Recombinant factor VIIa in paediatric bleeding disorders – a 2006 review
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Summary. Recombinant factor VIIa (rFVIIa) has been used in haemophilia bleeding since its introduction in 1996. It has been found to be safe and effective in the majority of patients with haemophilia who have developed inhibitors. There is increasing use of rFVIIa in many off‐label bleeding conditions, but there is a paucity of randomized studies regarding the use of rFVIIa in children. This review will attempt to address and summarize the studies focusing on the role of rFVIIa in both haemophilia and non‐haemophilia bleeding conditions in children. rFVIIa has been administered as both bolus and continuous infusions, and at varying doses. Furthermore, adverse events have not reportedly increased in children despite growing experience with its use in the paediatric population.Keywords:
Recombinant Factor VIIa
Factor VIIa
Recombinant factor VIIa (rFVIIa) has been used to treat bleeding complications in patients with hemophilia. It acts at the site of vessel injury, forming a complex with tissue factor to activate the clotting cascade. Recent reports have shown rFVIIa may be a useful hemostatic agent in patients after obstetrical, urologic, trauma, or transplant procedures. We report the first documented case of bleeding from hemorrhage pancreatitis treated with rFVIIa.
Recombinant Factor VIIa
Factor VIIa
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Coagulation cascade
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Many patients with haemophilia develop inhibitors to factor VIII and require bypassing agents to provide haemostatic cover for limb- or life-threatening bleeding episodes. Due to the reduced risk of blood-borne pathogen transmission with recombinant products, on-demand recombinant factor VIIa (rFVIIa; NovoSeven is the treatment of choice for children with inhibitors. In haemophiliac patients without inhibitors, primary prophylaxis has been clinical practice for several years. This paper summarises 13 case histories of rFVIIa secondary prophylaxis for haemophilia patients with inhibitors. This was a retrospective survey of adult and paediatric severe haemophilia patients with inhibitors treated with rFVIIa from ten European Haemophilia Centres. There was a wide variation in administered rFVIIa dose, from 200-250 microg kg(-1) per week to 220 microg kg(-1) daily. In many cases, this was lower than the recommended on-demand dose of rFVIIa. In 12/13 cases, prophylaxis with rFVIIa considerably reduced the number of bleeding episodes compared with previous treatment. Eight/nine patients were satisfied or very satisfied with rFVIIa treatment, and in cases reporting subjective quality of life (QoL), all were improved, much improved, or significantly improved. In haemophilia patients with inhibitors, prophylaxis with rFVIIa is highly effective in reducing the number of bleeding episodes and results in good patient compliance and improved QoL. Randomised controlled trials are needed to confirm these findings. Results of a recently completed clinical trial on secondary prophylaxis with rFVIIa in frequently bleeding haemophilia patients with inhibitors are expected in late 2006.
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Post‐traumatic bleeding from the gingiva in a 16‐month‐old boy with severe haemophilia A did not stop after treatment with factor VIII concentrate and tranexamic acid, and it was demonstrated that he had developed antibodies to factor VIII. Treatment with recombinant factor VIIa 60‐90 μg/kg body weight four to eight times daily, together with local measures, stopped the bleeding and no complications were seen.
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Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: The objective of this systematic review is to determine the optimal use of recombinant factor VIIa (rFVIIa) when used for the prophylactic or therapeutic management of haemorrhage in patients without haemophilia.
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Development of inhibitors is a known complication in some haemophiliacs receiving coagulation factor replacement therapy. We report on the successful management of a young boy with haemophilia A with inhibitor using recombinant factor VIIa. We had failed to control bleeding in this patient following his circumcision, despite infusion with high doses of factor VIII concentrate for 2 weeks. Recombinant factor VIIa is a useful ‘factor VIII bypassing agent’ for the control of bleeding in patients with haemophilia A and B who develop inhibitors. We suggest that severely affected haemophiliacs should be absolved of ritual circumcision as a protective measure against what might become a life‐threatening haemorrhage – especially in those with inhibitors.
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The development of inhibitor antibodies is one of the more important complications in the management of haemophilia patients. In a previous study, the prevalence of inhibitor varies between 5 and 52%, seems to be different for different types of concentrates, and is less frequent in multitransfused patients. In our prospective study we followed for 3 years 62 multitransfused haemophilia patients without inhibitor or past history of inhibitor. Thirty-seven haemophilia patients were treated with intermediate purity factor VIII concentrates, whereas 25 were given high purity concentrates (from the eighth month of the study five of these patients were treated with recombinant products). Factor VIII inhibitor antibody developed in seven of 25 haemophilia patients treated with high purity concentrates or recombinant products, whereas none of the haemophilia patients treated with intermediate purity concentrates had inhibitors. The difference was statistically significant (P < 0.001; OR = 0.06, 95% CI 0.001–0.3). In all patients, the titre of the inhibitor was low and no problem occurred in their management. Since inhibitors appeared in multitransfused patients when transfused with high purity concentrates and/or when the patients were switched to recombinant FVIII product, the development of inhibitor seems to be due to the administration of a new concentrate. Therefore this potential complication must be considered every time a new concentrate is administered.
