title: Utility of a high VWF: FVIII ratio in preventing FVIII accumulation: a study in VWF-deficient mice.
abstract: Treatment of von Willebrand disease typically requires multiple infusions of von Willebrand factor (VWF)/factor VIII (FVIII) concentrate. Accumulation of FVIII is a clinical concern due to potential risk for thromboembolism. This study sought to determine whether VWF/FVIII concentrate of high VWF:FVIII ratio can prevent FVIII accumulation. VWF-deficient knockout mice received four 150 IU/kg VWF:ristocetin cofactor (RCo) infusions at 3-h intervals, with VWF/FVIII concentrates of a high (Haemate P/Humate-P) or low (Wilate) VWF:FVIII ratio. After each infusion, trough FVIII and VWF levels in plasma were determined. Separately, pharmacokinetic analysis was performed after single 250-IU/kg VWF:RCo infusions of each concentrate. Over the course of the four infusions, trough FVIII increased significantly in the group receiving Wilate (P < 0.001), but not Haemate P/Humate P (P = 0.058). After the first infusion, mean trough FVIII level in the Wilate group (31.7 IU/dl) was greater by 82% (P = 0.017) than that in the Haemate P/Humate P group (17.4 IU/dl). After the final infusion, mean trough FVIII of animals receiving Wilate (55.1 IU/dl) continued to exceed that of Haemate P/Humate P recipients (30.2 IU/dl) significantly (P < 0.001). Trough VWF levels were similar in the two groups. The VWF pharmacokinetics of the two concentrates coincided closely; however, the FVIII peak concentration and area under the curve were approximately twice as great in the mice treated with Wilate. In a murine model of severe von Willebrand disease, a VWF/FVIII concentrate with a high VWF:FVIII ratio prevented persistent exposure to elevated trough FVIII levels.
authors.affiliation: aPreclinical Research and Development bMedical Affairs, Commercial Development Coagulation, CSL Behring GmbH, Marburg, Germany cProduct Development, CSL Behring AG, Bern, Switzerland.
authors.forename: Elmar
authors.initials: E
authors.lastname: Raquet
authors.forename: Marcus
authors.initials: M
authors.lastname: Stockschlaeder
authors.forename: Jochen
authors.initials: J
authors.lastname: Mueller-Cohrs
authors.forename: Sabine
authors.initials: S
authors.lastname: Zollner
authors.forename: Ingo
authors.initials: I
authors.lastname: Pragst
authors.forename: Gerhard
authors.initials: G
authors.lastname: Dickneite
mesh_terms: D000818:Animals; D004338:Drug Combinations; D005169:Factor VIII / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D014841:von Willebrand Factor
chemical_list: D004338:Drug Combinations; C509423:factor VIII, von Willebrand factor drug combination; D014841:von Willebrand Factor; C427184:recombinant factor VIII SQ; D005169:Factor VIII