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NCT Number: NCT02540187

Tissue Factor Pathway Inhibitor (TFPI) and Haemorrhagic Manifestations in Haemophilia A and B Patients

Haemophilia is a rare and serious congenital defect of blood coagulation due to a genetic mutation on a sexual chromosome. It affects quasi-essentially the men and it is responsible for bleeding. There are two types of haemophilia: Haemophilia A, (85 % of cases), due to a factor VIII (FVIII) deficiency and Haemophilia B (15 % of cases) due to factor IX (FIX) deficiency. According to the intensity of the defect, there are three forms of haemophilia: severe (FVIII or FIX lower than 1 %), moderate (factor level between 1 and 5 %), minor (factor level between 5 and 40 %). For a same level of factor VIII or IX, hemorrhagic manifestations are variable from one patient to the other. Moreover, several studies showed that haemophilic B patients bleed less and consume fewer anti-hemophilic concentrate that haemophilic A patients.

The main inhibitors of the coagulation are antithrombin, Protein C-Protein S-Thrombomodulin system, and tissue factor pathway inhibitor (TFPI). TFPI is the specific and exclusive inhibitor of tissue factor pathway that is the main way by which plasmatic coagulation starts. TFPI is a potent direct inhibitor of factor Xa and Xa-dependent inhibitor of the VIIa-Tissue Factor (TF) complex. In hemophilic patient, the production of Xa by the amplification pathway being strongly altered because of factor VIII or IX deficiency, thrombin generation (via Xa) comes exclusively from TFPI regulated tissue factor pathway. We can thus say that if haemophilic patients bleed, it is also because of the presence of TFPI that inhibits at the same time Xa and the complex TF-VIIa as soon as factor Xa is generated.

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Key information

Conditions

Hemophilia Blood Coagulation Disorders Blood Coagulation Disorders, Inherited Coagulation Protein Disorders Congenital, Hereditary, and Neonatal Diseases and Abnormalities Genetic Diseases, Inborn Hematologic Diseases Hemic and Lymphatic Diseases Hemophilia A Hemorrhagic Disorders

Age range

18 year–65 year

Sex eligibility

Male

Study type

Observational

Primary location

CHRU Lille, Lille, France

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Haemophilia A and B patients between 18 and 65 years old, whatever the severity of their disease, who have signed the informed consent form
  • On-demand or on prophylactic therapy.
  • Regular monitoring in investigator center.

Exclusion criteria

  • - Haemophilia patients under 18.
  • Presence of an inhibitor at any time before or during the study period.
  • Patients who received factor VIII concentrate less than 72 hours or factor IX concentrate less than 96 hours before blood collection
  • Patients who refused to sign informed consent
  • Patient data over the last 5 years at least not available.
  • No regular monitoring in haemophilia center (required at least one visit every 18 months for severe or moderate hemophiliac patients).

Treatment and study plan

blood specimen

Other

Primary outcomes

  1. Comparison for TFPI level between Haemophilia A and Haemophilia B

    Time frame: day 1

    Comparison for TFPI level between Haemophilia A and Haemophilia B

  2. Comparison for TFPI level between severe Haemophilia A and severe Haemophilia B

    Time frame: Day 1

    Comparison for TFPI level between severe Haemophilia A and severe Haemophilia B

  3. Comparison for TFPI level between moderate or mild Haemophilia A and moderate or mild Haemophilia B

    Time frame: Day 1

    Comparison for TFPI level between moderate or mild Haemophilia A and moderate or mild Haemophilia B

Secondary outcomes

  1. Correlation between free TFPI and hemorrhagic score

    Time frame: day 1

    Hemorrhagic score is established on the 5 to 10 last years. For severe hemophilic patients: it will use a composite scoring system designed to reflect the clinical severity of haemophilia and named HSS for Haemophilia Severity Score (HSS). It consists in the sum of three components: annual incidence of joint bleeds, orthopedic joint score and annual factor utilization. The orthopedic joint score combines pain and physical examination scores as recommended by the orthopedic Advisory Committee of the World Federation of Haemophilia.

    For mild or moderate hemophilic patients, HSS is not suitable. A composite measure will be used and consist in all bleeding events and consumption of factor concentrate in surgical situation.

    Free TFPI levels will be measured by ELISA according to the manufacturer's recommendations

  2. Correlation between TFPI activity and hemorrhagic score

    Time frame: day 1

    Hemorrhagic score is established on the 5 to 10 last years. For severe hemophilic patients: it will use a composite scoring system designed to reflect the clinical severity of haemophilia and named HSS for Haemophilia Severity Score. It consists in the sum of three components: annual incidence of joint bleeds, orthopedic joint score and annual factor utilization. The orthopedic joint score combines pain and physical examination scores as recommended by the orthopedic Advisory Committee of the World Federation of Haemophilia.

    For mild or moderate hemophilic patients, HSS is not suitable. A composite measure will be used and consist in all bleeding events and consumption of factor concentrate in surgical situation.

