Although the heritability of plasma levels of several coagulation factors is high, the underlying molecular mechanisms are only partially known. For instance, the FVIII D1241E polymorphism is the only intragenic variation found to be associated with FVIII levels (Scanavini, 2005). Genes encoding for proteins involved in the multi-step biosynthesis, and/or processing and survival in plasma of FVIII might play a part in determining factor levels. Oligosaccharide structures, like determinants of ABO blood groups, are implicated in FVIII catabolism and evidence for a strong effect of ABO locus on FVIII levels has been detected. Other genetic loci on chromosomes 18, 5 and 11 have been suggested to be involved in modulation of FVIII levels. A multifunctional member of the LDL receptor super-family has been demonstrated, in cellular and animal models, to participate in the regulation of distribution phase of FVIII by binding and directing FVIII molecules to the intracellular degradation pathways. We have recently found that LRP genotypes, predicting differential LRP expression, are associated with significant differences in FVIII activity in patients (17%, P<0.009) and that combined ABO/LRP genotypes are associated with 50% variations. These findings suggest that genes involved in the control of endogenous FVIII molecules could also modulate the decay of native/recombinant molecules infused for prophylactic or therapeutic purposes. Gene variation could produce significant individual differences in pharmacokinetics of infused FVIII concentrates. We propose a systematic screening of 200 hemophilia A patients attending the Hemophilia Center of Florence for genetic polymorphisms found in genes which are (direct or indirect) candidate to participate in FVIII removal from plasma. We also propose to genotype patients for polymorphisms located in genomic regions that have been suggested to encode FVIII level “modifiers”, whose function is still unknown. Taken into account the very different biological role of these genes (receptors, ligand, ligand modifier and cofactors) different parameters of infused FVIII removal could be positively or negatively influenced by the hypothesized genetic control. This study has important biological and clinical consequences to individualize the dosage of these very expensive drugs and to tailor both on demand and prophylactic therapy. More than 20 markers have been already set up in our lab for the study of hemophilia A patients. DNA extraction and identification of FVIII gene mutations will be performed in our local Genetic Service (Dr.sa F.Torricelli), the other genetic polymorphisms will be detected in Department of Biochemistry and Molecular Biology , University of Ferrara (Prof. F.Bernardi). Each patient will undergo a single dose pharmacokinetic study, designed according to the FVIII/IX SSC of ISTH. The concentrate, rDNA- or plasma-derived, will be the same regularly used by the patient. The timing of blood sample collection will be partially modified in order to have a detailed and good fitting of FVIII decay during the first hours after infusion (distribution phase). The decay data will be analyzed both by Model independent and Two-compartment methods. The association of specific genotypes with pharmacokinetic parameters (In Vivo Recovery, AUC, Clearance, MRT, VdArea, Terminal half-life) will be tested by Multivariate analysis.
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|Autori:||M. Morfini; F. Bernardi|
|Titolo:||Progetto Bayer Haemophilia Awards Program: Genetic components contributing to the pharmacokinetics of FVIII concentrates|
|Data di pubblicazione:||2006|
|Appare nelle tipologie:||08.1 Coordinamento Prog.Ricerca Naz. ed Internaz.|