Materiały źródłowe

• #1 Pathogenesis of Acquired Aplastic Anemia and the Role of the Bone Marrow Microenvironment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6290278/

  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. […] The high overall response rate of about 70-80% observed in patients with acquired AA treated with IST suggests that indeed in most cases the primary mechanism inducing BM hypoplasia is of auto-immune nature (e.g., cytotoxic T cells triggering apoptosis in BM cells).

• #2 Aplastic Anemia: Practice Essentials, Background, Etiology

  https://emedicine.medscape.com/article/198759-overview

  Aplastic anemia is a syndrome of bone marrow failure characterized by peripheral pancytopenia and marrow hypoplasia. […] The theoretical basis for marrow failure includes primary defects in or damage to the stem cell or the marrow microenvironment. […] Clinical and laboratory observations suggest that acquired aplastic anemia is an autoimmune disease. […] Fas-mediated apoptosis of CD34+ progenitor cells causes stem cell depletion. […] Data from in vitro colony-culture assays suggest profound functional loss of the hematopoietic progenitors, so much so that they are unresponsive even to high levels of hematopoietic growth factors. […] The conclusions from these studies led to the understanding that stem cell defect is the central mechanism in the majority of patients with aplastic anemia.

• #3 Aplastic Anemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK534212/

  Aplastic anemia refers to the syndrome of chronic primary hematopoietic failure from injury leading to diminished or absent hematopoietic precursors in the bone marrow and attendant pancytopenia. […] Two interrelated explanations exist for aplastic anemia: extrinsic immune-mediated suppression of hematopoietic stem cells and intrinsic abnormality of marrow progenitors. […] Damaged hematopoietic stem cells mature into self-reactive T-helper cells (T1) that release cytokines interferon- (IFN-) and tumor necrosis factor (TNF) to propagate a cytotoxic cascade to kill and suppress other hematopoietic stem cells. […] In the second theory, stem cells with inherent defects lose the capacity to differentiate and proliferate. Their inability to dedifferentiate can lead to clonal evolution into hematologic neoplasms, for example, myelodysplastic syndrome. […] Partial defects in telomeres, the component of DNA intertwined with cell division, lead to premature hematopoietic stem cell exhaustion and marrow aplasia as well. Shortened telomeres are present in cells of half the patients with aplastic anemia.

• #4 Aplastic Anemia: Practice Essentials, Background, Etiology

  https://emedicine.medscape.com/article/198759-overview

  In patients with severe aplastic anemia, stromal cells have normal function, including growth factor production. […] The role of an immune dysfunction was suggested in 1970, when autologous recovery was documented in a patient with aplastic anemia who failed to engraft after HCT. […] Since then, numerous studies have shown that, in approximately 70% of patients with acquired aplastic anemia, immunosuppressive therapy improves marrow function. […] Suppression of hematopoiesis is likely mediated by an expanded population of CD8+ HLA-DR+, cytotoxic T lymphocytes (CTLs) that are frequently detectable in the blood and bone marrow of patients with aplastic anemia. […] These cells produce inhibitory cytokines, such as gamma-interferon and tumor necrosis factor, which can suppress progenitor cell growth.

• #5 Aplastic anemia – Wikipedia

  https://en.wikipedia.org/wiki/Aplastic_anemia

  Aplastic anemia is a severe hematologic condition in which the body fails to make blood cells in sufficient numbers. […] The majority of cases are hypothesized to be the result of T-cell-mediated autoimmunity and destruction of the bone marrow, which leads to defective or nearly absent hematopoiesis. […] It is suggested that unidentified antigens cause a polyclonal expansion of dysregulated CD4+ T cells and overproduction of pro-inflammatory cytokines, such as interferon- and tumor necrosis factor-. […] Activated T cells also induce apoptosis in hematopoietic stem cells. […] Aplastic anemia is associated with increased levels of Th17 cells which produce pro-inflammatory cytokine IL-17 and interferon–producing cells in the peripheral blood and bone marrow. […] The hypothesis of aberrant, disordered T-cell populations as the initiators of aplastic anemia is supported by findings that immunosuppressive therapy for T-cells (for example, anti-thymocyte globulin and ciclosporin) results in a response in up to 80% of severe aplastic anemia patients.

