title: Activated protein C inhibitor for correction of thrombin generation in hemophilia A blood and plasma1.
abstract: BACKGROUND
  Replacement therapy for hemophilic patient treatment is costly, because of the high price of pharmacologic products, and is not affordable for the majority of patients in developing countries.
  
  
  OBJECTIVE
  To generate and evaluate low molecular weight agents that could be useful for hemophilia treatment.
  
  
  METHODS
  Potential agents were generated by synthesizing specific inhibitors [6-(Lys-Lys-Thr-[homo]Arg)amino-2-(Lys[carbobenzoxy]-Lys[carbobenzoxy]-O-benzyl)naphthalenesulfonamide] (PNASN-1)] for activated protein C (APC) and tested in plasma and fresh blood from hemophilia A patients.
  
  
  RESULTS
  In the activated partial thromboplastin time-based APC resistance assay, PNASN-1 partially neutralized the effect of APC. In calibrated automated thrombography, PNASN-1 neutralized the effect of APC on thrombin generation in normal and congenital factor VIII-deficient plasma (FVIII:C < 1%). The addition of PNASN-1 to tissue factor-triggered (5 pm) contact pathway-inhibited fresh blood from 15 hemophilia A patients with various degrees of FVIII deficiency (FVIII:C < 1-51%) increased the maximum level of thrombin generated from 78 to 162 nm, which approached that observed in blood from a healthy individual (201 nm). PNASN-1 also caused a 47% increase in clot weight in hemophilia A blood.
  
  
  CONCLUSIONS
  Specific APC inhibitors compensate to a significant extent for FVIII deficiency, and could be used for hemophilia treatment.
authors.affiliation: Department of Biochemistry, University of Vermont, Burlington, VT, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Brummel-Ziedins
authors.forename: M F
authors.initials: MF
authors.lastname: Whelihan
authors.forename: G E
authors.initials: GE
authors.lastname: Rivard
authors.forename: S
authors.initials: S
authors.lastname: Butenas
mesh_terms: D001769:Blood / Q000187:drug effects; D001777:Blood Coagulation / Q000187:drug effects; D001780:Blood Coagulation Tests; D016022:Case-Control Studies; D004341:Drug Evaluation; D006467:Hemophilia A / Q000188:drug therapy*; D006801:Humans; D010314:Partial Thromboplastin Time; D018046:Protein C Inhibitor / Q000138:chemical synthesis / Q000494:pharmacology*; D013917:Thrombin / Q000096:biosynthesis* / Q000187:drug effects
chemical_list: D018046:Protein C Inhibitor; D013917:Thrombin