History Of Paroxysmal Nocturnal Hemoglobinuria Research Articles

Danicopan As Add-on Therapy to Ravulizumab or Eculizumab Versus Placebo in Patients with Paroxysmal Nocturnal Hemoglobinuria and Clinically Significant Extravascular Hemolysis: Phase 3 Long-Term Data

Background C5 inhibitors eculizumab (Ecu) and ravulizumab (Rav) have transformed the natural history of paroxysmal nocturnal hemoglobinuria (PNH). Ecu resulted in patient (pt) survival comparable to that of the general population over 20 y of follow-up under real-world conditions. Overall survival rate at 6 years for pts treated with Rav was 98.4%. Where available, Rav is the standard of care for PNH, inhibiting terminal complement activation to prevent intravascular hemolysis (IVH) and thrombosis. Of pts with PNH treated with Rav/Ecu, 10-20% experience clinically significant extravascular hemolysis (cs-EVH). Efficacy and safety of the first-in-class oral factor D inhibitor danicopan (Dan; ALXN2040) as add-on treatment to Rav or Ecu for pts with PNH and cs-EVH were assessed in a phase 3, randomized, double-blind, placebo (Pbo)-controlled superiority clinical trial (ALPHA, NCT04469465). 12-wk data (double-blind treatment period [TP] 1) showing superiority of Dan vs Pbo on primary and key secondary endpoints were previously reported and represent the final analysis set for the trial. Open-label 24-wk (TP2) and ongoing long-term extension (LTE) data are presented. Methods Pts (≥18 y) with PNH and cs-EVH (hemoglobin [Hgb] ≤9.5 g/dL; absolute reticulocyte count [ARC] ≥120×10 9/L) on Rav/Ecu >6 mos were randomized double-blind 2:1 to Dan or Pbo add-on therapy for 12 wks (TP1). At wk 12, Pbo arm pts switched to Dan (Pbo-Dan) and Dan arm pts continued Dan (Dan-Dan) for another 12 wks (TP2), followed by a 1-y LTE in which all pts received Dan add-on therapy. The initial Dan dose of 150 mg 3 times daily (TID) could be escalated to 200 mg TID based on clinical response at investigator discretion. Primary endpoint was change from baseline (CFB) at wk 12 in Hgb. Other secondary endpoints: proportions of pts with Hgb increase ≥2 g/dL in absence of transfusion and with transfusion avoidance through wk 24; CFB in Hgb at wk 24; and CFB in ARC, lactate dehydrogenase (LDH), and C3 fragment deposition on PNH red blood cells at wks 12 and 24. Safety assessments included treatment-emergent adverse events (TEAEs) and laboratory abnormalities throughout the study. Results As of 20 September 2022, 86 pts were randomized; 60 completed TP2 (Dan n=40; Pbo n=20). Baseline characteristics were similar between arms ( Table). At wk 24 ( Fig), mean Hgb level was maintained in the Dan-Dan arm and increased from wk 12 in Pbo-Dan arm. ARC ( Fig) and other secondary endpoints were maintained in the Dan-Dan arm and improved in Pbo-Dan arm ( Table) at wk 24. The proportion of pts with Hgb increase of ≥2 g/dL in the absence of transfusion was maintained in the Dan-Dan arm and improved in the Pbo-Dan arm from wk 12 (Dan, 59.5%; Pbo, 0%) to wk 24 (Dan-Dan 46.3%; Pbo-Dan, 35.0%). Transfusion avoidance was maintained in the Dan-Dan arm and increased in Dan-Pbo arm from wk 12 (Dan, 83.3%; Pbo, 38.1%) to wk 24 (Dan-Dan 78.0%; Pbo-Dan, 90.0%). Mean LDH levels were maintained from wk 12 to 24 ( Table) and were near normal (<1.5×ULN) in both arms. Transfusions decreased in the Pbo-Dan arm from wk 12 (Pbo; mean [SD], 2.2 [2.3]) through 24 wks (Pbo-Dan; mean [SD], 0.1 [0.5]). The safety analysis included the n=80 pts exposed to Dan during the trial. At wk 24, study drug compliance was 98.8% (10.35) in the Dan-Dan arm and 98.3% (3.95) in Pbo-Dan arm. Escalation to 200 mg TID occurred for 41/57 (71.9%) pts in the Dan-Dan arm and 14/23 (60.9%) in Pbo-Dan arm. There were no deaths, meningococcal infections, or discontinuations due to hemolysis. Through data cut-off, 90% (72/80; 464 events) of pts had ≥1 TEAE after exposure to Dan. Serious AEs related to Dan were reported by 2 pts (gastrointestinal disorders/increased blood bilirubin; headache). 6 events in 4 pts led to withdrawal of study drug. 4 events were reported as breakthrough hemolysis (BTH) based on investigator discretion. Only 1 AE was associated with LDH >2×ULN (actual value 2.2×ULN) and potentially met the BTH definition used in other clinical studies. This AE was related to a complement-amplifying condition, COVID-19. This pt continued the study and BTH was resolved. Conclusions Danicopan as add-on to Rav or Ecu significantly improves Hgb and ARC levels and reduces the need for transfusion by addressing cs-EVH while maintaining control of IVH through 48 wks of treatment. Danicopan demonstrated a favorable benefit-risk profile with no deaths, meningococcal infections, or discontinuations due to hemolysis.

