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。

BACKGROUND & AIMS: OBJECTIVE:To report a case of comorbidity of constrictive pericarditis and hemophilia A. CLINICAL PRESENTATION AND INTERVENTION:A 21-year-old male with hemophilia A was referred to our clinic and was examined with the subsequent evaluation of shortness of breath, leg edema and ascites. Clinical and laboratory examinations were performed. The results were consistent with constrictive pericarditis (CP), and the symptoms were completely relieved following institution of medical therapy. CONCLUSION:Because hemophilia A and pericarditis may be coincidentally present clinical conditions, avoidance of surgical procedures in hemophilic patients is preferable unless the resolution of the symptoms of pericarditis cannot be effected by medical therapy.

背景与目标： 目的：报告一例缩窄性心包炎与血友病合并症。
临床表现和干预：一名21岁男性A型血友病患者被转诊至我们的诊所，并进行了检查，随后进行了呼吸急促，腿水肿和腹水的评估。进行了临床和实验室检查。结果与缩窄性心包炎（CP）一致，并且在接受药物治疗后症状完全缓解。
结论：由于甲型血友病和心包炎可能同时存在，因此除非在药物治疗不能解决心包炎症状的情况下，否则最好避免在血友病患者中进行手术。

BACKGROUND & AIMS: BACKGROUND:Managing hemophilia is challenging both in terms of medical treatment and its broad impact on many aspects of the individual's life, including self-perception. Several psychosocial issues are potentially relevant in the clinical management of hemophilia, including it being a chronic and incurable condition; e.g. people with hemophilia must adapt to optimally interact with peers and to practice sports - even choosing a sport represents an issue for perceived limitations, expectations and cultural influences on the individual and their family. People with hemophilia can react by denying their condition and its manifestations and not adhering to treatment. Due to the complexity of relationships surrounding genetic diseases, parents and relatives may have their own issues that contribute to making life easier or more difficult for the person with hemophilia. Anxiety, sadness and depression resulting in mental health disorders are reported in this population and may influence quality of life (QoL) depending on cultural background, religious beliefs, family support and other variables. OBJECTIVES:Primarily to assess the effectiveness of psychological therapies for improving the ability of people with hemophilia to cope with their chronic condition. SEARCH METHODS:We aimed to identify trials from the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, Embase and PsycINFO, CINAHL, MEDLINE and trial registries. We searched reference lists of included publications. Most recent search of the Group's register: 13 June 2019. SELECTION CRITERIA:Randomized controlled trials (RCTs) and quasi-RCTs in people with hemophilia of any age or gender, type A or B, any severity, with or without inhibitors, with or without HIV or hepatitis C virus. All psychological interventions for promoting emotional, intellectual and spiritual wellness. Individual, group or family group therapy interventions were eligible. DATA COLLECTION AND ANALYSIS:We independently assessed trials, extracted data and assessed the risk of bias and assessed the quality of the evidence using GRADE. MAIN RESULTS:Seven trials were included (362 participants randomized, data from 264 participants available for analysis); six of parallel design and one a partial cross-over