PURPOSE:

To report on isolated central retinal artery occlusion (CRAO) as an initial presentation in two patients with undiagnosed paroxysmal nocturnal hemoglobinuria (PNH).

METHODS:

CRAO related to the aggravation of PNH was observed in 2 of 98 consecutive PNH patients for 10 years. Ocular and systemic manifestations were evaluated before and after systemic steroid, eculizumab and anticoagulant administration with adjuvant ocular treatments.

RESULTS:

Two young patients presented with complaints of acute painless monocular vision loss. In both cases, fundus examination revealed retinal edema and a cherry-red spot in the macula, consistent with CRAO. On systemic evaluation, severe anemia and thrombocytopenia were observed, and simultaneously thrombogenic processes were suggested by increased D-dimers, fibrinogen degradation products and/or portal vein thrombosis. PNH testing of red blood cells revealed a CD55 and CD59 deficiency consistent with PNH in both cases. The systemic complications typically associated with thrombosis were not observed for the following several months with early conservative treatments including eculizumab.

CONCLUSIONS:

Acute blindness from CRAO can be a unique manifestation of undiagnosed PNH and its subsequent aggravation. Systemic evaluations including PNH testing, especially in young CRAO patients, are strongly recommended for early detection of the further systemic thrombogenic processes.

Renal involvement in paroxysmal nocturnal hemoglobinuria (PNH) is not usually apparent but in cases with clinical involvement varies from reversible acute dysfunction to chronic irreversible damage. Early diagnosis and treatment is crucial to prevent disease progression and irreversible chronic kidney disease (CKD). The ultimate outcome of CKD in many patients is the need for renal replacement therapy, which necessitates ever-growing dialysis and transplantation programs, thereby imposing a significant economic burden on the healthcare system. In a third-world country like Pakistan, increased burden due to CKD can be very hard on families. Doctor visits, hospitalization, and dialysis are all out-of-pocket expenses, therefore prevention, early detection, and timely intervention are the only cost-effective strategies. We report a case of acute kidney injury (AKI) due to PNH. This case shows AKI as one of the complications of PNH which may have a clinical course like acute tubular necrosis (ATN). This could be due to ATN or AKI superimposed on CKD due to hemosiderin deposits in the renal tubular epithelial cells. Our patient was dialyzed initially and discharged with a permanent catheter in place with advice to continue dialysis three times a week. He required dialysis for 1 week then started producing urine. His subsequent outpatient visits showed improved renal function. The permanent catheter was removed and maintenance dialysis was stopped. Here, we briefly review the literature on renal involvement in PNH, treatment options for PNH and pigment-induced nephropathy followed by a question-and-answer session at the clinicopathological conference held on March 4, 2011, at Sindh Institute of Urology and Transplantation in Karachi, Pakistan.

Antibody-mediated rejection, be it acute, subacute or chronic, is currently recognized as the major cause of graft loss in kidney transplant recipients. Anti-HLA donor-specific antibodies are deleterious to the graft fate whether they pre-exist to the transplantation or appear in the course of transplantation. The role of complement is therefore prominent in most instances. As well, the role of complement activation is crucial in the recurrence of atypical hemolytic uremic syndrome post-transplantation (aHUS) as well as following ischemia-reperfusion injury leading to delayed graft function. Eculizumab, a fully humanized monoclonal antibody directed against the C5 component of the complement cascade is efficient in chronically and safely blocking complement activation for example in paroxysmal nocturnal hemoglobinuria. In the setting of kidney transplantation, there is convincing but still limited evidence that eculizumab is efficient in preventing both acute and chronic antibody-mediated rejection in highly sensitized recipients requiring desensitization before getting a living donor kidney transplant. Studies are currently ongoing to determine its efficacy and safety in ABO incompatible transplantation, in the prevention of acute and chronic rejection either with a living or a deceased donor kidney as well as in the prevention of delayed graft function. Similar to its efficacy in aHUS on native kidneys, eculizumab prevents or treats recurrence after kidney transplantation. There is still a lot of research to be performed in order to determine precisely the exact indications and the length of treatment with this very active but also very expensive drug that will undoubtedly revolutionize the current management of patients with donor specific antibodies (DSAs) and at risk of HUS recurrence.

