title: Vitamin K-induced modification of coagulation phenotype in VKORC1 homozygous deficiency.
abstract: BACKGROUND
  Combined vitamin K-dependent clotting factor (VKCF) deficiency type 2 (VKCFD2) is a rare bleeding disorder caused by mutated vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1) gene.
  
  
  RESULTS
  An Italian patient with moderate to severe bleeding tendency was genotyped, and found to be homozygous for the unique VKORC1 mutation (Arg98Trp) so far detected in VKCFD2. The activity levels of VKCFs were differentially reduced, and inversely related to the previously estimated affinity of procoagulant factor propeptides for the gamma-carboxylase. The normal (factor IX) or reduced antigen levels (other VKCFs) produced a gradient in specific activities. Vitamin K supplementations resulted in reproducible, fast and sustained normalization of PT and APTT. At 24 h the activity/antigen ratios of VKCFs were close to normal, and activity levels were completely (factor VII and IX), virtually (prothrombin, factor X and protein C) or partially (protein S) restored. Thrombin generation assays showed a markedly shortened lag time. The time to peak observed at low tissue factor concentration, potentially mimicking the physiological trigger and able to highlight the effect of reduced protein S levels, was shorter than that in pooled normal plasma. At 72 h the thrombin generation times were normal, and the decrease in activity of procoagulant VKCFs was inversely related to their half-life in plasma. The improved coagulation phenotype permitted the uneventful clinical course after invasive diagnostic procedures.
  
  
  CONCLUSIONS
  Modification of coagulation phenotypes in VKCFD2 after vitamin K supplementation was clinically beneficial, and provided valuable patterns of factor specific biosynthesis, half-life and decay.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Marchetti
authors.forename: P
authors.initials: P
authors.lastname: Caruso
authors.forename: B
authors.initials: B
authors.lastname: Lunghi
authors.forename: M
authors.initials: M
authors.lastname: Pinotti
authors.forename: M
authors.initials: M
authors.lastname: Lapecorella
authors.forename: M
authors.initials: M
authors.lastname: Napolitano
authors.forename: A
authors.initials: A
authors.lastname: Canella
authors.forename: G
authors.initials: G
authors.lastname: Mariani
authors.forename: F
authors.initials: F
authors.lastname: Bernardi
mesh_terms: D000328:Adult; D001778:Blood Coagulation Disorders / Q000209:etiology / Q000235:genetics*; D001780:Blood Coagulation Tests; D005260:Female; D006207:Half-Life; D006720:Homozygote; D006801:Humans; D006899:Mixed Function Oxygenases / Q000172:deficiency / Q000235:genetics*; D009154:Mutation; D016896:Treatment Outcome; D014812:Vitamin K / Q000627:therapeutic use*; D064417:Vitamin K Epoxide Reductases
chemical_list: D014812:Vitamin K; D006899:Mixed Function Oxygenases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases