Pharmacology and clinical use of recombinant activated factor seven in neurosciences

Abstract

Recombinant activated factor VII (rFVIIa, NovoSeven, NovoNordisc, Danemark) has been approved for the treatment of patients with hemophilia with inhibitors, further indications, at least in some countries, include the treatment of factor VII deficiency and Glanzmann thrombasthenia refractory to conventional therapy. Apart from these indications, the agent is increasingly used for the treatment of severe and potentially life-threatening bleeding manifestations, irrespective of the underlying hemostatic abnormality. The agent has successfully been used for the treatment of both inherited and acquired coagulopathies as well as thrombocytopathia or thrombocytopenia, however, most information on off-label use derives from case reports and retrospective studies and therefore publication bias can-not be excluded. In this review, we focus on the use of rFVIIa for the treatment of spontaneous and perioperative intracranial hemorrhage as well as trauma patients. We review the current knowledge regarding the physiology of hemostasis, the pharmacology of rFVIIa, and its clinical use in neurosciences. Further studies are urgently needed to define the efficacy and safety of recombinant activated factor VII in patients without hemophilia, factor VII deficiency, or Glanzmann thrombasthenia. At time, its use can be justified in life-threatening bleeding situations refractory to conventional treatment.

Cerebellar hemorrhage as a first presentation of acquired Hemophilia A

“…Treatment of AHA requires two complementary strategies: control of the initial bleeding episode and suppressing production of the inhibitory antibody. In patients with high inhibitor titers (>5 BU/ml) or in patients with life-threatening acute bleeding episodes, administration of a bypassing agent such as recombinant activated factor VII (rFVIIa) or the activated prothrombin complex concentrate (aPCC) FVIII inhibitor bypassing activity (FEIBA) have been proven effective [2,10]. Therapy with rFVIIa should be instituted at 90-120 lg/kg intravenously every 2-3 h while aPCC can be administered at 50-100 IU/kg intravenously every 8-12 h until clinical response [2].…”

Rol del factor VII recombinante activado en pacientes neuroquirúrgicos y neurocríticos

“…También parece presentar eficacia en el bloqueo de los efectos de nuevos fármacos anticoagulantes como el fondaparinux, del que no dispone de antídoto específico 12,77,96 y el idraparinux, un pentasacárido con una vida media de 5,5 días 13 . La eficacia del aFVIIr puede disminuir cuando hay déficit de otros factores 122 , pero especialmente en presencia de la triada acidosis-hipotermia-hemodilución 53 . En caso 53,57,112 de acidosis importante (pH<7,1), hasta un 90% del aFVIIr puede inactivarse 10 .…”

“…La eficacia del aFVIIr puede disminuir cuando hay déficit de otros factores 122 , pero especialmente en presencia de la triada acidosis-hipotermia-hemodilución 53 . En caso 53,57,112 de acidosis importante (pH<7,1), hasta un 90% del aFVIIr puede inactivarse 10 . También parece menos eficaz cuando el paciente presenta lesión a nivel de varias cavidades corporales y en los casos graves con shock hemorrágico profundo 21 .…”

“…Por otro lado, el fármaco puede favorecer la liberación de citoquinas proinflamatorias 87 . Los eventos trombóticos se han situado en torno al 1-2% en los pacientes hemofílicos 77,85 , aunque la incidencia parece mayor en las indicaciones "off-label" 53,86,103,106,116 y con dosis elevadas del fármaco 86 . Una revisión de 13 ensayos clínicos realizados hasta 2005, en indicaciones ajenas a la hemofilia, mostró un 5,3% de eventos adversos en los pacientes que recibían placebo, frente a un 6,0% en los que recibían el tratamiento activo 78 .…”

Recombinant Factor VIIa and the Patient With Neurologic Bleeding

“…Although controversy exists as to the exact mechanisms involved, TF is exposed in traumatized vessels. Factor VIIa is attracted to the site of vascular damage where it binds with TF to produce high concentrations of TF/FVIIa complex (Hartmann & Sucker, 2007). In combination with FVa and FXa, this process ultimately results in thrombin generation.…”