Idiopathic aplastic anaemia

Hematology

Clinicals - History

Fact Explanation
Fatigue Due to the low red blood cells(RBC) causing hypoxia in the muscles.(1) Fatigue
Due to the low red blood cells(RBC) causing hypoxia in the muscles.(1)
Light headedness Due to the low RBC count ,oxygen carrying capacity is less to the brain.(1) Light headedness
Due to the low RBC count ,oxygen carrying capacity is less to the brain.(1)
Weakness Due to the low red blood cells,it causes hypoxia in the muscles.(1) Weakness
Due to the low red blood cells,it causes hypoxia in the muscles.(1)
Exertional dyspnoea Due to the low oxygen capacity caused by low RBC,to compensate this deficiency the body increases oxygenation by increasing respiratory rate.(1) Exertional dyspnoea
Due to the low oxygen capacity caused by low RBC,to compensate this deficiency the body increases oxygenation by increasing respiratory rate.(1)
Palpitations Due to the low RBC count ,to increase the oxygen carrying capacity ,heart works more to increase the blood flow by increasing the heart rate .This is felt as palpitations.(1) Palpitations
Due to the low RBC count ,to increase the oxygen carrying capacity ,heart works more to increase the blood flow by increasing the heart rate .This is felt as palpitations.(1)
Fever,cough,dysuria Due to the low white cell count immunity is lowered in the body.(1) Fever,cough,dysuria
Due to the low white cell count immunity is lowered in the body.(1)
Bleeding gums Due to thrombocytopenia(1) Bleeding gums
Due to thrombocytopenia(1)
Epistaxis Due to thrombocytopenia(1) Epistaxis
Due to thrombocytopenia(1)
Easy bruising Due to thrombocytopenia(1) Easy bruising
Due to thrombocytopenia(1)
Visual disturbances Retinal hemorrhages caused by thrombocytopenia.(1) Visual disturbances
Retinal hemorrhages caused by thrombocytopenia.(1)
History of drug usage Several classes of drugs such as antibiotics, anti-inflammatories, anti convulsants, anti thyroids, oral hypoglycemic have been implicated in causing aplastic anemia. History of drug usage
Several classes of drugs such as antibiotics, anti-inflammatories, anti convulsants, anti thyroids, oral hypoglycemic have been implicated in causing aplastic anemia.
History of occupational and environmental exposure to chemicals Benzene and other solvents, agricultural pesticides: organochlorines, organophosphates, pentachlorophenol ,DDT and carbamates. Cutting oils and lubricating agents.
Non-bottled water, non-medical needle injury, Farmers exposed to ducks, geese fertilizer.
Recreational drugs: methylenedioxy-methamphetamine (MDMA), ecstasy have been found to have an etiological origin to aplastic anemia.(1)
History of occupational and environmental exposure to chemicals
Benzene and other solvents, agricultural pesticides: organochlorines, organophosphates, pentachlorophenol ,DDT and carbamates. Cutting oils and lubricating agents.
Non-bottled water, non-medical needle injury, Farmers exposed to ducks, geese fertilizer.
Recreational drugs: methylenedioxy-methamphetamine (MDMA), ecstasy have been found to have an etiological origin to aplastic anemia.(1)
A preceding history of jaundice, usually 2–3 months back. This may indicate a post-hepatitic aplastic anaemia(1) A preceding history of jaundice, usually 2–3 months back.
This may indicate a post-hepatitic aplastic anaemia(1)

