Zusammenfassung
Fragestellung: Ein niedriger Protein-C-Spiegel in der schweren Sepsis scheint mit einer erhöhten
Morbidität und Mortalität assoziiert zu sein. Im Rahmen der vorliegenden Untersuchungen
sollte geklärt werden, inwieweit sich Protein-C-Plasmaspiegel bei Patienten mit einer
systemischen Entzündungsreaktion oder einer schweren Sepsis im Verlauf unterscheiden.
Des Weiteren sollte die Ursache für die verminderte Protein-C-Expression in der schweren
Sepsis untersucht werden. Methodik: In die Untersuchung wurden 32 Patienten mit der Diagnose einer schweren Sepsis und
10 Patienten mit einer systemischen Entzündungsreaktion nach großen chirurgischen
Eingriffen eingeschlossen. Bei den Patienten wurden im Verlauf des Aufenthaltes auf
der operativen Intensivstation zweimal pro Woche neben den Protein-C-Plasmaspiegeln
weitere Gerinnungsparameter, wie Thrombin-Antithrombin-Komplex, und Faktor VII bestimmt.
Ergebnisse: Die Patienten mit schwerer Sepsis und systemischer Entzündungsreaktion unterschieden
sich im Gruppenvergleich nicht signifikant im Hinblick auf die gemessenen Plasmaspiegel
von Protein C, Thrombin-Antithrombin-Komplex und Faktor VII. Die Unterscheidung zwischen
überlebenden und verstorbenen Patienten mit schwerer Sepsis ergab, dass Überlebende
signifikant höhere Plasmaspiegel für Protein C aufwiesen als Verstorbene. Die Plasmaspiegel
für Thrombin-Antithrombin-Komplex waren im Gruppenvergleich signifikant niedriger
bei den überlebenden Patienten mit schwerer Sepsis. Für den Faktor VII wurde kein
signifikanter Unterschied im Gruppenvergleich gefunden. Schlussfolgerung: Überlebende Patienten mit schwerer Sepsis hatten signifikant höhere Protein-C-Plasmaspiegel
als die Patienten, die im Rahmen der schweren Sepsis verstorben waren. Dabei wurde
bei den verstorbenen Patienten im Rahmen der gesteigerten Gerinnungsaktivierung offensichtlich
auch mehr Protein C als endogenes Antikoagulanz verbraucht.
Abstract
Objectives: Low concentration of protein C in severe sepsis may be associated with increased
morbidity and mortality. The present study was designed to clarify to what extent
there are differences in the time course of plasma concentrations of protein C in
patients with systemic inflammatory response syndrome or patients with severe sepsis.
In addition, the cause of decreased expression of protein C in severe sepsis was examined.
Methods: 32 patients with severe sepsis and 10 patients with systemic inflammatory response
syndrome admitted to a surgical intensive care unit were enrolled in the study. While
the patients stayed in the intensive care unit protein C plasma concentrations and
the clotting factors thrombin-antithrombin-complex and factor VII were determined
twice weekly. Results: Comparing patients with severe sepsis and systemic inflammatory response syndrome
there was no significant difference concerning plasma levels of protein C, thrombin-antithrombin-complex
and factor VII. In contrast, surviving patients with severe sepsis exhibited significant
higher protein C levels compared to non-survivors. In addition, significant lower
plasma levels of thrombin-antithrombin-complex were determined in survivors compared
to non-survivors. However, factor VII displayed no significant group difference. Conclusions: Surviving patients with severe sepsis exhibited higher plasma concentrations of protein
C than patients who died during severe sepsis. The lower plasma concentrations of
protein C in non-survivors may be caused by an increased turnover of protein C served
as endogenous anticoagulant in sepsis associated activation of coagulation.
Schlüsselwörter
Sepsis - Protein-C-Mangel - Gerinnung - Zytokine - aktiviertes Protein C
Key words
sepsis - protein C deficiency - coagulation - cytokines - activated protein C
Literatur
1
D'Angelo A, Vigano-D'Angelo S, Esmon C T, Comp P C.
Acquired deficiencies of protein S. Protein S activity during oral anticoagulation,
in liver disease, and disseminated intravascular coagulation.
J Clin Invest.
1988;
81
1445-1454
2
Balk R A.
Severe sepsis and septic shock. Definitions, epidemiology, and clinical manifestation.
Crit Care Clin.
2000;
16
179-192
3 Barthels M, Möller W, Oestereich C. Thrombin/Antithrombin III Komplex (TAT) Plasminogen-Aktivator-Inhibitor
(PAI): Neue Erkenntnisse zur klinischen Relevanz. In: Wisser H (Hrsg). Neue Methoden
in der Labordiagnostik. Medizinische Verlagsgesellschaft, Marburg 1990; 43-56
4
Bernard G R, Vincent J L, Laterre P F, LaRosa S P, Dhainaut J F, Lopez-Rodriguez A,
Steingrub J S, Garber G E, Helterbrand J D, Ely E W, Fisher C J.
Efficacy and safety of recombinant human activated protein C for severe sepsis.
N Eng Med.
2001;
344
699-709
5
Bone R C.
The pathogenesis of sepsis.
Ann Intern Med.
1991;
115
457-469
6
Bone R C.
Modulators of coagulation. A critical appraisal of their role in sepsis.
Arch Intern Med.
1992;
152
1381-1389
7
Bone R C, Balk R A, Cerra F B, Dellinger R P, Fein A M, Knaus W A, Schein R M, Sibbald W J.
American College of Chest Physicians/Society of Critical Care Medicine .
