Development of long-acting recombinant FVIII and FIX Fc fusion proteins for the management of hemophilia

Introduction: Prophylactic treatment with replacement clotting factor is the recommended regimen for patients with severe hemophilia to prevent bleeding episodes. However, currently available replacement clotting factors are limited by their relatively short half-lives and require intravenous injections up to three times weekly to maintain protective levels, which can impact compliance and, thus, patient outcomes.

Areas covered: The potential advantages of long-acting coagulation factors, including reduced injection frequency, increased treatment adherence, and improved clinical outcomes, are discussed. Fragment crystallizable (Fc) fusion technology is introduced and the development of long-acting recombinant factor VIII Fc (rFVIIIFc) and recombinant factor IX Fc (rFIXFc) fusion proteins for the treatment of hemophilia A and B, respectively, are described. Preclinical and clinical studies of rFVIIIFc and rFIXFc showing improved pharmacokinetics over currently available products are reviewed.

Expert opinion: Long-acting coagulation factors, including rFVIIIFc and rFIXFc, have the potential to change current paradigms of care for hemophilia A and B, respectively. Less frequent infusions may provide prolonged protection from bleeding and bleed resolution with fewer injections. In addition, long-acting coagulation factors provide an opportunity for improved individualized treatment for hemophilia.     

Coexistence of acquired hemophilia A and epidermolysis bullosa acquisita: Two case reports and published work review

Epidermolysis bullosa acquisita (EBA) is a rare chronic subepidermal bullous autoimmune disease. The occurrence of acquired hemophilia A (AHA) is low and so the coexistence of EBA and AHA is extremely rare. We herein described a case of EBA coexisting with AHA and a case of EBA coexisting with AHA and hepatitis B. These EBA may be related to the pathogenesis of AHA. In this study, we analyzed the clinical features in the two Chinese cases of EBA coexisting with AHA, and found esophageal hemorrhage and hematemesis were the main symptoms of both patients. Cyclosporin, prednisone and lamivudine effectively control EBA with AHA and hepatitis B. The dose of cyclosporin should be more than 4 mg/kg per day and the period of treatment should be longer than 5 months to reduce the risk of EBA co‐occurring with AHA.     

The CDC Hemophilia A Mutation Project (CHAMP) Mutation List: A New Online Resource

Genotyping efforts in hemophilia A (HA) populations in many countries have identified large numbers of unique mutations in the Factor VIII gene (F8). To assist HA researchers conducting genotyping analyses, we have developed a listing of F8 mutations including those listed in existing locus‐specific databases as well as those identified in patient populations and reported in the literature. Each mutation was reviewed and uniquely identified using Human Genome Variation Society (HGVS) nomenclature standards for coding DNA and predicted protein changes as well as traditional nomenclature based on the mature, processed protein. Listings also include the associated hemophilia severity classified by International Society of Thrombosis and Haemostasis (ISTH) criteria, associations of the mutations with inhibitors, and reference information. The mutation list currently contains 2,537 unique mutations known to cause HA. HA severity caused by the mutation is available for 2,022 mutations (80%) and information on inhibitors is available for 1,816 mutations (72%). The CDC Hemophilia A Mutation Project (CHAMP) Mutation List is available at http://www.cdc.gov/hemophiliamutations for download and search and will be updated quarterly based on periodic literature reviews and submitted reports.     

Risk of Bleeding and Inhibitor Development After Circumcision of Previously Untreated or Minimally Treated Severe Hemophilia A Children

Background: Surgery and intensive factor VIII (FVIII) replacement may be risk factors for development of inhibitors. Objective: To evaluate time and rate of inhibitor development postcircumcision over 12-month period, and to assess bleeding of children with severe hemophilia A after low-dose FVIII replacement and local hemostasis. Patients and Methods: Sixty-one previously untreated patients (PUPs) or minimally treated patients (MTPs) with severe hemophilia A less than 36 months were enrolled; 25 underwent circumcision during the 18-month enrollment period, and 36 matched patients were not circumcised. All patients were treated on demand with plasma-derived FVIII, and all were inhibitor negative at the time of enrollment. Intron 22 inversion was analyzed. A potent hemostatic agent (gelatin sponge) was applied on the site of surgery, and then dressed with gauze. Two doses of FVIII concentrate (25 U/kg) were given, 1 hour before circumcision and 1 hour before removal of dressing. The inhibitor was determined every 8 exposure days (EDs). Results: None of the patients had bleeding or infection, except one who had minimal transient bleeding 8 days after surgery, and was treated easily by a single dose of FVIII (50 U/kg). After a median of 16 EDs, high-titer inhibitors developed in seven patients: three patients in the circumcised group (12%) in contrast to four patients (11.1%) in the noncircumcised group. Conclusion: Two doses factor concentrate and gelatin sponge application were generally enough to prevent bleeding after circumcision of severe hemophilia A. Circumcision and low-dose FVIII protocol were not an additional risk for development of high-titer inhibitor.     

