Approach

The urgency with which anemia is evaluated depends on the severity at presentation and whether the patient has active or acute bleeding.

Initial assessment of patients with active or acute bleeding

Evaluation should include identification of any source of active or acute bleeding.

  • The initial goal in a patient with acute bleeding is rapid hemodynamic stabilization. Up to 30% of total blood volume may be lost before clinical manifestations are appreciated at rest.

  • Patients with an acute severe hemorrhage present with symptoms and signs of hypovolemia and the underlying cause.[4]

  • Key signs of hypovolemia include hypotension, pallor, cold clammy skin, thready pulse, tachycardia, dyspnea and altered mental status. Flat neck veins when supine indicate at least 30% to 40% total body volume loss. All orifices should be examined for bleeding.

  • History of prior episodes of gastrointestinal bleeding, gastritis, inflammatory bowel disease, non-steroidal anti-inflammatory drug (NSAID) or corticosteroid use, alcohol misuse, or cirrhosis should prompt suspicion of gastrointestinal bleeding. NSAIDs and corticosteroids are associated with peptic ulcer disease. Alcohol misuse and cirrhosis are associated with coagulation disorders and esophageal varices. A lower gastrointestinal bleed presents with fresh red rectal bleeding (hematochezia). Melena and/or hematemesis with or without abdominal pain indicate an upper gastrointestinal bleed.

  • Sudden tearing pain should prompt suspicion of a ruptured vascular aneurysm; the pain may be spontaneous, or precipitated by trauma or by cocaine or amphetamine use. Loss of consciousness may occur if a major vessel is involved. A history of hypertension or collagen disorders may also be present. A wide pulse pressure suggests a ruptured aneurysm. A pulsatile abdominal mass may indicate an abdominal aortic aneurysm. Flank or abdominal ecchymosis suggests intra-abdominal bleeding.

  • The mechanism and site of any trauma should be determined.

  • If there is a history of recent surgery, ongoing blood loss at the surgical site must be considered. A detailed history of the pre-, intra-, and postoperative course should be obtained, including any complications noted during the operation. Any antibiotics administered should be noted, as some can produce a decrease in platelet levels.

  • A history of bleeding disorders or excessive bruising may indicate an underlying coagulation disorder.

  • Jaundice, especially when accompanied by fatigue and pallor, with episodic dark urine suggests a hemolytic process, particularly in patients with recent infection, new medications, or history of malignancy.

Tests are guided by the history, exam, and suspected etiology of active bleeding, and many include the following:

  • Complete blood count (CBC), which shows a normocytic anemia with a high reticulocyte count (>2%) and a normal or decreased hematocrit (Hct). Dilution does not occur initially, so hemoglobin (Hb) and Hct do not accurately reflect the true severity of the anemia.

  • Prothrombin time/activated partial prothrombin time, which is usually normal, but tested to identify patients with decreased coagulation due to anticoagulants, underlying defects in hemostasis, or consumptive coagulopathy. In patients with upper gastrointestinal bleeding, elevated BUN may be seen, even in the absence of renal impairment, due to digestion of blood, which is a source of urea.

  • Abdominal ultrasound scan: allows rapid identification of intra-abdominal bleeding and indicated if abdominal trauma or a ruptured abdominal aortic aneurysm are suspected.

  • Joint x-rays, indicated in patients with trauma to identify fractures. Long-bone fractures can be a significant source of bleeding.

  • Computed tomography scanning of the body region affected by trauma or aneurysm rupture, which will identify internal injuries or the extent and nature of the aneurysm, and identify sources of bleeding.

  • Upper gastrointestinalI endoscopy, required to identify sources of upper gastrointestinal bleeding.[49][50]

  • Colonoscopy, required to identify sources of lower gastrointestinal bleeding.

  • Capsule endoscopy may have diagnostic, but not therapeutic, utility in situations where there is concern for gastrointestinal bleeding in inaccessible areas such as the small bowel.[51]

  • Exploratory laparotomy, which may be required in patients with abdominal bleeding to identify the source, especially if there is a history of abdominal trauma or previous abdominal surgery.

Patients without active or acute bleeding

Many anemic patients with no acute or active bleeding are asymptomatic, and the anemia is only noted on a CBC taken as part of the assessment of an unrelated condition. The duration of anemia must be investigated, if possible.

Generally, healthy individuals tolerate extreme anemia well, with cardiovascular status being the major limiting factor.

