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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
URN: urn:nbn:de:hebis:04-z2012-09333
DOI: https://doi.org/10.17192/z2012.0933
DDC: Medizin, Gesundheit
Titel(trans.):Thrombin generation by asparaginase
Publikationsdatum:2012-11-16
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

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

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.

Summary:
The bacterial enzyme asparaginase is an important antineoplastic drug used for the treatment of a variety of lymphoproliferative disorders and lymphomas, in particular acute lymphoblastic leukemia. Its capacity to modulate the plasmatic coagulation is a known clinical complication. As a side effect the asparaginase might pathologically activate or inactivate the intrinsic coagulation. The aim of the present research work is to analyze the action of different asparaginase drugs on the plasmatic thrombin generation in 118 individual normal plasma samples using the new ultra specific, ultra-sensitive and precise thrombin generation test recalcified coagulation activity assay (RECA). Three different asparaginases were utilized for the laboratory analytical experiments; two native Escherichia coli (E. coli) asparaginases and an E. coli asparaginase coupled to polyethylene glycol (PEG-asparaginase). The two native E. coli asparaginases only differed in their time of production (the first lot produced would be referred to as the old lot, whereas the second lot produced would be called the new lot). The RECA diagnosed the coagulation modulating (especially the prothrombotic) power of the present asparaginases. Therefore, the approximate (approx.) 200 % stimulatory concentration (SC200) or the approx. 50 % inhibitory concentration (IC50) was determined. The SC200 is the plasmatic asparaginase concentration that results in 200 % of the original thrombin generation. The IC50 is the asparaginase concentration that results in only 50 % of the original thrombin generation. The supplemented plasmas became procoagulant or anticoagulant, or stayed resistant to hemostasis modulation by asparaginase. The old lot asparaginase was procoagulant in every plasma sample with approx. SC200-values of 5.8 ± 5.4 unit per milliliter (U/ml) (mean value ± 1 standard deviation) [MV ± 1 SD]. By contrast, only 51 % of the plasma samples that were supplemented with the new lot asparaginase became procoagulant, 24.5 % of the supplemented plasmas had a combination of SC200 and IC50 (depending on coagulation reaction time), 21 % had just an IC50 (MV = 6 U/ml) and 3,5 % of the plasmas were resistant towards modulation of coagulation. This means that the new lot has less thrombotic potential compared to the old one. In contrast the analyzed IC50-values point out that it could have an anticoagulant effect on the plasmatic blood coagulation of the individual patient, which could lead to bleeding complications. The PEG-asparaginase has been described as a modified molecule of asparaginase with less side effects than unmodified native asparaginase. The comparative plasma samples supplemented with both asparaginase preparations demonstrated no difference between the native E. coli asparaginase and the PEG-asparaginase with regard to the blood coagulation. The approx. SC200-values of both asparaginases correlated with a correlation coefficient greater than 0.9 . This high correlation and the similar mean values indicated, that respective plasmatic thrombin generation the rather expensive modified PEG-asparaginase behaved similar as the native asparaginase. Thus the hemostatic system of every patient responds individually to certain asparaginase preparations. Using the RECA, the patient’s individual coagulation triggering response to asparaginase can be previewed and the drug dosage could be adjusted: it is suggested to diagnose the patient´s individual coagulation response to bacterial asparaginase prior to and during the administration of the drug. Patients with an increased risk for asparaginase-induced thrombosis should be treated with prophylactic to therapeutic concentrations of low molecular weight heparin (LMWH).

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