Zusammenfassung
Klinische Manifestation eines schweren Protein-C-Mangels ist die Purpura fulminans. Bei angeborenem Protein-C-Mangel tritt diese in der Neonatalperiode auf, bei weniger ausgeprägtem Protein-C-Mangel eventuell bei Einleitung einer Kumarintherapie in Form einer Kumarinnekrose. Erworbene Protein-C-Mangelzustände oder Beeinträchtigungen des Protein-C-Systems können ebenfalls mit einer Purpura fulminans einhergehen. Diese wird insbesondere bei Meningokokkensepsis, aber auch bei anderen Infektionserkrankungen beobachtet. Entwickelt sich eine Purpura fulminans nach Abklingen des akuten Infektes, finden sich häufig Autoantikörper gegen Komponenten des Protein-C-Systems. Niedrige Protein-C-Spiegel werden auch bei Patienten mit septischen Zustandsbildern ohne Purpura fulminans gemessen und besitzen einen prädiktiven Wert hinsichtlich des klinischen Resultates. Für die Therapie stehen Protein-C-Konzentrat aus Humanplasma sowie rekombinantes aktiviertes Protein C zur Verfügung. Indikation zur Substitution von Protein C ist der manifeste Protein-C-Mangel mit Purpura fulminans oder anderen thrombotischen Manifestationen, oder auch Kumarinnekrose, bei ungestörter endogener Protein-C-Aktivierung. Weitere Indikation ist die Prophylaxe thrombotischer Ereignisse bei angeborenem schwerem Protein-C-Mangel. Bei Patienten mit septischen Zustandsbildern kann die Aktivierung von Protein C durch MikroZirkulationsstörungen, Ablösung von Thrombomodulin vom Endothel sowie durch mikrovaskuläre Thrombosen beeinträchtigt sein. Hier erscheint die Gabe von ex vivo aktiviertem Protein C sinnvoll. In einer multizentrischen, plazebokontrollierten Doppelblindstudie zeigte sich eine deutliche Senkung der 28-Tage-Mortalität bei Patienten mit schwerer Sepsis durch Therapie mit rekombinantem aktiviertem Protein C.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
Literatur
Aiuto LT, Barone SR, Cohen PS, Boxer RA (1997) Recombinant tissue plasminogen activator restores perfusion in meningococcal purpura fulminans. Crit Care Med 25: 1079–1082
Alberio L, Lammle B, Esmon CT (2001) Protein C replacement in severe meningococcemia: rationale and clinical experience. Clin Infect Dis 32: 1338–1346
Al-Ismail S, Collins P, Najib R, James-Ellison M, O’Hagan M (1999) Postinfection purpura fulminans in a patient heterozygous for prothrombin G20210 A and acquired protein S resistance. Pediatr Hematol Oncol 16: 561–564
Auberger K (1992) Evaluation of a new protein C concentrate and comparison of protein C assays in a child with congenital protein C deficiency. Ann Hematol 64: 146–151
Bajzar L (2001) Thrombin activatable fibrinolysis inhibitor and an antifibrinolytic pathway. Arterioscler Thromb Vase Biol 20: 2511 - 2518
Bajzar L, Nesheim ME, Tracy PB (1996) The profibrinolytic effect of activated protein C in clots formed from plasma is TAFI-dependent. Blood 88: 2093–2100
Baliga V, Thwaites R, Tillyer ML, Minford A, Parapia L, Allgrove J (1995) Homozygous protein C deficiency-management with protein C concentrate. Eur J Pediatr 154: 534–538
Bergmann F, Hoyer PF, D’Angelo SV, Mazzola G, Oesterich C, Bartheis M, D’Angelo A (1995) Severe autoimmune protein C deficiency in a boy with idiopathic purpura fulminans. Br J Haematol 89: 610–614
Bernard GR, Ely EW, Wright TJ et al. (2001) Safety and dose relationship of recombinant human activated protein C for coagulopathy in severe sepsis. Crit Care Med 29: 2051–2059
