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Marchiafava Micheli syndrome [keywords]
- Misleading hemoglobin a1c levels in a patient with paroxysmal nocturnal hemoglobinuria. [Journal Article]
- Am J Clin Pathol 2014 Aug; 142(2):261-5.
We report a case of a patient with diabetes mellitus and unexpectedly low hemoglobin A1c results associated with paroxysmal nocturnal hemoglobinuria (PNH). We review the impact of shortened RBC half-life on the interpretation of hemoglobin A1c levels.Patient history and laboratory test results were obtained from electronic medical records and analyzed.The patient's hemoglobin A1c declined in parallel to worsening anemia after the diagnosis of PNH. However, elevated serum glucose (random), fructosamine, and glycated albumin suggest ongoing hyperglycemia. Together, these results argue that the decline in hemoglobin A1c was due to decreased RBC survival secondary to PNH.Hemoglobin A1c levels must be interpreted with caution in patients with hematologic diseases that change RBC survival. Serum fructosamine and glycated albumin measurements are alternative measures of time-averaged blood glucose control and may be useful in this subset of patients.
- Paroxysmal Nocturnal Hemoglobinuria Clones in Children with Acquired Aplastic Anemia: A Multicentre Study. [JOURNAL ARTICLE]
- PLoS One 2014; 9(7):e101948.
A multicentre study evaluating the presence of glycosil phosphatidyl-inositol (GPI)-negative populations was performed in 85 children with acquired aplastic anemia (AA). A GPI-negative population was observed in 41% of patients at diagnosis, 48% during immune-suppressive therapy (IST), and 45% in patients off-therapy. No association was found between the presence of a GPI-negative population at diagnosis and the response to IST. In addition, the response rate to IST did not differ between the patients who were GPI-positive at diagnosis and later developed GPI-negative populations and the 11 patients who remained GPI-positive. Two patients with a GPI-negative population >10%, and laboratory signs of hemolysis without hemoglobinuria were considered affected by paroxysmal nocturnal hemoglobinuria (PNH) secondary to AA; no thrombotic event was reported. Excluding the 2 patients with a GPI-negative population greater than 10%, we did not observe a significant correlation between LDH levels and GPI-negative population size. In this study monitoring for laboratory signs of hemolysis was sufficient to diagnose PNH in AA patients. The presence of minor GPI-negative populations at diagnosis in our series did not influence the therapeutic response. As occasionally the appearance of a GPI-negative population was observed at cyclosporine (CSA) tapering or AA relapse, a possible role of GPI-negative population monitoring during IST modulation may need further investigation.
- Opportunity Cost of Funding Drugs for Rare Diseases: The Cost-Effectiveness of Eculizumab in Paroxysmal Nocturnal Hemoglobinuria. [JOURNAL ARTICLE]
- Med Decis Making 2014 Jul 2.
. Both ethical and economics concerns have been raised with respect to the funding of drugs for rare diseases. This article reports both the cost-effectiveness of eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and its associated opportunity costs.. Analysis compared eculizumab plus current standard of care v. current standard of care from a publicly funded health care system perspective. A Markov model covered the major consequences of PNH and treatment. Cost-effectiveness was assessed in terms of the incremental cost per life year and per quality-adjusted life year (QALY) gained. Opportunity costs were assessed by the health gains foregone and the alternative uses for the additional resources.. Eculizumab is associated with greater life years (1.13), QALYs (2.45), and costs (CAN$5.24 million). The incremental cost per life year and per QALY gained is CAN$4.62 million and CAN$2.13 million, respectively. Based on established thresholds, the opportunity cost of funding eculizumab is 102.3 discounted QALYs per patient funded. Sensitivity and subgroup analysis confirmed the robustness of the results. If the acquisition cost of eculizumab was reduced by 98.5%, it could be considered cost-effective.. The nature of rare diseases means that data are often sparse for the conduct of economic evaluations. When data were limited, assumptions were made that biased results in favor of eculizumab.. This study demonstrates the feasibility of conducting economic evaluations in the context of rare diseases. Eculizumab may provide substantive benefits to patients with PNH in terms of life expectancy and quality of life but at a high incremental cost and a substantial opportunity cost. Decision makers should fully consider the opportunity costs before making positive reimbursement decisions.
- Malarial anemia: digestive vacuole of Plasmodium falciparum mediates complement deposition on bystander cells to provoke hemophagocytosis. [JOURNAL ARTICLE]
- Med Microbiol Immunol 2014 Jul 2.
