title: Pharmacodynamics of recombinant activated factor VII and plasma-derived factor VII in a cohort of severe FVII deficient patients.
abstract: Recombinant activated factor VII (rFVIIa) and plasma-derived factor VII (pdFVII) are used to prevent bleedings in severe FVII deficient patients, despite their short half-lifes. It is suggested that FVII levels of 15-20 IU/dL are sufficient to maintain hemostasis. We analyzed the pharmacodynamic effects of FVII substitution therapy in the Nijmegen Hemostasis Assay (NHA) that simultaneously measures thrombin and plasmin generation. Ten severe FVII deficient patients were treated with 20 μg/kg rFVIIa or 25 IU/kg pdFVII in a cross-over design. Thrombin generation lag-time (TG-LT) was identified as an effect-response parameter. Pharmacodynamic analysis using a maximum effect model showed 50% reduction of the TG-LT effect at ~2 IU/dL FVII activity for both rFVIIa and pdFVII. The FVII activity to obtain TG-LT comparable to the upper limit of normal range in healthy controls (4 min) was given by the effective concentration (ECnormal), showing sufficient hemostasis at 3-4 IU/dL FVII activity. No association was seen between FVII activity and other thrombin or plasmin generation parameters as measured by NHA. In conclusion, 3-4 IU/dL FVII activity seems sufficient to maintain hemostasis in patients with severe FVII deficiency during prophylaxis. These data may suggest a potential value for measurement of TG-LT in the monitoring of FVII(a) therapy.
authors.affiliation: Department of Laboratory Medicine, Laboratory for Hematology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: van Geffen
authors.forename: Natascha C J
authors.initials: NC
authors.lastname: Mathijssen
authors.forename: Pål A
authors.initials: PA
authors.lastname: Holme
authors.forename: Britta A P
authors.initials: BA
authors.lastname: Laros-van Gorkom
authors.forename: Marian G J
authors.initials: MG
authors.lastname: van Kraaij
authors.forename: Roselinde
authors.initials: R
authors.lastname: Masereeuw
authors.forename: Flora
authors.initials: F
authors.lastname: Peyvandi
authors.forename: Waander L
authors.initials: WL
authors.lastname: van Heerde
mesh_terms: D000328:Adult; D015331:Cohort Studies; D005167:Factor VII / Q000494:pharmacology / Q000627:therapeutic use*; D005168:Factor VII Deficiency / Q000097:blood* / Q000188:drug therapy* / Q000378:metabolism; D015942:Factor VIIa / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005341:Fibrinolysin / Q000378:metabolism; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D008297:Male; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013917:Thrombin / Q000378:metabolism; D013918:Thrombin Time; D055815:Young Adult
chemical_list: D011994:Recombinant Proteins; D005167:Factor VII; C103587:recombinant FVIIa; D015942:Factor VIIa; D013917:Thrombin; D005341:Fibrinolysin
keywords: Factor VII; Factor VII deficiency; Factor VIIa; Plasmin generation; Rare Bleeding Disorder; Thrombin generation