Hematology
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Beta-thalassemia is a genetic disorder with mutations in the β-globin gene that reduce or abolish β-globin protein production. Patients with β-thalassemia major (Cooley's anemia) become severely anemic by 6 to 18 months of age, and are transfusion dependent for life, while those with thalassemia intermedia, a less-severe form of thalassemia, are intermittently or rarely transfused. An allogeneically matched bone marrow transplant is curative, although it is restricted to those with matched donors. ⋯ Lentivirus vectors, on the other hand, have now been shown in several studies to correct mouse and animal models of thalassemia. The immediate challenges of the field as it moves toward clinical trials are to optimize gene transfer and engraftment of a high proportion of genetically modified HSCs and to minimize the adverse consequences that can result from random integration of vectors into the genome by improving current vector design or developing novel vectors. This article discusses the current state of the art in gene therapy for β-thalassemia and some of the challenges it faces in human trials.
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Recombinant human factor VIIa (rFVIIa) is approved by the US Food and Drug Administration for use in the setting of hemorrhage associated with factor VIII or factor IX inhibitors in patients with congenital or acquired hemophilia. This indication represents only a small number of bleeding conditions. Since it became available, rFVIIa has been increasingly used in the management of off-label indications, ranging from emergent hemostasis in traumatic hemorrhage to prophylactic hemostasis in patients undergoing major surgery. ⋯ Other occasions for use occur in patients with intact coagulation systems, with nontraumatic intracranial hemorrhage being the most common in this group. Uncertainties regarding the efficacy and safety associated with use of rFVIIa in these off-label scenarios have led to evidence-based assessments of patient outcomes, including mortality, the rate of thromboembolic adverse events, and posttreatment functional status. We review the evidence regarding the efficacy and safety of this important, but controversial, hemostatic agent in the off-label setting.
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Injury is the leading cause of life years lost in the United States, and uncontrolled hemorrhage is the leading cause of potentially preventable death. Traditionally, these patients have been serially resuscitated with large volumes of crystalloid and/or colloids and red blood cells, followed by smaller amounts of plasma and platelets. Transfusion data coming first from the ongoing war in Iraq and Afghanistan and followed by multiple civilian studies have brought into question this tradition-based practice. ⋯ Although there are strongly held opinions and long-standing traditions in their use, there are little quality data within which to logically guide resuscitation therapy. A multicenter prospective observational study is ongoing, and randomized trials are planned. This review will address the issues raised previously and describe recent trauma patient outcome data utilizing predetermined plasma:platelet:red blood cell transfusion ratios, and possibilities for future transfusion products and research.
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Pain is a frequent complaint of people living with sickle cell disease (SCD); however, the neurobiology of pain in SCD remains poorly understood. Whereas this pain has been thought to be primarily related to visceral and somatic tissue injury subsequent to vaso-occlusion events, emerging evidence from human and animal studies has suggested that a component of SCD pain may be related to neuropathic processes. ⋯ The latest evidence from our studies suggests that these pathways are important for SCD pain as well. Coupled with emerging animal models of SCD pain, we can now start to elucidate neurobiological mechanisms underlying pain in SCD, which may lead to better understanding and effective therapies.
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The use of high ratios of red blood cells to platelets and plasma in trauma resuscitation protocols is quickly gaining favor in civilian trauma centers. The use of higher ratios of coagulation factors to red blood cells has been shown to improve outcomes in both military and civilian centers, but does the evidence support the use of a 1:1:1 ratio, as has been suggested? There is growing evidence that the use of such high ratios may be excessive and potentially harmful, and there has not been enough emphasis on the other components of evidence-based "damage control" resuscitation.