J Oldenburg

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

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Publications (307)779.84 Total impact

  • M. Gothwal · J. Oldenburg · T. Woltering · L. Nakamura · J. Schelling · B. Zieger ·

    Klinische Pädiatrie 11/2015; 227(06/07):358-359. DOI:10.1055/s-0035-1564087 · 1.06 Impact Factor
  • A Tiede · J Oldenburg · T Lissitchkov · S Knaub · J Bichler · M J Manco-Johnson ·
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    ABSTRACT: Introduction: Haemophilia A is treated with FVIII, either prophylactically or on demand. Prophylaxis is the gold standard in children and evidence is accumulating in adults. Aims/methods: The aim of this analysis was to compare prophylaxis vs. on-demand treatment with Nuwiq(®) (Human-cl rhFVIII), a new-generation rFVIII expressed in a human cell line, in previously treated patients (PTPs) with severe haemophilia A. Data were analysed from two similarly designed, multinational, prospective, open-label studies with similar inclusion and exclusion criteria and comparable patient demographics. Human-cl rhFVIII was administered either prophylactically in a study of 32 adults or on-demand in a study of 22 patients (20 adults and two adolescents). Results: Patients treated prophylactically experienced 36 bleeds compared with 997 bleeds in patients treated on-demand (mean observation periods: 180 and 335 days respectively). Based on a negative binomial regression model, annualized bleeding rate (ABR) during prophylaxis was 2.30 (95% CI: 1.54, 3.44) compared with 57.74 (95% CI: 43.36, 76.91) during on-demand treatment, which equates to a 96% lower ABR during prophylaxis. 'Excellent' or 'good' efficacy in the treatment of bleeds was achieved with Human-cl rhFVIII in 100% of 28 evaluated bleeds during the prophylaxis study and 94.5% of 985 evaluated bleeds during the on-demand study. No inhibitors, treatment-related serious adverse events or severe adverse events were recorded during prophylaxis or or-demand treatment. Conclusions: Prophylaxis with Human-cl rhFVIII reduces recurrent bleeding in adult PTPs with severe haemophilia A and adds further supportive evidence for the benefits of prophylaxis in adults.
    Haemophilia 11/2015; DOI:10.1111/hae.12859 · 2.60 Impact Factor
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    ABSTRACT: Results: A novel heterozygous F13A1 gene nonsense mutation (p.Glu103Ter, c.307G>T) was found confirming heterozygous FXIII-A deficiency. The same mutation was detected in two further asymptomatic relatives. For further clinical management the patient was transfused with FXIII-concentrate and showed an adequate increase of FXIII ruling out FXIII deficiency to be induced by increased turnover. Despite this haemostatic management and antifibrinolytic treatment the patient had to undergo several revisions due to delayed, Hb relevant bleeding after cervical lymph nodes extirpation and resection of tonsil. Two chemotherapy cycles with paclitaxel and palliative radiotherapy of the neck area were performed, but the patient died unfortunately two months after diagnosis. Conclusions: It is a unique case showing the combination of a highly aggressive angiosarcoma and presence of inherited FXIII deficiency. It is also a rare example demonstrating the benefit of FXIII genotyping besides the expected acquired FXIII deficiency possibly due to neoplasm induced increased consumption by elevated crosslinking of fibrin fibers.
    Hamostaseologie 11/2015; 35(Suppl. 1):S32-S35. · 1.60 Impact Factor
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    ABSTRACT: This is a report of a novel fibrinogen point mutation (fibrinogen Innsbruck), a C/G point mutation at position 220 of exon two of the fibrinogen Bβ-chain leading to BβArg44Gly. The heterozygous mutation was found in a 16-year-old adolescent, hospitalized for the management of juvenile depression, who suffered from multiple epistaxis episodes during his stay at the university hospital in Innsbruck, Austria. Fibrinogen (based on the Clauss method) and fibrinogen antigen levels were highly discrepant (86 vs. 223 mg/dl) with thrombin time and reptilase time being in the respective upper reference ranges. Densitometric analysis of electrophoretic band pattern showed a reduction of α-polymers, indicating an impaired fibrin polymerization. This is in agreement with structural analysis, which showed a disturbance of the flexibility and structure of the region surrounding the fibrinoeptide B cleavage site. Fibrinogen Nijmegen, a mutation at the same position, is causative for thrombosis, whereas fibrinogen Innsbruck appears to lead to a bleeding tendency, illustrating that even mutations at the same position can cause contrary symptoms.
    Hamostaseologie 11/2015; 35(Suppl. 1):S22-S26. · 1.60 Impact Factor
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    ABSTRACT: Patients and methods: We report a 54-years old man presenting with a thrombophilic phenotype characterized by two episodes of unprovoked venous thrombosis and a deep vein thrombosis several weeks after myocardial infarction. Recently, he developed A. carotis communis thrombosis and died. Coagulation tests were done using standard procedures. FG genes were screened using direct sequencing. Effect on fibrin clot structure was analyzed by scanning electron microscopy (SEM) and FG chain polymerization was analysed using SDS-PAGE. Results: While thrombophilia testing was negative, we found a decreased concentration of clottable FG (126-148 mg/dl) compared to FG antigen (182-194 mg/dl of normal). The thrombin time was slightly prolonged, while aPTT and reptilase time were within the normal range. A novel deletion in FGG gene (c.637delT) resulting in a frameshift and the premature termination of the γ chain at amino acid position p.228 was identified. SDS-PAGE showed a time-shift in γ-γ and α-α cross linking. SEM showed no statistically significant differences between the patient´s and a healthy control´s fibrin clot structure. Conclusions: In addition to the reduction of FG concentration expected by the nature of the mutation also a functional defect (hypodysfibrinogenemia) was found. Moreover this mutation seems to increase the risk of thrombosis warranting long term anticoagulation possibly in a combination with antiplatelet drugs.
