181 results on '"G. Auerswald"'
Search Results
2. Muscle function deterioration in patients with haemophilia: Prospective experience from Costa Rica
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A. Seuser, Maria Elisa Mancuso, M. Navarrete-Duran, and G. Auerswald
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Adult ,Costa Rica ,Male ,medicine.medical_specialty ,Adolescent ,Vastus medialis ,Physical examination ,Electromyography ,030204 cardiovascular system & hematology ,Haemophilia ,Hemophilia A ,Biceps ,Hemophilia B ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Physical medicine and rehabilitation ,Isometric Contraction ,medicine ,Humans ,In patient ,Isotonic Contraction ,Prospective cohort study ,Child ,Genetics (clinical) ,biology ,medicine.diagnostic_test ,business.industry ,Muscles ,Hematology ,General Medicine ,biology.organism_classification ,medicine.disease ,Medius ,Child, Preschool ,Muscle Tonus ,Female ,business ,030215 immunology - Abstract
Introduction In haemophilia, recurrent joint bleeds are responsible for the development of chronic joint damage, because blood induces biochemical changes in joint structures. Joint degeneration is a long process, and structural damage is often preceded by joint dysfunction, which is represented by quantitative and qualitative changes in the contraction pattern of muscles around the joints. Muscle function in patients with haemophilia is still poorly investigated. Aim The aim of this 2-year prospective study was to assess the changes in muscle function of lower limbs in a group of patients affected with haemophilia in San Jose, Costa Rica. Methods Muscle function of lower limbs was assessed by means of surface electromyography (sEMG) accomplished at study enrolment and after 2 years of follow-up. Gluteus medius, vastus medialis, biceps femoris, gastrocnemius and tibialis anterior were examined. All patients underwent concurrent clinical examination using Haemophilia Joint Health Score (HJHS). Results Sixty patients aged 2-43 years with severe haemophilia underwent clinical and sEMG evaluation. Thirty-two patients (53%) had target joints. sEMG parameters were altered in all patients and were not correlated to the presence of target joints and/or an abnormal HJHS. Muscle function deterioration was observed after 2 years of follow-up despite an unmodified HJHS. Conclusions Muscle function of lower limbs as detected by means of sEMG was impaired in patients with haemophilia irrespective of the presence of overt joint damage. sEMG is a simple and sensitive assessment tool able to detect muscle dysfunction and so favouring the implementation of early rehabilitation therapy.
- Published
- 2018
3. Risk Factors for the Progression from Low to High Titres in 260 Children with Severe Haemophilia A and Newly Developed Inhibitors
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Gili Kenet, Elena Santagostino, Carmen Altisent, Angelo Claudio Molinari, Manuel Carcao, Rolf Ljung, Pia Petrini, Michael Williams, Johannes Oldenburg, Cristoph Königs, Hervé Chambost, Carmen Escuriola-Ettingshausen, Anne Mäkipernaa, Krista Fischer, Helen Platokouki, George E Rivard, Ana Rosa Cid, Maria Elisa Mancuso, G. Auerswald, Karin Kurnik, H. Marijke van den Berg, and Raina Liesner
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Male ,medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,Adolescent ,Haemophilia A ,haemophilia A ,030204 cardiovascular system & hematology ,Haemophilia ,Bethesda unit ,Hemophilia A ,03 medical and health sciences ,0302 clinical medicine ,children ,Risk Factors ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Blood Coagulation Factor Inhibitors ,Immune Tolerance ,Animals ,Humans ,Family history ,Child ,immune tolerance induction ,Hematology ,Factor VIII ,business.industry ,Inhibitors ,Odds ratio ,medicine.disease ,Confidence interval ,high titre ,3. Good health ,Child, Preschool ,Mutation ,Disease Progression ,Female ,business ,030215 immunology ,Follow-Up Studies - Abstract
In children with severe haemophilia A, inhibitors to factor VIII (FVIII) usually develop during the first 50 treatment exposure days and are classified as low or high titre depending on the peak inhibitor titre being greater or less than 5 Bethesda units/mL (BU/mL). Classification of the inhibitor may change with time, as some low-titre inhibitors progress to high titre following re-exposure to FVIII concentrate. The aim of this study was to investigate potential risk factors for such a progression in children with severe haemophilia A and newly diagnosed inhibitors. This study was a follow-up study of the PedNet Registry and included 260 children with severe haemophilia A and inhibitors born between 1990 and 2009 and recruited consecutively from 31 haemophilia centres. Clinical and laboratory data were collected from the date of each child's first positive inhibitor test for at least 3 years. At the time of first positive inhibitor test, 49% (n = 127) had low-titre inhibitors, with 50% of them progressing to high titre and only 25% maintaining low titres. The FVIII gene (F8) mutation type was known in 247 patients (95%), and included 202 (82%) null mutations. The progression to high-titre inhibitors was associated with null F8 mutations (odds ratio [OR]: 2.6; 95% confidence interval [CI]: 1.0–6.5), family history of inhibitors (OR: 7.2; 95% CI: 1.8–28.4) and the use of high-dose immune tolerance induction, defined as ≥100 IU FVIII concentrate/kg/d (OR: 3.9; 95% CI: 1.5–10.0). These results suggest that high-dose immune tolerance induction should be avoided as the initial strategy in patients who develop low-titre FVIII inhibitors.
- Published
- 2017
4. The EPIC study: a lesson to learn
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G, Auerswald, K, Kurnik, L M, Aledort, H, Chehadeh, A, Loew-Baselli, K, Steinitz, A J, Reininger, and I, Woznica-Karczmarz
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Pediatrics ,medicine.medical_specialty ,Factor VIII ,biology ,business.industry ,Incidence (epidemiology) ,Infant ,Hematology ,General Medicine ,EPIC ,Hemophilia A ,Haemophilia ,medicine.disease ,Antibodies ,Vaccination ,hemic and lymphatic diseases ,biology.protein ,medicine ,Humans ,Data monitoring committee ,Epic study ,Antibody ,Complication ,business ,Genetics (clinical) - Abstract
Introduction Inhibitory antibodies to factor VIII occur in about 30% of previously untreated patients (PUPs) and are the most serious complication of haemophilia A. It is unclear why some patients develop inhibitors and others do not. Aims The Early Prophylaxis Immunologic Challenge (EPIC) study was designed to test the hypothesis that inhibitor incidence in PUPs with severe or moderately severe haemophilia A could be reduced when a once-weekly FVIII prophylaxis starts with 25 IU kg−1 rAHF-PFM before 1 year of age and immunological danger signals are minimized. Methods These signals were minimized by avoiding: surgery; the first FVIII infusion during severe bleeding or an infection; central venous access devices and administering vaccinations intramuscularly 3–4 days before or after FVIII. Results Eight of the 19 treated subjects (42.1%) developed confirmed inhibitors. Eleven of the 19 treated subjects were PUPs without any prior exposure to FVIII. Three of them (27.3%) developed a confirmed inhibitor together with FVIII-binding antibodies. The study was stopped because the likelihood to reach the primary objective was minimal, a decision endorsed by the data safety monitoring board. Conclusion Because of early termination, the EPIC study hypothesis could not be corroborated. Nonetheless, our data analyses indicate that the current definition of an inhibitor only based on plasma inhibitor activity ≥0.6 BU mL−1 may not always reflect the presence of FVIII-neutralizing antibodies. The findings of this study teach us that low-level inhibitor activity results need in addition a confirmatory test and/or the assessment of the therapeutic response.
- Published
- 2015
5. Inhibitors and prophylaxis in paediatric haemophilia patients: Focus on the German experience
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Karin Kurnik, Wolfhart Kreuz, and G. Auerswald
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Pediatrics ,medicine.medical_specialty ,Factor VIII ,Blood Coagulation Factor Inhibitors ,business.industry ,Haemophilia A ,Hematology ,Odds ratio ,Hemophilia A ,Haemophilia ,medicine.disease ,Vaccination ,Regimen ,Germany ,hemic and lymphatic diseases ,medicine ,Humans ,Dosing ,Elective surgery ,Child ,Complication ,business - Abstract
Prophylaxis is now an established treatment standard in haemophilia in Western Europe and the US with multiple studies demonstrating the clinical benefits of prophylaxis over on-demand treatment. In Western Europe in particular, prophylactic use of factor VIII (FVIII) is high as a result of the findings from the early prophylaxis studies and adherence to national guidelines. Unfortunately, prophylaxis has not yet been implemented on a worldwide basis. The introduction of prophylaxis by haemophilia treatment centres in Bremen, Frankfurt and Munich, as recommended in German guidelines, has significantly improved outcomes for our young haemophilia patients. In the Frankfurt centre, a decreasing rate of inhibitors has been observed since prophylaxis was started early, dosing was individualized, and the importance of treatment continuity was recognized. The centres in Munich and Bremen have explored the possibility of further reducing inhibitor rates using early tolerization - a new prophylaxis regimen that introduces low FVIII doses administered once weekly as soon as a bleeding tendency is observed - with excellent results. All three centres avert the induction of immunological danger signals by avoiding the use of central venous catheters, postponing vaccination wherever possible and not undertaking elective surgery during the early FVIII exposure days. The benefits of using this approach have been confirmed by the remarkably low rates of inhibitors in previously untreated patients reported at these centres. Hopefully, as we and others explore new prophylaxis regimens for our paediatric patients, we can work towards the goal of one day overcoming this serious complication of haemophilia treatment.
