Manifestations Of Paroxysmal Nocturnal Hemoglobinuria Research Articles

Hemosiderin induced acute kidney injury requiring hemodialysis in patients with paroxysmal nocturnal hemoglobinuria: A case report.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematopoietic stem cell disease with features of hemolytic anemia, thrombosis, and bone marrow failure. Due to intravascular hemolysis and hemoglobinuria, renal dysfunction is often accompanied in PNH patients. A 25-year old woman presenting gross hematuria after coronavirus disease 2019 infection was admitted to our medical center. She had mild nausea and headache. She was diagnosed with iron deficiency anemia few years ago and had no other underlying disease. Her laboratory findings showed acute kidney injury (AKI) and severe anemia, with evidences of hemolysis. Renal biopsy was done to determine the cause of renal failure and the result was acute tubular necrosis with deposition of golden pigments, hemosiderin. With pathologic result and laboratory finding of hemolysis, we did flow cytometry for PNH, and the patient was finally diagnosed with PNH. With AKI and oliguria, the patient started to take hemodialysis. After taking 5 sessions of hemodialysis, the patient's renal function was recovered from AKI. With diagnosis of PNH, the patient is now being treated with complement C5 inhibitor. This challenging case tells us that we should consider the first manifestation of PNH as a cause of severe AKI requiring hemodialysis in a patient with anemia and evidence of hemolysis.

92 Acute Renal Failure as First Manifestation of Paroxysmal Nocturnal Hemoglobinuria: A Case Report

92 Acute Renal Failure as First Manifestation of Paroxysmal Nocturnal Hemoglobinuria: A Case Report

Improvement of Renal Function by Long-Term Sustained Eculizumab Treatment in a Patient with Paroxysmal Nocturnal Hemoglobinuria.

Chronic kidney disease (CKD) is one of the major manifestations of paroxysmal nocturnal hemoglobinuria (PNH). CKD in PNH is induced mainly by intravascular hemolysis of PNH-affected red blood cells (RBC) missing the glycosylphosphatidylinositol-anchored proteins with complement-regulatory activities, CD55 and CD59. CKD develops by heme absorption in the proximal tubules resulting in the interstitial deposition of iron in the kidneys. We administered eculizumab to a patient with PNH, who was one of 29 patients enrolled in the AEGIS clinical trial, an open-label study of eculizumab in Japan. The patient was complicated by stage 3 CKD with impaired estimated glomerular filtration rate (eGFR), at grade G3b, and had obvious proteinuria (2-3+, 1-2 g/day). In a two-year extension to the 12-week AEGIS study, eGFR improved significantly, and the eGFR has since been maintained at grade G2 without proteinuria by sustained eculizumab treatment (>6 years). Renal function improved and maintained by long-term sustained eculizumab treatment, presumably by clearance of iron from the kidney as well as inhibition of the production of anaphylatoxin C5a, even in advanced stages of CKD, is one of the benefits of eculizumab treatment in PNH.

Ineffective Corticosteroid Treatment for Hemolysis Management of Paroxysmal Nocturnal Hemoglobinuria

Background: The primary clinical manifestations of paroxysmal nocturnal hemoglobinuria (PNH) are hemolytic anemia, bone marrow failure (BMF), and thromboembolism (TE). For optimum management, the contribution of both hemolysis and BMF to the complex anemia of PNH should be determined. The treatment of a hemolytic episode should aim at diminishing hemolysis and preventing complications. Corticosteroids as treatment, for both chronic hemolysis and acute hemolytic exacerbations have been used with a variety of side effects of long term use. In the Korean PNH population, corticosteroid (77.4%) represented the most common supportive care which provided with patients who had a history of corticosteroid use during the disease course (Lee JW et al. IJH. 2013 Jun; 97:749-57). There are no experimental data that provide a plausible explanation for why steroids should ameliorate the hemolysis of PNH.Aims: To evaluate the role of corticosteroid for treating chronic hemolysis in patients with PNH enrolled in the Korean prospective PNH registry.Methods: Korean patients with a diagnosis of PNH are eligible for inclusion in the prospective registry study designed to identify disease burden of PNH. Patient medical information data and other laboratory parameters were collected at the last 6 month follow-up.Here we analyzed patients with corticosteroid use within the past 6 months. 97 patients who were followed up at least 6 months after study enrollment was categorized into two groups. Patients have received eculizumab treatment or bone marrow transplantation (BMT) during the last 6month of follow up was excluded.Results: Among the 97 patients, 23% (22 patients) had corticosteroid therapy in the past 6 months. Mean age was 46 years (range 20-87; standard deviation, 16.3) and 51 patients (53 %) were female. At the time of analysis, 74 of 97 patients had recorded lactate dehydrogenase (LDH) levels. The mean LDH at 6months follow up after enrollment was 4.75-fold above the upper limit of normal (ULN) of the patients with corticosteroid use and 4.16-fold above ULN was reported in patients without corticosteroid use for the past 6 months (p=0.446). Hemolysis (LDH≥1.5 x ULN) was reported in 86% of patients with corticosteroid use and 77% of patients without corticosteroid use; there was no statistically significant difference between these two patient populations (p=0.420). The mean granulocyte clone size at enrollment in patients with corticosteroid use was 50.7% (range 1-98) and patients without corticosteroid use reported 52.3% (range 1-99) (p=0.850). The mean reticulocyte percent between two groups was 4.87% and 4.0%, respectively (p=0.317). Red blood cell was transfused to 15 (68.1%) of the 22 patients with corticosteroid use and 23 (30.7.%) of patients without corticosteroid use during the last 6 month follow-up; there was a significant difference between the two groups for mean unit of transfusion (p=0.005) (Table1). There was no new thromboembolism event reported during the past 6 months. Each group experienced abdominal pain and dyspnea during the last 6 months of follow up: patients with corticosteroid use vs. patients without corticosteroid use (p=0.121 and p= 0.055, respectively) (Table1).Conclusions: In the past, the main value of corticosteroids may have been to treat chronic hemolysis although it is limited by toxicity and the harm that can accrue from long term use. However, our results demonstrated that the management of hemolysis of PNH with corticosteroid could be ineffective and unsatisfactory. These data confirm that PNH patients with corticosteroid had ineffective hemolysis management (LDH ≥1.5 x ULN) and also suffer from disabling clinical signs and symptoms, such as continuous transfusion requirement with anemia, abdominal pain and dyspnea. Awareness of the potentially debilitating effects of corticosteroid myopathy and sensitivity to the disfiguring consequences of long term use are essential for proper management and also careful follow-up should be recommended.[Table 1]Total (N=97)Patients with corticosteroid use (n=22)Patients without corticosteroid use (n=75)p -valueLDH fold above ULN (n=74), Mean (SD) Hemolysis (LDH ≥ 1.5xULN), n (%)4.75 fold (3.02) 18/21 (85.7)4.16 fold (2.89) 41/53 (77.4)0.446 0.420Transfusion (n=38), Mean unit (SD)6.1 (9.43)2.0 (3.99)0.005Abdominal pain (n=16) , n (%)6/22 (27.3)10/75 (11.2)0.121Dyspnea (n=11) , n (%)5/22 (22.7)6/75 (8.0)0.055 DisclosuresLee:Alexion Pharmaceuticals: Consultancy. Jang:Alexion Pharmaceuticals: Consultancy. Lee:Alexion Pharmaceuticals: Consultancy. Jo:Alexion Pharmaceuticals: Consultancy. Kim:Alexion Pharmaceuticals: Consultancy.

Transient appearance of GPI-deficient population in a patient with azathioprine-associated bone marrow aplasia

