阵发性睡眠性血红蛋白尿症的靶向治疗

阵发性睡眠性血红蛋白尿症（PNH）是一种罕见的造血干细胞克隆性的溶血性疾病,目前治疗困难。重组人源型抗补体蛋白C5单克隆抗体（eculizumab）的出现及临床应用开启了PNH靶向治疗的新篇章。eculizumab通过与补体C5结合,防止C5裂解形成C5b及膜攻击复合物,减少溶血,降低输血需求,提高患者生活质量。2007年,eculizumab分别被美国食品和药物管理局、欧盟委员会通过用于治疗PNH血管内溶血。现对PNH患者使用eculizumab靶向治疗作一综述。     

人源型抗C5单克隆抗体治疗阵发性睡眠性血红蛋白尿症的研究进展

阵发性睡眠性血红蛋白尿症(PNH)是一种获得性造血干细胞基因突变所致的难治性溶血性疾病,至今仍无有效治疗手段.骨髓移植是目前唯一可治愈PNH的手段,但仅适合于骨髓增生低下或反复发生严重血管栓塞的患者.重组人源型抗补体蛋白C5单克隆抗体(Eculizumab)的出现改写了PNH治疗的历史,其临床应用前景令人鼓舞.本文就Eculizumab药理学及其近年来在PNH治疗中的应用状况作一综述.     

阵发性睡眠性血红蛋白尿症的补体通路抑制药物研究进展

阵发性睡眠性血红蛋白尿症(PNH)是一种获得性造血干细胞基因突变引起的溶血性疾病,其溶血机制主要是由于红细胞表面抑制补体通路活化蛋白CD55、CD59缺失,导致红细胞对补体的敏感性增加,进而发生补体介导的血管内溶血.鉴于此,抑制补体通路活化成为控制PNH发生的治疗策略之一.笔者拟就PNH的病因及溶血机制,以及新型补体通路抑制药物的研究进展进行综述.     

七例以难治性缺铁性贫血为首发表现的阵发性睡眠性血红蛋白尿症患者临床特征分析

阵发性睡眠性血红蛋白尿症(PNH)是一种血管内溶血性疾病,以贫血及血红蛋白尿为主要临床表现.长期慢性血管内溶血,血红蛋白和(或)含铁血黄素随尿液排出,将引发缺铁性贫血(IDA).部分PNH所致IDA患者由于PNH病情隐匿,缺铁原因持续存在,补铁治疗多不易奏效,甚至由于补铁而加重PNH病情[1-2].我们分析7例以难治性IDA为首发表现的PNH患者临床资料,现报告如下.     

阵发性睡眠性血红蛋白尿症实验室诊断

阵发性睡眠性血红蛋白尿症(PNH)是一种后天获得的血细胞膜缺陷的克隆性疾病,临床上可表现血管内溶血、栓塞、全血细胞减少等,有时可出现骨髓衰竭。现已证实,大多数PNH患者异常克隆与正常造血并存,使本病的诊断和发病机制的研究受到限制。PNH患者红细胞膜表面缺乏加速衰变因子(DAF,CD55)、反应性溶血的膜抑制物(MIRL,CD59)和C8结合蛋白(或称同种限制因子,HRF)等,     

嗜水气单胞菌毒素溶血试验比色法诊断阵发性睡眠性血红蛋白尿症

本研究建立嗜水气单胞菌（HEC）毒素溶血试验比色法诊断阵发性睡眠性血红蛋白尿症（PNH）。方法为取正常人，贫血病人和PNH病人（各10例）外周血标本，用HEC毒素处理外周血红细胞并630nm测定吸光度，以定量溶血程度，所测结果与流式细胞术检测CD59^-细胞进行验证。结果表明，PNH病人的红细胞对HEC毒素溶血试验有抗性，而正常人和非PNH病人的红细胞几乎全部溶解，结论：HEC毒素溶血试验比色法对PNH是一种简便，快速，特异而又可靠的诊断方法。     

中西医结合使用化疗及中药治疗阵发性睡眠性血红蛋白尿症

阵发性睡眠性血红蛋白尿症(PNH)为干细胞的一种异常克隆增生所致成的继发性血管内溶血疾患。通常无特效疗法。基于PNH 的骨髓增生特点,我们设计了COAT 治疗方案。T 系中药,COA 系常用化疗西药。COAT 方案治疗5例男性患者。治疗后血红蛋白不同程度恢复,骨髓象恢复正常,Ham 试验治后转成阴性或极弱阳性。按1987年上海全国溶血会议疗效标准,1例近期治愈,2例近期明显进步,2例近期进步。在继续观察中。     

