Management Of Paroxysmal Nocturnal Hemoglobinuria Research Articles

Recent advances in the understanding and management of paroxysmal nocturnal hemoglobinuria

Recent advances in the understanding and management of paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal haemoglobinuria: diagnostic tests, advantages, & limitations

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare acquired clonal disorder of haematopoietic stem cells. The molecular defect in PNH is mutation in the phosphotidylinositol glycan complementation class A (PIGA gene) causing defect in glycosylphosphatidylinositol anchored proteins (Cell, 73, 1993, 703). The deficiency of these GPI-anchored proteins on the membranes of haematopoietic cells lead to the various clinical manifestations of PNH. Clinically PNH is classified into classic PNH, PNH in the setting of another specified bone marrow disorder and sub clinical PNH. Size of the PNH clone differs in these different subtypes. The management of PNH has been revolutionized by the advent of monoclonal antibody, eculizumab. Thus, today it is important to have sensitive tests to diagnose and monitor the clone size in patients of PNH. Before 1990, diagnosis of PNH was made using complement based tests. However in the last decade, flowcytometry has become the gold standard diagnostic test as it has increased sensitivity to detect small clones, ability to measure clone size and is not affected by blood transfusions. This review is aimed to focus mainly on the different methods available for the detection of PNH clone and the recent advances and recommendations for the flowcytometric diagnosis of PNH.

The Management of Paroxysmal Nocturnal Hemoglobinuria—Recent Advances in Diagnosis and Treatment, and New Hope for Patients

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare life-threatening and debilitating disorder of hematopoiesis. It is characterized by the clinical triad of Coombs-negative acquired extracorpuscular hemolytic anemia, thrombophilia, and bone marrow failure. The sequelae of intravascular hemolysis drastically affect the quality of life of patients. Cytopenia and in particular thrombophilia can cause life-threatening complications. Thromboembolic events are the major cause of death. The only curative treatment for PNH is allogeneic stem cell transplantation from a related or unrelated stem cell donor. Recent reports demonstrated favorable outcomes. Other treatments were generally supportive in nature. Recently, eculizumab, a humanized monoclonal antibody that inhibits complement factor C5, was approved. It is a targeted, disease-modifying treatment of PNH. This article will summarize major advances in the management of PNH during the last year, and in particular will discuss new results of eculizumab, treatment of thrombosis, and stem cell transplantation. Given the new advances there is hope for improved survival of these patients.

The Management of Paroxysmal Nocturnal Hemoglobinuria—Recent Advances in Diagnosis and Treatment, and New Hope for Patients

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare life-threatening and debilitating disorder of hematopoiesis. It is characterized by the clinical triad of Coombs-negative acquired extracorpuscular hemolytic anemia, thrombophilia, and bone marrow failure. The sequelae of intravascular hemolysis drastically affect the quality of life of patients. Cytopenia and in particular thrombophilia can cause life-threatening complications. Thromboembolic events are the major cause of death. The only curative treatment for PNH is allogeneic stem cell transplantation from a related or unrelated stem cell donor. Recent reports demonstrated favorable outcomes. Other treatments were generally supportive in nature. Recently, eculizumab, a humanized monoclonal antibody that inhibits complement factor C5, was approved. It is a targeted, disease-modifying treatment of PNH. This article will summarize major advances in the management of PNH during the last year, and in particular will discuss new results of eculizumab, treatment of thrombosis, and stem cell transplantation. Given the new advances there is hope for improved survival of these patients.

The Management of Paroxysmal Nocturnal Hemoglobinuria: Recent Advances in Diagnosis and Treatment and New Hope for Patients

PNH is a rare clonal hematopoietic stem disorder clinically characterized by the triad of chronic complement-mediated hemolysis, thrombosis, and bone marrow failure. While median survival has improved when historical data are compared to more recent data, thrombosis, the major cause of death in PNH, is still observed in approximately 40% of patients. The symptoms associated with this disorder–including fatigue, pain, esophageal spasm, and erectile dysfunction–are often severe and disabling. While PNH may be a curiosity to the physician, it forces the majority of patients to significantly modify their lives. Transplantation represents a curative option; however, the risks associated with this option are not insignificant. Eculizumab has been shown to significantly reduce hemolysis, improve anemia, reduce transfusion requirements, and significantly improve fatigue and other QoL scores. Clearly, targeted complement inhibition by eculizumab has the promise to significantly improve the lives of patients with PNH.