Clinicals - Examination

Fact Explanation
Pallor of skin and mucous membranes Due to low oxygenated hemoglobin level due to less oxygen carrying capacity caused by anemia(1) Pallor of skin and mucous membranes
Due to low oxygenated hemoglobin level due to less oxygen carrying capacity caused by anemia(1)
Petechiae and purpura Due to thrombocytopenia.(1) Petechiae and purpura
Due to thrombocytopenia.(1)
High pulse rate Due to the high cardiac output to compensate for anemia.(1) High pulse rate
Due to the high cardiac output to compensate for anemia.(1)
Fever Due to repeated infections caused by low white cell count.(1) Fever
Due to repeated infections caused by low white cell count.(1)
No lymphadenopathy To exclude other causes of pancytopenia such as a malignant hematological disorder.(1) No lymphadenopathy
To exclude other causes of pancytopenia such as a malignant hematological disorder.(1)
No hepatomegaly or splenomegaly Exclusion of other causes of pancytopenia which cause hepatomegaly and splenomegaly is necessary.(1) No hepatomegaly or splenomegaly
Exclusion of other causes of pancytopenia which cause hepatomegaly and splenomegaly is necessary.(1)
Short stature, café au lait spots and skeletal anomalies Inherited forms of aplastic anemia(Fanconi anemia) can present with these signs.(1) Short stature, café au lait spots and skeletal anomalies
Inherited forms of aplastic anemia(Fanconi anemia) can present with these signs.(1)
Leucoplakia, nail dystrophy and pigmentation of the skin These are characteristic of another inherited form of aplastic anemia, dyskeratosis congenita(1) Leucoplakia, nail dystrophy and pigmentation of the skin
These are characteristic of another inherited form of aplastic anemia, dyskeratosis congenita(1)

Investigations - Diagnosis

Fact Explanation
FBC and reticulocyte count FBC will show pancytopenia although the lymphocyte count is usually preserved. In majority of the cases the haemoglobin level, neutrophil and platelet counts are all uniformly depressed, but in the early stages isolated cytopenia, particularly thrombocytopenia, may occur. Anemia is accompanied by reticulocytopenia, and macrocytosis is commonly seen.(2) FBC and reticulocyte count
FBC will show pancytopenia although the lymphocyte count is usually preserved. In majority of the cases the haemoglobin level, neutrophil and platelet counts are all uniformly depressed, but in the early stages isolated cytopenia, particularly thrombocytopenia, may occur. Anemia is accompanied by reticulocytopenia, and macrocytosis is commonly seen.(2)
Blood film examination To exclude other differentials look should for the presence of dysplastic neutrophils , abnormal platelets, blast cells and other abnormal cells, such as hairy cells . In aplastic anaemia, anisopoikilocytosis is common and neutrophils may show toxic granulation. Thrombocytopenia is associated with small size of platelets.(2) Blood film examination
To exclude other differentials look should for the presence of dysplastic neutrophils , abnormal platelets, blast cells and other abnormal cells, such as hairy cells . In aplastic anaemia, anisopoikilocytosis is common and neutrophils may show toxic granulation. Thrombocytopenia is associated with small size of platelets.(2)
HbF% in children Fetal haemoglobin (HbF) should be measured pre-transfusion in children as this is an important prognostic factor in pediatric myelodysplastic syndrome (MDS) which may feature in the differential diagnosis of pancytopenia in children.(2) HbF% in children
Fetal haemoglobin (HbF) should be measured pre-transfusion in children as this is an important prognostic factor in pediatric myelodysplastic syndrome (MDS) which may feature in the differential diagnosis of pancytopenia in children.(2)
