[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: Unlabelled:
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.
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.
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.
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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
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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.
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).
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.
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.
[Show abstract][Hide abstract] 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.