• #6 Aplastic anemia | PPT

  https://www.slideshare.net/slideshow/aplastic-anemia-250119317/250119317

  Evidence suggests that majority of cases of idiopathic AA are due to immune suppression of the hematopoietic stem cell. […] Aplastic anemia pathophysiology intrinsic abnormality of stem cells which predisposes DNA damage and marrow aplasia reduction in number of haemopoietic pluripotential stem cells ——- defective production in the remaining stem cells. OR Immune reaction against stem cells. ——- suppression and killing of Haemopoietic progenitors in bone marrow unable to divide and differentiate sufficiently to produce blood cells. A reasonable theory suggests that exposure to an inciting antigen, cells and cytokines of the immune system destroy stem cells in the marrow resulting in pancytopenia. […] T-cells secrete -IFN (plays central role) and TNF, act as potent inhibitors of hematopoietic progenitor cells. Cyt T-cells secrete IL-2, which causes polyclonal expansion of T-cells. Additionally, -IFN mediates its hematopoietic suppressive activity through IRF-1. Direct cell-cell interactions between effective lymphocytes and targeted hematopoietic cells probably also occur. Oligoclonal expansion of CD41, CD81 T-cells supports an immune etiology.

• #7 Immunosuppressive Therapy | Aplastic Anemia and MDS International Foundation (AAMDSIF)

  https://www.aamds.org/treatment/immunosuppressive-therapy

  Immunosuppressive drug therapy lowers your body’s immune response. This prevents your immune system from attacking your bone marrow, allowing bone marrow stem cells to grow, which raises blood counts. […] ATG works by killing specific cells in your immune system called T-lymphocytes — the cells that are attacking bone marrow stem cells in aplastic anemia. This allows an aplastic anemia patient’s bone marrow to rebuild its supply of bone marrow stem cells, causing blood counts to go up. […] Cyclosporine prevents T-lymphocytes, a type of white blood cell, from becoming active. Once the T-lymphocytes are turned off by the cyclosporine, they stop attacking stem cells in the bone marrow. In aplastic anemia patients, this allows bone marrow stem cells to grow back and start making blood cells again.

• #8 Aplastic Anemia: Practice Essentials, Background, Etiology

  https://emedicine.medscape.com/article/198759-overview

  Polymorphisms in these cytokine genes that are associated with an increased immune response are more prevalent in patients with aplastic anemia. […] In addition, such cytokines induce nitric oxide synthase and nitric oxide production by marrow cells, which contributes to immune-mediated cytotoxicity and the elimination of hematopoietic cells. […] Constitutive expression of Tbet, a transcriptional regulator that is critical to type 1 T helper cell (Th1) polarization, occurs in a majority of aplastic anemia patients. […] The transcription factors FOXP3 and NFAT1 have key roles in regulatory T-cell (Treg) development and function, and Tregs play a role in autoimmunity. […] Tregs are decreased at presentation in almost all patients with aplastic anemia; FOXP3 protein and messenger RNA levels also are significantly lower in patients with this condition, and NFAT1 protein levels are decreased or absent.

• #9 Mesenchymal Stem Cells in Acquired Aplastic Anemia: The Spectrum from Basic to Clinical Utility

  https://www.mdpi.com/1422-0067/24/5/4464

  It has been demonstrated that the percentage of activated CD8+ cytotoxic T cells is increased in the both bone marrow and peripheral blood of patients with AA. […] Abnormalities in the number and function of CD4+ T cells have also been documented in AA, with increased T helper (Th)1, Th2, and Th17 cells. […] A decrease in the number of CD4+ CD25+ FOXP3+ Tregs was found in almost all patients with AA, and there was an inverse relationship between the numbers of Th17 cells and Tregs in the peripheral blood of patients. […] Meanwhile, hyperactive T cells in AA may release a variety of inflammatory cytokines, such as interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukin (IL)-17, thus with elevated concentrations in the serum and bone marrow plasma. […] The effectiveness of IST in the treatment of AA provides compelling clinical evidence for the immune-mediated nature of the disease.

• #10 Aplastic anemia pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Aplastic_anemia_pathophysiology

  The most defenitive feature in pathophysiology of aplastic anemia is loss of hematopoietic stem cells. […] Pathophysiologic mechanisms that result in loss of HSCs and cause aplastic anemia include: […] Drugs, chemicals, viruses, and different kind of mutations change the immunologic appearance of HSCs resulting in autoimmune destruction of marrow cells. […] In patients with acquired aplastic anemia, lymphocytes are responsible for the destruction of the hematopoietic cells. […] These T cells produces an inhibitory factor, interferons, tumor necrosis factor, and interleukin-2, resulting in hematopoietic cell death by apoptosis. […] CD4+CD25+FOXP3+ regulatory T cells are deficient in these patients, similar to what is seen in other autoimmune conditions. […] Deficiency of these regulatory T cells result in increase of T-bet protein levels in T cells, increased interferon (IFN)-,2 and stem cell destruction.