Bernard GR, Vincent JL, Laterre PF et al. (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344: 699–709
Busuttil DP, Hay CR, Lewis MA, Wynn RF (2000) Aggressive multiple modality therapy for varicella-associated purpura fulminans. Br J Haematol 110: 1012–1013
Carpenter CT, Kaiser AB (1997) Purpura fulminans in pneumococcal sepsis: case report and review. Scand J Infect Dis 29: 479–483
Clarke RC, Johnston JR, Mayne EE (2001) Meningococcal septicaemia: treatment with protein C concentrate. Intensive Care Med 26: 471–473
Cnota JF, Barton LL, Rhee KH (1999) Purpura fulminans associated with streptococcus pneumoniae infection in a child. Pedriatr Emerg Care 15: 187–188
Conlan MG, Bridges A, Williams E, Marlar R (1988) Familial type II protein C deficiency associated with warfarin-induced skin necrosis and bilateral adrenal hemorrhage. Am J Hematol 29: 226–229
Conway EM, Rosenberg RD (1988) Tumor necrosis factor suppresses transcription of the thrombomodulin gene in endothelial cells. Mol Cell Biol 8: 5588–5592
De Franzo AJ, Marasco P, Argenta LC (1995) Warfarin-induced necrosis of the skin. Ann Plast Surg 34: 203–208
De Stefano V, Mastrangelo S, Schwarz HP, Pola P, Flore R, Bizzi B, Leone G (1993) Replacement therapy with a purified protein C concentrate during initiation of oral anti-coagulation in severe protein C congenital deficiency. Thromb Haemost 70: 247–249
Dhainaut JF, Marin N, Mignon A, Vinsonneau C (2001) Hepatic response to sepsis: Interaction between coagulation and inflammatory processes. Crit Care Med 29: S42–S47
Dreyfus M, Magny JF, Bridey F, Schwarz HP, Planche C, Dehan M, Tchernia G (1991) Treatment of homozygous protein C deficiency and neonatal purpura fulminans with a purified protein C concentrate. N Engl J Med 325: 1565–1568
Ezer U, Misirlioglu ED, Colba V, Ogoz E, Kurt C (2001) Neonatal purpura fulminans due to homozygous protein C deficiency. Pediatr Hematol Oncol 18: 453–458
Faust SN, Levin M, Harrison OB et al. (2001) Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N Engl J Med 345: 408–416
Fijnvandraat K, Derkx B, Peters M et al. (1995) Coagulation activation and tissue necrosis in meningococcal septic shock: severely reduced protein C levels predict a high mortality. Thromb Haemost 73: 15–20
Galanakis A, Apokotou M, Alfadaki S, Gesouli E, Lapatsanis P (1999) Purpura fulminans complicating pneumococcal sepsis. Eur J Pediatr 158: 171
Gamba G, Montani N, Montecucco CM, Caporali R, Ascari E (1991) Purpura fulminans as clinical manifestation of atypical SLE with antiphospholipid antibodies: a case report. Haematologica 76: 426–428
Herrera R, Hobar PC, Ginsburg CM (1994) Surgical intervention for the complications of meningococal-induced purpura fulminans. Pediatr Infect Dis J 13: 734–737
Huang DB, Price M, Pokorny J, Gabriel KR, Lynch R, Paletta CE (1999) Reconstructive surgery in children after meningococcal purpura fulminans. J Pediatr Surg 34: 595–601
Inbal A, Kenet G, Zivelin A et al. (1997) Purpura fulminans induced by disseminated intravascular coagulation following infection in 2 unrelated children with double heterozygosity for factor V Leiden and protein S deficiency. Thromb Haemost 77: 1086–1089
Johansen K, Hansen ST (1992) Symmetrical peripheral gangrene (purpura fulminans) complicating pneumococcal sepsis. Am J Surg 41: 24–31
Josephson C, Nuss R, Jacobson L, Hacker MR, Murphy J, Weinberg A, Manco-Johnson MJ (2001) The varicella-autoantibody syndrome. Pediatr Res 50: 345–352
