title: A novel approach to improving recombinant factor VIIa activity with a preserved platelet preparation.
abstract: Recombinant activated factor VII (NovoSeven, rFVIIa) is used to abrogate bleeding in haemophiliacs with inhibitors and is hypothesised to work by increasing activated factor X generation on the platelet surface. We hypothesised that rFVIIa activity could be increased by the co-addition of platelet procoagulant surface. This study characterised the ability of a rehydrated, lyophilised (RL) platelet preparation to increase rFVIIa activity in haemophilic conditions. RL platelets supported thrombin generation in the presence of factors VIII and IX but, in the absence of factors VIII and IX, thrombin generation was significantly reduced. RL platelets supported rFVIIa-mediated thrombin generation in a rFVIIa-concentration dependent manner. In a cell-based in vitro model of haemophilia, the presence of RL platelets increased the rFVIIa-dependent thrombin generation rate 2.8-fold compared with rFVIIa alone. Similarly, the addition of RL platelets plus rFVIIa to the in vitro model of haemophilia and to haemophilic platelet-rich plasma shortened the onset of clot formation and increased clot stability in a fibrinolytic environment versus rFVIIa alone. These results suggest that RL platelets can support rFVIIa-mediated thrombin generation, and that co-administration of RL platelets with rFVIIa may increase the efficacy of rFVIIa in some patients.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599-7525, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Campbell
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Fischer
authors.forename: Alisa S
authors.initials: AS
authors.lastname: Wolberg
mesh_terms: D001777:Blood Coagulation; D001779:Blood Coagulation Factors / Q000627:therapeutic use*; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D005167:Factor VII / Q000627:therapeutic use*; D015942:Factor VIIa; D005337:Fibrin / Q000032:analysis; D006467:Hemophilia A / Q000097:blood / Q000628:therapy*; D006801:Humans; D009391:Nephelometry and Turbidimetry; D015539:Platelet Activation; D010973:Platelet Adhesiveness; D011994:Recombinant Proteins / Q000627:therapeutic use; D013917:Thrombin / Q000032:analysis; D014021:Tissue Preservation
chemical_list: D001779:Blood Coagulation Factors; D011994:Recombinant Proteins; C049426:platelet procoagulant factor; D005167:Factor VII; D005337:Fibrin; C103587:recombinant FVIIa; D015942:Factor VIIa; D013917:Thrombin