The Management of Paroxysmal Nocturnal Haemoglobinuria – Recent Advances in Diagnosis and Treatment, and New Hope for Patients

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare life-threatening and debilitating disorder of haematopoiesis. It is characterised by the clinical triad of Coombs-negative acquired extracorpuscular haemolytic anaemia, thrombophilia and bone marrow failure. The sequelae of intravascular haemolysis drastically affect the quality of life of patients. Cytopenia and in particular thrombophilia can cause life-threatening complications. Thromboembolic events are the major cause of death. The only curative treatment for PNH is allogeneic stem cell transplantation from a related or unrelated stem cell donor. Recent reports demonstrated favourable outcomes. Other treatments were generally supportive in nature. Recently, eculizumab, a humanised monoclonal antibody that inhibits complement factor C5, was approved. It is a targeted, disease-modifying treatment of PNH. This article will summarise major advances in the management of PNH during the last year and, in particular, will discuss new results of eculizumab, treatment of thrombosis and stem cell transplantation. Given the new advances there is hope for improved survival of these patients.

Successful Pregnancy Outcomes in Paroxysmal Nocturnal Hemoglobinuria with Long-Term Eculizumab Treatment

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by a lack of the terminal complement inhibitor CD59 on erythrocytes that renders these cells susceptible to chronic hemolysis resulting in anemia, fatigue, abdominal pain, kidney dysfunction, pulmonary hypertension, and life-threatening thromboembolism (TE). During pregnancy, hemolysis frequently worsens and the incidence of TE increases, posing a high risk of both fetal and maternal mortality. Eculizumab is a terminal complement inhibitor that reduces hemolysis, transfusion requirements, and TE while improving fatigue and quality of life in patients with PNH. Eculizumab contains a hybrid constant region with components of both IgG2 and IgG4. Whether eculizumab crosses the placenta is not known. The eculizumab clinical trial protocols specified withdrawal of patients who became pregnant during the study. There were 5 reported pregnancies during the PNH clinical trials (n=195) prior to withdrawal from the study. To evaluate the safety and efficacy of eculizumab in the management of PNH during pregnancy, we reviewed the physician-reported adverse events (AEs), PK/PD, and distribution of eculizumab, duration of drug exposure during gestation, complications during and after pregnancy, and general health of the newborn in patients with PNH who became pregnant during the eculizumab clinical trials. Of the 5 reported pregnancies, one patient elected termination and 3 patients withdrew from eculizumab therapy between 4 to 16 weeks of gestation and continued pregnancy through term. There were no apparent complications or AEs related to drug and all 3 patients delivered healthy newborns. One patient was treated with low molecular weight heparin (LMWH) from the time she discontinued eculizumab to three months after delivery. She developed hyperpyrexia and was diagnosed with fever of unknown origin shortly after delivery. She was treated and then discharged. There have been no reported postpartum complications in any of these deliveries to date. The fifth patient withdrew from the study but continued on eculizumab treatment throughout the whole pregnancy and post-partum. She initiated eculizumab treatment in 2002 reducing her LDH from 10,300U/L to 490 U/L (normal range 150 to 480 U/L). Her transfusion requirement reduced from 4 units every 6 weeks to 2 units per year in order to maintain her hemoglobin above 8 g/dl. She was commenced on LMWH at week 8 of gestation and she remained on it for the duration of her pregnancy and postpartum. During pregnancy, she was transfused more frequently to maintain her hemoglobin above 9 g/dl. At week 28 of gestation, she experienced an episode of hemoglobinuria and abdominal pain for 3–4 days prior to her next dose of eculizumab and therefore the dosing interval was adjusted from 14 to 12 days (11 days to avoid weekends) as per the approved 900mg dose. She had no further episodes of breakthrough and her LDH levels were maintained below 450 U/L. The patient was induced at term and delivered a healthy newborn. On the day of delivery, there was no detectable eculizumab in the cord blood (see table). At day 1 and 9 postpartum, there was no detectable eculizumab in breast milk samples. To date, the patient shows no clinical signs of thrombosis or other morbidities typically associated with PNH. The first evaluation of eculizumab treatment from conception to delivery in a patient with PNH treated with eculizumab demonstrated that the drug was tolerated and the pregnancy was successful. There was no evidence of thromboses or other morbidities during the postpartum period. There have been no reported events of congenital anomaly/birth defects in the offspring of any patient with PNH who became pregnant during participation in our clinical studies. Further, there are currently two patients being followed who received eculizumab treatment either during the last trimester (started eculizumab at week 26) or throughout gestation to term. Pregnancy in PNH is associated with an extremely high maternal risk. A review of the 5 clinical trial cases demonstrated that patients receiving eculizumab during pregnancy had no obvious complications through the post-partum period and that a slightly higher dose of eculizumab may be required during pregnancy than in non-pregnant patients with PNH. In addition, eculizumab does not appear to cross the placenta or to be secreted into breast milk. Eculizumab therapy may play a significant role in the management of pregnancy in patients with PNH.Table. Eculizumab levels at deliveryEculizumab Levels (μg/ml)*Post PartumDay 0Day1Day 9**Eculizumab serum levels in mother116.181.3146Eculizumab serum levels in cord blood0NMNMEculizumab in breast milk000NM. Not Measured*, a level of 35 μg/ml or more has been shown to completely block terminal complement activation**An additional dose was given between Day 1 and Day 9

