eMedicine Specialties > Hematology > Red Blood Cells and Disorders

Hemolytic Anemia: Differential Diagnoses & Workup

Author: Paul Schick, MD, Emeritus Professor, Department of Internal Medicine, Thomas Jefferson University Medical College; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital, Wynnewood, PA
Contributor Information and Disclosures

Updated: Apr 27, 2009

Differential Diagnoses

Disseminated Intravascular Coagulation
Systemic Lupus Erythematosus
Thrombotic Thrombocytopenic Purpura

Other Problems to Be Considered

  • Other causes for anemia
  • Other causes for fatigue, tachycardia, and dyspnea

Workup

Laboratory Studies

  • Complete blood cell (CBC) count
    • The test documents anemia, leukocyte counts, and differential counts.
    • Platelet counts help to exclude an underlying infection or hematologic malignancy. The platelet count is within the reference range in most hemolytic anemias.
    • Thrombocytopenia can occur in SLE, CLL, and microangiopathic hemolytic anemia (defective prosthetic cardiac valves, TTP, HUS, and DIC). Thrombocytopenia associated with a positive direct Coombs test result is known as Evans syndrome.7
  • Peripheral smear and morphologic examination
    • Identifies polychromasia, indicating RBC immaturity reticulocytosis (see Image 1 or below)
      Polychromasia.

      Polychromasia.

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      Polychromasia.

      Polychromasia.

    • Demonstrates spherocytes, suggesting congenital spherocytosis or autoimmune hemolytic anemia (AIHA, see Image 2 or below)
      Spherocytes. One arrow points to a spherocyte; th...

      Spherocytes. One arrow points to a spherocyte; the other, to a normal RBC with a central pallor.

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      Spherocytes. One arrow points to a spherocyte; th...

      Spherocytes. One arrow points to a spherocyte; the other, to a normal RBC with a central pallor.

    • Can identify schistocytes (fragmented red blood cells, suggesting TTP, HUS, or mechanical damage (see Image 3 or below)
      Schistocytes (thrombotic thrombocytopenic purpura...

      Schistocytes (thrombotic thrombocytopenic purpura).

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      Schistocytes (thrombotic thrombocytopenic purpura...

      Schistocytes (thrombotic thrombocytopenic purpura).

    • Can help diagnose a concomitant underlying hematologic malignancy associated with hemolysis (eg, CLL)
  • Red blood cell indices
    • These studies are performed when a CBC count is requested.
    • A low mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) are consistent with a microcytic hypochromic anemia, which may occur in chronic intravascular hemolysis (eg, PNH).
    • A high MCV is consistent with a macrocytic anemia. Macrocytosis is usually due to megaloblastic anemias but can occur in liver disease. A high number of reticulocytes also may cause a high MCH.
    • A high MCH and mean corpuscular hemoglobin concentration (MCHC) suggest spherocytosis.
  • Increased red blood cell distribution width (RDW) study
    • This study is usually performed when a CBC count is requested.
    • An increased RDW is a measure of anisocytosis, which is likely in hemolytic anemia.
  • Reticulocyte count
    • An increased reticulocyte count is a criterion for hemolysis but is not specific for hemolysis.
    • An increase may be caused by blood loss or a bone marrow response to iron, vitamin B-12, or folate deficiencies.
    • The reticulocyte count may be normal or low in patients with bone marrow suppression despite ongoing severe hemolysis.
  • LDH
    • Serum LDH elevation is a criterion for hemolysis. LDH is not specific because it is ubiquitous and can be released from the neoplastic cells of the liver or other damaged organs.
    • Although an increase in LDH isozyme 1 and 2 is more specific for red blood cell destruction, these enzymes are also increased in patients with myocardial infarction.
  • Serum haptoglobin
    • A low serum haptoglobin level is a criterion for moderate to severe hemolysis.
    • A decrease in serum haptoglobin is more likely in intravascular hemolysis than in extravascular hemolysis, but it is an acute phase reactant.
    • The presence of concomitant infection, other reactive states, or chronic hemolysis may mask the diagnosis by raising haptoglobin levels.
  • Indirect bilirubin
    • Unconjugated bilirubin is a criterion for hemolysis, but it is not specific because an elevated bilirubin also may indicate Gilbert disease.
    • With hemolysis, the level of indirect bilirubin usually is less than 4 mg/dL.
    • Higher levels of indirect bilirubin indicate compromised hepatic function or cholelithiasis and hemolysis.
  • Changes in the LDH and serum haptoglobin levels are the most sensitive general tests because the indirect bilirubin is not always increased.
  • Specific studies directed by history, physical examination, peripheral smear, and other laboratory findings
    • The DAT result is usually positive in autoimmune hemolytic anemia, but it may be occasionally negative in this disorder. DAT-negative autoimmune hemolytic anemias have been reviewed.8 From 5% to 10% of all autoimmune hemolytic anemias are DAT negative. The polybrene test can detect DAT-negative autoimmune hemolytic anemia.8 In addition, the immunoradiometric assay (IRMA) for red blood cell – bound IgG can be used to diagnose AIHA in patients whose autoantibody levels are too low to be detected by conventional DAT.9  
    • The urine free hemoglobin test reveals hemoglobinuria, which occurs with intravascular hemolysis when the amount of free hemoglobin exceeds the available haptoglobin. Urine may be dark due to hemoglobinuria, but myoglobinuria, porphyria, and other conditions can also cause dark urine.
    • Urine hemosiderin may suggest intravascular hemolysis. Hemosiderin is detected in spun urinary sediment as an iron stain in sloughed renal epithelial cells.
    • Red blood cell survival (chromium-51 [51 Cr] survival) is rarely used, but it can definitively demonstrate a shortened red blood cell survival (hemolysis). This test is ordered when the clinical history and laboratory studies cannot establish a diagnosis of hemolysis.
    • Cold agglutinin titer: A high titer of anti-I antibody may be found in mycoplasmal infections and a high titer of anti-i antibody may be found in hemolysis associated with infectious mononucleosis. An anti-P cold agglutinin may be seen in paroxysmal cold hemoglobinuria.
    • A G6PD screen can usually detect deficiency of this enzyme, but results are normal if the reticulocyte count is elevated (reticulocytes contain a considerable amount of G6PD). A Heinz body preparation also detects G6PD deficiency (see Image 5 or below).
      Supra vital stain in hemoglobin H disease that re...

