Hematology
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The hereditary periodic fevers are a group of Mendelian disorders characterized by seemingly unprovoked fever and localized inflammation. Recent data indicate that these illnesses represent inborn errors in the regulation of innate immunity. Pyrin, the protein mutated in familial Mediterranean fever, defines an N-terminal domain found in a large family of proteins involved in inflammation and apoptosis. ⋯ Somewhat unexpectedly, mutations in the 55 kDa receptor for tumor necrosis factor also give rise to a dominantly inherited periodic fever syndrome, rather than immunodeficiency, a finding that has stimulated important investigations into both pathogenesis and treatment. Finally, the discovery of the genetic basis of the hyperimmunoglobulinemia D with periodic fever syndrome suggests an as yet incompletely understood connection between the mevalonate pathway and the regulation of cytokine production. These insights extend our understanding of the regulation of innate immunity in man, while providing the conceptual basis for the rational design of targeted therapies, both for the hereditary periodic fevers themselves and other inflammatory disorders as well.
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The treatment of chronic myeloid leukemia (CML) has been revolutionized by the small molecule BCR-ABL-selective kinase inhibitor imatinib. Although imatinib is highly effective initially and generally well-tolerated, relapse is increasingly encountered clinically. Until recently, for the majority of CML patients with disease no longer responsive to imatinib, as well as for patients with imatinib intolerance, few effective therapeutic options existed. ⋯ Notably, neither of these compounds is effective against the imatinib-resistant BCR-ABL/T315I mutation. The potential availability of highly effective medications for the treatment of imatinib-resistant and intolerant cases of CML is expected to further complicate the timing of other effective therapies, such as allogeneic stem cell transplantation. Additionally, periodic genotyping of the BCR-ABL kinase domain to screen for drug-resistant mutations may play an increasingly important role in the future management of CML cases.
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Gene transfer for beta-thalassemia requires gene transfer into hematopoietic stem cells using integrating vectors that direct regulated expression of beta globin at therapeutic levels. Among integrating vectors, oncoretroviral vectors carrying the human beta-globin gene and portions of the locus control region (LCR) have suffered from problems of vector instability, low titers and variable expression. In recent studies, human immunodeficiency virus-based lentiviral (LV) vectors were shown to stably transmit the human beta-globin gene and a large LCR element, resulting in correction of beta-thalassemia intermedia in mice. ⋯ In summary, LV vectors have paved the way for clinical gene therapy trials for Cooley's anemia and other beta-globin disorders. SIN-LV vectors address several safety concerns of randomly integrating viral vectors by removing viral transcriptional elements and providing lineage-restricted expression. Flanking the proviral cassette with chromatin insulator elements, which additionally have enhancer-blocking properties, may further improve SIN-LV vector safety.
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Thrombotic thrombocytopenic purpura (TTP) is characterized by microangiopathic hemolytic anemia and thrombocytopenia, accompanied by microvascular thrombosis that causes variable degrees of tissue ischemia and infarction. Intravascular coagulation is not a prominent feature of the disorder. Plasma exchange can induce remissions in approximately 80% of patients with idiopathic TTP, but patients have a much worse prognosis when thrombotic microangiopathy is associated with cancer, certain drugs, infections, or tissue transplantation. ⋯ Severe ADAMTS13 deficiency is specific for idiopathic TTP and identifies a subgroup with a high likelihood of response to plasma exchange, and high-titer ADAMTS13 inhibitors correlate strongly with a high risk of relapsing disease. Patients with normal ADAMTS13 activity have a much worse prognosis, although many factors probably contribute to this difference. Longitudinal study of these patients will continue to clarify the relationship of ADAMTS13 deficiency to the clinical course of thrombotic microangiopathy.
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In the vein-to-vein flow of blood from donor to patient, the role of the transfusion medicine specialist has become increasingly centered at the bedside. Three clinically centered issues in blood safety and in blood conservation are presented in this chapter. In Section I, Dr. ⋯ In Section III, Dr. Lawrence Goodnough and colleagues present a transfusion medicine service approach to the utilization of recombinant factor VIIa (rFVIIa) in non-approved clinical settings. rFVIIa has a potential role as a hemostatic intervention in a variety of clinical settings, yet few clinical trials have been completed to date to guide indications for its use. The policies presented here are those in place at the authors' medical center, and will undergo periodic review and revision as relevant new information and data are generated.