T‐cell responses in two unrelated hemophilia A inhibitor subjects include an epitope at the factor VIII R593C missense site

Summary. Background: Development of neutralizing anti‐factor (F)VIII antibodies (‘inhibitors’) is a serious clinical problem in hemophilia A. Increased inhibitor risk has been associated with certain FVIII missense substitutions, including R593C in the A2 domain. Objectives: The aim of the present study was to identify T‐cell epitopes in FVIII and characterize T‐cell responses in two unrelated hemophilia A subjects sharing F8‐R593C and HLA‐DRB1*1101 genotypes. We hypothesized that the hemophilic substitution site coincides with an important T‐cell epitope. Patients/methods: The binding affinities of peptides for recombinant HLA‐DR proteins were measured and compared with epitope prediction results. CD4+ T cells were stimulated using peptides and stained with fluorescent, peptide‐loaded tetramers. Results: The inhibitor subjects, but not HLA‐matched controls, had high‐avidity HLA‐DRB1*1101‐restricted T‐cell responses against FVIII_589–608, which contains the hemophilic missense site. Antigen‐specific T cells secreted Th1 and Th2 cytokines and proliferated in response to FVIII and FVIII_592–603. FVIII_589–608 bound with physiologically relevant (micromolar) IC₅₀ values to recombinant DR0101, DR1101 and DR1501 proteins. Conclusions: Hemophilia A patients with R593C missense substitutions and these HLA haplotypes had an increased incidence of inhibitors in our cohorts, supporting a paradigm in which presentation of FVIII epitopes containing the wild‐type R593 influences inhibitor risk in this hemophilia A sub‐population.     

��άˮѡ���Լ��������ڶ�ͯѪ�Ѳ��Թǹؽڲ������ʾӦ�ü�ֵ�о�

??Objective To detect the value of 3D T1W-WATS sequence on cartilage display of hemophilic arthropathy using quantitative and qualitative assessment. Methods Totally 16 joints including 8 knees and 8 ankles ??13 joints with hemosiderin deposition?? from 16 hemophilia patients were scanned on a 3.0 T MR ??Achieva TX??Philips Health care??Best??The Netherlands?? with sagittal 3D T1W-WATS sequence and 2D T2*W sequence. Signal to noise ratio ??SNR?? of cartilage and relative contrast between cartilage and surrounding tissues were employed to measure the performance of two sequences quantitatively??SNRcartilage= SIcartilage/standard deviationnoise?? relative contrast=??SIcartilage-SIsurrounding tissues??/??SIcartilage+SIsurrounding tissues??. Cartilage of 13 joints were divided into 142 subareas according to the literature. The impact of hemosiderin deposition was evaluated by counting the number of subareas where the display of cartilage was affected qualitatively. Results SNR of 3D T1W-WATS sequence was??53.93±18.80????and SNR of 2D T2*W sequence was??52.96±24.32??. There was no statistical difference for SNR between two sequences??P??0.05????3D T1W-WATS sequence exhibited better relative contrast between cartilage and bone marrow?? cartilage and fat?? cartilage and fluid than 2D T2*W sequence??P??0.05????42 of 142 subareas of cartilage were covered with hemosiderin partially or completely in 2D T2*W sequence??while the number was only 16 in 3D T1W-WATS sequence??there being statistical difference ??P??0.05??. Conclusion 3D T1W-WATS sequence is superior in the evaluation of cartilage display for hemophiliac joints with better relative contrast and immunity to hemosiderin deposition?? compared with 2D T2*W sequence.