PMID- 34407556
OWN - NLM
STAT- MEDLINE
DCOM- 20220616
LR  - 20220809
IS  - 2567-689X (Electronic)
IS  - 0340-6245 (Linking)
VI  - 122
IP  - 5
DP  - 2022 May
TI  - The Asialoglycoprotein Receptor Minor Subunit Gene Contributes to 
      Pharmacokinetics of Factor VIII Concentrates in Hemophilia A.
PG  - 715-725
LID - 10.1055/a-1591-7869 [doi]
AB  - BACKGROUND: The asialoglycoprotein receptor (ASGPR) binds with high affinity 
      factor VIII (FVIII) through its N-linked oligosaccharides. However, its 
      contribution to the wide inter-individual variation of infused FVIII 
      pharmacokinetics (PK) in hemophilia A (HA) is unknown. OBJECTIVE: To investigate 
      the variability in FVIII PK outcomes in relation to genetic variation in the 
      ASGR2, encoding the ASGPR2 subunit. METHODS: Thirty-two HA patients with FVIII:C 
      </=2 IU/dL underwent 66 single-dose FVIII PK studies. PK parameters were evaluated 
      in relation to ASGR2 5' untranslated region (5'UTR) polymorphisms, which were 
      investigated by recombinant and white blood cell reverse transcription-polymerase 
      chain reaction approaches. RESULTS: The 5'UTR polymorphisms determine a frequent 
      and conserved haplotype (HT1) in a regulatory region. The HT1 homozygotes may 
      differ in the amounts of alternatively spliced mRNA transcripts and thus ASGPR2 
      isoforms. Compared with the other ASGR2 genotypes, the c.-95TT homozygotes 
      (n = 9), showed threefold longer Alpha HL (3.60 hours, 95% confidence interval: 
      1.44-5.76, p = 0.006), and the c.-95TC heterozygotes (n = 17) showed 25% shorter 
      mean residence time (MRT; 18.5 hours, 15.0-22.0, p = 0.038) and 32% shorter Beta 
      HL (13.5 hours, 10.9-16.0, p = 0.016). These differences were confirmed in 
      patients (n = 27) undergoing PK studies (n = 54) with full-length FVIII only. In 
      different linear regression models, the contribution of the ASGR2 genotypes 
      remained significant after adjustment by ABO genotypes and von Willebrand factor 
      (VWF) antigen levels, and explained 14% (MRT), 15 to 18% (Beta HL), and 22% 
      (Alpha HL) of parameter variability. CONCLUSION: Infused FVIII distribution was 
      modulated by frequent ASGR2 genotypes, independently from and together with ABO 
      and VWF antigen levels, which has potential implications for genetically tailored 
      substitutive treatment in HA.
CI  - Thieme. All rights reserved.
FAU - Lunghi, Barbara
AU  - Lunghi B
AD  - Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, 
      Italy.
FAU - Morfini, Massimo
AU  - Morfini M
AD  - Italian Association Hemophilia Centers (AICE), Naples, Italy.
FAU - Martinelli, Nicola
AU  - Martinelli N
AD  - Department of Medicine, University of Verona, Verona, Italy.
FAU - Balestra, Dario
AU  - Balestra D
AD  - Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, 
      Italy.
FAU - Linari, Silvia
AU  - Linari S
AD  - Department of Oncology, Center for Bleeding Disorders, Careggi University 
      Hospital, Florence, Italy.
FAU - Frusconi, Sabrina
AU  - Frusconi S
AD  - Genetic Diagnostics Unit, Laboratory Department, Careggi University Hospital, 
      Florence, Italy.
FAU - Branchini, Alessio
AU  - Branchini A
AUID- ORCID: 0000-0002-6113-2694
AD  - Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, 
      Italy.
FAU - Cervellera, Christian F
AU  - Cervellera CF
AD  - Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, 
      Italy.
FAU - Marchetti, Giovanna
AU  - Marchetti G
AD  - Department of Neuroscience and Rehabilitation, University of Ferrara, Ferrara, 
      Italy.
FAU - Castaman, Giancarlo
AU  - Castaman G
AD  - Department of Oncology, Center for Bleeding Disorders, Careggi University 
      Hospital, Florence, Italy.
FAU - Bernardi, Francesco
AU  - Bernardi F
AD  - Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, 
      Italy.
LA  - eng
GR  - Italian Medicines Agency/MRAR08T001/
PT  - Journal Article
DEP - 20211012
PL  - Germany
TA  - Thromb Haemost
JT  - Thrombosis and haemostasis
JID - 7608063
RN  - 0 (5' Untranslated Regions)
RN  - 0 (ASGR1 protein, human)
RN  - 0 (Asialoglycoprotein Receptor)
RN  - 0 (Hemostatics)
RN  - 0 (von Willebrand Factor)
RN  - 9001-27-8 (Factor VIII)
SB  - IM
MH  - 5' Untranslated Regions
MH  - *Asialoglycoprotein Receptor/genetics
MH  - *Factor VIII/pharmacokinetics
MH  - *Hemophilia A/drug therapy/genetics
MH  - *Hemostatics/pharmacokinetics
MH  - Humans
MH  - von Willebrand Factor/genetics/metabolism
COIS- M. Morfini reports personal fees from Kedrion, grants from Pfizer, personal fees 
      from Novo Nordisk, personal fees from Sobi, personal fees from Bayer, personal 
      fees from Bioverativ, personal fees from Octapharma, personal fees from CSL 
      Behring, outside the submitted work. D. Balestra reports grants and personal fees 
      from Bayer. A. Branchini reports grants and personal fees from Pfizer, grants 
      from Bayer, grants and nonfinancial support from Grifols, outside the submitted 
      work. G. Castaman reports personal fees from Roche, personal fees from Bayer, 
      personal fees from Shire, grants and personal fees from CSL Behring, grants and 
      personal fees from Sobi, personal fees from Uniqure, grants from Pfizer, personal 
      fees from Kedrion, personal fees from Novo Nordisk, personal fees from Werfen, 
      outside the submitted work. F. Bernardi reports grants from Bayer, during the 
      conduct of the study; grants from Pfizer, outside the submitted work. The other 
      authors state that they have no conflict of interest.
EDAT- 2021/08/19 06:00
MHDA- 2022/06/18 06:00
CRDT- 2021/08/18 20:11
PHST- 2021/08/18 00:00 [aheadofprint]
PHST- 2021/08/19 06:00 [pubmed]
PHST- 2022/06/18 06:00 [medline]
PHST- 2021/08/18 20:11 [entrez]
AID - 10.1055/a-1591-7869 [doi]
PST - ppublish
SO  - Thromb Haemost. 2022 May;122(5):715-725. doi: 10.1055/a-1591-7869. Epub 2021 Oct 
      12.