History

Fact Explanation
History of exposure to drugs Several classes of drugs can cause drug induced aplastic anaemia: Non steroidal anti-inflammatory drugs - indomethacin [3] , piroxicam, diclofenac, antibiotics- sulfonamides,penicilliN [4] , anti-thyroid drugs- propylthiouracil, carbonic anhydrase inhibitors -acetazolamide and methazolamide, oral hypoglycemics- tolbutamide, chlorpropamide, diuretics-furosemide, thiazides, [4] antimalarials- chloroquine, phenothiazines, allopurinol, anti-convulsants-carbemazepine [2] , phenytoin, valproic acid, chloramphenicol and amphetamine.
Fatigue Dose related reversible or dose independent idiosyncratic aplasia of bone marrow due to direct toxicity, causing anemia. [4]
Lethargy A symptom of anemia. [4]
Dizziness Due to anemia. [4]
Shortness of breath on exertion Same as above:due to anemia. [4]
Palpitations Due to the increased cardiac workload, this needed to maintain tissue oxygenation. [5]
Prolonged bleeding from cuts Thrombocytopenia is the cause for this,as platelets are an essential component in clotting mechanism. [4]
Nose bleeds / gum bleeds Mucosal bleeding due to thrombocytopenia. [1]
Blood in the stool Mucosal bleeding due to thrombocytopenia. [1]
Heavy menstrual bleeding Mucosal bleeding due to thrombocytopenia. [1]
Petechial rashes Cutaneous bleeding can occur in thrombocytopenia. [1]
Easy bruising Due to thrombocytopenia. [1]
Visual disturbances Retinal haemorrhages due to thrombocytopenia. [4]
Frequent infections Leucopenia [1] causes defects in the immune system, making individual vulnerable for infections.
References
  1. YOUNG NS, SCHEINBERG P, CALADO RT. APLASTIC ANEMIA Curr Opin Hematol [online] 2008 May, 15(3):162-168 [viewed 15 September 2014] Available from: doi:10.1097/MOH.0b013e3282fa7470
  2. GAYFORD JJ, REDPATH TH. The side-effects of carbamazepine. Proc R Soc Med [online] 1969 Jun, 62(6):615-616 [viewed 15 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1811081
  3. DAS U.N.. Prostaglandins and drug induced agranulocytosis, aplastic anaemia and leukemia. Prostaglandins and Medicine [online] 1979 March, 2(3):235-238 [viewed 15 September 2014] Available from: doi:10.1016/0161-4630(79)90040-5
  4. MARSH JUDITH C. W., BALL SARAH E., CAVENAGH JAMIE, DARBYSHIRE PHIL, DOKAL INDERJEET, GORDON-SMITH EDWARD C., KEIDAN JANE, LAURIE ANDREW, MARTIN ANNA, MERCIECA JANE, KILLICK SALLY B., STEWART RHONA, YIN JOHN A. L.. Guidelines for the diagnosis and management of aplastic anaemia. [online] 2009 October, 147(1):43-70 [viewed 30 May 2014] Available from: doi:10.1111/j.1365-2141.2009.07842.x
  5. KADAKIA KC, DANIELS PR. 35-Year-Old Woman With Recurrent Palpitations Mayo Clin Proc [online] 2011 Aug, 86(8):801-804 [viewed 15 September 2014] Available from: doi:10.4065/mcp.2010.0727