To ascertain the genetic basis of a PNH case without somatic mutations in PIGA, we performed deep next-generation sequencing on all exons of known genes of the GPI-anchor synthesis pathway. We identified a heterozygous germline splice site mutation in PIGT and a somatic 8MB deletion in granulocytes affecting the other copy of PIGT. PIGA is essential for GPI-anchor synthesis whereas PIGT is essential for attachment of preassembled GPI-anchor to proteins. While a single mutation event in the X-chromosomal gene PIGA is known to cause GPI-anchored protein deficiency, two such hits are required in the autosomal gene PIGT. Our data indicate that PNH can occur even in the presence of fully assembled GPI if its transfer to proteins is defective in hematopoietic stem cells.

To analyze the clinical characteristics and risk factors on responses and survival of myelodysplastic syndromes (MDS) patients with paroxysmal nocturnal hemoglobinuria (PNH) clones.The clinical data of 31 MDS cases with PNH clones from October 2004 to June 2012 were retrospectively analyzed to reveal the influence of PNH clone size on responses and survival.①The chromosome karyotypes were analyzed in all patients, 23 patients with normal karyotype, 7 patients with abnormal karyotype [including 3 patients with +8, 2 -Y, 1 del(7q) and 1 Xp+] and 1 patient with no mitosis. 1 patient belonged to low-risk, 27 intermediate-1 risk, 2 intermediate-2 risk and 1 high-risk groups, respectively, according to IPSS. There were significantly statistical differences between responders and nonresponders in terms of infection, ANC, Reticulocyte count and IPSS (P values were 0.049, 0.006, 0.031 and 0.043, respectively). ②The overall responsive rate was 67.7%, no patients progressed to acute leukemia (AL) during median follow-up of 19 months after immunosuppressive therapy (IST). The 3-year and 5-year overall survival rates were 82.7% and 55.1%,respectively. ③According to univariate analysis,age, infection and ANC had significant influence on survival (P values were 0.050, 0.031 and 0.026, respectively). ④The PNH clone size had no significant influence on survival through univariate and COX analyses (P=0.393).MDS patients with PNH clone had less cytogenetic abnormalities, higher probability of response to IST and lower probability of progression to AL; Furthermore, the PNH clone size had no significant influence on response and survival.

