Does the Thrombin Generation Test Performed During the Pharmacokinetic Profile of the Substitutive Factor VIII Bring Benefits to the Personalized Treatment of Pediatric Patients and Adult Hemophilia A Patients Under Prophylaxis ?

In the context of hemophilia, it is well know that the level of factor VIII alone does not reflect the clinical phenotype of the patients in an accurate way. At equal factor VIII levels, certain patients will bleed more than others.

The thrombin generation test (TGT) is a test that seems to provide a better prediction of the overall hemostatic status of an individual patient. In a previous study, the investigators have established normal reference values of the thrombin generation curve in children aged 6 months to 16 years and adults. The goal was to evaluate the use of this test in different clinical contexts and in severe hemophilia patients in particular. A pilot study showed that the patients having a thrombin generation <150 had a severe phenotype, whether those who received an appropriate prophylaxy had a thrombin generation superior to 150.

Moreover, the investigators now have access to a software tool that allows them to individually determine the pharmacokinetic profile of the factor VIII injected to each patient. The factor VIII concentration is measured at injection and 30 minutes, 1 hour, 2 hours and 24 hours afterwards. The introduction of these concentrations in the software allows to obtain the half-life of factor for a given patient, the maximum peak, and the minimum factor level (though level). The injected dosis might be sufficient (disappearance of substantial diminution of the bleedings) or unsufficient (persisting bleeding) for a given patient.

This study aims:

• to measure the pharmacokinetic profile of factor VIII by two different methods, the time-based method and the chromogenic method
• to correlate the results with the TGT results obtained at the same time points and determine which method gives the best correlation
• to link the clinical symptomatology (improved symptomatology or not) with the TGT results
• to determine which minimal TGT result is linked to a minimal bleeding rate
• to adapt the prophylactic dosis of the patient in a personalized way.

Study Overview

• Status: Recruiting
• Conditions: Hemophilia
• Intervention / Treatment: Device: Chronometric method; Device: Chromogenic method; Device: Thrombin generation test (TGT)

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Anne Demulder, MD; Phone Number: 024773990; Email: Anne.DEMULDER@chu-brugmann.be

Study Locations

• Belgium
  • Brussels, Belgium, 1020
    • Recruiting
    • CHU Brugmann
    • Contact: Anne Demulder, MD; Phone Number: 024773990; Email: Anne.DEMULDER@chu-brugmann.be
    • Principal Investigator: Anne Demulder, MD
  • Brussels, Belgium, 1020
    • Recruiting
    • Huderf
    • Principal Investigator: Anne Demulder, MD
    • Contact: Anne Demulder, MD; Phone Number: 02 477 39 90; Email: Anne.DEMULDER@chu-brugmann.be
  • Liège, Belgium, 4000
    • Recruiting
    • Centre Hospitalier Régional de la Citadelle de Liège
    • Contact: Jean-Marc Minon, MD; Phone Number: 32 4 223 87 81; Email: jean.marc.minon@chrcitadelle.be
    • Principal Investigator: Jean-Marc Minon, MD
  • Liège, Belgium, 4000
    • Recruiting
    • CHC de Liège
    • Contact: Laure Gilis, MD; Phone Number: 04.224.89.90; Email: Laure.gilis@chc.be
    • Principal Investigator: Laure Gilis, MD
  • Liège, Belgium, 4000
    • Recruiting
    • CHU Liège Sart Tilman
    • Contact: Pierre Peters, MD; Phone Number: 32 4 366.75.36; Email: pierre.peters@chu.ulg.ac.be
    • Principal Investigator: Pierre Peters, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients with severe or moderate hemophilia, on prophylaxis, and suffering from bleedings.

Exclusion Criteria:

• Patients with difficult venous access
• Patients who have had surgery or trauma in the month before, patients with acute disease (infection, inflammation)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: hemophilia; Patients with severe hemophilia (or moderate hemophilia if presence of hemorrhages) under prophylaxy and subjected to a pharmacokinetic profile of factor VIII

