title: Factor VIII-mediated global hemostasis in the absence of von Willebrand factor.
abstract: Although the efficacy of recombinant factor VIII (rFVIII) in the treatment of type 3 von Willebrand disease (VWD) has been reported, the mechanisms by which FVIII concentrates devoid of von Willebrand factor (VWF) induce improvements in hemostasis are poorly understood. To address the role of FVIII or intrinsic coagulation in the absence of VWF, we performed a hemostatic analysis. Blood samples were obtained before and after the administration of rFVIII to 2 patients with type 3 VWD. A rotating thromboelastometry assay was performed to examine global interactions in hemostasis. Studies of thrombin-and shear-induced platelet aggregation were also conducted to elucidate the effect on platelet activation. Furthermore, we assessed the rise in the thrombin-induced intracellular concentration of free calcium [Ca2+]i. Addition of rFVIII to preinfusion blood in vitro corrected thromboelastometric parameters and thrombin-induced aggregation. In ex vivo studies, thromboelastometry analysis showed that rFVIII shortened the onset and progression of the coagulation process. Furthermore, rFVIII corrected low shear-induced and thrombin-induced platelet aggregation in platelet-rich plasma. In addition, rFVIII improved thrombin-induced [Ca2+]i flux in washed platelets. Our observations suggested that FVIII is incorporated into platelets to activate them, as well as to act directly in intrinsic coagulation in the absence of VWF. FVIII may play a critical role even in the absence of VWF.
authors.affiliation: Department of Pediatrics, Nara Medical University School of Medicine, Kashihara, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Takeyama
authors.forename: Shogo
authors.initials: S
authors.lastname: Kasuda
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Sakurai
authors.forename: Midori
authors.initials: M
authors.lastname: Shima
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Takeda
authors.forename: Shoko
authors.initials: S
authors.lastname: Omura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Naka
authors.forename: Akira
authors.initials: A
authors.lastname: Yoshioka
mesh_terms: D001792:Blood Platelets / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002675:Child, Preschool; D005169:Factor VIII / Q000378:metabolism / Q000494:pharmacology*; D006487:Hemostasis / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects; D013916:Thrombelastography; D014842:von Willebrand Diseases / Q000097:blood* / Q000188:drug therapy*; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D014841:von Willebrand Factor; C078147:F8 protein, human; D005169:Factor VIII; D002118:Calcium