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- 2014
6. No inhibitor development after continuous infusion of factor concentrates in subjects with bleeding disorders undergoing surgery: a prospective study
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S. Masurat, C. Moorthi, D. Overberg, K. Haubold, A. Bade, and G. Auerswald
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Haemophilia A ,Hemophilia A ,Haemophilia ,Hemophilia B ,Factor IX ,Otolaryngology ,Young Adult ,Von Willebrand factor ,von Willebrand Factor ,medicine ,Humans ,Haemophilia B ,Prospective Studies ,Risk factor ,Child ,Adverse effect ,Prospective cohort study ,Genetics (clinical) ,Factor VIII ,Blood Coagulation Factor Inhibitors ,biology ,business.industry ,Hematology ,General Medicine ,Middle Aged ,medicine.disease ,Surgery ,von Willebrand Diseases ,Orthopedics ,Child, Preschool ,biology.protein ,Female ,business ,medicine.drug - Abstract
Inhibitor development against von Willebrand factor, factor VIII or factor IX is one of the most severe complications of treating patients with von Willebrand's disease (VWD), haemophilia A or haemophilia B respectively. Continuous infusion of factor concentrate has been implicated as a risk factor for inhibitor development. This prospective study investigated inhibitor development after continuous infusion of factor concentrate for surgical procedures in subjects with VWD or a severe form of haemophilia (factor activity
- Published
- 2012
7. The case for wider use of recombinant factor VIII concentrates
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Cedric Hermans, Hans-Hermann Brackmann, G. Auerswald, and Piercarla Schinco
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medicine.medical_specialty ,Hemophilia A ,Recombinant factor viii ,Drug Administration Schedule ,Plasma ,Immune Tolerance ,medicine ,Humans ,Intensive care medicine ,Clotting factor ,Clinical Trials as Topic ,Cross Infection ,Factor VIII ,business.industry ,Disease Management ,Hematology ,Surgery ,Oncology ,Virus Diseases ,Practice Guidelines as Topic ,Plasma chemistry ,Blood Component Removal ,Infectious risk ,Patient representatives ,Drug Contamination ,business - Abstract
The introduction of clotting factor concentrates led to major advances in hemophilia care. Rather than simply providing an alternative to plasma-derived concentrates, the introduction in the 1990s of recombinant concentrates added value to replacement therapy particularly with respect to prophylaxis and immune-tolerance induction. While the safety of plasma-derived concentrates has improved considerably, these concentrates may still pose an infectious risk through as-yet unknown pathogens and poor impurity constituent characterization. Recombinant concentrates are increasingly used because of their benefits in pathogen safety, convenience and the potential for unfettered supply. Yet worldwide they remain accessible only to a limited number of patients due to fear of the potential for inhibitor development, overestimation of their costs and underestimation of their benefits. This article reviews the characteristics and properties of recombinant FVIII concentrates to help physicians and patient representatives promote the right of access of patients to the safest products.
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- 2012
8. Muskelfunktionsmessung mit kinetischem Oberflächen-EMG bei Kindern mit Hämophilie
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M. Navarrete-Duran, A. Seuser, P. Böhm, M. Wendel, D. Fink, and G. Auerswald
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Hematology - Abstract
SummaryElectromyography (EMG) measures muscle electricity. It depends on muscle contraction and central motor control. Muscles react very sensitive on external signals (e. g. bleeding), The resulting changes can be shown in EMG. Patients, methods A first study included 51 children and young adults from Costa Rica. They underwent a clinical examination and EMG of the hip, knee and ankle joints. Resting muscle tone, maximal isometric contraction and three typical isotonic movements of the joints were measured. First step of analysis was to characterize typical pathogenic changes in the muscles and to find a corresponding physical therapy to minimize these changes. Results It showed that EMG is a good marker for muscle condition. It helps to individualize therapy and improve effectivity of physical and physiotherapeutic treatment of the locomotive system of children and young adults with hemophilia. It can help to recognize early subclinical changes and to control the outcome of therapeutic modalities.
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- 2011
9. Abstracts of the 3rd Annual Congress of the European Association for Haemophilia and Allied Disorders
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Elena Santagostino, Angiola Rocino, Rolf Ljung, G. Auerswald, Guy Young, Víctor Jiménez-Yuste, and Massimo Morfini
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medicine.medical_specialty ,business.industry ,Joint damage ,medicine ,Physical therapy ,Hematology ,General Medicine ,Intensive care medicine ,Haemophilia ,medicine.disease ,Prospective cohort study ,business ,Genetics (clinical) - Published
- 2010
10. Inhibitorentwicklung nach früher hoher Exposition und Hirnblutung
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C. Niekrens, K. Haubold, G. Auerswald, C. Moorthi, and A. Bade
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Hematology - Abstract
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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- 2010
11. New early prophylaxis regimen that avoids immunological danger signals can reduce FVIII inhibitor development
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Karin Kurnik, Christoph Bidlingmaier, B.M. Reipert, G. Auerswald, Werner Engl, and H. Chehadeh
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medicine.medical_specialty ,business.industry ,Incidence (epidemiology) ,Haemophilia A ,Hematology ,General Medicine ,Odds ratio ,Gene mutation ,medicine.disease ,Haemophilia ,Surgery ,Regimen ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Premedication ,business ,Complication ,Genetics (clinical) - Abstract
Summary. The most problematic complication of haemophilia A treatment is the development of inhibitors to FVIII. The highest risk of developing inhibitors is during the first 20 exposure days (EDs). If the patient can be brought through this high risk period without inhibitor development, the subsequent risk is low. Therefore, as a pilot project, we developed a prophylaxis regimen for the first 20‐50 EDs specifically designed to induce tolerance to the administered FVIII and to minimize inhibitor development by avoiding immunological danger signals. Twenty-six consecutive previously untreated patients (PUPs) with severe haemophilia A were treated with the new prophylaxis regimen and the incidence of inhibitor development in this group was compared with that in a historical control group of 30 consecutive PUPs treated with a standard joint protection prophylaxis regimen (40‐50 IU kg )1 , three times a week). There were no significant differences between the study and control groups in patient-related inhibitor risk factors such as ethnicity (all Caucasian), severity of haemophilia (all
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- 2009
12. Factor VII deficiency: clinical manifestation of 717 subjects from Europe and Latin America with mutations in the factor 7 gene
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F H, Herrmann, K, Wulff, G, Auerswald, S, Schulman, J, Astermark, A, Batorova, W, Kreuz, H, Pollmann, A, Ruiz-Saez, N, De Bosch, L, Salazar-Sanchez, and A, Boadas
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Adult ,Male ,Heterozygote ,Adolescent ,Base Sequence ,Genotype ,Factor VII Deficiency ,DNA Mutational Analysis ,Homozygote ,Molecular Sequence Data ,Hemorrhage ,Hematology ,General Medicine ,Factor VII ,Middle Aged ,Young Adult ,Phenotype ,Child, Preschool ,Mutation ,Humans ,Female ,Child ,Genetics (clinical) - Abstract
The congenital FVII deficiency (FVIID) is a rare haemorrhagic disorder with an autosomal recessive pattern of inheritance. Data on phenotype and the genotype from 717 subjects in Central Europe (six countries), Latin America (Costa Rica, Venezuela) and United States, enrolled in the Greifswald Registry of FVII Deficiency were analysed. We detected 131 different mutations in 73 homozygous, 145 compound heterozygous and 499 heterozygous subjects. Regional differences were observed in the mutation pattern and the clinical profile of the evaluated patients. Seventy-one per cent of homozygous and 50% of compound heterozygous subjects were symptomatic. The clinical manifestations of the homozygous subjects were characterized by intracranial haemorrhage (2%), gastrointestinal bleeding (17%), haemarthrosis (13%), epistaxis (58%), gum bleeding (38%), easy bruising (37%), haematoma (15%), haematuria (10%) and menorrhagia (19 of 26 females, 73%). The clinical variability and genotype-phenotype correlation was evaluated in the homozygous subjects. The pattern of bleeding symptoms among compound heterozygous patients was severe and similar to that of the homozygous patients. The large-scale analysis of 499 heterozygous subjects shows that 93 (19%) presented with spontaneous bleeding symptoms such as haemarthrosis (4%), epistaxis (54%), gum bleeding (14%), easy bruising (38%), haematoma (23%), haematuria (5%) and menorrhagia (19 of 45 females; 42%). The severe haemorrhages - intracranial and gastrointestinal - were not reported in heterozygous subjects. The clinical variability and the regional differences in the mutation pattern are discussed regarding care and treatment.
