History
Carefully obtain a history and perform a physical examination in every patient with anemia, because the findings usually provide important clues to the underlying disorder. From the standpoint of the investigation of the anemia, asking questions in addition to those conventionally explored during a routine examination is important. Areas of inquiry found valuable are briefly described below.
Often, the duration of anemia can be established by obtaining a history of previous blood studies and, if necessary, by acquiring those records. Similarly, a history of rejection as a blood donor or prior prescription of hematinics provides clues that anemia was detected previously.
Obtain a careful family history not only for anemia but also for jaundice, cholelithiasis, splenectomy, bleeding disorders, and abnormal hemoglobins. Carefully document the patient's occupation, hobbies, prior medical treatment, drugs (including over-the-counter medications and vitamins), and household exposures to potentially noxious agents. Patients are unlikely to volunteer exposures to tranquilizers, insecticides, paints, solvents, and hair dyes unless specifically queried.
In searching for blood loss, carefully document pregnancies, abortions, and menstrual loss. Estimates of menstrual losses are notoriously inaccurate if only routine inquiry is made.
Often, patients do not appreciate the significance of tarry stools. Changes in bowel habits can be useful in uncovering neoplasms of the colon. Hemorrhoidal blood loss is difficult to quantify, and it may be overlooked or overestimated from one patient to another. Obviously, seek a careful history of gastrointestinal complaints that may suggest gastritis, peptic ulcers, hiatal hernias, or diverticula. Abnormal urine color can occur in renal and hepatic disease and in hemolytic anemia.
A thorough dietary history is important in a patient who is anemic. This history must include foods that the patient eats and those that he/she avoids, as well as an estimate of their quantity. A meal-by-meal description is necessary to obtain appropriate estimates. Even then, patients frequently attempt to deceive the physician because of embarrassment regarding dietary idiosyncrasies or financial restrictions. In these circumstances, having a close and concerned family member participate in the dietary history can often be helpful, because this person is usually more objective than the patient.
Specifically question patients regarding consumption of either clay or laundry starch. This history will not be provided spontaneously. These substances render iron less absorbable. Changes in body weight are important with regard to dietary intake and can suggest the presence of malabsorption or an underlying wasting disease of infectious, metabolic, or neoplastic origin.
Nutritional deficiencies may be associated with unusual symptoms that can be elicited by a history. Patients with iron deficiencies frequently chew or suck ice (pagophagia). Occasionally, they complain of dysphagia, brittle fingernails, relative impotence, fatigue, and cramps in the calves on climbing stairs that are out of proportion to their anemia.
In vitamin B12 deficiency, early graying of the hair, a burning sensation in the tongue, and a loss of proprioception are common. Suspect a loss of proprioception if the patient stumbles in the dark or must look in order to put on pants in the morning. Paresthesia or unusual sensations frequently described as pain also occur in pernicious anemia.
Patients with folate deficiency may have a sore tongue, cheilosis, and symptoms associated with steatorrhea. Color, bulk, frequency, and odor of stools and whether the feces float or sink can be helpful in detecting malabsorption. More sensitive questions to detect steatorrhea include whether the toilet needs to be flushed more than once to rid it of stool and whether an oily substance is floating on the water surface after the first flush.
Obtain a history of fever or identify the presence of fever, because infections, neoplasms, and collagen vascular disease can cause anemia. Similarly, the occurrence of purpura, ecchymoses, and petechiae suggest the occurrence of either thrombocytopenia or other bleeding disorders; this may be an indication either that more than 1 bone marrow lineage is involved or that coagulopathy is a cause of the anemia because of bleeding.
Cold intolerance can be an important symptom of hypothyroidism or systemic lupus erythematosus, paroxysmal cold hemoglobinuria, and certain macroglobulinemias.
The relation of dark urine to either physical activity or time of day can be important in march hemoglobinuria and paroxysmal nocturnal hemoglobinuria.
Explore the presence or the absence of symptoms suggesting an underlying disease, such as cardiac, hepatic, and renal disease; chronic infection; endocrinopathy; or malignancy. A geographic history can also be important in establishing an etiology.
Physical Examination
Too often, the physician rushes into the physical examination without looking at the patient for an unusual habitus or appearance of underdevelopment, malnutrition, or chronic illness. These findings can be important clues to the underlying etiology of disease and provide information related to the duration of illness. The skin and mucous membranes are often bypassed, so that pallor, abnormal pigmentation, icterus, spider nevi, petechiae, purpura, angiomas, ulcerations, palmar erythema, coarseness of hair, puffiness of the face, thinning of the lateral aspects of the eyebrows, nail defects, and a usually prominent venous pattern on the abdominal wall are missed in the rush to examine the heart and the lungs.
Examine optic fundi carefully but not at the expense of the conjunctivae and the sclerae, which can show pallor, icterus, splinter hemorrhages, petechiae, comma signs in the conjunctival vessels, or telangiectasia that can be helpful in planning additional studies.
Perform systematic examination for palpable enlargement of lymph nodes for evidence of infection or neoplasia. Bilateral edema is useful in disclosing underlying cardiac, renal, or hepatic disease, whereas unilateral edema may portend lymphatic obstruction due to a malignancy that cannot be observed or palpated.
Carefully search for hepatomegaly and splenomegaly. Their presence or absence is important, as are the size, the tenderness, the firmness, and the presence or the absence of nodules. In patients with chronic disorders, these organs are firm, nontender, and nonnodular. In patients with carcinoma, they may be hard and nodular. The patient with an acute infection usually has a palpably softer and more tender organ.
