised model of blood coagulation. Science 1991; 253: 909-912
• 36 Naito K, Fujikawa K. Activation of human blood coagulation factor XI independent of factor XII. Factor XI is activated by thrombin and factor Xla in the presence of negatively charged surfaces J Biol Chem 1991; 266: 7353-7358