    Hamostaseologie 11/2015; 35(Suppl. 1):S27-S31. · 1.60 Impact Factor
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    ABSTRACT: IntroductionFractures in persons with haemophilia (PWH) are not uncommon and require an interdisciplinary approach to maintain haemostasis during surgical treatment.AimThe aim of this study was to evaluate the perioperative management and outcome in PWH following fracture fixation compared to a matched non-haemophilic control group.MethodsA cohort of 44 PWH who underwent 46 surgical fracture fixations was retrospectively compared to 46 non-haemophilic patients (matched-pair controls). Patients were classified according to the fracture localization: (i) proximal upper extremity (PrUEx; n = 7), (ii) distal upper extremity (DiUEx; n = 12), (iii) proximal lower extremity (PrLEx; n = 13) and (iv) distal lower extremity (DiLEx; n = 14). Both groups were assessed for length of hospital stay, duration of surgery, drainage use and complication rates.ResultsThere was no significant difference regarding the duration of the preoperative hospital stay between PWH and controls. Only PWH who were operated at the DiUEx stayed significantly longer in hospital (4.8 ± 3.7 days) than controls (2.2 ± 2.3 days; P = 0.039). Operation time was significantly longer in PWH with fractures treated at the DiLEx (64.9 ± 26.6 min) compared to the controls (49.8 ± 37.9 min; P = 0.035). Neither frequency nor duration of surgical drainage placement differed significantly between the two groups. The overall complication rate in both groups was low without a statistically significant difference.Conclusion An optimal interdisciplinary perioperative management provided the surgical treatment of fractures in PWH can be performed safely with a low complication rate.
    Haemophilia 10/2015; DOI:10.1111/hae.12803 · 2.60 Impact Factor
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    ABSTRACT: Introduction: Total knee arthroplasty (TKA) is an effective treatment option for patients with end-stage haemophilic arthropathy of the knee. However, the procedure is technically challenging, as knee motion is often restricted before the operation and complication rates are then thought to be higher than for patients with a normal range of motion (ROM). There is very limited information on the outcome of TKA in haemophilic patients presenting with stiff knees. The objective of the present study was to retrospectively analyse and compare the clinical results after TKA in haemophiliacs with stiff and non-stiff knees. Patients and Methods: The results of 50 TKA procedures in 41 haemophilic patients were retrospectively evaluated at a mean follow-up of 7.2 ± 4.9 years (range 2-25 years). 20 patients presenting with 23 stiff knees - defined by a preoperative ROM of 50° or less - were compared with 21 patients with 27 non-stiff knees. Knee motion (ROM, flexion, extension), Knee Society Score (KSS/KSS function), pain status (visual analogue scale, VAS), number of bleedings and patient satisfaction were evaluated. Results: The complication rate was 12 %, including two haematomas, one aseptic loosening, and three periprosthetic infections. The overall mean ROM increased from 58.6 ± 34.2° (range 0-120°) preoperatively to 85.9 ± 23.4 (35-130°) postoperatively (p < 0.005). Mean KSS and KSS function improved from 30.6 ± 11.0 points (range 10-49) and 43.4 ± 9.3 points (range 15-65) to 79.3 ± 9.6 points (range 49-95) and 68.9 ± 11.0 points (45-90), respectively (p < 0.005). The mean VAS score decreased significantly from 7.9 ± 0.8 points (range 6-9) to 1.8 ± 1.1 points (range 0-4; p < 0.005). In comparison to the non-stiff group, patients with stiff knees showed a significantly greater mean improvement in ROM (46.3 ± 21.8° [range - 10-85°] vs. 9.4 ± 16.9° [range - 30-35°]), flexion (32.8 ± 19.6° [range - 10-85°] vs. 5.2 ± 16.2° [range - 40-35°]), and flexion contracture (13.5 ± 9.6° [range 5-30°] vs. 5.9 ± 6.7° [range 5-20°]). Both KSS and KSS function were significantly inferior in stiff knees than with non-stiff knees. Nine patients with knee stiffness who underwent additional v-y quadricepsplasty to lengthen the extensor mechanism developed a mean extensor lag of 7-0° ± 4-8° (range 5-15°). At final follow-up, 37/41 patients were satisfied or very satisfied with the surgical result. Conclusion: TKA in haemophilic patients presenting with haemophilic arthropathy of the knee results in significant improvements in function and reduced pain. Although the ultimate clinical outcome in stiff knees is inferior to that with non-stiff knees, joint replacement surgery can be successfully performed in patients with restricted preoperative range of motion. Vy-quadricepsplasty for to facilitate exposure is associated with the development of a postoperative extensor lag and should therefore be performed restrictively. Patient satisfaction after TKA was equally high in the two groups.
    Zeitschrift fur Orthopadie und Unfallchirurgie 10/2015; 153(5):526-532. DOI:10.1055/s-0035-1557768 · 0.49 Impact Factor

