BACKGROUND & AIMS: :The aim of this study was to assess the relationships among the detection of p24 antigen, human immunodeficiency virus (HIV) RNA level, CD4 cell count, and disease progression in 111 males with hemophilia who were infected with HIV for < or =20 years. Sixty-four individuals (58%) developed p24 antigenemia a median of 11.6 years after seroconversion. The time to first detection of p24 antigen was shorter among those who were older (P=.04) and those with a high initial HIV RNA level (P=.006). The median HIV RNA level and CD4 cell count at the time of the detection of p24 antigen were 4.95 log(10) copies/mL and 100 cells/mm(3), respectively. In univariate analyses, p24 antigenemia was associated with more-rapid progression to AIDS (relative hazard [RH], 5.50; P=.0001). The effect was reduced (RH, 1.85; P=.06) after adjusting for CD4 cell counts and HIV RNA levels during follow-up, age, and calendar year. A significant relationship between p24 antigenemia and death was nonsignificant after adjusting for CD4 cell count.

背景与目标： ：这项研究的目的是评估111岁以下感染HIV或≤20年的血友病男性的p24抗原检测，人类免疫缺陷病毒（HIV）RNA水平，CD4细胞计数和疾病进展之间的关系。 。血清转化后的中位值是11.6年，其中有64个人（58％）患了p24抗原血症。在年龄较大的患者（P = .04）和初始HIV RNA水平高的患者（P = .006）中，首次检测p24抗原的时间较短。检测p24抗原时的HIV RNA中位数和CD4细胞计数中位数分别为4.95 log（10）个拷贝/ mL和100个细胞/ mm（3）。在单因素分析中，p24抗原血症与更快速地发展为AIDS有关（相对危险度[RH]，5.50； P = .0001）。在随访，年龄和日历年中调整CD4细胞计数和HIV RNA水平后，效果降低（RH，1.85； P = .06）。调整CD4细胞计数后，p24抗原血症与死亡之间的显着关系不显着。

BACKGROUND & AIMS: :Hemophilia B is an X-linked recessive bleeding disorder caused by abnormalities in the coagulation factor IX gene. Without prophylactic treatment, patients experience frequent spontaneous bleeding episodes. Well-characterized animal models are valuable for determining the pathobiology of the disease and testing novel therapeutic innovations. Here, we generated a porcine model of hemophilia B using a combination of CRISPR/Cas9 and somatic cell nuclear transfer. Moreover, we tested the possibility of hemophilia B therapy by gene insertion. Frequent spontaneous joint bleeding episodes that occurred in hemophilia B pigs allowed a thorough investigation of the pathological process of hemophilic arthropathy. In contrast to the hemophilia B pigs, which showed a severe bleeding tendency and joint damage, the transgenic pigs carrying human coagulation factor IX exhibited a partial improvement of bleeding. In summary, this study not only offers a translational hemophilia B model for exploring the pathological process of hemophilic arthropathy but also provides a possibility for the permanent correction of hemophilia in the future by genome editing in situ.

背景与目标： ：B型血友病是由凝血因子IX基因异常引起的X连锁隐性出血性疾病。如果不进行预防性治疗，患者会经历频繁的自发性出血发作。表征良好的动物模型对于确定疾病的病理生物学和测试新颖的治疗创新非常有价值。在这里，我们使用CRISPR / Cas9和体细胞核转移的组合生成了血友病B的猪模型。此外，我们通过基因插入测试了血友病B治疗的可能性。 B型血友病猪中频繁发生的自发性关节出血事件使对血友病性关节炎的病理过程进行了彻底的研究。与表现出严重的出血倾向和关节损伤的血友病B猪相反，携带人凝血因子IX的转基因猪表现出部分出血改善。总而言之，这项研究不仅为探讨血友病性关节炎的病理过程提供了一种转化型血友病B模型，而且还为将来通过原位基因组编辑对血友病进行永久性校正提供了可能性。

BACKGROUND & AIMS: The development of auto-antibodies against clotting factor VIII is a rare disease that occurs predominantly in adultsin pregnant women or people with various immunologic disorders or with no apparent underlying disease. As a consequence of an immune system dysregulation, the evolution of this condition is unpredictable. The aim of treatment is to restore normal factor VIII levels in circulation using desmopressin (DDAVP), massive doses of factor VIII (human or porcine), plasmapheresis and factor VIII infusions. In patients with high-titer inhibitors, products with 'bypasing' activity can be used. The most difficult task is to treat the immune disorder. High-dose infusions of immunoglobulins might be useful, due to the presence of anti-idiotypes to factor VIII inhibitors in the commercial preparations. Corticosteroids and cyclophosphamide are currently the most widely used treatments for the immune disease.