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To survey the entire population (n = 116) afflicted with severe haemophilia A or B born in Sweden over a 20-y period (1980-1999), and to examine the epidemiological, genetic and clinical aspects of development of inhibitors to factors VIII and IX (FVIII/FIX).One hundred of the subjects had haemophilia A and 16 had haemophilia B. All of these subjects had received prophylactic treatment and had a check-up of inhibitor status at least twice a year. Sixty-one were born between 1980 and 1989 and 55 between 1990 and 1999.Nineteen percent (19/100) of those with haemophilia A and 37% (6/16) with haemophilia B developed inhibitors at 12-18 mo of age, after exposure to FVIII/FIX concentrates for an average of 14 d in the case of haemophilia A and 16 d in haemophilia B. All patients with inhibitors carried mutations that impaired protein synthesis. The high incidence of FIX inhibitors may have been due to the large number of complete deletions (13%) in the Swedish haemophilia B population. Patients with haemophilia A showed no significant increase (p = 0.65) in incidence of inhibitors (n = 10/48, total incidence 21%) in the 1990s, when they were treated mainly with recombinant products, as compared to the 1980s (n = 9/52, 17%), when they received intermediate/high-purity plasma-derived concentrates.Our population-based study verifies that genotype has a general impact on the incidence of FVIII/FIX inhibitors, and that recombinant FIII/FIX concentrates are not a predisposing factor for inhibitor development.
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Aim : To survey the entire population ( n = 116) afflicted with severe haemophilia A or B born in Sweden over a 20‐y period (1980–1999), and to examine the epidemiological, genetic and clinical aspects of development of inhibitors to factors VIII and IX (FVIII/FIX). Methods : One hundred of the subjects had haemophilia A and 16 had haemophilia B. All of these subjects had received prophylactic treatment and had a check‐up of inhibitor status at least twice a year. Sixty‐one were born between 1980 and 1989 and 55 between 1990 and 1999. Results : Nineteen percent (19/100) of those with haemophilia A and 37% (6/16) with haemophilia B developed inhibitors at 12–18 mo of age, after exposure to FVIII/FIX concentrates for an average of 14 d in the case of haemophilia A and 16 d in haemophilia B. All patients with inhibitors carried mutations that impaired protein synthesis. The high incidence of FIX inhibitors may have been due to the large number of complete deletions (13%) in the Swedish haemophilia B population. Patients with haemophilia A showed no significant increase ( p = 0.65) in incidence of inhibitors ( n = 10/48, total incidence 21%) in the 1990s, when they were treated mainly with recombinant products, as compared to the 1980s ( n = 9/52,17%), when they received intermediate/high‐purity plasma‐derived concentrates. Conclusion : Our population‐based study verifies that genotype has a general impact on the incidence of FVIII/FIX inhibitors, and that recombinant FIII/FIX concentrates are not a predisposing factor for inhibitor development.
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Summary. Recombinant factor VIIa (rFVIIa) has been used in haemophilia bleeding since its introduction in 1996. It has been found to be safe and effective in the majority of patients with haemophilia who have developed inhibitors. There is increasing use of rFVIIa in many off‐label bleeding conditions, but there is a paucity of randomized studies regarding the use of rFVIIa in children. This review will attempt to address and summarize the studies focusing on the role of rFVIIa in both haemophilia and non‐haemophilia bleeding conditions in children. rFVIIa has been administered as both bolus and continuous infusions, and at varying doses. Furthermore, adverse events have not reportedly increased in children despite growing experience with its use in the paediatric population.
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Abstract Women and girls reported as “haemophilic females” may have complex genetic causes for their haemophilia phenotype. In addition, women and girls may have excessive bleeding requiring treatment simply because they are heterozygous for haemophilia alleles. While severe and moderate haemophilia are rare in females, 16% of patients with mild haemophilia A and almost one‐quarter of those with mild haemophilia B seen in U.S. haemophilia treatment centres are women and girls. A phenotypic female with a low level of factor VIII or factor IX may be classified into one of the following categories of causality: homozygosity (two identical haemophilia alleles), compound heterozygosity (two different haemophilia alleles), hemizygosity (one haemophilia allele and no normal allele), heterozygosity (one haemophilia allele and one normal allele), genetic causes other than haemophilia and non‐genetic causes. Studies required for classification may include coagulation parameters, F8 or F9 sequencing, F8 inversion testing, multiplex ligation‐dependent probe amplification, karyotyping and X chromosome inactivation studies performed on the patient and parents. Women and girls who are homozygous, compound heterozygous or hemizygous clearly have haemophilia, as they do not have a normal allele. Heterozygous women and girls with factor levels below the haemostatic range also meet the definitions used for haemophilia treatment.
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