Marchiafava Micheli syndrome [keywords]
- Eculizumab in the management of paroxysmal nocturnal hemoglobinuria: patient selection and special considerations. [Journal Article, Review]
- Ther Clin Risk Manag 2016.:1161-70.
Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal disorder resulting from somatic mutation in the PIG-A gene leading to a deficiency of the membrane-anchoring molecule glycosylphosphatidylinositol. The lack of expression of two glycosylphosphatidylinositol-anchored proteins involved in the regulation of the complement system renders PNH erythrocytes susceptible to complement-mediated lysis. Clinical manifestations include thromboembolic disease, chronic kidney injury, pulmonary hypertension, smooth muscle dysfunction, and chronic hemolysis. Until recently, treatment was mainly supportive with most patients suffering from significant morbidity and shortened survival compared to age-matched controls. The development of eculizumab, a humanized monoclonal antibody directed against the terminal complement protein C5, has resulted in dramatic improvements of survival and reduction in complications. In this paper, we review some special considerations pertaining to the use of eculizumab for PNH.
- Successful treatment of aplastic anemia-paroxysmal nocturnal hemoglobinuria associated with eosinophilic fasciitis with matched unrelated donor allogeneic peripheral blood stem cell transplantation. [Journal Article]
- Clin Case Rep 2016 Aug; 4(8):765-7.
We report the first patient case of successful treatment intervention for both eosinophilic fasciitis and aplastic anemia with allogeneic peripheral blood stem cell transplantation from a matched unrelated donor after multiple immunosuppressant failure.
- Stratification of responders towards eculizumab using a structural epitope mapping strategy. [Journal Article]
- Sci Rep 2016.:31365.
The complement component 5 (C5)-binding antibody eculizumab is used to treat patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical haemolytic uremic syndrome (aHUS). As recently reported there is a need for a precise classification of eculizumab responsive patients to allow for a safe and cost-effective treatment. To allow for such stratification, knowledge of the precise binding site of the drug on its target is crucial. Using a structural epitope mapping strategy based on bacterial surface display, flow cytometric sorting and validation via haemolytic activity testing, we identified six residues essential for binding of eculizumab to C5. This epitope co-localizes with the contact area recently identified by crystallography and includes positions in C5 mutated in non-responders. The identified epitope also includes residue W917, which is unique for human C5 and explains the observed lack of cross-reactivity for eculizumab with other primates. We could demonstrate that Ornithodorus moubata complement inhibitor (OmCI), in contrast to eculizumab, maintained anti-haemolytic function for mutations in any of the six epitope residues, thus representing a possible alternative treatment for patients non-responsive to eculizumab. The method for stratification of patients described here allows for precision medicine and should be applicable to several other diseases and therapeutics.
- [THE METHODICAL APPROACHES TO DIAGNOSTIC OF NIGHT PAROXYSMAL HEMOGLOBINURIA]. [English Abstract, Journal Article]
- Klin Lab Diagn 2016 Mar; 61(3):151-4, 167-8.
The article presents diagnostic of night paroxysmal hemoglobinuria. The night paroxysmal hemoglobinuria is an orphan disease characterized by absence of GPI-anchor on blood cells as a result of mutation of PIG-A gene on the short arm of X-chromosome. The particular proteins bounded with GPI-anchor implement function of defense from activation of components of complement and development of membrane-attacking complex. The erythrocytes exposed to destruction in bloodstream are among the most impacted. Therefore, one of the main signs of night paroxysmal hemoglobinuria is complement-depending intravascular hemolysis which indicators for a long time played a key role in diagnostic of night paroxysmal hemoglobinuria. The actual technique of diagnostic of night paroxysmal hemoglobinuria is flow cytometry. The analysis of night paroxysmal hemoglobinuria clone is recommended to patients with hemolysis of unclear genesis, thrombosis of cerebral and abdominal veins, thrombocytopenia and macrocytosis and also patients with AA, myelodysplastic syndrome, myelofibrosis. The international protocol recommended by the International Society of Clinical Cytometry (2010) is implemented to diagnose night paroxysmal hemoglobinuria. The original technique of evaluation of reticulocytes was developed with purpose to detect night paroxysmal hemoglobinuria clone. The high correlation was substantiated between size of night paroxysmal hemoglobinuria clone measured among reticulocytes according to proposed mode and night paroxysmal hemoglobinuria clone measured among granulocytes and monocytes detected according international standardized approach.
- Eculizumab epitope on complement C5: Progress towards a better understanding of the mechanism of action. [JOURNAL ARTICLE]
- Mol Immunol 2016 Aug 4.:126-131.
Eculizumab is an anti-complement C5 monoclonal antibody which has greatly improved the prognosis and outcomes of nocturnal paroxysmal hemoglobinuria and atypical hemolytic and uremic syndromes. It is also known to be very species-specific for human C5, despite an important degree of conservation of the targeted macroglobulin domain, MG7, with that of other primates. However, the published eculizumab linear epitope does not explain this species specificity. Sequence analysis, in silico docking and reverse phase protein array were implemented to fully characterize the eculizumab epitope on human complement C5. Several residues potentially involved in the species specificity were identified outside the known epitope by sequence analysis. In silico docking confirmed the implication of a beta-hairpin located between residues 913 and 922, outside the known epitope, in the binding of eculizumab to C5. This beta-hairpin spreads from S913 to I922 and contains a tryptophan residue on position 917 which is unique to humans. The contribution of both this peptide and the already known one epitope, which spreads between residues C883 and S891, was validated by reverse phase protein assay, clearly demonstrating the discontinuous nature of the epitope. Two residues in particular, Arg885 and Trp917, were defined as major participants in the interaction of C5 and eculizumab. Their important role was confirmed by the recent publication of a crystal structure of eculizumab Fab bound to C5. The beta-hairpin not only explains the fine species specificity of eculizumab but is also an important site at the C5/C5 convertase interface, revealing how eculizumab acts as a competitor of C5 convertases.
