title: Reversal of the International Normalized Ratio with recombinant activated factor VII in central nervous system bleeding during warfarin thromboprophylaxis: clinical and biochemical aspects.
abstract: Major bleeding is a frequent and hazardous complication associated with thromboprophylaxis using vitamin-K antagonists (VKA). Suggested regimens for control of highly elevated International Normalized Ratio (INR) and hemorrhagic events during VKA treatment include administration of vitamin K, infusion of fresh frozen plasma (FFP) or a prothrombin complex concentrate (PCC). In contrast, this communication present the first report on the efficacious use of recombinant factor VIIa (rFVIIa) as additional therapy in seven patients presenting with central nervous system (CNS) bleeding emergencies. Pre-treatment INRs ranged from 1.7 to 6.6, and 10 min after a single dose of rFVIIa (10-40 microg/kg) all INRs were </= 1.5. Six patients underwent drainage of the CNS hematoma and all patients survived. No untoward biochemical signs of coagulation activation were detected and no incidence of thromboembolism was observed. In ex-vivo experimental studies, profiles of continuous whole blood clot formation were evaluated by thrombelastography in 25 patients on VKA treatment (INR 1.7-4.3), demonstrating a significantly prolonged initiation phase and diminished propagation of clot formation. Ex-vivo supplementation with rFVIIa to blood of six patients returned a distinct reduction of the prolonged initiation but variable changes in the maximum velocity of clot formation. The ex-vivo experiments and our clinical data support recent suggestions that rFVIIa might substitute for infusion of FFP or PCC in acute reversal of VKA treatment.
authors.affiliation: Center for Haemophilia and Thrombosis, Department of Clinical Immunology, Aarhus University Hospital, Skejby Sygehus, Denmark.
authors.forename: Benny
authors.initials: B
authors.lastname: Sørensen
authors.forename: Peter
authors.initials: P
authors.lastname: Johansen
authors.forename: Gitte L
authors.initials: GL
authors.lastname: Nielsen
authors.forename: Jens C
authors.initials: JC
authors.lastname: Sørensen
authors.forename: Jørgen
authors.initials: J
authors.lastname: Ingerslev
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000009:adverse effects* / Q000627:therapeutic use; D001777:Blood Coagulation / Q000187:drug effects*; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000188:drug therapy*; D003199:Computer Systems; D004341:Drug Evaluation; D005167:Factor VII / Q000494:pharmacology* / Q000627:therapeutic use; D015942:Factor VIIa; D005260:Female; D006406:Hematoma / Q000139:chemically induced / Q000188:drug therapy / Q000601:surgery; D006490:Hemostatics / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D013916:Thrombelastography; D013923:Thromboembolism / Q000517:prevention & control*; D016896:Treatment Outcome; D014812:Vitamin K / Q000037:antagonists & inhibitors; D014859:Warfarin / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D006490:Hemostatics; D011994:Recombinant Proteins; D014812:Vitamin K; D014859:Warfarin; D005167:Factor VII; C103587:recombinant FVIIa; D015942:Factor VIIa