• #11 Aplastic anemia – Wikipedia

  https://en.wikipedia.org/wiki/Aplastic_anemia

  CD34+ progenitor cells and lymphocytes in the bone marrow over-express the Fas receptor, the main element in apoptotic signaling. […] This suggests that cytokine-induced and Fas-mediated apoptosis play roles in bone marrow failure because annihilation of CD34+ progenitor cells leads to hematopoietic stem cell deficiency.

• #12 Dioscin Regulating Bone Marrow Apoptosis in Aplastic Anemia | DDDT

  https://www.dovepress.com/dioscin-regulating-bone-marrow-apoptosis-in-aplastic-anemia-peer-reviewed-fulltext-article-DDDT

  Aplastic anemia (AA), a disease of bone marrow failure, is caused by CD8+T mediated apoptosis of hematopoietic cells. […] The apoptosis rate of BM-MCs in AA mice was significantly higher than the group control (P 0.01). After drug intervention for 14 days, compared with the group model, DNS significantly inhibited the apoptosis of BM-MCs, which indicated the anti-apoptotic effect of DNS on BM-MCs in AA mice. […] The study found that in early AA, the proportion of CD34+ bone marrow cells expressing Fas receptors increased significantly; moreover, with the disease recovering, the proportion of cells decreased again. Furthermore, the high-level expression of Fas receptors is a target of T cell-mediated destructing to CD34+ cells. […] The results indicated that Fas/FasL system participated in the pathophysiological process of bone marrow failure.

• #13 Aplastic anemia | PPT

  https://www.slideshare.net/slideshow/aplastic-anemia-250119317/250119317

  T-cells secrete Gamma-Interferon (-IFN) (plays central role) and TNF, act as potent inhibitors of both early and late hematopoietic progenitor cells. They suppress hematopoiesis by their effects on mitotic cycle and, more importantly, by the mechanism of cell killing (apoptosis). Cyt T-cells secrete IL-2, which causes polyclonal expansion of T-cells. Activation of Fas receptor on hematopoietic stem cell by the Fas ligand (present on lymphocytes) leads to apoptosis of targeted hematopoietic progenitor cells. Additionally, -IFN mediates its hematopoietic suppressive activity through IFN regulatory factor 1 (IRF-1), which inhibits transcription of cellular genes and their entry into cell cycle. -IFN induces production of nitric oxide, diffusion of which causes additional toxic effects on the hematopoietic progenitor cells.

• #14 Aplastic Anemia as a Roadmap for Bone Marrow Failure: An Overview and a Clinical Workflow

  https://www.mdpi.com/1422-0067/23/19/11765

  Understanding AA represented a breakthrough in understanding BM failure pathobiology. As a multifactorial disease due to an autoimmune attack on hematopoietic stem cells (HSC), AA is characterized by pathological alterations that can be identified in three discrete pathophysiological compartments that cooperate in inducing the disease: the HSC compartment, the immune niche, and the stroma milieu. […] The HSC compartment is crucial because in AA patients, there is both a quantitative and a qualitative defect of HSC. The number of residual multi-potent stem cells is characteristically <1% compared to a normal subject. From a qualitative point of view, 30–50% of leukocytes in AA patients have a shortened telomere, probably due to increased cell turnover and replicative stress, which predisposes to greater fragility of the HSC. The chromosomal instability and the impaired ability to repair DNA damage represent another archetypic pathophysiological mechanism for BM failure and MDS.

• #15 Mesenchymal Stem Cells in Acquired Aplastic Anemia: The Spectrum from Basic to Clinical Utility

  https://www.mdpi.com/1422-0067/24/5/4464

  There is evidence of primary deficiencies, both quantitative and qualitative, in AA HSCs. […] Patients with AA have decreased numbers of HSCs at diagnosis, and these cells were found to display poor plating efficiency for colony formation. […] The upregulated expression of Fas antigen, which is a receptor molecule in the death signaling pathway, was frequently found on CD34+ cells in AA. […] Genetic factors play an important role in the pathogenesis of AA. […] Several studies have reported the association between certain human leukocyte antigen (HLA) alleles and the predisposition of AA. […] The cellular elements, including endosteal, vascular, and perivascular cells, were found to be markedly decreased in the bone marrow of patients with AA, implicating the possibility of microenvironmental impairment in the bone marrow.

