First-in-human in vivo genome editing via AAV-zinc-finger nucleases for mucopolysaccharidosis I/II and hemophilia B

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Long-Term Follow-Up of the First in Human Intravascular Delivery of AAV for Gene Transfer: AAV2-hFIX16 for Severe Hemophilia B

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Does Hemophilia Increase Risk of Adverse Outcomes Following Total Hip and Knee Arthroplasty? A Propensity Score–Matched Analysis of a Nationwide,Population-Based Study

BackgroundEnd-stage hemophilic arthropathy is the result of recurrent joint hemarthrosis. Although total hip arthroplasty (THA) and total knee arthroplasty (TKA) can reduce severe joint pain and improve functional activity, controversy remains regarding outcomes after THA and TKA among patients with hemophilia. This study evaluated the risk of adverse outcomes of hemophilia patients who underwent THA and TKA.MethodsThis retrospective cohort study was conducted using data from the National Health Insurance Research Database. Patients who had hemophilia and underwent THA and TKA between 2000 and 2015 were identified. A total of 121 patients with hemophilia and 194,026 patients without hemophilia were included. Through propensity score matching, patients with hemophilia were matched at a 1:4 ratio to patients without hemophilia. Multivariable regression analysis was used to control for confounding variables and compare the risk of postoperative complications and mortality, differences in length of stay, and cost of care for the hospital.ResultsAfter propensity score matching and multivariate regression analysis, the adjusted hazard ratio of postoperative transfusion for hemophilia patients was 5.262 (95% confidence interval [CI] = 3.044-26.565, P < .001) in THA group and 6.279 (95% CI = 3.246-28.903, P < .001) in TKA group, when compared with the control group. Patients with hemophilia had longer length of hospital stay (THA group: 95% CI, 1.541-2.669, P < .001; TKA group: 95% CI, 1.568-2.786; P < .001) and higher total hospital charges (THA group: 95% CI, 3.518-8.293, P < .001; TKA group: 95% CI, 3.584-8.842; P < .001) compared to patients without hemophilia. Hemophiliacs had a higher yet nonsignificant 1-year infection rate (8.11% vs 3.38%, P = .206) in the THA group. There were no differences between the rates of 30-day and 90-day complications, 1-year infection, reoperation and mortality between the hemophilia and nonhemophilia groups.ConclusionHemophilia patients have higher rates of postoperative transfusion, hospital costs, and increased length of stay. There is an appreciable clinical difference in 1-year infection rates following THA but our analysis was limited by the small sample size. Other postoperative complications and mortality rates were comparable. Patients with hemophilia should be counseled that infection rate maybe as high as 8% following THA. Further investigation is needed to develop prophylactic and effective methods to decrease the rates of transfusions and associated adverse outcomes in hemophilia patients undergoing THA and TKA.     

Hémophilie acquise auto-immune : quelle est la place du rituximab dans la stratégie thérapeutique ? Réflexion à partir d’une série monocentrique de 8 patients et revue de la littérature

IntroductionAutoimmune acquired haemophilia is a rare autoimmune disease. The purpose of immunosuppressive therapy is to stop the production of autoantibodies that inhibit clotting factors VIII or IX. A corticosteroids-cyclophosphamide combination is recommanded as first-line therapy. From our experience at the University Hospital of Nîmes, we discuss the place of rituximab in the therapeutic arsenal.MethodsWe report a monocentric observational retrospective study. Our data are discussed in light of literature data, in particular cohorts EACH2 and SACHA.ResultsEight patients (7 with FVIII anibodies) were consecutively included from 2005. The average age was 68.5 years with a male predominance (62.5%). Bleeding manifestations were usually spontaneous and superficial. A pathology, mostly autoimmune or neoplastic, was associated in 5/8 patients. A “by-pass” haemostatic treatment was prescribed for 3/8 patients. Rituximab was prescribed for 5/8 patients, three times as first-line therapy, and always associated with corticosteroids. Three patients received a cyclophosphamid/cortisone combination, two were treated exclusively with oral corticosteroids. Remission was obtained in all patients, without subsequent relapse. The average time to obtain remission under rituximab (after the first injection) was 32.5 days (10–143). The results observed in our series of patients are consistent with the data from the literature.ConclusionsRituximab appears to be an effective and well-tolerated treatment for autoimmune acquired haemophilia. However, its place remains to be specified.     

