Aplastic anemia pathophysiology: Difference between revisions
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* Bone marrow is the primary site of hematopoiesis | * Bone marrow is the primary site of hematopoiesis | ||
* It is composed of hematopoietic cells, marrow adipose tissue, and stromal cells. | * It is composed of hematopoietic cells, marrow adipose tissue, and stromal cells. | ||
* Hematopoietic stem cells (HSC) in the bone marrow are the source of all mature cells in the peripheral blood and tissues and are multipotent. | |||
* HSC are recognized and isolated according to their immunophenotype. | |||
* HSCs make a small population within the CD34+/CD38 fraction of bone marrow cells. | |||
* The hematopoiesis is controlled by a various regulatory mechanisms, including growth factors. | * The hematopoiesis is controlled by a various regulatory mechanisms, including growth factors. | ||
* The normal bone marrow structure can be damaged or displaced by aplastic anemia, malignancies or infections. | * The normal bone marrow structure can be damaged or displaced by aplastic anemia, malignancies or infections. | ||
| Line 20: | Line 23: | ||
=== Pathogenesis === | === Pathogenesis === | ||
The most defenitive feature in pathophysiology of aplastic anemia is loss of hematopoietic stem cells.<ref name="pmid18024605">{{cite journal |vauthors=Bacigalupo A |title=Aplastic anemia: pathogenesis and treatment |journal=Hematology Am Soc Hematol Educ Program |volume= |issue= |pages=23–8 |date=2007 |pmid=18024605 |doi=10.1182/asheducation-2007.1.23 |url=}}</ref> | |||
Pathophysiologic mechanisms that result in loss of HSCs and cause aplastic anemia include: | |||
* | |||
* | ==== Hematopoietic Failure ==== | ||
* | * CD34 cells are almost absent aplastic anemia. | ||
* | * Progenitor cells capable of forming erythroid, myeloid, and megakaryocytic are greatly reduced. | ||
* | * The primitive hematopoietic cells which are closely related to stem cells are consistently deficient. | ||
* The white blood cells in aplastic anemia have short telomeres. | |||
* Telomeres are repeats at the end of eukaryotic chromosome and are essential for chromosome protection and complete DNA replication. | |||
==== Immune-mediated T-cell destruction of marrow ==== | |||
** 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, interferon-�., tumor necrosis factor, and interleukin-2, resulting in hematopoitic 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)-γ,2 and stem cell destruction. | |||
** Increased immune response, including tumor necrosis factor -α, IFNγ, and interleukin-6, are also very common in AA patients. | |||
==== Clonal Evolution ==== | |||
* AA may develop gradually into other hematologic disorder which include | |||
** Paroxysmal nocturnal hemoglobinuria [PNH] | |||
** Myelodysplastic syndromes [MDS] | |||
** Acute myeloid leukemia [AML]). | |||
* 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'' | |||
== Genetics == | == Genetics == | ||
Revision as of 19:16, 15 August 2018
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Priyamvada Singh, M.D. [2] Nazia Fuad M.D.
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Overview
Pathophysiology
Physiology
The normal physiology of bone marrow can be understood as follows:[1]
- Bone marrow is a spongy tissue, found within the spongy or cancellous portions of bones
- It is higly vascularized and richly innervated
- Bone marrow is the primary site of hematopoiesis
- It is composed of hematopoietic cells, marrow adipose tissue, and stromal cells.
- Hematopoietic stem cells (HSC) in the bone marrow are the source of all mature cells in the peripheral blood and tissues and are multipotent.
- HSC are recognized and isolated according to their immunophenotype.
- HSCs make a small population within the CD34+/CD38 fraction of bone marrow cells.
- The hematopoiesis is controlled by a various regulatory mechanisms, including growth factors.
- The normal bone marrow structure can be damaged or displaced by aplastic anemia, malignancies or infections.
- This leads to decrease production of blood cells and blood platelets.
.
Pathogenesis
The most defenitive feature in pathophysiology of aplastic anemia is loss of hematopoietic stem cells.[2]
Pathophysiologic mechanisms that result in loss of HSCs and cause aplastic anemia include:
Hematopoietic Failure
- CD34 cells are almost absent aplastic anemia.
- Progenitor cells capable of forming erythroid, myeloid, and megakaryocytic are greatly reduced.
- The primitive hematopoietic cells which are closely related to stem cells are consistently deficient.
- The white blood cells in aplastic anemia have short telomeres.
- Telomeres are repeats at the end of eukaryotic chromosome and are essential for chromosome protection and complete DNA replication.
Immune-mediated T-cell destruction of marrow
- 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, interferon-�., tumor necrosis factor, and interleukin-2, resulting in hematopoitic 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)-γ,2 and stem cell destruction.
- Increased immune response, including tumor necrosis factor -α, IFNγ, and interleukin-6, are also very common in AA patients.
Clonal Evolution
- AA may develop gradually into other hematologic disorder which include
- Paroxysmal nocturnal hemoglobinuria [PNH]
- Myelodysplastic syndromes [MDS]
- Acute myeloid leukemia [AML]).
- 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
Genetics
[Disease name] is transmitted in [mode of genetic transmission] pattern.
OR
Genes involved in the pathogenesis of [disease name] include:
- [Gene1]
- [Gene2]
- [Gene3]
OR
The development of [disease name] is the result of multiple genetic mutations such as:
- [Mutation 1]
- [Mutation 2]
- [Mutation 3]
Associated Conditions
Gross Pathology
On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
Microscopic Pathology
On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name]
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