Adeno-associated virus-mediated gene transfer for hemophilia B

Hemophilia is the bleeding diathesis caused by mutations in the gene encoding factor VIII (hemophilia A) or factor IX (hemophilia B). Currently, the disease is treated by intravenous infusion of the missing purified clotting factor. The goal of gene transfer for treating hemophilia is to achieve sustained expression of factor VIII or factor IX at levels high enough to improve the symptoms of the disease. Hemophilia has proven to be an attractive model for those interested in gene transfer, and multiple gene-transfer strategies are currently being investigated for the hemophilias. The most promising preclinical studies have been with adeno-associated viral vectors (AAV); introduction of AAV vectors expressing factor IX into skeletal muscle or liver in hemophilic dogs has resulted in the long-term expression of factor IX at levels that are adequate to improve disease symptoms. Efforts to translate these findings into the clinical arena have proceeded slowly because of the lack of prior clinical experience with parenteral administration of AAV. In a staged approach, AAV-factor IX (AAV-F.IX) was first administered at doses of up to 1.8 x 10(12) vector genomes/kg (vg/kg) into the skeletal muscles of men with hemophilia B. This trial established the safety of parenteral administration and also showed that general characteristics of AAV transduction were similar in mice, dogs, and humans. In an ongoing trial, AAV-F.IX is being administered into the hepatic circulation of men with severe hemophilia B. The goal of these studies is to identify a safe dose that reliably yields circulating levels of factor IX >2% of normal levels in all subjects. This goal has already been achieved in the hemophilia B dog model; the ongoing study will determine whether a similar result can be achieved in humans with hemophilia B.     

Calcifying splenic hematoma in a hemophilic newborn

A 7-day-old hemophilic newborn presented several hemorrhagic manifestations, notably, a large cephalohematoma, intracranial hemorrhage and a splenic hematoma. This was clearly identified on X-rays and at 4 weeks of age showed gross ring-like calcification. Involvement of the spleen in hemophilia is rare, at all ages. Also uncommon are hemorrhagic manifestations of hemophilia during the neonatal period. Calcified splenic hematomas in hemophilic patients have apparently never been described.     

Operated hepatocellular carcinoma in two HIV- and HCV-positive hemophilic patients

Some hemophilic patients in Japan suffer from infections with both human immunodeficiency virus (HIV) and hepatitis virus because they received contaminated nonheated blood products. Coinfection with HIV appears to accelerate the course of chronic hepatitis. Although powerful antiviral therapy was introduced as HIV treatment and the prognosis of HIV patients was dramatically improved, the risk of rapid progression of hepatitis and carcinogenesis remains for the patients. Recently, we performed surgery for hepatocellular carcinoma (HCC) in two hemophilic patients with HIV and hepatitis C virus (HCV) coinfection. Case 1 was a 52-years-old man who suffered from liver cirrhosis, hypersplenism, and hyperammonemia due to portosystemic shunt. A recent abdominal computed tomography (CT) scan had revealed a low-density area in segment VI of the liver. Splenectomy and partial resection of the liver were performed. Case 2 was a 66-year-old man who had been diagnosed with chronic hepatitis at age 50, and HIV infection at age 52 years. When his serum alpha-fetoprotein level was increased, CT scan of the liver revealed a mass in segment VIII. Subsegmentectmy of the liver was performed. Although the CD4 value in each patient was lower than 200µl, the operations were safely carried out and no major complication occurred. Because the chance of encountering HCC patients infected with HIV and HCV is increasing in Japan, we should consider the perioperative care of these patients, as well as the protection of medical workers against HIV infection.     