Definition for sepsis and organ failure and guidelines for the use of innovative therapies
in sepsis. The ACCP/SCCM Consensus Conference Committee.
Chest.
1992;
101
1644-1655
8
Brandtzaeg P, Sandest P M, Joo G B, 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
9 Cooper D N, Krawczak M. Venous thrombosis. From genes to clinical medicine. In:
BIOS Scientific, Oxford 1997; 289-293
10
Couture P, Demers C, Morisette J, Delage R, Jomphe M, Couture L, Simard J.
Type I protein C deficiency in French Canadians: evidence of a founder effect and
association of specific protein C gene mutations with plasma protein C levels.
Thromb Haemost.
1998;
80
551-556
11
Dettmeier P, Swindell B, Stroud M, Arkins N, Howard A.
Role of activated protein C in pathophysiology of severe sepsis.
Am J Crit Care.
2003;
12
518-524
12
Dhainaut J F, Shorr A F, Macias W L, Kollef M J, Levi M, Reinhart K, Nelson D R.
Dynamic evolution of coagulopathy in the first day of severe sepsis: Relationship
with mortality and organ failure.
Crit Care Med.
2005;
33
341-348
13
Esmon C T.
Structure and functions of the endothelial cell protein C receptor.
Crit Care Med.
2004;
32
298-301
14
Faust S N, Levin M, Harrison O B, Goldin R D, Lockhart M S, Kondaveeti S, Laszik Z,
Esmon C T, Heyderman R S.
Dysfunction of endothelial protein C activation in severe meningococcal sepsis.
N Engl J Med.
2001;
345
408-416
15
Fourrier F, Chopin C, Goudemand J, Hendrycs S, Caron C, Rime A, Marey A, Letavel 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
16
Gladson C L, Scharrer I, Hach V, Beck K H, Griffin J H.
The frequency of type I heterozygous protein S and protein C deficiency in 141 unrelated
young patients with venous thrombosis.
Thromb Haemost.
1988;
59
18-22
17
Heuer L, Blumenberg D.
Rekombinanter Faktor VII a (NovoSeven®) Ein Überblick über aktuelle und mögliche zukünftige
Indikationen.
Anaesthesist.
2002;
51
388-399
18
Joyce D E, Gelbert L, Ciaccia A, DeHoff B, Grinell B W.
Gene expression profile of antithrombotic protein C defines new mechanisms modulating
inflammation and apoptosis.
J Biol Chem.
2001;
276
11199-11203
19
Le Gall J R, Lemeshow S, Saulnier F.
A new Simplified Acute Physiology Score (SAPS II) based on European/North American
multicenter study.
JAMA.
1993;
270
2957-2963
20
Millar D S, Johansen B, Berntorp E, Minford A, Bolton-Maggs P, Wensley R, Kakkar V,
Schulman S, Torres A, Bosch N, Cooper D N.
Molecular genetic analysis of severe protein C deficiency.
Hum Genet.
2000;
106
646-653
21
O'Brien J M, Abraham E.
New approaches to the treatment of sepsis.
Clin Chest Med.
2003;
24
521-548
22
Patel G P, Gurka D P, Balk R A.
New treatment strategies for severe sepsis and septic shock.
Curr Opin Crit Care.
2003;
9
390-396
23
Reitsma P H.
Protein C deficiency: from gene defects to disease.
Thromb Haemost.
1997;
78
344-350
24
Riess H.
Hämostasestörungen im Umfeld von Sepsis und SIRS.
Internist.
1998;
39
479-484
25 Seitz R, Egbring R. Diagnostische Erfassung einer Aktivierung des Gerinnungssystems
durch Messung der Antithrombin-III-Komplexe. In: Bruhn HD (Hrsg). 6. Kongress der
Gesellschaft für Thrombose- und Hämostaseforschung. Schattauer, Stuttgart 1990; 109-111
26
Smith O P, White B.
Infectious purpura fulminans: Diagnosis and treatment.
Brit J Haematol.
1999;
104
202-207
27 Stenflo J. The biochemistry of protein C. In: Bertina RM (Hrsg). Protein C and
related proteins. Churchill Livingstone, Edinburgh 1988; 21-54
28
Tait R C, Walker I D, Reitsma P H, Islam S I, McCall F, Poort S R, Conkie J A, Bertina R M.
Prevalence of protein C deficiency in the healthy population.
Thromb Haemost.
1995;
73
87-93
29
Tuddenham E G, Takase T, Thomas A E, Awidi A S, Madanat F F, Abu Hajir M M, Kernhoff P B,
Hoffbrand A V.
Homozygous protein C deficiency with delayed onset of symptoms at 7 to 10 months.
Thromb Res.
1989;
53
475-484
30
Vincent J L, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart C K,
Suter P M, Thijs L G.
The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure.
On behalf of the Working Group on Sepsis-Related Problems of the European Society
of the Intensive Care Medicine.
Intensive Care Med.
1996;
22
707-710
31
Vincent J L, De Mendonca A, Cantraine F, Moreno R, Takala J, Suter P M, Sprung C L,
Colardyn F, Blecher S.
Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive
care units: results of a multicenter, prospective study. Working group on “sepsis-related
problems” of the European Society of Intensive Care Medicine.
Crit Care Med.
1998;
26
1793-1800
32
Wheeler A P, Bernhard G R.
Treating patients with severe Sepsis.
N Engl J Med.
1999;
340
207-214
33
Whithe B, Livingstone W, Murphy C, Hodgson A, Rafferty M, Smith O P.
An open-label study of the role of adjuvant hemostatic support with protein C replacement
therapy in purpura fulminans-associated meningococcemia.
Blood.
2000;
96
3719-3724
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