Dear Editor, Blood cells with glycosylphosphatidylinositol (GPI) deficiency are occasionally seen in bone marrow failure syndromes such as aplastic anemia [1–5]; they tend to persist for long time and may or may not be associated with clinical or laboratory evidence of hemolysis or other manifestations of paroxysmal nocturnal hemoglobinuria (PNH). We describe the first case of transient appearance of GPIdeficient population in a patient during azathioprineinduced marrow aplasia. The size of GPI-deficient population was large (67 %), but disappeared upon the marrow regeneration following discontinuation of the drug. An 8-year-old boy with active Crohn’s disease presented with fever and neutropenia. There was no discoloration of urine and there were no signs of clinically relevant intravascular hemolysis. His presentation followed a 3-month exposure to increasing doses of azathioprine from 12.5 to 50 mg/day with monitoring of blood counts, transaminase levels, and serum 6-thioguanine nucleotide metabolite (TGN) level. Laboratory investigations showed (Table 1) a total leukocyte count of 0.8×10/L, neutrophils of 0.43×10/L, hemoglobin of 88 g/L, platelet count of 131×10/L, and reticulocyte count of 3×10/L. The blood film did not show any blasts or features of dysplasia, megaloblastic state, or hemolysis. Serum LDH, cobalamin, and RBC folate levels were normal. Blood, urine, and stool cultures and serologic tests for hepatitis A, B, C, HIV, CMV, Parvovirus B19, and EBVwere negative. A repeat TGN level on azathioprine 50 mg daily was 327 pmole/8×10. Red blood cell level of 6-methyl mercaptopurine ribonucleotide metabolite was 807 pmole/8×10 RBC. A bone marrow aspirate and biopsy showed aplasia with cellularity of 5 %. Sugar water test was positive. Flow cytometric testing of blood for PNH at admission and a week later showed partial absence of CD55, 59, and fluorescent aerolysin (FLAER) on granulocytes, and of CD59 on RBCs. The size of the GPI-deficient clone was 67% by FLAER analysis of neutrophils (Fig. 1). The child was rehydrated and given antimicrobials and steroids. Azathioprine was discontinued. His clinical condition and blood counts recovered within 3 weeks. Repeat flow cytometric testing for PNH at 6 months showed complete disappearance of the GPIdeficient population. The patient was subsequently managed for Crohn’s disease with methotrexate, followed by infliximab and then adalimumab. He eventually underwent subtotal colectomy and end ileostomy and has remained well since then. Transient bone marrow aplasia caused by azathioprine exposure in patients with 6-thiopurine methyl transferase deficiency has been reported [6]; our patient showed partial deficiency of 6A. Z. Al Riyami : B. I. Dalal (*) Division of Laboratory Hematology, Vancouver General Hospital, Suite JPPN 1557, 910, 10th Avenue West, Vancouver BC V5Z 4E3, Canada e-mail: bakul.dalal@vch.ca

Quiz Page February 2012: Acute Kidney Injury in an Adolescent With a Family History of Autoimmune Disorders

Quiz Page February 2012: Acute Kidney Injury in an Adolescent With a Family History of Autoimmune Disorders

Budd-Chiari syndrome in a paroxysmal nocturnal hemoglobinuria patient with previous cerebral venous thrombosis

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal stem cell disorder characterized by intravascular hemolytic anemia that results from the clonal expansion of hematopoietic stem cells harboring somatic mutations in an X-linked gene, termed PIG-A (phosphatidylinositol glycan class A). PIG-A mutations block glycosylphosphatidylinositol (GPI) anchor biosynthesis, resulting in a deficiency or absence of all GPI-anchored proteins on the cell surface. CD55 and CD59 are GPI-anchored complement regulatory proteins. Their absence on PNH red cells is responsible for the complement-mediated intravascular hemolysis, leading to the release of free hemoglobin, which contributes to many of the clinical manifestations of PNH including fatigue, pain, esophageal spasm and possibly serious thrombotic episodes [1]. Allogeneic hematopoietic stem cell transplantation is the only curative therapy for PNH. The complement inhibitor eculizumab, a humanized monoclonal antibody against C5, that inhibits terminal complement activation, recently approved in the US, has been shown to reduce hemolysis, decrease the erythrocyte transfusion requirements and the risk for thrombosis, and to improve quality of life of PNH patients [2, 3]. Major morbidity and mortality with PNH are often ascribed to the development of venous thromboembolism (VTE) [1–6], and several patients have recurrent thromboses [7]. VTE in PNH patients occur mostly at unusual sites. Data from a recent review report hepatic vein thrombosis, leading to Budd-Chiari syndrome (BCS), as the most frequent (40.7%) thrombotic complication, accounting for the majority of deaths [8], followed by cerebral vein and sinus thromboses, superior sagittal sinus being the most frequently involved site [8]. Inherited thrombophilia may increase the risk of serious thromboembolic events in PNH patients [9]. In patients experiencing VTE, early anti-thrombotic therapy (heparin, thrombolysis) aimed to limit the extension of thrombosis, or to dissolve formed thrombi, should improve the prognosis of this severe complication. PNH patients suffering from VTE should be treated with anticoagulant drugs indefinitely [1]. Thrombocytopenia often complicates PNH, and this issue must be addressed when an anticoagulation management plan is formulated [1]. Recurrent, life-threatening thrombosis merits consideration for bone marrow transplantation (BMT) [1]. Over the past few years significant advances in other therapeutic approaches, such as transjugular intrahepatic portosystemic shunt (TIPS), have contributed to the improvement of survival in this setting [8]. We report the case of a 29-year-old woman, R. D. The family history was negative for VTE and cardiovascular disease. She was a non-smoker. And had been slightly overweight since childhood. When she was 19 years old, an isolated moderate thrombocytopaenia (50,000/mmc) was detected although in the absence of bleeding. As idiopathic thrombocytopaenia was diagnosed, she was treated with long-term steroids, with an improvement in the platelet count (120,000/mmc). At the age of 27, while on oral contraceptives for 3 months, she experienced a sudden occurrence of headache and visual loss, followed by seizures and coma. A computed tomography (CT scan) showed multiple cerebral venous thromboses. Screenings A. Tufano (&) N. Macarone Palmieri E. Cimino A. M. Cerbone Regional Reference Centre for Coagulation Disorders, Department of Clinical and Experimental Medicine, Federico II University of Naples, Via S. Pansini, 5, 80131 Naples, Italy e-mail: atufano@unina.it

Coagulation in the Pathophysiology of Hemolytic Anemias

Coagulation abnormalities are frequently reported in hemolytic anemias (HA). Several pathophysiologic mechanisms are common to different HA. In this review three different hemolytic disorders will be discussed. In sickle cell disease and in beta-thalassemia, a thrombophilic status has been well documented as multifactorial involving hemostatic changes and activation of the coagulation cascade. Moreover, in such disorders, elevated levels of endothelial adhesion protein (ICAM-1, ELAM-1, VCAM-1, von Willebrand factor, and thrombomodulin) are often increased, suggesting that endothelial activation may be involved in vascular occlusion. As an additional mechanism of hypercoagulability in thalassemia, a procoagulant status of thalassemic red cells was recognized. The main clinical manifestation of paroxysmal nocturnal hemoglobinuria (PNH) is HA, and the most common complications are thrombosis, pancytopenia, and myelodysplastic syndrome or acute leukemia. The intravascular hemolysis is explained by a deficiency of glycosil phosphatidylinositol (GPI)-anchored complement regulatory proteins such as CD59 and CD55 on the membrane of red blood cells (RBCs), but the mechanism responsible for the increased incidence of thrombotic events in PNH remains unclear. Recent advances have been made in understanding the coagulation involvement in a heterogeneous group of diseases, thrombotic microangiopathies (TMA) characterized by microangiopathic hemolytic anemia and thrombocytopenia due to platelet clumping in the microcirculation, leading to ischemic organ dysfunction with neurologic symptoms and renal impairment.

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.

Identification of a Novel Hematopoietic Cell Translocation in a Patient with Paroxysmal Nocturnal Hemoglobinuria (PNH).

