Larsen, Malte Selch;
Vestergaard Juul, Rasmus;
Zintner, Shannon M.;
T. Kristensen, Annemarie;
Margaritis, Paris;
Kjelgaard‐Hansen, Mads;
Wiinberg, Bo;
Simonsson, Ulrika S. H.;
Kreilgaard, Mads
Rotational thromboelastometry can predict the probability of bleeding events in a translational rat model of haemophilia A following gene‐based FVIIa prophylaxis
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Medientyp:
E-Artikel
Titel:
Rotational thromboelastometry can predict the probability of bleeding events in a translational rat model of haemophilia A following gene‐based FVIIa prophylaxis
Beteiligte:
Larsen, Malte Selch;
Vestergaard Juul, Rasmus;
Zintner, Shannon M.;
T. Kristensen, Annemarie;
Margaritis, Paris;
Kjelgaard‐Hansen, Mads;
Wiinberg, Bo;
Simonsson, Ulrika S. H.;
Kreilgaard, Mads
Erschienen:
Wiley, 2020
Erschienen in:
Haemophilia, 26 (2020) 1, Seite 164-172
Sprache:
Englisch
DOI:
10.1111/hae.13899
ISSN:
1351-8216;
1365-2516
Entstehung:
Anmerkungen:
Beschreibung:
AbstractIntroductionMonitoring of clinical effectiveness of bypassing agents in haemophilia patients is hampered by the lack of validated laboratory assays. Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) have been evaluated for predicting clinical effectiveness of bypassing agents, however, with limited success.AimApplication of a longitudinal model‐based approach may allow for a quantitative characterization of the link between ROTEM parameters and the probability of bleeding events.MethodsWe analyse longitudinal data from haemophilia A rats receiving gene‐based FVIIa prophylaxis in terms of total circulatory levels of FVII/FVIIa, clotting time (CT) measured using ROTEM and the probability of bleeding events.ResultsUsing population pharmacokinetic‐pharmacodynamic (PKPD) modelling, a PK‐CT‐repeated time‐to‐event (RTTE) model was developed composed of three submodels (a) a FVII/FVIIa PK model, (b) a PK‐CT model describing the relationship between predicted FVIIa expression and CT and (c) a RTTE model describing the probability of bleeding events as a function of CT. The developed PK‐CT‐RTTE model accurately described the vector dose‐dependent plasma concentration‐time profile of total FVII/FVIIa and the exposure‐response relationship between AAV‐derived FVIIa expression and CT. Importantly, the developed model accurately described the occurrence of bleeding events over time in a quantitative manner, revealing a linear relationship between predicted change from baseline CT and the probability of bleeding events.ConclusionUsing PK‐CT‐RTTE modelling, we demonstrated that ROTEM parameters can accurately predict the probability of bleeding events in a translational animal model of haemophilia A.