背景与目标： 抗凝血因子VIII自身抗体的发展是一种罕见的疾病，主要发生在孕妇或患有各种免疫疾病或无明显潜在疾病的成年人中。由于免疫系统失调，这种情况的发展是不可预测的。治疗的目的是使用去氨加压素（DDAVP），大剂量的VIII因子（人或猪），血浆置换和VIII因子输注来恢复血液中的正常VIII因子水平。在具有高滴度抑制剂的患者中，可以使用具有“止痛”活性的产品。最困难的任务是治疗免疫疾病。由于在商业制剂中存在针对因子VIII抑制剂的抗独特型，因此大剂量输注免疫球蛋白可能是有用的。皮质类固醇和环磷酰胺是目前最广泛用于免疫疾病的治疗方法。

BACKGROUND & AIMS: :In a family with a single case of hemophilia A genetic counselling was requested by the pregnant aunt of the propositus. The haplotypes generated by two extra-genic RFLPs, at DXS52 (St14/Taq1) and DXS15 (DX13/BglII), and one intragenic RFLP in F8C (647/BclI) indicated that: she was not a carrier; the case of hemophilia resulted from a de novo mutation in a grandfather's gamete.

背景与目标： ：在一个血友病单例的家庭中，怀孕的姨妈要求进行遗传咨询。 DXS52（St14 / Taq1）和DXS15（DX13 / BglII）的两个外源RFLP和F8C的一个内源RFLP（647 / BclI）产生的单倍型表明：她不是携带者；血友病病例是由祖父配子的从头突变引起的。

BACKGROUND & AIMS: BACKGROUND:Several clinical studies and experiments with transgenic mice have suggested that the severity of the bleeding phenotype in hemophilic patients is substantially reduced in association with impaired inactivation of factor (F) Va by activated protein C (APC) in the presence of the FV Leiden mutation. Experiments using a synthetic coagulation proteome model showed that the presence of FV Leiden significantly increased thrombin generation in the absence of FVIII or FIX. OBJECTIVE:To test the effect of APC inhibition on thrombin generation in hemophilia. METHODS:Prothrombinase and a synthetic coagulation proteome model of tissue factor-triggered thrombin generation were used. RESULTS:Peptide-based APC inhibitors, which mimic the P4-P4' residues surrounding the APC cleavage site at Arg306 of FVa, were synthesized. These compounds are specific and reversible inhibitors of APC, with Ki values as low as 1-2 microM; most have insignificant affinity for FXa or thrombin. The affinity for APC is dependent upon the location and character of the protecting groups. Representatives of this group of compounds inhibit FVa inactivation by APC and prolong FVa functional activity in the prothrombinase complex. When evaluated in a synthetic coagulation proteome model, one inhibitor partially compensated for the absence of FVIII. CONCLUSIONS:Synthetic APC inhibitors may be useful as adjuvants for hemophilia treatment.

背景与目标： 背景：关于转基因小鼠的多项临床研究和实验表明，血友病患者出血表型的严重程度与FV莱顿存在下活化蛋白C（APC）导致的因子（F）Va失活受损有关，从而大大降低了出血表型的严重性突变。使用合成凝血蛋白质组模型的实验表明，在没有FVIII或FIX的情况下，FV Leiden的存在会显着增加凝血酶的生成。
目的：检测APC抑制对血友病患者凝血酶产生的影响。
方法：使用凝血酶原酶和组织凝血酶促凝血酶生成的合成凝血蛋白质组模型。
结果：合成了基于肽的APC抑制剂，该抑制剂模拟了FVa Arg306上APC裂解位点周围的P4-P4'残基。这些化合物是APC的特异性和可逆抑制剂，Ki值低至1-2 microM。大多数对FXa或凝血酶的亲和力微不足道。对APC的亲和力取决于保护基的位置和特征。这组化合物的代表可抑制APC使FVa失活，并延长凝血酶原酶复合物中FVa的功能活性。在合成凝血蛋白质组模型中进行评估时，一种抑制剂可部分弥补FVIII的缺失。
结论：合成的APC抑制剂可用作血友病治疗的佐剂。