Symptoms of anemia may include fatigue, weakness, decreased exercise tolerance, shortness of breath with exercise, palpitations, dizziness, irritability and impaired concentration.[7]

There is a strong relationship between pica (a medical disorder in which children develop an appetite for non-nutritive substances) and iron deficiency. Information about pica should actively be sought in high-risk groups.[52]

Pallor is the most common sign in patients with anemia.[7] Jaundice is an additional sign seen in patients with hemolytic anemias. 

The first step in diagnosis is to identify the type of anemia that is present, using the results of the CBC.


Venepuncture and phlebotomy: animated demonstrationVenepuncture and phlebotomy: animated demonstration

Due to their relative reproducibility, mean corpuscular volume (MCV) and red cell width are the most useful components in the initial classification of most anemias.

The anemia may be:

  • Microcytic (MCV <80 femtoliters [fL]): serum iron studies should be performed.[2]

  • Normocytic (MCV 80-100 femtoliters [fL]): the reticulocyte count should be examined to determine if the anemia is hypoproliferative (<2%) or hyperproliferative (>2%).

  • Macrocytic (MCV >100 femtoliters [fL]): the peripheral smear should be examined for megaloblasts and hypersegmented neutrophils. If these cells are present, the anemia is megaloblastic. If they are absent, the anemia is nonmegaloblastic. com.bmj.content.model.assessment.Caption@370e0c71[Figure caption and citation for the preceding image starts]: Algorithm for the assessment of anemiaCreated by the BMJ Knowledge Centre [Citation ends].

Microcytic anemia: abnormal serum iron studies

A low serum iron, an elevated total iron-binding capacity, and a low ferritin indicate iron deficiency anemia. Serum ferritin is the most sensitive and specific test for iron deficiency.[2] Guidelines suggest using a ferritin cutoff of <45 nanograms/mL instead of 15 nanograms/mL.[10]

Iron deficiency produces an associated reactive thrombocytosis that provides an additional clue.

Iron deficiency is not a diagnosis and requires further investigation to elucidate the cause.

Associated symptoms may indicate a source of chronic bleeding e.g., heavy menstrual bleeding, coffee-ground vomiting, hematemesis, melena, rectal pain or rectal bleeding. Hemoptysis may indicate Goodpasture syndrome or idiopathic pulmonary hemosiderosis. A history of dark-colored urine may indicate paroxysmal nocturnal hemoglobinuria.

Enquire about the patient's diet. Diets low in meat may produce iron deficiency. Generalized malnutrition often produces combined vitamin B12 and/or folate deficiency, in which case the resulting anemia is normocytic. Children may have pica.

Alcohol misuse and cirrhosis are associated with coagulation disorders and esophageal varices.

Rarely, a history of excessive blood donation or self-harm may be elicited. Patients who are avid runners may have runner's anemia from repetitive mechanical trauma (also known as march hematuria). A history of gastric surgery, celiac disease, or extensive small bowel resection suggests malabsorption as the cause.[53] Pregnancy is a common cause of iron deficiency.[19]

Signs of iron deficiency include koilonychia, angular cheilosis, glossitis, and thinning hair. Peripheral blood smear may show pencil cells.[54] com.bmj.content.model.assessment.Caption@51ab6d4c[Figure caption and citation for the preceding image starts]: KoilonychiaReproduced with permission from Bickle Ian. Clinical exam skills: Hand signs BMJ 2004;329:0411402 [Citation ends].com.bmj.content.model.assessment.Caption@5a4a5a41[Figure caption and citation for the preceding image starts]: Angular cheilosisScience Photo Library [Citation ends].

Investigations are guided by the history and examination, and include the following:

  • Fecal occult blood testing, which should be done in all patients and is positive if gastrointestinal bleeding is present.

  • Upper gastrointestinal endoscopy, which should be performed if there is a history of upper gastrointestinal bleeding or a positive fecal occult blood test. It may identify sources of an upper gastrointestinal bleed (peptic ulcer disease, gastritis, esophageal varices), hiatus hernia, Meckel diverticulum, or increased gastric pH in achlorhydria.

  • Following negative endoscopy in the setting of persistent iron deficiency anemia, testing for Helicobacter pylori may be considered.[55]

  • Immunoglobulin A-tissue transglutaminase (IgA-tTG) test should be performed in all patients and is positive in celiac disease.