The digestive vacuole (DV) of Plasmodium falciparum, which is released into the bloodstream upon rupture of each parasitized red blood cell (RBC), was recently discovered to activate the alternative complement pathway. In the present work, we show that C3- and C5-convertases assembling on the parasitic organelle are able to provoke deposition of activated C3 and C5b-9 on non-infected bystander erythrocytes. Direct contact of DVs with cells is mandatory for the effect, and bystander complement deposition occurs focally, possibly at the sites of contact. Complement opsonization promotes protracted erythrophagocytosis by human macrophages, an effect that is magnified when ring-stage infected RBCs with reduced CD55 and CD59, or paroxysmal nocturnal hemoglobinuria (PNH)-RBCs lacking these complement inhibitors are employed as targets. Bystander attack can also directly induce lysis of PNH-RBCs. Direct evidence for complement activation and bystander attack mediated by DVs was obtained through immunohistochemical analyses of brain paraffin sections from autopsies of patients who had died of cerebral malaria. C3d and the assembled C5b-9 complex could be detected in all sections, colocalizing with and often extending locally beyond massive accumulations of DVs that were identified under polarized light. This is the first demonstration that a complement-activating particle can mediate opsonization of bystander cells to promote their antibody-independent phagocytosis. The phenomenon may act in concert with other pathomechanisms to promote the development of anemia in patients with severe malaria.
- CD8+HLA-DR+ T cells are increased in patients with severe aplastic anemia. [JOURNAL ARTICLE]
- Mol Med Rep 2014 Jun 18.
The aim of the present study was to investigate the number and function of CD8+HLA-DR+ cells, which are considered to be activated cytotoxic T lymphocytes (CTLs), in peripheral blood to further examine the pathogenesis of severe aplastic anemia (SAA). Thirty-eight patients with SAA were included in the present study. Patients were screened for paroxysmal nocturnal hemoglobinuria by flow cytometry using anti-CD55 and anti-CD59 antibodies. The number of CD8+HLA-DR+ T cells was measured by three-color flow cytometry using anti-CD8-peridinin chlorophyll, anti-CD3-fluorescein isothiocyanate (FITC) and anti-HLA-DR-FITC antibodies. The expression of perforin, granzyme B, tumor necrosis factor-β (TNF-β) and FasL in CD8+HLA-DR+ T cells was detected by flow cytometry with the appropriate monoclonal antibodies. Total RNA was prepared from purified CD8+HLA-DR+ cells of healthy controls and SAA patients, and then polymerase chain reaction (PCR) was performed. Apoptosis of CD8+HLA-DR+ cells was detected by flow cytometry following staining with Annexin V. The proportion of CD8+HLA-DR+ T cells was analyzed by flow cytometry in peripheral blood and was identified to be significantly higher in untreated SAA than in remission patients and in the controls. The expression of perforin, granzyme B, TNF-β and FasL in CD8+HLA-DR+ T cells was analyzed by flow cytometry and PCR, which revealed increased expression in the untreated SAA group compared with that in the control group. Furthermore, the apoptosis of CD3- bone marrow cells from normal individuals was enhanced following co-culture with CD8+HLA-DR+ T cells from untreated SAA patients. In conclusion, the present study demonstrated that CD8+HLA-DR+ T cells may contribute to bone marrow failure in SAA.
- Thrombotic Microangiopathies and the Linkage between von Willebrand Factor and the Alternative Complement Pathway. [JOURNAL ARTICLE]
- Semin Thromb Hemost 2014 Jun 26.
Molecular linkages between von Willebrand factor (VWF) and the alternative complement pathway (AP) have recently been discovered. Endothelial cell (EC)-anchored ultra-large (UL) VWF multimeric strings function as an activating surface for the AP. C3 (in active C3b form) binds to the EC-anchored ULVWF strings, and promotes the assembly of C3bBb (C3 convertase) and C3bBbC3b (C5 convertase). These linkages may help to explain enigmatic clinical problems related to thrombotic microangiopathies, including some cases of refractory thrombotic thrombocytopenic purpura (TTP), TTP associated with only mild-modest deficiencies of ADAMTS-13, the provocation (or exacerbation) of acute episodes in patients with the atypical hemolytic uremic syndrome, and thrombosis in paroxysmal nocturnal hemoglobinuria. Recent experiments have also demonstrated that complement factor H performs a dual role: participating in regulation of the AP by binding to EC-anchored ULVWF strings; and functioning as a reductase to decrease the size of soluble VWF multimers.
- Clinical relevance of CD157 for rapid and cost-effective simultaneous evaluation of PNH granulocytes and monocytes by flow cytometry. [JOURNAL ARTICLE]
- Int J Lab Hematol 2014 Jun 25.
