Factor VIII inhibitors: a 50‐year perspective

Summary. Inhibitors of factor VIII (FVIII) have been studied for more than 50 years, but diagnostic and therapeutic challenges remain. To describe the features that distinguish alloantibodies from autoantibodies, list predisposing factors, and review methods for tolerance induction and autoantibody suppression. Review of key articles published during the past half‐century that have advanced knowledge in this field. Alloantibodies generally bind to the A2 or C2 domains of FVIII and disrupt the formation of the FVIII–FIX complex. They exhibit type 1 reaction kinetics, are saturable by FVIII, and display anamnesis. In contrast, autoantibodies usually bind to the C2 domain of FVIII, interfering with phospholipid and von Willebrand factor binding. They have type‐2 kinetics and are poorly neutralized by FVIII. Repeated exposures to FVIII induce tolerance in 70–80% of haemophiliacs with inhibitors, whereas drugs that deplete B‐lymphocytes restore self‐tolerance to FVIII in a similar percentage of non‐haemophiliacs. Future work should focus on improving assays that detect and quantify inhibitors, examining the pathophysiology of inhibitor formation using contemporary immunologic tools, and investigating new treatment modalities. These should include agents to control bleeding with less thrombotic risk, more specific immunomodulating drugs to curtail antibody formation, and, for haemophilia patients, genetic therapies to provide FVIII resistant to or protected from inactivation by inhibitors.     

Development of steroid sulfatase inhibitors

Hydrolysis of biologically inactive steroid sulfates to unconjugated steroids by steroid sulfatase (STS) is strongly implicated in rendering estrogenic stimulation to hormone-dependent cancers such as those of the breast. Considerable progress has been made in the past two decades with regard to the discovery, design and development of STS inhibitors. We outline historical aspects of their development, cumulating in the discovery of the first clinical trial candidate STX64 (BN83495, Irosustat) and other sulfamate-based inhibitors. The development of reversible STS inhibitors and the design of dual inhibitors of both aromatase and STS is also discussed.     

Targeting low‐density lipoprotein cholesterol with PCSK9 inhibitors

Over the past quarter century, clinical trials have consistently demonstrated that lowering levels of low‐density lipoprotein cholesterol (LDL‐C) with statins reduces the rate of major adverse cardiovascular events. However, the findings that many patients continue to experience events or harbour inappropriately high LDL‐C levels despite intensive statin therapy and the clinical reality of statin intolerance suggests that additional therapeutic strategies are required in order to achieve more effective reductions in cardiovascular risk. The emergence of inhibitory monoclonal antibodies targeted against proprotein convertase subtilisin kexin type 9 (PCSK9) provides a novel approach to reducing LDL‐C levels. The current experience of PCSK9 inhibitors and implications for clinical use and cost effectiveness will be reviewed.     

肾素抑制剂和高血压

肾素抑制剂已被认为系一类新的抗高血压药物,为降压药物的发展提供了可观的前景。本文就其作用机制及第一个口服肾素抑制剂阿利吉仑(Aliskiren)的临床研究情况作一综述。     

The HCV NS5B nucleoside and non-nucleoside inhibitors

This article introduces one of the most diverse classes of direct-acting antivirals for hepatitis C, the nucleoside and non-nucleoside NS5B polymerase inhibitors. Through a systematic review of the published literature, we describe their structure, mechanism of action, issues with resistance, and clinical effectiveness shown in the latest clinical trials. Direct-acting antiviral combination trials that have already shown some early promising results even in the setting of interferon-sparing antiviral regimens are discussed.     

组蛋白去乙酰化酶抑制剂的抗纤维化作用

组蛋白乙酰化/去乙酰化修饰是基因转录调控的关键机制之一,这种修饰作用分别由组蛋白乙酰转移酶和组蛋白去乙酰化酶调控,最近的研究表明组蛋白去乙酰化酶与一些以慢性纤维化为主要特征的疾病相关.而体内外实验证明组蛋白去乙酰化酶抑制剂可抑制纤维化反应.本文针对组蛋白去乙酰化酶抑制剂的抗纤维化作用作一综述.     

