Genetic causes of haemophilia in women and girls
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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.Keywords:
Haemophilia B
A survey was conducted in 2002 to determine the pattern of factor prophylaxis use in boys or=45 weeks per year, was significantly higher for haemophilia A vs. haemophilia B cases (51% vs. 32%, P< 0.0001), and for boys with severe haemophilia A living in Canada vs. the USA (77% vs. 47%, P< 0.0001). Use of full-dose prophylaxis, defined as the infusion of 25-40 IU kg(-1) of factor VIII on alternate days (minimum three times per week) or 25-40 IU kg(-1) of factor IX twice weekly, was similar for boys
Haemophilia B
Bleed
Hemarthrosis
Factor IX
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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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The incidence of living haemophiliacs in Sweden (total population 8.1 millions) is about 1:15,000 males and about 1:30,000 of the entire population. The number of haemophiliacs born in Sweden in 5-year periods between 1931-1975 (June) has remained almost unchanged. The total number of haemophilia families in Sweden is 284 (77% haemophilia A, 23% haemophila B) with altogether 557 (436 with A and 121 with B) living haemophiliacs. Of the haemophilia A patients 40% have severe, 18% moderate, and 42% mild, haemophilia. The distribution of the haemophilia B patients is about the same. Inhibitors have been demonstrated in 8% of the patients with severe haemophilia A and in 10% of those with severe haemophilia B. There are 2 main Haemophilia Centres (Stockholm, Malmö) to which haemophiliacs from the whole of Sweden are admitted for diagnosis, follow-up and treatment for severe bleedings, joint defects and surgery. Minor bleedings are treated at local hospitals in cooperation with the Haemophilia Centres. The concentrates available for treatment in haemophilia A are human fraction I-0 (AHF-Kabi), cryoprecipitate, Antihaemophilic Factor (Hyland 4) and Kryobulin (Immuno, Wien). AHF-Kabi is the most commonly used preparation. The concentrates available for treatment in haemophilia B are Preconativ (Kabi) and Prothromplex (Immuno). Suffcient amounts of concentrates are available. In Sweden 3.2 million units of factor VIII and 1.0 millino units of factor IX are given per year. Treatment is free of charge. Only 5 patients receive domiciliary treatment, but since 1958 we in Sweden have practised prophylactic treatment of boys (4-18 years old) with severe haemophilia A. At about 5-10 days interval they receive AHF in amounts sufficient to raise the AHF level to 40-50%. This regimen has reduced severe haemophilia to moderate. The joint score is identical with that found in moderate haemophilia in the same age groups. For treatment of patients with haemophilia A and haemophilia B complicated by inhibitors we have used a large dose of antigen (factor VIII or factor IX) combined with cyclophosphamide. In most cases this treatment produced satisfactory haemostasis for 5 to 30 days and prevented the secondary antibody rise.
Haemophilia B
Cryoprecipitate
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Summary. Immunological studies were performed on a group of 44 haemophilia A and 15 haemophilia B patients who were treated exclusively with blood products manufactured by the Scottish National Blood Transfusion Service (SNBTS). All patients were HIV seronegative throughout the study. Of the haemophilia A patients 14 (32%) had CD4 + lymphocyte subset counts ≤ 0.5 × 10 9 /l, compared with one (6%) haemophilia B patient and four (8%) controls. The percentage of activated T cells was greater than 5% in 19/33 (57%) with haemophilia A, 5/9 (55%) haemophilia B and 14/50 (28%) of control subjects. β 2 microglobulin values ≥2.0 mg/l were observed in 19 (43%) haemophilia A and four (26%) haemophilia B patients, compared with one (2%) control. No significant increases in serum interleukin‐2 receptor concentrations were observed in 15 haemophilia A and one haemophilia B patients. Significantly elevated levels of IgG, IgM and IgA were observed in the haemophilia A group, but elevation of immunoglobulins was restricted to the IgG class in the haemophilia B group. Of the haemophilia A patients 16/30 (53%) and 6/11 (54%) haemophilia B patients had depression of cell‐mediated immunity (CMI) as assessed by delayed‐type hypersensitivity responses to intra‐dermally injected recall antigens. There was no correlation between factor VIII or factor IX usage and changes in lymphocyte subsets, β 2 microglobulin, and immunoglobulin levels. There was, however, a strong correlation between annual factor VIII usage and the degree of depression of CMI for those with haemophilia A but not for those with haemophilia B. No correlation between alterations in the immune parameters and disturbance of liver function tests was observed in either haemophilia A or haemophilia B patients. We conclude that alloantigen or non‐HIV viral exposure due to repeated administration of factor concentrates brings about alterations in the immune response, and that these changes are more marked following exposure to intermediate purity factor VIII compared with factor IX concentrate.
