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Monitoring the bioavailability of FEIBA with a thrombin generation assay

Varadi, K ; Negrier, C ; Berntorp, Erik LU ; Astermark, Jan LU ; Bordet, JC ; Morfini, M ; Linari, S ; Schwarz, HP and Turecek, PL (2003) In Journal of Thrombosis and Haemostasis 1(11). p.2374-2380
Abstract
Background: Hemophilia A patients with inhibitors are generally treated with preparations containing activated coagulation factors to achieve hemostasis by bypassing factor (F)VIII. Objectives: We developed an assay for monitoring the kinetic of thrombin generation in human FVIII inhibitor plasma reconstituted in vitro with activated prothrombin complex concentrate, FEIBA, and in plasma samples from hemophilia A patients taken after FEIBA treatment. Patients and methods: For pharmacokinetic studies three patients with severe hemophilia A and with a high-titer inhibitor received a single dose of FEIBA. Repeated FEIBA treatment was monitored in one patient with acquired hemophilia A. Coagulation was triggered in citrated plasma by adding a... (More)
Background: Hemophilia A patients with inhibitors are generally treated with preparations containing activated coagulation factors to achieve hemostasis by bypassing factor (F)VIII. Objectives: We developed an assay for monitoring the kinetic of thrombin generation in human FVIII inhibitor plasma reconstituted in vitro with activated prothrombin complex concentrate, FEIBA, and in plasma samples from hemophilia A patients taken after FEIBA treatment. Patients and methods: For pharmacokinetic studies three patients with severe hemophilia A and with a high-titer inhibitor received a single dose of FEIBA. Repeated FEIBA treatment was monitored in one patient with acquired hemophilia A. Coagulation was triggered in citrated plasma by adding a low concentration of tissue factor/phospholipid complex and CaCl2 in the presence of a fluorogenic thrombin substrate. The intensity of the fluorescence signal (FU) was continuously monitored, and the rate of increase in the fluorescence signal for every time point, which reflects the actual thrombin concentrations, was calculated. Results: The maximum rate of substrate conversion, which indicates the highest thrombin concentration, was approximately 1900 FU min(-1) in a normal plasma pool. Practically no thrombin generation was observed in the FVIII inhibitor plasma, but when it was spiked with FEIBA, the rate and the peak of thrombin generation increased dose-dependently to close to normal. Plasma samples from FVIII inhibitor patients treated with a single dose of FEIBA had an improved thrombin maximum within an hour after treatment, which gradually returned to baseline values with a half-life of 4-7 h. Changes in the characteristic parameters of thrombin generation coincided with the repeated administration of FEIBA in a patient with acquired hemophilia A. Conclusions: This assay enables the pharmacodynamic and pharmacokinetic properties of bypassing therapies to be monitored, thus helping to optimize treatment. (Less)
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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
thrombin generation, pharmacokinetics, FEIBA, hemophilia A inhibitor
in
Journal of Thrombosis and Haemostasis
volume
1
issue
11
pages
2374 - 2380
publisher
Elsevier
external identifiers
  • wos:000186822600019
  • pmid:14629472
  • scopus:3242737794
ISSN
1538-7933
DOI
10.1046/j.1538-7836.2003.00450.x
language
English
LU publication?
yes
additional info
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Emergency medicine/Medicine/Surgery (013240200), Clinical Coagulation Research Unit (013242510)
id
8ca86d19-ef47-41f8-8878-596941846eb1 (old id 899723)
date added to LUP
2016-04-01 12:28:31
date last changed
2025-01-02 19:14:40
@article{8ca86d19-ef47-41f8-8878-596941846eb1,
  abstract     = {{Background: Hemophilia A patients with inhibitors are generally treated with preparations containing activated coagulation factors to achieve hemostasis by bypassing factor (F)VIII. Objectives: We developed an assay for monitoring the kinetic of thrombin generation in human FVIII inhibitor plasma reconstituted in vitro with activated prothrombin complex concentrate, FEIBA, and in plasma samples from hemophilia A patients taken after FEIBA treatment. Patients and methods: For pharmacokinetic studies three patients with severe hemophilia A and with a high-titer inhibitor received a single dose of FEIBA. Repeated FEIBA treatment was monitored in one patient with acquired hemophilia A. Coagulation was triggered in citrated plasma by adding a low concentration of tissue factor/phospholipid complex and CaCl2 in the presence of a fluorogenic thrombin substrate. The intensity of the fluorescence signal (FU) was continuously monitored, and the rate of increase in the fluorescence signal for every time point, which reflects the actual thrombin concentrations, was calculated. Results: The maximum rate of substrate conversion, which indicates the highest thrombin concentration, was approximately 1900 FU min(-1) in a normal plasma pool. Practically no thrombin generation was observed in the FVIII inhibitor plasma, but when it was spiked with FEIBA, the rate and the peak of thrombin generation increased dose-dependently to close to normal. Plasma samples from FVIII inhibitor patients treated with a single dose of FEIBA had an improved thrombin maximum within an hour after treatment, which gradually returned to baseline values with a half-life of 4-7 h. Changes in the characteristic parameters of thrombin generation coincided with the repeated administration of FEIBA in a patient with acquired hemophilia A. Conclusions: This assay enables the pharmacodynamic and pharmacokinetic properties of bypassing therapies to be monitored, thus helping to optimize treatment.}},
  author       = {{Varadi, K and Negrier, C and Berntorp, Erik and Astermark, Jan and Bordet, JC and Morfini, M and Linari, S and Schwarz, HP and Turecek, PL}},
  issn         = {{1538-7933}},
  keywords     = {{thrombin generation; pharmacokinetics; FEIBA; hemophilia A inhibitor}},
  language     = {{eng}},
  number       = {{11}},
  pages        = {{2374--2380}},
  publisher    = {{Elsevier}},
  series       = {{Journal of Thrombosis and Haemostasis}},
  title        = {{Monitoring the bioavailability of FEIBA with a thrombin generation assay}},
  url          = {{http://dx.doi.org/10.1046/j.1538-7836.2003.00450.x}},
  doi          = {{10.1046/j.1538-7836.2003.00450.x}},
  volume       = {{1}},
  year         = {{2003}},
}