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 ?

Study Overview
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Brief Summary
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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.

Official Title
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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 ?

Conditions
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Hemophilia

Intervention / Treatment
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* Device: Chronometric method
* Device: Chromogenic method
* Device: Thrombin generation test (TGT)


Participation Criteria
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Eligibility Criteria
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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)
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: hemophilia<br>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<br>* Chronometric method of FVIII dosage on STA-R PLC automate (reactive Cephascreen STAGO, Unicalibrateur STAGO, plasma deficient Cryopep, Controls STAGO)<br>Device: Chromogenic method<br>* Chromogenic FVIII assay method ( BIOPHEN FVIII: C and BIOPHEN Factor IX of the firm Hyphen BioMed)<br>Device: Thrombin generation test (TGT)<br>* 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.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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thrombin generation test, factor VIII, hemophilia