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Marchiafava Micheli syndrome [keywords]
- First-Line Immunosuppressive Treatment in Children with Aplastic Anemia: Rabbit Antithymocyte Globulin. [JOURNAL ARTICLE]
- Adv Exp Med Biol 2014 Oct 14.
Immunosuppressive therapy is the treatment of choice in children with acquired severe aplastic anemia (AA) and no HLA-matched family donor. The paper presents results of a multicenter study of 63 children with AA treated with rabbit antithymocyte globulin (r-ATG) and cyclosporine A as the first line treatment in the years 1996-2012. Therapeutic effects were evaluated at Days 112, 180, and 360. At Day 112, remission was achieved in 28 out of the 63 patients (44.4 %), complete remission in 10 patients (15.9 %), and partial remission in 18 (28.5 %). At Day 180, 31 patients (49.2 %) were in remission including 15 cases in complete (23.8 %), and 16 cases in partial remission (25.4 %). One year after therapy onset, 34 patients (64.9 %) were in remission including 24 patients (38.0 %) in complete and 10 (15.9 %) in partial remission. Relapse occurred in 4 patients, from 8 months up to 2 years and 2 months after remission. One child, 5 years after remission, was diagnosed with paroxysmal nocturnal hemoglobinuria. The estimated 10-year overall survival rate and 10-year event-free survival rate were 67 % and 57 %, respectively.
- [C5: eculizumab]. [English Abstract, Journal Article]
- Brain Nerve 2014 Oct; 66(10):1191-9.
Abstract Eculizumab is a recombinant humanized monoclonal antibody that specifically binds to a C5 terminal complement and inhibits the cleavage of C5 to C5a and C5b through complement activation. Eculizumab has been used clinically for paroxysmal nocturnal hemoglobinuria. Clinical studies have been initiated for neurological disorders, such as, optic neuromyelitis and myasthenia gravis, mediated by the complement system. In addition, eculizumab is expected to be useful for the treatment of intractable neurological diseases.
- Treatment of autoimmune hemolytic anemias. [REVIEW]
- Haematologica 2014 Oct; 99(10):1547-1554.
Autoimmune hemolytic anemia (AIHA) is a relatively uncommon disorder caused by autoantibodies directed against self red blood cells. It can be idiopathic or secondary, and classified as warm, cold (cold hemagglutinin disease (CAD) and paroxysmal cold hemoglobinuria) or mixed, according to the thermal range of the autoantibody. AIHA may develop gradually, or have a fulminant onset with life-threatening anemia. The treatment of AIHA is still not evidence-based. The first-line therapy for warm AIHA are corticosteroids, which are effective in 70-85% of patients and should be slowly tapered over a time period of 6-12 months. For refractory/relapsed cases, the current sequence of second-line therapy is splenectomy (effective approx. in 2 out of 3 cases but with a presumed cure rate of up to 20%), rituximab (effective in approx. 80-90% of cases), and thereafter any of the immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporin, mycophenolate mofetil). Additional therapies are intravenous immunoglobulins, danazol, plasma-exchange, and alemtuzumab and high-dose cyclophosphamide as last resort option. As the experience with rituximab evolves, it is likely that this drug will be located at an earlier point in therapy of warm AIHA, before more toxic immunosuppressants, and in place of splenectomy in some cases. In CAD, rituximab is now recommended as first-line treatment.
- Deep sequencing reveals stepwise mutation acquisition in paroxysmal nocturnal hemoglobinuria. [JOURNAL ARTICLE]
- J Clin Invest 2014 Sep 17.
Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal disease of hematopoietic stem cells that is associated with hemolysis, marrow failure, and thrombophilia. PNH has been considered a monogenic disease that results from somatic mutations in the gene encoding PIGA, which is required for biosynthesis of glycosylphosphatidylinisotol-anchored (GPI-anchored) proteins. The loss of certain GPI-anchored proteins is hypothesized to provide the mutant clone with an extrinsic growth advantage, but some features of PNH argue that there are intrinsic drivers of clonal expansion. Here, we performed whole-exome sequencing of paired PNH+ and PNH- fractions on samples taken from 12 patients as well as targeted deep sequencing of an additional 36 PNH patients. We identified additional somatic mutations that resulted in a complex hierarchical clonal architecture, similar to that observed in myeloid neoplasms. In addition to mutations in PIGA, mutations were found in genes known to be involved in myeloid neoplasm pathogenesis, including TET2, SUZ12, U2AF1, and JAK2. Clonal analysis indicated that these additional mutations arose either as a subclone within the PIGA-mutant population, or prior to PIGA mutation. Together, our data indicate that in addition to PIGA mutations, accessory genetic events are frequent in PNH, suggesting a stepwise clonal evolution derived from a singular stem cell clone.