Electroconvulsive Therapy in Thrombocytopenic Patients: A Case Report and Literature Review

AbstractIntroductionElectroconvulsive therapy (ECT) continues to be one of the most effective treatments for severe and treatment-resistant major depression. Although there are no absolute contraindications to performing ECT, the risks and benefits need to be assessed in all patients. We present a patient with a history of paroxysmal nocturnal hemoglobinuria (PNH) with significant thrombocytopenia, who completed an index course of six ECT sessions without complication. Currently, there are only two published case reports which describe the use of ECT in patients with thrombocytopenia.MethodsAD is a 37-year-old female with a history significant for MDD, GAD, panic disorder, PNH, and Budd Chiari, who presented to ED for suicidal ideation. Initial labs showed pancytopenia (Hb 4.56 mg/dl, Absolute Neutrophil 0.7 x 103/mL). Given her history of multiple failed SSRIs, ECT was proposed to treat her depression. Anesthesia delayed her initial pre-operative assessment due to concerns regarding her platelet count and risk of bleeding. They recommended transfusion with a preprocedural platelet count goal of 50 x 103/mL. Psychiatry recommended a platelet goal of 20 x 103/mL given previous ECT literature. Patient underwent six ECT sessions without complications. Her platelets ranged from 24–40 x 103/mL and she did not require preprocedural platelet transfusion.ResultsDue to a lack of published literature, there are no formal guidelines for performing ECT in thrombocytopenic patients. The first case report details a 64-year-old female who underwent 12 ECT sessions without complication, while her platelet count ranged from 7–38 x 103/mL. The most recent case report describes a 74-year-old male who underwent nine ECT treatments without complications. The authors decided to transfuse prophylactically if pre-procedure platelet count was less than 20 x 103/mL. The patient underwent nine treatments, requiring eight transfusions. CT head did not show any signs of hemorrhage or structural changes. The authors remarked it is unclear whether the transfusions were necessary.ConclusionsEven though ECT has been in use for over 80 years, there is still much that is unknown about this treatment modality. This case highlights the lack of absolute contraindications to performing ECT. However, the lack of literature and studies regarding platelet goals in thrombocytopenic patients for ECT delayed patient care in this specific case. We add a third case report in a thrombocytopenic patient who underwent ECT without complications with a pre-procedure transfusion criterion if platelet count was less than 20 x 103/mL. More research needs to be conducted to determine risk and cut-off limits for platelet transfusion prior to performing ECT in thrombocytopenic patients.FundingNo funding

Coronary Artery By-Pass Grafting in Patient With Paroxysmal Nocturnal Hemoglobinuria (Case Report)

Paroxysmal nocturnal haemoglobinuria (PNH) is a clonal haematopoietic stem cell disease that presents with haemolytic anaemia, thrombosis and bone marrow failure. We report a case of a 51-year-old male with a history of PNH in treatment with Eculizumab admitted to our Hospital for acute chest pain and dyspnoea. The diagnosis was a triple vessel disease and patient was scheduled for coronary artery bypass grafting surgery. To balance the risk between thrombosis and bleeding in this particular clinical setting, we decided to use thromboelastography (TEG) as point of care solution and we used the R parameter as the target of our anticoagulant therapy. The R parameter between 11 and 14 sec can be used as a target value to balance the risk; in addition, there was no evidence of acute hemolysis during the surgery and supplemental dose of Eculizumab was administered in order to minimize any potential exacerbation of intravascular hemolysis.

Second-Generation C5 Inhibitors for Paroxysmal Nocturnal Hemoglobinuria.

The C5 targeting monoclonal antibody eculizumab has changed the natural history of paroxysmal nocturnal hemoglobinuria (PNH) in the last 10years. However, some unmet clinical needs persist, including persistent anemia with some patients requiring transfusions, incomplete C5 inhibition with breakthrough hemolysis (because of pharmacokinetic or pharmacodynamic issues such as infections, as well as conditions increasing complement activity), the underlying bone marrow failure, and the significant burden on patient quality of life (intravenous route of administration and frequency of infusions). Moreover, a subclass of patients carries C5 polymorphisms resistant to eculizumab inhibition. Several second-generation C5 inhibitors are under active study to overcome unmet clinical needs with eculizumab. Current strategies encompass increasing drug half-life, developing small molecule inhibitors of C5, and exploring new routes of administration (including subcutaneous and oral agents). In this review, we summarize available data on second-generation C5 inhibitors in PNH, including novel monoclonal antibodies, a small interfering RNA, and small molecules.

Meningococcal sepsis without cerebrospinal fluid abnormalities under treatment with eculizumab

Infections with Neisseriameningitidis are life-threatening conditions, generally presenting as meningitis. This case of ayoung woman who had a history of paroxysmal nocturnal hemoglobinuria under treatment with the complement inhibitor eculizumab had been presented with septic shock. While blood cultures were positive for Neisseria meningitidis, she showed no evidence for bacterial meningitis in the cerebrospinal fluid. This case shows that meningococcal sepsis without signs for bacterial meningitis despite repetitive vaccinations is possible in adults under eculizumab.

Diffuse Venous Thrombosis

A 29-year-old man presented with an 8-week history of lower extremity edema, neck vein distention, facial swelling, and headache. He had a 3-year history of paroxysmal nocturnal hemoglobinuria (PNH) managed with eculizumab. Computed tomography (CT) of the abdomen and pelvis revealed bilateral external iliac and common femoral venous occlusions with right-sided varicocele (Figure, A ). Computed tomography of the chest demonstrated bilateral obstruction of the internal jugular veins, innominate veins, superior vena cava (SVC), and collateralization (Figure, B). Magnetic resonance venography of the head showed thrombosis of the superior sagittal sinus associated with extensive collateralization within the scalp veins (Figure, C). Anticoagulation was started and angioplasty of the SVC was performed. Allogenic bone marrow transplantation was offered. Paroxysmal nocturnal hemoglobinuria is an acquired disorder affecting progenitor stem cells and thus all cell linages.1Devalet B. Mullier F. Chatelain B. Dogne J.M. Chatelain C. Pathophysiology, diagnosis, and treatment of paroxysmal nocturnal hemoglobinuria: a review.Eur J Haematol. 2015; 95: 190-198Crossref PubMed Scopus (68) Google Scholar A mutation of the PIGA gene results in a deficiency of the glycosyl phosphatidyl inositol anchor where CD55 and CD59 attach. This renders the PNH clonal cells prone to complement-mediated hemolysis with subsequent release of prothrombotic factors, nitric oxide depletion, and platelet activation leading to thrombosis, which is the leading cause of death.1Devalet B. Mullier F. Chatelain B. Dogne J.M. Chatelain C. Pathophysiology, diagnosis, and treatment of paroxysmal nocturnal hemoglobinuria: a review.Eur J Haematol. 2015; 95: 190-198Crossref PubMed Scopus (68) Google Scholar, 2Cornell L.F. Sacco K.A. Chirila R.M. 60-Year-old woman with headache and fatigue.Mayo Clin Proc. 2017; 92: e121-e125Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar, 3Hill A. Kelly R.J. Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria.Blood. 2013; 121 (quiz 5105): 4985-4996Crossref PubMed Scopus (292) Google Scholar Venous thromboses occur more often than arterial, and any site may be affected.4Brodsky R.A. Paroxysmal nocturnal hemoglobinuria.Blood. 2014; 124: 2804-2811Crossref PubMed Scopus (323) Google Scholar Because abdominal and cerebral veins are frequently involved, Budd-Chiari syndrome is the most common thrombotic event and superior sagittal sinus thrombosis the most common neurologic complication.3Hill A. Kelly R.J. Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria.Blood. 2013; 121 (quiz 5105): 4985-4996Crossref PubMed Scopus (292) Google Scholar, 4Brodsky R.A. Paroxysmal nocturnal hemoglobinuria.Blood. 2014; 124: 2804-2811Crossref PubMed Scopus (323) Google Scholar Anticoagulation and eculizumab are required, and thrombolysis or angioplasty may be used for life-threatening thromboses.1Devalet B. Mullier F. Chatelain B. Dogne J.M. Chatelain C. Pathophysiology, diagnosis, and treatment of paroxysmal nocturnal hemoglobinuria: a review.Eur J Haematol. 2015; 95: 190-198Crossref PubMed Scopus (68) Google Scholar, 3Hill A. Kelly R.J. Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria.Blood. 2013; 121 (quiz 5105): 4985-4996Crossref PubMed Scopus (292) Google Scholar Bone marrow transplantation is offered to patients who fail eculizumab, as in our case.2Cornell L.F. Sacco K.A. Chirila R.M. 60-Year-old woman with headache and fatigue.Mayo Clin Proc. 2017; 92: e121-e125Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar

Baseline characteristics and disease burden in patients in the International Paroxysmal Nocturnal Hemoglobinuria Registry.

Paroxysmal nocturnal hemoglobinuria is a rare, acquired disease associated with hemolytic anemia, bone marrow failure, thrombosis, and, frequently, poor quality of life. The International PNH Registry is a worldwide, observational, non-interventional study collecting safety, effectiveness, and quality-of-life data from patients with a confirmed paroxysmal nocturnal hemoglobinuria diagnosis or detectable paroxysmal nocturnal hemoglobinuria clone, irrespective of treatment. In addition to evaluating the long-term safety and effectiveness of eculizumab in a global population, the registry aims to improve diagnosis, optimize patient management and outcomes, and enhance the understanding of the natural history of paroxysmal nocturnal hemoglobinuria. Here we report the characteristics of the first 1610 patients enrolled. Median disease duration was 4.6 years. Median granulocyte paroxysmal nocturnal hemoglobinuria clone size was 68.1% (range 0.01-100%). Overall, 16% of patients had a history of thrombotic events and 14% a history of impaired renal function. Therapies included anticoagulation (31%), immunosuppression (19%), and eculizumab (25%). Frequently reported symptoms included fatigue (80%), dyspnea (64%), hemoglobinuria (62%), abdominal pain (44%), and chest pain (33%). Patients suffered from poor quality of life; 23% of patients had been hospitalized due to paroxysmal nocturnal hemoglobinuria-related complications and 17% stated that paroxysmal nocturnal hemoglobinuria was the reason they were not working or were working less. This international registry will provide an ongoing, valuable resource to further the clinical understanding of paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal haemoglobinuria, lupus and pregnancy

A 27-year-old patient, primigravida, with a 5-year history of paroxysmal nocturnal haemoglobinuria (PNH), visited the fetal medicine clinic at 12 weeks’ gestation. Her medical history reported pers...

Zoon’s balanitis with mucinous metaplasia: A case report and review of literature

Mucinous metaplasia of the squamous epithelium of the glans penis is very rarely seen in the setting of Zoon’s balanitis. We report a case of 40 year old male with a past medical history of paroxysmal nocturnal hemoglobinuria, status-post allogeneic hematopoietic cell transplantation from an HLA-matched sibling 6 years prior to evaluation, complicated by oral and cutaneous chronic graft-versus-host disease. Mucinous metaplasia was confirmed by PAS and Mucin stains, and plasmacytosis was confirmed by immunohistochemistry for CD138 and MUM1 markers. Kappa and Lambda immunostains revealed a polyclonal pattern. The etiology of zoon’s balanitis as well as the significance of mucinous metaplasia in these setting are unclear and need to be further investigated.

Thrombotic risk factors in Chinese Budd-Chiari syndrome patients

In Western countries, thrombotic risk factors for Budd-Chiari syndrome (BCS) are very common, including factor V Leiden mutation, prothrombin G20210A mutation, myeloproliferative neoplasms, paroxysmal nocturnal haemoglobinuria, etc. However, the data regarding thrombotic risk factors in Chinese BCS patients are extremely limited. An observational study was conducted to examine this issue. A total of 246 BCS patients who were consecutively admitted to our department between July 1999 and December 2011 were invited to be examined for thrombotic risk factors. Of these, 169 patients were enrolled. Neither factor V Leiden mutation nor prothrombin G20210A mutation was found in any of 136 patients tested. JAK2 V617F mutation was positive in four of 169 patients tested. Neither MPL W515L/K mutation nor JAK2 exon 12 mutation was found in any of 135 patients tested. Overt myeloproliferative neoplasms were diagnosed in five patients (polycythemia vera, n=3; essential thrombocythemia, n=1; idiopathic myelofibrosis, n=1). Two of them had positive JAK2 V617F mutation. Both CD55 and CD59 deficiencies were found in one of 166 patients tested. This patient had a previous history of paroxysmal nocturnal haemo-globinuria before BCS. Anticardiolipin IgG antibodies were positive or weakly positive in six of 166 patients tested. Hyperhomocysteinaemia was found in 64 of 128 patients tested. 5,10-methylenetetrahydrofolate reductase C677T mutation was found in 96 of 135 patients tested. In conclusion, factor V Leiden mutation, prothrombin G20210A mutation, myeloproliferative neoplasms, and paroxysmal nocturnal haemoglobinuria are very rare in Chinese BCS patients, suggesting that the etiological distribution of BCS might be different between Western countries and China.

An Unusual Case of a Hemolytic Crisis associated with the Initiation of an Aromatase Inhibitor in a Patient with Known History of Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare hemolytic disorder characterized by partial or complete absence of the glycosylphosphatidylinositol-anchored proteins (GPI-AP) on the cell membrane of erythrocytes, platelets, and granulocytes rendering them vulnerable to destruction by the complement system. Various medications can provoke hemolytic crises in PNH or healthy subjects. Aromatase inhibitors (AI), which have revolutionized breast cancer management, are not known to trigger hemolytic crises. We report on a case of a 70-year-old female with PNH who was also diagnosed with breast cancer. Following lumpectomy and adjuvant radiation therapy, she was started on an AI to decrease risk of breast cancer recurrence. A few weeks later, she developed malaise, insomnia, and gross hematuria. Diagnostic workup including flow cytometry revealed a hemolytic crisis related to her PNH. An exhaustive investigation to uncover a potential mechanism that may explain the relation between AI initiation and onset of hemolytic crisis was unrevealing.

Thrombotic complications in paroxysmal nocturnal haemoglobinuria: a literature review.

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, clonal haematopoietic stem cell disease caused by mutations in an X-linked gene called phosphatidylinositol glycan class A (PIG-A). The disease can present with bone marrow failure, haemolytic anaemia, smooth muscle dystonia and thrombosis. The PIG-A gene product is necessary for the first step in the biosynthesis of glycosylphosphatidyinositol (GPI) anchors - the transfer of GlcNAc from UDP-GlcNAc to form N-acetylglucosaminyl phosphatidylinositol (GlcNAc-PI) - where expansion and differentiation of the PIG-A mutant stem cell leads to clinical manifestations of the disease1. PNH may occur de novo (classical PNH) or in the setting of aplastic anaemia (hypoplastic PNH); the absence of GPI-linked complement regulatory proteins on PNH erythrocytes renders these cells susceptible to terminal complement-mediated haemolysis2. The natural history of PNH is highly variable, ranging from indolent to life-threatening. The median survival is 10 to 15 years, but the range is wide. Thrombosis is the leading cause of death, and an initial thrombotic event increases the relative risk of death by 5- to 10-fold in PNH3. Haemolysis most likely contributes to thromboembolism, as patients with larger PNH clones have a higher incidence of thromboembolism and events have been temporally associated with increased haemolysis. Although the mechanism is not fully understood, haemolysis has been implicated in the initiation of platelet activation and aggregation4. This review discusses the underlying mechanisms that lead to thrombosis in PNH and therapeutic approaches.

Paroxysmal nocturnal hemoglobinuria

The aim is to report on recent observations related to the natural history of paroxysmal nocturnal hemoglobinuria (PNH) and to review new therapeutic strategies for controlling the hemolysis of PNH. This review focuses on studies designed to characterize the long-term outcome of patients with PNH treated with eculizumab and to define the relationship between PNH and bone marrow failure syndromes. New therapeutic strategies aimed at controlling extravascular as well as intravascular hemolysis are also examined. Long-term safety and efficacy of eculizumab was observed in a large group of patients. Survival for the group was not different from that of a sex-matched and age-matched control group from the general population. Thrombotic complications were rare and deaths due to PNH or complications of therapy were not observed. These studies suggest that patients with clinical PNH who are treated with eculizumab have a benign clinical course. Patients with bone marrow failure who have PNH cells detected by high-sensitivity flow cytometry have aplastic anemia or low-risk myelodysplastic syndrome. For patients with a percentage of PNH cells that is below the threshold for producing laboratory evidence of hemolysis (subclinical PNH), expansion of the clone to a size sufficient to produce clinical PNH is not observed. Approximately 50% of patients with bone marrow failure who have clinical evidence of PNH at presentation will require PNH-specific therapy. Novel reagents that target the alternative pathway of complement C3 convertase are being developed with a goal of inhibiting both the extravascular and the intravascular hemolysis of PNH.

