Thrombin Generation Numerical Models Validation in Haemophilic Case

Personalized therapy in haemophilia has not been reached yet. Treatment is substitutive and its doses are only based on the levels of deficient factor VIII (for haemophilia A) or IX (for haemophilia B). The bleeding severity is not only related to the factor deficiency but also to levels of other coagulation factors (e.g. factor X, II, AT or TFPI). It's necessary to take them into account in order to individualize treatments; and Thrombin Generation Assay (TGA) with the CAT method (Calibrated Automated Thrombography) is a good way because it measures the result of the coagulation cascade. TGA on Platelet Rich Plasma (PRP) is even closer to physiological conditions than on Platelet Poor Plasma (PPP) because platelet influence is represented. It has already been shown (at least in PPP) that the bleeding tendency in haemophilic patients is usually well correlated to TG. Some TG parameters are used to characterize the individual coagulation phenotype, the most important being the Endogenous Thrombin Potential (ETP) and the Lag Time (LT). A hemorrhagic profile usually provides a longer lag time and / or a lower ETP. However, only few studies tried to determine the influence of each coagulation factor and inhibitor on TG. They were done on Platelet Poor Plasma (PPP) or on lyophilized plasma. So the relation between coagulation factors and the different TG parameters remains to be determined, especially in the haemophilic case. It is possible, experimentally, to find the optimal dose of the factor to be added by measuring TG in samples with different factor VIII or IX concentrations, but this method would be time consuming and expensive, especially because it should be done for each haemophilic patient. A better way consists in using TG numerical models. For a set of initial factor levels they simulate the TG and its associated parameters. It is now essential to validate the existing models, especially in haemophilic cases, in order to see whether they are reliable and can be used in clinical practice afterwards.The objective of this study is to validate thrombin generation numerical models which could predict the factor VIII or IX activity correction to reach a thrombin generation sufficient to avoid bleeding. A comparison between the TG observed in haemophilic patients and the TG predicted by the models is needed to validate the models. In order to define a 'safe' TG i.e. sufficient to avoid bleeding, normal ranges of TG parameters have to be measured.

Study Overview

• Status: Completed
• Conditions: Haemophilia A; Haemophilia B
• Intervention / Treatment: Other: blood sampling

• Study Type: Observational
• Enrollment (Actual): 40

Contacts and Locations

Study Locations

• France
  • Saint-Etienne, France, 42055
    • CHU Saint-Etienne

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

• Sampling Method: Non-Probability Sample

Study Population

volunteers witch work in CHU Saint-Etienne

Description

Inclusion Criteria:

• Signed consent form
• Age between 18 and 45 years old
• Male
• no smoker

Exclusion Criteria:

• other clinical research protocol participation during the 3 months before inclusion
• Personal or familial history of hemorrhagic disease (parents, brothers and sisters
• Personal history of thrombosis (arterial or venous)
• Familial history of thrombosis before 45 years old (parents, brothers and sisters)
• Drug treatments of aspirin or anti-inflammatory type during the week before sampling
• Surgery the month before sampling
• Chronic pathology responsible for inflammatory syndrome
• Infectious episode in course

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Volunteers; Blood sampling : 1 blood punction of 36.5 ml for each volunteer	Other: blood sampling; Samplings will be taken on 4 citrated S-monovette tubes, 3 citrated tubes and 1 EDTA tube, namely 36.5 ml for each volunteer

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endogenous Thrombin Potential (ETP) predicted by numerical models	ETP (i.e. the aera under the thrombin generation curve, nM.min) measured in haemophilic patients is compared to ETP predicted by numerical models.	up to 12 monthes
Lag Time of the thrombin generation curve predicted by numerical models	Lag time (min) measured in haemophilic patients is compared to the lag time predicted by numerical models	up to 12 monthes
Peak value of the thrombin generation curve predicted by numerical models	Peak value (nmol thrombin) measured in haemophilic patients is compared to the peak value predicted by numerical models	up to 12 monthes
Time to peak (TTP) of the thrombin generation curve predicted by numerical models	TTP (min) measured in haemophilic patients is compared to TTP predicted by numerical models	up to 12 monthes
Velocity Index (V) of the thrombin generation curve predicted by numerical models	Velocity Index measured in haemophilic patients is compared to TTP predicted by numerical models	up to 12 monthes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endogenous Thrombin Potential (ETP) for volunteers	ETP (i.e. the aera under the thrombin generation curve, nM.min) is measured by Thromboplastin Generation Tests (TGTs)	day 1
Lag Time of the thrombin generation curve for volunteers	Lag time (min) of the thrombin generation curve is measured by Thromboplastin Generation Tests (TGTs)	day 1
Peak value of the thrombin generation curve for volunteers	Peak value of the thrombin generation curve is measured by Thromboplastin Generation Tests (TGTs)	day 1
Time to peak (TTP) of the thrombin generation curve for volunteers	TTP of the thrombin generation curve is measured by Thromboplastin Generation Tests (TGTs)	day 1
Velocity Index (V) of the thrombin generation curve for volunteers	Velocity Index (V) of the thrombin generation curves measured by Thromboplastin Generation Tests (TGTs)	day 1

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Saint Etienne
• Collaborators: Pfizer; Ecole Normale Supérieure des Mines de Saint-Etienne
• Investigators: Principal Investigator: Brigitte TARDY-PONCET, MD, CHU Saint-Etienne

Study record dates

Study Major Dates

• Study Start: March 1, 2015
• Primary Completion (Actual): July 1, 2015
• Study Completion (Actual): July 1, 2015

Study Registration Dates

• First Submitted: November 18, 2014
• First Submitted That Met QC Criteria: November 21, 2014
• First Posted (Estimate): November 25, 2014

Study Record Updates

• Last Update Posted (Estimate): August 13, 2015
• Last Update Submitted That Met QC Criteria: August 12, 2015
• Last Verified: August 1, 2015

More Information

Terms related to this study

• Keywords: volunteers; Haemophilia; numerical models; thrombin generation; endogenous thrombin potential
• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Blood Coagulation Disorders; Hemophilia A; Hemophilia B
• Other Study ID Numbers: 1408185; 2014-A01734-43 (Other Identifier: ANSM - FRANCE)