Examination

Fact Explanation
Pallor Due to anemia. [2]
Dyspnoea Due to anemia. [2]
Tachycardia and arrhythmias Anemia increases the work load on the heart. [1]
Systolic murmur Anemia [1] 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. [1]
Other features of heart failure; Third heart sound Elevated jugular venous pressure Hepatomegaly Anemia causing heart failure, these are symptoms of heart failure. [1]
Petechiae/Purpura Due to thrombocytopenia. [2]
Bruises Due to thrombocytopenia. [2]
Haemorrhagic spots in the skin and mucous membrane Due to thrombocytopenia. [2]
Febrile Leucopenic patients are vulnerable to recurrent infections. [2]
Signs of infections(eg:- lung crepitations, skin infections) Recurrent infections due to leucopenia. [2]
References
  1. KADAKIA KC, DANIELS PR. 35-Year-Old Woman With Recurrent Palpitations Mayo Clin Proc [online] 2011 Aug, 86(8):801-804 [viewed 15 September 2014] Available from: doi:10.4065/mcp.2010.0727
  2. MARSH JUDITH C. W., BALL SARAH E., CAVENAGH JAMIE, DARBYSHIRE PHIL, DOKAL INDERJEET, GORDON-SMITH EDWARD C., KEIDAN JANE, LAURIE ANDREW, MARTIN ANNA, MERCIECA JANE, KILLICK SALLY B., STEWART RHONA, YIN JOHN A. L.. Guidelines for the diagnosis and management of aplastic anaemia. [online] 2009 October, 147(1):43-70 [viewed 30 May 2014] Available from: doi:10.1111/j.1365-2141.2009.07842.x

Differential Diagnoses

Fact Explanation
Inherited aplastic anaemias eg:- Fanconi anaemia [4], Dyskeratosis congenita, Diamond Blackfan syndrome Clinical features of Fanconi anaemia(FA) are growth retardation, microcephaly, café au lait spots and absent radius. [5] People with FA may have low blood counts from an early age. Some people with FA do not develop low blood counts as in aplastic anaemia. [5] In FA, chromosome breakage test is done to test the easily breaking chromosomes. Signs of dyskeratosis congenita [6] include abnormal skin pigmentation, abnormal nails and leukoplakia. People with this problem have a high risk of developing aplastic anemia.
Paroxysmal nocturnal haemoglobinuria [1] In this condition, abnormal red blood cells are destroyed by the immune system.These patients presents with features of anaemia [1] and dark urine.Unlike in the aplastic anaemia; pulmonary hypertension, abdominal pain, bloating, headaches, esophageal spasms, back pain, erectile dysfunction are common due to NO depletion by scavenging free hemoglobin. After several years of hemoglobinuria, progressive chronic renal failure can occur . The marrow failure may be a severe form causing aplastic anaemia.
Myelodysplastic syndrome [1] Disordered development of blood cells in bone marrow causing failure of normal blood cell production [2] , leads to low blood counts, giving the same clinical features of pancytopenia. [3] But many develops the condition slowly, where only the blood counts can detect the problem at an early stage.Patients with refractory anemia with excess blasts may have a small number of myeloblasts in the blood. When blasts are present in the blood it is always abnormal and often signals a bone marrow problem. Blood cells from MDS patients may also have certain abnormalities in size, shape, or other features that can be seen under the microscope.For a diagnosis of MDS, a patient must have less than 20% blasts in the bone marrow. These blast cells are not in the aplastic anemia. Immuno histochemistry is helpful in distinguishing different types of myelodysplastic syndromes from one another and from other diseases. Unlike in aplastic anaemia chromosome changes are commonly seen in MDS [3] that include deletions in chromosomes 5 and 7 or an extra chromosome 8.
Acute Lymphoblastic Leukaemia, Acute Myeloid Leukaemia or Hairy Cell Leukaemia [11] Leukaemias [10] can also cause symptoms of pancytopenia. Unlike in aplastic anaemia,there is hepatomegaly, splenomegaly and sometimes even lymphadenopathy. [11] A patient who has more than 20% blasts in the bone marrow is considered to have acute leukemia.
Lymphoma [7] Non specific symptoms include fever, chills,unexplained weight loss,night sweats and itching (up to 25% of patients develop this itch, most commonly in the lower extremity) On examination, there may be hepatomegaly, splenomegaly and lymphadenopathy. Definitive diagnosis by a lymph node biopsy, that reveals histopathological features of lymphoma. [8] After that variety of tests may be carried out to look for specific features characteristic of different types of lymphoma. These include:immuno-phenotyping, flow cytometry, FISH testing. [7]
Hypersplenism [9] Apart from the symptoms of pancytopenia (as in aplastic anaemia), patient might have an enlarged spleen. [9] Ultrasound and computed tomography scan may help to diagnose an enlarged spleen and possible underlying causes, Another test measures red blood cells in the liver and spleen after injection of a radioactive substance, and indicates areas where the spleen is holding on to large numbers of red cells or is destroying them.
References
  1. YOUNG NS, SCHEINBERG P, CALADO RT. APLASTIC ANEMIA Curr Opin Hematol [online] 2008 May, 15(3):162-168 [viewed 15 September 2014] Available from: doi:10.1097/MOH.0b013e3282fa7470
  2. DOLL DC, LIST AF. Myelodysplastic syndromes. West J Med [online] 1989 Aug, 151(2):161-167 [viewed 15 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1026906
  3. RAJ K, MUFTI GJ. Azacytidine (Vidaza(R)) in the treatment of myelodysplastic syndromes Ther Clin Risk Manag [online] 2006 Dec, 2(4):377-388 [viewed 15 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1936359
  4. DUCKWORTH-RYSIECKI G, HULTéN M, MANN J, TAYLOR AM. Clinical and cytogenetic diversity in Fanconi's anaemia. J Med Genet [online] 1984 Jun, 21(3):197-203 [viewed 15 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1049266
  5. HOLDEN ST, COX JJ, KESTERTON I, THOMAS NS, CARR C, WOODS CG. Fanconi anaemia complementation group B presenting as X linked VACTERL with hydrocephalus syndrome J Med Genet [online] 2006 Sep, 43(9):750-754 [viewed 15 September 2014] Available from: doi:10.1136/jmg.2006.041673
  6. DAVIDSON HR, CONNOR JM. Dyskeratosis congenita. J Med Genet [online] 1988 Dec, 25(12):843-846 [viewed 15 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1051614
  7. BRADY G, MACARTHUR GJ, FARRELL PJ. Epstein-Barr virus and Burkitt lymphoma J Clin Pathol [online] 2007 Dec, 60(12):1397-1402 [viewed 15 September 2014] Available from: doi:10.1136/jcp.2007.047977
  8. PITTALUGA S, JAFFE ES. T-cell/histiocyte-rich large B-cell lymphoma Haematologica [online] 2010 Mar, 95(3):352-356 [viewed 15 September 2014] Available from: doi:10.3324/haematol.2009.016931
  9. ZHAN XL, JI Y, WANG YD. Laparoscopic splenectomy for hypersplenism secondary to liver cirrhosis and portal hypertension World J Gastroenterol [online] 2014 May 21, 20(19):5794-5800 [viewed 15 September 2014] Available from: doi:10.3748/wjg.v20.i19.5794
  10. CRAGG SJ, JACOBS A, PARRY DH, WAGSTAFF M, WORWOOD M. Isoferritins in acute leukaemia. Br J Cancer [online] 1977 May, 35(5):635-642 [viewed 15 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2025487

