Drug-induced aplastic anaemia

Hematology

Clinicals - History

Fact Explanation
History of exposure to drugs Several classes of drugs can cause drug induced aplastic anaemia:
Non steroidal anti-inflammatory drugs - indomethacin , piroxicam, diclofenac, antibiotics- sulfonamides,penicilliN , anti-thyroid drugs- propylthiouracil, carbonic anhydrase inhibitors -acetazolamide and methazolamide, oral hypoglycemics- tolbutamide, chlorpropamide, diuretics-furosemide, thiazides, antimalarials- chloroquine, phenothiazines, allopurinol, anti-convulsants-carbemazepine , phenytoin, valproic acid, chloramphenicol and amphetamine.
History of exposure to drugs
Several classes of drugs can cause drug induced aplastic anaemia:
Non steroidal anti-inflammatory drugs - indomethacin , piroxicam, diclofenac, antibiotics- sulfonamides,penicilliN , anti-thyroid drugs- propylthiouracil, carbonic anhydrase inhibitors -acetazolamide and methazolamide, oral hypoglycemics- tolbutamide, chlorpropamide, diuretics-furosemide, thiazides, antimalarials- chloroquine, phenothiazines, allopurinol, anti-convulsants-carbemazepine , phenytoin, valproic acid, chloramphenicol and amphetamine.
Fatigue Dose related reversible or dose independent idiosyncratic aplasia of bone marrow due to direct toxicity, causing anemia. Fatigue
Dose related reversible or dose independent idiosyncratic aplasia of bone marrow due to direct toxicity, causing anemia.
Lethargy A symptom of anemia. Lethargy
A symptom of anemia.
Dizziness Due to anemia. Dizziness
Due to anemia.
Shortness of breath on exertion Same as above:due to anemia. Shortness of breath on exertion
Same as above:due to anemia.
Palpitations Due to the increased cardiac workload, this needed to maintain tissue oxygenation. Palpitations
Due to the increased cardiac workload, this needed to maintain tissue oxygenation.
Prolonged bleeding from cuts Thrombocytopenia is the cause for this,as platelets are an essential component in clotting mechanism. Prolonged bleeding from cuts
Thrombocytopenia is the cause for this,as platelets are an essential component in clotting mechanism.
Nose bleeds / gum bleeds Mucosal bleeding due to thrombocytopenia. Nose bleeds / gum bleeds
Mucosal bleeding due to thrombocytopenia.
Blood in the stool Mucosal bleeding due to thrombocytopenia. Blood in the stool
Mucosal bleeding due to thrombocytopenia.
Heavy menstrual bleeding Mucosal bleeding due to thrombocytopenia. Heavy menstrual bleeding
Mucosal bleeding due to thrombocytopenia.
Petechial rashes Cutaneous bleeding can occur in thrombocytopenia. Petechial rashes
Cutaneous bleeding can occur in thrombocytopenia.
Easy bruising Due to thrombocytopenia. Easy bruising
Due to thrombocytopenia.
Visual disturbances Retinal haemorrhages due to thrombocytopenia. Visual disturbances
Retinal haemorrhages due to thrombocytopenia.
Frequent infections Leucopenia causes defects in the immune system, making individual vulnerable for infections. Frequent infections
Leucopenia causes defects in the immune system, making individual vulnerable for infections.

Clinicals - Examination

Fact Explanation
Pallor Due to anemia. Pallor
Due to anemia.
Dyspnoea Due to anemia. Dyspnoea
Due to anemia.
Tachycardia and arrhythmias Anemia increases the work load on the heart. Tachycardia and arrhythmias
Anemia increases the work load on the heart.
Systolic murmur Anemia can cause flow murmurs, due to increased blow of blood through the aortic valve as the cardiac output rises. Systolic murmur
Anemia can cause flow murmurs, due to increased blow of blood through the aortic valve as the cardiac output rises.
Ankle oedema Anemia can precipitate heart failure. Ankle oedema
Anemia can precipitate heart failure.
Other features of heart failure; Third heart sound Elevated jugular venous pressure Hepatomegaly Anemia causing heart failure, these are symptoms of heart failure. Other features of heart failure; Third heart sound Elevated jugular venous pressure Hepatomegaly
Anemia causing heart failure, these are symptoms of heart failure.
Petechiae/Purpura Due to thrombocytopenia. Petechiae/Purpura
Due to thrombocytopenia.
Bruises Due to thrombocytopenia. Bruises
Due to thrombocytopenia.
Haemorrhagic spots in the skin and mucous membrane Due to thrombocytopenia. Haemorrhagic spots in the skin and mucous membrane
Due to thrombocytopenia.
Febrile Leucopenic patients are vulnerable to recurrent infections. Febrile
Leucopenic patients are vulnerable to recurrent infections.
Signs of infections(eg:- lung crepitations, skin infections) Recurrent infections due to leucopenia. Signs of infections(eg:- lung crepitations, skin infections)
Recurrent infections due to leucopenia.