  • Colonoscopy, which should be performed if there is a history of lower gastrointestinal bleeding or a positive fecal occult blood test. An occult blood test may reveal malignancy, diverticular disease, ulcerative colitis, or rare causes such as hereditary hemorrhagic telangiectasia. US and UK guidelines report risk thresholds for testing among low- to average-risk symptomatic populations.[56][57][58] UK guidelines recommend quantitative fecal immunochemical tests (FITs) for patients who do not have rectal bleeding and are:[57] 

    • ages 50 years and over with unexplained abdominal pain or weight loss, or

    • ages 60 years and under with changes in bowel habit or iron-deficiency anemia, or

    • ages 60 years and over and have anemia even without iron deficiency.

    Patients who have a positive quantitative FIT should be referred for an urgent appointment (within 2 weeks) through the suspected cancer referral pathway.[57] Refer to guidelines for information regarding the referral and/or testing of patients <50 years with signs or symptoms of colorectal cancer, including rectal bleeding, iron deficiency anemia, weight loss, or change in bowel habit.[59][57][58] One retrospective review of the medical records of a sample of patients with colorectal cancer found that anemia was one of the most common signs in those considered to have had a missed diagnostic opportunity (a clinical encounter where, even in the presence of presumptive symptoms of colorectal cancer, the diagnostic process was not started).[60] In the UK, the National Institute for Health and Care Excellence recommends that adults aged over 60 who have iron-deficiency anemia should be referred urgently for investigation for colorectal cancer.[61]

  • Flow cytometry should be considered if there is a history of passing red urine, or red blood cell (RBC) results consistent with a hemolytic anemia. It detects decreased expression of RBC surface proteins (CD55 and CD59) and is diagnostic of paroxysmal nocturnal hemoglobinuria.

  • Transvaginal ultrasound, which may reveal causes of menorrhagia including hyperplasia, dysplasia, fibroids, polyps or malignancy.

  • Stool microscopy, which may identify hookworm, whipworm, or Schistosoma eggs. This should be performed if clinical features suggest the diagnosis or there is a history of travel to endemic areas.

A low serum iron, a low total iron-binding capacity, and a low/normal ferritin suggest coexistence of anemia of chronic disease with iron deficiency.

  • A history of an underlying inflammatory process (infection, neoplasms, autoimmune reactions, and injury to tissue from trauma or major surgery) is usually present. Serum C-reactive protein may be raised.[16]

  • A serum erythropoietin level should be considered; the result is usually normal or mildly elevated. Ferritin is an acute phase protein and serum levels can rise in inflammatory conditions, liver disease and malignancy, even though iron stores are low.[62] Hypothyroidism and vitamin C deficiency may produce a falsely low ferritin level.[63]

Microcytic anemia: normal serum iron studies

The most important cause to exclude is thalassemia, especially in areas where it may coexist with iron deficiency. A family history is usually present. The disease is more common in individuals of Mediterranean, Middle Eastern, or Southeast Asian descent.[24][25]

Examination findings may be normal, or reveal splenomegaly, jaundice, abdominal distension, and icterus. Morphologic changes including skeletal abnormalities, a large head, chipmunk facies, and misaligned teeth are seen in beta-thalassemia intermedia and major.

Distinct features on the CBC that suggest the diagnosis include a marked decrease in MCV (usually close to 70 femtoliters [fL]) with a low mean corpuscular Hb, target cells on the peripheral smear, and an elevated reticulocyte count (>2%).[54] A Mentzer index (MCV/RBC) <13 is suggestive of thalassemia, and an index >14 suggests iron deficiency.[64] A meta-analysis of various mathematical indices used to distinguish between iron deficiency anemia and thalassemias concluded that none were sufficiently sensitive or specific to make definitive diagnoses.[65]

Thalassemia is diagnosed using Hb electrophoresis. The presence of Hb H, Hb Bart, and concomitant hemoglobinopathies (Hb E, Hb S, Hb C, Hb D) is diagnostic of alpha-thalassemia. Elevated HbF with low or absent HbA and mildly elevated HbA2 is diagnostic of beta-thalassemia. Conditions such as B12 or folate deficiency, or hypothyroidism, may cause elevation of HbA2 and confound diagnosis. Iron deficiency anemia can occasionally normalize HbA2 and mask beta-thalassemia minor. Significantly elevated HbF is typically seen in patients with beta-thalassemia major.

