J Oldenburg

University of Bonn, Bonn, North Rhine-Westphalia, Germany

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Publications (294)772.38 Total impact

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    ABSTRACT: In Acquired Haemophilia (AH) autoantibodies against blood coagulation factors, mainly FVIII, inhibit the blood coagulation cascade. The clinical symptoms can vary from minor to severe life threatening bleedings. At present it is unclear if the intensity of the treatment needs to be adapted to the severity of the disease. The clinical data and long term outcome from 20 patients suffering from minor severe AH were summarized. Bleedings requiring no blood transfusions were defined as less severe. In case of FVIII concentration <5% an immunosuppressive treatment (IT) consisting of cyclophosphamide 1-2 mg/kg BW/d and/or prednisolone 1-2 mg/kg BW/d was initiated. IT induced complete remission (CR) in only 40% of patients (8/20) after a mean time of 133.4 d (±90.7 d). Treatment associated severe side effects occurred in all patients. 15 patients required a factor substitution therapy due to proceeding bleedings. In 7 patients a partial remission (PR) of AH could be achieved; bleedings progressed in 5 of them and they underwent successfully second line immunoadsorption-based protocol. The inhibitor titer differed statistically significant between CR and PR with a mean of 3.7 BU vs. 16 BU. 5 patients had a fatal outcome mainly due to severe disease associated co morbidities. Immunosuppressive treatment failed in nearly a half of AH patients. Mortality was with 25% still high. The majority of patients required an intense long-term IT and developed severe treatment related side effect. Immediate start of IT did not control bleeding. In consequence, less severe AH also should be treated with a more rigorous regime because the occurrence of minors bleedings at initial presentation is not a predictive of clinical outcome. An Immunoadsorption-based protocol should be considered first line or even as a salvage strategy. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Atherosclerosis. Supplements 05/2015; 18. DOI:10.1016/j.atherosclerosissup.2015.02.015 · 9.67 Impact Factor
  • J E Bach, B Wolf, J Oldenburg, C R Müller, S Rost
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    ABSTRACT: Current screening methods for factor VIII gene (F8) mutations can reveal the causative alteration in the vast majority of haemophilia A patients. Yet, standard diagnostic methods fail in about 2 % of cases. This study aimed at analysing the entire intronic sequences of the F8 gene in 15 haemophilia A patients by next generation sequencing. All patients had a mild to moderate phenotype and no mutation in the coding sequence and splice sites of the F8 gene could be diagnosed so far. Next generation sequencing data revealed 23 deep intronic candidate variants in several F8 introns, including six recurrent variants and three variants that have been described before. One patient additionally showed a deletion of 9.2 kb in intron 1, mediated by Alu-type repeats. Several bioinformatic tools were used to score the variants in comparison to known pathogenic F8 mutations in order to predict their deleteriousness. Pedigree analyses showed a correct segregation pattern for three of the presumptive mutations. In each of the 15 patients analysed, at least one deep intronic variant in the F8 gene was identified and predicted to alter F8 mRNA splicing. Reduced F8 mRNA levels and/or stability would be well compatible with the patients' mild to moderate haemophilia A phenotypes. The next generation sequencing approach used proved an efficient method to screen the complete F8 gene and could be applied as a one-stop sequencing method for molecular diagnostics of haemophilia A.
    Thrombosis and Haemostasis 05/2015; 114(3). DOI:10.1160/TH14-12-1011 · 5.76 Impact Factor
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    ABSTRACT: Advanced haemophilic arthropathy of the knee is associated with progressive joint stiffness. Results after total knee arthroplasty (TKA) in stiff knees are considered to be inferior compared to those with less restricted preoperative range of motion (ROM). There is only very limited data on the results of primary TKA in haemophilic patients with stiff knees. The purpose of this retrospective study was to evaluate the clinical outcome after TKA performed in haemophilic patients with preoperative ROM of 50° or less. Twenty one patients (23 knees) undergoing TKA with stiff knees were retrospectively evaluated. Mean follow-up was 8.3 years (range, 2-25). Clinical assessment included ROM, degree of flexion contracture and complication rate. Functional evaluation and pain status were assessed using the Knee Society's Scoring System (KSS). Range of motion improved from 26.7° preoperatively to 73.0° postoperatively. Flexion contracture decreased from 21.7° to 8.3°. KSS increased from 22.9 to 72.9 points. Evaluation of pain revealed a decrease from 8.4 points preoperatively to 2.1 points postoperatively. All these differences were statistically significant (P < 0.005). The complication rate was 8.7% including one late periprosthetic infection, and one aseptic implant loosening. Nine patients who required VY-quadricepsplasty for knee exposure developed a mean postoperative extensor lag of 7°. Total knee arthroplasty in haemophilic patients presenting with stiff knees results in significant improvement of function and reduction in pain. Although the clinical outcome is inferior compared to nonstiff knees reported in the literature, joint replacement surgery can be successfully performed in this particular group of patients. © 2015 John Wiley & Sons Ltd.
