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DOI: 10.1055/s-0038-1651669
Coagulation Activation and Tissue Necrosis in Meningococcal Septic Shock: Severely Reduced Protein C Levels Predict a High Mortality
Publication History
Received 07 April 1994
Accepted after resubmission 29 September 1994
Publication Date:
09 July 2018 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/199501/lookinside/thumbnails/10-1055-s-0038-1651669-1.jpg)
Summary
In 35 consecutively admitted children (mean age: 4.3 years) with a clinical diagnosis of meningococcal septic shock (MSS), activation of the coagulation and fibrinolytic pathways was evaluated directly at admittance to the paediatric intensive care unit (ICU). The association of clinical signs and haemostatic abnormalities was assessed.
All patients had signs of extensive activation of the coagulation system. The 28-day mortality was 26%. Protein C activity was strongly reduced, especially in non-survivors in whom it was significantly lower than in survivors (5% versus 23%; p <0.0001). There was a strong negative correlation between protein C activity and the mean size of the skin lesions (r = -0.71, p <0.001). These results suggest that an acquired protein C deficiency in MSS is related to the pathogenesis of purpura fulminans.
Furthermore, no increase in C4b-binding protein (C4BP) and no decrease in the ratio free protein S/total protein S was observed, suggesting that a deficiency of free protein S as a result of increased C4BP does not play a pathogenetic role in meningococcal septic shock.
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References
- 1 Osterud B, Flaegstad T. Increased tissue thromboplastin activity in monocytes of patients with meningococcal infection: related to an unfavourable prognosis. Thromb Haemost 1983; 49: 5-7
- 2 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
- 3 Warr TA, Mohan Rao V, 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
- 4 Powars DR, Rogers ZR, Patch MJ, McGhee WG, Francis RB. Purpura fulminans in meningococcemia: association with acquired deficiencies of proteins C and S. N Engl J Med 1987; 317: 571-572
- 5 Seligsohn U, Berger A, Abend A, Rubin L, Attias D, Zivelin A, Rapaport SI. Homozygous protein C deficiency manifested by massive thrombosis in the newborn. N Engl J Med 1984; 310: 559-562
- 6 Marlar RA, Montgomery RR. Broekmans AW and the working party. Diagnosis and treatment of homozygous protein C deficiency J Pediatr 1989; 114: 528-533
- 7 McGhee WG, Klotz TA, Epstein J, Rapaport SI. Coumarin necrosis associated with hereditary protein C deficiency. Ann Intern Med 1984; 100: 59-60
- 8 Conard J, Hordellou MH, van Dreden P, Samama M, Poort S, Bertina RM. Homozygous protein C deficiency with late onset and recurrent coumarin- induced skin necrosis. Lancet 1992; 339: 743-744
- 9 Marlar RA, Kleiss AJ, Griffin JH. Mechanism of action of human activated protein C, a thrombin-dependent anticoagulant enzyme. Blood 1982; 59: 1067-1072
- 10 Esmon CT, Owen WG. Identification of an endothelial cell cofactor for thrombin-catalyzed activation of protein C. Proc Natl Acad Sci USA 1981; 78: 2249-2252
- 11 d’Angelo A, Vigano-D’Angelo S, Esmon CT, Comp PC. Acquired deficiencies of protein S. J Clin Invest 1988; 81: 1445-1454
- 12 Taylor jr FB, Chang A, Esmon CT, D’Angelo A, Vigano-D’Angelo S, Blick KE. Protein C prevents the coagulopathic and lethal effects of E. Coli infusion in the baboon J Clin Invest 1987; 79: 918-925
- 13 Taylor F, Chang A, Ferrell G, Mather T, Catlett R, Blick K, Esmon CT. C4b-Binding Protein exacerbates the host response to Escherichia coli. Blood 1991; 78: 357-363
- 14 Sinclair JF, Skeoch CH, Hallworh D. Prognosis of meningococcal septicaemia. Lancet 1987; 2: 38