Acquired hemophilia A associated with Epstein–Barr-virus-associated T/natural killer-cell lymphoproliferative disease: A case report

Introduction:Acquired hemophilia A (AHA) is a rare bleeding disorder caused by autoantibodies against factor VIII (FVIII). Hematological malignancies, especially lymphoid malignancies, are known to be underlying causes of AHA; however, thus far, there is no report of AHA associated with Epstein–Barr-virus-associated T/natural killer-cell lymphoproliferative disease (EBV-T/NK-LPD). Here, we present a case of AHA that developed during treatment for EBV-T/NK-LPD.History:A 69-year-old man visited our hospital because of general fatigue. Blood examination showed pancytopenia, and computed tomography revealed whole-body lymphadenopathy, but there were no findings indicating hematological malignancy from bone marrow aspiration and cervical lymph node biopsy. The level of EBV DNA in peripheral blood was extremely high, and he was diagnosed with EBV-T/NK-LPD. EBV-T/NK-LPD improved with prednisolone (PSL) administration. Seventeen months after starting treatment, the patient complained of back and right leg pain. At that time, he had been treated with low-dose PSL, and EBV-T/NK-LPD was well controlled. Imaging revealed hematoma of the right iliopsoas muscle. Prolonged activated partial thromboplastin time (APTT) was the only abnormal finding in a screening coagulation test. FVIII coagulant activity was below detection limit, and FVIII inhibitor level was increased. From these results, he was diagnosed with AHA.A higher dose of PSL was administered, and, after 1 month of treatment, FVIII activity gradually increased, and FVIII inhibitor level became undetectable. APTT also normalized, and complete remission was achieved and maintained for 13 months with low-dose PSL. During treatment, EBV-T/NK-LPD was well controlled.Conclusion:It is speculated that proliferating lymphocytes interfere with normal immune functions and that abnormal autoantibodies are produced from those lymphocytes in patients with LPD. Therefore, we speculate that EBV-infected and proliferating monoclonal NK cells might have modulated the immune system and produced autoantibodies against FVIII, thus causing AHA in this patient with EBV-T/NK-LPD.     

血友病患儿唇裂的手术治疗

血友病为一种X染色体伴隐性遗传的出血性疾病.血友病伴唇裂畸形病例更为少见.我院共收治3例血友病唇裂患儿,采用术前、术中、术后48小时内纠正凝血因子缺乏,使凝血因子Ⅷ、Ⅸ在血浆中的浓度术前分别保持在75%、50%以上,48小时后保持在30%、32%以上,手术年龄1岁左右,采用三角瓣法整复,术中注意减少创伤,缝合严密.3例经手术整复成功,无术后出血及复裂.     

Increased clearance of von Willebrand factor antigen post‐DDAVP in Type 1 von Willebrand disease: is it a potential pathogenic process?

Summary.  The mechanism of von Willebrand factor (VWF) clearance is not fully understood. The factors that affect VWF clearance, and the normal in vivo mechanism of clearance, may be relevant to the pathogenesis of Type 1 von Willebrand disease (VWD), in which there is a partial deficiency of VWF. In order to investigate the clearance of VWF in Type 1 VWD, the current study assessed the half-life of VWF antigen ( t _½ VWF:Ag) in Type 1 VWD patients and individuals with mild hemophilia A following the administration of 1-deamino-8- d -arginine vasopressin (DDAVP; desmopressin). To date 20 individuals have been assessed, 13 with Type 1 VWD and seven with mild hemophilia A. The median t _½ VWF:Ag in the Type 1 VWD and mild hemophilia A groups were 4.6 h and 9.5 h, respectively. The difference between the t _½ VWF:Ag for the two groups was significant, P  < 0.02. Analysis of the data showed a correlation between the t _½ VWF:Ag and the baseline VWF:Ag level prior to administration of DDAVP: lower baseline VWF:Ag levels were associated with a shorter t _½ VWF:Ag. These data suggest that increased clearance of VWF may be the pathogenic mechanism in some cases of Type 1 VWD.     

Effect of late prophylaxis in hemophilia on joint status: a randomized trial

Essentials

• High‐quality data are lacking on use of prophylaxis in adults with hemophilia and arthropathy.
• SPINART was a 3‐year randomized clinical trial of late/tertiary prophylaxis vs on‐demand therapy.
• Prophylaxis improved function, quality of life, activity and pain but not joint structure by MRI.
• Prophylaxis improves function but must start before joint bleeding onset to prevent arthropathy.