Recent developments in the understanding and management of paroxysmal nocturnal haemoglobinuria

Paroxysmal nocturnal haemoglobinuria (PNH) has been recognised as a discrete disease entity since 1882. Approximately a half of patients will eventually die as a result of having PNH. Many of the symptoms of PNH, including recurrent abdominal pain, dysphagia, severe lethargy and erectile dysfunction, result from intravascular haemolysis with absorption of nitric oxide by free haemoglobin from the plasma. These symptoms, as well as the occurrence of thrombosis and aplasia, significantly affect patients' quality of life; thrombosis is the leading cause of premature mortality. The syndrome of haemolytic-anaemia-associated pulmonary hypertension has been further identified in PNH patients. There is currently an air of excitement surrounding therapies for PNH as recent therapeutic developments, particularly the use of the complement inhibitor eculizumab, promise to radically alter the symptomatology and natural history of haemolytic PNH.

Clinical Management of Paroxysmal Nocturnal Hemoglobinuria in Pregnancy: A Case Report and Updated Review

Because women with paroxysmal nocturnal hemoglobinuria (PNH) are especially vulnerable to thromboembolic phenomena, pregnancy is a time of increased risk for both mother and fetus. However, pregnancies in affected women are rare; only case reports and small studies have been reported so far. We present the case of a 20-year-old woman with PNH who, while undergoing medical tests in preparation for a bone marrow transplant, was discovered to be pregnant. We also review the obstetric literature on pregnancy complicated by PNH, which indicates that both maternal and fetal mortality is exceptionally high (11.6% and 7.2%) with the major cause of maternal mortality being thromboembolism. Major maternal complications are more frequent postpartum (30.2%) than antepartum or intrapartum (16.3%). Obstetricians & Gynecologists, Family Physicians. After completion of this article, the reader should be able to recall that paroxysmal nocturnal hemoglobinuria (PNH) during pregnancy increases adverse events for both the mother and the fetus, state that maternal and fetal mortality are both high, and explain that the major complications occur in the postpartum period.

Diagnosis and management of paroxysmal nocturnal hemoglobinuria

The primary clinical manifestations of paroxysmal nocturnal hemoglobinuria (PNH) are hemolytic anemia, marrow failure, and thrombophilia. However, PNH is not a simple binary diagnosis and both flow cytometric characterization of glycosyl phosphatidylinositol–anchored protein expression on peripheral blood cells and marrow analysis are required for comprehensive disease classification. For optimum management, the contribution of both hemolysis and marrow failure to the complex anemia of PNH should be determined. Complement inhibition by eculizumab is a promising new approach to treating the hemolytic anemia. Stem cell transplantation is potentially curative, but the decision on use is best made on a case-by-case basis because of the heterogeneous natural history of the disease. PNH clone size and ethnic/geographic factors appear to influence thrombophilic propensity, but a consensus on prophylactic anticoagulation has not been reached. Involvement of unusual sites (hepatic, mesenteric, cerebral, dermal veins) is characteristic of the thrombophilia of PNH. Indefinite anticoagulation is recommended following a thromboembolic event and thrombolytic therapy should be considered for acute hepatic vein thrombosis (Budd-Chiari syndrome). Pregnancy in a patient with PNH is complicated and requires careful management including prophylactic anticoagulation. To obtain a broad overview of the natural history, approaches to management, and outcome, the International PNH Registry was recently established.

Pathogenesis and management of paroxysmal nocturnal haemoglobinuria

Over the past 30 years, our understanding of the pathogenesis of paroxysmal nocturnal haemoglobinuria (PNH) has increased dramatically. During that time, the events during complement activation and regulation have been described, the molecular basis for the exaggerated complement sensitivity of PNH cells has been uncovered, and the responsible gene mutation has been identified. It is now possible to relate almost all the protean manifestations of PNH to a single gene mutation in a haematopoietic stem cell. Unfortunately, our ability to manage these patients has not kept pace, and, with the exception of bone marrow transplantation, our major efforts are still directed toward control of complications rather than interruption of the disease process.

Observations on the Diagnosis and Management of Paroxysmal Nocturnal Haemoglobinuria: With Report of a Case

Observations on the Diagnosis and Management of Paroxysmal Nocturnal Haemoglobinuria: With Report of a Case