Targeting TFPI With Concizumab to Improve Haemostasis in Glanzmann Thrombasthenia Patients: an in Vitro Study

Summary

Glanzmann thrombasthenia is a rare genetic disorder caused by the absence or the dysfunction of the main receptor present on the surface of platelets, integrin αIIbβ3 or GPIIb-IIIa.

The lack of this protein on the surface of platelets no longer allows these blood cells to bind to each other. This binding corresponds to the process of platelet aggregation.

Generally, local measures will control nasal and superficial bleeding whereas platelet transfusions are used to control or prevent life-threatening.

The main complication of this treatment is the risk of developing anti-αIIbβ3 antibodies directed against the absent protein and platelet transfusion therapy can become ineffective.

Activated recombinant factor VII (rFVIIa) provides an alternative treatment for GT patients who develop such antibodies. However, this therapy has a short duration of efficacy, requiring repeated intravenous administrations every 2 to 3 hours.

There is a new treatment, Concizumab, which has not yet been marketed. This treatment acts on TFPI (tissue factor pathway inhibitor). TFPI is a protein that occurs naturally in the body and prevents blood cells from binding to each other.

Concizumab works by blocking TFPI, which may allow sufficient clotting to prevent bleeding.

This treatment could replace recombinant activated factor VII (rFVIIa) because it has the advantage of a much longer duration of efficacy (about 3 days) and is administered subcutaneously.

Conditions

• Glanzmann Thrombasthenia

Interventions

OTHER

Clot formation in whole blood under flow in a microfluidic flow chamber coated with tissue factor and collagen

TTAS (single measurements) Clot formation in whole blood under flow (2000 s-1) in a microfluidic flow chamber coated with tissue factor and collagen (T-TAS with AR chip) 1. 500 µL of whole blood for each point; 2. 7 points for each condition; 3. Around 4 mL of whole blood will be needed for each patient or healthy subject; 4. Values for Area Under the Curve (Aritrary Unit), Occlusion Starting Time (min), Occlusion Time (min.) will be reported.

OTHER

: PRP viscoelastic changes under clot formation measured by thromboelastometry using RoTEM

ROTEM (single measurements) 1. ROTEM cups will be added * 20 µL calcium reagent (STARTEM) * 20 µL of 2,940-fold prediluted r-ExTEM reagent (50,000 fold dilution relative to 340 µL in the cup) added * 300 µL spiked PRP at 250 G/L (2.5 mL of PRP/patient) 2. Values for clot time (CT sec, clot formation time (CFT) sec, maximum clot formation (mm) will be reported.

OTHER

Thrombin Generation Assay (TGA) in PRP using TF trigger

TGA (single measurements) 1. The following will be added to well: * 20 uL of PRP-Reagent * 80 uL of spiked PRP (600 µL/patient at 100 G/L) * 20 uL FluCa 2. Values for thrombin activity versus time and the derived parameters incl. lag-time (min), time to peak (min), time to peak (min), ETP (Arbitrary Unit) will be reported.

OTHER

Global fibrinolytic capacity in PRP using reagents for in vitro triggering of the clot and its lysis

Global fibrinolytic capacity (Lysis Timer) in 100 µL of PRP (250 G/L) using reagents for in vitro triggering of the clot (thrombin and calcium) and its lysis (tissue-plasminogenactivator (t-PA). Around 1 mL of PRP in total Lysis time in min

OTHER

Concizumab

Thrombin generation assay (TGA), microchip flow-chamber assay (T-TAS, rotational thromboelastometry and global fibrinolytic capacity to investigate and compare the effects of mixing concizumab (200, 1000 and 4000 ng/mL) with the main bleed treatment options for persons with GT

Sponsors & Collaborators

• University Hospital, Bordeaux

  lead OTHER

Principal Investigators

• Mathieu FIORE · University Hospital, Bordeaux

Study Design

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2023-04-06

Primary Completion

2023-07-17

Completion

2023-07-17

Countries

• France

Study Locations