• #16 Aplastic Anemia: Practice Essentials, Background, Etiology

  https://emedicine.medscape.com/article/198759-overview

  Variations in telomere length in peripheral blood cells, especially neutrophils, have been reported in severe aplastic anemia, but the clinical significance of this finding is uncertain. […] A faster reduction in telomere length in aplastic anemia leads to decreased expression of cell cycle checkpoint genes such as CDK2/6 and MYC, and a high number of mutations is observed in the telomere reverse transcriptase (TERT) gene. […] However, although telomere length was unrelated to response, it has been associated with the risk of relapse, clonal evolution, and overall survival in patients with severe aplastic anemia. […] Studies in murine models also suggest a role of thrombopoietin (TPO) and associated signalling pathway during normal hematopoiesis. […] Raised levels of TPO have been observed in aplastic anemia, most likely due to compensatory response to diminished stem cells function.

• #17 Aplastic anemia (AA) | MLL

  https://www.mll.com/en/other-malignant-and-benign-diseases/aplastic-anemia-aa

  Acquired aplastic anemias (AA) are characterized by bi- or tricytopenias resulting from hypo- or aplasia in the bone marrow. […] Patients with aplastic anemia typically initially experience benign oligoclonal hematopoiesis due to a reduction in the stem cell pool resulting from immune-mediated pathogenesis, in which autoreactive T cells appear to play a major role. […] During the pathogenesis of aplastic anemia, the majority of bone marrow cells are replaced by adipocytes. […] Genetic alterations detected by sequencing and SNP array analyses are present in approximately 50% of patients with aplastic anemia. […] Cytogenetic aberrations have been described in 5-15% of adult patients with severe aplastic anemia (SAA), and these patients were generally younger than patients with normal karyotype.

• #18

  https://haematologica.org/article/view/haematol.2023.284312

  Aplastic anemia (AA) is a disease characterized by failure of hematopoiesis, bone marrow aplasia, and pancytopenia. It can be inherited or acquired. Although acquired AA is believed to be immune-mediated and random, new evidence suggests an underlying genetic predisposition. […] These variants, associated with inherited bone marrow failure syndromes and inborn errors of immunity, contribute to the disease, possibly through mechanisms including gene homeostasis, DNA repair, and immune injury. […] However, immune system involvement alone cannot fully explain the pathogenesis and progression of acquired AA. The specific triggering factors and antigen targets responsible for the hyperactivity of T cells in acquired AA remain unclear. […] With the advancement and application of next-generation sequencing and whole-exome sequencing, HSC defects in acquired AA patients have been progressively revealed.

• #19 Aplastic anemia (AA) | MLL

  https://www.mll.com/en/other-malignant-and-benign-diseases/aplastic-anemia-aa

  In aplastic anemia, mutations occur that are also observed in MDS, but with different frequencies. […] Most commonly, mutations are found in the genes BCOR, BCORL1, DNMT3A, PIGA and ASXL1. […] In addition, an association between the presence of a mutation in the genes ASXL1 or DNMT3A and an increased risk of transformation to MDS or AML, respectively, has been demonstrated. […] The risk of leukemic transformation is significantly increased when cytogenetic alterations are detected in chromosome banding analysis. […] Depending on the type of cytogenetic alteration, response to immunosuppressive therapy (IST) and prognosis may be worse (-7, complex karyotype, 5q syndrome) or better (+8, -13q). […] In contrast to mutations in BCOR, BCORL1, and PIGA, patients with mutations in DNMT3A, ASXL1, TP53, and RUNX1 show poorer response to IST and poorer overall or progression-free survival.

• #20 Aplastic anemia pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Aplastic_anemia_pathophysiology

  Increased immune response, including tumor necrosis factor -, IFN, and interleukin-6, are also very common in AA patients. […] AA may develop gradually into other hematologic disorder which include […] Clonal evolution in AA can occur due to mutations or cytogenetic abnormalities. […] The genes that are commonly found to be mutated are DMNT3A, ASXL1, BCOR, BCORL1, PIGA.

• #21 Pathogenesis of Acquired Aplastic Anemia and the Role of the Bone Marrow Microenvironment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6290278/

  The cause of acquired AA was not clear for many years. While initially toxic effects were postulated as the reason of a quantitative HSC defect, nowadays autoimmune processes are considered mainly responsible for acquired AA occurring in the absence of a positive medical history of predisposing drugs, toxic agents or infections. […] In fact, while several pathomechanisms have been proposed, the greatest proportion of cases is likely due to uniform T-cell mediated auto-immunity and marrow destruction leading to defective, nearly absent hematopoiesis. […] Given the close interaction and regulatory feedback loops between resident hematopoietic and niche cells, it is not surprising that AA also associates with defects in non-hematopoietic BM microenvironment components. […] Impairments in osteoblastic, vascular, and perivascular HSC niches might contribute to defective hematopoiesis in patients with AA. […] Taken together, a disturbed microenvironment with abnormal functioning MSCs is, next to BM hypoplasia, a further hallmark in patients with acquired AA.

