Cross‐reacting recombinant porcine FVIII inhibitors in patients with acquired haemophilia A
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Abstract Introduction Acquired haemophilia A (AHA) is a rare bleeding disorder caused by the development of autoantibodies to endogenous human factor VIII (hFVIII). If treatment of bleeding is required, one option is recombinant porcine FVIII (rpFVIII). Cross‐reactivity between factor VIII inhibitors and rpFVIII has previously been described. Aim The aim of this study was to retrospectively assess the incidence of cross‐reacting anti‐porcine inhibitors in patients diagnosed with AHA in two UK centres. Methods The plasma of fifty‐one patients diagnosed with AHA via reduced FVIII:C and positive FVIII inhibitor titre as detected with a Nijmegen‐Bethesda assay (NBA) was also tested by a porcine Bethesda assay (PBA). The NBA was modified by replacement of human FVIII with rpFVIII in the PBA, with determination of residual FVIII by one‐stage clotting assay. Results The median FVIII inhibitor titre by NBA was 22.8 BU/mL (range: 0.8‐1000 BU/mL). 37% of samples exhibited linear, type 1 kinetics in the NBA. Negative PBA was observed in 26 patients, and 25 were positive (median PBA: 3.5 BU/mL; range: 0.8‐120 BU/mL). Type 1 kinetics were observed in 40% of PBA‐positive patients. At NBA tires of greater than 100 BU/mL, the positive predictive value for the presence of porcine cross‐reactivity was 100%. At NBA below 5 BU/mL, the negative predictive value for the presence of porcine cross‐reactivity was 71%. Conclusion Cross‐reactivity between FVIII inhibitors and rpFVIII was observed in 49% of patients. The presence of inhibitors to rpFVIII may influence the treatment choice for patients with acquired haemophilia A.Keywords:
Recombinant Factor VIIa
Clotting factor
Carriers of haemophilia are known to have a wide range of clotting factor levels and bleeding symptoms. This study aimed at investigating whether carriers of severe and moderate haemophilia had an increased bleeding tendency, compared with a control group, using a condensed version of a bleeding assessment tool developed by the Molecular and Clinical Markers for the Diagnosis and Management of Type 1 VWD study group (MCMDM-1VWD). One hundred and twenty-six genetically verified carriers of severe and moderate haemophilia and 90 controls were interviewed regarding bleeding symptoms. A bleeding score of at least 4 was considered positive, indicating a significant bleeding tendency. Clotting factor levels were tested in the carriers.Nineteen of the women were carriers of haemophilia B, with a mean factor (F)IX:C level of 0.54 (± 0.27) kIU/l, and 107 were carriers of haemophilia A, with a mean FVIII:C level of 0.74 (± 0.32) kIU/l. The median bleeding score was 2 (-3-12) among carriers and -1 (-3-8) among controls (P < 0.001). The bleeding score was weakly correlated to clotting factor levels in carriers of haemophilia A (rs = -0.36, P < 0.001). We conclude that the bleeding tendency in our cohort of carriers differed significantly from that in the controls and that clotting factor levels might not be sufficient to predict the bleeding tendency.
Clotting factor
Factor IX
Haemophilia B
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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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Haemophilia is an X-linked inherited clotting disorder with a prevalence of 1 per 5000 men. A deficiency of clotting factor VIII (FVIII; haemophilia A) or IX (FIX; haemophilia B) causes haemophilia patients to suffer from spontaneous bleeding and excessive blood-loss following surgery or trauma. Prophylactic administration of a factor VIII- or factor IX-concentrate is the standard treatment for children with severe haemophilia. Women who are carriers of the F8 or F9 gene mutation can have a lowered plasma concentration of factor VIII or IX, and thus suffer from a mild form of haemophilia. Drugs that have a negative influence on blood clotting, such as NSAIDs, can lead to life-threatening bleeding in haemophilia patients. One of the main complications of haemophilia treatment is the formation of inhibiting antibodies that inactivate FVIII or FIX. Haemophilia patients should be treated by a multidisciplinary team in a hospital with a haemophilia treatment centre.
Haemophilia B
Clotting factor
Factor IX
Blood clotting
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Consumption
Blood product
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Haemophilia A and B are rare inherited bleeding disorders due to reduced factor VIII (FVIII) or factor IX (FIX) activity, occurring in 1 in 10,000 and 1 in 50,000 of the population respectively1,2. Several other bleeding disorders such as deficiencies of factors I, II, V, VII, X, XI and XIII are even rarer. When the deficiency is severe these disorders present with spontaneous bleeding whilst for milder disorders traumatic bleeding is observed3. When bleeding occurs patients are treated with clotting factor concentrates which can be plasma derived or recombinant. Individuals with inherited bleeding disorders are cared for in Haemophilia Centres. There is major disparity in patient access to Haemophilia Centres throughout Europe4, although it must be appreciated that this publication was based on data from the individual country patient organisations and was not based on national registries. There is a need for harmonisation of the data available in care centres, national data sources and patient organisations and these activities are planned to be improved by the European Haemophilia Network (EUHANET) project. There is also variation in the number of Haemophilia Centres within European countries and whilst in some there are over 80 Haemophilia Centres in others there is only a single centre.
