ABSTRACT
Mutations in the transcription factors GATA binding factor 1 (GATA1), growth factor independence 1B (GFI1B), and Runt-related transcription factor 1 (RUNX1) cause familial platelet and bleeding disorders. Mutant platelets exhibit common abnormalities including an α-granule reduction resulting in a grayish appearance in blood smears. This suggests that similar pathways are deregulated by different transcription factor mutations. To identify common factors, full platelet proteomes from 11 individuals with mutant GATA1R216Q, GFI1BQ287*, RUNX1Q154Rfs, or RUNX1TD2-6 and 28 healthy controls were examined by label-free quantitative mass spectrometry. In total, 2875 platelet proteins were reliably quantified. Clustering analysis of more than 300 differentially expressed proteins revealed profound differences between cases and controls. Among cases, 44 of 143 significantly downregulated proteins were assigned to platelet function, hemostasis, and granule biology, in line with platelet dysfunction and bleedings. Remarkably, none of these proteins were significantly diminished in all affected cases. Similarly, no proteins were commonly overrepresented in all affected cases compared with controls. These data indicate that the studied transcription factor mutations alter platelet proteomes in distinct largely nonoverlapping manners. This work provides the quantitative landscape of proteins that affect platelet function when deregulated by mutated transcription factors in inherited bleeding disorders.
Subject(s)
Blood Platelet Disorders/metabolism , Blood Platelets/metabolism , Core Binding Factor Alpha 2 Subunit/metabolism , GATA1 Transcription Factor/metabolism , Proteome/metabolism , Proto-Oncogene Proteins/metabolism , Repressor Proteins/metabolism , Homeostasis , Humans , Mutation/genetics , Signal Transduction , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
BACKGROUND AND OBJECTIVES: Evidence-based guidelines on optimal triggers for red blood cell (RBC) transfusion in patients with haematological malignancies exist, but the evidence is weak. Secondary iron overload is an often overlooked chronic complication of RBC transfusions, and also here, guidelines are either lacking or lack international consensus. Our aim was to evaluate the triggers for RBC transfusion support and management of secondary iron overload among haematologists in the Netherlands. MATERIALS AND METHODS: For this cross-sectional study, all haematologists and haematologists in training in the Netherlands were sent a web-based, 25-question survey including three clinical scenarios. The survey distribution took place between 19 November 2015 and 26 January 2016. RESULTS: Seventy-seven responses were received (24%), well distributed among community and university hospitals. A wide variation in haemoglobin triggers existed: 5·6-9·5 g/dl (median: 8·0 g/dl). Personalization of this trigger was mostly based on (estimated) cardiopulmonary compensation capacity of patients. About 65% of respondents reported two RBC units per transfusion episode (range 1-3). For monitoring secondary iron overload, serum ferritin was most frequently measured (97%), while a value of 1000-1500 µg/l was the most common cut-off to initiate treatment (39%). For 81% of respondents, phlebotomies were the first choice of treatment, although often the haemoglobin level was considered a limiting factor. CONCLUSION: Our results confirm large reported variation in daily practice among haematologists in the Netherlands regarding RBC transfusion support and management of secondary iron overload. Future studies providing better evidence are needed to improve guidelines specific for patients with haematological malignancies.
Subject(s)
Erythrocyte Transfusion/standards , Hematologic Neoplasms/therapy , Iron Overload/prevention & control , Adult , Erythrocyte Transfusion/adverse effects , Erythrocyte Transfusion/methods , Evidence-Based Practice/methods , Hemoglobins/metabolism , Humans , Iron Overload/etiology , Male , Middle Aged , Netherlands , Practice Guidelines as Topic , Surveys and QuestionnairesSubject(s)
Antidepressive Agents/adverse effects , Antiemetics/adverse effects , Carcinoma/drug therapy , Dibenzothiazepines/adverse effects , Laryngeal Neoplasms/drug therapy , Morpholines/adverse effects , Adult , Antidepressive Agents/administration & dosage , Antidepressive Agents/metabolism , Antiemetics/administration & dosage , Antiemetics/metabolism , Antineoplastic Agents/administration & dosage , Aprepitant , Chemoradiotherapy , Cisplatin/administration & dosage , Citalopram/administration & dosage , Depression/drug therapy , Dexamethasone/administration & dosage , Dibenzothiazepines/administration & dosage , Dibenzothiazepines/metabolism , Drug Interactions , Humans , Male , Morpholines/administration & dosage , Morpholines/metabolism , Ondansetron/administration & dosage , Quetiapine FumarateABSTRACT
Phenylketonuria (PKU) is a classical example of an inherited metabolic disease, in which mental retardation can be prevented successfully by using a diet. However, in adult PKU new problems occur, such as vitamin deficiencies, osteoporosis and the maternal PKU syndrome. The aim of this review article is to provide guidelines for the clinician to understand and manage PKU in adults.