CD157 has been reported as a potentially useful marker for paroxysmal nocturnal hemoglobinuria (PNH) testing by flow cytometry (FCM).We determined the performance characteristics of a CD157-based five-color assay and compared results from patient analysis with results obtained with a previously validated CD14/CD24-based six-color protocol.Coefficient of variation (CV) for intra-/interassay precision analysis of granulocytes ranged from 0.88/0.09% to 3.02/3.71% and from 0.20/0.08% to 8.83/4.04% for the five- and six-color protocol, respectively. For monocyte, CV ranged from 0.42/0.49% to 8.13/4.80% for the five-color protocol and from 0.28/0.70% to 5.41/3.19% for the six-color protocol within various PNH clones. Coefficient of determination (r(2) ) for linear regression analysis of PNH clones ranging from 0.3 to 99.8% was >0.99 in all cases, Wilcoxon ranks test showed no statistically significant differences (P > 0.05), and Bland-Altman analysis demonstrated agreement with mean bias ranging from -0.02 to 0.38.Our results confirm very good performance characteristics for both intra- and interassay precision analyses, excellent correlation, and agreement between approaches. In agreement with recently published data, our experience supports the clinical relevance of CD157 for a rapid and cost-effective simultaneous evaluation of PNH leukocytes by flow cytometry.
- Paroxysmal nocturnal hemoglobinuria with copy number-neutral 6pLOH in GPI (+) but not in GPI (-) granulocytes. [Journal Article]
- Eur J Haematol 2014 May; 92(5):450-3.
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired bone marrow disorder caused by expansion of a clone of hematopoietic cells lacking glycosylphosphatidylinositol (GPI)-anchored membrane proteins. Multiple lines of evidence suggest immune attack on normal hematopoietic stem cells provides a selective growth advantage to PNH clones. Recently, frequent loss of HLA alleles associated with copy number-neutral loss of heterozygosity in chromosome 6p (CN-6pLOH) in aplastic anemia (AA) patients was reported, suggesting that AA hematopoiesis 'escaped' from immune attack by loss of HLA alleles. We report here the first case of CN-6pLOH in a Japanese PNH patient only in GPI-anchored protein positive (59%) granulocytes, but not in GPI-anchored protein negative (41%) granulocytes. CN-6pLOH resulted in loss of the alleles A*02:06-DRB1*15:01-DQB1*06:02, which have been reported to be dominant in Japanese PNH patients. Our patient had maintained nearly normal blood count for several years. Our case supports the hypothesis that a hostile immune environment drives selection of resistant hematopoietic cell clones and indicates that clonal evolution may occur also in normal phenotype (non-PNH) cells in some cases.
- Pilot study using tacrolimus rather than cyclosporine plus antithymocyte globulin as an immunosuppressive therapy regimen option for severe aplastic anemia in adults. [JOURNAL ARTICLE]
- Blood Cells Mol Dis 2014 Jun 12.
Severe aplastic anemia (SAA), which is considered to be an immune-mediated destruction of bone marrow stem cells with pancytopenia and hypoplasia, can be successfully treated with immunosuppressive therapy or hematopoietic stem cell transplantation (HSCT). Between January 2009 and December 2012, thirteen patients diagnosed with SAA were treated with tacrolimus plus rabbit antithymocyte globulin (ATG)-based immunosuppressive therapy (IST). The outcomes were then compared with our previous data for twenty-four patients administered with cyclosporine (CsA) plus rabbit ATG-based IST. All 37 cases accepted methylpredenisolone and recombinant human granulocyte colony-stimulating factor (rhG-CSF) from the first day that rabbit ATG was initiated. A total of 7 (54%) of the 13 patients in the tacrolimus group and 10 (42%) of the 24 cases in the ATG+CsA group achieved the criteria for complete response (CR); the partial response (PR) rate was 31% in the tacrolimus group and 33% in the ATG+CsA group. The median follow-up duration of the tacrolimus group and ATG+CsA group patients was 28months and 27months, respectively. Two patients in the tacrolimus group who were red blood cell- and platelet transfusion-dependent died, one of sepsis and the other of cerebral hemorrhage, whereas one patient died from serious infection on the 5th day after ATG was initiated in the ATG+CsA group. No clonal transformation to paroxysmal nocturnal hemoglobinuria (PNH) was observed in either group. Our data provide a possibility of using tacrolimus as part of an IST regimen for SAA in adults who have no opportunity of HSCT from human leukocyte antigen (HLA)-matched sibling donors.
- Severe aplastic anemia-paroxysmal nocturnal hemoglobinuria syndrome in a patient with non-A-E hepatitis virus infection. [JOURNAL ARTICLE]
- Ann Hepatol 2014 Jul-Aug 2014; 13(4):466-467.