阵发性睡眠性血红蛋白尿症误诊缺铁性贫血一例

阵发性血红蛋白尿症 （ paroxysmal nocturnal hemoglobi nuria, PNH ） 是一种获得性造血干细胞克隆缺陷性疾病,其血细胞膜对补体异常敏感的一种慢性血管内溶血。临床表现常有与睡眠有关的间断发作的血红蛋白尿为特征,可伴有全血细胞减少或反复血栓形成。本病的误诊率高,据报道,起病后3个月内确诊者只有16．4％,起病后1年内确诊者仅35．5％,首次诊断即明确为PNH者只有7％。作者报道一例PNH误诊为缺铁性贫血10年的病例并结合文献复习以提高临床对PNH的认识。     

阵发性睡眠性血红蛋白尿症靶向治疗策略

阵发性睡眠性血红蛋白尿症(PNH)为一种获得性造血干细胞(HSC)磷脂酰肌醇聚糖-A类(PIG-A)基因突变所致的难治性溶血性疾病。临床上，PNH多以对症治疗为主，但其不能根治，且需长期维持治疗。随着PNH发病机制研究的不断深入，诸如HSC移植、基因治疗、糖基磷脂酰肌醇(GPI)锚链蛋白输注等靶向治疗日益受到重视，新近特异性抗补体单克隆抗体的出现为PNH患者的靶向治疗带来希望[1-2]。我们旨在对PNH靶向治疗策略作一综述。     

阵发性睡眠性血红蛋白尿症实验室诊断

阵发性睡眠性血红蛋白尿症(PNH)是一种后天获得 的血细胞膜缺陷的克隆性疾病,临床上可表现血管内溶 血、栓塞、全血细胞减少等,有时可出现骨髓衰竭[1]。现 已证实,大多数PNH患者异常克隆与正常造血并存,使本 病的诊断和发病机制的研究受到限制。PNH患者红细胞 膜表面缺乏加速衰变因子(DAF,CD55)、反应性溶血的膜 抑制物(MIRL,CD59)和C8结合蛋白(或称同种限制因 子,HRF)等,使红细胞对补体敏感而溶血。上述3种蛋 白都经糖基化磷脂酰肌醇(GPl)连接在细胞膜上[2]。近 年来,由于各种检测技术的发展使得PNH发病机制的研 究、PNH…     

Mechanisms and clinical implications of thrombosis in paroxysmal nocturnal hemoglobinuria

Summary. Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disease characterized by a clone of blood cells lacking glycosyl phosphatidylinositol (GPI)‐anchored proteins at the cell membrane. Deficiency of the GPI‐anchored complement inhibitors CD55 and CD59 on erythrocytes leads to intravascular hemolysis upon complement activation. Apart from hemolysis, another prominent feature is a highly increased risk of thrombosis. Thrombosis in PNH results in high morbidity and mortality. Often, thrombosis occurs at unusual locations, with the Budd–Chiari syndrome being the most frequent manifestation. Primary prophylaxis with vitamin K antagonists reduces the risk but does not completely prevent thrombosis. Eculizumab, a mAb against complement factor C5, effectively reduces intravascular hemolysis and also thrombotic risk. Therefore, eculizumab treatment has dramatically improved the prognosis of PNH. The mechanism of thrombosis in PNH is still unknown, but the highly beneficial effect of eculizumab on thrombotic risk suggests a major role for complement activation. Additionally, a deficiency of GPI‐anchored proteins involved in hemostasis may be implicated.     

Increased eculizumab requirements during pregnancy in a patient with paroxysmal nocturnal hemoglobinuria: case report and review of the literature

Paroxysmal nocturnal hemoglobinuria (PNH) results from reduced complement regulatory proteins on hematopoietic cells, predisposing patients to intravascular hemolysis, thrombophilia, and cytopenias. Women diagnosed in pregnancy can experience significant maternofetal complications. Trials of eculizumab in PNH excluded pregnant women. Here, we report the first Canadian patient taken through pregnancy on eculizumab.     

