Vocational experiences and career support opportunities among Canadian men with moderate and severe haemophilia

SummaryThe development of neutralizing alloanti-bodies (inhibitors) to factor VIII (FVIII) is one of the most serious complications in the treatment of haemophiliacs. Inhibitors occur in approximately 20 to 30% of previously untreated patients (PUPs), predominantly children, with severe haemophilia A within the first 50 exposure days (ED). Immune tolerance induction (ITI) leads to complete elimination of the inhibitor in up to 80% of the patients and offers the possibility to restore regular FVIII prophylaxis. However, patients with high titre inhibitors, in whom standard ITI fails, usually impose with high morbidity and mortality and therefore prompting physicians to alternate therapy regimens. Rituximab, an anti-CD 20 monoclonal antibody has been successfully used in children and adults for the management of B-cell mediated disorders. We report on the use of a new protocol including rituximab in two adolescents with severe haemophilia A and high titre inhibitors, severe bleeding tendency and high clotting factor consumption after failing standard ITI. Both patients received a concomitant treatment with FVIII according to the Bonn protocol, cyclosporine A and immunoglobulin. Treatment with rituximab resulted in a temporary B-cell depletion leading to the disappearance of the inhibitor. FVIII recovery and half-life turned towards normal ranges. In patient 1 the inhibitor reappeared 14 months after the last rituximab administration. In patient 2 complete immune tolerance could be achieved for 60 months. Bleeding frequency diminished significantly and clinical joint status improved in both patients. In patient 1 the treatment course was complicated by aspergillosis and hepatitis B infection. Conclusion: Rituximab may be favourable for patients with congenital haemophilia, high-titre inhibitors and a severe clinical course in whom standard ITI has failed. Prospective studies are required to determine safety, efficacy and predictors of success.

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Inhibitorentwicklung nach früher hoher Exposition und Hirnblutung

Hämostaseologie ◽

10.1055/s-0037-1619091 ◽

2010 ◽

Vol 30 (S 01) ◽

pp. S115-S118

Author(s):

C. Moorthi ◽

A. Bade ◽

C. Niekrens ◽

G. Auerswald ◽

K. Haubold

Keyword(s):

High Titer ◽

Cerebral Haemorrhage ◽

High Dose ◽

Haemophilia A ◽

Severe Haemophilia ◽

Intron 22 Inversion ◽

Neurosurgical Intervention

SummarySevere haemophilia A was diagnosed postpartum in a newborn. The mother was known as a conductor (intron 22 inversion) and an uncle had a persistently high titer inhibitor after failed ITI.Due to a cephalhaematoma, a high-dose pdFVIII substitution was given within the first days after birth. At the age of six month a severe cerebral haemorrhage occurred, making a high-dose pdFVIII substitution and neurosurgical intervention necessary. Several days later a porth-a-cath-system was implanted. The development of a high titer inhibitor occured six days later, an ITI was started according to the Bonn Protocol. Initially rFVIIa was given in addition to the pdFVIII substitution. Seven days after the beginning of treatment the inhibitor was no longer detectable. At monthly intervals the FVIII dosage was reduced until the dosage complied with a prophylaxis in severe haemophilia A.The duration of the ITI was nine months. A total of 30 mg rFVIIa and 276 000 IU pdFVIII were used; costs in total: 280 173.60 Euro.

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Performances of an Artificial Reagent for the One-stage Factor IX Assay

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647848 ◽

1975 ◽

Vol 33 (03) ◽

pp. 547-552 ◽

Cited By ~ 4

Author(s):

L Meunier ◽

J. P Allain ◽

D Frommel

Keyword(s):

Human Plasma ◽

Factor Ix ◽

Severe Haemophilia ◽

Normal Human Plasma ◽

Haemophilia B ◽

One Stage ◽

Normal Human ◽

The One

SummaryA mixture of adsorbed normal human plasma and chicken plasma was prepared as reagent for factor IX measurement using a one-stage method. The substrate was found to be specific for factor IX. Its performances tested on samples displaying factor IX activity ranging from <l%–2,500% compared favorably with those obtained when using the plasma of severe haemophilia B patients as substrate.

