Gerinnungstherapeutische Ansätze bei Sepsis

Zusammenfassung

Ausgehend von dem zunehmenden Verständnis der bei Patienten mit Sepsis beobachteten Gerinnungsstörung sowie den bisher erfolglosen Versuchen durch Modulation der Zytokinantwort die Prognose von Sepsispatienten zu verbessern, wurden in den vergangenen Jahren gerinnungstherapeutische Ansätze der Sepsisbehandlung intensiver untersucht. Während die Phase-III-Studien mit den Gerinnungsinhibitoren, Antithrombin und TFPI (tissue factor pathway inhibitor) für das Gesamtkollektiv der Patienten mit schwerer Sepsis keine Prognoseverbesserung zeigten, fand sich für rekombinantes humanes aktiviertes Protein C (rhAPC) eine signifikante, 19%ige relative Reduktion der Sterblichkeit. Weitere Analysen verdeutlichten, dass die Therapie mit rhAPC insbesondere bei Patientengruppen mit hoher Sterblichkeit im Plazeboarm zu klinisch relevanten Ergebnisverbesserungen führt.

Die durch natürliche Gerinnungsinhibitoren bewirkte Hemmung der Gerinnselbildung, spiegelt sich in allen drei Studien in einer, z.T. signifikanten Zunahme der Sepsis-immanenten Blutungsneigung wider, wobei im Falle von Antithrombin die gleichzeitige Heparingabe das Blutungsrisiko deutlich erhöht und möglicherweise dem erhofften Antithrombineffekt auf die Patientenprognose entgegenwirkt. Hinweise auf einen möglicherweise positiven Effekt von Heparin in den Plazeboarmen einerseits, andererseits auf nachteilige Effekte von Heparin in den Therapiearmen (v. a. mit Antithrombin bzw. TFPI) führen zur kontroversen Diskussion des Nutzen/Risiko-Verhältnisses von Heparin in prophylaktischer Dosis bei Patienten mit schwerer Sepsis. Während die Bedeutung und optimale Applikation von Heparin bei schwerer Sepsis der weiteren Klärung bedarf, haben die Studiendaten zu rhAPC zur Zulassung dieses Therapieprinzips und seiner Verankerung in den Empfehlungen zur Behandlung von Patienten mit schwerer Sepsis geführt.

Summary

Based on the increasing knowledge of defects in haemostasis in patients with sepsis as well as on the nonconclusive results of studies which tried to increase the prognosis by modulating cytokine response of the patients, in the last years the impact of therapeutic modulation of coagulation in sepsis has been investigated. In contrast to the results of phase III studies with the coagulation inhibitors antithrombin and tissue factor pathway inhibitor recombinant human activated protein C (rhAPC) resulted in a significant reduction in mortality for the whole study population. Data analyses showed, that treatment with rhAPC was clinically beneficial especially in patient groups who showed a high mortality in the placebo arm.

Inhibition of thrombus formation due to the therapy with natural coagulation inhibitors resulted in an increase of sepsis-immanent haemorrhage, which became significant in some studies. Treatment with antithrombin and heparin resulted in a considerable increase in bleeding complications and on the other hand, may have antagonized the expected effect of antithrombin on the patient's prognosis. Some results suggesting beneficial effects of heparin on patient prognosis in the placebo arms and on the other hand negative effects of heparin in the verum arms – especially with antithrombin or tissue factor pathway inhibitor – let to a controversial discussion of the risk/benefit relation of heparin, given in prophylactic doses to patients with severe sepsis.

Whereas the impact and optimal application of heparin to patients with severe sepsis needs to be clarified study results with rhAPC resulted in the approval of this therapy and the implementation in the guidelines of the treatment of patients with severe sepsis.

Schlüsselwörter

Sepsis - Antithrombin - aktiviertes Protein C - TFPI - Heparin

Keywords

Sepsis - antithrombin - activated protein C - tisse factor pathway inhibitor - heparin

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