Investigations - for Diagnosis

Fact Explanation
Full blood count There may be low platelets due to thrombocytopenia. [1] Low red blood cell count and Hb due to anaemia. Low white blood cell count due to granulocytopenia. [1]
Reticulocyte count Low reticulocyte count due to bone marrow hypoplasia. [2]
Serum folate, B12, Fe To exclude the other causes of anaemia such as Fe, B12 and folate defficiency. [2]
Blood film Macrocytosis is commonly noted. Blood film is essential to exclude [2] 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 [3] Normal bone marrow contains many cells that produce the different types of blood cells. An “empty” bone marrow indicates the diagnosis of aplastic anemia. [2] 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. [2,4]
Flow cytometry To exclude paroxysmal nocturnal haemoglobinuria (PNH) clones (50% of patients with aplastic anaemia have small PNH clones). [2]
References
  1. DAS U.N.. Prostaglandins and drug induced agranulocytosis, aplastic anaemia and leukemia. Prostaglandins and Medicine [online] 1979 March, 2(3):235-238 [viewed 15 September 2014] Available from: doi:10.1016/0161-4630(79)90040-5
  2. MARSH JUDITH C. W., BALL SARAH E., CAVENAGH JAMIE, DARBYSHIRE PHIL, DOKAL INDERJEET, GORDON-SMITH EDWARD C., KEIDAN JANE, LAURIE ANDREW, MARTIN ANNA, MERCIECA JANE, KILLICK SALLY B., STEWART RHONA, YIN JOHN A. L.. Guidelines for the diagnosis and management of aplastic anaemia. [online] 2009 October, 147(1):43-70 [viewed 30 May 2014] Available from: doi:10.1111/j.1365-2141.2009.07842.x
  3. YOUNG N. S., CALADO R. T., SCHEINBERG P.. Current concepts in the pathophysiology and treatment of aplastic anemia. Blood [online] 2006 October, 108(8):2509-2519 [viewed 30 May 2014] Available from: doi:10.1182/blood-2006-03-010777
  4. DUCKWORTH-RYSIECKI G, HULTéN M, MANN J, TAYLOR AM. Clinical and cytogenetic diversity in Fanconi's anaemia. J Med Genet [online] 1984 Jun, 21(3):197-203 [viewed 15 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1049266

