- Frequent STAT3 mutations in CD8+ T cells from patients with pure red cell aplasia. [Journal Article]
- BABlood Adv 2018 Oct 23; 2(20):2704-2712
- Dysregulation of T-cell-mediated immunity is responsible for acquired pure red cell aplasia (PRCA). Although STAT3 mutations are frequently detected in patients with T-cell large granular lymphocytic...
Dysregulation of T-cell-mediated immunity is responsible for acquired pure red cell aplasia (PRCA). Although STAT3 mutations are frequently detected in patients with T-cell large granular lymphocytic leukemia (T-LGLL), which is often complicated by PRCA and which is also reported to be associated with acquired aplastic anemia (AA) and myelodysplastic syndrome (MDS), whether STAT3-mutated T cells are involved in the pathophysiology of PRCA and other types of bone marrow failure remains unknown. We performed STAT3 mutation analyses of the peripheral blood mononuclear cells from PRCA patients (n = 42), AA (n = 54), AA-paroxysmal nocturnal hemoglobinuria (AA-PNH; n = 7), and MDS (n = 21) using an allele-specific polymerase chain reaction and amplicon sequencing. STAT3 mutations were not detected in any of the 82 patients with AA/PNH/MDS but were detected in 43% of the 42 PRCA patients. In all 7 STAT3-mutation-positive patients who were studied, the STAT3 mutations were restricted to sorted CD8+ T cells. The prevalence of STAT3 mutation in idiopathic, thymoma-associated, autoimmune disorder-associated, and T-LGLL-associated PRCA was 33% (5 of 15), 29% (2 of 7), 20% (1 of 5), and 77% (10 of 13), respectively. The STAT3-mutation-positive patients were younger (median age, 63 vs 73 years; P= .026) and less responsive to cyclosporine (46% [6 of 13] vs 100% [8 of 8]; P= .0092) in comparison with STAT3-mutation-negative patients. The data suggest that STAT3-mutated CD8+ T cells may be closely involved in the selective inhibition of erythroid progenitors in PRCA patients.
- Revisiting acquired aplastic anaemia: Current concepts in diagnosis and management. [Review]
- IMIntern Med J 2018 Oct 15
- Acquired aplastic anaemia is a rare, serious, immunologically-mediated bone marrow failure syndrome, characterised by marrow hypoplasia of varying severity and significant pancytopenia. Careful atten...
Acquired aplastic anaemia is a rare, serious, immunologically-mediated bone marrow failure syndrome, characterised by marrow hypoplasia of varying severity and significant pancytopenia. Careful attention and investigation, including molecular testing, is required to confirm the diagnosis and exclude other mimicking conditions, such as inherited bone marrow failure syndromes. In a proportion of patients, the disease evolves to myelodysplasia or acute myeloid leukaemia and in some there is an association with paroxysmal nocturnal haemoglobinuria. The disease has a major impact on patient quality of life. Haematopoietic stem/progenitor cell transplantation for eligible patients with an available donor is the only current curative therapy. Other patients may receive immunosuppression, most commonly with anti-thymocyte globulin and cyclosporin. An initial response to immunosuppression is often encouraging but relapse is common. Supportive care, including management of transfusion requirements and infections, is central to management. Promising new diagnostic tools and emerging therapies will likely transform approaches to this important, chronic and life-threatening condition. This article is protected by copyright. All rights reserved.
- Iron Deficiency in Patients with Paroxysmal Nocturnal Hemoglobinuria: A Cross-Sectional Survey from a Single Institution in China. [Journal Article]
- MSMed Sci Monit 2018 Oct 11; 24:7256-7263
- CONCLUSIONS: This survey shows that PNH patients were prone to iron deficiency, especially patients with classical PNH.
- Rare thrombophilic conditions. [Review]
- ATAnn Transl Med 2018; 6(17):342
- Thrombophilia, either acquired or inherited, can be defined as a predisposition to developing thromboembolic complications. Since the discovery of antithrombin deficiency in the 1965, many other cond...
Thrombophilia, either acquired or inherited, can be defined as a predisposition to developing thromboembolic complications. Since the discovery of antithrombin deficiency in the 1965, many other conditions have been described so far, which have then allowed to currently detect an inherited or acquired predisposition in approximately 60-70% of patients with thromboembolic disorders. These prothrombotic risk factors mainly include qualitative or quantitative defects of endogenous coagulation factor inhibitors, increased concentration or function of clotting proteins, defects in the fibrinolytic system, impaired platelet function, and hyperhomocysteinemia. In this review article, we aim to provide an overview on epidemiologic, clinic and laboratory aspects of both acquired and inherited rare thrombophilic risk factors, especially including dysfibrinogenemia, heparin cofactor II, thrombomodulin, lipoprotein(a), sticky platelet syndrome, plasminogen activator inhibitor-1 apolipoprotein E, tissue factor pathway inhibitor, paroxysmal nocturnal haemoglobinuria and heparin-induced thrombocytopenia.