  • Acta haematologica Polonica 09/2015; 46:8. DOI:10.1016/j.achaem.2015.07.337
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    ABSTRACT: Nuwiq(®) [human cell line-derived recombinant factor VIII (human-cl rhFVIII)] is a new generation rFVIII protein, without chemical modification or fusion to any other protein, produced in a human cell line. This prospective, open-label, multinational phase III study assessed the efficacy and safety of human-cl rhFVIII in 32 adult previously treated patients (PTPs) with severe haemophilia A during standard prophylaxis for ≥6 months and ≥50 exposure days. Efficacy in treating bleeds and during surgical prophylaxis was also assessed. Prophylactic efficacy, based on mean monthly bleeding rate, was rated as 'excellent' or 'good' in 97% of patients for all bleeds and in 100% of patients for spontaneous bleeds. Mean (SD) annualized bleeding rate was 2.28 (3.73) [median = 0.9] for all bleeds, 1.16 (2.57) [median = 0] for spontaneous bleeds and 1.00 (1.79) [median = 0] for traumatic bleeds. There were no bleeds in 50% of patients and there were no major, life-threatening bleeds. Efficacy was 'excellent' or 'good' in treating 28 (100%) of 28 bleeds. Overall efficacy was rated as 'excellent' during four surgical procedures (three major, one minor) and 'moderate' during one major surgery. Incremental in vivo recovery (IVR) data were comparable with the one-stage and chromogenic assays. IVR was >2.0% per IU kg(-1) for all measurements and stable over 6 months. No patients developed FVIII inhibitors and there were no treatment-related serious or severe adverse events. These results in adult PTPs indicate that human-cl rhFVIII is effective for the prevention and treatment of bleeds in adults with severe haemophilia A. © 2015 The Authors. Haemophilia Published by John Wiley & Sons Ltd.
    Haemophilia 08/2015; DOI:10.1111/hae.12793 · 2.60 Impact Factor
  • A Tiede · R Klamroth · J Oldenburg ·
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    ABSTRACT: Turoctocog alfa (NovoEight®) is a new recombinant factor VIII (rFVIII) with a truncated B domain and a high degree of tyrosine sulphation, similar to plasma-derived FVIII products. The manufacturing process includes double nanofiltration with a 20-nm pore size and immunoaffinity chromatography with monoclonal F25 anti-FVIII antibodies. Treatment with turoctocog alfa can be monitored with both one-stage and chromogenic substrate assays without a product-specific laboratory standard. In total, 213 previously-treated patients with severe haemophilia A participated in the pivotal part of the clinical trial programme guardianTM. The median annualised bleeding rate during turoctocog alfa prophylaxis was 3.7 and 3.0 in adolescents/adults and children, respectively, with marked differences between participating countries. The success rate for the treatment of breakthrough bleeds was 85% (adults/adolescents) and 94% (children). A total of 41 surgical procedures (15 major, 26 minor) were performed in 33 patients, with a successful haemostatic response reported in all cases. No patient developed confirmed inhibitors in any of the trials.
    Hamostaseologie 08/2015; 35(20150814). DOI:10.5482/HAMO-15-06-0019 · 1.60 Impact Factor
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    ABSTRACT: Development of neutralizing inhibitors against factor VIII (FVIII) is a major complication of haemophilia A treatment. The ongoing, international, open-label, uncontrolled, observational immune tolerance induction (ObsITI) study evaluates ITI, the standard of care in patients with inhibitors. Forty-eight prospective patients in this interim analysis received a single plasma-derived, von Willebrand factor-stabilized, FVIII concentrate (pdFVIII/VWF) for ITI. According to recommended Bonn protocol, 'low responders' at ITI start (<5 BU) received 50-100 IU FVIII kg(-1) daily, or every other day; 'high responders' (≥5 BU) received 100 IU FVIII kg(-1) every 12 h. Forty of 48 patients (83.3%), had at least one risk factor for poor ITI-prognosis at ITI start (i.e. age ≥7 years, >2 years since inhibitor diagnosis, inhibitor titre ≥10 BU at the start of ITI, or prior ITI failure). Nonetheless, 34 patients (70.8%) achieved complete success, 3 (6.3%) partial success, 1 (2.1%) partial response; ITI failed in 10 patients (20.8%), all with poor prognosis factors. All six low responders achieved complete success. ITI outcome was significantly associated with inhibitor titre level at ITI start (P = 0.0068), number of poor prognosis factors for ITI success (P = 0.0187), monthly bleeding rate during ITI (P = 0.0005) and peak inhibitor titre during ITI (P = 0.0007). Twenty-two of 35 high responder patients (62.9%) with ≥1 poor prognosis factor achieved complete success. Treatment with a single pdFVIII/VWF concentrate, mainly according to the Bonn protocol, resulted in a high ITI success rate in haemophilia A patients with inhibitors and poor prognosis for ITI success. © 2015 John Wiley & Sons Ltd.
    Haemophilia 07/2015; DOI:10.1111/hae.12774 · 2.60 Impact Factor