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- 2009
13. Relevance of a single dose of 270 μg/kg recombinant factor VIIa for the treatment of patients with haemophilia and inhibitors
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W. Schramm, I Pabinger-Fasching, Wolfgang Muntean, Manuela Krause, R B Zotz, Karin Kurnik, Robert Klamroth, Johannes Oldenburg, Bettina Kemkes-Matthes, G. Auerswald, and R. Zimmermann
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Bleeding episodes ,medicine.medical_specialty ,biology ,business.industry ,Haemophilia A ,Hematology ,Haemophilia ,medicine.disease ,Multiple dosing ,Expert group ,Surgery ,Quality of life ,Recombinant factor VIIa ,Anesthesia ,medicine ,biology.protein ,In patient ,business - Abstract
SummaryRecombinant activated factor VII (rFVIIa; Novo Seven®) is, besides other indications, authorised for the treatment of bleeding episodes in patients with hereditary haemophilia A or B and inhibitors. Based on the results of three clinical studies, marketing authorisation was granted for the single dose of 270 μg/kg body weight rFVIIa for the treatment of mild-to-moderate bleeding episodes in patients with haemophilia A or B with inhibitors in March 2007. Thereupon, an expert group analysed the relevance of this additional treatment option for clinical routine. Compared with the repeated application of 90 μg/kg body weight rFVIIa, quality of life may be improved if the single dose of 270 μg/kg body weight rFVIIa reduces the number of injections. The single dose has a benefit for those patients who require several rFVIIa applications or who do not respond adequately to low doses. Moreover, patients with poor venous access or who fear injections or reject them (especially children) may benefit from the single dose. The prescription of 270 μg/kg body weight rFVIIa as a single dose instead of multiple dosing of 90 μg/kg body weight is basically an individual and indication-related decision.
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- 2009
14. Hämophilie bei Kindern
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G. Auerswald, Monika Girisch, Karin Kurnik, Johannes Oldenburg, and Wolfhart Kreuz
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- 2008
15. Secondary prophylaxis with recombinant activated factor VII improves health-related quality of life of haemophilia patients with inhibitors
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H. R. Roberts, Liselotte S. Ebbesen, Rolf Ljung, Barbara A. Konkle, W. K. Hoots, G. Auerswald, James Weatherall, and J.-M. Ferran
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Adult ,medicine.medical_specialty ,Pediatrics ,Adolescent ,Visual analogue scale ,Factor VIIa ,Hemophilia A ,Haemophilia ,Hemophilia B ,Acquired immunodeficiency syndrome (AIDS) ,Quality of life ,Internal medicine ,Hemarthrosis ,Outcome Assessment, Health Care ,medicine ,Humans ,Prospective Studies ,Child ,Prospective cohort study ,Genetics (clinical) ,Hematology ,Coagulants ,business.industry ,Secondary prophylaxis ,General Medicine ,medicine.disease ,Recombinant Proteins ,humanities ,Quality-adjusted life year ,Child, Preschool ,Quality of Life ,Quality-Adjusted Life Years ,business - Abstract
Haemophilia patients with inhibitors characteristically have impaired joint function and reduced health-related quality of life (HRQoL). This analysis examined whether secondary prophylaxis with recombinant activated factor VII (rFVIIa) improves HRQoL vs. conventional on-demand therapy in patients with haemophilia with inhibitors and frequent bleeds. After a 3-month preprophylaxis period, 22 patients received daily rFVIIa prophylaxis (90 or 270 microg kg(-1)) for 3 months, followed by 3 months' postprophylaxis. Days of hospitalization, absence from school/work and mobility aids requirements were recorded. HRQoL was assessed by EuroQoL (EQ-5D) questionnaire, visual analogue scale (VAS), derived Time to Trade-Off (TTO) scores and Quality Adjusted Life Years (QALYs). rFVIIa prophylaxis significantly (P < 0.0001) reduced bleeding frequency vs. prior on-demand therapy. Hospitalization (5.9% vs. 13.5%; P = 0.0026) and absenteeism from school/work (16.7% vs. 38.7%; P = 0.0127) decreased during prophylaxis; these effects tended to be maintained during postprophylaxis. HRQoL (evaluated by EQ-5D) tended to improve during and after rFVIIa prophylaxis. Notably, pain decreased and mobility increased in 40.9% and 27.3% of patients, respectively, at the end of the postprophylaxis period vs. preprophylaxis. Median VAS score increased from 66 to 73 (P = 0.048), and TTO scores suggested better HRQoL (0.62 vs. 0.76; P = 0.054) during postprophylaxis than preprophylaxis. Small to moderate changes in effect sizes were reported for VAS and TTO scores. Median QALYs were 0.68 (VAS) and 0.73 (TTO). Reductions in bleeding frequency with secondary rFVIIa prophylaxis were associated with improved HRQoL vs. on-demand therapy.
- Published
- 2008
16. PHYSICAL EXAMINATION IN PATIENTS WITH SEVERE HEMOPHILIA UNDER PROPHYLACTIC TREATMENT - EFFICACY OF AN EARLY LONG-TERM PROPHYLAXIS?
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A. Takla, G. Auerswald, K. Christensen, S. Masurat, T. Spranger, and A. Weidenhammer
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Pediatrics ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,medicine ,Physical therapy ,Long term prophylaxis ,In patient ,Physical examination ,Hematology ,business ,Prophylactic treatment - Published
- 2007
17. Langzeitprophylaxe bei kongenitaler Hämophilie mit Hemmkörpern
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G. Auerswald
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Gynecology ,medicine.medical_specialty ,biology ,business.industry ,Factor VIII inhibitor ,Haemophilia A ,Long term prophylaxis ,Hematology ,medicine.disease ,Haemophilia ,Recombinant factor VIIa ,biology.protein ,Medicine ,business - Abstract
ZusammenfassungEin Problem in der Therapie der Hämophilie ist die Entwicklung von Antikörpern gegen den zugeführten Faktor VIII. Patienten mit Antikörpern sind bei spontanen Blutungen, Operationen oder Traumata besonders gefährdet. Ist die Immuntoleranztherapie mit hohen i.v.-Dosen von Faktor VIII nicht erfolgreich, kommt eine Behandlung mit rekombinantem Faktor VIIa oder aktiviertem Prothrombinkomplex in Betracht. Dieser Artikel fasst die Daten dreier Patienten mit einer schweren Form der Hämophilie A und einer Intron- 22-Inversion im FVIII-Gen, die Antikörper gegen FVIII entwickelt haben, zusammen.Die Gabe von rFVIIa erwies sich bei diesen Patienten nicht nur als effektiv, sondern auch als sicher. Darüber hinaus zeigte sich unter der prophylaktischen Therapie mit rFVIIa in individueller Dosierung von 180 bis 270 μg/kg Körpergewicht einmal pro Tag eine deutliche Reduktion der spontanen Blutungsereignisse (Target Joints, Muskulatur, andere Lokalisation). Die verminderte Blutungsfrequenz führte zum Rückgang der Gelenk-und Muskelschmerzen und verhalf den jungen Patienten zu größerer Mobilität und deutlich besserer Lebensqualität.
- Published
- 2007
18. Factor X deficiency: clinical manifestation of 102 subjects from Europe and Latin America with mutations in the factor 10 gene
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M Navarrete, Karin Wulff, G. Auerswald, Falko H. Herrmann, A Ruiz-Saez, S. Lopaciuk, Angelika Batorova, and H. Pollmann
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Adult ,Costa Rica ,Male ,Heterozygote ,medicine.medical_specialty ,Pediatrics ,Adolescent ,Hemorrhage ,Clinical manifestation ,Factor X deficiency ,medicine.disease_cause ,Compound heterozygosity ,Gastroenterology ,Internal medicine ,Hemarthrosis ,Genotype ,Prevalence ,medicine ,Humans ,Child ,Factor X Deficiency ,Gene ,Genetics (clinical) ,Aged ,Hematoma ,Mutation ,business.industry ,Homozygote ,Heterozygote advantage ,Hematology ,General Medicine ,Middle Aged ,Venezuela ,Phenotype ,Europe ,Epistaxis ,Child, Preschool ,Factor X ,Female ,business - Abstract
Inherited factor X deficiency (FXD) is a rare (1:1,000,000) recessive bleeding disorder. The clinical and laboratory phenotypes of FXD are poorly correlated and few regional studies on the genotype and the clinical manifestations of FXD are known. To understand the association between clinical manifestations and causative genotype, detailed evaluation of bleeding pattern in a high number of patients is needed. This international study analysed the phenotype and genotype of 102 subjects from Central Europe (Germany, Poland and Slovakia) and Latin America (Costa Rica and Venezuela) with causative mutations in the F10 gene, via sequencing. Twenty-eight homozygous, seven compound-heterozygous and 67 heterozygous FXD subjects were characterized. Twenty-nine different causative mutations, including 15 novel mutations, were analysed. Spontaneous bleeding symptoms in 42 symptomatic individuals (26 homozygous, seven compound heterozygous and nine heterozygous) comprised easy bruising (55%), haematoma (43%), epistaxis (36%), haemarthrosis (33%), intracranial haemorrhage (ICH; 21%), and gastrointestinal (GI) haemorrhage (12%). The manifestation of bleeding symptoms in 9 of 67 (13%) symptomatic heterozygous subjects is described. The bleeding patterns of the enrolled patients showed differences that are associated with the types of F10 mutation, and the corresponding genotypes. The homozygous patients were evaluated for genotype-phenotype correlation. The results suggested that ICH seems to be associated with the F10 mutation Gly380Arg, and possibly with the mutations IVS7-1G>A and Tyr163delAT. A tentative association of other mutations to severe symptoms such as haemarthrosis and GI haemorrhage is reported. The severity of FXD, the genotype-phenotype association, and the results of regional studies are discussed.