BACKGROUND & AIMS: :Recent advances in liver tissue engineering have encouraged further investigation into the evaluation of therapeutic benefits based on animal disease models. In the present study, liver tissues were engineered in coagulation factor IX knockout (FIX-KO) mice, a mouse model of hemophilia B, to determine if the tissue engineering approach would provide therapeutic benefits. Primary hepatocytes were isolated from the liver of wild-type mice and suspended in a mixture of culture medium and extracellular matrix components. The hepatocyte suspension was injected into the space under the bilateral kidney capsules of the FIX-KO mice to engineer liver tissues. The plasma FIX activities (FIX:C) of the untreated FIX-KO mice were undetectable at any time point. In contrast, the liver tissue engineered FIX-KO mice achieved 1.5-2.5% of plasma FIX activities (FIX:C) and this elevated FIX:C level persisted throughout the 90 day experimental period. Significant FIX mRNA expression levels were found in the engineered liver tissues at levels similar to the wild-type livers. The present study demonstrates that liver tissue engineering could provide therapeutic benefits in the treatment of hemophilia B.

背景与目标： ：肝脏组织工程学的最新进展鼓励进一步研究基于动物疾病模型的治疗效果评估。在本研究中，对血友病B的小鼠凝血因子IX敲除（FIX-KO）小鼠进行了肝组织工程研究，以确定组织工程方法是否可提供治疗益处。从野生型小鼠的肝脏中分离出原代肝细胞，并将其悬浮在培养基和细胞外基质成分的混合物中。将肝细胞悬液注射到FIX-KO小鼠的双侧肾囊下的空间中，以工程化肝组织。未经处理的FIX-KO小鼠的血浆FIX活性（FIX：C）在任何时间点都无法检测到。相反，经肝脏组织工程改造的FIX-KO小鼠达到了血浆FIX活性的1.5-2.5％（FIX：C），并且这种升高的FIX：C水平在整个90天的实验期间一直持续存在。在工程肝组织中发现了显着的FIX mRNA表达水平，其水平与野生型肝脏相似。本研究表明，肝组织工程可以在血友病B的治疗中提供治疗益处。

BACKGROUND & AIMS: :Hemophilia A (HemA) patients are currently treated with costly and inconvenient replacement therapy of short-lived factor VIII (FVIII) protein. Development of lipid nanoparticle (LNP)-encapsulated mRNA encoding FVIII can change this paradigm. LNP technology constitutes a biocompatible and scalable system to efficiently package and deliver mRNA to the target site. Mice intravenously infused with the luciferase mRNA LNPs showed luminescence signals predominantly in the liver 4 h after injection. Repeated injections of LNPs did not induce elevation of liver transaminases. We next injected LNPs carrying mRNAs encoding different variants of human FVIII (F8 LNPs) into HemA mice. A single injection of B domain-deleted F8 LNPs using different dosing regimens achieved a wide range of therapeutic activities rapidly, which can be beneficial for various usages in hemophilia treatment. The expression slowly declined yet remained above therapeutic levels up to 5-7 days post-injection. Furthermore, routine repeated injections of F8 LNPs in immunodeficient mice produced consistent expression of FVIII over time. In conclusion, F8 LNP treatment produced rapid and prolonged duration of FVIII expression that could be applied to prophylactic treatment and potentially various other treatment options. Our study showed potential for a safe and effective platform of new mRNA therapies for HemA.

