Abstract
recombinant activated factor VII (rFVIIa) is used off-label for massive bleeding. There is no convincing evidence of the benefits of this practice and the minimal effective dose is unknown. The aim of the study was to evaluate our in-house guideline recommending a low dose of 60 μg/kg for off-label use of rFVIIa. observational cohort study at the Inselspital Bern, a tertiary care University Hospital in Switzerland. All patients with massive bleeding treated off-label with rFVIIa between January 2005 and December 2007 were included. Survival, change of bleeding and transfusion rates, coagulation parameters and complications were analysed. seventy-three patients received rFVIIa. Severe haemorrhage was documented by a bleeding rate of 1000 mL/h (median; interquartile range 350-3000) and total volume replacement of 11.9 L (6.6-15.2) before administration of rFVIIa. The median rFVIIa-dose was 64 μg/kg (56-71). rFVIIa was administered once in 79% patients, twice in 18%. The bleeding rate was reduced in 82% of the patients. Transfused packed red blood cells decreased from 14 units (8-22) over 4.9 h (2.5-8.8) before rFVIIa to 2 (0-6) in 24 h thereafter, platelet concentrates from 2 units (1-3) to 1 (0-2) and FFP from 11 units (6-16) to 2 (0-9). In-hospital mortality was 14% within 24 h and 32% at day 30. There were two arterial thromboembolic complications possibly related to rFVIIa. a single injection of 60 μg/kg rFVIIa, a lower dose than usually recommended, appears to be efficacious in controlling massive bleeding with a very low complication rate.
Highlights
Recombinant activated factor VII has been licensed in Europe for use in patients with haemophilia A or B with inhibitory alloantibodies, with acquired haemophilia, with congenital deficiency of coagulation factor VII, or with Glanzmann’s thrombasthenia [1]
While published meta-analyses did show no significant difference between patients who received recombinant factor VIIa (rFVIIa) and patients who received placebo with respect to the incidence of venous thromboembolic events [4, 22], treatment with rFVIIa significantly increased the risk of arterial thromboembolic events [4, 22], in particular among elderly patients [22]
In 2004, we had chosen to employ for off-label use at our institution a low rFVIIa dose of 60 μg/kg because it leads to a plasmatic rFVIIa concentration which still is 5-6 times higher than the minimal effective level [26], and because high rFVIIa doses could theoretically lead to excessive thrombin generation with consecutive activation of the anticoagulant protein C pathway by means of thrombin binding thrombomodulin [27]
Summary
Recombinant activated factor VII (rFVIIa) has been licensed in Europe for use in patients with haemophilia A or B with inhibitory alloantibodies, with acquired haemophilia, with congenital deficiency of coagulation factor VII, or with Glanzmann’s thrombasthenia [1]. A recently published meta-analysis of 26 randomised controlled studies in non-haemophilic patients found in 12 therapeutic trials a non-significant decrease in mortality and no difference in control of bleeding or red blood cell administration [6]. Many publications on off-label use of rFVIIa reported an effective median dose similar to that of standard indications, 90 μg/kg body weight [4, 23], or even much higher, up to 200 μg/kg body weight [10], there are some studies indicating a therapeutic effect already at lower doses, in particular in certain indications, such as acute intracerebral haemorrhage [8], traumatic bleeding [11, 12], retropubic prostatectomy [15] or cardiac surgery [24, 25].
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