title: Prophylactic efficacy and pharmacokinetically guided dosing of a von Willebrand factor/factor VIII concentrate in adults and children with von Willebrand's disease undergoing elective surgery: a pooled and comparative analysis of data from USA and European Union clinical trials.
abstract: BACKGROUND
  Surgical intervention may pose significant risk of life-threatening bleeding in patients with von Willebrand's disease; prophylactic treatment with von Willebrand factor/factor VIII concentrate is generally indicated for von Willebrand's disease characterized by moderate to severe qualitative and quantitative deficiencies of Willebrand factor to raise and maintain both Willebrand factor and FVIII at haemostatic levels for surgical prophylaxis.
  
  
  METHODS
  Since prospective clinical data in such situations were lacking, two recent, prospective, multicentre studies evaluated the prophylactic perioperative use of the on Willebrand factor/ factor VIII concentrates, Humate-P® and Haemate P. Despite some differences in the two studies, one conducted in the USA (n =35) and one in the European Union (n =27), the designs were similar enough to allow for a limited pooled analysis of data. In both studies, preoperative loading doses and subsequent maintenance doses were calculated using individual subject-derived incremental in vivo recovery values, although von Willebrand factor:ristocetin cofactor and FVIII:coagulation activity target levels differed between the protocols. Efficacy was rated daily by the investigator as excellent, good, moderate, or poor.
  
  
  RESULTS
  Overall haemostatic efficacy (rating of excellent/good), assessed 24 hours after the last infusion (USA) or taken as the worst rating between surgery and day 14 (EU), was achieved in 95% of the pooled population of 62 adults and children. Efficacy did not appear to be affected by dosing variations. The rate of possibly related adverse events was low (8 subjects; 13%); one of these events was considered serious (pulmonary embolism).
  
  
  CONCLUSIONS
  This pooled analysis of a relatively large number of patients for a rare disease confirms the feasibility of pharmacokinetically guided dosing of von Willebrand factor/factor VIII concentrate and highlights its efficacy and safety in the prevention of excessive perioperative bleeding.
authors.affiliation: Scientific Direction, IRCCS Ca' Granda Maggiore Policlinico Foundation, Milan, Italy.
authors.forename: Pier
authors.initials: P
authors.lastname: Mannuccio Mannucci
authors.affiliation: Department of Medicine I, Medical University of Vienna, Vienna, Austria.
authors.forename: Paul Alexander
authors.initials: PA
authors.lastname: Kyrle
authors.affiliation: Department of Medicine, McMaster University and Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada.
authors.forename: Sam
authors.initials: S
authors.lastname: Schulman
authors.affiliation: University of Colorado Denver School of Medicine, Aurora, CO, United States of America.
authors.forename: Jorge
authors.initials: J
authors.lastname: Di Paola
authors.affiliation: Department of Paediatric Haematology and Oncology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Schneppenheim
authors.affiliation: Comprehensive Center for Bleeding Disorders, Blood Center of Wisconsin, Medical College of Wisconsin, Milwaukee, WI, United States of America.
authors.forename: Joan
authors.initials: J
authors.lastname: Cox Gill
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004338:Drug Combinations; D005169:Factor VIII / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D006490:Hemostatics / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D014842:von Willebrand Diseases / Q000097:blood* / Q000188:drug therapy*; D014841:von Willebrand Factor / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D004338:Drug Combinations; D006490:Hemostatics; C509423:factor VIII, von Willebrand factor drug combination; D014841:von Willebrand Factor; C078147:F8 protein, human; D005169:Factor VIII