title: Assessment of recombinant factor VIIa as an antidote for bleeding induced in the rabbit by low molecular weight heparin.
abstract: While protamine sulfate reverses the anticoagulant effect of standard heparin, there currently is no effective antidote for low molecular weight heparin (LMWH)-induced bleeding. Recently, recombinant activated factor VII (rFVIIa) was approved by the FDA for use in hemophilia patients with factor (F)VIII or FIX inhibitors. However, this new pro-hemostatic agent has potential utility in other clinical scenarios. In this study, we utilized a well-characterized rabbit ear puncture model to test the efficacy of rFVIIa to reverse LMWH-induced prolonged bleeding. Animals were first treated with bolus intravenous LMWH (1800 anti-FXa U kg(-1)) which increased the primary bleeding time approximately fourfold and raised the plasma anti-FXa activity immediately and continuously throughout the 90-min experiment. In a randomized and blinded fashion, animals then received either rFVIIa (400 microg kg(-1)) or placebo by bolus intravenous injection, following which the ear puncture bleeding times were measured, along with blood levels of heparin (anti-FXa activity) and FVII. FVII activity increased 5.3-fold over baseline in treated animals, decreasing by only 24% over the full observation period. The rFVIIa-treated animals showed a slight decrease in bleeding time immediately after injection, but there was no statistically significant difference in bleeding after rFVIIa or placebo administration. In this study using a rabbit ear bleeding model, rFVIIa was not an effective antidote to LMWH-induced bleeding. However, the bolus injection of LMWH produced a very high blood anti-FXa level, which may have precluded rFVIIa effectiveness.
authors.affiliation: Vascular Medicine Program, Los Angeles Orthopaedic Hospital, Los Angeles, CA 90007, USA.
authors.forename: S
authors.initials: S
authors.lastname: Chan
authors.forename: M
authors.initials: M
authors.lastname: Kong
authors.forename: D M
authors.initials: DM
authors.lastname: Minning
authors.forename: U
authors.initials: U
authors.lastname: Hedner
authors.forename: V J
authors.initials: VJ
authors.lastname: Marder
mesh_terms: D000818:Animals; D000931:Antidotes; D001760:Bleeding Time; D004341:Drug Evaluation; D005167:Factor VII / Q000494:pharmacology / Q000627:therapeutic use*; D015942:Factor VIIa; D006470:Hemorrhage / Q000139:chemically induced / Q000188:drug therapy*; D006487:Hemostasis / Q000187:drug effects; D006495:Heparin, Low-Molecular-Weight / Q000009:adverse effects*; D007700:Kinetics; D008297:Male; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D000078222:Tinzaparin
chemical_list: D000931:Antidotes; D006495:Heparin, Low-Molecular-Weight; D011994:Recombinant Proteins; D000078222:Tinzaparin; D005167:Factor VII; C103587:recombinant FVIIa; D015942:Factor VIIa