Device: Chronometric method; Chronometric method of FVIII dosage on STA-R PLC automate (reactive Cephascreen STAGO, Unicalibrateur STAGO, plasma deficient Cryopep, Controls STAGO); Device: Chromogenic method; Chromogenic FVIII assay method ( "BIOPHEN FVIII: C" and "BIOPHEN Factor IX" of the firm Hyphen BioMed); Device: Thrombin generation test (TGT); Briefly: the measurement of thrombin generation is performed by the technique of calibrated and automated Thrombinography (CAT) developed by Hemker HC. This technique allows the simultaneous analysis of multiple samples using a fluorometer (Fluoroscan Ascent, ThermoLabsystems OY, Helsinki, Finland) and a Thrombinoscope® software that converts the fluorescence intensity obtained by concentration of active thrombin. The reagent "PPP-reagent Low" respectively containing 1pm FT and 4μM phospholipid (PL) as a final concentration will be used.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Factor VIII blood concentration - chronometric method	Chronometric method of FVIII dosage on STA-R PLC automate (reactive Cephascreen STAGO, Unicalibrateur STAGO, plasma deficient Cryopep, Controls STAGO)	baseline: at factor VIII injection
Factor VIII blood concentration - chronometric method	Chronometric method of FVIII dosage on STA-R PLC automate (reactive Cephascreen STAGO, Unicalibrateur STAGO, plasma deficient Cryopep, Controls STAGO)	30 minutes after factor VIII injection
Factor VIII blood concentration - chronometric method	Chronometric method of FVIII dosage on STA-R PLC automate (reactive Cephascreen STAGO, Unicalibrateur STAGO, plasma deficient Cryopep, Controls STAGO)	60 minutes after factor VIII injection
Factor VIII blood concentration - chronometric method	Chronometric method of FVIII dosage on STA-R PLC automate (reactive Cephascreen STAGO, Unicalibrateur STAGO, plasma deficient Cryopep, Controls STAGO)	120 minutes after factor VIII injection
Factor VIII blood concentration - chronometric method	Chronometric method of FVIII dosage on STA-R PLC automate (reactive Cephascreen STAGO, Unicalibrateur STAGO, plasma deficient Cryopep, Controls STAGO)	24h after factor VIII injection
Factor VIII blood concentration - Chromogenic method	Chromogenic FVIII assay method ( "BIOPHEN FVIII: C" and "BIOPHEN Factor IX" of the firm Hyphen BioMed)	baseline: at factor VIII injection
Factor VIII blood concentration - Chromogenic method	Chromogenic FVIII assay method ( "BIOPHEN FVIII: C" and "BIOPHEN Factor IX" of the firm Hyphen BioMed)	30 minutes after factor VIII injection
Factor VIII blood concentration - Chromogenic method	Chromogenic FVIII assay method ( "BIOPHEN FVIII: C" and "BIOPHEN Factor IX" of the firm Hyphen BioMed)	60 minutes after factor VIII injection
Factor VIII blood concentration - Chromogenic method	Chromogenic FVIII assay method ( "BIOPHEN FVIII: C" and "BIOPHEN Factor IX" of the firm Hyphen BioMed)	120 minutes after factor VIII injection
Factor VIII blood concentration - Chromogenic method	Chromogenic FVIII assay method ( "BIOPHEN FVIII: C" and "BIOPHEN Factor IX" of the firm Hyphen BioMed)	24h after factor VIII injection
total thrombin generation	the measurement of thrombin generation is performed by the technique of calibrated and automated Thrombinography (CAT) developed by Hemker HC. This technique allows the simultaneous analysis of multiple samples using a fluorometer (Fluoroscan Ascent, ThermoLabsystems OY, Helsinki, Finland) and a Thrombinoscope® software that converts the fluorescence intensity obtained by concentration of active thrombin.	baseline: at factor VIII injection
total thrombin generation	the measurement of thrombin generation is performed by the technique of calibrated and automated Thrombinography (CAT) developed by Hemker HC. This technique allows the simultaneous analysis of multiple samples using a fluorometer (Fluoroscan Ascent, ThermoLabsystems OY, Helsinki, Finland) and a Thrombinoscope® software that converts the fluorescence intensity obtained by concentration of active thrombin.	30 minutes after factor VIII injection
total thrombin generation	the measurement of thrombin generation is performed by the technique of calibrated and automated Thrombinography (CAT) developed by Hemker HC. This technique allows the simultaneous analysis of multiple samples using a fluorometer (Fluoroscan Ascent, ThermoLabsystems OY, Helsinki, Finland) and a Thrombinoscope® software that converts the fluorescence intensity obtained by concentration of active thrombin.	60 minutes after factor VIII injection
total thrombin generation	the measurement of thrombin generation is performed by the technique of calibrated and automated Thrombinography (CAT) developed by Hemker HC. This technique allows the simultaneous analysis of multiple samples using a fluorometer (Fluoroscan Ascent, ThermoLabsystems OY, Helsinki, Finland) and a Thrombinoscope® software that converts the fluorescence intensity obtained by concentration of active thrombin.	120 minutes after factor VIII injection
total thrombin generation	the measurement of thrombin generation is performed by the technique of calibrated and automated Thrombinography (CAT) developed by Hemker HC. This technique allows the simultaneous analysis of multiple samples using a fluorometer (Fluoroscan Ascent, ThermoLabsystems OY, Helsinki, Finland) and a Thrombinoscope® software that converts the fluorescence intensity obtained by concentration of active thrombin.	24h after factor VIII injection

Collaborators and Investigators

• Sponsor: Brugmann University Hospital
• Investigators: Principal Investigator: Anne Demulder, MD, CHU Brugmann

Publications and helpful links

General Publications

• Hemker HC, Giesen P, AlDieri R, Regnault V, de Smed E, Wagenvoord R, Lecompte T, Beguin S. The calibrated automated thrombogram (CAT): a universal routine test for hyper- and hypocoagulability. Pathophysiol Haemost Thromb. 2002 Sep-Dec;32(5-6):249-53. doi: 10.1159/000073575.
• Filippin L, Debaugnies F, Noubouossie D, Le PQ, Ferster A, Demulder A. [Thrombin generation test: establishment of reference values according to age and tissue factor concentration is essential before implementation into the laboratory]. Rev Med Brux. 2011 Mar-Apr;32(2):69-73. French.
• van den Berg HM, De Groot PH, Fischer K. Phenotypic heterogeneity in severe hemophilia. J Thromb Haemost. 2007 Jul;5 Suppl 1:151-6. doi: 10.1111/j.1538-7836.2007.02503.x.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2017
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: June 14, 2016
• First Submitted That Met QC Criteria: June 14, 2016
• First Posted (Estimated): June 17, 2016

Study Record Updates

• Last Update Posted (Actual): July 28, 2023
• Last Update Submitted That Met QC Criteria: July 27, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: hemophilia; factor VIII; thrombin generation test
• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Hemophilia A; Hemostatics; Coagulants; Thrombin
• Other Study ID Numbers: CHUB-PK TGT