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. 2022 Jan 29;11(3):733.
doi: 10.3390/jcm11030733.

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

Barbara Lunghi  1 , Massimo Morfini  2 , Nicola Martinelli  3 , Silvia Linari  4 , Giancarlo Castaman  4 , Francesco Bernardi  1
Affiliations

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

Barbara Lunghi et al. J Clin Med. .

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.

Keywords: ABO; CLEC4M; CLEC4M SNPs; clearance; factor VIII; haemophilia A; half-life; pharmacokinetics.

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Conflict of interest statement

M.M. 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. G.C. 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.B. 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.

Figures

Figure 1
Figure 1
(A) K 1-0 HL and (B) clearance PK parameters in combined CLEC4M rs868875 A/G and ABO genotypes in the 26 HA patients treated with FL FVIII products. Mean values ± standard deviation are reported. p, Mann–Whitney test.
See this image and copyright information in PMC

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