Hemophilia, Prophylaxis, Rebalancing Agents
Conditions
Brief summary
During the development of anti-TFPI antibodies, thrombin generation assay (TGA) was employed using both in vitro measurements (antibodies added to blood samples) and ex vivo approaches (blood samples from patients in phase II and III trials). While a significant improvement in thrombin generation was observed in all samples from patients with severe hemophilia, no correlation with clinical outcomes could be established. Notably, thrombin peak levels were consistently improved even in patients who experienced bleeding episodes. These measurements were conducted in platelet-poor plasma (PPP) with standard reagents, which may not adequately reflect the hemostatic efficacy of anti-TFPI antibodies given their mechanism of action. It is hypothesized that optimizing reagents and utilizing more appropriate biological materials could enhance TGA sensitivity, as previously demonstrated for monitoring emicizumab. The absence of a laboratory assay to monitor anti-TFPI (tissue factor pathway inhibitor) antibodies poses a significant challenge for managing patients in surgical settings and treating acute severe bleeding. This study aims to develop a reliable assay to evaluate the hemostatic efficacy of anti-TFPI antibodies and their combined procoagulant effect with factor concentrates (FVIII or FIX) or bypassing agents.
Interventions
BIOLOGICALblood sampling
One-time peripheral blood draw (10.8 mL total, 4 citrated tubes) collected during a routine clinical visit for thrombin generation testing on platelet-rich and platelet-poor plasma. No additional medical procedures or treatments are involved in the study.
Sponsors
Hospices Civils de Lyon
Study design
Observational model
CASE_ONLY
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Inclusion Criteria : * \- Male Patient * 18 years old * severe hemophilia patients A or B (FVIII \< 1%,FIX\<=2%) * on prophylaxis with FVIII or IX concentrates after an adequate washout period of 48h for SHL FVIII molecules, at least 4 days for EHL-FVIII Fc and at least 10 days for EHL-FIX molecules. * On prophylaxis with Marstacimab * Willing to participate * Capable of following protocol procedures under investigator appreciation *
Exclusion criteria
: * \- patients refusing to provide 4 additional blood tubes for research * Patient with an other coagulation disorder * patients who received an injection of FVIII or FIX during the required washout period
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Development of a Laboratory Assay to Assess Hemostatic Efficacy of Anti-TFPI Antibodies | At time of sample analysis (single visit; Day 0) | Assessment of the thrombin generation assay's ability to evaluate the procoagulant effect of anti-TFPI antibodies alone and in combination with factor concentrates (FVIII or FIX) or bypassing agents (rFVIIa, aPCC). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Analytical Sensitivity of TGA to Anti-TFPI Antibodies | Day 0 | Evaluate the effect of different TGA conditions (e.g., low TF concentration, use of PRP, CTI) to enhance sensitivity to anti-TFPI antibodies. |
| Identification of Optimal TGA Parameters for Monitoring Anti-TFPI Effect | Day 0 | Determine which parameters (e.g., thrombin peak, ETP, lag time, velocity, time to peak) best reflect the action of anti-TFPI antibodies under optimized assay conditions. |
| Correlation Between TGA Parameters and Clinical Use of Anti-TFPI Therapies | Day 0 | Compare TGA results from 5 patients treated with marstacimab and 3 patients with concizumab to assess correlation with clinical treatment exposure. |
| Detection of Hypercoagulability from Combined Therapy in TGA | Day 0 | In vitro testing of anti-TFPI antibodies in combination with FVIII, FIX, rFVIIa, or aPCC to assess risk of excessive thrombin generation. |
Countries
France
Contacts
CONTACTYesim DARGAUD, Pr
CONTACTSandra DURANTEL
Outcome results
None listed