Reduced activation of the Gla19Ala FX variant via the extrinsic coagulation pathway results in symptomatic CRMred FX deficiency.
We characterized a symptomatic CRMred factor X (FX) deficiency produced by the Glu19Ala mutation in the gamma-carboxyglutamic-rich domain. FX activity levels in plasma were markedly reduced in prothrombin time assays (< 1-5%), whereas in activated partial thromboplastin assays (16%) and in RVV assays (17%) the reduction in activity mirrored that in antigen levels (17%). Activation of recombinant 19Ala-FX by factor IXa/factor VIIIa or RVV, and the activity in thrombin generation assays, were comparable to those of wild-type FX. Differently, complete activation of recombinant 19Ala-FX required a factor VIIa/TF concentration 30-fold higher than that of wild-type FX. The recombinant FVIIa significantly reduced PT values in 19Ala-FX reconstituted plasma, thus suggesting an alternative approach for treatment of FX deficiencies characterized by defective FX activation. The study of this FX deficiency provides an "in vivo" and "in vitro" model for the investigation of Gla domain interactions.
Dipartimento di Biochimica e Biologia Molecolare, Università di Ferrara, Ferrara, Italy.
M
M
Pinotti
G
G
Marchetti
M
M
Baroni
F
F
Cinotti
M
M
Morfini
F
F
Bernardi
D001777:Blood Coagulation / Q000235:genetics*; D001780:Blood Coagulation Tests; D002460:Cell Line; D005170:Factor X / Q000235:genetics* / Q000378:metabolism*; D005171:Factor X Deficiency / Q000235:genetics*; D005192:Family Health; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D014162:Transfection
D005170:Factor X