    Haemophilia 04/2015; DOI:10.1111/hae.12698 · 2.47 Impact Factor
  • B. Pezeshkpoor, J. Oldenburg
    Haemophilia 04/2015; DOI:10.1111/hae.12687 · 2.47 Impact Factor
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    ABSTRACT: Haemophilia A is an X-linked bleeding disorder caused by heterogeneous mutations in the F8 gene. Two inversion hotspots in intron 22 and intron 1, as well as point mutations, small insertions and deletions in the F8 gene account for causal mutations leading to severe haemophilia A. Rarely, novel molecular mechanisms lead to a haemophilia A phenotype which cannot be completely characterized by routine molecular diagnostic methods. Here, we characterized the molecular abnormality in a boy with a severe haemophilia A phenotype. On investigation by PCR and DNA sequencing, exon 18 of F8 repeatedly failed to amplify. However, analysis by multiplex ligation-dependent probe amplification demonstrated the presence of exon 18 sequence, suggesting a more complex rearrangement than a single exon deletion. The analysis of exon 18 and its flanking regions by inverse PCR revealed a complex mutation comprising insertions of extragenic sequences from Xq28 along with a partial duplication of exon 18. Based on the successful analysis and characterization of the familial breakpoint, we developed a PCR-based diagnostic approach to detect this defect in family members in whom no diagnostic test could be offered until this time.
    Haemophilia 01/2015; 21(3). DOI:10.1111/hae.12606 · 2.47 Impact Factor
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    ABSTRACT: Inhibitor development is the most serious and challenging complication in the treatment of severe haemophilia A. Up to 38% of such patients develop inhibitors with current recombinant factor VIII (rFVIII) products produced in hamster cell lines. Human-cl rhFVIII is a new generation fully sulfated B-domain-deleted FVIII coagulant glycoprotein, which is generated from a human cell line. Thus, there are no non-human epitopes which would be potentially immunogenic. This molecule has significantly higher VWF-binding affinity compared with existing full-length rFVIII produced in hamster cell lines. The development aim of Human-cl rhFVIII is to address the challenges of FVIII inhibitors and frequent infusions during prophylaxis. Human-cl rhFVIII's mean half-life is very comparable to some of the newer products which involve modification of the FVIII molecule to extend the circulating half-life. There are promising data concerning the use of a personalized prophylaxis regimen with Human-cl rhFVIII. Preliminary data indicate a median dosing interval of 3.5 days with 66.7% of the patients on a twice per week or fewer infusions schedule combined with a low bleeding rate and no increased FVIII consumption when compared to standard prophylaxis. No product-specific laboratory assay is required to monitor the coagulation activity for Human-cl rhFVIII. The results of registration clinical trials with Human-cl rhFVIII as well as the ongoing studies in previously untreated patients (NuProtect) and personalized prophylaxis study in previously treated patients (NuPreviq), will be discussed. The manufacturer has received marketing authorization for Human-cl rhFVIII in Europe and Canada under the name Nuwiq(®) and plans to launch it in the USA and globally in 2015. © 2014 John Wiley & Sons Ltd.