Kemahli S, Alhenc-Gelas M, Gandrille S, Aiach M, Akar N, Cin S (1998) Homozygous protein C deficiency with a double variant His 202 to Tyr and Ala 346 to Thr. Blood Coagul Fibrinolysis 9: 351–354
Kondaveeti S, Hibberd ML, Booy R, Nadel S, Levin M (1999) Effect of factor V Leiden mutation on the severity of meningococcal disease. Pediatr Infect Dis J 18: 893–896
Levin M, Eley BS, Louis J, Cohen H, Young L, Heyderman RS (1995) Postinfectious purpura fulminans caused by an autoantibody directed against protein S. J Pediatr 127: 355–363
Lorente JA, Garcia-Frade LJ, Landin L, de Pablo R, Torrado C, Renes E, Garcia-Avello A (1993) Time course of hemostatic abnormalities in sepsis and its relation to outcome. Chest 103: 1536–1542
Manco-Johnson MJ, Abshire TC, Jacobson LJ, Marlar RA (1991) Severe neonatal protein C deficiency: prevalence and thrombotic risk. J Pediatr 119: 793–798
Manco-Johnson MJ, Nuss R, Key N et al. (1996) Lupus anticoagulant and protein S deficiency in children with postvaricella purpura fulminans or thrombosis. J Pediatr 128: 319–323
Marlar RA, Montgomery RR, Broekmans AW (1989) Diagnosis and treatment of homozygous protein C deficiency. Report of the working party on homozygous protein C deficiency of the subcommittee on protein C and protein S, International Committee on Thrombosis and Haemostasis. J Pediatr 114: 528–534
Marlar RA, Sills RH, Groncy PK, Montgomery RR, Madden RM (1992) Protein C survival during replacement therapy in homozygous protein C deficiency. Am J Hematol 41: 24–31
Mesters RM, Heiterbrand J, Utterback BG et al. (2001) Prognostic value of protein C concentrations in neutropenic patients at high risk of severe septic complications. Crit Care Med 28: 2209–2216
Minford AM, Parapia LA, Stainforth C, Lee D (1996) Treatment of homozygous protein C deficiency with subcutaneous protein C concentrate. Br J Haematol 93: 215–216
Mosnier LO, Meijers JC, Bouma BN (2001) Regulation of fibrinolysis in plasma by TAFI and protein C is dependent on the concentration of thrombomodulin. Thromb Haemost 85: 5–11
Muller FM, Ehrenthal W, Hafner G, Schranz D (1996) Purpura fulminans in severe congenital protein C deficiency: monitoring of treatment with protein C concentrate. Eur J Pediatr 155: 20–25
Nadel S, De Munter C, Britto J, Habibi P, Levin M (1998) Recombinant tissue plasminogen activator restores perfusion in meningococcal purpura fulminans. Crit Care Med 26: 971–972
Nguyen P, Reynaud J, Pouzol P, Munzer M, Richard O, Francois P (1994) Varicella and thrombotic complications associated with transient protein C and protein S deficiencies in children. Eur J Pediatr 153: 646–649
Nolan J, Sinclair R (2001) Review of management of purpura fulminans and two case reports. Br J Anaesth 86: 581–586
Powars D, Larsen R, Johnson J et al. (1993) Epidemie meningococcemia and purpura fulminans with induced protein C deficiency. Clin Infect Dis 17: 254–261
Powars DR, Rogers ZR, Patch MJ, McGehee WG, Francis RB Jr (1987) Purpura fulminans in meningococcemia: association with acquired deficiencies of proteins C and S. N Engl J Med 317: 571–572
Rintala E, Kauppila M, Seppala OP, Voipio-Pulkki LM, Pettila V, Rasi V, Kotilainen P (2000) Protein C substitution in sepsis-associated purpura fulminans. Crit Care Med 28: 2373–2378
Rintala E, Seppala OP, Kotilainen P, Pettila V, Rasi V (1998) Protein C in the treatment of coagulopathy in meningococcal disease. Crit Care Med 26: 965–968
Rivard GE, David M, Farrell C, Schwarz HP (1995) Treatment of purpura fulminans in meningococcemia with protein C concentrate. J Pediatr 126: 646–652