- Published
- 2006
19. Invasive procedures and minor surgery in factor VII deficiency
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M. Napolitano, Guglielmo Mariani, Jørgen Ingerslev, A. R. De Saez, M. N. D. Di Minno, Annarita Tagliaferri, G. Auerswald, Alberto Dolce, Muriel Giansily-Blaizot, and Angelika Batorova
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medicine.medical_specialty ,business.industry ,Minor surgical procedure ,MEDLINE ,Hematology ,General Medicine ,Surgical procedures ,Surgery ,Minor surgery ,Blood loss ,Hemostasis ,Medicine ,Young adult ,business ,Factor VII deficiency ,Genetics (clinical) - Published
- 2012
20. Detection of all anti-factor VIII antibodies in haemophilia A patients by the Bethesda assay and a more sensitive immunoprecipitation assay
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G. Auerswald, Ulrich Budde, H. J. Klose, H. Lenk, Dorothea Scandella, Wolfhart Kreuz, and J. Klinge
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biology ,Immunoprecipitation ,Anti-factor VIII ,business.industry ,Haemophilia A ,Hematology ,General Medicine ,medicine.disease ,Virology ,medicine ,biology.protein ,Antibody ,business ,Genetics (clinical) ,Antibody detection - Published
- 2001
21. Prospective study of continuous infusion with Beriate® P in patients with severe haemophilia A undergoing surgery - a subgroup analysis
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Carolin Moorthi, Kirstin Haubold, Sylvia Masurat, David Overberg, G. Auerswald, Andrea Bade, and Julia Johne
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Adult ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Blood Safety ,Haemophilia A ,Subgroup analysis ,Bethesda unit ,Hemophilia A ,chemistry.chemical_compound ,Young Adult ,hemic and lymphatic diseases ,medicine ,Internal fixation ,Humans ,Prospective Studies ,Young adult ,Prospective cohort study ,Child ,Factor VII ,business.industry ,Hematology ,medicine.disease ,Surgery ,chemistry ,Administration, Intravenous ,Female ,Complication ,business - Abstract
Inhibitor development in severe haemophilia A patients is currently the most serious complication of factor VIII (FVIII) treatment. Although continuous infusion (CI) of FVIII concentrate during surgical procedures in haemophilia A patients has been shown to be beneficial, some publications suggest that CI increases the risk of inhibitor generation. We conducted a prospective subgroup analysis to investigate if CI of the high-purity, pasteurized, plasma-derived FVIII concentrate Beriate(®) P during surgery increases the risk of inhibitor formation.Patients with severe haemophilia A (FVIII:C1%) were included if they presented with a negative history of previous inhibitors, had ≥ 50 exposure days, and had been scheduled for a planned surgical procedure. A bolus infusion (30-50 IU/kg body weight) of Beriate(®) P was administered intravenously and followed by CI at a rate of 3-4 IU/kg body weight/hour. Dose adjustments were subsequently made based on daily measurements of plasma FVIII activity.Five patients (aged 8-34 years) with severe haemophilia A were included. The surgical procedures ranged from teeth extraction to internal fixation of a fracture. There was no inhibitor generation with CI of Beriate(®) P in patients undergoing surgery, and we did not observe any complications due to re-bleeding or virus transmission.Beriate(®) P was efficacious, safe, and well tolerated during CI.
- Published
- 2013
22. Blutungen: Koagulopathien in der Pädiatrie
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G. Auerswald
- Subjects
Gynecology ,medicine.medical_specialty ,business.industry ,Vascular biology ,Medicine ,Hematology ,Medical journal ,business - Abstract
ZusammenfassungDie häufigsten kongenitalen hämorrhagischen Diathesen sind Störungen der plasmatischen Gerinnung. Ursache ist die verminderte oder fehlende Aktivierbarkeit eines oder mehrerer Gerinnungsfaktoren infolge einer quantitativen Verminderung oder eines qualitativen Defekts der entsprechenden Faktoren oder die Präsenz eines Inhibitors (Hemmkörper gegen einen Faktor), der ihre Aktivierung blockiert. Die häufigsten Störungen sind die Hämophilie A und B (X-chromosomal-rezessiver Erbgang) und das Von-Willebrand-Jürgens-Syndrom (autosomal-dominant/rezessiv). Sehr selten sind die autosomal-rezessiv vererbten Mangelzustände der Gerinnungsfaktoren I, II, V, VII, X, XI, XII und XIII (1). Eine kausale Therapie ist bisher nicht möglich. Das quantitative und qualitative Ausmaß der Defekte bestimmt die klinische Blutungsneigung, wobei die hämostatische Mindestaktivität für jeden einzelnen Gerinnungsfaktor unterschiedlich ist. Ebenso sind die Aktivitäten bei vielen Gerinnungsfaktoren im Neugeborenen- und Säuglingsalter teilweise gegenüber dem späteren Lebensalter vermindert.
- Published
- 2000
23. Treatment of children with severe haemophilia A and inhibitors: a health economic evaluation for Germany
- Author
-
D. Eheberg, D. Schopohl, G. Auerswald, Karin Berger, W. Schramm, and Karin Kurnik
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,National Health Programs ,Cost-Benefit Analysis ,Hemophilia A ,Drug Administration Schedule ,Decision Support Techniques ,Health care rationing ,Rare Diseases ,Germany ,Hemarthrosis ,medicine ,Immune Tolerance ,Humans ,Mathematical Computing ,Evidence-Based Medicine ,Factor VIII ,Health Care Rationing ,Cost–benefit analysis ,Dose-Response Relationship, Drug ,business.industry ,Evidence-based medicine ,Bleed ,Length of Stay ,medicine.disease ,Markov Chains ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Economic evaluation ,Severe haemophilia A ,Risk assessment ,business ,Models, Econometric - Abstract
BACKGROUND: Decision makers request increasingly for high levels of evidence when allocating resources in medical care. This is hardly feasible for rare diseases. The objective was to analyze clinical and economic aspects of different immune tolerance induction (ITI) strategies for children with severe haemophilia A and inhibitors. METHODS: A decision model, time frame 18 years (base case: 2 year old boy), was constructed from a German statutory health insurance (SHI) perspective. Compared were high-dose (HD) ITI, low-dose (LD) ITI, 'ITI with risk assessment', on-demand (OD) treatment with bypassing agents. Clinical data were derived from structured literature research and expert opinion. Sensitivity analyses were conducted for parameters with wide statistical ranges. RESULTS: Base case analysis: total costs for HD ITI amounted to €3.4 million with 40.9% ITI costs, 51 joint bleeds, 36 hospital days; LD ITI, €2.4 million with 21.4% ITI costs, 74 joint bleeds, 52 hospital days; 'ITI with risk assessment', €2.7 million with 27.6% ITI costs, 53 joint bleeds, 37 hospital days; OD treatment, €1.7 million, 146 joint bleeds, 104 hospital days. Incremental costs per bleed avoided with HD ITI decreased from €1 million to €0.15 million with increase of joint bleeds from 3 to 20 per year, when compared to 'ITI with risk assessment' in sensitivity analysis. CONCLUSION: 'ITI with risk assessment' is cost-saving with comparable outcomes to HD ITI. However, patient-related factors like bleeding frequency have to determine treatment decisions in individual patients. More clinical data is needed to increase the significance of model -calculations.
- Published
- 2013
24. Correlation between phenotype and genotype in a large unselected cohort of children with severe hemophilia A
- Author
-
Manuel D. Carcao, H. Marijke van den Berg, Rolf Ljung, Maria Elisa Mancuso, C Altisent, G Auerswald, E Chalmers, H Chambost, A Cid, S Claeyssens, N Clausen, K Fischer, Van Creveld Kliniek, Ch van Geet, K Peerlinck, R Kobelt, W Kreuz, C Escuriola, K Kurnik, R Liesner, R Ljung, A Mäkipernaa, A Molinari, W Muntean, J Oldenburg, R Pérez Garrido, P Petrini, H Platokouki, A Rafowicz, E Santagostino, ME Mancuso, A Thomas, M Williams, SC Gouw, HM van den Berg, G Kenet, M Carcao, and G Rivard
- Subjects
Adult ,medicine.medical_specialty ,Adolescent ,Genotype ,Immunology ,Hemorrhage ,medicine.disease_cause ,Hemophilia A ,Biochemistry ,Severity of Illness Index ,Correlation ,Cohort Studies ,Genetic Heterogeneity ,Young Adult ,Internal medicine ,Medicine ,Humans ,Child ,Gene ,Genetic Association Studies ,Mutation ,Hematology ,Factor VIII ,business.industry ,Cell Biology ,Bleed ,Phenotype ,Surgery ,Codon, Nonsense ,Child, Preschool ,Sample Size ,Cohort ,business - Abstract
Phenotypic variability is well recognized in severe hemophilia A. A few studies, mainly in adults treated lifelong on demand, suggest that bleeding phenotype correlates with factor VIII gene (F8) mutation type. Because treatment regimens influence outcomes to a large extent, examining bleeding phenotype during the first years of life may be the most suitable way to define this variability. We set out to analyze the very early phenotypic expression of severe hemophilia A in 621 consecutively enrolled, well-characterized previously untreated patients and to correlate this with patients' F8 mutation. Detailed information was collected on bleeds and treatment of the first 75 exposure days or until inhibitor development. F8 mutation type was known for 531 patients; 402 had null mutations and 129 had non-null mutations. Considering only patients who had not started prophylaxis or developed an inhibitor before select bleeding events, we found that patients with null mutations experienced their first bleed and first joint bleed at younger median ages than patients with non-null mutations (9.7 vs 10.9 months and 13.8 vs 16.1 months, respectively). We conclude that F8 mutation type accounts for only a small component of the significant phenotypic variability found among patients with severe hemophilia A.