Natural history of paroxysmal nocturnal hemoglobinuria clones in patients presenting as aplastic anemia

To investigate the natural history of paroxysmal nocturnal hemoglobinuria (PNH) clones in patients with acquired aplastic anemia (AA). Twenty-seven patients with AA and a detectable PNH clone were monitored for a median of 5.7 years (range 1.5-11.5 years). Twenty-two patients received high-dose cyclophosphamide (HiCy) therapy. The erythrocyte and granulocyte PNH clone sizes were measured using flow cytometry and analyzed via CellQuest software. PE-conjugated anti-glycophorin A, anti-CD15, FITC-conjugated anti-CD59, and FLAER staining were used to define glycosylphosphatidylinositol-AP-deficient cells. We found a linear relationship between PNH clone size and the development of intravascular hemolysis, assessed by lactate dehydrogenase (LDH) values (Pearson correlation coefficient = 0.80, P < 0.001 for erythrocyte PNH clones; and Pearson correlation coefficient = 0.73, P < 0.0001 for granulocyte PNH clones). An erythrocyte PNH size of 3-5% and granulocyte PNH size of 23% were the thresholds to predict hemolysis as measured by an elevated LDH (receiver operating characteristic analyses with AUC = 0.96 for erythrocyte PNH clone sizes and AUC = 0.88 for granulocyte PNH clone sizes). Patients with small (≤15%) initial PNH clone sizes were less likely to develop an elevated LDH (mean ± SD: 236.9 ± 109.9 vs. 423.1 ± 248.8; P = 0.02). Over time, the PNH clone sizes remained stable in 25.9% of patients; 48.1% experienced a rise in the PNH clone size; and 25.9% experienced a decrease. The risk of developing clinically significant PNH after HiCy therapy appears to be low in AA patients with PNH clones, especially for those with small initial PNH clones and for those who respond to HiCy therapy.

Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories

AbstractThe natural history of paroxysmal nocturnal hemoglobinuria (PNH) clinical subcategories (classic PNH and aplastic anemia [AA]/PNH syndrome) is still unknown. We retrospectively studied 460 PNH patients diagnosed in 58 French hematologic centers from 1950 to 2005. The median (SE) follow-up time was 6.8 (0.5) years. The median survival time (SE) was 22 (2.5) years. We identified 113 patients with classic PNH, 224 patients with AA-PNH syndrome, and 93 (22%) intermediate patients who did not fit within these 2 categories. At presentation, classic PNH patients were older, with more frequent abdominal pain and displayed higher levels of GPI-AP–deficient granulocytes. A time-dependent improved survival was observed. In classic PNH, diagnoses before 1986 (hazard ratio [HR]: 3.6; P = .01) and increasing age (P < .001) were associated with worse survival prognoses, whereas use of androgens within the first year after diagnosis was protective (HR, 0.17; P = .01). Transfusions before 1996 (HR, 2.7; P = .007) led to lower survival rates in patients with AA-PNH syndrome, whereas immunosuppressive treatment was associated with better outcomes (HR, 0.33; P = .03). Evolution to thrombosis affected survival in both subcategories (classic PNH: HR, 7.8 [P < .001]; AA-PNH syndrome: HR, 33.0 [P < .001]). Evolution to bicytopenia or pancytopenia for classic PNH (HR, 7.3, P < .001) and malignancies for AA-PNH syndrome (HR, 48.8; P < .001) were associated with worse outcomes. Although clinical presenta-tion and prognosis factors are different, classic PNH and AA-PNH syndrome present roughly similar outcomes, affected mainly by complications.