Sanz-Rodriguez C, Gil-Fernandez J J, Zapater P et al. (1999) Long-term management of homozygous protein C deficiency: replacement therapy with subcutaneous purified protein C concentrate. Thromb Haemost 81: 887–890
Schramm W, Spannagl M, Bauer KA, Rosenberg RD, Birkner B, Linnau Y, Schwarz HP (1993) Treatment of coumarin-induced skin necrosis with a monoclonal antibody purified protein C concentrate. Arch Dermatol 129: 753–756
Scully MF, Toh CH, Hoogendoorn H, Manuel RP, Nesheim ME, Solymoss S, Giles AR (1993) Activation of protein C and its distribution between its inhibitors, protein C inhibitor, alpha 1-antitrypsin and alpha 2-macroglobulin, in patients with disseminated intravascular coagulation. Thromb Haemost 69: 448–453
Smith OP, White B, Vaughan D, Rafferty M, Claffey L, Lyons B, Casey W (1997) Use of protein-C concentrate, heparin, and haemodiafiltration in meningococcus-induced purpura fulminans. Lancet 350: 1590–1593
Takano S, Kimura S, Odama S, Aoki N (1990) Plasma thrombomodulin in health and diseases. Blood 76: 2024–2029
Tambyah PA, Kumarasinghe G, Chan HL, Lee KO (1997) Streptococcus suis infection complicated by purpura fulminans and rhabdomyolysis: case report and review. Clin Infect Dis 24: 710–712
Vary TC, Kimball SC (1992) Regulation of hepatic protein synthesis in chronic inflammation and sepsis. Am J Physiol 262: C445–C452
Vukovich T, Auberger K, Weil J, Engelmann H, Knobl P, Hadorn HB (1988) Replacement therapy for a homozygous protein C deficiency state using a concentrate of human protein C and S. Br J Haematol 70: 435–440
Warren BL, Eid A, Singer P. (2001) High-dose antithrombin III in severe sepsis. A randomized controlled trial. JAMA 286: 1869–1878
Watanabe R, Wada H, Sakakura M et al. (2001) Plasma levels of activated protein C-protein C inhibitor complex in patients with hypercoagulable states. Am J Hematol 65: 35–40
Wermes C, Bergmann F, Reller B, Sykora KW (1999) Severe protein C deficiency and aseptic osteonecrosis of the hip joint: a case report. Eur J Pediatr 158 (Suppl 3): S159–S161
White B, Livingstone W, Murphy C, Hodgson A, Rafferty M, Smith OP (2001) An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia. Blood 96: 3719–3724
Woods CR, Johnson CA (1998) Varicella purpura fulminans associated with heterozygosity for factor V Leiden and transient protein S deficiency. Pediatrics 102: 1208–1210
Yan SB, Heiterbrand JD, Hartman DL, Wright TJ, Bernard GR (2001) Low levels of protein c are associated with poor outcome in severe sepsis. Chest 120: 915–922
Zenz W, Bodo Z, Zobel G, Fanconi S, Rettenbacher A (1998) Recombinant tissue plasminogen activator restores perfusion in meningococcal purpura fulminans. Crit Care Med 26: 969–971
Zenz W, Muntean W, Zobel G, Grubbauer HM, Gallistl S (1995) Treatment of fulminant meningococcemia with recombinant tissue plasminogen activator. Thromb Haemost 74: 802–803
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2002 Springer-Verlag Berlin Heidelberg
About this paper
Cite this paper
Dempfle, CE. (2002). Klinische Ergebnisse der Protein-C- und rhAPC-Substitution. In: Martin, E., Nawroth, P. (eds) Fachübergreifende Aspekte der Hämostaseologie V. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-93394-3_7
Download citation
DOI: https://doi.org/10.1007/978-3-642-93394-3_7
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-540-43350-7
Online ISBN: 978-3-642-93394-3
eBook Packages: Springer Book Archive