Immunoadsorption for removal of inhibitors: update on treatments in Malmö–Lund between 1980 and 1995

Treatment of severe bleeding and the performance of surgery in Haemophilia patients with inhibitors creates severe problems. It is generally agreed that treatment is most effective if circulating levels of factor VIII/IX can be achieved long enough for control of heamostasis. Immunoadsorption with protein A for the removal of inhibitor has improved treatment for patients with initial inhibitor titres too high to neutralize by infusion alone.
  This is a summary of our experience in Malmö regarding immunoadsorption and heamostatis. A total of 19 applications with immunoadsorption in 10 patients were performed. On all occasions it was possible to eliminate totally the inhibitor or reduce it to low levels that could easily be neutralized with factor concentrate. Heamostatic levels of coagulation factors could be maintained for 5–9 days in all but one patient. This period was sufficient to stop ongoing heamorrhage or prevent excessive bleeding at surgical interventions.     

Glycoprotein IIb-IIIa inhibitors

Platelets play a pivotal role in the pathogenesis of coronary artery disease and myocardial infarction. Therefore, great interests have been focused in the last decades on improvement in antiplatelet therapies, that currently are regarded as main pillars in the prevention and treatment of coronary artery disease, with special attention to glycoprotein IIb-IIIa (GP IIb-IIIa) receptors, that mediates the final stage of platelet activation. GP IIb-IIIa inhibitors, especially abciximab, have been shown to improve clinical outcome in patients undergoing primary angioplasty for STEMI. Upstream administration cannot routinely recommended, but may potentially be considered among high-risk patients within the first 4 h from symptoms onset. In case of periprocedural administration of antithrombotic therapy, Bivalirudin should be considered, especially in patients at high risk for bleeding complications. Among high-risk patients with acute coronary syndromes, an early invasive strategy with selective downstream administration of GP IIb-IIIa inhibitors is the strategy of choice, whereas bivalirudin should be considered in patients at high risk for bleeding complications. Among patients with unstable angina GP IIb-IIIa inhibitors should be considered only in case of evidence of intracoronary thrombus or in case of thrombotic complications (as provisional use). Further, randomized trials are certainly needed in the era of new oral antiplatelet therapies, and with strategies to prevent bleeding complications such as larger use of radial approach, mechanical closure devices, bivalirudin, or postprocedural protamine administration to promote early sheat removal.     

Haemophilia pseudotumours in patients with inhibitors

Development of inhibitors against factor VIII (FVIII) or FIX is the most serious complication of replacement therapy in patients with haemophilia. Haemophilic pseudotumours in a patient with inhibitors can lead to devastating consequences. The aim of this study is to show our experience in the treatment of 10 pseudotumours in 7 patients with inhibitors who were treated by the same multidisciplinary team in the period between January 2000 and March 2013. Seven severe haemophilia A patients were treated at the Haemophilia Foundation in Buenos Aires, Argentina, for 10 pseudotumours. Eight were bone pseudotumours and two soft tissue. All patients underwent imaging studies at baseline to assess the size and content of the lesion. The patients received Buenos Aires protocol as conservative treatment of their pseudotumours for 6 weeks, after which they were evaluated. Only one patient responded to conservative treatment. Surgery was performed on the others six patients, since their pseudotumours did not shrink to less than half their original size. Any bleeding in the musculoskeletal system must be treated promptly in order to prevent pseudotumours. When pseudotumours do appear in inhibitor patients, they can be surgically removed when patients received proper haemostatic coverage, improving the quality of life of these patients.     

Role of epsilon amino caproic acid in the management of haemophilic patients with inhibitors