Paroxysmal Nocturnal Hemoglobinuria: An Historical Overview

The clinical hallmark of paroxysmal nocturnal hemoglobinuria (PNH) is episodic hemoglobinuria, and it was this feature that captured the attention of European physicians in the latter half of the 19th century, resulting in careful observational studies that established PNH as an entity distinct from paroxysmal cold hemoglobinuria and march hemoglobinuria. Curiosity about the etiology of the nocturnal aspects of the hemoglobinuria led the German physician Paul Strübing to develop the prescient hypothesis that the erythrocytes of PNH are abnormally sensitive to hemolysis when the plasma is acidified during sleep because of accumulation of carbon dioxide and lactic acid as a result of slowing of the circulation. Investigation of the intricate pathophysiology that underlies the abnormal sensitivity of PNH erythrocytes to hemolysis in acidified serum produced a number of remarkable scientific achievements that involved discovery of the alternative pathway of complement, identification of the membrane proteins that regulate complement, discovery of a novel mechanism for attachment of proteins to the cell surface, and identification of the genetic basis of the disease. These discoveries were made steadily over a period of more than 100 years, and each generation of physicians and scientists made important contributions to the field. The mysteries of PNH have been solved in a particularly satisfying way because the precision and orderliness of the solutions made clearly understandable what had seemed at the times prior to resolution to be problems of nearly insurmountable complexity. The history of PNH is an inspirational reminder of the elegant complexity of nature, the rewards of curiosity and the power and beauty of science.

Purpura fulminans in paroxysmal nocturnal haemoglobinuria

A 29-year-old woman with a 1-year history of paroxysmal nocturnal haemoglobinuria (PNH) presented to our accident and emergency department with pyrexia, a swollen left knee and small non-blanching purpuric lesions on her torso (top left). Blood cultures and knee aspiration were performed. She was commenced on flucloxacillin and gentamicin because of suspected staphylococcus infection. All cultures were negative. This may have been because she had been prescribed oral amoxicillin and metronidazole for her swollen knee the previous day. No blood cultures had been taken. Her rash continued to progress after admission; she continued to be pyrexial and unwell, despite the addition of imipenem, liposomal amphotericin and aciclovir. She was reviewed by a dermatologist and was commenced on prednisolone 1 mg/kg as a vasculitic process was suspected. Skin biopsies were taken, which showed skin necrosis, thrombosis and infarction without evidence of vasculitis (bottom). A diagnosis of purpura fulminans was made. She was commenced on recombinant activated protein C and full dose low molecular weight heparin. The lesions dramatically improved as shown by the second clinical picture, taken 48 h after the first (top right). She was continued on protein C for 7 d then fully anticoagulated with warfarin. The lesions completely resolved without scarring. She remained extremely prothrombotic over the next 12 months, developing multiple thrombi in hepatic vein and an axillary vein and infarcting her small bowel despite anti-coagulation. Her parents had normal thrombophilia screens. We conclude that she had purpura fulminans secondary to PNH causing a prothrombotic tendency.

Successful Treatment of Hemolysis and Severe Anemia without Transfusion in a Jehovah's Witness PNH Patient with the Terminal Complement Inhibitor Eculizumab.

In hemolytic paroxysmal nocturnal hemoglobinuria (PNH) patients, hemoglobin levels are typically maintained by transfusions, without which severe anemia can occur. The terminal complement inhibitor eculizumab was previously shown to effectively control intravascular hemolysis and the need for transfusions in PNH patients. We now report on compassionate use of eculizumab in a severely anemic Jehovah's Witness PNH patient. RF is a 61 year old Hispanic woman with a 10 year history of PNH and s/p nephrectomy. In Jan 2004 she was hospitalized for a severe hemolytic paroxysm with jaundice, weakness, lower abdominal pain, vomiting, hemoglobinuria, LDH of 15,000 IU/L, hemoglobin (Hgb) of 5–6 g/dL, and 40–50,000/mm3 platelets. Flow cytometry showed 41% RBC and 70% granulocyte PNH clone sizes. To her prednisone (80 mg qd), Procrit 40,000 U thrice per week and coumadin 2.5 mg qd were added. In Feb, she improved somewhat after high dose IVIG but remained icteric and had a bed-chair existence. In mid-March, her Hgb was 5.1 g/dL, LDH 5000 IU/L, and haptoglobin <26 mg/dL. Walking 5–10 feet resulted in shortness of breath and tachycardia. From Apr through Oct she generally stabilized with chronic fatigue, a bed-chair existence, LDH in the 3–4000's IU/L, and 80–100,000 platelets/mm3; prednisone was now 20 mg qd. Her Hgb decreased from 5–7 g/dL through mid Jul, to 4–6 g/dL through Oct. She then worsened during a febrile illness: Hgb dropped to 3.6 g/dL. An investigator sponsored IND was granted by the FDA and the local Institutional Review Board approved the single patient open label trial; the patient was consented for use of eculizumab. Eculizumab therapy (600 mg/week for four weeks, then 900 mg on week 5 and every other week thereafter) was initiated on Nov 2 at which time she had severe hemoglobinuria, Hgb of 4.1 g/dL, LDH of 4326 IU/L, haptoglobin of <26 mg/dL and reticulocyte count of 250,000; she was bed-wheel chair bound, using supplemental O2. One week after the first dose, she noted clear urine, her Hgb rose almost 2 g to 5.4 g/dL, LDH dropped to 1019 IU/L, haptoglobin increased to 46 mg/dL, and she was no longer icteric. She was now able to walk short distances. At two weeks her LDH was 473 IU/L. Within a month was able to walk several blocks without difficulty. After 6 weeks of eculizumab therapy, her Hgb had risen to 9.3 g/dL and her LDH was in the normal range. Flow cytometry in Jan 2005 showed a 95% PNH RBC clone size. Her Procrit was converted to Aranesp. From Jan to early Mar her Hgb ranged from 8.1 to 9.1 g/dL with LDH remaining in the normal range; in Mar her Hgb dropped to 6.5 g/dL but without hemoglobinuria or intravascular hemolysis (LDH remained < 250 IU/L), and PNH RBC clone size was 90%. There was no evidence of GI blood loss. Though fatigued, she was still able to perform her normal daily routines. In Apr she was hospitalized with a Klebsiella UTI with a Hgb of 3.7 g/dL, but recovered to 6.6–8.0 g/dL after the resolution of the infection and initiation of IV iron supplementation. Currently, she is on Aranesp 300 mcg q2wk, prednisone 15 mg qd, oral and IV iron, folate, and 900 mg eculizumab q2wk. Her LDH is normal and Hgb is 8 g/dL. She has no hemoglobinuria, feels well, performs her daily routines and is “leading a normal life”. This case report demonstrates that intravascular hemolysis can cause severe anemia in PNH, and that eculizumab can rapidly improve Hgb through resolution of hemolysis and protection of the PNH RBC clone.

