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Titel:Thrombin-Generierung durch Asparaginase
Autor:Chalkitis, Danuta
Weitere Beteiligte: Stief, T. (Dr.)
Veröffentlicht:2012
URI:https://archiv.ub.uni-marburg.de/diss/z2012/0933
DOI: https://doi.org/10.17192/z2012.0933
URN: urn:nbn:de:hebis:04-z2012-09333
DDC: Medizin
Titel (trans.):Thrombin generation by asparaginase
Publikationsdatum:2012-11-16
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Thrombin, SC200, Thrombin, Asparaginase, SC200, Asparaginase, RECA, RECA

Zusammenfassung:
Das bakterielle Enzym Asparaginase ist ein sehr effektives Zytostatikum in der Therapie lymphoproliferativer Erkrankungen. Die Eigenschaft des Enzyms, die plasmatische Blutgerinnung zu verändern, ist eine bekannte klinische Komplikation. Nebenwirkungen der Asparaginase können sowohl Blutungen als auch disseminierte intravaskuläre Thrombosen sein. Das Ziel der vorliegenden laboranalytischen Arbeit war es, die Auswirkungen unterschiedlicher Asparaginasen auf die plasmatische intrinsische Thrombin-Generierung in 118 individuellen normalen Plasmaproben mittels eines neuen hochsensitiven, hochspezifischen Thrombin-Generierungstests, dem „recalcified coagulation activity assay“ (RECA) zu bestimmen. Für die Versuche wurden drei verschiedene Asparaginasen verwendet; zwei native E. coli Asparaginasen, die sich nur in ihrem Herstellungs- datum unterschieden (alte Charge/neue Charge) und eine modifizierte Form der Asparaginase, die Polyethylenglykol (PEG)-Asparaginase, eine E. coli Asparaginase gekoppelt an Polyethylenglykol. Mit Hilfe des RECA wurden die Auswirkungen (besonders die prothrombotische) der jeweiligen Asparaginasepräparation auf die plasmatische Gerinnung ermittelt. Dafür wurde für jedes normale Plasma die approximative 200 % stimulatory concentration (approx. SC200) oder die approximative 50 % inhibitory concentration (approx. IC50) bestimmt. Die approx. SC200 ist die Asparaginasekonzentration, bei der 200 % der Thrombin-Generierung von unsupplementiertem Plasma erreicht werden. Die approx. IC50 ist die Asparaginase-Konzentration, bei der nur noch 50 % der Thrombin-Generierung von unsupplementiertem Plasma erreicht werden. Die supplementierten Plasmen verhielten sich prokoagulatorisch, antikoagulatorisch oder Gerinnungs-resistent hinsichtlich der Hämostase-modulierenden Eigenschaft der Asparaginase. Bei der alten Charge Asparaginase zeigten alle Proben uneingeschränkt ein prothrombotisches Verhalten mit approx. SC200-Werten von 5,8 ± 5,4 U/ml (Mittelwert ± 1 Standardabweichung; Bereich: 1 - 25 U/ml). Im Gegensatz dazu demonstrierten bei der neuen Charge nur 51 % der untersuchten Plasmen ein prothrombotisches Verhalten, 24,5 % besaßen eine Kombination aus IC50 und SC200 (abhängig von der Gerinnungs-Reaktions-Zeit), 21 % der Proben verfügten über eine alleinige IC50 (Mittelwert = 6 U/ml) und 3,5 % der Plasmen erwiesen sich als gerinnungs- modulationsresistent. Dies bedeutet, dass die neue Charge Asparaginase im Vergleich zur alten weniger thrombogen wirkt. Hingegen deuten die ermittelten IC50-Werte jedoch an, dass die neue Charge empfindliche Plasmen stark antikoagulieren könnte. Die PEG-Asparaginase als modifizierte Form der nativen E. coli Asparaginase wird als weniger nebenwirkungsreich beschrieben. Hinsichtlich der Gerinnung ergab sich jedoch kein signifikanter Unterschied zwischen der nativen E. coli Asparaginase und der PEG-Asparaginase. Beide modulierten gleichermaßen die Gerinnung. Die approx. SC200-Werte von beiden Asparaginasen korrelierten mit einem Korrelationskoeffizienten größer 0,9. Diese hohe Korrelation und die ähnlichen Durchschnittswerte verdeutlichen, dass sich die (teurere) PEG-Asparaginase bezüglich der plasmatischen Thrombin-Generierung ähnlich wie die native E. coli Asparaginase verhielt. Die Ergebnisse zeigen, dass das Hämostase-System jedes Patienten individuell empfindlich auf die jeweilige Asparaginasepräparation reagiert. Mit Hilfe des RECA kann die individuelle prothrombotische Antwort des intrinsischen Gerinnungssystems jedes einzelnen Patienten auf Asparaginase vor Gabe bestimmt werden. Es sollte der differenzierte Gerinnungsstatus des individuellen Patienten und seine Veränderung durch Asparaginase in vitro vor und während der Therapie ermittelt werden. So kann insbesondere eine prokoagulatorische Tendenz des Zytostatikums auf das Patientenplasma diagnostiziert werden. Dies erlaubt vor Asparaginase-Gabe Risikopatienten zu erkennen und ggf. mit niedermolekularem Heparin prophylaktisch stärker entgegenzusteuern.

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