The 40-fold increase in childhood megakaryocyte-erythroid and B-cell leukemia in Down syndrome implicates trisomy 21 (T21) in perturbing fetal hematopoiesis. Here, we show that compared with primary disomic controls, primary T21 fetal liver (FL) hematopoietic stem cells (HSC) and megakaryocyte-erythroid progenitors are markedly increased, whereas granulocyte-macrophage progenitors are reduced. Commensurately, HSC and megakaryocyte-erythroid progenitors show higher clonogenicity, with increased megakaryocyte, megakaryocyte-erythroid, and replatable blast colonies. Biased megakaryocyte-erythroid-primed gene expression was detected as early as the HSC compartment. In lymphopoiesis, T21 FL lymphoid-primed multipotential progenitors and early lymphoid progenitor numbers are maintained, but there was a 10-fold reduction in committed PreproB-lymphoid progenitors and the functional B-cell potential of HSC and early lymphoid progenitor is severely impaired, in tandem with reduced early lymphoid gene expression. The same pattern was seen in all T21 FL samples and no samples had GATA1 mutations. Therefore, T21 itself causes multiple distinct defects in FL myelo-and lymphopoiesis.transient myeloproliferative disorder | aneuploidy | human fetus C onstitutional trisomy 21 (T21) causes Down syndrome (DS), the most common syndrome-associated chromosomal anomaly in humans (1). As well as with neurodevelopmental, cardiac, and gut anomalies (2), there is a striking increase in childhood acute leukemia in DS, even though the risk of solid tumors is much lower than with the general population (3). Intriguingly, this susceptibility to hematopoietic tumors manifests as an increased risk both of acute megakaryocyte (MK)-erythroid leukemia (known as ML-DS) by 150-fold and of acute B-lymphoblastic leukemia (B-ALL) by 33-fold (3, 4).DS leukemias display distinct characteristics that support a crucial role for T21 in their pathogenesis. Hallmarks of ML-DS are the megakaryoblastic phenotype, clinical presentation confined to the first 5 y of childhood (5, 6), an antecedent clonally linked preleukemic condition (termed transient myeloproliferative disorder, TMD) in most cases, and acquired N-terminal truncating mutations in the erythroid-MK transcription factor GATA1 (7-9). Such mutations in GATA1 are present in both ML-DS and TMD (9) but are not found in patients without DS who develop megakaryoblastic leukemia (7) and are not leukemogenic in the absence of T21 (10).Molecular, biologic, and clinical data indicate that TMD is initiated before birth (9,(11)(12)(13)(14). We previously reported that by the second trimester, the T21 fetal liver (FL) myeloid progenitor compartment is abnormal and that this occurs in the absence of GATA1 mutation (11, 12). Specifically, the MK-erythroid progenitor (MEP) population is expanded with increased cell-intrinsic MK and erythroid lineage proliferation from CD34 + cells. These data suggest that T21-mediated developmental alterations to FL myeloid progenitor development provide a cell-specific substrate for...

Children with constitutional trisomy 21 (Down syndrome (DS)) have a unique predisposition to develop myeloid leukaemia of Down syndrome (ML-DS). This disorder is preceded by a transient neonatal preleukaemic syndrome, transient abnormal myelopoiesis (TAM). TAM and ML-DS are caused by co-operation between trisomy 21, which itself perturbs fetal haematopoiesis and acquired mutations in the key haematopoietic transcription factor gene GATA1. These mutations are found in almost one third of DS neonates and are frequently clinically and haematologcially ‘silent’. While the majority of cases of TAM undergo spontaneous remission, ∼10 % will progress to ML-DS by acquiring transforming mutations in additional oncogenes. Recent advances in the unique biological, cytogenetic and molecular characteristics of TAM and ML-DS are reviewed here.

Key Points EBF1-PDGFRB fusion accounts for ∼0.5% of B-cell precursor acute lymphoblastic leukemia and 2.7% of the B-other subtype. EBF1-PDGFRB-positive patients are MRD positive and are slow early responders who respond to imatinib.

This guideline was compiled according to the British Society for Haematology (BSH) process at https://b-s-h.org.uk/med ia/16732/bsh-guidance-development-process-dec-5-18.pdf. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http:// www.gradeworkinggroup.org. The references to support the recommendations are listed in the preceding discussion. Literature review The information contained in this review was gathered from several sources. These included references from a search of MEDLINE, EMBASE and the Cochrane databases to identify studies and reviews relevant to prophylaxis in patients with haemophilia, abstracts from international meetings and references known to the authors (Appendix S1). Review of the manuscript The writing group produced the draft guideline, which was subsequently revised by consensus. Review of the manuscript was performed by the BSH Guidelines Committee Haemostasis and Thrombosis Taskforce, the BSH Guidelines Committee and the Haemostasis and Thrombosis sounding board of the BSH. It was also on the members section of the BSH website for comment. It has also been reviewed by members of the United Kingdom Haemophilia Centre Doctors' Organisation (UKHCDO) Advisory Board, Haemophilia Nurses Association (HNA), Haemophilia Chartered Physiotherapists Association (HCPA); these organisations do not necessarily approve or endorse the contents.

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Intracranial haemorrhage occurs most frequently in children with severe IBDs, during the first 2 years of life and in children not receiving prophylaxis. Intracranial haemorrhage often occurs without documented trauma.

Among a cohort of adolescents with VTE, a small proportion (13%) had an indication to consider chemical thromboprophylaxis but did not receive it. VTE risk assessment and prevention should focus on adolescents with immobility or surgery, particularly in those with malignancy.