- The mutational landscape of paroxysmal nocturnal hemoglobinuria revealed: new insights into clonal dominance. [JOURNAL ARTICLE]
- J Clin Invest 2014 Sep 17.:1-4.
Paroxysmal nocturnal hemoglobinuria (PNH) is a disorder of hematopoietic stem cells that has largely been considered a monogenic disorder due to acquisition of mutations in the gene encoding PIGA, which is required for glycosylphosphatidylinositol (GPI) anchor biosynthesis. In this issue of the JCI, Shen et al. discovered that PNH is in fact a complex genetic disorder orchestrated by many genetic alterations in addition to PIGA mutations. Some of these mutations predate the acquisition of PIGA mutations, while others occur later. Surprisingly, this work indicates that PNH has a clonal evolution and architecture strikingly similar to that of other myeloid neoplasms, highlighting a potentially broader mechanism of disease pathogenesis in this disorder.
- Paroxysmal nocturnal hemoglobinuria. [JOURNAL ARTICLE]
- Blood 2014 Sep 18.
Paroxysmal nocturnal hemoblobinuria (PNH) is a rare bone marrow failure disorder that manifests with hemolytic anemia, thrombosis and peripheral blood cytopenias. The absence of two GPI-anchored proteins, CD55 and CD59, leads to uncontrolled complement activation that accounts for hemolysis and other PNH manifestations. GPI anchor protein deficiency is almost always due to somatic mutations in PIGA, a gene involved in the first step of GPI anchor biosynthesis; however, alternative mutations that cause PNH have recently been discovered. In addition, hypomorphic germline PIGA that do not cause PNH have been shown to be responsible for a condition known as multiple congenital anomalies-hypotonia-seizures syndrome 2. Eculizumab, first-in-class monoclonal antibody that inhibits terminal complement, is the treatment of choice for patients with severe manifestations of PNH. Bone marrow transplantation remains the only cure for PNH but should be reserved for patients with suboptimal response to eculizumab.
- Complement in paroxysmal nocturnal hemoglobinuria: exploiting our current knowledge to improve the treatment landscape. [Journal Article]
- Expert Rev Hematol 2014 Oct; 7(5):583-98.
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disorder associated with an acquired deficiency in glycophosphatidylinositol-anchor biosynthesis that renders erythrocytes susceptible to complement attack. Intravascular hemolysis via the membrane attack complex is a clinical hallmark of the disease, and C5 blockade is currently the only approved treatment for PNH. However, residual anemia is an emerging observation for many PNH patients receiving anti-C5 treatment. A range of complement-targeted therapeutic approaches, encompassing surface-directed inhibition of C3 convertases, blockade of membrane attack complex assembly or C3 interception using peptidic inhibitors, has yielded promising results and offers leverage for even more effective treatment of PNH. This article discusses recent advances in this rapidly evolving field, integrating critical perspectives from preclinical PNH models and diverse complement modulation strategies with genetic insights and therapy response profiles. It also evaluates the relative efficacy, limitations and benefits afforded by C3 or C5 inhibition in the context of PNH therapeutics.
- Successful eculizumab treatment for multiple coronary thrombosis complicated in paroxysmal nocturnal hemoglobinuria. [Journal Article]
- Rinsho Ketsueki 2014 Aug; 55(8):965-9.
We herein report a rare case of paroxysmal nocturnal hemoglobinuria (PNH) who repeatedly developed coronary arterial thromboembolism. Anticoagulant therapies including heparin, aspirin as an antiplatelet agent and even drug-eluting stent placement in the coronary artery failed to prevent the recurrence of ischemic heart disease. Of note, initiating the administration of a humanized anti-C5 antibody, eculizumab, achieved prompt thrombolysis and maintenance treatment with eculizumab prevented the recurrence of thromboembolic disease in this patient. Taking these observations together, we suggest that the use of eculizumab be considered for treatment or prevention of arterial thrombosis complicated by PNH, although arterial thrombosis is an extremely rare event in the Japanese population.
- [Case report; Two cases of paroxysmal nocturnal hemoglobinuria with preceding cytopenia]. [Journal Article]
- Nihon Naika Gakkai Zasshi 2014 Jun 10; 103(6):1385-7.
- Paroxysmal nocturnal hemoglobinuria presenting as cerebral venous sinus thrombosis: a case report. [Journal Article]
- Int Arch Med 2014.:39.
Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare type of acquired hemolytic anemia that is frequently associated with thrombophilia. It may rarely present with cerebral venous sinus thrombosis, which manifests clinically with signs of raised intracranial pressure and requires lifelong anticoagulation therapy. One such rare presentation was seen in a 28 years old male who had history of recurrent episodes of passing red colored urine and this time presented with severe headache. He was diagnosed to have cerebral venous sinus thrombosis and on further workup was found to be suffering from PNH.