背景与目标： ：A血友病（HemA）患者目前正在接受昂贵且不便的短期VIII因子（FVIII）蛋白替代疗法。脂质纳米颗粒（LNP）封装的编码FVIII的mRNA的开发可以改变这种范例。 LNP技术构成了一种生物相容性和可扩展的系统，可以有效地包装mRNA并将其传递至目标部位。静脉内注入萤光素酶mRNA LNP的小鼠在注射后4小时内主要在肝脏中显示发光信号。重复注射LNP不会引起肝转氨酶升高。接下来，我们将携带编码人类FVIII（F8 LNPs）不同变体的mRNA的LNP注射到HemA小鼠中。使用不同的给药方案单次注射缺失B结构域的F8 LNP可以快速实现广泛的治疗活性，这对于血友病治疗中的各种用途可能是有益的。直至注射后5-7天，表达缓慢下降，但仍高于治疗水平。此外，在免疫缺陷小鼠中常规重复注射F8 LNP会随着时间的推移产生FVIII的一致表达。总之，F8 LNP治疗可快速延长FVIII表达的持续时间，可用于预防性治疗和可能的其他多种治疗选择。我们的研究显示了针对HemA的新mRNA治疗的安全有效平台的潜力。

BACKGROUND & AIMS: :During factor VIII prophylaxis for severe hemophilia A, bleeding risk increases with time when factor VIII activity is below 1%. Maintaining trough activity above 1% does not protect all patients from bleeding. The relationship between factor VIII activity during prophylaxis and bleeding risk has not been thoroughly studied. We investigated factor VIII activity and annualized bleeding rate for spontaneous bleeds during prophylaxis. A population pharmacokinetic model derived from three clinical trials was combined with dosing data and bleed information from patient diaries. Each patients' time on prophylaxis was divided into five categories of predicted activity (0-1%, >1-5%, >5-15%, >15-50%, and >50%). Exposure time, mean factor VIII activity, and bleed number (from patient diaries) were calculated for each activity category, and annualized bleeding rates estimated using negative binomial regression and a parametric model. Relationships between these bleeding rates and factor VIII activity were evaluated by trial phase (pivotal vs. extension) and age (adults/adolescents [≥12 years] vs. children [0-<12 years]). In total (N=187; 815 patient-years' exposure), factor VIII activity was predicted to reach >1% for 85.64% of the time. Annualized bleeding rate decreased as factor VIII activity increased in each trial phase and age group. However, for a given activity level, bleeding rate differed substantially by trial phase, and age. This suggests that bleeding risk can change over time and is influenced by factors independent of factor VIII pharmacokinetics and trough levels. Target trough and prophylactic regimen should consider patient age, joint disease activity, and other bleeding risk determinants.

背景与目标： ：在预防严重的A型血友病的VIII因子治疗期间，当VIII因子活性低于1％时出血风险随时间增加。维持食槽活动高于1％并不能保护所有患者免于流血。预防期间VIII因子活性与出血风险之间的关系尚未得到彻底研究。我们调查了预防期间自发性出血的凝血因子VIII活性和年度出血率。将源自三项临床试验的总体药代动力学模型与剂量数据和患者日记中的出血信息相结合。将每个患者的预防时间分为五类预测活动（0-1％，> 1-5％，> 5-15％，> 15-50％和> 50％）。计算每种活动类别的暴露时间，平均VIII因子活性和出血数（来自患者日记），并使用负二项式回归和参数模型估算年化出血率。通过试验阶段（枢纽性与扩展性）和年龄（成人/青少年[≥12岁]对儿童[0- <12岁]）评估了这些出血率与VIII因子活性之间的关系。总计（N = 187； 815患者-年的暴露量），因子VIII的活性预计将在85.64％的时间内达到> 1％。在每个试验阶段和年龄组中，随着因子VIII活性的增加，年度出血率降低。但是，对于给定的活动水平，出血率因试验阶段和年龄而有很大差异。这表明出血风险可以随时间变化，并且受与因子VIII药代动力学和谷值水平无关的因素影响。目标槽和预防方案应考虑患者年龄，关节疾病活动和其他出血风险决定因素。

