Factor VIII pharmacokinetics associates with genetic modifiers of VWF and FVIII clearance in an adult hemophilia A population

Ogiwara, Kenichi; Swystun, Laura L.; Paine, Abby; Kepa, Sylvia; Choi, Seon Jae; Rejtő, Judit; Hopman, Wilma M.; Pabinger, Ingrid; Lillicrap, David

doi:10.1111/jth.15183

Cited by 14 publications

(45 citation statements)

References 36 publications

(106 reference statements)

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“…PK variables (Table 2 and Table 3) the influence of the ASGR2 c.-95T/C polymorphism with those previously observed for VWF levels 1,2 and ABO genotypes, 5,[7][8][9][10][11] and in addition estimated the proportion of variability explained by these predictors (R 2 values). The contribution of the ASGR2 c.-95T/C genotypes, categorized as TT vs TC + CC (Table 2), remained significant for several PK parameters, and particularly for the Alpha HL (β coefficient -0.492, p = 0.006).…”

Section: Accepted Manuscriptmentioning

confidence: 66%

“…Concerning the ABO genotypes, the non-O group showed lower K 2-1 values (p ¼ 0.009), prolonged Alpha HL (p ¼ 0.037), and lower CLD2 (p ¼ 0.012). The distribution of ASGR2 genotypes did not differ in ABO blood groups (O vs. non-O, X 2 , p ¼ 0.78).We compared in linear regression models of PK variables (►Tables 2 and 3) the influence of the ASGR2 c.-95T/C polymorphism with those previously observed for VWF levels 1,2 and ABO genotypes, 5,[7][8][9][10][11] and in addition estimated the proportion of variability explained by these predictors (R 2 values). The contribution of the ASGR2 c.-95T/C genotypes, categorized as TT versus TC þ CC (►Table 2), remained significant for several PK parameters, and particularly for the Alpha HL (β coefficient À0.492, p ¼ 0.006).…”

Section: Influence On Fviii Pk Of Asgr2 and Ldlr Genotypesmentioning

confidence: 99%

“…[3][4][5][6] Among genetic components, the ABO blood group has been consistently observed to influence FVIII clearance in several studies. 5,[7][8][9][10][11] The ABO blood group, VWF levels and age have been reported to explain about one third of the total inter-individual variation in FVIII clearance in severe HA. 12 An increasing number of cell surface receptors [13][14][15][16] has also been experimentally implicated in modulating VWF-FVIII-binding interactions, but the relative importance of these receptors for the clearance of free-and VWF-bound FVIII remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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The Asialoglycoprotein Receptor Minor Subunit Gene Contributes to Pharmacokinetics of Factor VIII Concentrates in Hemophilia A

Lunghi

Morfini²,

Martinelli

et al. 2021

Thromb Haemost

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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. Patients/Methods Thirty‐two HA patients with FVIII:C ≤ 2 IU/dL underwent 66 single dose FVIII PKs. PK parameters were evaluated in relation to ASGR2 5’ untranslated region (5’UTR) polymorphisms, that were investigated by recombinant and white blood cell RT-PCR 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 to the other ASGR2 genotypes, the c.-95TT homozygotes (n=9), showed three-fold longer Alpha HL (3.60 h, 95% CI 1.44-5.76, p=0.006), and the c.-95TC heterozygotes (n=17) showed 25% shorter MRT (18.5 h, 15.0-22.0, p=0.038) and 32% shorter Beta HL (13.5 h, 10.9-16.0, p=0.016). These differences were confirmed in patients (n=27) undergoing PKs (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 VWF:Ag levels, and explained 14% (MRT), 15-18% (Beta HL) and 22% (Alpha HL) of parameter variability. Conclusions 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.

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Section: Accepted Manuscriptmentioning

confidence: 66%

Section: Influence On Fviii Pk Of Asgr2 and Ldlr Genotypesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Asialoglycoprotein Receptor Minor Subunit Gene Contributes to Pharmacokinetics of Factor VIII Concentrates in Hemophilia A

Lunghi

Morfini²,

Martinelli

et al. 2021

Thromb Haemost

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“…Common variants at the CLEC4M locus were associated with the FVIII PK profile in a population of severe pediatric HA patients, and in populations of adult moderate/severe HA patients [9,17,18]. These observations have been obtained by the infusion of different plasma-derived (pd-) or recombinant (r-) standard half-life FVIII concentrates, and by different PK analysis approaches, the PopPK [17], and the model-independent method individual PK [9,18].…”

Section: Introductionmentioning

confidence: 99%

Combination of CLEC4M rs868875 G-Carriership and ABO O Genotypes May Predict Faster Decay of FVIII Infused in Hemophilia A Patients

