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Anemia Workup

  • Author: Joseph E Maakaron, MD; Chief Editor: Emmanuel C Besa, MD  more...
 
Updated: Jul 22, 2016
 

Approach Considerations

The first step in the diagnosis of anemia is detection with reliable, accurate tests so that important clues to underlying disease are not overlooked and patients are not subjected to unnecessary tests for and treatment of nonexistent anemia. Detection of anemia involves the adoption of arbitrary criteria.

The World Health Organization (WHO) criterion for anemia in adults is a hemoglobin (Hb) value of less than 12.5 g/dL. Children aged 6 months to 6 years are considered anemic at Hb levels less than 11 g/dL, and children aged 6-14 years are considered anemic when Hb levels are less than 12 g/dL. The disadvantage of such arbitrary criteria is that a few healthy individuals fall below the reference range, and some people with an underlying disorder fall within the reference range for Hb concentration.

Usually, thresholds in the United States are slightly higher. Anemia is suggested in males with Hb levels less than 13.5 g/dL and in females with Hb levels less than 12.5 g/dL. Higher values are anticipated in individuals living in altitudes significantly above sea level. Conditions with an increase in plasma volume, such as during the last trimester of pregnancy, are associated with lower values without an existent anemia, because the red cell mass is normal.

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Investigation for Pathogenesis

Once the existence of anemia is established, investigate the pathogenesis. If an adequate history has been taken and a physical examination has been performed, the etiology may be obvious, and confirmatory studies and appropriate therapy can be undertaken with a minimum of investigation. If this is not the case, initiate a definite plan of investigation, considering the cost to the patient along with a determination of the etiology of the abnormality.

Often, the etiology of a patient’s anemia can be determined if the red blood cells (RBCs) are altered in either size or shape or if they contain certain inclusion bodies. For example, Plasmodium falciparum malaria is suggested by the presence of more than one ring form in an RBC, and the infection produces pan-hemolysis of RBCs of all ages.

A rational approach to determining etiology is to begin by examining the peripheral smear and laboratory values obtained on the blood count. If the anemia is microcytic (mean corpuscular volume [MCV] <84 fL) or macrocytic (MCV >96 fL) or if certain abnormal RBCs or white blood cells (WBCs) are observed in the blood smear, the investigative approach can be limited.

Presently, RBC cellular indices are computer calculated and automatically placed on laboratory reports. The formulae for calculating these values follow (reference ranges are in parentheses). RBC is per million cells.

  • MCV = Hct × 10/RBC (84-96 fL)
  • Mean corpuscular Hb (MCH) = Hb × 10/RBC (26-36 pg)
  • Mean corpuscular Hb concentration (MCHC) = Hb × 10/Hct (32-36%)

A rapid method of determining whether cellular indices are normocytic and normochromic is to multiply the RBC and Hb by 3. The RBC multiplied by 3 should equal the Hb, and the Hb multiplied by 3 should equal the Hct. Deviation from the calculated values suggests microcytosis, macrocytosis, or hypochromia versus the presence of spherocytes (MCHC >36).

Conditions associated with microcytic hypochromic anemia, macrocytic anemia, and specific RBC forms are outlined in Tables 1, 2, and 3, below.

Table 1. Microcytic Hypochromic Anemia (MCV < 83; MCHC < 31) (Open Table in a new window)

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.

Table 2. Macrocytic Anemia (MCV >95) (Open Table in a new window)

Megaloblastic bone marrow Deficiency of vitamin B-12
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

Table 3. Various Forms of RBCs (Open Table in a new window)

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 B-12 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

In microcytic hypochromic anemia, seek a source of bleeding. The appropriate laboratory tests are serum iron level and TIBC and either serum ferritin level or stain of bone marrow specimen for iron. If the serum iron level is decreased and the TIBC is increased, a diagnosis of iron deficiency can be made, therapy can be initiated, and a search for the cause of the iron deficiency can be started. If this cannot be demonstrated, suspect each of the other causes of a microcytic anemia listed in Table 1, and the order of investigation can be influenced by findings in the history, physical examination, or peripheral smear.