- Published
- 2013
25. Novel coagulation factor concentrates: issues relating to their clinical implementation and pharmacokinetic assessment for optimal prophylaxis in haemophilia patients
- Author
-
Gary Benson, Massimo Morfini, Benny Sørensen, Rolf Ljung, Silva Zupančić Šalek, G. Auerswald, Alexander Jetter, Víctor Jiménez-Yuste, Eduardo Remor, Thierry Lambert, University of Zurich, and Ljung, R
- Subjects
medicine.medical_specialty ,2716 Genetics (clinical) ,Population ,2720 Hematology ,610 Medicine & health ,Haemophilia ,Hemophilia A ,Joint disease ,Pharmacokinetics ,Breakthrough bleeding ,medicine ,Humans ,Dosing ,Precision Medicine ,Intensive care medicine ,education ,Genetics (clinical) ,education.field_of_study ,Dose-Response Relationship, Drug ,business.industry ,Hematology ,General Medicine ,medicine.disease ,Blood Coagulation Factors ,Regimen ,Coagulation ,10199 Clinic for Clinical Pharmacology and Toxicology ,Patient Compliance ,medicine.symptom ,business - Abstract
Prophylaxis is considered the optimal treatment regimen for patients with severe haemophilia, and may be especially important in the prevention of joint disease. Novel coagulation factor concentrates with prolonged half-lives promise to improve patient treatment by enabling prophylaxis with less frequent dosing. With the call to individualize therapy in haemophilia, there is growing awareness of the need to use pharmacokinetic (PK) assessments to tailor prophylaxis. However, for new factor concentrates, it is not yet known which PK values will be most informative for optimizing prophylaxis. This topic was explored at the Eighth Zurich Haemophilia Forum. On the basis of our clinical experience and a discussion of the literature, we report key issues relating to the PK assessment of new coagulation factors and include suggestions on the implementation of PK data to optimize therapy. As both inter- and intra-individual variability in factor half-life have been reported, we suggest that frequent PK assessments should be conducted. However, to diminish the burden of more frequent sampling, sparser sampling strategies and the use of population modelling should be considered. Guidelines on how to assay new factor concentrates, and which PK parameters should be measured, are needed. Concerns were raised regarding the possibility of breakthrough bleeding, and current thinking on how to prevent breakthrough bleeding may no longer be appropriate. Finally, as treatment adherence may be more important to ensure that a therapeutic level of a new coagulation factor concentrate is maintained, behavioural techniques could be implemented to help to improve treatment adherence.
- Published
- 2012
26. Patient-to-patient transmission of hepatitis C virus
- Author
-
Astrid Gruber, Patrice Lefevre, G. Auerswald, Jean Marc Durand, Bruce B. King, Jacques Soubeyrand, Gilles Kaplanski, Tobias Allander, M. Gonella, June Munro, Sharon Fitzpatrick, E. Lenz, B. Kornhuber, MatsA.A. Persson, K. Auberger, G. Vagelli, G. Calabrese, ElizabethA.B. McCruden, W. Kreuz, W. Roth, D. Klarmann, and J. Douglas Briggs
- Subjects
Transmission (medicine) ,Hepatitis B virus DNA polymerase ,business.industry ,Hepatitis C virus ,medicine ,General Medicine ,medicine.disease_cause ,business ,Virology - Published
- 1995
27. Immune tolerance therapy in paediatric haemophiliacs with factor VIII inhibitors: 14 years follow-up
- Author
-
T. Beeg, J. Joseph-Steiner, Wolfhart Kreuz, D. Klarman, S. Ehrenforth, M. Funk, Bernhard Kornhuber, G. Auerswald, D. Mentzer, and Inge Scharrer
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,High responder ,business.industry ,animal diseases ,Hematology ,General Medicine ,Gastroenterology ,Low responder ,Immune tolerance ,Median time ,hemic and lymphatic diseases ,Concomitant ,Internal medicine ,Immunology ,Medicine ,business ,Activated prothrombin complex concentrate ,Genetics (clinical) ,Antibody formation ,Severe complication - Abstract
Summary. We report our clinical experience in the first inhibitor detection and onset of IT therapy and to immune tolerance (IT) therapy of 21 paediatric haemo- interruption of IT therapy. For a rapid elimination of philiacs with FVIII inhibitor: high responders (16 HR) FVIII inhibitors it is important to start continuous received initially FVIII twice daily at a dosage of 50- administration of high-dose FVIII (2100 FVIII U/kg/ 300U/kg/day, 11/16 received a concomitant treatment day) before repeated exposure to FVIII, in order to with activated prothrombin complex concentrate (100- prevent rebooster effects, prolongation of elimination 200 U/kg/day). Low responders (five LR) received 20- time, and to reduce expense. 100 FVllI U/kg every second or third day. Inhibitor elimination was achieved in 19/21 patients in a median time of 4 months in HR and 1.5 months in LR. The outcome and length of time needed to induce IT was Keywords: factor VIII inhibitors, children with haemo- philia A, immune tolerance therapy, requirements for successful FVIII inhibitor elimination. significantly correlated with FVIII exposure between the Antibody formation against substituted factor VIII (FVIII) represents the most severe complication
- Published
- 1995
28. Invasive procedures and minor surgery in factor VII deficiency
- Author
-
G, Mariani, A, Dolce, M, Napolitano, J, Ingerslev, M, Giansily-Blaizot, M D, Di Minno, G, Auerswald, A R, De Saez, A, Tagliaferri, A, Batorova, and A, Orecchioni
- Subjects
Adult ,Male ,Hemostasis ,Adolescent ,Coagulants ,Factor VII Deficiency ,Blood Loss, Surgical ,Infant ,Hemorrhage ,Factor VII ,Middle Aged ,Young Adult ,Child, Preschool ,Surgical Procedures, Operative ,Humans ,Female ,Minor Surgical Procedures ,Child ,Aged - Published
- 2012
29. Early Tolerization to Minimize Inhibitors in PUPs with Hemophilia A
- Author
-
Karin Kurnik and G. Auerswald
- Subjects
business.industry ,Immunology ,Medicine ,business - Published
- 2011
30. When should prophylaxis therapy in inhibitor patients be considered?
- Author
-
G, Young, G, Auerswald, V, Jimenez-Yuste, B A, Konkle, T, Lambert, M, Morfini, E, Santagostino, and V, Blanchette
- Subjects
Blood Coagulation Factor Inhibitors ,Hemarthrosis ,Immune Tolerance ,Humans ,Factor VIIa ,Hemophilia A ,Blood Coagulation Factors ,Recombinant Proteins - Abstract
Currently, patients with severe haemophilia can expect to lead a relatively normal life including prevention of disabling arthropathy as a result of the development of factor replacement therapy and advances in the understanding of the use of such therapy given prophylactically. Unfortunately, a subset of patients develops neutralizing antibodies termed inhibitors rendering such therapy ineffective. These patients frequently develop recurrent joint bleeding resulting in arthropathy. Until recently, prophylactic therapy was not considered for patients with inhibitors because of the perceived lack of an effective therapeutic agent. However, an accumulation of case reports and a recent prospective study have suggested that prophylaxis with the currently available bypassing agents could be effective and appears to be safe in selected cases. This report will review the current data on prophylaxis with bypassing agents and suggest specific situations in which prophylaxis in inhibitor patients could be considered.
- Published
- 2011
31. When should prophylaxis therapy in inhibitor patients be considered?
- Author
-
Barbara A. Konkle, Massimo Morfini, T. Lambert, Elena Santagostino, G. Auerswald, Guy Young, Víctor Jiménez-Yuste, and Victor S. Blanchette
- Subjects
medicine.medical_specialty ,Factor replacement ,business.industry ,Hematology ,General Medicine ,Haemophilia ,medicine.disease ,Surgery ,Arthropathy ,Medicine ,Joint bleeding ,business ,Prospective cohort study ,Intensive care medicine ,Genetics (clinical) - Abstract
Currently, patients with severe haemophilia can expect to lead a relatively normal life including prevention of disabling arthropathy as a result of the development of factor replacement therapy and advances in the understanding of the use of such therapy given prophylactically. Unfortunately, a subset of patients develops neutralizing antibodies termed inhibitors rendering such therapy ineffective. These patients frequently develop recurrent joint bleeding resulting in arthropathy. Until recently, prophylactic therapy was not considered for patients with inhibitors because of the perceived lack of an effective therapeutic agent. However, an accumulation of case reports and a recent prospective study have suggested that prophylaxis with the currently available bypassing agents could be effective and appears to be safe in selected cases. This report will review the current data on prophylaxis with bypassing agents and suggest specific situations in which prophylaxis in inhibitor patients could be considered.
- Published
- 2011
32. [Analysis of muscle function with kinetic superficial EMG in children with haemophilia - recognizing subclinical changes, establishing individual therapy, quality control]
- Author
-
A, Seuser, M, Wendel, M, Navarrete-Duran, D, Fink, G, Auerswald, and P, Böhm
- Subjects
Adult ,Male ,Adolescent ,Electromyography ,Reproducibility of Results ,Hemophilia A ,Sensitivity and Specificity ,Young Adult ,Muscular Diseases ,Child, Preschool ,Humans ,Female ,Child ,Muscle, Skeletal ,Muscle Contraction - Abstract
Electromyography (EMG) measures muscle electricity. It depends on muscle contraction and central motor control. Muscles react very sensitive on external signals (e. g. bleeding), The resulting changes can be shown in EMG.A first study included 51 children and young adults from Costa Rica. They underwent a clinical examination and EMG of the hip, knee and ankle joints. Resting muscle tone, maximal isometric contraction and three typical isotonic movements of the joints were measured. First step of analysis was to characterize typical pathogenic changes in the muscles and to find a corresponding physical therapy to minimize these changes.It showed that EMG is a good marker for muscle condition. It helps to individualize therapy and improve effectivity of physical and physiotherapeutic treatment of the locomotive system of children and young adults with hemophilia. It can help to recognize early subclinical changes and to control the outcome of therapeutic modalities.
