Recombinant factor VIIa reduces bleeding in severely thrombocytopenic rabbits.
Severe thrombocytopenia is a common complication to intensive chemotherapeutic regimens. For bleeding episodes associated with severe thrombocytopenia, the current standard treatment is platelet transfusion. However, due to several transfusion complications such as transfusion-transmitted diseases, platelet refractoriness and immunomodulation, as well as increasing problems with sufficient supply of platelet products, it is imperative to search for alternatives to platelet transfusion. To test the efficacy of recombinant activated human coagulation factor VII (rFVIIa, NovoSeven) in thrombocytopenia, a preclinical study was conducted in thrombocytopenic rabbits. Thrombocytopenia was induced by a combination of gamma-irradiation and the use of platelet antibodies, and the effect of rFVIIa on nail cuticle bleeding was determined. Administration of rFVIIa at 2 mg/kg significantly shortened the prolonged bleeding time in thrombocytopenic animals (rFVIIa vs. control, median 23 min 41 s vs. 60 min, p=0.016) as well as significantly reducing the blood loss (rFVIIa vs. control, median: 8.8 vs. 12.2 nmol hemoglobin/ml, p=0.016). This effect was also reflected by a significant reduction of the prothrombin time, activated partial thromboplastin time, as well as improvement in clotting parameters in an in vitro thromboelastography thrombocytopenia model. Histopathological evaluation of kidney biopsies for the presence of micro thrombi did not reveal evidence of prothrombotic effects of rFVIIa in this model. These data demonstrate the haemostatic efficacy of rFVIIa in a rabbit model of severe thrombocytopenia. Clinical trials will be needed to further explore the potential of NovoSeven as a haemostatic agent in thrombocytopenic patients.
Tranholm
Mikael
M
Pharmacology Research 5, Pharmacology Research and Development, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Maaloev, Denmark. mitr@novonordisk.com
Rojkjaer
Rasmus
R
Pyke
Charles
C
Kristensen
Annemarie T
AT
Klitgaard
Birgitte
B
Lollike
Karsten
K
Blajchman
Morris A
MA
D000818:Animals; D001760:Bleeding Time; D001772:Blood Cell Count; D001780:Blood Coagulation Tests; D004353:Drug Evaluation, Preclinical; D005167:Factor VII / Q000494:pharmacology*; D015942:Factor VIIa; D006470:Hemorrhage / Q000188:drug therapy / Q000517:prevention & control*; D006487:Hemostasis / Q000187:drug effects; D007668:Kidney / Q000187:drug effects; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology*; D013921:Thrombocytopenia / Q000150:complications / Q000188:drug therapy*
D011994:Recombinant Proteins; D005167:Factor VII; C103587:recombinant FVIIa; D015942:Factor VIIa