PNH is an acquired disorder of clonal hematopoiesis, in which the affected hematopoietic stem cells (HSC’s) have a mutation of the X-linked PIG-A gene. PIG-A is required for synthesis of the glycosylphosphatidyl inositol (GPI) moiety that serves as an anchor for a functionally diverse group of membrane proteins. Consequently all GPI-anchored proteins are deficient on progeny of affected HSC’s. GPI-anchor protein deficiency clearly accounts for some of the clinical manifestations of PNH but does not explain either clonal selection or clonal expansion. Further, it is not clear if clonal selection and clonal expansion are independent processes. Observations reported herein suggest that clonal selection and clonal expansion are part of the same process and that PNH is an example of non-malignant clonal evolution. A 31 y/o female presented with complaints of fatigue, fever, numbness in the lower extremity and dark urine. CBC revealed a WBC of 4100/μl, hemoglobin 3.8 gram%, hematocrit of 12.9% and platelet count of 171,000/μl. Laboratory studies were indicative of intravascular hemolysis, and subsequent flow cytometric analysis of the peripheral blood showed that 88% of the PMN were GPI-anchor protein deficient. Bone marrow biopsy showed a normocellular marrow with a relative erythrocytosis but with no evidence of dysplasia. Cytogenetic studies of the bone marrow demonstrated 46XX, ins (12) (p12~13q13q12) in all 20 metaphase cells analyzed. The findings were that of a female with an apparently balanced intrachromosomal inverted insertion at the 400 band level. FISH probes supported the conventional cytogenetics and indicated that the insertion split the TEL locus at 12p13. Subsequent analysis of mitogen stimulated peripheral blood lymphocytes revealed a normal karyotype. These finding show that the rearrangement of chromosome 12 identified in the bone marrow cells is an acquired cytogenetic abnormality and suggest a causal relationship with PNH in this case. TEL, a member of the ETS family of transcription factors is a fusion partner in a number of translocation that result in hematopoietic cell malignancies (e. g., ALL, AML, MDS). While the rearrangement described herein appear to be novel, deletions of 12p12 have been observed in other patients with PNH, and a structural rearrangement of 12q13 (one of the three breakpoints in the insertion in this case) has also been reported in a patient with PNH. Together, these findings suggest the following: (1) non-random cytogenetic abnormalities may be associated with PNH; (2) PNH may be an example of non-malignant clonal evolution in which the PIG-A mutation contributes directly to clonal expansion (in this specific case by acting in concert with a non-transforming proliferative advantage arising from the rearrangement involving TEL); (3) clonal selection and clonal dominance may not be independent process in PNH. Studies designed to characterize the consequences of the structural rearrangement of chromosome 12 in this case are in progress.

Clinical Manifestations of Paroxysmal Nocturnal Hemoglobinuria: Present State and Future Problems

The clinical pathology of paroxysmal nocturnal hemoglobinuria (PNH) involves 3 complications: hemolytic anemia, thrombosis, and hematopoietic deficiency. The first 2 are clearly the result of the cellular defect in PNH, the lack of proteins anchored to the membrane by the glycosylphosphatidylinositol anchor. The hemolytic anemia results in syndromes primarily related to the fact that the hemolysis is extracellular. Thrombosis is most significant in veins within the abdomen, although a number of other thrombotic syndromes have been described. The hematopoietic deficiency may be the same as that in aplastic anemia, a closely related disorder, and may not be due to the primary biochemical defect. The relationship to aplastic anemia suggests a nomenclature that emphasizes the predominant clinical manifestations in a patient. This relationship does not explain cases that appear to be related to myelodysplastic syndromes or the transition of some cases of PNH to leukemia. Treatment, except for bone marrow transplantation, remains noncurative and in need of improvement.

Genetic and environmental effects in paroxysmal nocturnal hemoglobinuria: this little PIG-A goes “Why? Why? Why?”

Genetic and environmental effects in paroxysmal nocturnal hemoglobinuria: this little PIG-A goes “Why? Why? Why?”

Urologic Manifestations of Paroxysmal Nocturnal Hemoglobinuria

A long-term study of 17 patients with paroxysmal nocturnal hemoglobinuria revealed an unexpectedly high incidence of functional and anatomic renal abnormalities. All patients demonstrated varying degrees of hematuria and proteinuria distinct from hemoglobinuria. All patients also had granular casts in multiple urinalyses. Evaluation of renal function revealed hyposthenuria, abnormal tubular function and declining creatinine clearance. Radiologically, one or more of these demonstrated enlarged kidneys, renal cortical infarcts and thinning, papillary necrosis, acute renal atrophy, retroperitoneal hematoma and ureteral infarction, which were confirmed by autopsy studies. Hypertension developed in 7 patients. Urinary tract infection was uncommon and no patient had a clinical history compatible with chronic or acute pyelonephritis. Contrary to usual opinion our studies clearly showed evidence of frequent and widespread renal pathology in paroxysmal nocturnal hemoglobinuria most likely due to repeated microvascular thromboses similar to the venous thrombosis involving other organs in this disorder. Since most of these patients present initially to urologists knowledge of this entity is mandatory.