Similarly, a reasonable approach with macrocytic anemia is to determine if the bone marrow aspirate is megaloblastic. If so, attempt to incriminate either vitamin B-12 or folic acid deficiency with appropriate laboratory studies. Similar to the establishment of a diagnosis of iron deficiency anemia, a diagnosis of vitamin B-12 or folic acid deficiency does not stop with an abnormal laboratory value for one of these vitamins. Prompt treatment can be instituted, but a continued search for an underlying cause of the vitamin deficiency is indicated (see Pernicious Anemia).

When a normocytic normochromic anemia is encountered, classify the anemia into three possible etiologies (ie, blood loss, hemolysis, decreased production). In most anemias, one of these causes is the dominant factor. However, in certain anemias, more than a single cause may play an important role. For example, pernicious anemia is predominantly due to decreased production of erythrocytes, but hemolysis adds significantly to the severity of anemia.

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Evaluation for Blood Loss

Obviously, significant hemorrhage produces anemia. Immediately after blood loss, the Hct cannot be used as a reliable method to determine the quantity of lost blood, because the patient loses plasma as well as RBCs. After acute hemorrhage, the Hct falls for 24-48 hours until the plasma volume is replaced. At that time, anemia is normochromic and normocytic with normal cellular indices, because the cells in the peripheral blood have been produced prior to bleeding (see Iron Deficiency Anemia).

If the patient had adequate iron stores, accelerated production of RBCs occurs, so that 1 week after bleeding, a larger-than-normal number of young RBCs and reticulocytes are circulating in the peripheral blood. Because reticulocytes and young RBCs have a larger volume (MCV of approximately 120), macrocytes may be observed in the peripheral smear, and a slight increase in the MCV occurs.

If hemorrhage was sufficient to deplete iron stores (1-2 L of blood, 500-1000 mg of iron), newly formed erythrocytes are microcytic and hypochromic and gradually replace normal erythrocytes in the circulation that were produced prior to the induction of iron deficiency. Because RBCs normally survive for 120 days in circulation, maximal changes in the MCV and MCHC are not observed until that time. Iron deficiency and the depletion of iron stores can be detected several weeks after bleeding by measurements of the serum iron level and the TIBC (the patient has low serum iron levels and an elevated TIBC) and/or special stains of bone marrow specimens showing an absence of storage iron. A low serum ferritin level provides confirmation of the diagnosis of iron deficiency anemia. The presence of microcytosis and hypochromia is helpful but not diagnostic.

The patient notices hemorrhage from most body organs. Epistaxis, hemoptysis, or hematuria of sufficient degree to cause anemia is usually reported to the physician long b

  • Workup(active tab)

efore iron deficiency ensues. However, bleeding from either the uterus or the GI tract may be disregarded by the patient or be totally undetected until the anemia becomes profound and symptomatic.

Menstrual bleeding among healthy females varies monthly from 10-250 mL. Unless the patient observes a change in menses, she relates that menses are normal unless specific questions are asked. The presence of clots, abdominal cramps, excessive gushing of blood upon removal of tampons, the need for both tampons and pads, and the use of an unusual number of pads or tampons can be used to determine if menstrual bleeding may be sufficient to induce iron deficiency anemia.

GI bleeding is the other occult cause of anemia due to blood loss. If hemorrhage is profuse, it is usually detected before evidence of iron deficiency anemia occurs, because hematochezia or melena causes the patient to seek medical attention. However, if the bleeding occurs slowly, it is usually undetected until anemia ensues, because stools appear normal.

Every patient with iron deficiency anemia should have a stool examination for occult blood. A positive result necessitates a careful search of the GI tract to identify the site of bleeding. Unfortunately, a negative result does not exclude GI blood loss, because bleeding can be intermittent and require several examinations for detection. Also, less than 20-30 mL of blood in the stool per day may go undetected due to the insensitivity of the test.

The two methods used to detect small daily losses of blood from the gut are as follows: (1) placing the patient on a meat-free diet for several days and using more sensitive methods, such as a benzidine test, and (2) labeling the patient's RBCs with chromium 51 and collecting stool specimens for the detection of the radioisotope. In addition, GI bleeding can be investigated using endoscopy and radiographic studies (see Imaging and Procedures).