  • Haemophilia 07/2015; 21(6). DOI:10.1111/hae.12752 · 2.60 Impact Factor
  • G. Goldmann · N. Marquardt · S. Horneff · J. Oldenburg · H. Zeitler ·
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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 · 2.29 Impact Factor
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    J. Elisa 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 · 4.98 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; 21(4). DOI:10.1111/hae.12698 · 2.60 Impact Factor
  • B. Pezeshkpoor · J. Oldenburg ·

    Haemophilia 04/2015; 21(4). DOI:10.1111/hae.12687 · 2.60 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 · 2.60 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 · 2.60 Impact Factor
  • G Goldmann · C Berens · N Marquardt · R Reich · J Oldenburg · M Wenghoefer ·
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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; 19(2). 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 · 2.60 Impact Factor

Publication Stats

4k Citations
779.84 Total Impact Points


  • 1988-2015
    • University of Bonn
      • • Institute of Experimental Haematology and Transfusion Medicine (IHT)
      • • Institute of Experimental Immunology
      • • Institute of Medical Microbiology, Immunology and Parasitology
      • • Kekulé Institute of Organic Chemistry and Biochemistry
      Bonn, North Rhine-Westphalia, Germany
  • 2013
    • Instytut Hematologii i Transfuzjologii
      Warszawa, Masovian Voivodeship, Poland
  • 2007-2011
    • University of Bonn - Medical Center
      Bonn, North Rhine-Westphalia, Germany
  • 2010
    • University of Turku
      • MediCity Research Laboratory
      Turku, Varsinais-Suomi, Finland
  • 2008
    • Royal Free London NHS Foundation Trust
      Londinium, England, United Kingdom
  • 1997-2008
    • University of Wuerzburg
      • Institute for Human Genetics
      Würzburg, Bavaria, Germany
  • 2006
    • Universitätsklinikum Jena
      Jena, Thuringia, Germany
    • University Hospital Frankfurt
      Frankfurt, Hesse, Germany
    • Hospital Frankfurt Hoechst
      Frankfurt, Hesse, Germany
  • 2005-2006
    • University of Freiburg
      Freiburg, Baden-Württemberg, Germany
  • 2004
    • University of Maryland, Baltimore
      Baltimore, Maryland, United States
  • 1994-2000
    • Sigmund-Freud-Institut
      Frankfurt, Hesse, Germany