Hematopoietic stem cell transplantation (HSCT) is a new window to therapy of many diseases. From March 1991 through April 2011, a total of 3237 HSCT were performed in the Hematology-Oncology and Stem Cell Transplantation Research Center, affiliated to Tehran University of Medical Sciences. Here we report 20 years experience of HSCT.Our strategy and aim include the protraction of cytogenetic and molecular biological diagnostic tests, the expansion of the first Iranian Cord Blood Bank (ICBB) and development of the first Iranian Stem Cell Donor Program (ISCDP), and improvement the researches in new therapeutic fields.Totally, 3237 patients were undergone HSCT. Of these transplants, 2205 were allogeneic stem cell transplantation, 1016 autologous and 16 syngeneic. Among 2205 patients who were undergone allogenic-HSCT, 34 received cord blood stem cells as stem cell source for transplantation. It is important to point out that cord blood bank at our center provides reliable storage of cord blood stem cells for our patients. Stem cell transplantation was performed for treatment of various diseases such as acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, chronic lymphoblastic leukemia, beta-thalassemia major, sickle- cell thalassemia, sickle- cell disease, multiple myeloma, myelodysplasia, mucopolysaccharidosis, paroxysmal nocturnal hemoglobinuria, non-Hodgkin's lymphoma, Hodgkin's disease, severe aplastic anemia, plasma cell leukemia, Niemann-Pick disease, Fanconi anemia, severe combined immunodeficiency, congenital neutropenia, leukocyte adhesion deficiencies, Chediak-Higashi syndrome, osteopetrosis, histiocytosis X, Hurler syndrome, amyloidosis, systemic sclerosis, breast cancer, Ewing's sarcoma, testicular cancer, germ cell tumors, neuroblastoma, medulloblastoma, renal cell carcinoma, nasopharyngeal carcinoma, ovarian cancer, Wilms' tumor, rhabdomyosarcoma, pancreatoblastoma, and multiple sclerosis. Also, we had 220 cellular therapies for post-myocardial infarction, multiple sclerosis, cirrhosis, head of femur necrosis, Diabetes Mellitus and GvHD treatment. 45 patients were undergone retransplantation in this center.About 78.2% of the patients (2530 of 3237) remained alive between one to 211 months after stem cell transplantation. Nearly, 21.8% (707) of our patients died after stem cell transplantation. The main causes of death were relapse, infection, hemorrhagic cystitis, graft-versus- host disease and etc.In Iran, HSCT has been successfully adapted in routine clinical care. Recently, new methods such as double cord blood and haploidentical transplantation have been used to treat many life-threatening diseases.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired clonal disorder characterized by chronic complement-mediated hemolysis. The humanized anti-C5 antibody eculizumab binds to the C5 protein and suppresses hemolysis by inhibiting C5b-9 generation. Here, we report on a 27-year-old woman who was found to have PNH in 1997 (at 13 years of age), without subsequent transfusions, thrombosis, or renal disorder. She had been experiencing frequent malaise and fatigue and was sometimes unable to participate in social activities. She had also experienced repeated hemolytic episodes due to infection, and the hemoglobin level had decreased from 7.0 to 5.0 g/dL several times since February 2010. Red blood cell transfusion was necessary, and 6 months later, treatment with eculizumab was started. The hemoglobin level stabilized, and the patient became transfusion-independent. Furthermore, the patient showed significant improvements in fatigue scale scores and quality of life. Six months after the start of eculizumab therapy, the percentage of PNH-type red blood cells was found to have increased from 82.0% (1.95 × 10(12) cells/L) to 89.1% (2.78 × 10(12) cells/L). Furthermore, during treatment with eculizumab, intravascular hemolysis occurred due to a viral infection accompanied by a high fever. We also observed a persistent elevation in reticulocytes and total bilirubin levels, as well as a persistent reduction in haptoglobin levels. Extravascular hemolytic findings were also observed. Because treatment with eculizumab was started at a young age (27 years) and will be continued for many years, careful observation of the patient is required.

A 69-year-old man with advanced heart failure treated with a continuous-flow left ventricular assist device presented for evaluation of dark urine and severe dysphagia. Because of evidence of ongoing intravascular hemolysis with device dysfunction, there was a clinical suspicion for pump thrombosis. He had progressive end-organ dysfunction and was therefore treated with tissue plasminogen activator with prompt resolution in hemolysis and dysphagia. Although symptoms of smooth muscle dystonia could represent worsening heart failure in the setting of device failure, the observation may also be related to intravascular hemolysis as described in the prototypic hemolytic disease, paroxysmal nocturnal hemoglobinuria.

Aplastic anemia (AA), myelodysplastic syndrome (MDS), and paroxysmal nocturnal hemoglobinuria (PNH) are rare disorders of bone marrow failure. Once considered distinct entities, these three diseases are now believed to have overlapping pathophysiologies. The Aplastic Anemia and MDS International Foundation, a nonprofit organization that supports patients and families living with bone marrow failure disorders, sponsored a scientific symposium in Bethesda, MD, in March 2012. This report summarizes the symposium presentations by 30 of the world's leading AA, MDS, and PNH researchers on recent findings, current areas of controversy, and recommendations for basic and clinical research to advance the field.