Administration of Fibrinogen Concentrate for Refractory Bleeding

Study Overview
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Brief Summary
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Platelet transfusions are widely employed to prevent or treat bleeding episodes in patients with thrombocytopenia. Patients with bone marrow failure secondary to haematological malignancy and chemotherapy frequently receive prophylactic platelet transfusion when platelet level reaches 10x109.L-1, to avoid spontaneous major bleeding. Due to immune or nonimmune factors, platelet refractoriness may be observed and is defined as a repeated suboptimal response to platelet transfusions with lower-than-expected post-transfusion count increments. The management of patients with alloimmunization is complex and prophylactic platelet support is no longer indicated. Therefore, platelet refractoriness remains a clinically challenging complication.

Detailed Description
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To date, no specific therapeutic strategy has been proposed for platelet refractoriness, in cancer patients who are both at high risk of bleeding and thrombosis. Interestingly, fibrinogen is a critical hemostatic protein required for both prevention and treatment of bleeding as it provides a matrix and mesh network essential for clot formation, amplification and strength. Fibrinogen repletion, primarily with the use of fibrinogen concentrates for acquired bleeding, has been reported in clinical settings including surgery, trauma, and obstetrics. However, its use as adjuvant therapy for patients requiring massive transfusion is not yet a widely approved indication, especially in hematological patients. Therefore, the evidence regarding timing, efficacy and safety of fibrinogen administration in massively transfused hematological patients is scarce. This study aims at evaluating whether fibrinogen administration to transfused and refractory patients with on-going bleeding could affect the viscoelastic test of clotting function.

Official Title
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Administration of Fibrinogen Concentrate for Refractory Bleeding in Hematological Patients With Intensive Chemotherapy-induced Thrombocytopenia - Analysis Using Viscoelastic Haemostatic Assay (FORMAT)

Conditions
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Hematological Patients, Bleeding, Platelet Refractoriness

Intervention / Treatment
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* Drug: Fibrinogen Concentrate Human


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient affiliated to a social security regimen or beneficiary of the same Signed written informed consent form Confirmed diagnosis of a hematological malignancy and undergoing intensive chemotherapy, autologous stem cell transplantation or allogeneic stem cell transplantation Grade ≥ II hemorrhagic symptoms according to WWorld Health Organization classification Failure or impossibility to use Human Leucocyte Antigen-matched platelet unit Body weight between 38 and 78 Kgs Transfusion refractoriness as defined by Corrected count increment ≤ 5 and platelet level < 20.109.L-1 Exclusion Criteria: Pregnant women Patient under guardianship or deprived of his liberty or any condition that may affect the patient's ability to understand and sign the informed consent Refusing participation Patient presenting non-malignant hematological disease Patient with high plasmatic concentration of fibrinogen (>5g/L) Patient who received fibrinogen within 20 days before inclusion Contra-indication to fibrinogen (fibrinogen concentrate) or any excipient (fibrinogen concentrate) Patient with disseminated intravascular coagulopathy Patient with thromboembolic history Patient who received L-Asparaginase or acquired hypofibrinogenemia following treatment by L-Asparaginase Patient with known risk of thrombophilia (deficiency for antithrombin 3, C protein or factor V) Patient with anti-thrombotic treatment (anti-platelet or anti-coagulant therapy) at the time of enrolment Elevated body temperature ≥ 38.5°C Hospital stay for invasive surgery Patient with acute myeloid leukemia during the induction phase of chemotherapy.

Ages Eligible for Study
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Minimum Age: 18 Years

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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fibrinogen<br>Patients with refractory thrombocytopenia, following intensive chemotherapy, and presenting grade ≥ 2 hemorrhagic symptoms, will receive adjuvant fibrinogen administration and platelet transfusions. | Drug: Fibrinogen Concentrate Human<br>* Refractory transfused patients who present grade ≥ 2 hemorrhagic symptoms will receive a single injection of fibrinogen concentrate (1.5g) followed by platelet transfusion within 2 hours. Blood sampling will be done at different time points to measure clot viscoelasticity: at baseline, after fibrinogen injection, after platelet transfusion and the day after transfusion or before the next platelet transfusion if < 24 hours.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal clot elasticity (viscoelastic test of clotting function) | Measurement of viscoelastic test of clotting function represented by the maximal clot elasticity based on the maximal clot firmness from the EXTEM (EXtrinsically activated test) curve, between blood sampling before fibrinogen administration and blood sampling after platelet transfusion | 3 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of viscoelastic test of clotting function before and after treatment using EXTEM (EXtrinsically activated test) and FIBTEM (fibrin clot obtained by platelet inhibition with cytochalasin D) curves (Fibrinogen) | Measurement of viscoelastic test of clotting function to determine the contribution of fibrinogen in clotting (before fibrinogen, after fibrinogen, after fibrinogen + platelet transfusion) | 24 hours | 
| Comparison of viscoelastic test of clotting function before and after treatment using EXTEM (EXtrinsically activated test) and FIBTEM (fibrin clot obtained by platelet inhibition with cytochalasin D) curves (platelets) | Measurement of viscoelastic test of clotting function to determine the contribution of platelets in clotting (baseline, after fibrinogen + platelet transfusion) | 24 hours | 
| Comparison of viscoelastic test of clotting function before and after treatment using EXTEM (EXtrinsically activated test) and FIBTEM (fibrin clot obtained by platelet inhibition with cytochalasin D) curves (platelets) | Measurement of viscoelastic test of clotting function and comparison depending on platelet characteristics | 24 hours | 
| Incidence of hemorrhagic and thrombotic events | Proportions of patients experiencing bleeding and thrombotic events | 2 months | 
| Incidence of adverse events | Proportions of patients experiencing adverse events | 2 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hematology, intensive chemotherapy, platelet transfusion, thrombocytopenia, fibrinogen