Mechanism of action, development and clinical experience of recombinant FVIIa.
Recombinant FVIIa has been developed for treatment of bleedings in hemophilia patients with inhibitors, and has been found to induce hemostasis even during major surgery such as major orthopedic surgery. Recombinant FVIIa is being produced in BHK cell cultures and has been shown to be very similar to plasma-derived FVIIa. The use of rFVIIa in hemophilia treatment is a new concept of treatment and is based on the low affinity binding of FVIIa to the surface of thrombin activated platelets demonstrated in a cell-based in vitro model. By the administration of pharmacological doses of exogenous rFVIIa the thrombin generation on the platelet surface at the site of injury is enhanced independently of the presence of FVIII/FIX. As a result of the increased and rapid thrombin formation, a tight fibrin hemostatic plug is being formed. A tight fibrin structure has been found to be more resistant to fibrinolytic degradation thereby helping to maintain hemostasis. The general mechanism of action of pharmacological doses of rFVIIa shown to induce hemostasis not only in hemophilia, but also in patients with platelet defects, and with profuse bleedings triggered by extensive surgery or trauma, may very well be the capacity of generating a tight fibrin hemostatic plug through the increased thrombin generation. Such a fibrin plug will help to resist the overwhelming mostly local release of fibrinolytic activity triggered by the vast tissue damage occurring in extensive trauma. A release of fibrinlytic activity locally has also been demonstrated to occur in the gastrointestinal tract as well as during profuse postpartum bleedings. Pharmacological doses of rFVIIa have in fact, also been shown to induce hemostasis in such cases.
Hedner
Ulla
U
University of Lund, Sweden. UHe@novonordisk.com
D005167:Factor VII / Q000494:pharmacology* / Q000627:therapeutic use; D015942:Factor VIIa; D006467:Hemophilia A / Q000188:drug therapy* / Q000601:surgery; D006801:Humans; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013915:Thrombasthenia / Q000188:drug therapy*
D011994:Recombinant Proteins; D005167:Factor VII; C103587:recombinant FVIIa; D015942:Factor VIIa