- Published
- 2011
33. A New Type of Congenital Dysfibrinogen, Fibrinogen Bremen, with an Aα Gly-17 to Val Substitution Associated with Hemorrhagic Diathesis and Delayed Wound Healing
- Author
-
Kazuki Niwa, M Nakanishi, Hisato Maekawa, Michio Matsuda, M Popp, Teruko Sugo, G. Auerswald, Y Wada, and Shinji Asakura
- Subjects
chemistry.chemical_classification ,biology ,Tetrapeptide ,business.industry ,Peptide ,Hematology ,Molecular biology ,Fibrin Monomer ,Fibrin ,Amino acid ,Biochemistry ,chemistry ,Polymerization ,Valine ,biology.protein ,Medicine ,business ,Peptide sequence - Abstract
SummaryWe have identified a new type of Aα Gly-17 to Val substitution in a congenital dysfibrinogen, fibrinogen Bremen, derived from a 15-year-old boy having manifested easy bruising and delayed wound healing. The functional abnormality was characterized by altered fibrin monomer polymerization, which became evident by increasing the salt concentration and pH. A synthetic tetrapeptide with a sequence of the amino-terminal segment of normal fibrin α-chain, Gly-Pro-Arg-Val, substantially inhibited polymerization of both normal and the patient-derived fibrin monomers. A synthetic tetrapeptide with the Bremen type sequence of Val-Pro-Arg-Val inhibited polymerization of the patient’s fibrin monomers partially at a peptide: fibrin monomer molar ratio of 4,000:1, and that of normal one at a much higher ratio of 10,000:1. Likewise, a synthetic peptide Ala-Pro-Arg-Val with a replacement of the Gly residue by another aliphatic amino acid Ala inhibited similarly the patient’s fibrin monomer polymerization. Thus, the hypothetical two-pronged socket-like structure consisting of the α-amino group of the amino-terminal Gly and the guanidino group of an Arg at position 3 of the normal fibrin α-chain seems to be restored considerably in the mutant fibrin α-chain at low ionic strengths and pH’s, despite the replacement of the amino-terminal Gly by another aliphatic amino acid Val.
- Published
- 1993
34. [Inhibitor development after early high exposure and cerebral haemorrhage. Costs and factor demand for a successful immunotolerance induction therapy]
- Author
-
K, Haubold, C, Moorthi, A, Bade, C, Niekrens, and G, Auerswald
- Subjects
Hematoma ,Factor VIII ,Cost of Illness ,Dose-Response Relationship, Drug ,Infant, Newborn ,Humans ,Female ,Factor VIIa ,Hemophilia A ,Introns ,Recombinant Proteins - Abstract
Severe 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 276000 IU pdFVIII were used; costs in total: 280173.60 Euro.
- Published
- 2010
35. New early prophylaxis regimen that avoids immunological danger signals can reduce FVIII inhibitor development
- Author
-
K, Kurnik, C, Bidlingmaier, W, Engl, H, Chehadeh, B, Reipert, and G, Auerswald
- Subjects
Factor VIII ,Time Factors ,Blood Coagulation Factor Inhibitors ,Coagulants ,Premedication ,Infant ,Hemorrhage ,Pilot Projects ,Hemophilia A ,Drug Administration Schedule ,Immunocompromised Host ,Logistic Models ,Child, Preschool ,Germany ,Humans ,Child - Abstract
The most problematic complication of haemophilia A treatment is the development of inhibitors to FVIII. The highest risk of developing inhibitors is during the first 20 exposure days (EDs). If the patient can be brought through this high risk period without inhibitor development, the subsequent risk is low. Therefore, as a pilot project, we developed a prophylaxis regimen for the first 20-50 EDs specifically designed to induce tolerance to the administered FVIII and to minimize inhibitor development by avoiding immunological danger signals. Twenty-six consecutive previously untreated patients (PUPs) with severe haemophilia A were treated with the new prophylaxis regimen and the incidence of inhibitor development in this group was compared with that in a historical control group of 30 consecutive PUPs treated with a standard joint protection prophylaxis regimen (40-50 IU kg(-1), three times a week). There were no significant differences between the study and control groups in patient-related inhibitor risk factors such as ethnicity (all Caucasian), severity of haemophilia (all1% FVIII), severity of FVIII gene mutation (P0.0006) nor in some treatment-related factors such as product type, age at first exposure, vaccination regimen or the need for surgery. 14 of 30 subjects given standard prophylaxis but only one of the 26 subjects given the new regimen developed an inhibitor (P = 0.0003, odds ratio 0.048, 95% CI: 0.001-0.372). Our results indicate that minimizing danger signals during the first 20 EDs with FVIII may reduce the risk of inhibitor formation. These results should be confirmed in a larger prospective clinical study.
- Published
- 2009
36. [Diagnosis of coagulation disorders: first steps to be done]
- Author
-
G, Auerswald
- Subjects
Diagnosis, Differential ,von Willebrand Diseases ,Humans ,Female ,Blood Coagulation Tests ,Child ,Hemorrhagic Disorders ,Menorrhagia ,Referral and Consultation ,Algorithms ,Purpura - Published
- 2009
37. Haemophilia care in children--benefits of early prophylaxis for inhibitor prevention
- Author
-
Elena Santagostino, G. Auerswald, Luis Graca, and Maria Elisa Mancuso
- Subjects
medicine.medical_specialty ,Laboratory monitoring ,Haemophilia A ,Haemophilia ,Hemophilia A ,Drug Administration Schedule ,Immune system ,Hemarthrosis ,medicine ,Immune Tolerance ,Humans ,Intensive care medicine ,Child ,Genetics (clinical) ,Haemophilic arthropathy ,Factor VIII ,Blood Coagulation Factor Inhibitors ,business.industry ,Coagulants ,Infant, Newborn ,Infant ,Hematology ,General Medicine ,medicine.disease ,Antibody production ,Regimen ,Child, Preschool ,Immunology ,Complication ,business - Abstract
Summary. Haemophilia therapy is aimed at treating and preventing bleeding episodes and related complications and clinical studies have shown that regular prophylaxis, started at an early age, is able to reduce physical impairment from haemophilic arthropathy. Today, the development of anti-Factor VIII (FVIII) inhibitors is the most serious treatment-related complication of haemophilia therapy and a number of genetic and environmental risk factors have been identified in the past years. Clinical data show that early start of prophylaxis and the avoidance of intensive treatment periods may protect patients from inhibitor development. The mechanisms are not completely understood; yet, recent experimental data suggest that pro-inflammatory or ‘danger signals’ may be involved in inducing tolerance vs. an effector immune response. So, exposure to a factor concentrate by itself may not be enough to trigger an immune response, while an intensive exposure to FVIII in the presence of such ‘danger signals’ can activate antigen-presenting cells, up-regulating co-stimulatory signals for T lymphocytes and ultimately enhancing antibody production. The ‘optimal’ regimen for primary prophylaxis is still not identified and barriers to prophylaxis implementation remain relevant. Key issues include the optimal age at prophylaxis onset, the optimal dosage/schedule, the proper clinical and laboratory monitoring and patients’ compliance. Practical approaches to early prophylaxis as implemented in the haemophilia centres in Milan and Bremen are discussed in this respect.
- Published
- 2009
38. Paediatric haemophilia with inhibitors: existing management options, treatment gaps and unmet needs
- Author
-
Elena Santagostino, G. Auerswald, Gary Benson, Silva Zupančić Šalek, Thierry Lambert, Rolf Ljung, Víctor Jiménez-Yuste, Peter Salaj, and Massimo Morfini
- Subjects
Male ,medicine.medical_specialty ,Evidence-based practice ,MEDLINE ,Factor VIIa ,Haemophilia ,Hemophilia A ,Unmet needs ,Quality of life ,Internal medicine ,Arthropathy ,Hemarthrosis ,medicine ,Humans ,Intensive care medicine ,Child ,Activated prothrombin complex concentrate ,Genetics (clinical) ,Hematology ,business.industry ,General Medicine ,activated prothrombin complex concentrate. haemophilia. inhibitors. paediatric. prophylaxis. recombinant activated factor vii ,medicine.disease ,Blood Coagulation Factors ,Recombinant Proteins ,Evidence-Based Practice ,Quality of Life ,Medical emergency ,business ,Needs Assessment - Abstract
Development of inhibitors is a severe complication of haemophilia posing many management challenges. While a long-term goal in inhibitor patients is eradication of inhibitors through immune tolerance induction, bypassing agents such as recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrate (aPCC) are essential for control of bleeding episodes. Paediatric patients with haemophilia and inhibitors are at particular risk of recurrent haemarthroses, and management of these patients should seek to avoid joint damage and support the child's full social and physical development. Current options for management of bleeding complications include on-demand treatment of acute bleeding episodes, secondary prophylaxis to avoid recurrent bleeds and surgery to treat affected joints. There is also a rationale for adopting prophylactic approaches to prevent bleeding in inhibitor patients, allowing this group similar opportunities for protection against arthropathy development as are given to non-inhibitor patients. This paper, based on a roundtable meeting of haematology experts at the first Zurich Haemophilia Forum in May 2008, reviews the current evidence supporting more intense and prophylactic approaches to manage bleeding risk in paediatric haemophilia patients with inhibitors, and highlights the need for investigations of primary prophylaxis in this vulnerable patient group, to support best long-term outcome.