design. One multicenter trial was conducted in Canada; the remaining six were single centre undertaken in the UK, USA, Iran and in the Netherlands. All trials had a high risk of bias for participant blinding and use of patient-reported outcomes. Evidence was retrieved on four interventions: psycho-education (DVD plus information booklet versus information booklet alone; computerised learning versus no intervention); cognitive therapy (auto-hypnosis (self-hypnosis) versus control); and behavioural therapy (relaxation (progressive or self control) versus no treatment). We also aimed to assess psychodynamic therapy and systemic therapy, but no trials were identified. Heterogeneity of the outcome measures and measurements precluded meta-analyses. No trial reported the cost of the psychological intervention and family adjustment. DVD plus information booklet compared to information booklet alone One trial (108 participants) showed coping strategies may lower pre-contemplation scores and negative thoughts, mean difference (MD) -0.24 (95%CI -0.48 - 0.00, low-certainty evidence), however, other measures of coping strategies in the same trial suggest little or no difference between groups, e.g. contemplation, MD (-0.09, 95%CI -0.32 - 0.14, low-certainty evidence). The same trial measured QoL and showed little or no difference between treatment groups for the physical domain, MD 0.59 (95% CI -3.66 to 4.84, low-certainty evidence), but may improve scores in the mental health domain for those receiving the booklet plus DVD compared to booklet alone, MD (4.70, 95% CI 0.33 to 9.07, low-certainty evidence). Mood or personal well-being were not reported. Computerised learning compared to no intervention Two trials (57 participants) reported on interventions aimed at children and adolescents and their impact on promoting a sense of self-efficacy (primary outcome 'Mood and personal well-being'), but only one showed an increase, MD 7.46 (95%CI 3.21 to 11.71, 17 participants, very low-certainty evidence); the second did not report control group data. One trial (30 participants) showed the intervention did not improve self-efficacy in adults, but appropriate data could not be extracted. Two trials (47 participants) reported coping strategies; one only reported within-group differences from baseline, the second showed an increase from baseline in coping strategies in the Internet program group compared to the no intervention group (disease-specific knowledge, MD 2.45 (95% CI 0.89 to 4.01); self-management ability and transition readiness, MD 19.90 (95% CI 3.61 to 36.19; low-certainty evidence). One trial reported QoL but with insufficient information to calculate changes from baseline; no difference in post-treatment scores was seen between groups, MD -8.65, 95% CI -18.30 to 1.00, very low-certainty evidence). Auto-hypnosis (self-hypnosis) compared to control There were two older trials that reported on this intervention (50 participants) focusing mainly on the secondary outcome 'physical health'; only one trial reported the primary outcome 'mood and personal well-being' (only within-group differences in the treatment group). Coping strategies and QoL were not assessed in the trials. Relaxation (progressive or self control) compared to no treatment Only one trial (seven