Recent advances in the diagnosis, monitoring, and management of patients with paroxysmal nocturnal hemoglobinuria

Until recently, there has been no specific therapy for PNH with clinical management mainly supportive in terms of cytopenias and control of thrombotic risk. Currently, the only curative procedure for PNH is bone marrow transplantation although for the majority of patients the associated risks are too great to justify transplantation. The pioneering use of the therapeutic monoclonal antibody eculizumab, which binds to and prevents the activation of the complement protein C5, represents a significant advance in treatment for patients with PNH and is set to become the future standard therapy for hemolytic PNH. In both an initial pilot study and two phase III clinical trials, eculizumab has been shown to dramatically reduce intravascular hemolysis, hemoglobinuria, and transfusion requirements thus improving the quality of life in patients with PNH. As a clinical entity, PNH is synonymous with glycosylphosphatidylinositol (GPI) deficiency, and is an acquired clonal disorder associated with somatic mutations of the X-linked PIGA gene in hematopoietic stem cells. A recent study identified a novel autosomal recessively inherited form of GPI-deficiency involving a mutation in a promotor component of the pig-m gene and characterized by a thrombotic tendency and seizures. In both these developments, flow cytometry played a critical role. In the first instance, in monitoring direct response to a new therapeutic agent; second, in demonstrating the phenotypic/genotypic link in a new form of GPI deficiency.     

Expression of cryptantigen Th on paroxysmal nocturnal hemoglobinuria erythrocytes in association with a hemolytic exacerbation.

Paroxysmal nocturnal hemoglobinuria (PNH) erythrocytes lack complement regulatory membrane proteins and are susceptible to complement. Although the critical role of complement in intravascular hemolysis in PNH is accepted, the precise mechanism of complement activation in vivo is unknown. Accordingly, in a PNH patient who was suffering from a hemolytic precipitation soon after a common cold-like upper respiratory infection, we analyzed the erythrocytes with lectins and by flow cytometry to detect membrane alteration that lead to complement activation. The lectin reactivity of erythrocytes showed the expression of cryptantigen Th. The patient serum at the time of the hemolysis induced the expression of Th on erythrocytes from PNH patients and from healthy volunteers in vitro, whereas neither the patient serum after recovery from the hemolysis nor blood type-matched control serum from healthy donor showed this activity. Moreover, autologous serum selectively hemolyzed Th+ PNH erythrocytes, but not Th- PNH erythrocytes, or Th+ control erythrocytes. Hemolysis was not observed either in complement-inactivated serum or in blood type-matched cord blood serum, which lacks natural antibodies to cryptantigens. These findings indicate that the immunoreaction of infection-induced Th with natural antibody on PNH erythrocytes is a trigger of the complement activation, leading to intravascular hemolysis.     

Posthepatectomy jaundice induced by paroxysmal nocturnal hemoglobinuria: A case report

BACKGROUNDJaundice is a major manifestation of posthepatectomy liver failure, a feared complication after hepatic resection. Herein, we report a case of posthepatectomy jaundice that was not caused by liver failure but by paroxysmal nocturnal hemoglobinuria (PNH)-induced hemolysis.CASE SUMMARYA 56-year-old woman underwent right hepatectomy and biliary tract exploration surgery due to hepatic duct stones. Prior to surgery, the patient was mildly anemic. The direct antiglobulin test was negative. A bone marrow biopsy showed mild histiocyte hyperplasia. After surgery, the patient suffered a progressive increase in serum bilirubin. Meanwhile, the patient developed hemolytic symptoms after blood transfusion. She was ultimately diagnosed with PNH. PNH is a rare bone marrow failure disorder that manifests as complement-dependent intravascular hemolysis with varying severity. After steroid treatment, the patient’s jaundice gradually decreased, and the patient was discharged on the 35^th postoperative day.CONCLUSIONPNH-induced hemolysis is a rare cause of posthepatectomy jaundice. It should be suspected in patients having posthepatectomy hyperbilirubinemia without other signs of liver failure. Steroid therapy can be considered for the treatment of PNH in such cases.     

Drugs that inhibit complement

The complement system is an important part of the innate immune system. Complement plays a crucial role in the pathophysiology of many disorders.Despite the pivotal role of the complement system, an approved targeted inhibitor of a complement factor became available only recently. Eculizumab is a humanized monoclonal antibody that inhibits complement factor C5. It is a targeted, disease modifying, treatment of paroxysmal nocturnal hemoglobinuria (PNH). It was approved be the US FDA and the European Commission in 2007. In this review we will update the experience with eculizumab in PNH and discuss potential use of eculizumab in other disorders (e.g. cold agglutinin disease; atypical HUS) and new approaches to complement inhibition with drugs other than eculizumab.     

