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Marchiafava Micheli syndrome [keywords]
- 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.
- Paroxysmal nocturnal hemoglobinuria in an 86 year old woman. [JOURNAL ARTICLE]
- Rev Clin Esp 2014 Aug 12.
- Delayed duodenal obstruction after intramural hematoma in a patient with paroxysmal nocturnal hemoglobinuria: A case report. [JOURNAL ARTICLE]
- Int J Surg Case Rep 2014 Jul 24; 5(9):605-607.
Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal stem cell disorder of hematopoietic cells. Gastrointestinal complications of PNH are rare and mostly related with intravascular thrombosis or intramural hematoma.We describe a case of a man with PNH complicated by intramural duodenal hematoma initially treated with supportive care. Three months after his first admission; he was admitted to the emergency department with abdominal pain, nausea and vomiting. He had undergone to surgery because of duodenal obstruction was treated with duodenojejunal by-pass surgery.Patients were healed from gastrointestinal complications could suffer from gastrointestinal strictures, which cause wide spread symptoms ranging from chronic abdominal pain and anorexia to intestinal obstruction.We report a rare intestinal obstruction case caused by stricture at the level of ligamentum Treitz with PNH. The possibility simply has to be borne in mind that strictures can be occurring at hematoma, ischemia or inflammation site of gastrointestinal tract.
- A novel CRIg-targeted complement inhibitor protects cells from complement damage. [JOURNAL ARTICLE]
- FASEB J 2014 Aug 11.
The inappropriate activation of complement may contribute to various immune diseases. The alternative pathway (AP) predominates during complement activation regardless of the initiating pathways. Hence, the main AP regulator factor H (FH) holds great potential as an attractive therapeutic intervention. In addition, complement receptor of the immunoglobulin superfamily (CRIg) has been demonstrated to inhibit AP and, more notably, still specifically binds to C3b/iC3b. We thus developed novel CRIg-targeted complement inhibitors by connecting the functional domains of CRIg and FH, which we termed CRIg-FH and CRIg-L-FH. CRIg-L-FH, slightly more potent than CRIg-FH, considerably inhibited both AP- and also classical pathway (CP)-mediated hemolysis and successfully eliminated the deposition of C3b/iC3b. Kinetic analysis further revealed that the binding affinity constant (KD) of CRIg/FH was in the micromolar range, consistent with its long-lasting binding to complement-attacked cells. CRIg-L-FH efficiently protected aberrant erythrocytes of patients with paroxysmal nocturnal hemoglobinuria (PNH) from AP- and CP-mediated complement damage (IC50 was 22.43 and 64.69 nM, respectively). Moreover, CRIg-L-FH was found to inhibit complement activation induced by the anti-Thy1 antibody in a mesangioproliferative glomerulonephritis (MPGN) rat model. Hence, CRIg-L-FH protects glomerular mesangial cells (GMCs) from complement-mediated injury and proliferative lesions. These findings strongly suggest that CRIg/FH is a potential therapeutic drug candidate for a range of complement-mediated diseases.-Qiao, Q., Teng, X., Wang, N., Lu, R., Guo, L., Zhang, X., Du, Y., Wang, W., Chen, S., Wu, Q., He, G., Wang, Y., and Hu, W. A novel CRIg-targeted complement inhibitor protects cells from complement damage.