    Haemophilia 01/2015; 21 Suppl 1:1-12. DOI:10.1111/hae.12582 · 2.47 Impact Factor
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    ABSTRACT: In order to evaluate complication rates of dentoalveolar surgery in patients with congenital bleeding disorders, a retrospective case-control study was performed. A collective of patients with congenital bleeding disorders (n = 69), who received common oral surgery procedures in combination with intense perioperative monitoring and coagulation factor substitution at the University Hospital of Bonn between 1992 and 2011, was matched with patients without bleeding disorders by age, sex, and type of surgery. In addition to the rates of perioperative bleeding and other complications, the duration of surgery and the use of local hemostatic agents were compared between both cohorts. There were no significant differences between the two groups regarding the rate of postoperative bleeding (2.9 vs 1.4 %, patients with congenital bleeding disorders vs controls) and the rate of other complications (7.2 vs 21.7 %). Furthermore, no significant difference in operation time (54 min in patients with congenital bleeding disorders vs 45 min in controls) was observed. However, there was a significant difference (p < 0.001) regarding the use of local hemostatic measures, which were applied in all patients with hereditary bleeding disorders but in only one of the controls. All patients with bleeding disorders were inpatients, while all controls were treated in an outpatient setting. If adequate measures are taken, the complication rate following oral surgery in patients with hereditary bleeding disorders can be reduced to that of patients without bleeding disorders. However, these results are reached at significant costs due to coagulation factor replacement and inpatient treatment.
    Oral and Maxillofacial Surgery 12/2014; DOI:10.1007/s10006-014-0476-z
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    ABSTRACT: Combined coagulation factor VII (FVII) and factor X (FX) deficiency (combined FVII/FX deficiency) belongs to the group of bleeding disorders in which both factors show reduced plasma activity. It may arise from coincidental inheritance of separate coagulation factor deficiencies or a common cause as large deletions comprising both gene loci. The F7 and F10 genes are located on the long arm of chromosome 13. Here, we describe 10 cases with combined FVII/FX deficiency representing both genetic mechanisms of occurrence. Genetic analyses included direct sequencing of the F7 and F10 genes and MLPA (multiplex ligation-dependent probe amplification) for detection of heterozygous large deletions. In four patients, the combined deficiency was due to a large deletion within the terminal end of chromosome 13. In the remaining six cases the deficiency resulted from coincidental inheritance of different genetic alterations affecting both genes independently. In most cases, the genetic defects were heterozygous, presenting with prolonged PT, normal aPTT and mild or no bleeding symptoms. Only in one case compound heterozygous mutations were detected in the F10, resulting in prolonged aPTT and a more severe bleeding phenotype. To avoid a misdiagnosis of combined FVII/FX deficiency, analyses of single factor activities have to be performed in all cases with prolonged PT even if aPTT is normal. Genetic analyses are substantial for correct prediction of an inheritance pattern and a proper genetic counselling.
    Haemophilia 12/2014; 21(3). DOI:10.1111/hae.12604 · 2.47 Impact Factor
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    ABSTRACT: Total knee arthroplasty (TKA) provides significant pain relief and better function in patients with end-stage haemophilic knee arthropathy. Peri- and postoperative care tends to be more complex than in non-haemophilic patients undergoing TKA and requires a multidisciplinary team approach. Aim: The implementation of standardized clinical pathways in non-haemophilic patients undergoing TKA has been shown to increase quality of care and to reduce postoperative complication rates. Consequently, the use of clinical pathways in haemophilic patients undergoing TKA may be beneficial to this particular subpopulation of patients. Methods: A clinical pathway for TKA for haemophilic patients was designed in a consensus process involving all participating departments. Results: We propose a specifically adjusted clinical pathway for TKA for haemophilic patients to show that standardization of elective orthopaedic surgery in haemophilia is feasible. Conclusion: The authors emphasize that there are limitations on categorizing haemophilic patients and stress that individual interdisciplinary treatment should take precedence over a standardized approach.
    Hamostaseologie 11/2014; 34 Suppl 1(4A):S23-9. DOI:10.5482/HAMO-14-01-0004 · 1.59 Impact Factor
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    ABSTRACT: After ankle and knee, the elbow is the most frequent joint affected by haemophilic arthropathy. The objective of this retrospective single centre study is to evaluate the results of treatment of elbow arthropathy after failed conservative therapy. Patients, methods: In 21 consecutive patients, 11 radiosynoviortheses (RSO), four arthroscopic and six open synovectomies were performed, among them four with additional resection of the radial head. The mean duration of follow-up was 4.8 (RSO) and 5.3 years (surgery), respectively. Pain status (visual analogue scale, VAS), bleeding frequency, range of motion (ROM) as well as patient satisfaction were evaluated. Results: Both, RSO and surgical synovectomy, achieved a significant reduction of pain and bleeding frequency (p < 0.05). Surgical synovectomies were associated with a marked yet not statistically significant increase of postoperative ROM. Radial head resection improved forearm rotation in all cases. No complications occurred. 20 out of 21 patients were satisfied or highly satisfied with the result of the treatment and would undergo the respective procedure again. Conclusion: Due to the effectiveness and safety RSO is considered to be the primary treatment option in haemophilic arthropathy of the elbow after failed conservative therapy. Arthroscopic synovectomy should be considered if RSO shows inadequate effect or in the presence of contraindications. Open synovectomy with resection of the radial head yields good results in the case of advanced arthropathy with radial head impingement.