Additional considerations

Iron deficiency anemia in an adult in the United States should be attributed to bleeding unless other causes can be proved. Aside from recent multiparity, other causes are relatively uncommon and include prolonged dietary idiosyncrasies (eg, clay eating, laundry starch consumption, protein deprivation for several years), urinary loss of iron due to intravascular hemolysis (eg, artificial aortic valves, paroxysmal nocturnal hemoglobinuria), gastrectomy or other upper GI surgery, and upper GI disease.

Microcytic hypochromic anemia is observed in conditions other than iron deficiency anemia. Certain types of these disorders are iron-overloading states in which the administration of iron can be deleterious to the patient (see Table 1). Similarly, low serum iron levels can be observed in chronic inflammatory states with normal body stores of iron. However, in the latter, the TIBC is usually decreased rather than increased, and stainable iron can be demonstrated in bone marrow aspirates. Whenever the diagnosis of iron deficiency anemia is in doubt, follow-up blood work after administration of iron to show correction of the anemia can be helpful in confirming the diagnosis.

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Evaluation for Hemolysis

Normally, RBCs survive in the circulation for 120 days. If the erythrocytic life span is shortened significantly (< 40 d), the patient has a hemolytic disorder that may be demonstrated by showing increased production of erythrocytes, increased destruction, or both. The former is revealed most readily by the presence of sustained reticulocytosis and the latter by the occurrence of indirect bilirubinemia (see Table 4, below). Other laboratory tests are available to detect hemolysis, but they are either more expensive or less reliable.

Table 4. Classification of the Hemolytic Disorders (Open Table in a new window)

  Hereditary Acquired
Intracorpuscular defect Hereditary spherocytosis



Hereditary elliptocytosis



Hemoglobinopathies



Thalassemias



Congenital dyserythropoietic anemias



Hereditary RBC enzymatic deficiencies



Rarer hereditary abnormalities



Vitamin B-12 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)



Anemia solely due to hemolysis does not occur until RBCs are being destroyed at 6-8 times the normal rate, reducing the mean RBC life span to less than 20 days because of the bone marrow's capacity to undergo 6-fold hypertrophy and hyperplasia. Thus, if the clinician relies on the presence of anemia to detect hemolytic states, the clinician misses most of them and, perhaps, an important clue to an underlying disorder. On the other hand, if reticulocytosis and indirect bilirubinemia are used to detect hemolytic states, they are usually found when the mean life span is less than 40-50 days. More sophisticated methods, such as measurements of RBC lifespan, are required to detect less severe shortening of erythrocyte life span (50-100 d) and are only occasionally needed in clinical practice.

All patients with reticulocytosis and indirect bilirubinemia have a hemolytic disorder. All patients with sustained reticulocytosis have a hemolytic disorder. Unfortunately, the contrary is not the case, and significant hemolysis can occur without reticulocytosis if the bone marrow is unable to produce cells at an accelerated rate (eg, pernicious anemia, leukemia, aplasia).

A single demonstration of an elevated reticulocyte count is insufficient to establish a diagnosis of hemolysis, because transient reticulocytosis may occur without hemolysis (eg, in the treatment of iron deficiency anemia).

Almost all patients with indirect bilirubinemia have a hemolytic disorder. In adults, the exception is patients with Gilbert disease. These patients can be distinguished from those with hemolytic disorders and those who have no other obvious stigmata of hemolysis (eg, anemia, reticulocytosis, Coombs test) by having the patient fast for 3 days. In Gilbert disease, indirect bilirubin doubles with starvation, whereas in hemolytic disorders, it does not. Once the presence of hemolysis has been established, the etiology of the increased rate of RBC destruction can be sought.

All causes of hemolytic disorders are either hereditary or acquired. Similarly, they are due to either an intrinsic abnormality of the RBC (intracorpuscular defect) or external factors that shorten the erythrocyte life span (extracorpuscular). Using this nomenclature, only 4 groups of hemolytic disorders are possible—hereditary intracorpuscular, hereditary extracorpuscular, acquired intracorpuscular, and acquired extracorpuscular.

