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Coagulation Disorders


Evidence Supporting the Use of Recombinant Activated Factor VII in Congenital Bleeding Disorders


Pär I Johansson1 and Sisse R Ostrowski2 1. Medical Director; 2. Consultant, Section for Transfusion Medicine, Capital Region Blood Bank, Rigshospitalet, University of Copenhagen


Abstract


Recombinant activated factor VII ([rFVIIa] NovoSeven) was introduced in 1996 for the treatment of haemophilia patients with inhibitors (HPIs) to factor VIII or IX. This article reviews the evidence for the use of rFVIIa in congenital bleeding disorders. English-language databases were searched in September 2009 for reports of randomised controlled trials (RCTs) evaluating the effect of rFVIIa on haemostasis in congenital bleeding disorders. Eight RCTs comprising 256 HPIs were identified. The evidence for the use of rFVIIa in HPIs in terms of dose, clinical setting, modes of administration, efficacy and adverse events was weak, given the limited number of patients included and the heterogeneity of the RCTs. Overall, the haemostatic efficacy of rFVIIa varied from 25 to 100% in the studies reviewed; <1% of the patients receiving rFVIIa developed a thromboembolic adverse event. The authors suggest that the addition FVIIa therapy to HPIs should be based on the patient’s ability to generate thrombin and form a clot, rather than being based on weight alone. Assays reflecting thrombin generation, such as whole-blood thrombelastography, have the potential to significantly improve the treatment of these patients.


Keywords Recombinant activated factor VII (rFVIIa), haemophilia, randomised controlled trials (RCTs), bleeding, monitoring, thrombelastography


Disclosure: The authors have no conflicts of interest to declare. Received: 16 September 2010 Accepted: 18 January 2011 Citation: European Oncology & Haematology, 2011;7(1):71–5 Correspondence: Pär I Johansson, Medical Director, Section for Transfusion Medicine, Capital Region Blood Bank, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. E: per.johansson@rh.regionh.dk


Patients with haemophilia are subject to recurrent bleeding episodes. Those with severe haemophilia have a reduced life expectancy, with liver disease/hepatocellular carcinoma and intracranial haemorrhage being the primary causes of death.1


Some patients with haemophilia


develop antibodies against the replaced coagulation factors, commonly denoted inhibitors, because they inactivate the biological activity of the replaced factors.2 mortality in these patients.3


This is a major cause of morbidity and Surgery is avoided where possible as the


presence of inhibitors makes it difficult to secure peri-operative haemostasis, although those with low-titre inhibitors face fewer clinical problems since haemostasis can usually be achieved by saturating the inhibitor with higher doses of the deficient factor.


However, in patients with high-titre inhibitors other treatment modalities must be used (plasmapheresis, immunoabsorption, immune tolerance induction) and/or their activity bypassed.


Factor Eight Inhibitor Bypassing Activity Factor eight inhibitor bypassing activity (FEIBA), an activated prothrombin complex concentrate, has been used as a haemostatic bypassing agent in patients with high-responding inhibitors for decades.4


Recombinant activated factor VII ([rFVIIa] NovoSeven) was introduced as a haemostatic bypassing agent in 1996. It was initially used for the treatment of bleeds in patients with inhibitors, with a recommended dosing schedule of 90µg/kg rFVIIa every two to three hours until haemostasis was achieved.5


In 2007, the European Medicines Agency (EMEA) approved the use of single-dose rFVIIa © TOUCH BRIEFINGS 2011


270µg/kg for the treatment of mild-to-moderate bleeds in haemophilia patients with inhibitors.6


rFVIIa is currently a first-line treatment for


In Europe, rFVIIa therapy has also been approved for the treatment of patients with congenital FVII deficiency or Glanzmann’s thrombasthenia refractory to platelet transfusions.


bleeding episodes in patients with congenital haemophilia A and B with inhibitors and is used to treat patients with acquired haemophilia.7–9


The administration of pharmacological doses of rFVIIa (90µg/kg) induces haemostasis in the absence of FVIII or FIX. It probably does this by enhancing thrombin generation on the surface of the activated platelet leading to clot formation, with a stable near-normal fibrin clot network forming a strong haemostatic plug.5


rFVIIa also inhibits


fibrinolysis in vitro in haemophilia A by induction of thrombin- activatable fibrinolysis inhibitor (TAFI) activation, improving clot stability.10


This article presents the evidence for the use of rFVIIa in congenital bleeding disorders. Methods of the Studies Included


English-language databases were searched, including MEDLINE, ScienceDirect, CINAHL and Blackwell Science, for reports of randomised controlled trials (RCTs) that tested the effect of rFVIIa on haemostasis in patients with congenital haemophilia A and B, congenital FVII deficiency or Glanzmann’s thrombastenia. The inclusion criteria were prospective RCT, use of rFVIIa and presence of a control group. End-points investigated were the achievement of haemostasis and the development of thromboembolic complications.


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