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Successful Electroconvulsive Treatment of a Schizophrenic Patient Suffering from Severe Haemophilia A

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650408 ◽

1996 ◽

Vol 75 (06) ◽

pp. 978-978 ◽

Cited By ~ 1

Author(s):

Theodora Glaub ◽

Bela Telek ◽

Zoltan Boda ◽

Sandor Szabo ◽

Geza Krall ◽

...

Keyword(s):

Schizophrenic Patient ◽

Haemophilia A ◽

Severe Haemophilia ◽

Electroconvulsive Treatment

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Management of Haemophilia in Sweden

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647991 ◽

1976 ◽

Vol 35 (03) ◽

pp. 510-521 ◽

Cited By ~ 13

Author(s):

Inga Marie Nilsson

Keyword(s):

Factor Viii ◽

Total Population ◽

Age Groups ◽

Factor Ix ◽

Haemophilia A ◽

Severe Haemophilia ◽

Haemophilia B ◽

Human Fraction ◽

Mild Haemophilia

SummaryThe 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% haemophilia 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, Malmo) 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 1-0 (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). Sufficient amounts of concentrates are available. In Sweden 3.2 million units of factor VIII and 1.0 million 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.

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HLA Genotype of Patients with Severe Haemophilia A due to Intron 22 Inversion with and without Inhibitors of Factor VIII

Thrombosis and Haemostasis ◽

10.1055/s-0038-1655945 ◽

1997 ◽

Vol 77 (02) ◽

pp. 238-242 ◽

Cited By ~ 129

Author(s):

J Oldenburg ◽

J K Picard ◽

R Schwaab ◽

H H Brackmann ◽

E G D Tuddenham ◽

...

Keyword(s):

Factor Viii ◽

Major Gene ◽

Statistical Significance ◽

Strong Association ◽

Molecular Genetic ◽

Single Mutation ◽

Severe Haemophilia ◽

Extended Haplotype ◽

Intron 22 Inversion ◽

Hla Genotype

SummaryMolecular genetic studies have shown that development of antibodies to factor VIII (inhibitors) occurs most frequently in patients with severe haemophilia due to major gene lesions including inversions, stop codons and large deletions. Previous studies of HLA type were performed on inhibitor and non-inhibitor patients with diverse uncharacterised mutations which may have confounded detection of significant associations. We therefore selected a group of patients with a single mutation type, the prevalent intron 22 inversion, with or without inhibitors, to determine HLA genotype. Seventy-one such patients, 42 without and 29 with inhibitors (13 high, 9 low and 7 transient responders) were genotyped for MHC Class I HLA-A, -B, -C and Class II HLA-DQA, -DQB and -DRB loci. No strong correlation of any HLA-allele to inhibitor or non-inhibitor status was found. However, alleles of the haplotype HLA-A3, HLA-B7, HLA-C7, HLA-DQA0102, HLA-DQB0602, HLA-DR15 occurred more often in inhibitor patients. Since the alleles of this extended haplotype are common in the North European population only a very strong association would achieve statistical significance. Further studies of groups of patients similar to those studied here will be needed to confirm or exclude this association.

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The Effects of Age, Gene Source and Familial Severity on Factor VIII in Normals and Haemophilia Carriers: Analysis by Multiple Regression

Thrombosis and Haemostasis ◽

10.1055/s-0038-1665295 ◽

1983 ◽

Vol 50 (03) ◽

pp. 722-725 ◽

Cited By ~ 1

Author(s):

Bruce M Duncan ◽

Lynn J Tunbridge ◽

John V Lloyd

Keyword(s):

Factor Viii ◽

Multiple Regression ◽

Analysis Of Covariance ◽

Severe Haemophilia ◽

Factor Viii Related Antigen ◽

Defective Gene ◽

Coagulant Activity

SummaryThere are conflicting views on the effects of age, gene source and familial severity on levels of factor VIII in carriers of haemophilia. Different workers have found that factor VIII increases with age, is higher in paternal carriers, and is higher in carriers from families with more severe haemophilia. Other workers have disagreed with these findings. In this study we explored some of the causes of this conflict. We measured factor VIII related antigen and factor VIII coagulant activity on 40 normal females and 48 carriers, and analysed the results by multiple regression and analysis of covariance. Our results indicated that both factor VIII coagulant activity and factor VIII related antigen increased with age, but were unaffected by the familial severity of haemophilia or whether the defective gene came from the mother or the father. We found that the conflicting reports of previous authors were due to high inter-correlations of the studied variables.

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