Revisiting acquired aplastic anaemia: current concepts in diagnosis and management

Clucas, Danielle; Fox, Lucy; Wood, Erica M.; Hong, Frank; Gibson, John; Bajel, Ashish; Szer, Jeffrey; Blombery, Piers; McQuilten, Zoe; Hiwase, Devendra; Firkin, Frank; Cole‐Sinclair, Merrole

doi:10.1111/imj.14140

Cited by 17 publications

(20 citation statements)

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“…Acquired aplastic anemia (AA) is characterized by a hypoplastic, fatty bone marrow (BM) with profound reductions in hematopoietic stem/progenitor cells (HSCs/HPCs) that lead to defective mature blood cell production and peripheral pancytopenia (1–3). Diagnosis of AA requires per definition at least two of the following criteria: Hemoglobin <100 g/L, platelets <50 G/L and neutrophils <1.5 G/L, together with a hypocellular BM and in the absence of abnormal infiltrates or fibrosis (4). The description of AA as an “empty” BM in which hematopoietic cells have been replaced by fat cells was first made by Paul Ehrlich (5).…”

Section: Introductionmentioning

confidence: 99%

“…The description of AA as an “empty” BM in which hematopoietic cells have been replaced by fat cells was first made by Paul Ehrlich (5). Nowadays, AA is defined by decreased numbers of BM HSCs and HPCs resulting in a hypo- or aplastic BM with precocious fat replacement (1, 4).…”

Section: Introductionmentioning

confidence: 99%

“…Next to the disease cause, disease severity and patient's age influence treatment choices. In symptomatic acquired AA, supportive treatment with erythrocyte and platelet transfusions and infection prevention is provided (4, 7). For severe cases, the first-line treatment is allo-HCT from a matched sibling donor in young patients (7–10) and IST in older patients without a well-matched donor (15, 17, 18).…”

Section: Introductionmentioning

confidence: 99%

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Pathogenesis of Acquired Aplastic Anemia and the Role of the Bone Marrow Microenvironment

et al. 2018

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Aplastic anemia (AA) is characterized by bone marrow (BM) hypocellularity, resulting in peripheral cytopenias. An antigen-driven and likely auto-immune dysregulated T-cell homeostasis results in hematopoietic stem cell injury, which ultimately leads to the pathogenesis of the acquired form of this disease. Auto-immune and inflammatory processes further influence the disease course as well as response rate to therapy, mainly consisting of intensive immunosuppressive therapy and allogeneic hematopoietic cell transplantation. Bone marrow hematopoietic stem and progenitor cells are strongly regulated by the crosstalk with the surrounding microenvironment and its components like mesenchymal stromal cells, also consistently altered in AA. Whether latter is a contributing cause or rather consequence of the disease remains an open question. Overall, niche disruption may contribute to disease progression, sustain pancytopenia and promote clonal evolution. Here we review the existing knowledge on BM microenvironmental changes in acquired AA and discuss their relevance for the pathogenesis and therapy.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pathogenesis of Acquired Aplastic Anemia and the Role of the Bone Marrow Microenvironment

et al. 2018

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“…23 Augmented expression of granzymes B and C and perforin in DGKζ -/mouse BM denotes an increase in cytotoxic T cells (CTL) similar to that described in AA patients. 24 Activated T lymphocytes cause BM destruction in AA; 25 DGKζ -/mice showed reduced BM cellularity ( Figure 1D). Analysis of the TER-119 + erythroid lineage populations did not show differences between DGKζ -/and WT mice ( Figure 1E).…”

Section: Resultsmentioning

confidence: 99%

Diacylglycerol kinase ζ deficiency triggers early signs of aplastic anemia in mice