- 15 Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 237
- 16 Pelzer H, Stuber W. Markers of hemostatic activation: new perspectives using immunochemical methods for determination of prothrombin fragment F1+2and thrombin-antithrombin-III complex. Thromb Haemost 1989; 62: 165
- 17 Amiral JV, Plassart T. Minard. Measurement and clinical relevance of d-dimer by ELISA. Presented at the fibrinogen Workshop Giessen/FRG. 21.05.1986. using commercially available ELISA AsserachromR Stago; Asnières, France:
- 18 Whitaker AN, Delms MJ, Masci PP, Bundesen PG, Rylatt DB, Webber AJ, Buner IH. Measurement of crosslinked fibrin derivatives in plasma: an immunoassay using monoclonal antibodies. J Clin Pathol 1984; 37: 882-887
- 19 Vinazzer H, Pangraz U. Protein C: Comparison of different assays in normal and abnormal plasma samples. Thromb Res 1987; 46: 1-8
- 20 Sturk A, Morriën-Salomons WM, Huisman MV, Borm JJ J, Büller H, Cate JW ten. Analytical and clinical evaluation of commercial Protein C assays. Clin Chim Acta 1987; 165: 263-270
- 21 Woodhams BJ. The simultaneous measurement of total and free Protein S by ELISA. Thromb Res 1988; 50: 213-220
- 22 Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L. Maturation of the hemostatic system during childhood. Blood 1992; 80: 1998-2005
- 23 van Teunenbroek A, Peters M, Sturk A, Borm J, Breederveld C. Protein C activity and antigen levels in childhood. Eur J Pediatr 1990; 149: 774-778
- 24 Madden RM, Gill JC, Marlar RA. Protein C and protein S levels in two patients with acquired purpura fulminans. Br J Haematol 1990; 75: 112-117
- 25 Brandtzaeg P, Sandset PM, Joo GB, Ovestebo 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
- 26 Fourrier F, Lestavel P, Chopin C, Marey A, Goudemand J, Rime A, Man-galaboyi J. Meningococcaemia and purpura fulminans in adults: acute deficiencies of protein C and S and early treatment with antithrombin III concentrates. Intensive Care Med 1990; 16: 121-124
- 27 Leclerc F, Hazelzet J, Jude B, Hofhuis W, Hue V, Martinot A, Van der Voort E. Protein C and S deficiency in severe infectious purpura of children: a collaborative study of 40 cases. Intensive Care Med 1992; 18: 202-205
- 28 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
- 29 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
- 30 Epstein DJ, Bergum PW, Bajaj SP, Rapaport SI. Radioimmunoassays for protein C and factor X: plasma antigen levels in abnormal hemostatic states. Am J Clin Pathol 1984; 82: 573-581
- 31 Rodeghiero F, Mannucci PM, Viagno S, Barbui T, Gugliotta L, Cortellaro M, Dini E. Liver dysfunction rather than intravascular coagulation as the main cause of low protein C and antithrombin III in acute leukemia. Blood 1984; 63: 965-969
- 32 Espana F, Vicente V, Tabernero D, Scharrer I, Griffin JH. Determination of plasma protein C inhibitor and of two activated protein C-inhibitor complexes in normals and in patients with intravascular coagulation and thrombotic disease. Thromb Res 1990; 59: 593-608
- 33 Heeb MJ, Mosher D, Griffin JH. Activation and complexation of protein C and cleavage and decrease of protein S in plasma of patients with intravascular coagulation. Blood 1989; 73: 455-461
- 34 Bertina RM, van Wijngaarden A, Reinalda-Poot J, Poort SR, Bom VJ J. Determination of plasma protein S – The protein cofactor of activated protein C. Thromb Haemost 1985; 53: 268-272
- 35 Brandtzaeg P, Mollnes TE, Kierulf P. Complement activation and endotoxin levels in systemic meningococcal disease. J Infect Dis 1989; 160: 58-65
- 36 Hesselvik JF, Malm J, Dahlback B, Blombäck M. Protein C, Protein S and C4b-binding protein in severe infection and septic shock. Thromb Haemost 1991; 65: 126-129