- Ecthyma Gangrenosum in Paroxysmal Nocturnal Hemoglobinuria. [Letter]
- AHActa Haematol 2018 Oct 09; 140(3):166-168
- Significant hemolysis is not required for thrombosis in paroxysmal nocturnal hemoglobinuria. [Journal Article]
- HHaematologica 2018 Oct 04
- Centipede envenomation: Clinical importance and the underlying molecular mechanisms. [Journal Article]
- TToxicon 2018; 154:60-68
- Centipede bites are usually characterized by mildly to moderately painful encounters with humans, however, they are relatively infrequent. The vast majority of centipede envenomations do not cause se...
Centipede bites are usually characterized by mildly to moderately painful encounters with humans, however, they are relatively infrequent. The vast majority of centipede envenomations do not cause severe symptoms and only in very rare cases more serious symptoms such as myocardial ischemia and infarction, hematuria, hemoglobinuria, rhabdomyolysis, hemorrhage, pruritus, eosinophilic cellulitis, as well as anaphylaxis are observed. More prevalent are symptoms including pain, paresthesia, lethargy, localized necrosis, headache, dizziness and nausea. The numerous symptoms and complications elicited by these envenomations indicate that centipede venom possesses an arsenal of chemical components with functional diversity. Centipede venom is a rich and complex natural source of bioactive proteins, peptides and other small molecules that aid in predation or defense. The venom can induce myotoxic, cardiotoxic, neurotoxic and other toxic effects. The constituents target different cellular processes and pathways which in turn trigger a cascade of physiological reactions in the victim. The venom components are potent and selective on peripheral targets; thus, they are valuable in studying the molecular basis of these envenomation symptoms and complications. This review highlights the clinical importance of centipede envenomation and the recent discoveries on the underlying molecular mechanisms of the resulting symptoms which is crucial in therapy.
- Recurrent aseptic meningitis with PIGT mutations: a novel pathogenesis of recurrent meningitis successfully treated by eculizumab. [Journal Article]
- BCBMJ Case Rep 2018 Sep 27; 2018
- We report the case of a patient with PIGT mutations who experienced recurrent aseptic meningitis 121 times over 16 years before developing paroxysmal nocturnal haemoglobinuria (PNH). Each episode was...
We report the case of a patient with PIGT mutations who experienced recurrent aseptic meningitis 121 times over 16 years before developing paroxysmal nocturnal haemoglobinuria (PNH). Each episode was preceded by urticaria and arthralgia. After developing PNH, haemolysis occurred prior to meningitis. Flow cytometry revealed deficiency of the glycophosphatidylinositol (GPI)-anchored complement regulatory proteins, CD59 and CD55, and he was diagnosed with PNH. All the symptoms disappeared on administering eculizumab, an anti-C5 antibody. We did not detect mutation in PIGA, which is regarded as the cause of PNH. However, we detected a germ-line mutation and a somatic microdeletion in chromosome 20q including PIGT; PIGT is essential for transferring GPI anchor to the precursors of CD59 and CD55, which play important roles in complement regulation. Loss of these proteins leads to complement overactivation, causing inflammatory symptoms, including recurrent meningitis. PIGT mutations should be considered a novel pathogenesis of recurrent meningitis of unknown aetiology.
- The Risk of Clonal Evolution of Granulocyte Colony-Stimulating Factor for Acquired Aplastic Anemia: A Systematic Review and Meta-Analysis. [Journal Article]
- AHActa Haematol 2018 Sep 25; 140(3):141-145
- CONCLUSIONS: G-CSF for patients with AA is not associated with a higher occurrence of secondary malignant neoplasm, mainly MDS/AML, or PNH.
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- How we treat paroxysmal nocturnal hemoglobinuria: a consensus statement of the Canadian PNH Network and review of the national registry. [Review]
- EJEur J Haematol 2018 Sep 22
- Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease characterized by intravascular hemolysis, thrombophilia, and marrow failure. Its phenotype is due to absent or reduced expressi...
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease characterized by intravascular hemolysis, thrombophilia, and marrow failure. Its phenotype is due to absent or reduced expression of GPI-linked complement regulators and subsequent sensitivity of hematopoietic cells to complement-mediated damage and lysis. Introduction of the terminal complement inhibitor eculizumab drastically improved outcomes in PNH patients; however, despite this improvement, there remain several challenges faced by PNH patients and physicians who care for them. One of the most important is increasing awareness of the heterogeneity with which patients can present, which can lead to significant delays in recognition. Data from the Canadian PNH Registry are presented to demonstrate the variety of presenting symptoms. In Canada, geography precludes consolidation of care to just a few centres, so management is distributed across academic hospitals, linked together as the Canadian PNH Network. The Network over the last several years has developed educational programs, clinical check-lists, and has worked to standardize access to diagnostics across the country. Herein we address some of the common diagnostic and therapeutic challenges faced by PNH physicians and give our recommendations. Gaps in knowledge are also addressed and, where appropriate, consensus opinion is provided. This article is protected by copyright. All rights reserved.