Martin-Salgado¹,

Andrada

Liébana³

et al. 2020

Preprint

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Key points• DGKζ-deficiency in mice results in larger numbers of CD69-positive T cells in bone marrow, with enhanced expression of IFNγ and lytic enzymes.• DGKζ loss recapitulates many clinical aspects of human aplastic anemia, identifying a critical hub for immune system-dependent bone marrow failure. Visual abstractAbstract Acquired aplastic anemia (AA) is a rare blood disorder that results from immune-mediated destruction of bone marrow (BM) progenitor cells. Improved understanding of the mechanisms that favor T cell attack in BM could help to improve early diagnosis and disease treatment. Diacylglycerol kinase ζ (DGKζ) limits T cell responses through phosphorylation of diacylglycerol into phosphatidic acid. This reaction attenuates diacylglycerol-dependent activation of the Ras/ERK/CD69 and PKCθ/NFκB pathways in response to antigen. Here we show that, in contrast to the lack of basal activation observed in peripheral lymphoid organs, DGKζ -/mice showed increased numbers of activated T cells in BM, together with a significant increase in IFNγ as well as perforin and granzyme B and C levels. The enhanced presence of T cells in DGKζ -/mouse BM correlates with reduced BM cellularity, impaired hematopoiesis, and lower frequency of circulating red cells, granulocytes, and platelets. Our studies coincide with the recent characterization of lower DGKζ expression in T cells isolated from the BM of patients with acquired AA, and suggest that limited DGKζ expression and/or functions predispose to T cell-mediated BM destruction. This study identifies the BM as a niche particularly sensitive to DGKζ deficiency and indicates that this mouse model could be of interest for studying the mechanism that contributes to AA development.

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“…Acquired bone marrow failure (BMF) occurs more commonly and may be the result of exogenous marrow insult with drugs, toxins or viruses. A further important subcategory of acquired BMF is idiopathic aplastic anaemia (AA), a nonmalignant but potentially life‐threatening disease caused by autoimmune destruction of the haemopoietic progenitor/stem cell compartment 1 . An additional important acquired BMF subcategory is the hypocellular form of myelodysplastic syndrome (MDS).…”

Section: Introductionmentioning

confidence: 99%

Diagnostic evaluation and considerations in hypocellular bone marrow failure—A focus on genomics

Fox

Wood

Ritchie

et al. 2020

Int J Lab Hematology

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Hypocellular bone marrow failure (BMF) has myriad differential diagnoses, most simply considered as acquired and inherited disorders, which are frequently indistinguishable upon morphologic examination of the blood and bone marrow. Accurate diagnosis is critical to optimization of management and begins with a detailed history (including family history) and physical examination. Next‐generation sequencing technologies complement traditional testing techniques (such as chromosomal fragility and telomere length assessment) and have a broad application in the diagnosis and prognostication of BMF, with the importance of detection of both germline changes and also somatic variants increasingly well understood and appreciated. There is increasing awareness of germline predisposition to haematological malignancy, which incorporates but is not limited to the traditional inherited BMF syndromes and which raises challenges for counselling, monitoring and treatment of people who harbour a germline lesion. There are many benefits to both patients and their kindred of accurate determination of the precise germline change underlying heritable bone marrow diseases, along with its associated mode of inheritance. While individually, these diseases are rare, collectively they are not so and there are many collaborative efforts underway to document the natural history of these disorders, the associated phenotypes and the ever‐increasing list of variants which have sufficient evidence to warrant the ascription of a pathogenic classification. We describe the many diagnostic considerations when evaluating newly presenting patients with hypocellular BMF, with a focus on genomic assessment, which is relevant in both germline and acquired diseases.

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Revisiting acquired aplastic anaemia: current concepts in diagnosis and management

Cited by 17 publications

References 50 publications

Pathogenesis of Acquired Aplastic Anemia and the Role of the Bone Marrow Microenvironment

Pathogenesis of Acquired Aplastic Anemia and the Role of the Bone Marrow Microenvironment

Diacylglycerol kinase ζ deficiency triggers early signs of aplastic anemia in mice

Diagnostic evaluation and considerations in hypocellular bone marrow failure—A focus on genomics

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