血友病患者健康教育需求调查与对策

目的了解血友病患者对健康教育的需求,并制定出相对应的健康教育方式。方法采用自制调查表的方法对92例患者进行问卷调查。结果94.6%的患者对健康教育的需求为需要或非常需要。结论通过对健康教育需求的调查,采取一系列行之有效的措施,增强了患者战胜疾病的信心,也极大地提高了血友病的防治效果。     

中国大陆血友病患者治疗现状和经济负担的系统评价

目的了解中国大陆血友病患者（people with hemophilia,PWH）的治疗现状及经济负担,并探讨血友病在中国的最佳治疗方案。方法于2011年6月系统检索《中国生物医学文献数据库》（CBM）、《中国期刊全文数据库》（CNKI）、《中国科技期刊数据库》（VIP）、万方数据库等中文数据库,以及PubMed、EMbase和The Cochrane Library（2011年第6期）等英文数据库中收录的1980—2011年发表的有关PWH治疗及经济负担的研究。结果中国PWH诊断、治疗滞后;超30％的PWH不治疗或偶尔治疗,不足10％的PWH接受预防治疗;仍有相当一部分患者使用新鲜冷冻血浆（FFP）或冷沉淀等容易导致血源性病毒传播疾病的传统血制品;大于50％的PWH家庭只能支付很少或完全支付不起医疗费用。低剂量预防治疗相对于足量按需治疗更经济。以目前中国PWH实际治疗情况计算,每例PWH每年多投入53844元即可实现低剂量预防治疗．从而减少80％的出血。结论中国大陆PWH的治疗现状差,经济负担重,推行综合关怀模式,采用低剂量预防治疗是最佳治疗方案。     

Economic evaluation of major knee surgery with recombinant activated factor VII in hemophilia patients with high titer inhibitors and advanced knee arthropathy: exploratory results via literature-based modeling

ABSTRACT

Objectives: People with severe hemophilia suffer from frequent intra-articular hemorrhages, leading to pain, swelling, reduced flexion, and arthropathy. Elective orthopedic surgery using factor VIII (FVIII) replacement to prevent uncontrolled bleeding has been endorsed as an effective treatment option for patients with severe or advanced hemophilic arthropathy. These surgeries reduce pain, restore mobility and function, and reduce the frequency of recurrent joint bleeds. Unfortunately, some patients with hemophilia develop inhibitors to FVIII, which neutralize FVIII activity and render the use of even massive amounts of FVIII replacement ineffective and surgery very risky. For this reason, elective surgical procedures in high-titer inhibitor patients had largely been abandoned until the introduction of new agents, such as recombinant activated factor VII (rFVIIa, NovoSeven, Novo Nordisk A/S, Denmark). rFVIIa has been shown effective for prophylaxis during elective surgery and has therefore improved the feasibility of orthopedic surgery in hemophilia patients with high-titer inhibitors. The present research explored, from a modified US payer perspective, the direct economic and quality of life benefits of four different elective knee surgeries (total knee replacement [TKR], knee arthrodesis [KA], proximal tibial osteotomy, and distal femoral osteotomy) with rFVIIa coverage in hemophilia patients with high-titer inhibitors.

Methods: An exploratory literature-based life-table model was developed to compare the direct medical costs and quality of life of two hypothetical cohorts of high-titer inhibitor patients with frequent bleeding episodes: one undergoing and the other not undergoing elective knee surgery. Knee surgery costs included perioperative rFVIIa costs, inpatient and rehabilitation care, and repeat procedures due to surgery failure, prosthesis loosening or deep infection. Based on efficacy studies, knee surgery was assumed to reduce mean annual bleeding episodes at the affected joint from 9.13 to 1.64. The cost of managing each bleeding episode was estimated at $15?298. Thus, by reducing bleeding episodes, surgery was expected to result in related cost offsets. All costs were expressed in 2006 US dollars. Surgery was also assumed to result in gains in quality of life by reducing pain and reducing bleeding episodes. The impact of pain reduction on quality of life and utility was estimated by simulating EQ-5D scores for a typical patient with and without knee surgery.

