title: Factor XIII combined with recombinant factor VIIa: a new means of treating severe hemophilia A.
abstract: BACKGROUND
  Abnormal thrombin generation is considered the key defect in hemophilia. Conventional treatment seeks to correct this using coagulation factor replacement or bypassing agents, for example recombinant factor VIIa (rFVIIa). Previous studies demonstrate abnormal FXIII activation in patients with hemophilia. FXIII activation is essential for formation of structurally normal, stable clots.
  
  
  OBJECTIVE
  The present study challenges the hypothesis that in hemophilia the use of plasma-derived FXIII (pdFXIII) in combination with rFVIIa will produce a greater improvement in clot stability than promotion of thrombin generation alone.
  
  
  METHODS
  Fourteen individuals with severe hemophila A were enrolled. Whole blood was spiked ex vivo with buffer, rFVIIa (2 μg mL(-1)) or rFVIIa (2 μg mL(-1)) plus pdFXIII (10 μg mL(-1)). Whole blood thromboelastometry assessed clot stability, after activation with tissue factor (TF) (0.15 pm) plus tissue-type plasminogen activator (tPa) (2 nm). The primary outcome measure of clot stability was area under the elasticity curve (AUEC).
  
  
  RESULTS
  The combination of pdFXIII and rFVIIa significantly improved clot stability as measured by AUEC (P < 0.05) compared with rFVIIa alone.
  
  
  CONCLUSIONS
  The use of pdFXIII resulted in superior clot stability compared with solely enhancing thrombin generation and we suggest that increasing thrombin generation alone fails to fully correct dysregulation of clot-stabilizing mechanisms associated with bleeding disorders. Hemorrhage control in hemophilia may be improved using clot stabilizing drugs. FXIII shows potential as a novel agent.
authors.affiliation: Haemostasis Research Unit, Guy's & St Thomas' NHS Foundation Trust and King's College London School of Medicine, London, UK.
authors.forename: C J
authors.initials: CJ
authors.lastname: Rea
authors.forename: J H
authors.initials: JH
authors.lastname: Foley
authors.forename: J
authors.initials: J
authors.lastname: Ingerslev
authors.forename: B
authors.initials: B
authors.lastname: Sørensen
mesh_terms: D000328:Adult; D001777:Blood Coagulation / Q000187:drug effects; D004359:Drug Therapy, Combination; D015942:Factor VIIa / Q000008:administration & dosage*; D005176:Factor XIII / Q000008:administration & dosage*; D006467:Hemophilia A / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000008:administration & dosage; D013916:Thrombelastography; D013917:Thrombin / Q000096:biosynthesis; D055815:Young Adult
chemical_list: D011994:Recombinant Proteins; D005176:Factor XIII; C103587:recombinant FVIIa; D015942:Factor VIIa; D013917:Thrombin