Hereditary hemolytic disorders

All hereditary hemolytic disorders are due to intracorpuscular defects, and most acquired disorders are due to extracorpuscular abnormalities (see Table 4). Hereditary etiologies of hemolytic disease are suggested strongly in any patient with a family history of anemia, jaundice, cholelithiasis, or splenectomy. Whenever possible, family members, particularly parents, siblings, and children, should undergo a hematologic examination, including a hemogram with reticulocyte count, an indirect bilirubin determination, and a careful examination of the peripheral smear.

If a specific hereditary hemolytic disorder (eg, hereditary spherocytosis, hemoglobinopathy) is suggested in a patient, examine blood from family members for that entity by appropriate laboratory methods. Establishment of a hemolytic defect in other closely related family members permits a presumptive diagnosis of hereditary intracorpuscular hemolytic disorder in the patient. Showing a similar RBC abnormality (eg, spherocytes, abnormal Hb, G-6-PD deficiency) among family members establishes the basic etiology. Once the probability of a hereditary hemolytic disorder is established, a planned approach to determine the definitive abnormality is usually simple.

A careful examination of the peripheral smear may reveal spherocytes in hereditary spherocytosis, ovalocytes in hereditary elliptocytosis, sickle cells in patients with major hemoglobinopathies associated with sickle Hb, target cells in patients with Hb C or E disease, and marked poikilocytosis with target cells, microcytes, and hypochromic RBCs in thalassemia. (See the images below.)

Microcytic anemia. Microcytic anemia.
Peripheral smear showing classic spherocytes with Peripheral smear showing classic spherocytes with loss of central pallor in the erythrocytes.

Even in certain rare disorders, abnormal erythrocyte morphology may provide an important clue. Examples are acanthocytosis in abetalipoproteinemia, stomatocytosis in the hereditary disorder of this name, and numerous target cells in lecithin cholesterol acyltransferase deficiency. Other laboratory studies of value in the hereditary hemolytic disorders include the following:[12]

  • Hereditary spherocytosis - MCHC greater than 36%, incubated osmotic fragility in oxalate, and detection of the underlying molecular defect
  • Hemoglobinopathies - Sickle cell preparation, Hb electrophoresis at 1 or more pH, heat denaturation test for unstable Hbs, oxygen disassociation for Hbs with abnormal oxygen affinity
  • Thalassemia - A2 and fetal Hb, Hb electrophoresis, characterization of the molecular defect, quantification of alpha and beta chains
  • Congenital dyserythropoietic anemias - Demonstration of abnormalities of erythroid precursors in bone marrow aspirates, positive acid hemolysis (Ham) test, with normal result of sucrose hemolysis test in one form of this disease (hereditary erythroblastic multinuclearity with a positive acidified serum test [HEMPAS])
  • Hereditary RBC enzymatic deficiencies - Specific RBC enzyme assay

In clinical practice, approximately 90% of hereditary RBC enzymatic deficiencies with significant clinical manifestations are either G-6-PD deficiencies or abnormalities of pyruvic kinase. The age at which a hemolytic disorder is detected is not always helpful in determining whether the disorder is hereditary. Although the abnormality is inherited, congenital manifestations may be unusual. An infant with sickle cell anemia or beta thalassemia appears healthy at birth. Clinical manifestations usually do not occur in infants younger than 6 months, because fetal Hb has not been replaced by adult Hb until that age.

Usually, thalassemia minor is not detected until a routine hemogram is performed, and, then, it is often mistaken for iron deficiency anemia because of the microcytosis and hypochromia. Thus, the physician dealing with adult patients must be as aware of these disorders as the pediatrician.

The most commonplace of the hereditary disorders is G-6-PD deficiency, because it occurs in 10% of the African American population living in the United States. In this population, G-6-PD deficiency usually remains undetected until oxidant drugs are administered. Then, it produces a mild to moderate hemolytic anemia that is transient in nature. In white populations of Mediterranean derivation, G-6-PD deficiency can produce a chronic hemolytic anemia without exposure to drugs. Exposure to oxidant drugs can produce lethal hemolysis.