Bone marrow aspirate and trephine biopsy, including cytogenetics In aplastic anemia,the bone marrow is hypocellular with prominent fat spaces and variable amounts of residual haemopoietic cells. Erythropoiesis is reduced or absent, dyserythropoiesis is very common. Dysplastic megakaryocytes and granulocytic cells are not seen in aplastic anaemia. Lymphocytes, macrophages, plasma cells and mast cells appear prominent. In the early stages of the disease, one may also see prominent haemophagocytosis by macrophages, as well as background eosinophilic staining representing interstitial oedema. A trephine is crucial to assess overall cellularity, to assess the morphology of residual haemopoietic cells and to exclude an abnormal infiltrate.(2) Bone marrow aspirate and trephine biopsy, including cytogenetics
In aplastic anemia,the bone marrow is hypocellular with prominent fat spaces and variable amounts of residual haemopoietic cells. Erythropoiesis is reduced or absent, dyserythropoiesis is very common. Dysplastic megakaryocytes and granulocytic cells are not seen in aplastic anaemia. Lymphocytes, macrophages, plasma cells and mast cells appear prominent. In the early stages of the disease, one may also see prominent haemophagocytosis by macrophages, as well as background eosinophilic staining representing interstitial oedema. A trephine is crucial to assess overall cellularity, to assess the morphology of residual haemopoietic cells and to exclude an abnormal infiltrate.(2)
Peripheral blood lymphocytes is tested for spontaneous and diepoxybutane (DEB) or mitomycin C (MMC)-induced chromosomal breakage. To detect or to exclude Fanconi Anemia. In Fanconi Anemia there is increased chromosomal breakage.(2) Peripheral blood lymphocytes is tested for spontaneous and diepoxybutane (DEB) or mitomycin C (MMC)-induced chromosomal breakage.
To detect or to exclude Fanconi Anemia. In Fanconi Anemia there is increased chromosomal breakage.(2)
Flow cytometry for GPI (glycerophosphatidylinositol)-anchored proteins This a sensitive and quantitative test for Paroxysmal Nocturnal Haemoglobinuria(PNH) enabling the detection of small PNH clones which occur in up to 50% of patients with aplastic anaemia.(2) Flow cytometry for GPI (glycerophosphatidylinositol)-anchored proteins
This a sensitive and quantitative test for Paroxysmal Nocturnal Haemoglobinuria(PNH) enabling the detection of small PNH clones which occur in up to 50% of patients with aplastic anaemia.(2)
Urine hemosiderin if GPI-anchored protein deficiency To detect if PNH clone causes intravascular hemolysis.(2) Urine hemosiderin if GPI-anchored protein deficiency
To detect if PNH clone causes intravascular hemolysis.(2)
Vitamin B12 and folate To exclude megaloblastic anaemia which, when severe, can present with pancytopenia.(2) Vitamin B12 and folate
To exclude megaloblastic anaemia which, when severe, can present with pancytopenia.(2)
Abdominal ultrasound scan To exclude malignant hematological disorders which causes lymphadenopathy and/ splenomegaly.In aplastic anemia occurring in the absence of an infection splenomegaly is not seen. (2) Abdominal ultrasound scan
To exclude malignant hematological disorders which causes lymphadenopathy and/ splenomegaly.In aplastic anemia occurring in the absence of an infection splenomegaly is not seen. (2)
Liver function tests To detect antecedent hepatitis blood should be tested for hepatitis A antibody, hepatitis B surface antigen, hepatitis C antibody and Epstein–Barr virus (EBV).(2) Liver function tests
To detect antecedent hepatitis blood should be tested for hepatitis A antibody, hepatitis B surface antigen, hepatitis C antibody and Epstein–Barr virus (EBV).(2)
Anti-nuclear antibody and Anti-DNA antibody To detect Systemic Lupus Erythematosus (SLE) which can present with pancytopenia.(2) Anti-nuclear antibody and Anti-DNA antibody
To detect Systemic Lupus Erythematosus (SLE) which can present with pancytopenia.(2)