BACKGROUND & AIMS: INTRODUCTION:Patients affected by hemophilia A often require frequent prophylactic and therapeutic self-infusion. For those who develop inhibitors, treatment options are limited and mortality is increased. Emicizumab, a bispecific antibody to Factors IXa and X that carries out the function of Factor VIII (FVIII), represents a novel therapeutic approach. Areas covered: We review the clinical trials and key laboratory assay research for emicizumab. Emicizumab reduced the annualized bleeding rate by 87% compared to placebo in patients with inhibitors. For patients without inhibitors, emicizumab reduced the annualized bleeding rate 96-97% compared to no prophylaxis and 68% compared to prior FVIII prophylaxis. Three patients developed a thrombotic microangiopathy (TMA) and two patients had thrombotic events while on emicizumab in combination with activated prothrombin complex concentration (aPCC) alone or concurrent with activated recombinant factor FVII (rFVIIa). Expert opinion: Emicizumab represents a much-needed alternative approach to managing Factor VIII deficiency, especially for those with inhibitors or limited ability to self-infuse. For patients with inhibitors, thrombotic complications including TMA, not seen with other bypassing agents, raises concern about the use of emicizumab in combination with aPCC and how patients who have breakthrough bleeding can be safely managed.

背景与目标： 简介：受血友病A感染的患者通常需要频繁的预防和治疗性自我输注。对于那些产生抑制剂的人，治疗选择受到限制，死亡率增加。 Emicizumab是一种针对因子IXa和X的双特异性抗体，具有因子VIII（FVIII）的功能，代表了一种新颖的治疗方法。涵盖领域：我们回顾了艾米单抗的临床试验和关键实验室测定研究。与安慰剂相比，在使用抑制剂的患者中，Emicizumab的年出血率降低了87％。对于没有抑制剂的患者，艾米珠单抗与无预防措施相比，年出血率降低了96-97％，与先前的FVIII预防措施相比，降低了68％。 3例患者发生了血栓性微血管病（TMA），2例患者在使用艾米单抗联合单独使用活化凝血酶原复合物浓度（aPCC）或同时使用活化重组凝血因子FVII（rFVIIa）时发生了血栓事件。专家意见：Emicizumab是解决VIII因子缺乏症的一种急需的替代方法，特别是对于那些具有抑制剂或自我注入能力有限的患者。对于有抑制剂的患者，血栓并发症（包括TMA）（其他旁路药物未见）引起了人们对艾米单抗联合aPCC的使用以及如何安全治疗突破性出血的患者的关注。

BACKGROUND & AIMS: :The development of alloantibodies or inhibitors is the most serious complication a patient with severe hemophilia can experience from treatment with clotting factor concentrates. Although common in previously untreated patients, inhibitor development is rare in multiply exposed, well-tolerized patients. There has been a nonevidence-based reluctance to change concentrate because of a perceived greater inhibitor risk after the switch, even though most patients are now likely to be using a concentrate on which they did not begin. Inhibitors in previously treated patients are observed in approximately 2 per 1000 patient/years, which makes it difficult to study and compare rates among different products. Because the baseline inhibitor risk in previously treated patients may vary over time, it is important to compare the risk in patients switching to a new product with that in a parallel control group of nonswitching patients or within a case-controlled study. The study designs imposed by regulators are suboptimal in detecting immunogenicity signals. The issue of immunogenicity of new products is likely to gain more relevance in the near future, with a call for effective postmarketing surveillance studies for all of the new engineered factor VIII concentrates with prolonged half-lives that are likely to enter clinical practice.

背景与目标： ：同种抗体或抑制剂的开发是重度血友病患者浓缩凝血因子治疗后可能遇到的最严重的并发症。尽管在以前未经治疗的患者中很常见，但在多重暴露，耐受性良好的患者中很少出现抑制剂的产生。尽管由于大多数患者现在很可能正在使用尚未开始使用的浓缩物，但由于在切换后发现更大的抑制剂风险，因此不存在基于证据的不愿更换浓缩物的情况。在每1000名患者/年中，大约有2种患者在以前接受过治疗的患者中观察到抑制剂，这使得难以研究和比较不同产品之间的比率。由于先前接受治疗的患者的基线抑制剂风险可能会随时间而变化，因此，重要的是，将使用新产品的患者与未接受治疗的平行对照组或病例对照研究中的患者进行比较。监管机构强加的研究设计在检测免疫原性信号方面欠佳。在不久的将来，新产品的免疫原性问题可能会变得越来越重要，因此呼吁对所有具有较长半衰期的新工程化VIII因子浓缩物进行有效的上市后监测研究，并有可能进入临床实践。