Acquired hemolytic disorders

Acquired hemolytic disorders occur in a large number of disease states and can vary considerably in severity. In addition, hemolysis may be observed as a result of physical injury to the RBC or following exposure to drugs, chemicals, or venoms. In many patients, the etiology of the hemolytic disorder is apparent because of other manifestations of the disease (eg, infections, collagen vascular disease).

A confirmed positive Coombs test result can be extremely helpful in this group of disorders. It provides assurance that the hemolytic disorder is an acquired extracorpuscular defect and limits it to the group of disorders associated with autoimmune hemolytic anemia; these disorders include the following:

  • Drug-dependent antibodies (eg, to penicillin, quinidine, alpha methyldopa)
  • Coexistence of an underlying disease (eg, hematologic malignancies, lupus erythematosus, certain viral infections)
  • Idiopathic groups in which an underlying disease cannot be demonstrated

Usually, the acquired hemolytic disorders with intracorpuscular defects are not difficult to diagnose. Vitamin B-12 and folic acid deficiencies are associated with macrocytic anemia, the presence of hypersegmented polymorphonuclear leukocytes in the peripheral smear, megaloblastic bone marrow, physical findings of the underlying cause of the deficiency state, and abnormal serum levels for the deficient vitamin.

Iron deficiency in the United States is rarely of sufficient severity to cause significant hemolysis and is merely mentioned herein for the sake of completeness.

Paroxysmal nocturnal hemoglobinuria is diagnosed only if the physician considers it in the differential diagnosis, and it may manifest by either a pancytopenia or a hemoglobinuria. However, flow cytometry to detect the absence or reduced expression of CD59 and CD55 on the patient's RBCs can help to exclude this cause of hemolysis.

Additional considerations

The major diagnostic problems encountered with hemolytic disorders are when the known causes for hemolysis have been excluded by history, physical examination, and laboratory studies; the Coombs test result is negative; and not enough family members can be tested to differentiate between hereditary intracorpuscular hemolytic disorders and acquired extracorpuscular defects.

A donor cell chromium survival study can be helpful in differentiating between a hereditary hemolytic disorder and an acquired hemolytic disorder. Labeled RBCs from a healthy blood donor in a compatible blood group allow for a normal survival rate in patients with hereditary hemolytic disease and a shortened life span in those with an acquired extracorpuscular defect.

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Evaluation for Decreased RBC Production

Diminished production of RBCs is suggested in all patients without evidence of either blood loss or hemolysis. Thus, a patient with anemia without evidence of bleeding or iron deficiency, with normal indirect bilirubin and normal or decreased reticulocyte count, probably has a defect in the production of erythrocytes. Many of these patients have pancytopenia or other abnormalities of the leukocytes or the platelets that can be detected with an examination of a peripheral smear.

When this group of disorders is suspected, the most important laboratory test is a bone marrow biopsy and aspiration (see Imaging and Procedures). The bone marrow biopsy permits categorization of these disorders into the following three separate groups, as shown in the image below:

  • Aplastic or hypoplastic
  • Hyperplastic
  • Bone marrow replaced with nonhematopoietic elements (infiltration of bone marrow)
    Anemia. Decreased production of red blood cells is 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.

Whenever possible, a cause for the aplastic anemia should be uncovered, because cessation of exposure may lead to recovery. Identification of the offending agent is likewise important in determining the prognosis.

Infiltration of the bone marrow with fibrous tissue, neoplastic cells, or other cells that replace normal hematopoietic tissue can diminish the production of RBCs, granulocytes, and platelets. The diagnosis of myelofibrosis or neoplastic involvement of bone marrow is often suggested by evidence of myeloid metaplasia in the peripheral smear (ie, erythroid and granulocyte precursors).