Altered red cell and platelet adhesion in hemolytic diseases: Hereditary spherocytosis,paroxysmal nocturnal hemoglobinuria and sickle cell disease

Objectives

Intravascular hemolysis may have important pathophysiological consequences, such as the induction of cellular adhesion and vasculopathy. We compared the adhesive properties of red cells (RBC) and platelets in hereditary spherocytosis (HS), paroxysmal nocturnal hemoglobinuria (PNH) and sickle cell disease (SCD) patients.

Design and methods

The adhesion of RBC and platelets, from patients and healthy subjects, was determined using static adhesion assays. RBC surface markers were characterized by flow cytometry and lactate dehydrogenase (LDH), plasma hemoglobin (pHb) and TNF-α were assayed in serum/plasma samples.

Results

pHb levels were elevated in all three hemolytic diseases, indicating the incidence of intravascular hemolysis. RBC adhesion and TNF-α were augmented in HS and SCD, but not in PNH. Reticulocyte counts were raised in the three diseases, but were higher in HS and SCD than in PNH; high expressions of CD71, CD36 and CD49d were observed on SCD RBC, while CD71 alone was increased on HS and PNH RBC. Splenectomy was associated with reversals of increased pHb, RBC adhesion, reticulocytes, RBC marker expression and inflammation in HS. In contrast, platelet adhesion was elevated in SCD and PNH, but not HS. Platelet adhesion correlated significantly with serum LDH, but not pHb, in the hemolytic disease cohort; interestingly, LDH did not correlate with reticulocytes or pHb levels.

Conclusions

Results indicate that extravascular, rather than intravascular, hemolysis (and ensuing RBC production) may contribute to elevations in RBC adhesive properties in HS and SCD, while mechanisms peculiar to each disease may augment platelet adhesion in SCD and PNH.     

Paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal stem cell disorder resulting from a somatic mutation in the hematopoietic stem cell. It is characterized by intravascular hemolysis, cytopenias, frequent infections, bone marrow hypoplasia, and a high incidence of life-threatening venous thrombosis. An absent glycosylphosphatidylinositol (GPI)-anchored receptor prevents several proteins from binding to the erythrocyte membrane. These include the complement-regulatory proteins, CD55 and CD59, whose absence results in enhanced complement-mediated lysis. Patients present with anemia and hemoglobinuria. Laboratory diagnosis includes the sucrose hemolysis test, Ham acid hemolysis test, and fluorescent-activated cell analysis. There is considerable overlap between PNH, aplastic anemia, and myelodysplastic syndrome and some cases evolve into acute leukemia. Treatment is mainly supportive consisting of transfusion therapy, anticoagulation, and antibiotic therapy. Hematopoietic stem cell transplantation may be curative.     

Apparent hemolysis following intravenous antithymocyte globulin treatment in a patient with marrow failure and a paroxysmal nocturnal hemoglobinuria clone

BACKGROUND: Antithymocyte globulin (ATG) is a commonly used medication in the treatment of aplastic anemia. Although serum sickness has been described with the use of ATG, few cases of acute intravascular hemolysis have been reported. We report a case of apparent ATG-related hemolysis in a patient with aplastic anemia and a paroxysmal nocturnal hemoglobinuria (PNH) clone. CASE REPORT: A 62-year-old, group A, RhoD+ man with aplastic anemia and an 11.6 percent glycosylphosphatidylinositol (GPI)-anchored protein-negative population of red cells (RBCs), representing approximately 190 mL of his RBC volume, and 90 percent GPI-negative neutrophils were scheduled to receive equine ATG at 40 mg per kg per day for 4 days. After the first infusion, he developed a 1.6 g per dL decline in hemoglobin concentration and an increase in serum lactate dehydrogenase (normal, 113-226 U/L) from 284 to 1127 U per L. The hemolytic process was complicated by acute renal failure characterized by an increase in serum creatinine from 0.9 to 4.2 mg per dL and the appearance of dark-colored urine. Pre- and post-ATG direct antiglobulin tests were negative. CONCLUSION: The temporal association of intravenous ATG to lysis of complement-sensitive RBCs suggests a causal relationship. Although intravascular hemolysis after ATG administration appears to be uncommon, the clinical consequences may be severe, and determining the pathophysiology may yield clues to the mechanism of intravascular hemolysis.