We managed bleeding crisis in 10 consecutive severe haemophilic patients with inhibitors (eight had an inhibitor level of >5 BU mL(-1)) mainly with the antifibrinolytic agent, i.e. epsilon amino caproic acid (EACA). EACA was used by local, oral or intravenous routes either in combination or separately. Five patients developed inhibitors postoperatively and among the remaining five, four had recurrent haemarthrosis or soft tissue bleeds and one patient presented with severe gastrointestinal bleeding without demonstrable lesion. In all the patients, addition of EACA to their management protocol resulted in stoppage and/or reduced frequency of bleeding. In six of 10 patients, the results were excellent; of these six patients, five developed inhibitors postoperatively. Although a reduction in the frequency of bleeding was observed in patients with haemarthrosis and soft tissue bleed, it was not spectacular and the patients required additional therapy. Hence the results could be described as poor. No patient needed to stop the medicine because of the side-effect of EACA. Symptoms like mild nausea and vertigo were seen as the side-effects of this medicine when high intravenous dosage was administered. EACA thus appears to be an excellent adjuvant therapy for haemophilic patients with inhibitors. Besides its well-recognized antifibrinolytic activity, EACA may have additional mechanisms of action in haemophilic patients with inhibitors. More extensive use of this cheap and safe product is warranted in haemophilic patients with inhibitors. If larger studies confirm this observation, then using antifibrinolytics will allow substantial reduction of FEIBA or activated prothrombin complex (APCC) usage in such patients without necessarily increasing the thrombotic complications or reduction of the clinical efficacy, when compared with higher dosage of FEIBA or APCC alone. This will lead to substantial financial savings in countries where up to 35% of severe haemophilia A patients develop inhibitors.     

Factor VIII inhibitors: A clinical overview

There is much evidence to indicate that inhibitors to Factor VIII in patients with classical hemophilia are the result of an immunological response to exposure to material (VIII:C or VIII:CAg) that is absent or present in reduced amounts in these patients. The inhibitor is an antibody that is usually restricted in immunochemical composition and in many instances contains predominantly or exclusively γG3 or γG4 heavy chains. Exposure to Factor VIII in many inhibitor patients leads to typical anamnestic responses with marked increases in the level of the inhibitor. The tendency to develop inhibitors and the clinical characteristics of the inhibitor may be affected by genetic factors, basal levels of Factor VIII:C and/or VIII:CAg, and the nature and amount of the “immunizing” material. Currently accepted therapeutic modalities are aimed primarily at the management of acute bleeding episodes.     

免疫检查点抑制剂相关肾损伤

免疫检查点抑制剂已被批准用于多种肿瘤的治疗,在杀伤肿瘤细胞的同时也可造成肾脏损伤,影响患者的预后。免疫检查点抑制剂损伤肾脏的机制包括诱导产生自身抗体、与正常组织上的受体相结合触发免疫反应、新生或者反应性T细胞与肾组织发生交叉反应、诱导潜伏状态的药物特异性T细胞再活化、促使T细胞释放炎症因子和趋化因子等,临床主要表现为无症状的急性肾损伤,而主要病理特点是小管间质损伤,但有时可合并肾小球病变,此时可出现不同程度的尿检异常。治疗上,在明确肾脏损伤的病因后,可根据血清肌酐升高的程度决定是否需要停药及使用糖皮质激素,动态监测肌酐,调整治疗方案。本文将对免疫检查点抑制剂相关肾损伤的发病机制、临床表现、病理特点和诊治策略进行综述,以帮助更好地认识和处理这一并发症。     

New oral Xa and IIa inhibitors: updates on clinical trial results

Heparins and VKAs have been the cornerstones of anticoagulation therapy for several decades and these agents have become most important drugs in the primary and secondary prevention of venous and arterial thromboembolic disease. Although effective, their use has been hampered by numerous limitations. In the search for new agents matching the ‘ideal’ anticoagulant profile, a number of different steps in the coagulation cascade have been targeted, including direct thrombin inhibition, and direct inhibition of Factor Xa. There are currently a host of promising new agents at various stages of development and clinical evaluation. With potential benefits including predictable efficacy, rapid onset of action, ability to bind clot-bound coagulation factors and no requirement for therapeutic monitoring, these new agents are set to improve the management of thromboembolic disorders.     

免疫检查点抑制剂相关致命性不良反应及管理策略

免疫检查点抑制剂(immune checkpointinhibitors, ICIs)是针对程序性死亡受体1(programmed cell death protein 1,PD-1)/程序性死亡受体配体1(programmed cell death protein ligand1,PD-L1)和细胞毒性T淋巴细胞相关抗原4(cytotoxic T lymphocyte associated antigen-4,CTLA-4)的单克隆抗体,主要通过阻断上述免疫检查点通路的抑制性免疫调节作用从而增强人体的抗肿瘤免疫反应。