    Hamostaseologie 11/2014; 34 Suppl 1(4A):S17-22. DOI:10.5482/HAMO-14-01-0009 · 1.59 Impact Factor
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    ABSTRACT: Missense mutations are the most common F8 gene defects among the patients with non-severe haemophilia A. This type of mutation is typically associated with low (5%) inhibitor risk. In the present retrospective study we analysed the clinical data of 16 haemophiliacs with the T295A missense mutation treated at Bonn Haemophilia Centre. In total, three patients developed inhibitors: two patients experienced low-titer and one high-titer inhibitors. Both patients with low titer inhibitors underwent successful ITI. The third patient, at the age of 81, developed initially low-titer inhibitors (3 BU/ml) after rFVIII therapy because of knee surgery. He experienced spontaneous multiple large skin haematomas and haemarthrosis. Immunosuppressive therapy was not applicable because of the infectious origin of discitis (Th3-Th4). Immunoadsorption was performed, but the inhibitor titer increased up to 42 BU/ml nine weeks after termination. A successful treatment of discitis with antibiotics finally allowed a weekly therapy (four times) with rituximab (375 mg/m²). This resulted in a decrease of inhibitor titre to 0.7 BU/ml eight weeks after the fourth rituximab application. Patient had endogenous FVIII levels of 3-5%. Twelve months after rituximab therapy (after B cells recovery) he relapsed with low-titer inhibitors and therefore was treated with single rituximab dose (375 mg/m²) again. This resulted in his depletion of B cells, measurable endogenous FVIII levels and non measurable inhibitors. This study demonstrated T295A variant to be associated with significantly increased (3/16 patients, 17%) inhibitor development.
    Hamostaseologie 11/2014; 34 Suppl 1(4A):S9-S12. DOI:10.5482/HAMO-14-02-0013 · 1.59 Impact Factor
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    ABSTRACT: The outcome and clinical features during long term follow-up of 10 haemophilia patients (haemophilia A n = 9, haemophilia B n = 1), who underwent successful orthotopic liver transplantation (OLT) due to hepatitis associated liver disease, are summarised. Patients: Eight patients were HIV/HCV co-infected. Despite severe postoperative complications, which were not bleeding-associated, all patients survived OLT. Results: Long-term survival was 70% after in mean 8 years follow-up. Twelve years after OLT one patient developed a cyclosporine-induced nephropathy requiring haemodialysis. HIV-HAART was initiated in all patients after OLT, and allowed a successful HCV treatment in 6 patients. Factor VIII production was sufficient in mean 72 h after OLT and remained stable at subnormal to normal FVIII levels of in median 30% (range 14-96%) also during long-term follow-up. Post-OLT spontaneous bleeding events were rare compared to pre-OLT, therefore, the performance status improved in all patients. Discussion: OLT substitutes the hepatic FVIII but has no effect on the extra-hepatic endothelial FVIII production, suggesting that in case of severe tissue injury enhanced bleeding might occur. Additionally, after OLT there is no acute phase reaction of the FVIII protein. Therefore, our OLT patients received in case of a reduced FVIII activity a peri-interventional prophylactic short-term FVIII substitution in surgical and diagnostic interventions with high bleeding risk. Conclusion: Bleeding and wound healing disturbances were not seen.