Results: Based on the model, average knee surgery costs are predicted to range from a low of $694?000 (for KA) to a high of $855?000 (for TKR). However, knee surgery is also expected to reduce the subsequent number of bleeding episodes and resultant costs, leading to long-term costs savings. Due to improvement in pain levels, surgical patients are expected to experience improvements in quality-adjusted life-years (QALYs). Thus, surgery appears to be the preferred strategy (i.e., saves costs and increases QALYs). Based on the assumptions used in the model, the initial cost of knee surgery was offset during the 8th and 10th years for KA and TKR, respectively, with intermediate break-even time for the other surgeries. As expected, cost savings and gains in QALYs increased over time, as well as the cost effective­ness of knee surgery. Specifically, the cost per QALY with KA and TKR fell under $50?000/QALY during the 6th and 8th years, respectively, with intermediate time for the other surgeries.

Conclusions: The present exploratory analysis is based on the long-term extrapolation of data from a small number of patients without inhibitors and short-term studies. It suggests that major knee surgery utilizing rFVIIa in hemophilia patients with inhibitors may be cost-effective on average, with expected cost savings apparent within a decade of knee surgery. The present exploratory results should be validated with real-world, longitudinal patient data.     

Deletions with inversions: Report of a mutation and review of the literature

Herein we report a 10.9 kb deletion and a 95 bp inversion in a patient with severe hemophilia B (factor IX_HB209). With the addition of factor IX_HB209, three of six characterized deletions in the factor IX gene are now known to include inversions. A high frequency of combined deletions and inversions has not previously been described in a human gene. © 1993 Wiley-Liss, Inc.     

两个特殊血友病A患者家系的基因诊断

目的 探讨特殊血友病A(HA)家系的基因诊断。方法 用内含子22倒位检测及FⅧ基因内外4个位点的多态性进行遗传连锁分析;用核酸直接测序法对FⅧ各外显子及其侧翼序列进行检测。结果 家系1先证者表型为重型HA,FⅧ内含子22倒位检测及FⅧ基因内外4个位点的多态性遗传连锁分析未获得诊断信息;直接核酸测序证实先证者及其妹FⅧ基因24号外显子第2209位氨基酸存在R2209Q错义突变,后者胎儿DNA检测为正常男性。家系2中HA先证者已去世,一名要求做携带者检测的女性表型正常,内含子22倒位检测及直接核酸测序没有发现基因缺陷,用FⅧ基因内外4个位点的多态性遗传连锁分析均显示该成员未携带血友病A基因。结论 联合应用直接核酸测序法及多态性遗传连锁分析可以对特殊血友病A家系进行基因诊断。     

1例颅脑损伤合并乙型血友病患儿的围手术期护理

本文介绍了1例颅脑损伤合并乙型血友病患儿的围手术期护理。术前护理侧重于全面评估、心理护理、头皮血肿护理、预防出血和纠正凝血机制异常。术后护理措施包括病情观察、发热护理、预防感染、饮食护理和出院宣教。患儿术后未见颅内出血,住院20 d后痊愈出院。     

A study of reported factor VIII use around the world

Summary.  The effect of replacement therapy has significantly improved the morbidity and mortality of people with haemophilia A in high income countries, a recent socio-economic development as the availability of safe concentrates has been matched by a willingness for their provision through reimbursement. In the developing world, however, this state has not been achieved, primarily because of the low visibility of haemophilia coupled with its expense, leading to inadequate treatment with its sequelae of severe pain, joint deformities, arthropathy, disabilities, and even death in childhood or early adult life. The objective of this paper was to study the reported factor VIII (FVIII) use on a country-by-country basis. Data on the reported FVIII use for 104 countries were obtained from the Marketing Research Bureau, Inc. and the World Federation of Hemophilia. The results show that FVIII use varies considerably among countries, even among the wealthiest of countries. The use of FVIII concentrate increases as economic capacity increases; in addition, consumption of FVIII has been increasing at a greater rate in high income countries. Given these trends, there probably will be a global increase in FVIII concentrates usage. Such information is critical for national healthcare agencies to determine realistic budget priorities in planning for an increased allocation of resources required to improve the treatment of patients with haemophilia A. This information is also important for pharmaceutical manufacturers to adequately plan for increased production of FVIII concentrates.