The use of clotting factor concentrates has been associated with major adverse effects. Patients treated with plasma derived clotting concentrates prior to 1985 had an almost 100% risk of being infected with hepatitis C (HCV) and a 30–60% risk of Human Immunodeficiency Virus (HIV) infection5. Although the HCV/HIV viruses were eliminated following the introduction of viral inactivation, improvements in diagnostic tools used for the biological qualification of blood donations and the use of recombinant concentrates, other adverse events such as alloantibodies to FVIII or FIX remain6. The rarity of these disorders makes it difficult to determine the precise frequency of the adverse events because large numbers of patients are required which are not available in single centres. To overcome this problem, the European Haemophilia Safety Surveillance (EUHASS) system was set up in 20087. This was a collaboration of over 70 European Haemophilia Centres in 26 countries which agreed to prospectively report adverse events occurring in their patients. The project was funded by the European Commission with pharmaceutical industry support. The EUHASS project demonstrated the willingness of these Haemophilia Centres to work together so the EUHANET was set up. This is a collaboration in four separate areas, the certification of Haemophilia Centres, the set up of a haemophilia website, the expansion of the EUHASS system and the establishment of a prospective project on afibrinogenemia and FXIII deficiency.
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Factor IX
Hepatitis C
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In order to describe the progression of HIV disease in a cohort of Dutch HIV-1-infected patients with haemophilia and to study the influence of clinical and clotting factors, we performed a 15-year longitudinal clinical and laboratory study.The progression to AIDS in relation to type of haemophilia, antibodies against factor VIII, age, cytomegalovirus (CMV) infection, and type and total amount of clotting factor consumption was studied in 52 haemophilic patients infected with HIV-1 between 1981 and July 1985.The progression to AIDS was faster in the group of patients with antibodies against factor VIII (inhibitors) and in the group of patients with haemophilia B than in the group of patients with haemophilia A without inhibitors.We concluded that HIV-infected patients with haemophilia A with inhibitors and patients with haemophilia B show a significantly faster progression to AIDS than do HIV-infected patients with haemophilia A without inhibitors. These differences are independent of the total amount of clotting factor used and other known risk factors such as age at seroconversion and CMV infection and may be due to the type of clotting product used.
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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 Introduction Certain haemophilia carriers demonstrate an increased bleeding tendency, mainly related to clotting factor deficiency. No study has so far formally compared the bleeding phenotype of women and girls with mild FVIII or FIX deficiency and associated management with that of male patients affected by mild haemophilia A and B. Material and methods We retrospectively evaluated 44 women and girls with mild FVIII or FIX deficiency (FVIII or FIX 0.05‐0.5 IU/mL) and 77 male patients with mild haemophilia A or B and compared them with respect to clotting factor level, age at and trigger for diagnosis, as well as treatment modalities. Results After excluding gender‐related haemorrhagic symptoms, haemophilia carriers with plasma factor levels in the mild haemophilia range and male patients affected by mild haemophilia present a comparable haemorrhagic profile, mainly characterized by mucocutaneous and postinjury bleeding. Haemophilia carriers with clotting factor deficiency, however, distinguish themselves in terms of later age at diagnosis, higher mean factor levels and trigger for diagnosis. Conclusions Women and girls with mild FVIII or FIX deficiency should be considered as mild haemophilia patients and have access to care and management inspired from male haemophilia patients while integrating differences and specificities. Larger international studies comparing the clinical presentation and treatment modalities of mild clotting FVIII and FIX deficiencies in both haemophilia males and females should be encouraged.
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Haemophilia B
Mucocutaneous zone
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The annual amount of clotting factor used by patients at the Royal Free Haemophilia Centre increased significantly from 4 million iu in 1980 to over 15 million iu by 1994 (P < 0.0001). In order to assess the reasons for this increase, data on concentrate usage over this period were retrospectively collected for patients who had haemophilia or von Willebrand's disease. Only patients who were registered exclusively at the Centre were included in the study. In total, 498 patients met the inclusion criterion. The median age of the cohort on 1 January 1980 was 21 (range < 1-69) years. During the period there were 88 births and 45 deaths. The majority of patients had haemophilia A (55%). The median follow-up period per patient was 2.1 (range 0-14.8) years. Despite adjusting for increases in the number of patients and changes in body weight, statistically significant increases in clotting factor usage were detected for some subgroups of patients, in particularly for those with severe haemophilia A and B and from the late 1980s onwards, for patients with von Willebrand's disease. Two reasons for this increase in clotting factor usage were identified as being the introduction of improved products and prophylaxis. However, the increased cost of clotting factor provision that has resulted from these changes in treatment policy should not be analysed in isolation but should be balanced off against cost decreases in other areas and against increases in the effectiveness of treatment.
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Haemophilia B
Factor IX
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'Haemophilia' is a term referring to a group of genetically transmitted life-long blood clotting disorders which are caused by a defect in one or more of the plasma clotting factors. The most common are sex-linked recessive disorders, haemophilia A (classic haemophilia) and haemophilia B (Christmas disease), which are due to an isolated deficiency of the clotting activity of factor VIII or of factor IX, respectively. People with these disorders suffer bleeding into soft tissues, for example, joints, muscles or internal organs, which can happen after trauma or spontaneously. These bleeds can be very painful, and repeated episodes lead to weakening and crippling of joints. Bleeds into internal organs and the brain can be life-threatening. There is no cure for haemophilia.
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