Emicizumab Improves Ex Vivo Clotting Function in Patients with Mild/Moderate Hemophilia A.
Antibodies, Bispecific
/ pharmacology
Antibodies, Monoclonal, Humanized
/ pharmacology
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Factor VIII
/ genetics
Hemophilia A
/ blood
Hemorrhage
/ prevention & control
Humans
In Vitro Techniques
Mutation, Missense
Partial Thromboplastin Time
Plasma
Prothrombin Time
Recombinant Proteins
/ pharmacology
Journal
Thrombosis and haemostasis
ISSN: 2567-689X
Titre abrégé: Thromb Haemost
Pays: Germany
ID NLM: 7608063
Informations de publication
Date de publication:
Jun 2020
Jun 2020
Historique:
pubmed:
10
5
2020
medline:
13
7
2021
entrez:
9
5
2020
Statut:
ppublish
Résumé
Emicizumab prophylaxis is a promising treatment that reduces bleeding events in severely affected patients with hemophilia A (PwHA). It is anticipated that emicizumab could be similarly effective in mild/moderate PwHA (PwMHA) although this effect has not been investigated. We evaluated Clot waveform analysis (CWA) triggered by prothrombin time/activated partial prothrombin time-mixed reagents was utilized to examine coagulant effects of emicizumabin factor (F)VIII-deficient plasma mixed with recombinant (r)FVIIIand in native plasmas from 16 PwMHA. The CWA parameter, adjusted-|min1| (Ad|min1|), was used. Increases in Ad|min1| (ΔAd|min1|) mediated by emicizumab were calculated from the slopes of regression lines in the presence of rFVIII. Ad|min1| in FVIII-deficient plasma with various concentrations of rFVIII negatively correlated with ΔAd|min1|by adding emicizumab, and these data were defined as standard reference values. Ad|min1| (4.57 ± 0.50) in 16 PwMHA increased to 5.05 ± 0.54 and 5.37 ± 0.60 by adding emicizumab at 50 and 100 μg/mL, respectively, but remained lower than the normal range (7.22 ± 0.21). ΔAd|min1| levels were 1.5 to 2-fold higher in five cases and 0.4 to 0.6-fold lower in four cases, compared with reference values determined by rFVIII. In some cases, genetic analyses suggested that specific point mutations could have contributed to these findings. Further studies using rFVIII mutants indicated, however, that the differences in ΔAd|min1| were not related to individual FVIII gene defects. Emicizumab enhances coagulation potential in PwMHA. Assessment of
Sections du résumé
BACKGROUND
BACKGROUND
Emicizumab prophylaxis is a promising treatment that reduces bleeding events in severely affected patients with hemophilia A (PwHA). It is anticipated that emicizumab could be similarly effective in mild/moderate PwHA (PwMHA) although this effect has not been investigated.
AIM
OBJECTIVE
We evaluated
METHODS
METHODS
Clot waveform analysis (CWA) triggered by prothrombin time/activated partial prothrombin time-mixed reagents was utilized to examine coagulant effects of emicizumabin factor (F)VIII-deficient plasma mixed with recombinant (r)FVIIIand in native plasmas from 16 PwMHA. The CWA parameter, adjusted-|min1| (Ad|min1|), was used. Increases in Ad|min1| (ΔAd|min1|) mediated by emicizumab were calculated from the slopes of regression lines in the presence of rFVIII.
RESULTS
RESULTS
Ad|min1| in FVIII-deficient plasma with various concentrations of rFVIII negatively correlated with ΔAd|min1|by adding emicizumab, and these data were defined as standard reference values. Ad|min1| (4.57 ± 0.50) in 16 PwMHA increased to 5.05 ± 0.54 and 5.37 ± 0.60 by adding emicizumab at 50 and 100 μg/mL, respectively, but remained lower than the normal range (7.22 ± 0.21). ΔAd|min1| levels were 1.5 to 2-fold higher in five cases and 0.4 to 0.6-fold lower in four cases, compared with reference values determined by rFVIII. In some cases, genetic analyses suggested that specific point mutations could have contributed to these findings. Further studies using rFVIII mutants indicated, however, that the differences in ΔAd|min1| were not related to individual FVIII gene defects.
CONCLUSION
CONCLUSIONS
Emicizumab enhances coagulation potential in PwMHA. Assessment of
Identifiants
pubmed: 32384547
doi: 10.1055/s-0040-1710315
doi:
Substances chimiques
Antibodies, Bispecific
0
Antibodies, Monoclonal, Humanized
0
Recombinant Proteins
0
emicizumab
7NL2E3F6K3
Factor VIII
9001-27-8
Types de publication
Comparative Study
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
968-976Subventions
Organisme : 18K07885
ID : Ministry of Education, Culture, Sports, Science and Technology (MEXT)
Informations de copyright
Georg Thieme Verlag KG Stuttgart · New York.
Déclaration de conflit d'intérêts
Y.N., K.N., K.Y., S.F., and M.S. receive research support from Chugai Pharmaceutical Co., Ltd. (Chugai), and are engaged in clinical studies sponsored by Chugai and F. Hoffmann-La Roche. K.N. and M.S. receive (consulting) honoraria from these companies and are inventors of the patents relating to emicizumab. K.Y. teaches a course endowed by Takeda. S.F. teaches a course endowed by CSL Behring. M.N.S. and M.H. are employees of Chugai. M.H. possesses Chugai's stock.