• #22 Mesenchymal Stem Cells in Acquired Aplastic Anemia: The Spectrum from Basic to Clinical Utility

  https://www.mdpi.com/1422-0067/24/5/4464

  Aplastic anemia (AA), a rare but potentially life-threatening disease, is a paradigm of bone marrow failure syndromes characterized by pancytopenia in the peripheral blood and hypocellularity in the bone marrow. […] The pathophysiology of acquired idiopathic AA is quite complex. Mesenchymal stem cells (MSCs), an important component of the bone marrow, are crucial in providing the specialized microenvironment for hematopoiesis. MSC dysfunction may result in an insufficient bone marrow and may be associated with the development of AA. […] The pathogenesis of acquired idiopathic AA is complex, and we summarized the current concepts in the following sections. […] The immune-mediated destruction of hematopoietic stem cells (HSCs) is the most widely accepted mechanism of hematopoietic failure in AA.

• #23 Mesenchymal Stem Cells in Acquired Aplastic Anemia: The Spectrum from Basic to Clinical Utility

  https://www.mdpi.com/1422-0067/24/5/4464

  MSCs play a central role in the establishment of the bone marrow niche, and their defects may lead to the development of AA. […] The regulation of hematopoiesis depends on the interaction between HSCs and various cells within the bone marrow niche. […] Several studies have demonstrated the involvement of MSCs in the functional restriction of HSCs in AA. […] Impaired proliferative potential is the hallmark of MSCs in AA. […] Immune-mediated HSC destruction is an important pathogenic mechanism of idiopathic AA, and MSCs have great immunomodulatory functions. […] The dysregulation of immune cells from MSCs may impact immune homeostasis in the bone marrow microenvironment. […] Collectively, these data provide evidence for the disordered immunomodulatory function of MSCs in AA. […] Acquired idiopathic AA is a rare but life-threatening bone marrow failure syndrome, with a complex pathophysiology. […] On the whole, MSCs are promising for the management of AA, especially when co-transplanted during HSCT.

• #24 Alternative Immune-Mediated-Based Methods in the Aplastic Anemia Treatment | IntechOpen

  https://www.intechopen.com/chapters/68976

  Many studies have hypothesized that the onset of the immune imbalance in AA begins by stimulating APCs through an unknown antigen resulting in the T cells activation. […] Another important mechanism of MSCs is the immunomodulation mechanism. […] MSCs can act directly on AA imbalance by T cells suppression, inhibiting activation and proliferation of T cells. […] MSCs also inhibit the secretion of two important cytokines present in the pathology of AA, the INF- and TNF- and stimulate the proliferation of Treg, promoting the production of the anti-inflammatory cytokine IL-10.

• #25 Aplastic Anemia as a Roadmap for Bone Marrow Failure: An Overview and a Clinical Workflow

  https://www.mdpi.com/1422-0067/23/19/11765

  The current multifactorial pathogenic model of AA, while presenting aspects that are not completely understood, contemplates an initial event that can be a viral infection or a genetic mutation in the compartment of the HSCs that determines either the generation of neo-antigens or an incorrect presentation of an antigen by the major histocompatibility complex. This leads to the formation of self-reactive T cells that expand and release myelosuppressive cytokines including TNF-alpha and IFN-gamma. By causing excess apoptosis of the HSC, these trigger a depopulation of the hematopoietic component of the BM. […] The pathogenic role of self-reactive T cell clones specific to the glycosylphosphatidylinositol (GPI) complex expressed on the HSC has recently been documented in subjects affected by AA. GPI absence determines complement-mediated lysis of the red blood cells, that generates the intravascular hemolysis characteristic of active PNH. This allows the identification of these molecules as one of the targets of the autoimmune attack on the BM, thus explaining, also the emergence and coexistence of PNH clones (which are GPI negative) with AA in addition to the onset of BM failure, frequently observed in the course of the disease.

• #26 Aplastic Anemia

  https://elsevier.health/en-US/preview/aplastic-anemia-co

  Immune-mediated destruction of hematopoietic cells. […] Clonality may be present as an intrinsic feature of aplastic anemia but increases after immunosuppressive therapy. […] Paroxysmal nocturnal hemoglobinuria is the most common clonal hematopoietic disorder arising in patients with aplastic anemia.

