Hematology
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Review
Heparin-induced thrombocytopenia: when a low platelet count is a mandate for anticoagulation.
Heparin-induced thrombocytopenia (HIT) is an immune-mediated disorder caused by the development of antibodies to platelet factor 4 (PF4) and heparin. The thrombocytopenia is typically moderate, with a median platelet count nadir of approximately 50 to 60 x 10(9) platelets/L. Severe thrombocytopenia has been described in patients with HIT, and in these patients antibody levels are high and severe clinical outcomes have been reported (eg, disseminated intravascular coagulation with microvascular thrombosis). ⋯ Alternative agents that have been used effectively in patients with HIT include lepirudin, argatroban, bivalirudin, and danaparoid, although the last agent is not available in North America. Fondaparinux has been used in a small number of patients with HIT and generally appears to be safe. Warfarin therapy should not be initiated until the platelet count has recovered and the patient is systemically anticoagulated, and vitamin K should be administered to patients receiving warfarin at the time of diagnosis of HIT.
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Erythrocytosis results when there is an increased red cell mass and thus an increased hemoglobin. The causes can be divided into primary intrinsic defects of the erythroid progenitor cell and secondary defects, where factors external to the erythroid compartment are responsible. Both can then be further divided into congenital and acquired categories. ⋯ Having eliminated the common entity polycythemia vera, further direction for investigation is guided by the erythropoietin level. Clinical consequences of the various erythrocytoses are not clear, but in some groups thromboembolic events have been described in young patients. Evidence is lacking to define best management, but aspirin and venesection to a target hematocrit should be considered.
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Hematopoietic stem cell (HSC)-targeted gene transfer is an attractive approach for the treatment of a number of hematopoietic disorders caused by single gene defects. Indeed, in a series of gene transfer trials for two different primary immunodeficiencies beginning early in this decade, outstanding success has been achieved. Despite generally low levels of engrafted, genetically modified HSCs, these trials were successful because of the marked selective advantage of gene-corrected lymphoid precursors that allowed reconstitution of the immune system. ⋯ Encouragingly, gene transfer levels in this range have recently been reported in a lentiviral vector gene transfer clinical trial for children with adrenoleukodystrophy. A clinical gene transfer trial for beta-thalassemia has begun in France, and one patient with transfusion-dependent HbE/beta-thalassemia has demonstrated a therapeutic effect after transplantation with autologous CD34(+) cells genetically modified with a beta-globin lentiviral vector. Here, the development and recent progress of gene therapy for the hemoglobin disorders is reviewed.
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The emergence of resistance to imatinib has become a significant problem despite the remarkable clinical results achieved with this tyrosine kinase inhibitor in the treatment of chronic myeloid leukaemia. The most common cause of imatinib resistance is the selection of leukemic clones with point mutations in the Abl kinase domain. These mutations lead to amino acid substitutions and prevent the appropriate binding of imatinib. ⋯ A multitude of novel agents have been developed and have shown in vitro and in vivo efficacy in overcoming imatinib resistance. In this review, we will discuss the current status of the ATP-competitive and non-ATP-competitive Bcr-Abl tyrosine kinase inhibitors. We will also describe inhibitors acting on targets found in signaling pathways downstream of Bcr-Abl, such as the Ras-Raf-mitogen-activated protein kinase and phosphatidylinositol-3 kinase-Akt-mammalian target of rapamycin pathways, and targets without established links with Bcr-Abl.
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Systematic reviews can help practitioners keep abreast of the medical literature by summarizing large bodies of evidence and helping to explain differences among studies on the same question. A systematic review involves the application of scientific strategies, in ways that limit bias, to the assembly, critical appraisal, and synthesis of all relevant studies that address a specific clinical question. ⋯ Used increasingly to inform medical decision making, plan future research agendas, and establish clinical policy, systematic reviews may strengthen the link between best research evidence and optimal health care. In this article, we discuss key steps in how to critically appraise and how to conduct a systematic review or meta-analysis.