    Hamostaseologie 11/2014; 35(1). DOI:10.5482/HAMO-14-07-0027 · 1.59 Impact Factor
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    ABSTRACT: Glanzmann thrombasthenia (GT) is an autosomal recessive bleeding disorder characterised by quantitative and/or qualitative defects of the platelet glycoprotein (GP) IIb/IIIa complex, also called integrin αIIbβ3. αIIbβ3 is well known as a platelet fibrinogen receptor and mediates platelet aggregation, firm adhesion, and spreading. This study describes the molecular genetic analyses of 19 patients with GT who were diagnosed on the basis of clinical parameters and platelet analyses. The patients' bleeding signs include epistaxis, mucocutaneous bleeding, haematomas, petechiae, gastrointestinal bleeding, and menorrhagia. Homozygous or compound heterozygous mutations in ITGA2B or ITGB3 were identified as causing GT through sequencing of genomic DNA. All exons including exon/intron boundaries of both genes were analysed. In a patient with an intronic mutation, splicing of mRNA was analysed using reverse transcriptase (RT)-PCR of platelet-derived RNA. In short, 16 of 19 patients revealed 27 different mutations (ITGA2B: n=17, ITGB3: n=10). Seventeen of these mutations have not been published to date. Mutations in ITGA2B or ITGB3 were identified as causing GT in 16 patients. We detected a total of 27 mutations in ITGA2B and ITGB3 including 17 novel missense, nonsense, frameshift and splice site mutations. In addition, three patients revealed no molecular genetic anomalies in ITGA2B or ITGB3 that could explain the suspected diagnosis of GT. We assume that these patients may harbour defects in a regulatory element affecting the transcription of these genes, or other proteins may exist that are important for activating the αIIbβ3 complex that may be affected.
    Thrombosis and Haemostasis 11/2014; 113(3). DOI:10.1160/TH14-05-0479 · 5.76 Impact Factor
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    ABSTRACT: Prophylaxis in adults can be necessary and reasonable for clinical reasons. The aim was to evaluate from an economic viewpoint prophylactic factor VIII substitution in adult patients' with haemophilia in Germany. Patients, methods: A decision model (time frame: one year; perspective: statutory health insurance; reference patient (RP) and 2 patient profiles) was developed. Calculations are based on data from a structured literature search and a pharmacovigilance study: therapy switch on-demand/prophylaxis (OD/Proph). Results: RP: 45 years, 20 bleeds p.a. OD, 16 bleeds avoided with 8.5 I.U./kg/d Proph, additional cost Euro 141 113 p.a.; profile 1:50 years, 55 bleeds p.a. OD, factor consumption per bleed 20 I.U./kg higher than RP, 39 bleeds avoided with 8.5 I.U./kg/d Proph, additional cost Euro 19 134 p.a.; profile 2: 60 years, 35 bleeds p.a. OD, factor consumption per bleed 40-80 I.U./kg higher than RP, 34 bleeds avoided with 11 I.U./kg/d Proph, cost reduction Euro 660 p.a. Conclusions: Prophylactic factor VIII substitution in adult haemophilia patients is depending on the individual clinical situation not only clinically but also economically reasonable. To evaluate this effects in the future comprehensively, longitudinal real-life data from patient-centered care are needed including clinical outcomes, quality of life and adherence.
    Hamostaseologie 11/2014; 34(4):291-300. DOI:10.5482/HAMO-14-03-0017 · 1.59 Impact Factor
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    ABSTRACT: In patients with haemophilia A, factor VIII (FVIII) prophylaxis reduces bleeding frequency and joint damage compared with on-demand therapy. To assess the effect of prophylaxis initiation age, magnetic resonance imaging (MRI) was used to evaluate bone and cartilage damage in patients with severe haemophilia A. In this cross-sectional, multinational investigation, patients aged 12–35 years were assigned to 1 of 5 groups: primary prophylaxis started at age <2 years (group 1); secondary prophylaxis started at age 2 to <6 years (group 2), 6 to <12 years (group 3), or 12−18 years (group 4); or on-demand treatment (group 5). Joint status at ankles and knees was assessed using Compatible Additive MRI scoring (maximum and mean ankle; maximum and mean of all 4 joints) and Gilbert scores in the per-protocol population (n = 118). All prophylaxis groups had better MRI joint scores than the on-demand group. MRI scores generally increased with current patient age and later start of prophylaxis. Ankles were the most affected joints. In group 1 patients currently aged 27−35 years, the median of maximum ankle scores was 0.0; corresponding values in groups 4 and 5 were 17.0 and 18.0, respectively [medians of mean index joint scores: 0.0 (group 1), 8.1 (group 2) and 13.8 (group 4)]. Gilbert scores revealed outcomes less pronounced than MRI scores. MRI scores identified pathologic joint status with high sensitivity. Prophylaxis groups had lower annualized joint bleeds and MRI scores vs. the on-demand group. Primary prophylaxis demonstrated protective effects against joint deterioration compared with secondary prophylaxis.
