DMT1 mutation: response of anemia to darbepoetin administration and implications for iron homeostasis.

Blood (Impact Factor: 9.78). 08/2006; 108(1):404-5. DOI: 10.1182/blood-2006-02-003962
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    ABSTRACT: Abstract Aim To assess thromboprophylaxis prescribing patterns against current guidelines and report thromboembolism (TE) incidence in multiple myeloma (MM) patients treated with thalidomide (thal) or lenalidomide (len) at a specialist cancer hospital over a one-year period. Method Dispensing records of thal and len, diagnosis of MM, patients’ characteristics, disease status, co-prescribed medicines including thromboprophylaxis and incidence of TE were extracted from patients’ records and a patient survey conducted to identify patients who sourced thromboprophylactic medicines outside the hospital. Results Enoxaparin was most the commonly prescribed thromboprophylactic agent (43%), followed by low-dose aspirin (26%) and therapeutic warfarin (6%). The thromboprophylactic strategy (including no prophylaxis) could not be determined for 22% of patients. TE incidence (with any thromboprophylaxis) was 9.3 and 9.1% in thal-based and len-based regimens, respectively. Conclusion Both aspirin and enoxaparin thromboprophylaxis were prescribed for patients on both low-risk and high-risk immunomodulatory drug-based regimens, deviating from current consensus guidelines. Treatment of comorbidities constituted the rationale for maintenance on therapeutic warfarin. Fixed low-dose warfarin was not prescribed. TE event rates (with any thromboprophylaxis) were consistent with those reported in the literature. Documentation of a chosen strategy was lacking for nearly a quarter of patients, resulting in uncertainty of treatment plan for other members of the multidisciplinary treating team. Centers need to work towards evidence-based institutional guidelines and improving documentation practices for thromboprophylaxis in their MM patients.
    Asia-Pacific Journal of Clinical Oncology 09/2012; 9(2):2012. DOI:10.1111/ajco.12013 · 1.06 Impact Factor
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    ABSTRACT: Background Hypochromic microcytic anemia associated with ineffective erythropoiesis caused by recessive mutations in divalent metal transporter 1 (DMT1) can be improved with high-dose erythropoietin supplementation. The aim of this study was to characterize and compare erythropoiesis in samples from a DMT1-mutant patient before and after treatment with erythropoietin, as well as in a mouse model with a DMT1 mutation, the mk/mk mice. DESIGN AND METHODS: Colony assays were used to compare the in vitro growth of pre-treatment and post-treatment erythroid progenitors in a DMT1-mutant patient. To enable a comparison with human data, high doses of erythropoietin were administered to mk/mk mice. The apoptotic status of erythroblasts, the expression of anti-apoptotic proteins, and the key components of the bone marrow-hepcidin axis were evaluated. RESULTS: Erythropoietin therapy in vivo or the addition of a broad-spectrum caspase inhibitor in vitro significantly improved the growth of human DMT1-mutant erythroid progenitors. A decreased number of apoptotic erythroblasts was detected in the patient's bone marrow after erythropoietin treatment. In mk/mk mice, erythropoietin administration increased activation of signal transducer and activator of transcription 5 (STAT5) and reduced apoptosis in bone marrow and spleen erythroblasts. mk/mk mice propagated on the 129S6/SvEvTac background resembled DMT1-mutant patients in having increased plasma iron but differed by having functional iron deficiency after erythropoietin administration. Co-regulation of hepcidin and growth differentiation factor 15 (GDF15) levels was observed in mk/mk mice but not in the patient. Conclusions Erythropoietin inhibits apoptosis of DMT1-mutant erythroid progenitors and differentiating erythroblasts. Ineffective erythropoiesis associated with defective erythroid iron utilization due to DMT1 mutations has specific biological and clinical features.
    Haematologica 05/2012; 97(10):1480-8. DOI:10.3324/haematol.2011.059550 · 5.87 Impact Factor
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    ABSTRACT: Divalent metal transporter 1 (DMT1) is the protein that allows elemental iron entry into the duodenal cell. It is expressed ubiquitously and it also allows the iron exit from the endosomes. This protein plays a central role in iron metabolism and it is strictly regulated. Several animal models elucidate its role in physiology. Recently three patients affected with DMT1 deficiency have been described. This recessively inherited condition appears at birth with severe microcytic anemia. Serum markers could be particularly useful to establish a correct diagnosis: high serum iron, normal total iron-binding capacity (TIBC), increased saturation of transferrin (Tf), slightly elevated ferritin, and increased soluble transferrin receptor (sTfR). Increased free erythrocyte protoporphyrins (FEPs) could address the diagnosis to iron-deficient anemia. All patients appeared to respond to erythropoietin (Epo) administration. Because mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) did not change during Epo treatment, it was concluded that Epo did not improve iron utilization of the erythroblasts but likely reduced the degree or intensity of apoptosis, affecting erythropoiesis. Moreover liver iron overload was present and documented in all of the affected patients. In this review we analyze the role of DMT1 in iron metabolism and the major causes of reduction and their consequences in animal models as well in humans, and we attempt to define the correct treatment for human mutants.
    Seminars in Hematology 10/2009; 46(4):358-70. DOI:10.1053/j.seminhematol.2009.06.005 · 2.46 Impact Factor