Differential diagnosis of microcytic anemia is important in children, especially in regions where iron-deficiency anemia and thalassemia are both prevalent. One study conducted in Turkey found that serum iron, ferritin, TIBC, MCV, and Mentzer index were all valuable markers in diagnosing iron-deficiency anemia and were significantly different compared with patients with beta-thalassemia trait; red cell distribution width was not different between the two groups.[66]

Normocytic anemia: hypoproliferative

Hematological malignancies and aplastic anemia are the most important diagnoses to exclude, and are usually associated with multiple cytopenias.[19] An isolated anemia is usually due to pure red cell aplasia. Chronic kidney disease or hypothyroidism can also cause an isolated anemia.[14]

History

  • Symptoms of bleeding, easy bruising, night sweats, or weight loss suggest hematologic malignancy or aplastic anemia. Enquire about symptoms and risk factors for infections which can cause self-limiting pure red cell aplasia, such as parvovirus infection, infectious mononucleosis, viral hepatitis, malaria, respiratory infections, gastroenteritis, and mumps.

  • Medication: phenytoin, carbamazepine, sodium valproate, azathioprine, sulfonamides, isoniazid and procainamide cause pure red cell aplasia. Benzene, penicillamine, and gold can cause aplastic anemia. Chloramphenicol can cause either aplastic anemia or pure red cell aplasia. Chemotherapy causes pancytopenia.[67]

  • Radiation therapy, especially to pelvic or sternal areas, can cause pancytopenia.

  • A history of autoimmune disease or chronic hepatitis suggests persistent pure red cell aplasia.

  • There may be a history or features of chronic kidney disease or hypothyroidism.

Exam

  • Ecchymoses or petechiae due to thrombocytopenia suggest hematologic malignancy, myelodysplastic syndrome, or aplastic anemia. Lymphadenopathy or fever suggest malignancy or infections. Splenomegaly may be seen in hematologic malignancies. Massive splenomegaly may be seen in patients with hairy cell leukemia.

Initial investigations

  • Should be guided by the history and examination findings.

  • CBC may show an associated cytopenia and characteristic changes specific to a hematological malignancy. A pancytopenia suggests aplastic anemia, or may be due to chemotherapy or radiation therapy. An isolated anemia suggests pure red cell aplasia or anemia due to chronic kidney disease.

  • Bone marrow biopsy is required for the definitive diagnosis of acute leukemia (acute lymphocytic leukemia, acute myeloid leukemia), chronic myelogenous leukemia, aplastic anemia, or bone marrow metastases.

  • Antiparvovirus antibodies are positive in parvovirus infection, the most common infectious cause of pure red cell aplasia.

Other tests to consider

  • Hepatitis serology, to exclude acute or chronic active hepatitis

  • Monospot test (heterophile antibodies) or Epstein-Barr virus-specific antibodies, to exclude infectious mononucleosis. Viral capsid antigen-IgM (VCA-IgM) is detectable in most patients with symptom onset

  • Thick and thin peripheral smear, to exclude malaria if history and clinical findings suggest the diagnosis

  • Thyroid function tests; thyroid-stimulating hormone is elevated and free thyroxine reduced in hypothyroidism

  • Antinuclear antibodies, which are positive in systemic lupus erythematosus or scleroderma

  • Rheumatoid factor, which may be positive in rheumatoid arthritis

  • Serum creatine kinase, which is elevated in dermatomyositis

  • Erythropoietin levels, which may be inappropriately decreased in patients with chronic kidney disease. Serum calcium and parathyroid hormone levels should be considered if associated secondary hyperparathyroidism is suspected

  • Chest x-ray, which may show infiltrates in atypical pneumonia or a smooth mass in thymoma.

Normocytic anemia: hyperproliferative

Potential diagnoses include hemorrhage and hemolytic anemias.

History

  • Drugs that can cause hemolysis include penicillin, methyldopa, levodopa, quinidines, cephalosporins, and some NSAIDs. Cyclosporine, tacrolimus, clopidogrel, oral contraceptive pills, and some chemotherapy drugs may cause hemolytic uremic syndrome.

  • There may be a history suggestive of microangiopathic disease. Known triggers of disseminated intravascular coagulation (DIC) include ongoing severe infection, sepsis, malignancy, obstetric emergency, trauma, burns, pancreatitis, liver failure, envenomation, drug overdose, or any cause of endothelial damage.