Correction of aplastic anaemia complicating paroxysmal nocturnal haemoglobinuria: absence of eradication of the PNH clone and dependence of response on cyclosporin A administration

Paroxysmal nocturnal haemoglobinuria (PNH) is defined as a somatic mutation of a clonal population of stem cells. Consequently, when aplastic anaemia (AA) occurs in patients with a history of PNH, allogeneic bone marrow transplantation is considered as the only effective treatment. The impact of immunosuppressive therapy has not been reported in this situation. We present observations of three PNH patients who developed AA and were effectively treated with cyclosporin A (CSA). Because of lack of improvement with other treatments, CSA alone was given at a dose of 5-10mg/kg/d. Complete response (CR) was obtained in two patients after 6 and 24 months respectively. A partial response (PR) was observed in the third patient after 12 months. Transient elevated LDH and haemosiderinuria persisted in all cases. DAF and MIRL deficiency were still documented in the two patients in CR. Two patients (one CR, one PR) ceased CSA therapy after 12 months and relapsed within 3-6 months. CSA was reinitiated and led to platelet recovery in one patient after 6 months. The persistence of the abnormal PNH clone is coherent with the hypothesis that CSA does not act directly on the PNH clone but probably acts through regulation of the inhibitory effects of immunocompetent cells on haemopoiesis. These observations suggest that patients suffering from severe AA complicated PNH should not be excluded from immunosuppressive therapy.

Deficiency of complement decay-accelerating factor (DAF, CD55) in non-Hodgkin's lymphoma

We have assessed levels of surface-expressed complement regulatory proteins, decay-accelerating factor (DAF) and membrane cofactor protein (MCP) on cells from patients with hematological malignancies. Neither malignant cells nor unaffected nucleated blood cells from the patients lacked MCP. On the other hand, complete deficiency of DAF was found in 2/10 of non-Hodgkin's lymphoma (NHL), while none of the 38 patients with acute nonlymphocytic leukemia (ANLL) (14 cases), chronic myelogenous leukemia (CML) (6 cases), acute lymphocytic leukemia (ALL) (12 cases) and chronic lymphocytic leukemia (CLL) (6 cases) lacked DAF. The two patients with DAF-negative NHL had no history of paroxysmal nocturnal hemoglobinuria (PNH), and their peripheral blood cells were DAF-positive. One DAF-negative NHL exhibited T cell markers and the other those of B cell. In both cases, treatment of the DAF-negative lymphoma cells with antibody against MCP (M177) followed by Mg(2+)-EGTA-serum resulted in efficient deposition of homologous C3. These results infer that some NHL specifically lack DAF and, through treatment with M177, are targeted by homologous C3.