participants) from 1985, was included which focused on 'physical health' and did not report on any of our primary outcomes. AUTHORS' CONCLUSIONS:Not all of the seven included trials analysed the effects of the interventions on our primary outcomes (mood and personal well-being, coping strategies and QoL). Three trials were conducted in the 1970s and 1980s using techniques of auto-hypnosis or relaxation and, in accordance with the needs and therapeutic possibilities of the time, they focused on secondary outcomes, e.g. frequency of bleeding (physical health) and adherence to the intervention. The four newer trials assessed psycho-educational interventions all mediated by the use of technologies (DVD or computer) and often created according to age needs of the target group. In these cases, attention was shifted to our pre-defined primary outcomes. This review has identified low- and very low-certainty evidence, prompting caution in its interpretation. The major problem we encountered was the heterogeneity of trial designs, of interventions and of outcome measures used across the trials. We strongly suggest that researchers consider developing a core outcome set to streamline future research; randomization was proven to be safe and acceptable, and blinding should be considered for those assessing patient-reported outcomes.

背景与目标： 背景：管理血友病在药物治疗及其对个人生活许多方面（包括自我知觉）的广泛影响方面都具有挑战性。血友病的临床管理中可能涉及几个社会心理问题，包括慢性病和不治之症；例如血友病患者必须适应与同龄人之间的最佳互动，并进行体育运动-甚至选择一项体育运动也意味着个人，家庭受到局限，期望和文化影响。血友病患者可以通过否认自己的病情和表现而不坚持治疗来做出反应。由于遗传疾病之间关系的复杂性，父母和亲戚可能会遇到自己的问题，这会使血友病患者的生活更轻松或更困难。据报道，该人群的焦虑，悲伤和沮丧会导致精神健康障碍，并可能会影响生活质量（QoL），具体取决于文化背景，宗教信仰，家庭支持和其他变量。
目的：从根本上评估心理疗法对提高血友病患者应对慢性病能力的有效性。
搜索方法：我们旨在鉴定来自Cochrane囊性纤维化和遗传疾病小组Coagulopathies试验注册，Embase和PsycINFO，CINAHL，MEDLINE和试验注册中心的试验。我们搜索了包含出版物的参考清单。专家组登记册的最新搜索：2019年6月13日。
选择标准：针对任何年龄或性别，A型或B型，任何严重程度，有或没有抑制剂，有或没有HIV或丙型肝炎病毒的血友病患者的随机对照试验（RCT）和准RCT。用于促进情感，智力和精神健康的所有心理干预措施。个人，团体或家庭团体的治疗干预措施均符合条件。
数据收集与分析：我们使用GRADE独立评估试验，提取数据并评估偏倚风险并评估证据质量。
主要结果：纳入七项试验（362名参与者随机分组，来自264名参与者的数据可用于分析）。六个是并行设计，一个是部分交叉设计。在加拿大进行了一项多中心试验；其余六个是在英国，美国，伊朗和荷兰设立的单一中心。所有试验都有很高的偏见风险，即参与者盲目性和使用患者报告的结局。检索了以下四种干预措施的证据：心理教育（DVD加信息手册与仅信息手册的对比；计算机学习与无干预的对比）；认知疗法（自我催眠（自我催眠）与对照）；和行为疗法（放松（渐进式或自我控制）与不进行治疗）。我们还旨在评估心理动力疗法和全身疗法，但未确定任何试验。结果测量和测量的异质性排除了荟萃分析的必要。没有试验报告心理干预和家庭适应的费用。 DVD +信息手册与单独的信息手册相比一项试验（108名参与者）表明，应对策略可能会降低沉思前评分和负面想法，平均差异（MD）-0.24（95％CI -0.48-0.00，低确定性证据），然而，同一项试验中其他应对策略的措施表明，各组之间几乎没有差异，例如沉思，MD（-0.09，95％CI -0.32-0.14，低确定性证据）。同一项试验对QoL进行了测量，结果显示物理组各治疗组之间的差异不大，即MD 0.59（95％CI -3.66至4.84，低确定性证据），但对于那些接受该手册的人来说，可能会改善其心理健康领域的得分加上DVD相比，单独的MD手册（4.70，95％CI为0.33至9.07，低确定性证据）。没有关于情绪或个人幸福的报道。与没有干预相比的计算机化学习两项试验（57名参与者）报告了针对儿童和青少年的干预措施及其对提高自我效能感的影响（主要结果为“情绪和个人幸福感”），但只有一项表明有所增加，MD 7.46（95％CI 3.21至11.71，17位参与者，不确定性非常低的证据）；第二个没有报告对照组数据。一项试验（30名参与者）表明，该干预措施并未提高成人的自我效能，但无法提取适当的数据。两项试验（47名参与者）报告了应对策略；一个仅报告了与基线相比的组内差异，第二个表明与不进行干预的组相比，互联网程序组的应对策略相对于基线有所增加（疾病特定知识，MD 2.45（95％CI 0.89至4.01）；自我管理能力和过渡准备状态，医学博士19.90（95％CI 3.61至36.19；低确定性证据）一项试验报告了QoL，但资料不足以计算基线的变化；各组之间的治疗后评分无差异，医学博士- 8.65，95％CI -18.30到1.00，非常低的确定性证据）。与催眠相比，自我催眠（自我催眠）有两项较早的试验报道了这种干预措施（50名参与者），主要集中在次要结果“身体健康”上。只有一项试验报告了主要结局“情绪和个人幸福感”（仅治疗组的组内差异）。试验中未评估应对策略和生活质量。与不进行治疗相比，放松（进行性或自我控制）仅包括1985年以来的一项试验（七名参与者），该试验侧重于“身体健康”，并且没有报告我们的任何主要结局。
