Genetic mosaicism in haemophilia: A practical review to help evaluate the risk of transmitting the disease

SummarySince 1978 an annual multicentric survey regarding the epidemiology of patients suffering of haemophilia is performed with support of haemophilia treating centres of any size. Again the actual compilation is resting upon a broad database returning to over 30 years of inquiry well representing both the actual and retrospective status of mortality. Prompted was exclusively information about patients with haemophilia A, B and von Willebrand disease. In particular anonymous data concerning the last 12 months about number of treated patients, type and severity of illness, HIV-status and detailed information about causes of death was inquired. This data was merged with existing data and analyzed statistically. In the 2007/2008 survey, a total

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Inhibitor treatment by rituximabin congenital haemophilia A

Hämostaseologie ◽

10.1055/s-0037-1617028 ◽

2009 ◽

Vol 29 (02) ◽

pp. 151-154 ◽

Cited By ~ 13

Author(s):

Escuriola Ettingshausen ◽

R. Linde ◽

G. Kropshofer ◽

L.-B. Zimmerhackl ◽

W. Kreuz ◽

...

Keyword(s):

B Cell ◽

Immune Tolerance ◽

High Titre ◽

Clotting Factor ◽

Severe Bleeding ◽

High Morbidity ◽

Haemophilia A ◽

Concomitant Treatment ◽

Bleeding Tendency ◽

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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Molecular genetic background of haemophilia A patients with discrepancy between one-stage and two-stage factor VIII assays

Hämostaseologie ◽

10.1055/s-0037-1619100 ◽

2010 ◽

Vol 30 (S 01) ◽

pp. S153-S155

Author(s):

D. Delev ◽

S. Pahl ◽

J. Driesen ◽

H. Brondke ◽

J. Oldenburg ◽

...

Keyword(s):

Factor Viii ◽

Genetic Background ◽

Molecular Genetic ◽

Haemophilia A ◽

Two Stage ◽

One Stage

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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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Management of acute haemarthrosis in haemophilia A

Hämostaseologie ◽

10.1055/s-0037-1619070 ◽

2010 ◽

Vol 30 (S 01) ◽

pp. S44-S45

Author(s):

R. Klamroth ◽

M. von Depka ◽

M. Richards ◽

P. de Moerloose ◽

K. Fischer ◽

...

Keyword(s):

Haemophilia A

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Clinical features and outcome of acquired haemophilia A

Hämostaseologie ◽

10.1055/s-0037-1619050 ◽

2010 ◽

Vol 30 (03) ◽

pp. 156-161 ◽

Cited By ~ 9

Author(s):

R. Gheisari ◽

B. Bomke ◽

T. Hoffmann ◽

R. E. Scharf

Keyword(s):

Respiratory Diseases ◽

Care Center ◽

Treatment Algorithm ◽

Early Death ◽

Underlying Disease ◽

Pulmonary Sarcoidosis ◽

Relative Increase ◽

Laboratory Evaluation ◽

Haemophilia A ◽

Acquired Haemophilia

SummaryWe have performed a monocenter study on 29 consecutive patients with acquired haemophilia A who were referred for diagnosis and treatment to the Düsseldorf Haemophilia Comprehensive Care Center between March 2001 and February 2010. Patients, methods: 18 men (age: 44–86 years) and 11 women (age: 20–83 years). For laboratory evaluation, a standardized staged protocol of aPTT, FVIII : C activity and concentration, mixing studies with patient and normal plasma, and quantification of inhibitor titers (Bethesda assay) was used. Diagnostic work-up included elaborate examinations for any underlying disease. Results: In 18 (62%) of the 29 patients with acquired haemophilia A, an underlying disorder was identified, including 9 patients with respiratory diseases (31%), 7 patients with autoimmune disorders (24%), one with malignancy, and one with postpartum state, while in 11 patients (38%) acquired haemophilia A remained idiopathic. Haemotherapy of bleeding, suppression or elimination of the inhibitor, and induction of immunotolerance to endogenous FVIII:C were performed according to a treatment algorithm. Predefined clinical endpoints were control of bleeding, eradication of the inhibitor, complete or partial remission (CR, PR), relapse, or early death (≤30 days). Of the 29 patients in total, 22 individuals achieved CR (76%), three had PR, one relapsed, and three died within 30 days (one of acute myocardial infarction while on anti-haemorrhagic treatment, one of sepsis while on immunosuppression due to active acquired haemophilia A, one of lung bleeding in association with pre-existing pulmonary sarcoidosis). Conclusion: This monocenter study demonstrates that control of life-threatening bleeding, eradication of the inhibitor, and induction of tolerance to endogenous FVIII have significantly improved the clinical outcome of acquired haemophilia A. Our data also suggest a shift in underlying disorders associated with acquired haemophilia A, whereby, in comparison to published studies, a relative increase in the proportion of patients with respiratory diseases is present.

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Anticardiolipin Antibodies Are Elevated in HIV-1 Infected Haemophiliacs but Do Not Predict for Disease Progression

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646531 ◽

1989 ◽

Vol 61 (01) ◽

pp. 081-085 ◽

Cited By ~ 22

Author(s):

Simon Panzer ◽

Christoph Stain ◽

Hubert Hartl ◽

Robert Dudczak ◽

Klaus Lechner

Keyword(s):

Normal Values ◽

Anticardiolipin Antibodies ◽

Haemophilia A ◽

Serum Samples ◽

Factor Viii Concentrates ◽

Patient Groups ◽

Anti Hiv ◽

Hiv 1 ◽

Cd4 Lymphocytes

SummaryLevels of anticardiolipin antibodies (ACA) were measured in 55 patients with haemophilia A in serum samples obtained in 1983 and in 1987. Twenty-one patients were negative for anti HIV-1 antibodies in 1983 and remained negative in 1987; 34 patients had anti HIV-1 antibodies in 1983; 17 of these latter patients remained asymptomatic, whereas 17 patients developed ARC or AIDS during the 4 years follow-up. Thirteen anti HIV-1 negative patients had elevated ACA levels in 1983; subsequently, a significant decrease was observed in all these subjects (p <0.001). All anti HIV-1 positive patients had elevated ACA levels in 1983; normal values were found in 9 patients in 1987. Yet, these changes were not significant (p >0.05). ACA levels were significantly higher in HIV-1 infected patients than in those without anti HIV-1 antibodies (p <0.05). There was no difference of ACA levels between the two anti HIV-1 positive patient groups, be it in 1983 or be it in 1987 (p >0.05). There was no correlation of ACA levels with serum IgG concentrations, CD4+ lymphocytes, or the consumption of factor VIII concentrates.

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