A rectal and pelvic examination cannot be neglected, because tumor or infection of these organs can be the cause of anemia.
The neurologic examination should include tests of position sense and vibratory sense, examination of the cranial nerves, and testing for tendon reflexes. The heart should not be ignored, because enlargement may provide evidence of the duration and the severity of the anemia, and murmurs may be the first evidence of a bacterial endocarditis that could explain the etiology of the anemia.
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Anemia. Decreased production of red blood cells is suggested in certain patients with anemia. Bone marrow biopsy specimen allows categorization of patients with anemia without evidence of blood loss or hemolysis into 3 groups: aplastic or hypoplastic disorder, hyperplastic disorder, or infiltration disorder. Each category and its associated causes are listed in this image.
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Microcytic anemia.
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Peripheral smear showing classic spherocytes with loss of central pallor in the erythrocytes.
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Bone marrow aspirate containing increased numbers of plasma cells.
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Bone marrow aspirate showing erythroid hyperplasia and many binucleated erythroid precursors.
Tables
Condition |
Serum Iron |
Total Iron-Binding Capacity (TIBC) |
Bone Marrow Iron |
Comment |
Iron deficiency |
↓ |
↑ |
0 |
Responsive to iron therapy |
Chronic inflammation |
↓ |
↓ |
++ |
Unresponsive to iron therapy |
Thalassemia major |
↑ |
N |
++++ |
Reticulocytosis and indirect bilirubinemia |
Thalassemia minor |
N |
N - ↓ |
++ |
Elevation of fetal hemoglobin and Hb A2, target cells, and poikilocytosis |
Lead poisoning |
N |
N |
++ |
Basophilic stippling of RBCs |
Sideroblastic |
↑ |
N |
++++ |
Ring sideroblasts in marrow |
Hemoglobin |
N |
N |
++ |
Hemoglobin electrophoresis |
↓ = decreased; ↑ = increased; 0 = absent; +'s indicate the amount of stainable iron in bone marrow specimens, on a scale of 0-4; N = normal. |
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Megaloblastic bone marrow |
Deficiency of vitamin B12 |
Deficiency of folic acid |
|
Drugs affecting deoxyribonucleic acid (DNA) synthesis |
|
Inherited disorders of DNA synthesis |
|
Nonmegaloblastic bone marrow |
Liver disease |
Hypothyroidism and hypopituitarism |
|
Accelerated erythropoiesis (reticulocytes) |
|
Hypoplastic and aplastic anemia |
|
Infiltrated bone marrow |
Macrocyte |
Larger than normal (> 8.5 µm diameter). See Table 2. |
Microcyte |
Smaller than normal (< 7 µm diameter). See Table 1. |
Hypochromic |
Less hemoglobin in cell. Enlarged area of central pallor. See Table 1. |
Spherocyte |
Loss of central pallor, stains more densely, often microcytic. Hereditary spherocytosis and certain acquired hemolytic anemias |
Target cell |
Hypochromic with central "target" of hemoglobin. Liver disease, thalassemia, hemoglobin D, and postsplenectomy |
Leptocyte |
Hypochromic cell with a normal diameter and decreased MCV. Thalassemia |
Elliptocyte |
Oval to cigar shaped. Hereditary elliptocytosis, certain anemias (particularly vitamin B12 and folate deficiency) |
Schistocyte |
Fragmented helmet- or triangular-shaped RBCs. Microangiopathic anemia, artificial heart valves, uremia, and malignant hypertension |
Stomatocyte |
Slitlike area of central pallor in erythrocyte. Liver disease, acute alcoholism, malignancies, hereditary stomatocytosis, and artifact |
Tear-shaped RBCs |
Drop-shaped erythrocyte, often microcytic. Myelofibrosis and infiltration of marrow with tumor. Thalassemia |
Acanthocyte |
Five to 10 spicules of various lengths and at irregular intervals on surface of RBCs |
Echinocyte |
Evenly distributed spicules on surface of RBCs, usually 10-30. Uremia, peptic ulcer, gastric carcinoma, pyruvic kinase deficiency, and preparative artifact |
Sickle cell |
Elongated cell with pointed ends. Hemoglobin S and certain types of hemoglobin C and l |
|
Hereditary |
Acquired |
Intracorpuscular defect |
Hereditary spherocytosis Hereditary elliptocytosis Hemoglobinopathies Thalassemias Congenital dyserythropoietic anemias Hereditary RBC enzymatic deficiencies Rarer hereditary abnormalities |
Vitamin B12 and folic acid deficiency Paroxysmal nocturnal hemoglobinuria Severe iron deficiency |
Extracorpuscular defect |
|
Physical agents: Burns, cold exposure Traumatic: Prosthetic heart valves, march hemoglobinuria, disseminated intravascular coagulation (DIC), graft rejection Chemicals: Drugs and venoms Infectious agents: Malaria, toxoplasmosis, mononucleosis, hepatitis, primary atypical pneumonia, clostridial infections, bartonellosis, leishmaniasis Hepatic and renal disease Collagen vascular disease Malignancies: Particularly hematologic neoplasia Transfusion of incompatible blood Hemolytic disease of the newborn Cold hemagglutinin disease Autoimmune hemolytic anemia Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) |