• #27 Aplastic anemia – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/aplastic-anemia/symptoms-causes/syc-20355015

  Aplastic anemia is a condition that happens when your bone marrow stops making enough new blood cells. […] In aplastic anemia, stem cells are damaged. As a result, the bone marrow makes fewer new blood cells. […] The most common cause of aplastic anemia is from your immune system attacking the stem cells in your bone marrow. […] Aplastic anemia can be a temporary side effect of these treatments. […] Toxic chemicals, such as some used in pesticides and insecticides, and benzene, an ingredient in gasoline, have been linked to aplastic anemia. […] Some medicines, such as those used to treat rheumatoid arthritis and some antibiotics, can cause aplastic anemia. […] An autoimmune disorder, in which your immune system attacks healthy cells, might involve stem cells in your bone marrow.

• #28 Aplastic Anemia – Aplastic Anemias – Anemia and Other Nonmalignant Blood Disorders – Hematology – Diseases – McMaster Textbook of Internal Medicine

  https://empendium.com/mcmtextbook/chapter/B31.II.15.1.7.

  Aplastic anemias (AAs) are a group of bone marrow failure syndromes characterized by pancytopenia with complications of life-threatening infections in the setting of neutropenia, bleeding due to thrombocytopenia, and severe anemia leading to transfusion dependence. […] Acquired AA is typically due to damage to hematopoietic stem cells or the bone marrow microenvironment, which leads to the inhibition of cellular proliferation and differentiation. […] Acquired AA (up to 80% of cases): a) Idiopathic factors (50%). […] b) Infectious causes: Viral hepatitis (usually acute hepatitis A, B, or C that may occur 2-3 months prior to AA), Epstein-Barr virus, HIV, parvovirus B19 (eg, in the setting of sickle cell disease), mycobacteria. […] c) Exposure to ionizing radiation. […] d) Transfusion-associated graft-versus-host disease (GVHD): Donor T cells cause GVHD in patients with hematologic malignancies who receive purine analogues such as bendamustine or fludarabine; after autologous or allogeneic hematopoietic stem cell transplant (HSCT).

• #29 Aplastic Anemia – Aplastic Anemias – Anemia and Other Nonmalignant Blood Disorders – Hematology – Diseases – McMaster Textbook of Internal Medicine

  https://empendium.com/mcmtextbook/chapter/B31.II.15.1.7.

  e) Chemicals such as benzene, organic solvents, trinitrotoluene, pesticides, and herbicides. […] f) Autoimmune or connective tissue diseases. […] g) Anorexia nervosa, severe nutritional deficiencies (vitamin B12, folate). […] h) Paroxysmal nocturnal hemoglobinuria (PNH). […] i) Drugs: Nonsteroidal anti-inflammatory drugs (NSAIDs), busulfan, cyclophosphamide, anthracyclines, methotrexate, antibiotics such as chloramphenicol and sulfonamides, gold compounds, chloroquine, chlorpropamide, phenytoin, allopurinol, and thiazides. […] j) Pregnancy (rare).

• #30 Aplastic anemia – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/aplastic-anemia/symptoms-causes/syc-20355015

  Viral infections that affect bone marrow can play a role in the development of aplastic anemia. […] Your immune system might attack your bone marrow during pregnancy. […] In many cases, doctors aren’t able to identify the cause of aplastic anemia. This is called idiopathic aplastic anemia. […] Some people with aplastic anemia also have a rare disorder known as paroxysmal nocturnal hemoglobinuria, which causes red blood cells to break down too soon. […] Fanconi’s anemia is a rare, inherited disease that leads to aplastic anemia.

• #31 Aplastic Anemia: Symptoms, Causes & Treatment

  https://my.clevelandclinic.org/health/diseases/16747-aplastic-anemia

  Medical conditions that can increase your risk include autoimmune diseases like lupus. […] Viral infections such as Epstein-Barr virus, cytomegalovirus (CMV), parvovirus B19 and human immunodeficiency virus (HIV). […] Certain medical treatments put you at a higher risk of developing aplastic anemia, such as autoimmune disease treatments. […] Extended exposure to carcinogens, such as arsenic and benzene, may also increase your risk of developing aplastic anemia. […] Treatments for more serious forms of aplastic anemia include immunosuppressants. These medicines hold back your immune system so it stops attacking your stem cells. […] Allogeneic stem cell transplantation. Providers replace damaged stem cells in your bone marrow with healthy stem cells from donated blood or bone marrow.

• #32

  https://haematologica.org/article/view/haematol.2023.284312

  Approximately 5%30% of young patients diagnosed with AA carry IBMFS-associated germline variants, potentially leading to adverse outcomes. […] Despite lacking typical symptoms due to their mild pathogenicity, individuals carrying germline variants associated with IBMFS and inborn errors of immunity eventually experience immune-mediated bone marrow destruction as deleterious factors accumulate. […] The immune escape mechanisms of paroxysmal nocturnal hemoglobinuria (PNH) and HLA class I allelic gene loss, along with the immune characteristics of TCR-V oligoclonal expansion, collectively serve as markers for acquired AA, providing diagnostic references with high positive predictive value and specificity. […] In patients with acquired AA, genetic reports of individuals characterized by more severe phenotypes or unfavorable treatment responses often show common occurrences of germline heterozygous recessive variants, as well as VUS or B/LB variants in dominant genes.