Investigations - Fitness for Management

Fact Explanation
Chest X-ray A chest X-ray is useful at presentation to exclude infection and for comparison with subsequent films. [1]
References
  1. MARSH JUDITH C. W., BALL SARAH E., CAVENAGH JAMIE, DARBYSHIRE PHIL, DOKAL INDERJEET, GORDON-SMITH EDWARD C., KEIDAN JANE, LAURIE ANDREW, MARTIN ANNA, MERCIECA JANE, KILLICK SALLY B., STEWART RHONA, YIN JOHN A. L.. Guidelines for the diagnosis and management of aplastic anaemia. [online] 2009 October, 147(1):43-70 [viewed 30 May 2014] Available from: doi:10.1111/j.1365-2141.2009.07842.x

Investigations - Followup

Fact Explanation
Full blood count Red blood cell and platelet count can be monitored for check the response to treatment [2] , 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.[1]
Blood film Blood film is important to monitor for evidence of MDS. [1]
Bone marrow examinations with cytogenetics Indicated if there is evidence of relapse or other change in the blood count or blood film. [1]
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. [1,2]
References
  1. MARSH JUDITH C. W., BALL SARAH E., CAVENAGH JAMIE, DARBYSHIRE PHIL, DOKAL INDERJEET, GORDON-SMITH EDWARD C., KEIDAN JANE, LAURIE ANDREW, MARTIN ANNA, MERCIECA JANE, KILLICK SALLY B., STEWART RHONA, YIN JOHN A. L.. Guidelines for the diagnosis and management of aplastic anaemia. [online] 2009 October, 147(1):43-70 [viewed 30 May 2014] Available from: doi:10.1111/j.1365-2141.2009.07842.x
  2. KOJIMA S.. Outcome of 154 patients with severe aplastic anemia who received transplants from unrelated donors: the Japan Marrow Donor Program. [online] 2002 July, 100(3):799-803 [viewed 15 September 2014] Available from: doi:10.1182/blood.V100.3.799

Investigations - Screening/Staging

Fact Explanation
Full blood count (neutrophil count, platelet count) Aplastic anaemia can be categorized into three groups. [1] 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 [1] (Platelet count <20 × 109/l, Neutrophil count <0·5 × 109/l,Reticulocyte count <20 × 109/l) indicate severe aplastic anaemia.
References
  1. MARSH JUDITH C. W., BALL SARAH E., CAVENAGH JAMIE, DARBYSHIRE PHIL, DOKAL INDERJEET, GORDON-SMITH EDWARD C., KEIDAN JANE, LAURIE ANDREW, MARTIN ANNA, MERCIECA JANE, KILLICK SALLY B., STEWART RHONA, YIN JOHN A. L.. Guidelines for the diagnosis and management of aplastic anaemia. [online] 2009 October, 147(1):43-70 [viewed 30 May 2014] Available from: doi:10.1111/j.1365-2141.2009.07842.x