  • The presence of acute-onset neurologic symptoms, including headache, confusion, focal weakness, seizures, or coma, should prompt suspicion of thrombotic thrombocytopenic purpura. Female patients may have associated menorrhagia.

  • Sudden-onset dizziness, headache, mental status changes, loss of sensation or motor strength, chest pain or pressure, dyspnea, or edema in a patient with known hypertension should prompt suspicion of malignant hypertension; a history of renal failure or eclampsia may also be present.

  • An expanding vascular skin lesion in a young infant or child should prompt suspicion of a hemangioma.

  • A history of prosthetic valve replacement may indicate hemolysis induced by the prosthesis.

  • Bloody diarrhea should prompt suspicion of Escherichia coli infection and hemolytic uremic syndrome.

  • Persistent pain in the skeleton, chest, or abdomen; priapism; lower-extremity skin ulcers; or an acute pneumonia-like syndrome suggest sickle cell anemia.

  • Patients with inherited hemolytic anemias such as sickle cell anemia, hereditary spherocytosis, or glucose-6-phosphate dehydrogenase (G6PD) deficiency may have a positive family history.

  • There may be a previous history of autoimmune disease (e.g., systemic lupus erythematosus, rheumatoid arthritis, or scleroderma) or lymphoproliferative disorders (usually non-Hodgkin lymphoma or chronic lymphocytic leukemia), which can lead to autoimmune hemolytic anemia. Note that autoimmune diseases may also cause pure red cell aplasia, in which case the reticulocyte count would be low, with normal lactate dehydrogenase, haptoglobin, and bilirubin levels.

  • Recent blood transfusion may indicate hemolysis due to a transfusion reaction.

  • Occupational or home exposure to lead should prompt suspicion of lead toxicity.

Examination

  • Features of microangiopathic disease: there may be purpura or ecchymosis due to bleeding. Systolic BP >210 mmHg and diastolic BP >130 mmHg indicate malignant hypertension; associated signs may include new murmurs, third heart sound on auscultation of the heart, jugular venous distension, rales or lower-extremity edema, oliguria or polyuria, focal neurologic signs, and hypertensive retinopathy. Cutaneous reddish-brown or violaceous vascular lesions may indicate hemangioma.[31]

  • Splenomegaly is seen in hereditary spherocytosis. Clinical features of underlying autoimmune diseases may be present. Lymphadenopathy may indicate infectious mononucleosis, leukemia, lymphoma, or autoimmune disease.

Initial investigations

  • The CBC and peripheral blood smear should be examined for clues to the underlying cause. A thrombocytopenia with schistocytes strongly suggests a microangiopathic hemolytic anemia. Spherocytes suggest autoimmune hemolytic anemia or hereditary spherocytosis. Hereditary spherocytosis is also associated with increased mean corpuscular Hb. Sickling of RBCs is diagnostic of sickle cell anemia.[24] Heinz bodies, eccentrocytes, or bite cells are seen in G6PD deficiency.

  • If hemolytic anemia is suspected, serum lactate dehydrogenase, haptoglobin, and bilirubin should be measured. Elevated lactate dehydrogenase and bilirubin levels with a decreased haptoglobin are strongly suggestive of hemolytic anemia. Clinical jaundice is seen once bilirubin levels rise above 2 to 4 mg/dL.

Tests to consider in suspected microangiopathic hemolytic anemias

  • Serum creatinine, which may be elevated in patients with hemolytic uremic syndrome or malignant hypertension.

  • Urine dipstick, which may show hematuria and/or proteinuria in hemolytic uremic syndrome.

  • Stool tests: culture, polymerase chain reaction for enterohemorrhagic E. coli genes, or enzyme-linked immunosorbent assay for Shiga toxin in hemolytic uremic syndrome.[68]

  • Prothrombin time and activated partial prothrombin time, which are prolonged in disseminated intravascular coagulation (DIC) but normal in other microangiopathic hemolytic anemias.

  • DIC panel shows elevated D-dimers and fibrin degradation products with low fibrinogen in patients with DIC.

  • X-rays and magnetic resonance imaging scanning of suspected regions reveal internal hemangiomas.

Tests to consider in other hemolytic anemias

  • Direct antiglobulin (Coombs) test, which is positive in autoimmune hemolytic anemia.

  • Tests to identify hereditary causes. Sickle cell anemia is diagnosed on CBC. Osmotic fragility test is positive in hereditary spherocytosis; cells lyse on exposure to hypo-osmotic solution. G6PD assays identify deficiencies of the enzyme.

