Approach

Patients may present in several ways. The urgency with which anemia is evaluated depends on the severity at presentation. Patients with an acute severe hemorrhage present with hypovolemia and symptoms and signs of the underlying cause. [9]

Initial assessment

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 (TBV) may be lost before clinical manifestations are appreciated at rest. Key signs include hypotension, pallor, cold clammy skin, a thready pulse, tachycardia, dyspnea or air hunger, altered mental status, confusion, and coma. Flat neck veins when supine indicate at least 30% to 40% total body volume loss. All orifices should be examined for bleeding. The mechanism and site of any trauma should also be determined.

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

  • 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. A history of bleeding disorders or excessive bruising may indicate an underlying coagulation disorder. Any antibiotics administered should be noted, as some can produce a decrease in platelet levels.

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

  • Tests are guided by the history and exam and the suspected etiology of active bleeding. These may include the following procedures.

    • 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 GI bleeding, elevated BUN may be seen, even in absence of renal issues, 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.

    • Upper GI endoscopy, required to identify sources of upper GI bleeding. Nasogastric lavage with saline is no longer routinely recommended in initial management unless it is done to facilitate subsequent direct visualization for endoscopic procedures. [55] [56] [57]

    • Colonoscopy, required to identify sources of lower GI bleeding. A retrospective review of the medical records of a sample of patients with colorectal cancer found that anemia was one of the commonest symptoms/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 colorectal cancer diagnostic process was not started). [58]

    • Capsule endoscopy may have diagnostic, but not therapeutic, utility in situations where there is concern for GI bleeding in inaccessible areas such as the small bowel. [59]

    • 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.

    • Computed tomography (CT) 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.

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. Symptoms of anemia may include pallor, fatigue, weakness, decreased exercise tolerance, and shortness of breath with exercise. A CBC should be ordered if these symptoms are present. 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. Due to their relative reproducibility, mean corpuscular volume (MCV) and red cell width (RDW) 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. [60]

  • 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@7980d726 [Figure caption and citation for the preceding image starts]: Algorithm for the assessment of anemia Created by the BMJ Knowledge Centre [Citation ends].

Microcytic anemia: abnormal serum iron studies

A low serum iron, an elevated total iron-binding capacity (TIBC), and a low ferritin indicate iron deficiency anemia.

  • 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. [13] [14] [15]

  • Diets low in meat 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.

  • There may be a history of bleeding. Females may have a history of excessive menstrual losses. Coffee-ground vomiting, hematemesis, or melena indicate upper GI bleeding. NSAIDs and corticosteroids are associated with peptic ulcer disease. Alcohol use and cirrhosis are associated with coagulation disorders and esophageal varices. Fresh red rectal bleeding indicates a lower GI bleed. Rectal pain may indicate hemorrhoids, which will be seen on rectal examination. Hemoptysis may indicate Goodpasture syndrome or idiopathic pulmonary hemosiderosis. 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. Pregnancy is a common cause. [20] A history of dark-colored urine may indicate paroxysmal nocturnal hemoglobinuria.

  • Signs of iron deficiency include koilonychia, angular cheilosis, glossitis, and thinning hair.

  • 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 GI bleeding is present.

    • Upper GI endoscopy, which should be performed if there is a history of upper GI bleeding or a positive fecal occult blood test. It may identify sources of an upper GI 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,   Helicobacter pylori may be considered when malignancies, B12 deficiency, and idiopathic thrombocytopenic purpura have been excluded. [61]

    • 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 GI bleeding or a positive fecal occult blood test. It may reveal malignancy, diverticulosis, ulcerative colitis, or rare causes such as hereditary hemorrhagic telangiectasia; malignancy should be considered in all patients aged over 40 years with symptoms of rectal bleeding or a positive fecal occult blood test.

    • 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, or polyps; malignancy should be considered in patients with menorrhagia who are over 40 years old.

    • 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. A serum erythropoietin level should be considered; the result is usually normal or mildly elevated. Hypothyroidism and vitamin C deficiency may produce a falsely low ferritin level. [62]

Microcytic anemia: normal serum iron studies

The most important cause to exclude is thalassemia. A family history is usually present. The disease is more common in individuals of Mediterranean, Middle Eastern, or Southeast Asian descent. The severity ranges from asymptomatic to severe transfusion-dependent symptoms. [30] [31]

The 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%). A Mentzer index (MCV/RBC) <13 is suggestive of thalassemia, and an index >14 suggests iron deficiency. [63] In a meta-analysis of various mathematical indices used to distinguish between iron deficiency anemia and thalassemias, the microcytic to hypochromic RBC ratio (M/H) showed the best performance, although the authors concluded that none were high enough to make definitive diagnoses. [64] 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. A high HbF with minimal or absent HbA and an elevated HbA2 is diagnostic of beta-thalassemia.