• #33 Acquired aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis – UpToDate

  https://www.uptodate.com/contents/aplastic-anemia-pathogenesis-clinical-manifestations-and-diagnosis

  Aplastic anemia (AA) refers to pancytopenia in association with bone marrow hypoplasia. […] Most cases of AA are associated with an autoimmune attack on hematopoietic stem cells, but the trigger is often unidentified. […] AA is a clinicopathologic diagnosis based on the presence of ≥2 cytopenias and bone marrow hypoplasia. […] The diagnostic evaluation must distinguish AA from transient cytopenias (eg, from infections or drugs) and other causes of persistent pancytopenia, including megaloblastic anemia, various malignancies, bone marrow infiltrative disorders, and inherited bone marrow failure syndromes (IBMFS).

• #34 Aplastic Anemia – Hematology and Oncology – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/hematology-and-oncology/anemias-caused-by-deficient-erythropoiesis/aplastic-anemia

  Aplastic anemia is a disorder of the hematopoietic stem cell that results in a loss of blood cell precursors, hypoplasia or aplasia of bone marrow, and cytopenias in two or more cell lines (red blood cells, white blood cells, and/or platelets). […] The precise mechanism remains unclear, but in the majority of acquired cases, the mechanism involves an immune attack on the hematopoietic stem cell. […] Aplastic anemia involves panhypoplasia of the bone marrow with anemia, leukopenia, and thrombocytopenia. […] Many cases are idiopathic, but chemicals, medications or drugs, or radiation may be causes. […] Bone marrow examination shows a variable degree of hypocellularity. […] Treatment is with stem cell transplant or immunosuppression with equine antithymocyte globulin and cyclosporine, with or without eltrombopag.

• #35 Aplastic Anemia | Concise Medical Knowledge

  https://www.lecturio.com/concepts/aplastic-anemia/

  Aplastic anemia is a rare, life-threatening condition characterized by pancytopenia and hypocellularity of the bone marrow reflecting damage to hematopoietic stem cells. Aplastic anemia can be acquired or inherited; however, most cases are acquired and caused by autoimmune damage to hematopoietic stem cells. Specifically known acquired causes and associations of aplastic anemia include medications, chemicals, high doses of whole-body radiation, viral infections, immune diseases, and pregnancy. Inherited or constitutional syndromes associated with aplastic anemia include Fanconi anemia, dyskeratosis, and Down syndrome. […] Acquired aplastic anemia is often due to autoimmune or other types of damage to hematopoietic stem cells. Idiopathic cases account for most instances, with immune-mediated mechanisms involving increased numbers of activated cytotoxic T cell clones. […] Bone marrow in aplastic anemia is hypocellular for age, with no abnormal cells or marrow fibrosis. The condition leads to a decrease in all three cell lines, including white blood cells, red blood cells, and platelets, resulting in pancytopenia.

• #36 Aplastic Anemia: Symptoms, Causes & Treatment

  https://my.clevelandclinic.org/health/diseases/16747-aplastic-anemia

  Aplastic anemia increases bacterial infection risk. Antibiotics help treat infections. […] Depending on your situation, a successful allogeneic stem cell transplantation may cure the condition. […] Aplastic anemia is a rare but serious blood disorder. It typically happens when your immune system attacks your bone marrow so it cant make the blood cells and platelets your body needs.

• #37 Aplastic anemia | Bone Marrow Failure, Immune Disorders, Blood Transfusions | Britannica

  https://www.britannica.com/science/aplastic-anemia

  aplastic anemia, disease in which the bone marrow fails to produce an adequate number of blood cells. There may be a lack of all cell typeswhite blood cells (leukocytes), red blood cells (erythrocytes), and plateletsresulting in a form of the disease called pancytopenia, or there may be a lack of one or more cell types. Rarely, the disease may be congenital (Fanconi anemia); more commonly, it is acquired by exposure to certain drugs (e.g., the antibiotic chloramphenicol) or chemicals (e.g., benzene) or to ionizing radiation. About half of all cases are idiopathic (cause unknown). […] Aplastic anemia is most common in persons 15 to 30 years of age. Onset of the disease may be abrupt, becoming quickly severe and possibly fatal; more commonly, it is insidious, running a chronic course of several years. […] If white blood cells (specifically, neutrophils) are lacking, resistance to infection is much lowered and infection becomes the major cause of death. When platelets are very low, bleeding may be severe.