  • Tests to identify infection. Monospot test or Epstein-Barr virus IgM is positive in infectious mononucleosis. Cytomegalovirus (CMV) IgM is positive in CMV infection. Double-sandwich IgM enzyme-linked immunosorbent assay (ELISA) or IgG avidity test is positive for IgM in acute toxoplasmosis. Splenic or bone marrow aspirate shows amastigotes of the parasite in leishmaniasis.

  • Blood lead levels, which are elevated in lead toxicity.

Macrocytic anemia: megaloblastic

The main causes to consider are vitamin B12 or folate deficiency, or drugs that interfere with DNA synthesis. Autoimmune thyroid disease may coexist with pernicious anemia and atrophic gastritis, which decrease B12 absorption. Therefore, screening for B12 deficiency when the etiology of hypothyroidism is thought to be autoimmune is recommended.[69]

History

  • Poor intake due to malnutrition, alcohol misuse, or strict vegan or low-protein diets can produce deficiency of vitamin B12 and/or folate.

  • A history of celiac disease, tropical sprue, Crohn disease, previous gastric or intestinal surgery, or bacterial overgrowth may indicate malabsorption.

  • A swollen, red, painful tongue; angular stomatitis; patchy hyperpigmentation of the skin and mucous membranes; and a persistent mild pyrexia are symptoms of folate deficiency.

  • Drug history: known causative medications include purine analogs, pyrimidine analogs, reductase inhibitors, methotrexate, trimethoprim, anticonvulsants, oral contraceptives, cycloserine, p-aminosalicylic acid, metformin, colchicine, neomycin, and biguanides. Hydroxyurea, in particular, is known to cause oval macrocytosis with MCV>110 femtoliters (fL).

Initial investigations

  • When investigating macrocytic anemia, determining the vitamin B12 levels is more relevant and cost-efficient than determining folate levels. Serum vitamin B12 levels are decreased and serum methylmalonic acid levels are elevated in vitamin B12 deficiency.[70] The latter is more sensitive and should be used to definitively exclude vitamin B12 deficiency. An MCV of >115 fL is typically seen in nutritional deficiency.

  • Serum folate levels are low in folate deficiency. If folate levels are low, serum vitamin B12 and methylmalonic acid levels should be measured to exclude concurrent vitamin B12 deficiency before folate levels are corrected. Normal serum homocysteine levels make folate deficiency unlikely. Serum folate is rapidly affected by diet and short term supplementation; RBC folate represents longer term body stores. In most cases, however, serum folate is preferred, and correlates well with RBC folate.

  • Anti-intrinsic factor and parietal cell antibodies are positive in pernicious anemia.

  • All adult patients with chronic gastrointestinal symptoms should be considered for celiac disease screening.[71]

Macrocytic anemia: nonmegaloblastic

Potential diagnoses

  • Causes to consider include alcohol misuse, myelodysplastic syndrome, chronic liver disease, and congenital bone marrow failure syndromes.

History

  • High alcohol intake indicates alcohol-induced anemia, which usually persists for months after total abstinence. A history of chronic liver disease indicates liver disease-induced anemia.

  • History of prior exposure to petroleum distillates (especially benzene), chemotherapy, or radiation therapy should prompt suspicion of myelodysplastic syndrome.

  • A history of fever, chills, fatigue, weakness, recurrent infection, anorexia, night sweats, shortness of breath, and easy bruising should prompt suspicion of myelodysplastic syndrome.

  • Recurrent infections in an infant should prompt suspicion of congenital bone marrow failure syndromes.

Exam

  • May reveal stigmata of chronic alcoholism or chronic liver disease.

  • Pallor, petechiae and purpura may be present in myelodysplastic syndrome.

  • Dyskeratosis congenita is characterized by the triad of abnormal nails, reticulated skin rash, and leukoplakia.

Investigations

  • CBC shows associated neutropenia and thrombocytopenia with macro-ovalocytes in myelodysplastic syndrome.

  • Bone marrow aspiration and biopsy shows myeloblasts with immature precursors in myelodysplastic syndrome. Diagnostic features of congenital bone marrow failure syndromes are also identified.

  • Cytogenetics reveal chromosomal translocations in myelodysplastic syndrome.

  • Additional tests for congenital bone marrow syndromes: diepoxybutane or mitomycin-c fragility test is positive in Fanconi anemia. Genetic testing reveals underlying mutations.

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