BACKGROUND & AIMS: BACKGROUND:Emicizumab is a bispecific monoclonal antibody developed for routine prophylaxis of bleeding in people with hemophilia A (PwHA). This work characterizes the pharmacokinetics of emicizumab in adult and pediatric PwHA, identifies factors contributing to its between-person variabilities, compares the pharmacokinetics following different dosing regimens, and makes a descriptive assessment of the exposure-bleeding events relationship. METHODS:A population pharmacokinetic model was developed, using a database of 389 PwHA from five clinical studies. Potential baseline covariate effects were assessed, including body size, age, race, presence of factor VIII inhibitors, and albumin levels. Using the population pharmacokinetic model, the estimated individual average exposures over the administration period were compared across categories of annualized bleeding rate. RESULTS:A linear one-compartment model with first-order absorption and elimination processes and no lag time best described the emicizumab pharmacokinetics. Body weight, albumin levels, age, and black race were statistically correlated with primary pharmacokinetic parameters, but only body weight had an important influence on exposure. Dosing regimens of 1.5 mg/kg weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks provided similar average concentrations at steady state. A trend for lower exposure was observed in the small proportion of PwHA having an annualized bleeding rate > 4 (11.9%), suggesting that reducing exposure to lower levels may potentially increase the bleeding risk. CONCLUSIONS:Emicizumab pharmacokinetics in PwHA was described with dose-independent parameters. Body weight was an important predictor of emicizumab pharmacokinetics. All three dosing regimens are predicted to achieve similar exposure associated with clinically meaningful prevention of bleeding.

背景与目标： 背景：艾米珠单抗是一种双特异性单克隆抗体，开发用于常规预防A型血友病（PwHA）出血。这项工作表征了艾米珠单抗在成人和儿科PwHA中的药代动力学，确定了导致其人际变异的因素，比较了不同给药方案后的药代动力学，并对暴露-出血事件之间的关系进行了描述性评估。
方法：使用来自五个临床研究的389 PwHA数据库建立了群体药代动力学模型。评估了潜在的基线协变量影响，包括体重，年龄，种族，VIII因子抑制剂的存在和白蛋白水平。使用总体药代动力学模型，比较了年平均出血率类别中估计的整个给药期间的个人平均暴露水平。
结果：具有一阶吸收和消除过程且无滞后时间的线性单室模型最能恰当地描述艾米珠单抗的药代动力学。体重，白蛋白水平，年龄和黑种人与主要药代动力学参数在统计学上相关，但仅体重对暴露有重要影响。每周1.5 mg / kg，每2周3 mg / kg或每4周6 mg / kg的给药方案在稳态下提供相似的平均浓度。在低比例的PwHA中观察到较低的暴露趋势，年出血率≥4（11.9％），这表明减少暴露于较低水平可能会增加出血风险。
结论：用剂量无关参数描述了艾美珠单抗在PwHA中的药代动力学。体重是艾米珠单抗药代动力学的重要预测指标。预计所有这三种给药方案都将实现与临床上有意义的出血预防相关的相似暴露。

BACKGROUND & AIMS: :One of the most dramatic dangers in treating nephrolithiasis by ESWL is the development of intra- and perirenal bleeding, which requires therapeutic intervention. Even in patients whose blood parameters suggest they are healthy, hematomas are found in up to 80%. Therefore, ESWL must be regarded as contraindicated in patients with blood disorders. A case of a patient suffering from hemophilia B and from a large renal pelvic stone is reported, whom we treated by ESWL twice after sufficient substitution. X-ray revealed that the patient was stone-free on the 25th day after the first ESWL session. ESWL. A review of the literature is presented.

背景与目标： ：ESWL治疗肾结石的最显着危险之一是肾内和肾周出血的发生，这需要治疗干预。即使在血液参数表明他们健康的患者中，血肿的比例也高达80％。因此，在患有血液疾病的患者中必须将ESWL视为禁忌症。据报道有一例患有血友病B和肾盂大结石的患者，在充分替代后我们用ESWL对其进行了两次治疗。 X射线检查显示患者在第一次ESWL疗程后第25天无结石。 ESWL。介绍了文献综述。

BACKGROUND & AIMS: :Little is known about the challenging treatment of pediatric patients with hemophilia B and inhibitors due to disease rarity. We describe three patients diagnosed in childhood and followed up to 9 years. All three had allergic reactions to Factor IX, but two were later safely treated for bleeding episodes with activated prothrombin complex concentrates (APCC = FEIBA). The third was given only recombinant activated Factor VIIa. Based on ex vivo thrombin generation analysis, a new alternative treatment of combined bypassing agents was administered for bleeding episodes and several minor surgical procedures with no treatment-associated adverse events or thrombosis.