Investigations - Diagnosis

Fact Explanation
Full blood count There may be low platelets due to thrombocytopenia.
Low red blood cell count and Hb due to anaemia. Low white blood cell count due to granulocytopenia.
Full blood count
There may be low platelets due to thrombocytopenia.
Low red blood cell count and Hb due to anaemia. Low white blood cell count due to granulocytopenia.
Reticulocyte count Low reticulocyte count due to bone marrow hypoplasia. Reticulocyte count
Low reticulocyte count due to bone marrow hypoplasia.
Serum folate, B12, Fe To exclude the other causes of anaemia such as Fe, B12 and folate defficiency. Serum folate, B12, Fe
To exclude the other causes of anaemia such as Fe, B12 and folate defficiency.
Blood film Macrocytosis is commonly noted. Blood film is essential to exclude the presence of dysplastic neutrophils and abnormal platelets, blasts and other abnormal cells, such as hairy cells (as seen in hairy cell leukaemia). In aplastic anaemia, anisopoikilocytosis is common and neutrophils may show toxic granulation. Blood film
Macrocytosis is commonly noted. Blood film is essential to exclude the presence of dysplastic neutrophils and abnormal platelets, blasts and other abnormal cells, such as hairy cells (as seen in hairy cell leukaemia). In aplastic anaemia, anisopoikilocytosis is common and neutrophils may show toxic granulation.
Bone marrow biopsy Normal bone marrow contains many cells that produce the different types of blood cells. An “empty” bone marrow indicates the diagnosis of aplastic anemia.
Leukemia or other kinds of cancers can also cause low blood counts, but in that case the bone marrow would be filled with leukemia cells or other cancer cells.
Bone marrow biopsy
Normal bone marrow contains many cells that produce the different types of blood cells. An “empty” bone marrow indicates the diagnosis of aplastic anemia.
Leukemia or other kinds of cancers can also cause low blood counts, but in that case the bone marrow would be filled with leukemia cells or other cancer cells.
Peripheral blood cytogenetics To exclude Fanconi's anaemia if under 35 years old. Peripheral blood cytogenetics
To exclude Fanconi's anaemia if under 35 years old.
Flow cytometry To exclude paroxysmal nocturnal haemoglobinuria (PNH) clones (50% of patients with aplastic anaemia have small PNH clones). Flow cytometry
To exclude paroxysmal nocturnal haemoglobinuria (PNH) clones (50% of patients with aplastic anaemia have small PNH clones).

Investigations - Management

Fact Explanation
Full blood count Red blood cell and platelet count can be monitored for check the response to treatment , deterioration, evidence of relapse, and also for later clonal disorders such as PNH, MDS and AML. Full blood count
Red blood cell and platelet count can be monitored for check the response to treatment , deterioration, evidence of relapse, and also for later clonal disorders such as PNH, MDS and AML.
Haemoglobin level Can be used to monitor the level of anaemia and do the transfusions as and when needed. Haemoglobin level
Can be used to monitor the level of anaemia and do the transfusions as and when needed.
Blood film Blood film is important to monitor for evidence of MDS. Blood film
Blood film is important to monitor for evidence of MDS.
Bone marrow examinations with cytogenetics Indicated if there is evidence of relapse or other change in the blood count or blood film. Bone marrow examinations with cytogenetics
Indicated if there is evidence of relapse or other change in the blood count or blood film.
Screen for paroxysmal nocturnal haemoglobinuria At 3–4 months post-ATG, a screen for PNH should be performed. It is suggested that a PNH screen is performed annually in all patients. Screen for paroxysmal nocturnal haemoglobinuria
At 3–4 months post-ATG, a screen for PNH should be performed. It is suggested that a PNH screen is performed annually in all patients.
Chest X-ray A chest X-ray is useful at presentation to exclude infection and for comparison with subsequent films. Chest X-ray
A chest X-ray is useful at presentation to exclude infection and for comparison with subsequent films.
Full blood count (neutrophil count, platelet count) Aplastic anaemia can be categorized into three groups.
Moderate aplastic anemia – blood counts are low, but not as low as with severe aplastic anemia. may have few or no symptoms.
Severe aplastic anemia–neutrophil count is less than 500 cells per microliter.
Very severe aplastic anemia- neutrophil count is less than 200 cells per microliter.
Full blood count (neutrophil count, platelet count)
Aplastic anaemia can be categorized into three groups.
Moderate aplastic anemia – blood counts are low, but not as low as with severe aplastic anemia. may have few or no symptoms.
Severe aplastic anemia–neutrophil count is less than 500 cells per microliter.
Very severe aplastic anemia- neutrophil count is less than 200 cells per microliter.
Bone marrow BM cellularity <25%, or 25–50% with <30% residual hemopoietic cells together with two of the followings (Platelet count <20 × 109/l, Neutrophil count <0·5 × 109/l,Reticulocyte count <20 × 109/l) indicate severe aplastic anaemia. Bone marrow
BM cellularity <25%, or 25–50% with <30% residual hemopoietic cells together with two of the followings (Platelet count <20 × 109/l, Neutrophil count <0·5 × 109/l,Reticulocyte count <20 × 109/l) indicate severe aplastic anaemia.