Management - General Measures

Fact Explanation
Red blood cell transfusion Improve the symptoms of anaemia, Iron chelating agents are needed in a case of repeated blood transfusions. [1]
Platelets transfusion Used to treat the bleeding manifestations due to low platelets. [2] 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 [2] may be considered in patients with life-threatening neutropenic sepsis.
Antibiotics Needed at the earliest point of infection [2] as their blood counts are low. Infection risk is depends on the patient’s neutrophil and monocyte counts. [2] 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. [2]
Psychological support Aplastic anaemia is a rare disease and requires careful explanation of its nature, [2] 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. [2]
References
  1. DEEG HJ, O'DONNELL M, TOLAR J, AGARWAL R, HARRIS RE, FEIG SA, TERRITO MC, COLLINS RH, MCSWEENEY PA, COPELAN EA, KHAN SP, WOOLFREY A, STORER B. Optimization of conditioning for marrow transplantation from unrelated donors for patients with aplastic anemia after failure of immunosuppressive therapy Blood [online] 2006 Sep 1, 108(5):1485-1491 [viewed 15 September 2014] Available from: doi:10.1182/blood-2006-03-005041
  2. MARSH JUDITH C. W., BALL SARAH E., CAVENAGH JAMIE, DARBYSHIRE PHIL, DOKAL INDERJEET, GORDON-SMITH EDWARD C., KEIDAN JANE, LAURIE ANDREW, MARTIN ANNA, MERCIECA JANE, KILLICK SALLY B., STEWART RHONA, YIN JOHN A. L.. Guidelines for the diagnosis and management of aplastic anaemia. [online] 2009 October, 147(1):43-70 [viewed 30 May 2014] Available from: doi:10.1111/j.1365-2141.2009.07842.x

Management - Specific Treatments

Fact Explanation
Immune suppression eg:- Anti lymphocytic globulin (ALG), Anti thymocyte globulin (ATG) Treatment modality for most patients with aplastic anaemia, [2] which induces hematologic recovery in 35%-70% ATG reduces the number of T lymphocytes in the blood. [1]
Bone marrow transplantation Bone marrow transplantation from an HLA-matched sibling donor [4] emains the choice of treatment [1] and accounts for 70% long-term survivors. This is used for newly diagnosed patients if they have severe or very severe aplastic anaemia, [2] who are <40 years old and have an HLA-compatible sibling donor. There can be complications like graft rejection after the procedure. [3]
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. [1]
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, [1] Alemtuzumab is a new monoclonal antibody that targets the CD52 Ag on T cells. [2]
References
  1. YOUNG NS, SCHEINBERG P, CALADO RT. APLASTIC ANEMIA Curr Opin Hematol [online] 2008 May, 15(3):162-168 [viewed 15 September 2014] Available from: doi:10.1097/MOH.0b013e3282fa7470
  2. MARSH JUDITH C. W., BALL SARAH E., CAVENAGH JAMIE, DARBYSHIRE PHIL, DOKAL INDERJEET, GORDON-SMITH EDWARD C., KEIDAN JANE, LAURIE ANDREW, MARTIN ANNA, MERCIECA JANE, KILLICK SALLY B., STEWART RHONA, YIN JOHN A. L.. Guidelines for the diagnosis and management of aplastic anaemia. [online] 2009 October, 147(1):43-70 [viewed 30 May 2014] Available from: doi:10.1111/j.1365-2141.2009.07842.x
  3. KOJIMA S.. Outcome of 154 patients with severe aplastic anemia who received transplants from unrelated donors: the Japan Marrow Donor Program. [online] 2002 July, 100(3):799-803 [viewed 15 September 2014] Available from: doi:10.1182/blood.V100.3.799
  4. SCHREZENMEIER H, PASSWEG JR, MARSH JC, BACIGALUPO A, BREDESON CN, BULLORSKY E, CAMITTA BM, CHAMPLIN RE, GALE RP, FUHRER M, KLEIN JP, LOCASCIULLI A, ONETO R, SCHATTENBERG AV, SOCIE G, EAPEN M. Worse outcome and more chronic GVHD with peripheral blood progenitor cells than bone marrow in HLA-matched sibling donor transplants for young patients with severe acquired aplastic anemia Blood [online] 2007 Aug 15, 110(4):1397-1400 [viewed 15 September 2014] Available from: doi:10.1182/blood-2007-03-081596