背景与目标： ：由于疾病罕见，对血友病B和抑制剂对小儿患者的具有挑战性的治疗知之甚少。我们描述了三名在儿童时期被诊断并随访至9年的患者。所有三个人对IX因子都有过敏反应，但其中两个以后用活化的凝血酶原复合物浓缩物（APCC = FEIBA）安全治疗出血事件。第三只给予重组活化的VIIa因子。基于离体凝血酶生成分析，针对出血事件和几种较小的外科手术程序，采用了一种新的替代旁路联合治疗药物，没有与治疗相关的不良事件或血栓形成。

BACKGROUND & AIMS: :Hemophilia A (HA) is an X-linked hereditary bleeding disorder defined by a qualitative and/or quantitative factor VIII (FVIII) deficiency. The molecular diagnosis of HA is challenging because of the high number of different causative mutations that are distributed throughout the large F8 gene. The putative role of the novel mutations, especially missense mutations, may be difficult to interpret as causing HA. We identified 95 novel mutations out of 180 different mutations responsible for HA in 515 patients from 406 unrelated families followed up at a single hemophilia treatment center of the Bicêtre university hospital (Assistance Publique-Hôpitaux de Paris [AP-HP], Le Kremlin-Bicêtre). These 95 novel mutations comprised 55 missense mutations, 12 nonsense mutations, 11 splice site mutations, and 17 small insertions/deletions. We therefore developed a mutation analysis based on a body of proof that combines the familial segregation of the mutation, the resulting biological and clinical HA phenotype, and the molecular consequences of the amino acid (AA) substitution. For the latter, we studied the putative biochemical modifications: its conservation status with cross-species FVIII and homologous proteins, its putative location in known FVIII functional regions, and its spatial position in the available FVIII 3D structures. The usefulness of such a strategy in interpreting the causality of novel F8 mutations is emphasized.

背景与目标： ：A血友病（HA）是X连锁遗传性出血性疾病，由定性和/或定量因子VIII（FVIII）缺乏症定义。 HA的分子诊断具有挑战性，因为分布在整个F8大基因中的大量不同的致病突变。新突变（尤其是错义突变）的推定作用可能难以解释为引起HA。我们在比塞特尔大学医院的一个血友病治疗中心（巴黎援助医院-巴黎大学[AP-HP]，勒·克里姆林宫-比塞特尔医院）的一个血友病治疗中心对406个无关家庭的515名患者中的负责HA的180种不同突变中鉴定出95种新突变。 ）。这95个新突变包括55个错义突变，12个无意义突变，11个剪接位点突变和17个小插入/缺失。因此，我们基于证据集开发了一种突变分析方法，该方法结合了突变的家族分离，产生的生物学和临床HA表型以及氨基酸（AA）取代的分子后果。对于后者，我们研究了假定的生化修饰：其在跨物种FVIII和同源蛋白中的保存状态，在已知FVIII功能区中的假定位置以及在可用FVIII 3D结构中的空间位置。强调了这种策略在解释新型F8突变的因果关系方面的有用性。

