Residual factor VII activity and different hemorrhagic phenotypes in CRM+ factor VII deficiencies (Gly331Ser and Gly283Ser)

Two cross-reacting material–positive (CRM+) factor VII (FVII) mutations, associated with similar reductions in coagulant activity (2.5%) but with mild to asymptomatic (Gly331Ser, c184 [in chymotrypsin numbering]) or severe (Gly283Ser, c140) hemorrhagic phenotypes, were investigated. The affected gly...

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Veröffentlicht in:Blood 2002-02, Vol.99 (4), p.1495-1497
Hauptverfasser: Pinotti, Mirko, Etro, Daniela, Bindini, Debora, Papa, Maria Luisa, Rodorigo, Giuseppina, Rocino, Angiola, Mariani, Guglielmo, Ciavarella, Nicola, Bernardi, Francesco
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Sprache:eng
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Zusammenfassung:Two cross-reacting material–positive (CRM+) factor VII (FVII) mutations, associated with similar reductions in coagulant activity (2.5%) but with mild to asymptomatic (Gly331Ser, c184 [in chymotrypsin numbering]) or severe (Gly283Ser, c140) hemorrhagic phenotypes, were investigated. The affected glycines belong to structurally conserved regions in the c184 through c193 and c140s activation domain loops, respectively. The natural mutants 331Ser-FVII and 283Ser-FVII were expressed, and in addition 331Ala-FVII and 283Ala-FVII were expressed because 3 functional serine-proteases bear alanine at these positions. The 331Ser-FVII, present in several asymptomatic subjects, showed detectable factor Xa generation activity in patient plasma (0.7% ± 0.2%) and in reconstituted system with the recombinant molecules (2.7% ± 1.1%). The reduced activity of recombinant 283Ala-FVII (7.2% ± 2.2%) indicates that the full function of FVII requires glycine at this position, and the undetectable activity of 283Ser-FVII suggests that the oxydrile group of Ser283 participates in causing severe CRM+ deficiency. Furthermore, in a plasma system with limiting thromboplastin concentration, 283Ser-FVII inhibited wild-type FVIIa activity in a dose-dependent manner.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood.V99.4.1495