Normocytic anemia: hypoproliferative

Potential diagnoses

  • These include disorders that decrease RBC production.

  • Hematological malignancies and aplastic anemia [20] are the most important diagnoses to exclude, and are usually associated with multiple cytopenias.

  • An isolated anemia is usually due to pure red cell aplasia, which may be self-limited or persistent. Chronic kidney disease [25] or hypothyroidism can also cause an isolated anemia.

  • Secondary hyperparathyroidism exacerbates the anemia of chronic kidney disease.

History

  • Symptoms of bleeding, easy bruising, night sweats, or weight loss suggest hematologic malignancy or aplastic anemia. Parvovirus infection, infectious mononucleosis, viral hepatitis, malaria, respiratory infections, gastroenteritis, primary atypical pneumonia, and mumps can result in a self-limited pure red cell aplasia, and these should be excluded.

  • Antiepileptic medications (phenytoin, carbamazepine, valproate sodium), 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. [65] Discontinuation of causative medications leads to resolution of the anemia.

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

  • A history of immunosuppression 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 (e.g., infectious mononucleosis). Splenomegaly may be seen in hematologic malignancies.

  • Clinical features of systemic lupus erythematosus, rheumatoid arthritis, dermatomyositis, polyarteritis nodosa, or scleroderma resulting in persistent pure red cell aplasia may be present. Abnormal lung exam (if lung cancer is the primary cancer) or a breast mass (if breast cancer is the primary) may be present.

  • A positive Trousseau sign or Chvostek sign in patients with chronic kidney disease indicates hypocalcemia, probably due to associated secondary hyperparathyroidism.

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 myelogenous leukemia), chronic myelogenous leukemia (CML), 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 or Epstein-Barr virus (EBV) IgM, to exclude infectious mononucleosis

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

  • Thyroid function tests; thyroid-stimulating hormone (TSH) is elevated and free thyroxine (T4) reduced in hypothyroidism

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

  • Rheumatoid factor, which is positive in rheumatoid arthritis

  • Serum creatine kinase (CK), which is elevated in dermatomyositis

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

  • 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.

Normocytic anemia: hyperproliferative

Potential diagnoses

  • Include hemolytic anemias.

  • These conditions can be caused by microangiopathic hemolytic anemias, autoimmune hemolytic anemia, drugs, infections, inherited conditions, transfusion reactions, or burns.

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. Discontinuation of causative medications leads to resolution of the anemia.

  • 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, 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 (TTP). 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.

  • Cutaneous burns affecting more than 10% of the body surface area can cause a hemolytic anemia, or trigger DIC.

  • Infective causes include cytomegalovirus (CMV), infectious mononucleosis, toxoplasmosis, and leishmaniasis. Bloody diarrhea should prompt suspicion of Escherichia coli infection and hemolytic uremic syndrome.

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

  • 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 ecchymoses due to bleeding. Systolic BP >210 mmHg and diastolic BP >130 mmHg indicate malignant hypertension; associated signs may include new murmurs, S3 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. [34]

  • 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. [30] 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 a 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. Kidney biopsy provides a definitive diagnosis of hemolytic uremic syndrome.

  • Prothrombin time and activated partial prothrombin time, which are prolonged in 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 (MRI) 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 EBV IgM is positive in infectious mononucleosis. 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

Potential diagnoses

  • 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. [66]

  • Discontinuation of causative medications leads to resolution of the anemia.

History

  • Poor intake due to malnutrition, alcohol abuse, 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

  • Serum vitamin B12 levels are decreased and serum methylmalonic acid levels are elevated in vitamin B12 deficiency. 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. RBC folate is a more accurate indicator of folate deficiency than serum folate level.

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

Macrocytic anemia: nonmegaloblastic

Potential diagnoses

  • Causes to consider include alcohol abuse, 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.

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

  • Skeletal abnormalities and growth retardation are seen in Shwachman-Diamond syndrome.

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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