- Published
- 2009
39. Short-range order in yttria-stabilized zirconia: an EXAFS study
- Author
-
E. Zschech, B.N. Novgorodov, G. Auerswald, and E.-D. Klinkenberg
- Subjects
Physics ,Nuclear and High Energy Physics ,Extended X-ray absorption fine structure ,Coprecipitation ,Spectral line ,Ion ,symbols.namesake ,Tetragonal crystal system ,Fourier transform ,symbols ,Physical chemistry ,Instrumentation ,Ball mill ,Yttria-stabilized zirconia - Abstract
The short-range order of ZrO2-3 mol% Y2O3 powders is studied by EXAFS spectroscopy in relation to the powder preparation process. For powders prepared by both ball milling and coprecipitation, the Fourier transforms of the Y3+ and Zr4+ K-EXAFS spectra are analyzed. For both preparation processes, the stabilizing Y3+ ions predominantly substitute Zr4+ ions in the tetragonal ZrO2 modification. Clusters with Y2O3 short-range order were not detected in this study.
- Published
- 1991
40. Haemate P/Humate-P for the treatment of von Willebrand disease: considerations for use and clinical experience
- Author
-
G. Auerswald and Wolfhart Kreuz
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Gastroenterology ,Von Willebrand factor ,hemic and lymphatic diseases ,Internal medicine ,von Willebrand Factor ,medicine ,Von Willebrand disease ,Humans ,Adverse effect ,Desmopressin ,Genetics (clinical) ,Paediatric patients ,Factor VIII ,biology ,business.industry ,Coagulants ,Hematology ,General Medicine ,medicine.disease ,Thrombosis ,Clinical trial ,Drug Combinations ,von Willebrand Diseases ,Treatment Outcome ,Immunology ,biology.protein ,Female ,business ,Haemate p ,medicine.drug - Abstract
von Willebrand disease (VWD) is a heterogeneous bleeding disorder with symptoms in affected patients ranging from mild effects to potentially devastating haemorrhagic events. Desmopressin (DDAVP) and von Willebrand factor/factor VIII (VWF/FVIII) concentrates are the principal treatments. Haemate P/Humate-P is an intermediate-purity VWF/FVIII concentrate with extensive clinical experience in VWD. This concentrate has been shown to correct haemostatic defects of VWD, with efficacy ratings of good/excellent in nearly all patients treated for bleeding or surgical events. Haemate P/Humate-P has a high content of the high molecular weight (HMW) VWF multimer fraction, which has been shown to be very effective in achieving haemostasis. The HMW VWF multimer pattern in Haemate P/Humate-P is more similar to that of normal human plasma (94% for Haemate P/Humate-P vs. 100% for normal human plasma) than that of other VWF/FVIII concentrates and correlates with functional VWF activities including ristocetin cofactor activity (VWF:RCo) and collagen-binding activity. The recommended dosing of Haemate P/Humate-P is based preferentially on VWF:RCo activity, which is approximately twice that of FVIII:C (2.4:1). Haemate P/Humate-P has been shown to be safe; no serious adverse events or cases of thrombosis have been observed in clinical trials and no documented cases of viral transmission in nearly three decades of clinical use. While DDAVP is effective in a large proportion of VWD patients, it may not provide adequate haemostasis in all situations. In such cases, Haemate P/Humate-P is an effective replacement concentrate for all types of VWD in both adult and paediatric patients.
- Published
- 2008
41. Characterization of a Mutation in Exon 1 of the FVII Gene — a Case of RNA Editing?
- Author
-
W. Schröder, R. Tech, K. Wulff, G. Auerswald, F. H. Herrmann, and S. Becker
- Subjects
Genetics ,Mutation ,Sequence analysis ,Nonsense mutation ,Biology ,medicine.disease_cause ,Exon ,hemic and lymphatic diseases ,RNA splicing ,medicine ,Missense mutation ,splice ,cardiovascular diseases ,Gene - Abstract
FVII is a vitamin K-dependent coagulation protease essential for the initiation phase of normal hemostasis. Hereditary FVII deficiency is a rare autosomal recessive bleeding disorder with a variable phenotype. There is a poor correlation between FVII levels, clinical picture and the underlying genetic defect [1, 2]. In the Greifswald FVII deficiency study more than 126 different causative mutations have been characterized by sequence analysis up to now. Among them 67% were missense mutations, 6.3% nonsense mutations, 7% small deletions and 0.7% insertions. 8% of the mutations were located in the 5’ flanking region of the FVII gene and 11% of the mutations affected splice sites [3, 4, 5, 6].
- Published
- 2008
42. Therapeutical Options for Congenital FVII Deficiency — The HK 7 Project of the International Greifswald Registry of the Congenital FVII Deficiency (GR-HK-7)
- Author
-
K. Zwiauer, D. Franke, C. Wermes, A. Huth-Kühne, K. Wulff, A. Siegemund, G. Jiménez-Cruz, R. M. Loreth, F. Botha, E. Schomerus, G. Auerswald, R. Eisert, B. Niemann, J. Ingerslev, Lizbeth Salazar-Sánchez, O. Anders, M. Girisch, F. H. Herrmann, A. Gerhardt, Ch. Schubert, and K. Erdlenbruch
- Subjects
Pediatrics ,medicine.medical_specialty ,business.industry ,Oral surgery ,hemic and lymphatic diseases ,education ,Genotype ,Medicine ,cardiovascular diseases ,Joint bleeding ,business ,Factor VII deficiency ,Phenotype - Abstract
The congenital Factor VII deficiency (FVIID) is a rare hemorrhagic disorderwith an autosomal recessive pattern of inheritance and a prevalence of 1:500,000. In 1994 the International Greifswald Registry of congenital FVII deficiency was initiated [1]. We analyzed the phenotype and genotype of subjects,who presented with reduced FVII activities.
- Published
- 2008
43. Prophylactic treatment of haemophilia patients with inhibitors: clinical experience with recombinant factor VIIa in European Haemophilia Centres
- Author
-
G. Auerswald, Carmen Altisent, F. A. Scaraggi, V. Rossi, Jan Blatny, G. F. Rivolta, Massimo Morfini, Rainer Kobelt, A. Borel-Derlon, and J. Rodriguez-Martorell
- Subjects
Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Hemorrhage ,Factor VIIa ,030204 cardiovascular system & hematology ,Haemophilia ,Hemophilia A ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Hemarthrosis ,medicine ,Humans ,Patient compliance ,Child ,Genetics (clinical) ,Retrospective Studies ,Factor VII ,biology ,business.industry ,Coagulants ,Retrospective cohort study ,Hematology ,General Medicine ,medicine.disease ,Recombinant Proteins ,3. Good health ,Clinical trial ,Europe ,Treatment Outcome ,chemistry ,Recombinant factor VIIa ,Child, Preschool ,biology.protein ,Patient Compliance ,Female ,business ,030215 immunology ,Prophylactic treatment - Abstract
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.
- Published
- 2007
44. Pharmacokinetics, efficacy and safety of IMMUNATE solvent/detergent (IMMUNATE S/D) in previously treated patients with severe hemophilia A: results of a prospective, multicenter, open-label phase III study
- Author
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L. Nemes, Werner Engl, Borislava G. Pavlova, R. Zimmermann, Hartmut J. Ehrlich, G. Auerswald, V. Komrska, A. Klukowska, Toshko Lissitchkov, G. Dobaczewski, and B. Abbühl
- Subjects
medicine.medical_specialty ,Drug-Related Side Effects and Adverse Reactions ,animal diseases ,Treatment outcome ,chemical and pharmacologic phenomena ,Hemorrhage ,Severe hemophilia A ,Hemophilia A ,Gastroenterology ,Antibodies ,Pharmacokinetics ,hemic and lymphatic diseases ,Internal medicine ,von Willebrand Factor ,medicine ,Solvent detergent ,Humans ,Drug toxicity ,Factor VIII ,business.industry ,Hematology ,General Medicine ,biochemical phenomena, metabolism, and nutrition ,Surgery ,Treatment Outcome ,bacteria ,Open label ,Previously treated ,business - Abstract
IMMUNATE Solvent/Detergent (S/D) is a plasma-derived, human factor VIII (FVIII)/von Willebrand factor (VWF) complex subjected to S/D and vapor heat treatment.This prospective clinical study evaluated the pharmacokinetics (PK) (compared to IMMUNATE), efficacy and safety of IMMUNATE S/D in 56 previously treated patients with severe hemophilia A. Subjects received IMMUNATE S/D either on-demand (47/56), as a prophylactic regimen (49/56), or both (40/56).IMMUNATE and IMMUNATES/D were equivalent with respect to the FVIII and VWF PK parameters assessed. Bleeding episodes (623) were reported in 47/56 subjects. For 89% of episodes, subjects required only 1 infusion with a mean dose of 29.6 IU/kg and 96% of episodes had an excellent or good response. The duration of prophylaxis ranged from 0.1 to 5.2 months. The median number of bleeds per month in subjects on prophylaxis was 0 (range 0-10). No FVIII inhibitory antibodies were observed in 56 subjects after 2,646 treatment exposure days. No related serious adverse events were reported.The introduction of S/D treatment did not alter the PK characteristics and function of VWF and FVIII molecules in IMMUNATE S/D which is effective and safe for treatment of bleeding episodes, management of surgical procedures and prophylaxis.
