PB0817 - Emicizumab ameliorates hemostasis in von Willebrand Disease type 3 but not type 2A murine models

Monday, July 11, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: In-Person

Presenting Author(s)

Geneviève Mc Cluskey, PhD

Post-doc
Inserm U1176 - HITh
Le Kremlin-Bicetre, Ile-de-France, France

Co-Author(s)

OC

Olivier D. Christophe

Principal Investigator, Director of research
Laboratory for Hemostasis, Inflammation and Thrombosis, Unité Mixte de Recherche S1176, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Le Kremlin-Bicêtre, France
Paris, Ile-de-France, France
Peter J. Lenting, PhD

Principal Investigator, Director of research
Laboratory for Hemostasis, Inflammation and Thrombosis, Unité Mixte de Recherche S1176, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Le Kremlin-Bicêtre, France
Paris, Ile-de-France, France
Cécile V. Denis, PhD

Principal investigator, Director of Research
Laboratory for Hemostasis, Inflammation and Thrombosis, Unité Mixte de Recherche S1176, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Le Kremlin-Bicêtre, France
Le Kremlin-Bicêtre, Ile-de-France, France
Caterina Casari, PhD

Principal Investigator
UMR_S 1176
PARIS, Ile-de-France, France

Background: Emicizumab is a bi-specific antibody used to treat hemophilia A patients. Von Willebrand Disease (VWD) is characterised by quantative/qualitative defects of von Willebrand factor (VWF) that can lead to secondary factor VIII (FVIII) deficiency. Successful off-label use of emicizumab has been reported in VWD-type 3 patients, re-igniting the question of whether restoring FVIII-like activity improves the bleeding phenotype in VWD patients.

Aims: To assess the effects of emicizumab on the bleeding profiles of VWD mouse models.

Methods: A tail-vein-transection (TVT) bleeding assay was applied to mouse models of VWD-type 3 (Vwf-/-) and VWD-type 2A(IIA) (VWFp.R1597W+/+/GP1BA+/+). Emicizumab (5mg/kg), in conjunction with human factors IX and X, or FVIII (10%-100%), were injected.

Results: In VWD-type 3 mice, one-third of emicizumab-receiving mice (5 out of 15) displayed a normal haemostatic response to the injury (blood lost < 150µl), whereas all buffer-injected mice (n=10) displayed severe bleeding phenotypes (p=0.01). Consistently, 10/15 (66.7%) emicizumab-treated mice spontaneously formed an occlusive clot, temporarily arresting the bleeding, compared to 2/10 (20%) buffer-injected mice (p=0.02). In contrast, emicizumab had no effect on the bleeding profiles of VWD-type 2A mice (blood lost: 491+/-267µl buffer-injected, 503+/-279µl emicizumab-treated, p>0.99). As control, we next compared emicizumab- and FVIII-treatment in VWD-type 2A mice subjected to TVT and, consistent with emicizumab treatment, replenishing 10- or 100% of FVIII activity was not sufficient to correct the bleeding phenotype of these mice (474+/-208µl buffer-injected, 382+/-170µl 10% FVIII, p=0.38; 306+/-241µl 100% FVIII, p=0.17).

Conclusion(s): As observed in patients, emicizumab improved the bleeding phenotypes in a mouse model of VWD-type 3, suggesting that emicizumab assists in restoring primary clot formation in the absence of VWF. However, no amelioration was observed in VWD-type 2A mice, suggesting that degraded VWF, even at low concentrations, has a negative effect on clot formation in a TVT bleeding model.