Investigations - Management

Fact Explanation
FBC and reticulocyte count If the condition improves there will be increase in the RBC, white blood cells and platelet counts with increased reticulocytes.(1) FBC and reticulocyte count
If the condition improves there will be increase in the RBC, white blood cells and platelet counts with increased reticulocytes.(1)
Blood Film If the condition improves there will be increase in the RBC, white blood cells and platelet counts with increased reticulocytes. However If it converts to a pathological condition, the following changes will be seen. Teardrop poikilocytes and leukoerythroblastic changes will suggest an infiltrative process. Dyserythropoietic RBCs and neutrophils with hypolobulation, hypogranulation, or apoptotic nuclei which are reaching to the edges of the cytoplasm with hypogranular monocytes will be seen in myelodysplasia. A leukemic process causes blasts cells on the peripheral smear. (1) Blood Film
If the condition improves there will be increase in the RBC, white blood cells and platelet counts with increased reticulocytes. However If it converts to a pathological condition, the following changes will be seen. Teardrop poikilocytes and leukoerythroblastic changes will suggest an infiltrative process. Dyserythropoietic RBCs and neutrophils with hypolobulation, hypogranulation, or apoptotic nuclei which are reaching to the edges of the cytoplasm with hypogranular monocytes will be seen in myelodysplasia. A leukemic process causes blasts cells on the peripheral smear. (1)
Bone marrow aspirate and biopsy. If improvement occurs it will show increase cellularity in the bone marrrow. Conversion to leukemia, myelodysplasia or myelofibrosis will show blast cells, dysplastic cells and fibrotic areas respectively.(1) Bone marrow aspirate and biopsy.
If improvement occurs it will show increase cellularity in the bone marrrow. Conversion to leukemia, myelodysplasia or myelofibrosis will show blast cells, dysplastic cells and fibrotic areas respectively.(1)
Chest x-ray To detect any respiratory infections.(1) Chest x-ray
To detect any respiratory infections.(1)
Full blood count In severe aplastic anemia
neutrophil count is <0·5 × 109/l, platelet count <20 × 109/l
In very severe AA neutrophils count is <0·2 × 109/l(1)
Full blood count
In severe aplastic anemia
neutrophil count is <0·5 × 109/l, platelet count <20 × 109/l
In very severe AA neutrophils count is <0·2 × 109/l(1)
Reticulocyte count In severe and in very severe aplastic anemia reticulocyte count is <20 × 109/l(1) Reticulocyte count
In severe and in very severe aplastic anemia reticulocyte count is <20 × 109/l(1)
Bone marrow biopsy In Severe and in very severe aplastic anemia ,bone marrow cellularity is <25%, or 25–50% with <30% residual haemopoietic cells.(1) Bone marrow biopsy
In Severe and in very severe aplastic anemia ,bone marrow cellularity is <25%, or 25–50% with <30% residual haemopoietic cells.(1)

Management - Supportive

Fact Explanation
Transfusional support Red cell transfusion: If bone marrow transplant or immunosuppressive treatment is planned irradiated blood is given to raise the hemoglobin level.
Prophylactic platelet transfusion should be considered when the platelet count is <10 × 109/l (there is an increased risk of cerebral hemorrhages,extensive retinal hemorrhages, buccal hemorrhages or rapidly spreading purpura)or if the platelet count is <20 × 109/l in the presence of fever platelet transfusion is recommended.(2)
Transfusional support
Red cell transfusion: If bone marrow transplant or immunosuppressive treatment is planned irradiated blood is given to raise the hemoglobin level.
Prophylactic platelet transfusion should be considered when the platelet count is <10 × 109/l (there is an increased risk of cerebral hemorrhages,extensive retinal hemorrhages, buccal hemorrhages or rapidly spreading purpura)or if the platelet count is <20 × 109/l in the presence of fever platelet transfusion is recommended.(2)
Prevention of infection If the patient is severely neutropenic (<0·5 × 109/l) he/she should be nursed in isolation and receive prophylactic antibiotics and antifungals. Regular mouth care including an antiseptic mouthwash, such as chlorhexidine, and food of low bacterial content, should be included in the nursing care. Antibiotics are given to prevent Gram-negative sepsis. Anti fungals are given since there is a high risk of fungal infection, such as Aspergillus.
Prophylactic Antivirals (such as Aciclovir) are given to all transplanted patients and is commonly given during and for the first 3–4 weeks after immunosuppressive therapy with antithymocyte globulin (ATG). Prophylaxis against Pneumocystis jirovecii (PCP) is essential for all patients after bone marrrow transplant regardless of the diagnosis. (2)
Prevention of infection
If the patient is severely neutropenic (<0·5 × 109/l) he/she should be nursed in isolation and receive prophylactic antibiotics and antifungals. Regular mouth care including an antiseptic mouthwash, such as chlorhexidine, and food of low bacterial content, should be included in the nursing care. Antibiotics are given to prevent Gram-negative sepsis. Anti fungals are given since there is a high risk of fungal infection, such as Aspergillus.
Prophylactic Antivirals (such as Aciclovir) are given to all transplanted patients and is commonly given during and for the first 3–4 weeks after immunosuppressive therapy with antithymocyte globulin (ATG). Prophylaxis against Pneumocystis jirovecii (PCP) is essential for all patients after bone marrrow transplant regardless of the diagnosis. (2)
Treatment of infection In febrile neutropenia since controlling infection fast is essential, immediate hospitalisation and treatment with empirical antibiotics and anti fungals is needed.
A short course of subcutaneous G-CSF (granulocyte colony stimulating factor)at a dose of 5 μg/kg per day may be considered for severe systemic infections that are not responding to intravenous antibiotics and antifungals.
G-CSF may produce a temporary neutrophil response but usually only in those patients with residual marrow granulocytic activity (that is, those with non-severe disease. If there is no response by 1 week, it is then recommended to discontinue the drug. GM-CSF is not generally recommended for the treatment of severe infection in patients with aplastic anemia as it can induce severe hemorrhage and other serious toxicity. Irradiated granulocyte infusion can also be given as an option to control the infection.(2)
Treatment of infection
In febrile neutropenia since controlling infection fast is essential, immediate hospitalisation and treatment with empirical antibiotics and anti fungals is needed.
A short course of subcutaneous G-CSF (granulocyte colony stimulating factor)at a dose of 5 μg/kg per day may be considered for severe systemic infections that are not responding to intravenous antibiotics and antifungals.
G-CSF may produce a temporary neutrophil response but usually only in those patients with residual marrow granulocytic activity (that is, those with non-severe disease. If there is no response by 1 week, it is then recommended to discontinue the drug. GM-CSF is not generally recommended for the treatment of severe infection in patients with aplastic anemia as it can induce severe hemorrhage and other serious toxicity. Irradiated granulocyte infusion can also be given as an option to control the infection.(2)
Iron chelation therapy Subcutaneous desferrioxamine should commence when the serum ferritin is >1000 μg/l since iron overload can occur with multiple blood transfusions.(2) Iron chelation therapy
Subcutaneous desferrioxamine should commence when the serum ferritin is >1000 μg/l since iron overload can occur with multiple blood transfusions.(2)
Psychological support Chronic nature of the disease and late response to treatment needs effective counseling(2). Psychological support
Chronic nature of the disease and late response to treatment needs effective counseling(2).