Lunghi

Morfini²,

Martinelli

et al. 2022

JCM

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The C-type lectin CLEC4M binds and internalizes factor VIII (FVIII). Common CLEC4M variants have been associated with FVIII pharmacokinetic (PK) profiles in hemophilia A (HA) patients. The two-compartment PK analysis of plasma-derived (pd-) and full length recombinant FVIII concentrates was conducted in twenty-six patients (FVIII:C ≤ 2 IU/dL). F8, ABO blood-groups, and the CLEC4M rs868875A/G polymorphism were genotyped. CLEC4M genotype groups differed for the elimination rate constant K 1-0 (p < 0.001), half-life (K 1-0 HL), and the Beta rate constant. Patients treated with pd-FVIII also differed in the Alpha phase. In linear regression models, the contribution of the CLEC4M genotypes to FVIII PK parameters remained significant after correction for ABO, age, and VWF antigen levels at PK. Combined CLEC4M rs868875A/G and ABO genotypes displayed significant interaction (K 1-0, p = 0.014). Compared to other combined genotypes, the G-carriers/O genotypes showed half-reduced K 1-0 HL (p = 0.008), and faster FVIII clearance (mean 7.1 ± 2.2 mL/h/kg SE) than in the G-carriers/non-O (mean 2.4 ± 0.3 mL/h/kg SE), (p = 0.038). Comparison in HA patients recruited in several countries suggests that CLEC4M genotypes coherently influence infused FVIII half-life and clearance. Our analysis supports substantially faster FVIII decay associated with the rs868875 G-carrier/ABO O genotypes, which has potential implications for genetically tailored substitutive HA treatment.

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“… 63 To shed light on this issue, several genetic polymorphisms have recently been evaluated to examine their impact on FVIII individual PK parameters in hemophilia A patients. These polymorphisms include LDLR, 64 CLEC4M, 65 genetic modifiers of VWF, 66 and ASGR2 5ʹ UTR haplotype. 67…”

Section: A Predictor Of the Efficacy Of Replacement Therapy: Pharmacokineticsmentioning

confidence: 99%

Recent Advances in the Treatment of Hemophilia: A Review

Marchesini¹,

Morfini²,

Valentino³

2021

BTT

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Progress in hemophilia therapy has been remarkable in the first 20 years of the third millennium, but the innovation began with the description the fractionation of plasma in 1946. The first concentrates followed the discovery of FVIII in the cryoprecipitate of frozen plasma and FIX in the supernatant in the early 1960s, which led to the initial attempts at replacement therapy. Unfortunately, the lack of screening methods for viral pathogens resulted in people with hemophilia (PWH) receiving concentrates contaminated by hepatitis A virus, hepatitis C virus, and human immunodeficiency virus, as these concentrates were made from large industrial pools of plasma derived from thousands of donors. Fortunately, by 1985, viral screening methods and proper virucidal techniques were developed that made concentrates safe. Increasingly pure products followed the introduction of chromatography steps with monoclonal antibodies in the production process. The problem of immunogenicity of exogenously administered concentrates has not yet had a complete solution. The development of alloantibodies against FVIII in about 25–35% of PWH is the most serious adverse effect of replacement therapy. The next major advance followed the cloning of the F8 gene and later the F9 genes, which paved the way to produce concentrates of factors obtained by the recombinant DNA technology. The injected FVIII and FIX molecules had a relatively short circulating half-life in the plasma of people with hemophilia A and B, approximately 12 and 18 hours, respectively. The ability to prolong the plasma half-life and extend the interval between injections followed the application of methods to conjugate the factor molecule with the fragment crystallizable of IgG1 or albumin or by adding polyethylene glycol, which has led to an increase in the half-life of concentrates, especially for rFIX. The next frontier in hemophilia therapy is the application of durable and potentially curative therapies such as with gene addition therapy. Experiments in hemophilia B have demonstrated durable responses. Unfortunately, the results with gene therapy for hemophilia A have not been as remarkable and the durability must still be demonstrated. Nonetheless, the long-term safety, predictability, durability, and efficacy of gene therapy for hemophilia A and B remain an open question. At present, only healthy adult PWH have been enrolled in gene therapy clinical trials. The application of gene therapy to children and those with pre-existing antibodies against the delivery vector must also be studied before this therapy becomes widespread.

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Factor VIII pharmacokinetics associates with genetic modifiers of VWF and FVIII clearance in an adult hemophilia A population

Cited by 14 publications

References 36 publications

The Asialoglycoprotein Receptor Minor Subunit Gene Contributes to Pharmacokinetics of Factor VIII Concentrates in Hemophilia A

The Asialoglycoprotein Receptor Minor Subunit Gene Contributes to Pharmacokinetics of Factor VIII Concentrates in Hemophilia A

Combination of CLEC4M rs868875 G-Carriership and ABO O Genotypes May Predict Faster Decay of FVIII Infused in Hemophilia A Patients

Recent Advances in the Treatment of Hemophilia: A Review

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