      Supra vital stain in hemoglobin H disease that reveals Heinz bodies (golf ball appearance).

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      Supra vital stain in hemoglobin H disease that re...

      Supra vital stain in hemoglobin H disease that reveals Heinz bodies (golf ball appearance).


    • Screen for sickle cell syndrome: This is done by demonstrating sickling under reduced conditions (sickle cell preparations) and testing for hemoglobin solubility (see Image 4 or below). Hemoglobin electrophoresis confirms the presence of abnormal hemoglobin.
      Peripheral blood smear with sickled cells at 1000...

      Peripheral blood smear with sickled cells at 1000X magnification. Image courtesy of Ulrich Woermann, MD.

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      Peripheral blood smear with sickled cells at 1000...

      Peripheral blood smear with sickled cells at 1000X magnification. Image courtesy of Ulrich Woermann, MD.

  • Other tests depend on the possibility of sickle cell anemia, hereditary spherocytosis, SLE, a hematologic malignancy, and types of hemolytic anemias that are more rare.

Imaging Studies

  • Use ultrasonography to estimate the spleen size. The physical examination occasionally does not detect significant splenomegaly.
  • Chest radiography is used to evaluate cardiopulmonary status.

Other Tests

  • Electrocardiography (ECG) and other studies are used to evaluate cardiopulmonary status.

More on Hemolytic Anemia

Overview: Hemolytic Anemia
Differential Diagnoses & Workup: Hemolytic Anemia
Treatment & Medication: Hemolytic Anemia
Follow-up: Hemolytic Anemia
Multimedia: Hemolytic Anemia
References
Further Reading
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References

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  14. Erslev AJ. Traumatic cardiac hemolytic anemia. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, eds. Williams Hematology. 5th ed. New York, NY: McGraw Hill; 1995:663-4.

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  17. Ideguchi H, Ishikawa A, Futata Y, et al. A comprehensive scheme for the systematic investigation of hemolytic anemia. Ann Clin Lab Sci. Sep-Oct 1994;24(5):412-21. [Medline].

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Further Reading

Related eMedicine Topics

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National Guidelines Clearinghouse

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Keywords

hemolytic anemia, autoimmune hemolytic anemia, anemia, hemolysis, microangiopathic anemia, premature erythrocyte destruction, hereditary hemoglobin abnormalities, glucose-6-phosphate dehydrogenase deficiency, G6PD deficiency, G-6-PD deficiency, hereditary spherocytosis, sickle cell anemia, sickle cell trait, sickle cell disease, AIHA, disseminated intravascular coagulation, DIC, hemolytic uremic syndrome, HUS, hemolytic-uremic syndrome, TTP, thrombotic thrombocytopenic purpura, defective prosthetic cardiac valves, parvovirus B19 infection

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Contributor Information and Disclosures

Author

Paul Schick, MD, Emeritus Professor, Department of Internal Medicine, Thomas Jefferson University Medical College; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital, Wynnewood, PA
Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society of Hematology, International Society on Thrombosis and Haemostasis, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Medical Editor

Rodger L Bick, MD, PhD, FACP, Clinical Professor of Medicine, University of Texas Southwestern Medical Center; Director, Dallas and Pacific Thrombosis Hemostasis and Vascular Medicine Clinical Center
Rodger L Bick, MD, PhD, FACP is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Blood Banks, American Cancer Society, American College of Angiology, American College of Physicians, American Geriatrics Society, American Heart Association, American Medical Association, American Society for Clinical Pathology, American Society of Hematology, Association of Clinical Scientists, California Medical Association, California Thoracic Society, International College of Angiology, International Society of Hematology, International Society on Thrombosis and Haemostasis, New York Academy of Sciences, and Southwest Oncology Group
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Ronald A Sacher, MB, BCh, MD, FRCPC, Director of the Hoxworth Blood Center, Professor, Departments of Internal Medicine and Pathology, University of Cincinnati Medical Center
Ronald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies: American Society of Hematology
Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris Honoraria Board membership

CME Editor

Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

 
 
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