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

Barbara Lunghi,Giancarlo Castaman,Francesco Bernardi,Massimo Morfini,Nicola Martinelli,Silvia Linari

doi:10.3390/jcm11030733

Barbara Lunghi, Giancarlo Castaman + Show 4 more

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https://doi.org/10.3390/jcm11030733

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Abstract

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.

Highlights

Genetic components, together with environmental factors [1,2,3,4,5,6], provide explanation only for a small portion of the large inter-patient variability of factor VIII (FVIII) pharmacokinetics (PK) in hemophilia A (HA) patients
We focused on the interaction between C-type lectin domain family 4 member M (CLEC4M) gene variation and ABO genotypes, which are well recognized genetic components of FVIII PK outcomes [1,8,19,20]
The relationship between the CLEC4M rs868875 genotypes and FVIII PK parameters was investigated in the cohort of Italian HA patients (n = 26) infused with pd- and full length (FL) r-FVIII products (54 PKs)

Summary

Introduction

Together with environmental factors [1,2,3,4,5,6], provide explanation only for a small portion of the large inter-patient variability of factor VIII (FVIII) pharmacokinetics (PK) in hemophilia A (HA) patients. Von Willebrand factor (VWF) levels, and the ABO blood group altogether explain 30% of such variability in severe HA [1,2,3,4,5]. Among the candidate scavenger receptors [7] for circulating FVIII/VWF, the lowdensity lipoprotein receptor (LDLR), the stabilin 2 (STAB2), and the asialoglycoprotein receptor minor subunit gene (ASGR2) have been recently associated with FVIII pharmacokinetics (PK) through gene variation in small size HA cohorts [8,9,10], independently from ABO blood-group for the LDLR and ASGR2 [8,10] genotypes. In cellular and animal models, CLEC4M binds and internalizes FVIII in a VWF-dependent and -independent manner [15]. CLEC4M can act as a cell-adhesion and pathogenrecognition receptor, which could provide a link between coagulation and infection [16]

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