Haemophilia B
Beta-2 microglobulin
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Summary. This survey provides new information on the severity of factor IX deficiencies among patients being treated for haemophilia B and on the prevalence of factor IX inhibitors in this population. A questionnaire was sent to 150 haemophilia treatment centres in the United States and Canada. 82 centres responded and provided data on 1967 patients with haemophilia B. 37% of these patients had severe haemophilia B (<1% of the normal level of factor IX), 33% had moderate haemophilia B (1–5% of the normal level of factor IX), and 30% had mild haemophilia B (>5% of the normal level of factor IX). Only 29 (1.5%) of the patients had factor IX inhibitors; 28 of these patients (96.6%) had severe haemophilia B, and one of these patients (3.4%) had moderate haemophilia B. Factor IX inhibitor titres were 0.6–1 Bethesda unit (BU) in seven patients, > 1–5 BU in four patients, > 5–10 BU in one patient, and > 10 BU in 17 patients. Factor IX inhibitors are much less common in patients with haemophilia B than in patients with haemophilia A.
Haemophilia B
Factor IX
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Summary. In an analysis of 804 haemophilia pedigrees, mild to moderate haemophilia A or B was found to be clearly familial in 70% of cases, severe haemophilia B in 57% of cases and severe haemophilia A in 45% of cases. The rest of the patients were ‘sporadic’ i.e., either isolated cases or brothers in the first affected sibship. In sporadic families, 88% of mothers but only 19% of maternal grandmothers had the relevant mutation in their white blood cells. Among patients with familial haemophilia, half the patients with mild haemophilia and those with severe haemophilia B had a direct male ancestor with haemophilia, but only 28% of patients with severe haemophilia A had such a progenitor.
Haemophilia B
Pedigree chart
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Summary. Prophylaxis is standard of care for boys with severe haemophilia A. Indications for prophylaxis in adulthood, non‐severe haemophilia A, haemophilia B and haemophilia with inhibitors are less well defined. This survey, conducted in 2006, aimed to describe prophylaxis use in patients of all ages and severities with haemophilia A or haemophilia B in Canada. Data on 2663 individuals (2161 haemophilia A; 502 haemophilia B), including 78 inhibitor‐positive patients, were returned by 22/25 Canadian haemophilia treatment centres. This represented 98% of the Canadian haemophilia population. Frequency of prophylaxis use, defined as infusion of factor VIII/IX concentrate at least once weekly for ≥45 weeks of the year, was highest in individuals with severe haemophilia A (69%). It was lower in individuals with severe haemophilia B (32%), moderate haemophilia A (18%) or B (5%) and mild haemophilia A (1%) or B (1%). Among individuals with severe haemophilia A, the frequency of prophylaxis use was 84% in children (≤18 years) and 55% in adults (>18 years). Thirteen per cent of inhibitor‐positive individuals were receiving prophylaxis with bypassing agents. Comparison with data obtained from a 2002 Canadian survey showed a greater use of prophylaxis in children ≤5 years of age with severe haemophilia A (73% vs. 49%). Prophylaxis is no longer confined to children with severe haemophilia A, but is used in a significant proportion of adults with severe haemophilia A and individuals with severe haemophilia B or moderate haemophilia A. Prophylaxis is being started earlier in boys with severe haemophilia A.
Haemophilia B
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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.
Haemophilia B
Factor IX
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All known surviving haemophiliacs A and B and their relatives were reexamined by laboratory and clinical methods and evaluated by a genetic-epidemiologic approach in 4 north-western countries of Hungary. The prevalence of haemophilia A and B patients born in the fifties was 2.73 and 0.25 per 10,000 persons, respectively. The reproductive fitness was found to be 0.3 in haemophilia A, and 0.8 in haemophilia B patients. The mutation rates calculated by the indirect method were 6.3 x 10(-5) for haemophilia A and 0.2 x 10(-5) for haemophilia B.
Haemophilia B
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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.
Haemophilia B
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