Replacement of bone marrow with nonhemopoietic cells leads to activation of fetal sites of blood production in organs such as the liver and the spleen, with release of abnormally shaped erythrocytes and normoblasts, immature granulocytes and normoblasts, immature granulocytes, and large platelets into the peripheral blood. Myeloid metaplasia does not occur in aplastic disease. Thus, its presence in a patient who is anemic suggests bone marrow infiltration, even before the biopsy specimen is obtained.

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Imaging and Procedures

Imaging studies are useful in the workup for anemia when a neoplastic etiology is suggested. They permit discovery of the neoplasm or centrally located adenopathy. Occasionally, they are useful in detecting or confirming the existence of splenomegaly.

Investigate GI bleeding by endoscopy and radiographic studies to identify the bleeding site. However, even these methods may leave a source of GI bleeding undetected, because these procedures do not detect the bleeding site or the lesion if small. Examples of these causes include the following:

  • Coagulation abnormalities induced by aspirin or platelet dysfunction
  • Hookworm infestation
  • Hemangiomas of the small bowel
  • Lymphosarcoma and other tumors
  • Adenomas of the gallbladder
  • Self-administration of anticoagulants

Bone marrow aspirates and biopsy findings are particularly useful in establishing the etiology of anemia in patients with decreased production of RBCs. They help to differentiate aplasia; megaloblastic hyperplasia; and infiltration of marrow with neoplasia, myelodysplasia, and myelofibrosis. In addition, they lead to a definitive histologic diagnosis of leukemias, lymphomas, myelomas, and metastatic carcinomas. These procedures are less useful in detecting hemolytic anemia (except to detect lymphoma or leukemia), and they are also less useful in diagnosing congenital dyserythropoietic anemia, in which they reveal the multinuclearity of erythroid precursors. Iron stains of the bone marrow aspirate can be used to document the existence of iron deficiency anemia or the sideroblastic anemias. (See the image below.)

Bone marrow aspirate containing increased numbers Bone marrow aspirate containing increased numbers of plasma cells.
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Contributor Information and Disclosures
Author

Joseph E Maakaron, MD Research Fellow, Department of Internal Medicine, Division of Hematology/Oncology, American University of Beirut Medical Center, Lebanon

Disclosure: Nothing to disclose.

Coauthor(s)

Ali T Taher, MD, PhD, FRCP Professor of Medicine, Associate Chair of Research, Department of Internal Medicine, Division of Hematology/Oncology, Director of Research, NK Basile Cancer Center, American University of Beirut Medical Center, Lebanon

Disclosure: Nothing to disclose.

Marcel E Conrad, MD Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, SWOG

Disclosure: Partner received none from No financial interests for none.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Acknowledgements

Jose A Perez Jr, MD, MBA, MSEd Consulting Staff, Department of Medicine, Methodist Hospital; Associate Professor of Clinical Medicine, Weill Cornell Medical College

Jose A Perez Jr, MD, MBA, MSEd is a member of the following medical societies: American College of Physician Executives, American College of Physicians, Society of General Internal Medicine, and Society of Hospital Medicine

Disclosure: Nothing to disclose.

Ronald A Sacher, MB, BCh, MD, FRCPC Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, and Royal College of Physicians and Surgeons of Canada

Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris Honoraria Board membership

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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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.
Microcytic anemia.
Peripheral smear showing classic spherocytes with loss of central pallor in the erythrocytes.
Bone marrow aspirate containing increased numbers of plasma cells.
Bone marrow aspirate showing erythroid hyperplasia and many binucleated erythroid precursors.
Table 1. Microcytic Hypochromic Anemia (MCV < 83; MCHC < 31)
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.
Table 2. Macrocytic Anemia (MCV >95)
Megaloblastic bone marrow Deficiency of vitamin B-12
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
Table 3. Various Forms of RBCs
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 B-12 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
Table 4. Classification of the Hemolytic Disorders
  Hereditary Acquired
Intracorpuscular defect Hereditary spherocytosis



Hereditary elliptocytosis



Hemoglobinopathies



Thalassemias



Congenital dyserythropoietic anemias



Hereditary RBC enzymatic deficiencies



Rarer hereditary abnormalities



Vitamin B-12 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)



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