Management - Specific

Fact Explanation
Allogeneic stem cell transplantation from an HLA-identical sibling donor. To replenish the hemopoetic cells, bone marrow transplantation is done.(2) Allogeneic stem cell transplantation from an HLA-identical sibling donor.
To replenish the hemopoetic cells, bone marrow transplantation is done.(2)
Immunosuppressive therapy with a combination of (ATG) and ciclosporin. Since the pathology of aplastic anemia has a autoimmune origin immunosuppressives are given to suppress the lymphocyte activity.(2) Immunosuppressive therapy with a combination of (ATG) and ciclosporin.
Since the pathology of aplastic anemia has a autoimmune origin immunosuppressives are given to suppress the lymphocyte activity.(2)

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  1. AGNEW G Harvey. Idiopathic Aplastic Anaemia in a Child. Can Med Assoc J [online]. 1924 Sep, 14(9):859-861 [viewed 19 May 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1707625
  2. DAVIES JK, GUINAN EC. An update on the management of severe idiopathic aplastic anaemia in children. Br J Haematol [online] 2007 February, 136(4):549-564 [viewed 13 May 2014] Available from: doi:10.1111/j.1365-2141.2006.06461.x
  3. DOLBERG Osnay Jarchowsky, LEVY Yair. Idiopathic aplastic anemia: Diagnosis and classification. Autoimmunity Reviews [online] 2014 April, 13(4-5):569-573 [viewed 13 May 2014]
  4. DOLBERG Osnay Jarchowsky, LEVY Yair. Idiopathic aplastic anemia: Diagnosis and classification. Autoimmunity Reviews [online] 2014 April, 13(4-5):569-573 [viewed 13 May 2014]
  5. MARSH JCW, KULASEKARARAJ AG. Management of the refractory aplastic anemia patient: what are the options?. Hematology [online] December, 2013(1):87-94 [viewed 19 May 2014] Available from: doi:10.1182/asheducation-2013.1.87
  6. MARSH Judith C. W., BALL Sarah E., CAVENAGH Jamie, DARBYSHIRE Phil, DOKAL Inderjeet et al. Guidelines for the diagnosis and management of aplastic anaemia. [online] 2009 October, 147(1):43-70 [viewed 15 May 2014] Available from: doi:10.1111/j.1365-2141.2009.07842.x