- Published
- 2007
45. [Long-term prophylaxis in congenital haemophilia with inhibitors - experiences with rFVIIa]
- Author
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G, Auerswald
- Subjects
Adult ,Male ,Humans ,Prothrombin ,Child ,Hemophilia A ,Factor VIIIa ,Recombinant Proteins - Abstract
A major challenge in the treatment of haemophilia patients is the development of autoantibodies against factor VIII. These patients are at particular risk if spontaneous bleedings or traumata occur or if surgery is necessary. In case of an unsuccessful immune tolerance therapy with high i.v. doses of factor VIII, treatment with recombinant factor VIIa or activated prothrombin complex should be considered. This article summarises data of three patients with severe haemophila A due to an inversion of intron 22 in the FVIII gen. All three patients had autoantibodies against FVIII. The therapy of these patients with rFVIIIa was safe and effective. Furthermore a prophylactic therapy with rFVIIa (at an individual dose of 180-270 microg/kg body weight) reduced the number of spontaneous bleedings in joints and muscles as well as in other locations significantly. The reduced rate of spontaneous bleedings improved the mobility and the quality of life in the young patients studied.
- Published
- 2007
46. Fit for Life Competition: Everyone’s a Winner
- Author
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P. Böhm, W. Eberl, S. Gutsche, G. Auerswald, R. Klamroth, A. Seuser, and A. Kurme
- Subjects
Competition (economics) ,Matching (statistics) ,Fit for Life ,Operations research ,Computer science ,Back muscles - Abstract
The 5-item fitness check has now been conducted in more than 200 children with hemophilia. The results show that hemophilia is associated with specific limitations in terms of fitness. However, these skills can only improve if everybody concerned is motivated enough to perform suitable exercises several times a week. A sport recommendation program was written on the basis of an algorithm and upgraded to create an option for matching specific exercises with the individual fitness requirement. The children’s motivation was further enhanced by a competition based on the 5-item fitness check.
- Published
- 2007
47. Evaluation of pharmacokinetics, efficacy and safety of Immunate solvent detergent in previously treated patients with severe haemophilia A
- Author
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L. Nemes, Toshko Lissitchkov, Hartmut J. Ehrlich, Werner Engl, B. Abbühl, R. Zimmermann, V. Komrska, Anna Klukowska, Borislava G. Pavlova, G. Auerswald, and G. Dobaczewski
- Subjects
animal diseases ,Population ,Detergents ,Pain ,Hemorrhage ,Haemophilia ,Hemophilia A ,law.invention ,Pharmacokinetics ,Randomized controlled trial ,Von Willebrand factor ,law ,hemic and lymphatic diseases ,medicine ,Humans ,Prospective Studies ,Adverse effect ,Prospective cohort study ,education ,Genetics (clinical) ,education.field_of_study ,Factor VIII ,biology ,business.industry ,Hematology ,General Medicine ,medicine.disease ,Regimen ,Treatment Outcome ,Anesthesia ,biology.protein ,Solvents ,Virus Inactivation ,Safety ,business - Abstract
Immunate Solvent Detergent (S/D) is a plasma derived, purified, human factor VIII (FVIII) - von Willebrand factor (VWF) complex subjected to two virus inactivation/removal processes: S/D and vapor heat treatment. This prospective, multicentre, three-part clinical study evaluated the pharmacokinetics (in comparison to the predecessor product Immunate), efficacy and safety of Immunate S/D in 56 previously treated patients with severe haemophilia A. Subjects received Immunate S/D on-demand, as a prophylactic regimen or both. The results of the pharmacokinetic population demonstrate that Immunate and Immunate S/D were equivalent with respect to the FVIII - and to the retrospectively VWF - parameters assessed. A total of 623 bleeding episodes were reported in 47/56 subjects. The duration of prophylaxis ranged from 0.1-5.2 months with a total of 175.6 months. The median number of bleeds per month in subjects on prophylaxis was 0 (range 0-10). Ninety-six percent of bleeding episodes were rated as having an excellent or good response. For most bleeding episodes (89%), subjects required only one infusion with a mean dose of 29.6 IU kg(-1). No FVIII inhibitory antibodies were observed in any subject. No related serious adverse events were reported. Thus, the introduction of S/D treatment did not alter the PK characteristics and function of VWF and FVIII molecules of Immunate S/D which is effective and safe for treatment of bleeding episodes, management of surgical procedures, and prophylaxis.
- Published
- 2007
48. Clinical Investigation of Orthopedic Outcome in Patients with Severe Hemophilia — Advantage of an Early Prophylactic Treatment?
- Author
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G. Auerswald, S. Meister, T. Spranger, K. Christensen, and A. Weidenhammer
- Subjects
medicine.medical_specialty ,Pediatrics ,medicine.diagnostic_test ,business.industry ,Hemophilic arthropathy ,Physical examination ,Chronic synovitis ,Clinical investigation ,Orthopedic surgery ,Joint damage ,medicine ,In patient ,business ,Prophylactic treatment - Abstract
A substantial goal in treatment of hemophilia is the avoidance of hemophilic arthropathy secondary to recurrent hemarthroses and chronic synovitis. In order to prevent joint damage effective prophylaxis should be started in an early age. Efficacy of early prophylactic treatment has been shown within recent years. Physical examination and joint status was performed to determine whether early long-term prophylaxis is favorable.
- Published
- 2006
49. Inhibitor Incidence in Previously Untreated Patients (PUPs) with Hemophilia A and B. A Prospective Multi-Center Study of the Pediatric Committee of the German, Swiss and Austrian Society for Thrombosis and Hemostasis Research (GTH)
- Author
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G. Auerswald, W. Kreuz, Ulrich Budde, H. J. Klose, and H. Lenk
- Subjects
Pediatrics ,medicine.medical_specialty ,Current generation ,business.industry ,Plasma derived ,Incidence (epidemiology) ,medicine.disease ,Severe hemophilia A ,Thrombosis ,Multi center study ,Hemostasis ,medicine ,business ,Mild disease - Abstract
One of the most serious complications in the treatment of the current generation of hemophiliacs is the development of inhibitors occurring in about 30% of patients with severe hemophilia A and to a lesser extent in those with moderate and mild disease [4]. The development of inhibitors in hemophilia B is rare (0–9%) and affects predominantly severe hemophiliacs with major factor (F) IX gene defects. In order to observe inhibitor development in previously untreated patients (PUPs) with hemophilia A and B a prospective multi-center study was started in 1993 by the Pediatric Committee of the GTH (German, Swiss and Austrian Society for Thrombosis and Hemostasis Research). PUPs with hemophilia A and B are recruited prospectively all over Germany, Austria and Switzerland (32 hemophilia centers) since 1993 (observation period: 11 years/update June 2004) in this ongoing study (recruitment period 15 years). The patients are restricted to one single plasma derived (pd) or recombinant (r) concentrate available on the market throughout the whole study period. The study protocol provides rigorous inhibitor testing: – prior to the first exposure – every 3rd to 4th exposure day (ED) for the first 20 EDs – until the 200th ED every 10th ED – after the 200th ED every 3 months – additional testing in any situation if inhibitor development is suspected – rarely exposed patients should be controlled every 3 months
- Published
- 2006
50. Unusual Prolonged Course of an Immune Tolerance Therapy (ITT) in a Patient with Severe Hemophilia A and a High-Titer Inhibitor Development
- Author
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T. Spranger, S. Meister, G. Auerswald, H.-H. Brackmann, and K. Christensen
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,business.industry ,animal diseases ,Bleed ,medicine.disease ,Severe hemophilia A ,Bethesda unit ,Gastroenterology ,Thrombosis ,Surgery ,Immune tolerance ,Sepsis ,Titer ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Family history ,business - Abstract
Severe hemophilia A (FVIII rest-activity < 1%) was diagnosed post partum due to positive family history. At the age of eight months, first FVIII therapy was given to stop a mucosal bleed. Other FVIII substitutions followed on demand. In September 1989, at the age of two years, he developed a high-titer inhibitor. An immune tolerance therapy (ITT) was started with 180 IU/kg FVIII (plasma derived (pd), containing VWF) twice daily according to the »Bonn Protocol«. The inhibitor first increased to 16 Bethesda units/ml (BU/ml) and decreased afterwards to 1 BU/ml. FVIIIactivity was detectable whereas the FVIII-recovery did not normalize. FVIII administration got more difficult, a central venous line was implanted. The course of therapy was complicated by several infections of the central venous line, thrombosis, sepsis and severe joint bleeds. The central venous line had to be taken out twice; in addition, compliance was difficult. Therapy was not given continuously. The inhibitor titer ranged between 1 and 88 BU/ml over several years. Since severe bleeds could not be avoided, therapy was continued with aPCC twice daily in addition to FVIII. After six years of ITT and still a high-titer inhibitor, the FVIII and
- Published
- 2006
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