    Haemophilia 11/2014; 21(2). DOI:10.1111/hae.12539 · 2.47 Impact Factor
  • Geburtshilfe und Frauenheilkunde 09/2014; 74(S 01). DOI:10.1055/s-0034-1387983 · 0.96 Impact Factor
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    J. Oldenburg, S. K. Austin, C. M. Kessler
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    ABSTRACT: The development of alloantibody inhibitors against factor VIII (FVIII) represents the most significant complication of haemophilia care. Inhibitors tend to develop early in the course of treatment in about 20–30% of patients with severe haemophilia who receive on-demand or prophylactic FVIII therapy. Many factors are associated with inhibitor formation, including disease severity, major FVIII gene defects, family history and non-Caucasian race, as well as age at first treatment, intensity of early treatment, use of prophylaxis and product choice. As these latter treatment-related variables are modifiable, they provide opportunity to minimize inhibitor incidence at the clinical level. Data from the Bonn Centre in Germany have indicated an overall success rate of 78% for immune tolerance induction (ITI) therapy, with a failure rate of 15% and with some treatments either ongoing (3%) or withdrawn (4%). Similarly, data from the G-ITI study, the largest international multicentre ITI study using a single plasma-derived (pd) FVIII/von Willebrand factor (VWF) product, have demonstrated success rates (complete and partial) in primary and rescue ITI of 87% and 74%, respectively, with 85% of poor prognosis patients achieving success. Favourable clinical results based on success rates and time to tolerization continue to be reported for use of pdFVIII/VWF in ITI, with pdFVIII/VWF having a particular role in patients who require rescue ITI and those with a poor prognosis for success. Data from prospective, randomized, controlled clinical studies, such as RES.I.ST (Rescue Immune Tolerance Study), are eagerly awaited. Another factor to consider with ITI therapy is cost; preliminary data from an updated decision analytic model have provided early evidence that ITI has an economic advantage compared with on-demand or prophylactic therapy.
    Haemophilia 09/2014; 20(s6). DOI:10.1111/hae.12466 · 2.47 Impact Factor
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    ABSTRACT: A Post-Authorization Safety Study (PASS) global program was designed to assess safety and effectiveness of rAHF-PFM (ADVATE) use in haemophilia patients in routine clinical settings. The main aim of this project was to estimate the rate of inhibitors and other adverse events across ADVATE-PASS studies by meta-analysing individual patient data (IPD). Eligible Studies: PASS studies conducted in different countries, between 2003 and 2013, for which IPD were provided. Eligible patients: haemophilia A patients with baseline FVIII:C < 5%, with a known number of prior exposure days (EDs). Primary outcome: de novo inhibitors in severe, previously treated patients (PTPs) with > 150 EDs. Secondary outcomes: de novo inhibitors according to prior exposure and disease severity; other adverse events; annualized bleeding rate (ABR). Analysis: random-effects logistic regression. Five of seven registered ADVATE-PASS (Australia, Europe, Japan, Italy and USA) and 1188 patients were included (median follow-up 384 days). Among severe PTPs with > 150 EDs, 1/669 developed de novo inhibitors (1.5 per 1000; 95% confidence interval [CI] 0.2, 10.6 per 1000). Among all patients included in the PASS studies, 21 developed any type of inhibitors (2.0%, 95% CI: 0.8%, 4.7%). Less than 1% of patients presented with other serious adverse events possibly related to ADVATE. The overall median ABR was 3.83 bleeds/year (first, third quartiles: 0.60, 12.90); 1.66 (0, 4.78) in the 557 patients continuously on prophylaxis ≥ twice/week. Meta-analysing PASS data from different countries confirmed the overall favourable safety and effectiveness profile of ADVATE in routine clinical settings.