BACKGROUND & AIMS: BACKGROUND:People with severe hemophilia A or B, X-linked bleeding disorders due to decreased blood levels of coagulants, suffer recurrent bleeding into joints and soft tissues. Before clotting factor concentrates were available, most people with severe hemophilia developed crippling musculoskeletal deformities. Clotting factor concentrate prophylaxis aims to preserve joint function by converting severe hemophilia (factor VIII or IX less than 1%) into a clinically milder form of the disease. Prophylaxis has long been used in Sweden, but not universally adopted because of medical, psychosocial, and cost controversies. Use of clotting factor concentrates is the single largest predictor of cost in treating hemophilia. OBJECTIVES:To determine the effectiveness of clotting factor concentrate prophylaxis in the management of people with hemophilia A or B. SEARCH STRATEGY:We searched the Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references from comprehensive electronic database searches and handsearches of journals and abstract books. Reference lists of relevant articles were reviewed. Most recent search: November 2005. SELECTION CRITERIA:Randomized controlled trials (RCTs) evaluating people with severe hemophilia A or B, receiving prophylactic clotting factor concentrates. DATA COLLECTION AND ANALYSIS:Two authors independently reviewed studies for eligibility, assessed methodological quality and extracted data. MAIN RESULTS:Twenty-nine studies were identified; four studies (including 37 participants) were eligible for inclusion. Three studies evaluated hemophilia A; one showed a decrease in frequency of joint bleeds with prophylaxis compared to placebo (non-physiological dose), with a rate difference (RD) -10.80 (95% confidence interval (CI) -16.33 to -5.27) bleeds per year. The remaining two studies evaluating hemophilia A compared two prophylaxis regimens, one study showed no difference in joint bleed frequency, RD -5.04 (95%CI -17.02 to 6.94) bleeds per year and another failed to demonstrate an advantage of factor VIII dosing based on individual pharmacokinetic data over the standard prophylaxis regimen with RD -0.14 (95% CI -1.34 to 1.05) bleeds per year. The fourth study evaluated hemophilia B and showed fewer joint bleeds with weekly (15 IU/kg) versus bi-weekly (7.5 IU/kg) prophylaxis, RD -3.30 (95% CI -5.50 to - 1.10) bleeds per year. AUTHORS' CONCLUSIONS:There is insufficient evidence from randomised controlled trials to determine whether prophylactic clotting factor concentrates decrease bleeding and bleeding-related complications in hemophilia A or B, compared to placebo, on-demand treatment, or prophylaxis based on pharmacokinetic data from individuals. Well-designed RCTs are needed to assess the effectiveness of prophylactic clotting factor concentrates. Two clinical trials are ongoing.

背景与目标： 背景：患有严重血友病A或B的人，由于凝血剂血药浓度降低而导致X链接的出血性疾病，并反复出现关节和软组织出血。在获得浓缩凝血因子之前，大多数重度血友病患者会发展为严重的肌肉骨骼畸形。凝血因子浓缩物的预防旨在通过将严重的血友病（凝血因子VIII或IX小于1％）转化为临床上较温和的疾病形式来保留关节功能。预防在瑞典早已被使用，但由于医学，社会心理和成本方面的争议而未得到普遍采用。浓缩凝血因子的使用是治疗血友病费用的最大预测指标。
目的：确定凝血因子浓缩物预防在A型或B型血友病患者管理中的有效性。
搜索策略：我们搜索了囊性纤维化和遗传疾病组的试验注册簿，其中包括来自全面电子数据库搜索以及对期刊和摘要书籍的人工搜索的参考。审查了相关文章的参考清单。最近的搜索：2005年11月。
选择标准：随机对照试验（RCT）对接受预防性凝血因子浓缩的严重血友病A或B的人进行评估。
数据收集与分析：两位作者独立审查了研究的资格，评估了方法学质量并提取了数据。
主要结果：鉴定了29项研究。有四项研究（包括37名参与者）符合纳入条件。三项研究评估了甲型血友病。一项研究显示，与安慰剂（非生理剂量）相比，预防性关节出血的频率降低，每年出血率（RD）-10.80（95％置信区间（CI）-16.33至-5.27）。其余两项评估A型血友病的研究比较了两种预防方案，一项研究显示联合出血频率无差异，每年RD -5.04（95％CI -17.02至6.94）出血，另一项未能证明基于VIII因子给药的优势每年通过RD -0.14（95％CI -1.34至1.05）出血的标准预防方案获得的个别药代动力学数据。第四项研究评估了B型血友病，并显示预防性每周出血（15 IU / kg）相对于每两周一次（7.5 IU / kg）关节出血少，每年RD -3.30（95％CI -5.50--1.10）出血。
作者的结论：根据个体药代动力学数据，与安慰剂，按需治疗或预防相比，随机对照试验尚无充分证据来确定预防性凝血因子浓缩物是否能减少血友病A或B的出血和与出血有关的并发症。需要设计良好的RCT来评估预防性凝血因子浓缩物的有效性。正在进行两项临床试验。