Seminars in hematology
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Seminars in hematology · Jul 2015
ReviewEpigenetic Therapy in Acute Myeloid Leukemia: Current and Future Directions.
Epigenetic modifications affect gene expression without changes in the actual DNA sequence. Two of the most important mechanisms include DNA methylation and histone tail modifications (especially acetylation and methylation). Epigenetic modulation is a part of normal physiologic development; its dysregulation is an important mechanism of pathogenesis of some cancers, including acute myeloid leukemia (AML). ⋯ Currently, no epigenetic therapy is approved for the treatment of AML, although two DNA methyltransferase inhibitors (azacitidine and decitabine) are commonly used in clinical practice. Among the other epigenetic modifiers undergoing research in AML, the histone deacetylase inhibitors are the most studied. Other promising drugs, such as inhibitors of histone methylation (eg, EZH2 and DOT1L inhibitors), inhibitors of histone demethylases (eg, LSD1 inhibitors), inhibitors of bromodomain-containing epigenetic "reader" BET proteins, and inhibitors of mutant isocitrate dehydrogenases, are at early stages of clinical evaluation.
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The treatment of aplastic anemia is currently with immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) and cyclosporine, to which two thirds of patients respond. However, a significant proportion of these responders relapse and many have persistent cytopenias. The management of these patients is challenging. ⋯ A recent trial has shown that eltrombopag, a thrombopoeitin mimetic, is efficacious in the treatment of patients with severe aplastic anemia (SAA) refractory to IST. There is evidence that this drug works by directly stimulating marrow stem and progenitor cells thereby promoting hematopoietic recovery in patients with bone marrow failure. Several trials are ongoing in our institution using this very promising drug in combination therapy in the upfront treatment of SAA, in IST-refractory SAA and in moderate disease.
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Seminars in hematology · Apr 2014
ReviewDirect oral anticoagulants in the prevention of venous thromboembolism: evidence from major clinical trials.
Hospitalized medical and surgical patients encompass a group of patients in whom venous thromboembolism (VTE) poses a major concern on morbidity and mortality. Recently, direct oral anticoagulants for the prevention of VTE have been developed to overcome the drawbacks of the food/drug interactions and the need for frequent laboratory monitoring and dose adjustments associated with the use of vitamin K antagonists and the inconvenience of the subcutaneous administration of low-molecular-weight heparins and fondaparinux. The novel oral anticoagulants that have been tested in major clinical trials for VTE prevention in medical and surgical patients are the thrombin inhibitor dabigatran and the factor Xa inhibitors apixaban, rivaroxaban, and edoxaban, which will be the focus of this review. While the new drugs proved to be highly effective and safe in the prevention of VTE following major orthopedic surgery, they failed to show a favorable benefit-to-risk profile in hospitalized medical patients receiving extended anticoagulation beyond the hospital stay.
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Seminars in hematology · Apr 2014
ReviewPerioperative management issues of direct oral anticoagulants.
The treatment repertoire of oral anticoagulation has changed dramatically over the past few years from one class of vitamin K1 antagonists to an increasing number of direct oral anticoagulants (DOACs). Clinicians are confronted with the problem of managing patients on novel agents in the critical setting before, during, and after surgery, where the risk of bleeding and thrombosis are increased simultaneously. ⋯ The following review considers perioperative management issues in various categories, including minor elective surgery, major elective surgery, and acute surgery. This review is a credo to personalized medicine where the patient's underlying thromboembolic risk status, the potential bleeding risk, or actual hemorrhagic manifestation determine the selection of multi-modal targeted management strategies.
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Seminars in hematology · Apr 2014
Direct oral anticoagulants--pharmacology, drug interactions, and side effects.
The direct thrombin inhibitor, dabigatran, as well as the direct factor Xa inhibtors rivaroxaban, apixaban, and edoxaban, display pharmacodynamic features quite similar to low-molecular-weight heparins, with a time to peak level of 1-4 hours after oral administration, and a half-life between 5 and 14 hours. All drugs display a linear relationship and a high degree of correlation between drug levels in plasma, and the anticoagulant effect. Major differences are the extent of renal elimination (with 80% or more for dabigatran, 66% for rivaroxaban [33% unchanged, active drug, and 33% inactive metabolites], 33% for edoxaban, and finally, 25% for apixaban), and bioavailability, which determines the amount of drug required for attaining the target plasma concentration of the drug. Due to the reliable pharmacokinetics and pharmacodynamics, no routine laboratory monitoring is necessary, although dedicated laboratory assays are available for emergencies and some other specific conditions.