作者的结论：并非所有纳入的七个试验都分析了干预措施对我们主要结果（情绪和个人幸福感，应对策略和生活质量）的影响。在1970年代和1980年代使用自动催眠或放松技术进行了三项试验，并根据当时的需求和治疗可能性，将研究重点放在了次要结局上，例如出血频率（身体健康）和对干预的依从性。这四项较新的试验评估了全部由技术（DVD或计算机）的使用介导的心理教育干预措施，并且通常根据目标人群的年龄需求而创建。在这些情况下，注意力转移到了我们预先定义的主要结果上。这篇综述鉴定了低和非常低的证据，促使其解释时要谨慎。我们遇到的主要问题是试验设计，干预措施和整个试验中使用的结果指标的异质性。我们强烈建议研究人员考虑开发一套核心成果，以简化未来的研究；随机分组被证明是安全且可以接受的，评估患者报告结果的患者应考虑盲法。

BACKGROUND & AIMS: :Gly-48 is in the conserved DGDQC sequence (residues 47-51 of human factor IX) of the first EGF (EGF-1)-like domain of factor IX. The importance of the Gly-48 is manifested by two hemophilia B patients; factor IXTainan and factor IXMalmo27, with Gly-48 replaced by arginine (designated IXG48R) and valine (IXG48V), respectively. Both patients were CRM+ exhibiting mild hemophilic episodes with 25% (former) and 19% (latter) normal clotting activities. We characterize both factor IX variants to show the roles of Gly-48 and the conservation of the DGDQC sequence in factor IX. Purified plasma and recombinant factor IX variants exhibited approximately 26%-27% normal factor IX's clotting activities with G48R or G48V mutation. Both variants depicted normal quenching of the intrinsic fluorescence by increasing concentrations of calcium ions and Tb3+, indicating that arginine and valine substitution for Gly-48 did not perturb the calcium site in the EGF-1 domain. Activation of both mutants by factor XIa appeared normal. The reduced clotting activity of factors IXG48R and IXG48V was attributed to the failure of both mutants to cleavage factor X: in the presence of only phospholipids and calcium ions, both mutants showed a 4 to approximately 7-fold elevation in Km, and by adding factor VIIIa to the system, although factor VIIIa potentiated the activation of factor X by the mutants factor IXaG48R and factor IXaG48V, a 2 to approximately 3-fold decrease in the catalytic function was observed with the mutant factor IXa's, despite that they bound factor VIIIa on the phospholipid vesicles with only slightly reduced affinity when compared to wild-type factor IXa. The apparent Kd for factor VIIIa binding was 0.83 nM for normal factor IXa, 1.74 nM for IXaG48R and 1.4 nM for IXaG48V. Strikingly, when interaction with the factor VIIa-TF complex was examined, both mutations were barely activated by the VIIa-TF complex and they also showed abnormal interaction with VIIa-TF in bovine thromboplastin-based PT assays. Taken together, our results suggest that mutations at Gly-48 altered the interaction of factor IX with its extrinsic pathway activator (VIIa-TF complex), its macromolecular substrate (factor X), and its cofactor (factor VIIIa).

背景与目标： ：Gly-48在因子IX的第一个EGF（EGF-1）样结构域的保守DGDQC序列（人因子IX的残基47-51）中。 Gly-48的重要性由两名血友病B患者证明。 IXTainan因子和IXMalmo27因子，其中Gly-48分别被精氨酸（命名为IXG48R）和缬氨酸（IXG48V）代替。两名患者均表现出轻度的血友病发作，正常凝血活动为25％（前者）和19％（后为）。我们表征两个因子IX变体，以显示Gly-48的作用以及因子IX中DGDQC序列的保守性。纯化的血浆和重组因子IX变体表现出约26％-27％的正常因子IX具有G48R或G48V突变的凝血活性。这两个变异体均通过增加钙离子和Tb3的浓度来正常淬灭固有荧光，表明精氨酸和缬氨酸取代Gly-48不会干扰EGF-1结构域中的钙位点。 XIa因子对两种突变体的激活似乎都是正常的。因子IXG48R和IXG48V的凝结活性降低归因于两个突变体均未能裂解X因子：在仅存在磷脂和钙离子的情况下，两个突变体的Km值均升高了4至7倍左右，并加上了因子VIIIa对系统的影响，尽管VIIIa因子通过突变体IXaG48R和IXaG48V增强了X因子的激活，但突变因子IXa的催化功能却降低了2到3倍，尽管它们结合了VIIIa因子。与野生型因子IXa相比，磷脂囊泡的亲和力仅略有降低。对于正常因子IXa，因子VIIIa结合的表观Kd为0.83 nM，对于IXaG48R为1.74 nM，对于IXaG48V为1.4 nM。令人惊讶的是，当检查与因子VIIa-TF复合物的相互作用时，两种突变几乎都没有被VIIa-TF复合物激活，并且在基于牛凝血活酶的PT分析中，它们还显示出与VIIa-TF的异常相互作用。综上所述，我们的结果表明，Gly-48处的突变改变了因子IX与其外在途径激活剂（VIIa-TF复合物），其大分子底物（因子X）和其辅因子（因子VIIIa）之间的相互作用。