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Marchiafava Micheli syndrome [keywords]
- Humanized cobra venom factor: Structure, activity, and therapeutic efficacy in preclinical disease models. [JOURNAL ARTICLE]
- Mol Immunol 2014 Jul 22.
The complement system is an integral component of both innate and adaptive immunity. However, complement is also a pathogenetic factor in many diseases. The development of agents for therapeutic complement inhibition is the topic of intense investigations by many investigators. We have developed a distinctly different therapeutic approach: complement depletion rather than inhibition. This approach is based on cobra venom factor (CVF), a C3 analog known to be able to safely deplete complement. This manuscript will briefly review the structure and activity of CVF, along with its similarities and differences to C3. Exploiting the knowledge of the structure/function relationship of CVF and C3, we created derivatives of human C3 which display the CVF-like activity of depleting complement, referred to as humanized CVF (hCVF). This review describes the structure and activity of hCVF, including the important property of not cleaving C5. The efficacy of hCVF for therapeutic complement depletion in nine preclinical models diseases with complement pathology is reviewed, including reperfusion injury, age-related macular degeneration (AMD), paroxysmal nocturnal hemoglobinuria (PNH), and immunogenicity of Factor VIII in hemophilia A. Complement depletion is characterized by the absence of toxicity, even after intra-arterial injection into the pulmonary artery of primates. No immunogenicity has been observed.
- [Abnormal WT1 gene expression in paroxysmal nocturnal hemoglobinuria]. [English Abstract, Journal Article]
- Zhonghua Xue Ye Xue Za Zhi 2014 Jul 14; 35(7):596-600.
To explore the pathogenesis of abnormal WT1 expression in paroxysmal nocturnal hemoglobinuria (PNH).The expression of WT1 mRNA in CD59⁻ and CD59⁺ bone marrow mononuclear cells (BMMNC) were measured by semi-quantitative reverse transcription PCR. After WT1 gene silence by RNA interference (RNAi) technology, biological characteristics of BMMNC were investigated by flow cytometry.The relative expression of WT1 mRNA in PNH CD59⁻ BMMNC (1.06±0.12) was significantly higher than that in PNH CD59⁺ BMMNC (0.90±0.12) and normal BMMNC (0.86±0.05, P<0.05), but there was no significant difference between PNH CD59⁺ BMMNC and normal BMMNC (P>0.05). WT1 mRNA expression in PNH was positively correlated with the proportion of CD59⁻ cells (r²=0.490, P=0.016), but had no relationship with the proportion of CD59⁺ cells. After WT1 gene silence by siRNA in PNH CD59⁻ BMMNC, WT1 mRNA expression was decreased. The proportions of G0/G1 phase in PNH CD59⁻ cell blank control group and siRNA-scr transfected group were (92.73±3.71)% and (93.06±4.14)%, and the proportions of S phase were (6.99±3.61)% and (6.73±4.08)%, respectively. The proportions of G0/G1 and S phase in siRNA-WT1 transfected group was (94.46±3.71)% and (5.40±3.55)%, respectively. There were significant differences in the proportions of G0/G1 phase and S phase among the controls, siRNA-WT1 transfected group and siRNA-scr transfected group (P<0.05). The rate of apoptosis in siRNA-WT1 transfected group [(35.91±22.36)%] was significantly higher than those in controls [(26.12±17.10)%] and siRNA-scr transfected group [(27.39±18.99)%] (P<0.05).siRNA-WT1 could effectively suppress the WT1 gene expression of CD59⁻ clone in PNH patients, inhibit its proliferation, and promote its apoptosis. WT1 gene expression might contribute to PNH clone proliferation.
- Two case studies and a review of paroxysmal cold hemoglobinuria. [Journal Article]
- Lab Med 2014; 45(3):253-8.
Paroxysmal cold hemoglobinuria (PCH) is an acquired hemolytic anemia caused by immunoglobulin G (IgG) antibodies that sensitize red blood cells (RBCs) at cold temperatures by fixing complement to the RBCs causing intravascular hemolysis on rewarming. PCH usually appears in young children as recurrent high fevers, chills, and passage of red-brown urine. The diagnostic test for PCH is the Donath-Landsteiner test, an in vitro assay for biphasic hemolysis. Herein, we present 2 cases of PCH that occurred within 12 months of each other. We quickly diagnosed the second case and treated the patient successfully, in part due to our recognition of its characteristics based on the first case. PCH is a hemolytic anemia for which there is a specific diagnostic test; the timely recognition of this entity by physicians and laboratory staff will allow prompt, supportive therapy and will raise the odds of quick resolution of hemolysis.
- Complement Blockade with a C1 Esterase Inhibitor in Paroxysmal Nocturnal Hemoglobinuria. [JOURNAL ARTICLE]
- Exp Hematol 2014 Jul 14.
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, clonal, hematopoietic stem cell disorder that manifests with a complement-mediated hemolytic anemia, bone marrow failure and a propensity for thrombosis. These patients experience both intra- and extravascular hemolysis in the context of underlying complement activation. Currently eculizumab effectively blocks the intravascular hemolysis PNH. There remains an unmet clinical need for a complement inhibitor with activity early in the complement cascade to block complement at the classical and alternative pathways. C1 esterase inhibitor (C1INH) is an endogenous human plasma protein that has broad inhibitory activity in the complement pathway through inhibition of the classical pathway by binding C1r and C1s and inhibits the mannose-binding lectin-associated serine proteases in the lectin pathway. In this study, we show that commercially available plasma derived C1INH prevents lysis induced by the alternative complement pathway, of PNH erythrocytes in human serum. Importantly, C1INH was able to block the accumulation of C3 degradation products on CD55 deficient erythrocytes from PNH patient on eculizumab therapy. This could suggest a role for inhibition of earlier phases of the complement cascade than that currently inhibited by eculizumab for incomplete or non-responders to that therapy.
- 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 Sep; 10(3):1252-8.
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.