• #38 Current Concepts of the Pathogenesis of Aplastic Anemia

  https://www.eurekaselect.com/article/97280

  Abnormal activation of the immune system plays an important role in the pathogenesis of aplastic anemia (AA). Various immune cells and cytokines constitute a complex immune network, leading to bone marrow failure. The known pathogenesis is an increase of the myeloid dendritic cell (mDC)/ plasmacytoid dendritic cell (pDC) ratio, which causes the ratio of T helper (Th)1/Th2 to be skewed in favor of Th1 and eventually leads to an abnormal activation of cytotoxic T lymphocyte (CTL). […] In this process, regulatory T (Treg), Th17, natural killer (NK) cell, memory T cell and negative hematopoietic regulatory factors are also involved. In addition, genetic background (e.g., chromosomal abnormalities, telomere attrition, somatic cell mutations), abnormal bone marrow hematopoietic microenvironment and viral infection may also contribute to the pathogenesis of AA.

• #39

  https://haematologica.org/article/view/haematol.2023.284312

  DNA damage repair has a crucial role in maintaining the response of HSC to both external and internal stimuli, as well as their self-renewal process. […] Some patients with acquired AA carry immune-related germline variants, exacerbating the immune response in disease progression. […] The association between acquired AA and immune-related variants appears to be non-incidental. […] In conclusion, heterozygous recessive variants or VUS in dominant genes may lead to aberrant responses or incomplete reactions to antigens, ultimately resulting in the development of acquired AA due to the failure of feedback regulatory mechanisms. […] In acquired AA, individuals carrying certain germline heterozygous recessive variants, along with VUS or B/LB variants in dominant genes, constitute a distinct subgroup. They manifest typical features of acquired AA, with variations in disease severity and treatment response. The variants they carry induce and aggravate AA through various mechanisms such as gene homeostasis, DNA repair, and immune injury, representing risk factors for the development of acquired AA.

• #40

  https://www.alliedacademies.org/articles/exploring-the-pathogenesis-clinical-features-and-treatment-options-for-aplastic-anemia-26889.html

  Aplastic anemia is an uncommon form of bone marrow failure syndrome that causes pancytopenia due to a severe decrease in the generation of all three hematopoietic cell lineages. […] The loss of hematopoietic stem cells, which results in bone marrow failure, is greatly influenced by immune dysregulation. T-cell dysfunction, cytokine profiles, and regulatory pathways have all been linked to abnormalities that contribute to the immune system’s death of hematopoietic cells. […] Pancytopenia, caused by immune-mediated death of hematopoietic stem cells and a compromised hematopoietic microenvironment, characterizes the complex and uncommon bone marrow failure disease known as aplastic anemia. This review has examined the pathogenesis, clinical characteristics, and available treatments for aplastic anemia, emphasizing the significance of comprehending these elements for precise diagnosis and the best care of those who are affected.

• #41 Causal role of immune cells in aplastic anemia: Mendelian randomization (MR) study | Scientific Reports

  https://www.nature.com/articles/s41598-024-69104-0

  However, the specific antigens triggering T cell responses in AA are still unknown. […] Further, regulatory T cells (Treg), Th17 cells, natural killer (NK) cells, memory T cells, and negative hematopoietic regulatory factors also play roles in this process. […] Nonetheless, the precise contribution of immune cells to the development of AA remains elusive, possibly due to the intricate nature of the immune system, flaws in study design, limited sample sizes, and the influence of confounding factors not fully addressed in existing research. […] The results of this study demonstrate a close link between immune cells and AA by genetic means, thereby improving the current understanding of the interaction between immune cells and AA risk and providing guidance for future clinical research.

• #42

  https://link.springer.com/article/10.1007/BF03165246

  Aplastic anemia (AA) remains an elusive disease. Its pathophysiology is not only fascinating by the seemingly simple findings of cytopenia and marrow hypoplasia, but may also contain key information to the understanding of other fundamental processes such as stem cell regeneration, evolution, and immune control of clonal diseases. […] In spite of the recognition of immune pathways of hematopoietic inhibition and apoptosis in AA, the fundamental question about the nature of the antigen(s) inciting or maintaining the pathologic immune response that ultimately leads to bone marrow failure, remains open. However, recognition of the immune targets may aid in understanding not only the pathogenesis but also many of clinical associations and the late squelae of AA. […] Clonal proliferation of large granular lymphocytosis could represent an example of an exaggerated response to an immunodominant hematopoietic antigen.

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