- Generation of induced pluripotent stem cells as a potential source of hematopoietic stem cells for transplant in PNH patients. [Journal Article]
- Ann Hematol 2016 Oct; 95(10):1617-25.
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia caused by lack of CD55 and CD59 on blood cell membrane leading to increased sensitivity of blood cells to complement. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for PNH, however, lack of HLA-matched donors and post-transplant complications are major concerns. Induced pluripotent stem cells (iPSCs) derived from patients are an attractive source for generating autologous HSCs to avoid adverse effects resulting from allogeneic HSCT. The disease involves only HSCs and their progeny; therefore, other tissues are not affected by the mutation and may be used to produce disease-free autologous HSCs. This study aimed to derive PNH patient-specific iPSCs from human dermal fibroblasts (HDFs), characterize and differentiate to hematopoietic cells using a feeder-free protocol. Analysis of CD55 and CD59 expression was performed before and after reprogramming, and hematopoietic differentiation. Patients' dermal fibroblasts expressed CD55 and CD59 at normal levels and the normal expression remained after reprogramming. The iPSCs derived from PNH patients had typical pluripotent properties and differentiation capacities with normal karyotype. After hematopoietic differentiation, the differentiated cells expressed early hematopoietic markers (CD34 and CD43) with normal CD59 expression. The iPSCs derived from HDFs of PNH patients have normal levels of CD55 and CD59 expression and hold promise as a potential source of HSCs for autologous transplantation to cure PNH patients.
- Interim analysis of post-marketing surveillance of eculizumab for paroxysmal nocturnal hemoglobinuria in Japan. [JOURNAL ARTICLE]
- Int J Hematol 2016 Jul 27.
Data characterizing the safety and effectiveness of eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH) are limited. We describe the safety and effectiveness of eculizumab in PNH patients enrolled in a post-marketing surveillance study. Types and frequencies of observed adverse events were similar to those reported in previous clinical trials and no meningococcal infection was reported. Effectiveness outcomes included the reduction of intravascular hemolysis, the change in hemoglobin (Hb) level, the withdrawal of transfusion and corticosteroids, the change of renal function, and overall survival. The effect of eculizumab on intravascular hemolysis was demonstrated by a reduction in lactate dehydrogenase levels at all measurements after baseline. Significant increases in Hb levels from baseline were also observed after 1 month's treatment with eculizumab (p < 0.01). Of those who were transfusion-dependent at baseline, the median number of transfusions decreased significantly from 18 to 0 unit/year after 1 year of treatment with eculizumab (p < 0.001). An increase in Hb and a high rate of transfusion independence were observed, especially in patients with platelet count ≥150 × 10(9)/L. Approximately 97 % of patients showed maintenance or improvement of renal function. Overall survival rate was about 90 % (median follow-up 1.9 years). These results suggest an acceptable safety profile and favorable prognosis after eculizumab intervention.
- Bilateral central serous retinopathy in a patient with paroxysmal nocturnal hemoglobinuria treated with deferoxamine. [JOURNAL ARTICLE]
- Eur J Ophthalmol 2016 Jul 18.:0.
To report a case of acute bilateral central serous retinopathy associated with deferoxamine therapy in the context of paroxysmal nocturnal hemoglobinuria.Spectral-domain optical coherence tomography and fundus autofluorescence were used to investigate posterior segment changes.A 76-year-old man with paroxysmal nocturnal hemoglobinuria and hereditary spherocytosis was started on deferoxamine for iron overload secondary to previous blood transfusions. Four days after initiation of treatment, he developed bilateral reduced vision and metamorphopsia. He was noted to have bilateral central serous retinopathy. Symptoms and serous retinal detachment resolved rapidly following discontinuation of treatment.This case represents the first report of acute bilateral central serous retinopathy associated with deferoxamine therapy. Cessation of deferoxamine resulted in rapid visual recovery.
- Notes from the Field: Meningococcal Disease in an International Traveler on Eculizumab Therapy - United States, 2015. [Journal Article]
- MMWR Morb Mortal Wkly Rep 2016; 65(27):696-7.
On June 2, 2015, CDC was notified that a male airline passenger, aged 41 years, with a fever of 105.4°F, headache, nausea, photophobia, diarrhea, and vomiting, which began approximately 3 hours after departure, was arriving to San Francisco, California, on a flight from Frankfurt, Germany. His symptoms reportedly started with neck stiffness 1 day earlier. Upon arrival, the patient was immediately transported to a local hospital, where he was in septic shock, which was followed by multisystem organ failure. Cerebrospinal fluid, obtained approximately 12 hours after initiation of treatment, was Gram stain- and culture-negative. Blood cultures, which were drawn before antibiotic treatment, were positive for Neisseria meningitides of indeterminate serogroup. A review of the patient's medical records revealed a history of paroxysmal nocturnal hemoglobinuria and current biweekly eculizumab (Soliris) therapy.