    Haemophilia 06/2014; 20(6). DOI:10.1111/hae.12480 · 2.47 Impact Factor
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    A. C. Goodeve, A. Pavlova, J. Oldenburg
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    ABSTRACT: Molecular genetic tools are widely applied in inherited bleeding disorders. New genes involved in haemorrhagic disorders have been identified by genome wide linkage analysis on families with a specific phenotype. LMNA1 or MCFD in combined FV/FVIII-deficiency and VKORC1 in vitamin K coagulation factor deficiency type 2 are two examples. Identification of the causative gene mutation has become standard for most bleeding disorders. Knowledge of the causative mutation allows genetic counselling in affected families and most importantly adds to the pathophysiological understanding of phenotypes. Haemophilia A represents a model as the F8 gene mutation predicts the risk of developing an inhibitor and more recently also the bleeding phenotype. In this review novel genetic diagnostic strategies for bleeding disorders are outlined and inhibitor formation is presented as an example for clinical relevant phenotype/genotype correlation studies.
    Haemophilia 05/2014; 20(s4). DOI:10.1111/hae.12424 · 2.47 Impact Factor
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    J. Oldenburg, T. Albert
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    ABSTRACT: Currently, new clotting factor concentrates are becoming available or are in advanced clinical studies that will significantly improve the treatment of patients with Haemophilia A or Haemophilia B. Various technologies are applied to extend half-life and/or allow for alternative routes of administration, e.g. subcutaneous route. Today, the advances for recombinant factor IX are significantly with half-life extensions to up to 100 h, allowing substitution intervals of 1–2 weeks. For recombinant factor VIII (FVIII) products the effect so far is only moderate, as the half-life extension is limited to about 15–18 h by the clearance of FVIII through its binding to von Willebrand factor. However, novel products applying new technologies with significantly extended half-life are already at the horizont, as a bispecific antibody that mimics FVIII. The pharmacokinetic improvements of the new products will lead to a revision of our current treatment regimens, with regard to intended trough levels, number of tolerated bleeds and likely will drive a greater individualization of regimens. Clearly, the potential of anti drug antibody response for these modified proteins must not be higher than with our current products. Another challenge are the increasingly diverse biochemical characteristics of the new products, that have to be considered when determining potencies and also when monitoring treatment in patients with the various available assays. Despite these challenges, the new products will significantly improve treatment and quality of life for our patients with haemophilia.
    Haemophilia 05/2014; 20(s4). DOI:10.1111/hae.12428 · 2.47 Impact Factor

Publication Stats

3k Citations
772.38 Total Impact Points

Institutions

  • 1988–2015
    • University of Bonn
      • • Institute of Experimental Haematology and Transfusion Medicine (IHT)
      • • Institute of Medical Microbiology, Immunology and Parasitology
      • • Kekulé Institute of Organic Chemistry and Biochemistry
      Bonn, North Rhine-Westphalia, Germany
  • 1998–2012
    • Instytut Hematologii i Transfuzjologii
      Warszawa, Masovian Voivodeship, Poland
  • 2007–2011
    • University of Bonn - Medical Center
      Bonn, North Rhine-Westphalia, Germany
  • 1997–2011
    • University of Wuerzburg
      • Institute for Human Genetics
      Würzburg, Bavaria, Germany
  • 2010
    • University of Costa Rica
      San José, San José, Costa Rica
    • University of Turku
      • MediCity Research Laboratory
      Turku, Varsinais-Suomi, Finland
  • 2008
    • Hannover Medical School
      • Clinic for Haematology, Haemostaseology and Oncology
      Hannover, Lower Saxony, Germany
  • 2006
    • University Hospital Frankfurt
      Frankfurt, Hesse, Germany
    • St. Josef-Hospital Troisdorf
      Troisdorf, North Rhine-Westphalia, Germany
    • Hospital Frankfurt Hoechst
      Frankfurt, Hesse, Germany
    • Universitätsklinikum Jena
      Jena, Thuringia, Germany
  • 2005–2006
    • University of Freiburg
      Freiburg, Baden-Württemberg, Germany
  • 2004
    • University of Maryland, Baltimore
      Baltimore, Maryland, United States
  • 2001
    • University of Hamburg
      Hamburg, Hamburg, Germany
  • 1994
    • Sigmund-Freud-Institut
      Frankfurt, Hesse, Germany
  • 1991
    • Institut National de la Transfusion Sanguine, Paris
      Lutetia Parisorum, Île-de-France, France