Management - Supportive

Fact Explanation
Red blood cell transfusion Improve the symptoms of anaemia, Iron chelating agents are needed in a case of repeated blood transfusions. Red blood cell transfusion
Improve the symptoms of anaemia, Iron chelating agents are needed in a case of repeated blood transfusions.
Platelets transfusion Used to treat the bleeding manifestations due to low platelets. Prophylactic platelet transfusions should be given when the platelet count is <10 × 109/l (or <20 × 109/l in the presence of fever). Platelets transfusion
Used to treat the bleeding manifestations due to low platelets. Prophylactic platelet transfusions should be given when the platelet count is <10 × 109/l (or <20 × 109/l in the presence of fever).
Granulocyte transfusions Transfusion of irradiated granulocyte transfusions may be considered in patients with life-threatening neutropenic sepsis. Granulocyte transfusions
Transfusion of irradiated granulocyte transfusions may be considered in patients with life-threatening neutropenic sepsis.
Antibiotics Needed at the earliest point of infection as their blood counts are low. Infection risk is depends on the patient’s neutrophil and monocyte counts. Prophylactic antibiotic and antifungal drugs should be given to patients with neutrophil count <0·5 × 109/l. Antibiotics
Needed at the earliest point of infection as their blood counts are low. Infection risk is depends on the patient’s neutrophil and monocyte counts. Prophylactic antibiotic and antifungal drugs should be given to patients with neutrophil count <0·5 × 109/l.
Prevention of infections and safety As the patient is vulnerable for infections and bleeding, it is advisable to protect from germs and avoid contact sports. Patients who are severely neutropenic (<0·5 × 109/l) should ideally be nursed in isolation. Prevention of infections and safety
As the patient is vulnerable for infections and bleeding, it is advisable to protect from germs and avoid contact sports. Patients who are severely neutropenic (<0·5 × 109/l) should ideally be nursed in isolation.
Psychological support Aplastic anaemia is a rare disease and requires careful explanation of its nature, prognosis, as well as discussions on important issues such as pregnancy. Psychological support
Aplastic anaemia is a rare disease and requires careful explanation of its nature, prognosis, as well as discussions on important issues such as pregnancy.
Avoidance of offending drug in the future This should be a part of patient education, to prevent relapses. Avoidance of offending drug in the future
This should be a part of patient education, to prevent relapses.

Management - Specific

Fact Explanation
Immune suppression eg:- Anti lymphocytic globulin (ALG), Anti thymocyte globulin (ATG) Treatment modality for most patients with aplastic anaemia, which induces hematologic recovery in 35%-70%
ATG reduces the number of T lymphocytes in the blood.
Immune suppression eg:- Anti lymphocytic globulin (ALG), Anti thymocyte globulin (ATG)
Treatment modality for most patients with aplastic anaemia, which induces hematologic recovery in 35%-70%
ATG reduces the number of T lymphocytes in the blood.
Bone marrow transplantation Bone marrow transplantation from an HLA-matched sibling donor emains the choice of treatment and accounts for 70% long-term survivors. This is used for newly diagnosed patients if they have severe or very severe aplastic anaemia, who are <40 years old and have an HLA-compatible sibling donor. There can be complications like graft rejection after the procedure. Bone marrow transplantation
Bone marrow transplantation from an HLA-matched sibling donor emains the choice of treatment and accounts for 70% long-term survivors. This is used for newly diagnosed patients if they have severe or very severe aplastic anaemia, who are <40 years old and have an HLA-compatible sibling donor. There can be complications like graft rejection after the procedure.
Colony stimulating factors eg:-filgrastin, sargrastim Filgrastin is a granulocyte colony stimulating factor, Sargrastim is a granulocyte macrophage colony stimulating factor.These act as bone marrow stimulants to increase the production of blood cells. Colony stimulating factors eg:-filgrastin, sargrastim
Filgrastin is a granulocyte colony stimulating factor, Sargrastim is a granulocyte macrophage colony stimulating factor.These act as bone marrow stimulants to increase the production of blood cells.
Other immune suppressants such as cyclosporine, novel immune suppressants and early and late growth factors These agents can enhance the response to ALG and ATG, Alemtuzumab is a new monoclonal antibody that targets the CD52 Ag on T cells. Other immune suppressants such as cyclosporine, novel immune suppressants and early and late growth factors
These agents can enhance the response to ALG and ATG, Alemtuzumab is a new monoclonal antibody that targets the CD52 Ag on T cells.

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