    TFPI activity will be measured according to the technique described and modified by Sandset

  3. Correlation between Endogenous Thrombin Potential (ETP) and free TFPI

    Time frame: day 1

    Endogenous Thrombin Potential (i.e. the aera under the thrombin generation curve, nM.min) is measured by thromboplastin Generation Test (TGTs) Free TFPI levels will be measured by ELISA according to the manufacturer's recommendations

  4. Correlation between Lag Time and free TFPI

    Time frame: day 1

    Lag time (min) of the thrombin Generation curve is measured by thromboplastin Generation Test (TGTs) Free TFPI levels will be measured by ELISA according to the manufacturer's recommendations

  5. Correlation between Peak value and free TFPI

    Time frame: day 1

    Peak Value (PV, nmol thrombin) of the thrombin Generation curve is measured by thromboplastin Generation Test (TGTs) Free TFPI levels will be measured by ELISA according to the manufacturer's recommendations

  6. Correlation between Time to Peak and free TFPI

    Time frame: day 1

    Time to Peak (TTP, min) of the thrombin Generation curve is measured by thromboplastin Generation Test (TGTs) Free TFPI levels will be measured by ELISA according to the manufacturer's recommendations

  7. Correlation between ETP and hemorrhagic score

    Time frame: day 1

    Endogenous Thrombin Potential (i.e. the aera under the thrombin generation curve, nM.min) is measured by Thromboplastin Generation Test (TGTs) Hemorrhagic score is established on the 5 to 10 last years. For severe hemophilic patients: it will use a composite scoring system designed to reflect the clinical severity of haemophilia and named HSS for Haemophilia Severity Score. It consists in the sum of three components: annual incidence of joint bleeds, orthopedic joint score and annual factor utilization. The orthopedic joint score combines pain and physical examination scores as recommended by the orthopedic Advisory Committee of the World Federation of Haemophilia.

    For mild or moderate hemophilic patients, HSS is not suitable. A composite measure will be used and consist in all bleeding events and consumption of factor concentrate in surgical situation.

  8. Correlation between Lag Time and hemorrhagic score

    Time frame: day 1

    Lag time (min) of the thrombin generation curve is measured by thromboplastin Generation Test (TGTs) Hemorrhagic score is established on the 5 to 10 last years. For severe hemophilic patients: it will use a composite scoring system designed to reflect the clinical severity of haemophilia and named HSS for Haemophilia Severity Score. It consists in the sum of three components: annual incidence of joint bleeds, orthopedic joint score and annual factor utilization. The orthopedic joint score combines pain and physical examination scores as recommended by the orthopedic Advisory Committee of the World Federation of Haemophilia.

    For mild or moderate hemophilic patients, HSS is not suitable. A composite measure will be used and consist in all bleeding events and consumption of factor concentrate in surgical situation.

  9. Correlation between Peak Value and hemorrhagic score

    Time frame: day 1

    Peak Value (PV, nmol thrombin) of the thrombin generation curve is measured by thromboplastin Generation Test (TGTs) Hemorrhagic score is established on the 5 to 10 last years. For severe hemophilic patients: it will use a composite scoring system designed to reflect the clinical severity of haemophilia and named HSS for Haemophilia Severity Score. It consists in the sum of three components: annual incidence of joint bleeds, orthopedic joint score and annual factor utilization. The orthopedic joint score combines pain and physical examination scores as recommended by the orthopedic Advisory Committee of the World Federation of Haemophilia.

    For mild or moderate hemophilic patients, HSS is not suitable. A composite measure will be used and consist in all bleeding events and consumption of factor concentrate in surgical situation.

  10. Correlation between Time to Peak and hemorrhagic score

    Time frame: day 1

    Time to Peak (TTP, min) of the thrombin generation curve is measured by thromboplastin Generation Test (TGTs) Hemorrhagic score is established on the 5 to 10 last years. For severe hemophilic patients: it will use a composite scoring system designed to reflect the clinical severity of haemophilia and named HSS for Haemophilia Severity Score. It consists in the sum of three components: annual incidence of joint bleeds, orthopedic joint score and annual factor utilization. The orthopedic joint score combines pain and physical examination scores as recommended by the orthopedic Advisory Committee of the World Federation of Haemophilia.

    For mild or moderate hemophilic patients, HSS is not suitable. A composite measure will be used and consist in all bleeding events and consumption of factor concentrate in surgical situation.

  11. Comparison for ETP between haemophilia A et Haemophilia B

    Time frame: Day 1

    Endogenous Thrombin Potential (i.e. the aera under the thrombin generation curve, nM.min) is measured by Thromboplastin Generation Test (TGTs)

  12. Comparison for lag time between haemophilia A et Haemophilia B

    Time frame: Day 1

    Lag time (min) of the thrombin generation curve is measured by thromboplastin Generation Test (TGTs)

  13. Comparison for Peak Value between haemophilia A et Haemophilia B

    Time frame: Day 1

    Peak Value (PV, nmol thrombin) of the thrombin generation curve is measured by thromboplastin Generation Test (TGTs)

  14. Comparison for Time to Peak between haemophilia A et Haemophilia B

    Time frame: day 1

    Time to Peak (TTP, min) of the thrombin generation curve is measured by thromboplastin Generation Test (TGTs)

Sponsors and collaborators

Lead sponsor

Centre Hospitalier Universitaire de Saint Etienne

Other

Collaborators

  • Pfizer

Registry information

Important dates

Study start
2012
Primary completion
2016
Study completion
2016
First posted
Sep 3, 2015
Registry last updated
Mar 10, 2016

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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