Antithrombin (AT) - Wirkung:
Experimentelle und klinische
Ergebnisse

Zusammenfassung.

Zielsetzung: Der Einsatz von Antithrombin (AT, Antithrombin III) bei Patienten mit Verbrauchskoagulopathie (DIC) und/oder Sepsis wird wegen inkonsistenter experimenteller und klinischer Ergebnisse hinsichtlich der Beeinflussung der Letalität kontrovers diskutiert. Inzwischen sind zahlreiche klinische Studien beendet worden, und experimentelle Untersuchungen haben den Wirkmechanismus des AT weiter aufgeklärt. In einer systematischen Zusammenfassung der Literatur (Medline, Handsuche) werden die gesicherten Ergebnisse der Physiologie und Pathophysiologie der AT-Wirkung sowie die experimentellen und klinischen Effekte der AT-Zufuhr analysiert. Ergebnisse: AT bindet physiologischerweise an endotheliale Mucopolysaccharide, die Glykosaminoglykane (GAG). Erst diese Bindung führt zu einer Konformationsänderung des AT, die seine Aktivität gegenüber aktivierten Gerinnungsfaktoren steigert. Experimente zeigen, daß die AT-Zufuhr die DIC verkürzt und zu geringeren Fibrinablagerungen in den Organen führt. Die hochdosierte Zufuhr von AT - im Experiment werden bei mehr als 250 E kg^-1 i. v. in der Regel nach ca. 4 h Aktivitäten von 200 bis 500 % erreicht - senkt die Letalität bei DIC und hat außerdem antiinflammatorische Effekte, die wahrscheinlich auf einer Steigerung der endothelialen Prostacyclinsynthese durch Bindung des AT an den endothelialen GAGs beruhen. Diese Effekte bestehen in einer Senkung der Konzentration proinflammatorischer Mediatoren, der Verminderung der leukozytären Adhäsion (rolling und sticking) und der Verbesserung von Organfunktionen. Im Experiment verhindert Heparin diese gewünschten Effekte, da es AT bindet und es somit von seinen endothelialen Bindungspartnern, den Glykosaminoglykanen, fernhält. Die Zufuhr von AT-Konzentraten führt bei Patienten mit DIC zu einer signifikanten Verringerung der laboratoriumsdiagnostisch erkennbaren pathologischen Gerinnungsaktivierung. Auch bei septischen Patienten kommt es zu einer Verkürzung der DIC und zu einer Verbesserung von Organfunktionen. Signifikante Überlebensvorteile konnten jedoch weder für Patienten mit DIC noch in einer multizentrischen Studie mit über 2000 Patienten mit Sepsis nachgewiesen werden. Schlussfolgerung: Die AT-Substitution senkt im Experiment und beim Menschen den Aktivierungsgrad der Prokoagulatoren und kann damit die systemische Thrombinbildung signifikant reduzieren. Als therapeutische Option ist die Verkürzung der Dauer einer klinisch und laboratoriumsmedizinisch definierten DIC durch AT-Konzentrate anzusehen, die nicht nur experimentell, sondern auch bei Patienten nachgewiesen ist. An den bisher untersuchten Patientenzahlen konnte eine statistische Signifikanz hinsichtlich der Verbesserung der Letalität der Patienten allerdings nicht gezeigt werden. Die Diagnose „Sepsis / SIRS” stellt nach den jetzt vorliegenden Studienergebnissen keine Indikation für eine hochdosierte AT-Substitution mit 30.000 E über 4 Tage dar.

Actions of Antithrombin (AT): Experimental and Clinical Results.

Objective: Experimental and clinical effects of antithrombin (AT) have been studied widely. However, the therapeutic use of antithrombin concentrates remains controversial due to a major discrepancy between experimental and clinical data concerning AT induced effects on mortality. Meanwhile, studies including larger numbers of patients have been performed, and experimental data have elucidated the mechanisms by which AT may induce antiinflammatory effects. A systematical review of experimental and clinical studies was performed using databases (Medline) and hand-search. Results: Binding of AT to endothelial glycosaminoglycans has been established as a prerequisite for coagulation factor inhibition and induction of endothelial prostacyclin production. Heparin shifts AT activity away from endothelium related effects towards systemic anticoagulation. Animals given more than 250 U AT show significantly reduced mortality in DIC and sepsis or septic shock. Antiinflammatory effects are mediated by prostacyclin and include the reduction of proinflammatory mediators, the reduction of leucocyte rolling and sticking, and improvement of organ function. AT concentrates have been shown to reduce procoagulant turnover in patients with DIC. Laboratory markers of DIC normalize within significantly shorter time periods when AT is administered. In septic patients DIC is markedly attenuated and organ function can be improved significantly. However, survival has never been shown to improve with AT-therapy. Even a multicenter trial including more than 2000 patients with sepsis could not demonstrate a better outcome when 30.000 U AT were given within four days. Of note, 90-day mortality was significantly reduced only in patients without heparin. Whether heparin abolishes antiinflammatory effects of AT in man deserves further study. Conclusions: AT-infusion in patients with DIC aimed at activities of 80-100% reduces procoagulant turnover and hence attenuates disseminated fibrin deposition and coagulation factor and inhibitor consumption. So far, high-dose AT-infusions for 4 days in septic patients without DIC are not indicated since no effect on survival could be shown.

Schlüsselwörter:

Antithrombin - Blutgerinnung - DIC, disseminierte intravasale Gerinnung - Sepsis - Septischer Schock

Key words:

Antithrombin (Antithrombin III) - Coagulation - DIC - Sepsis - Septic Shock

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