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Disease Categories > Hematologic Disease

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Hemolytic Anemias

Hemolytic anemias result from premature destruction of red blood cells (RBC).

For information regarding hemoglobinopathies, unstable hemoglobinopathies and thalassemias, refer to the specific topic in ARUP Consult®.

Epidemiology

Hemolytic anemia is not an uncommon disorder
Prevalence depends on etiology of hemolysis

Classification

Molecular defect hemoglobinopathies
- Sickle cell anemia and other qualitative hemoglobin disorders
- Alpha and beta thalassemias
Abnormality in RBC membrane structure or RBC enzymatic defects
- Glucose-6-phosphate dehydrogenase deficiency (G-6-PD)
- Pyruvate kinase deficiency
- Hereditary spherocytosis, stomatocytosis
- Hereditary paroxysmal nocturnal hemoglobinuria
Environmental factor (physical disruption) or antibody
- Autoimmune (acquired) cold agglutinin
- Drug-induced
- Warm antibody-induced
- Lymphoproliferative disorder or disseminated malignancy
  - Chronic lymphocytic leukemia
- Mechanical valves
- Microangiopathic red cell destruction
  - Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremia syndrome (HUS)
  - Disseminated intravascular coagulation (DIC)
  - HELLP syndrome (Hemolysis, Elevated Liver enzyme levels, Low Platelet count)
Infectious
- Cytomegalovirus, Epstein-Barr virus, hepatitis, HIV, leptospira, malaria, mycoplasma
- Toxins

Pathophysiology

Processes cause breaking up (hemolysis) of red blood cells into various sizes and shapes
Manifested by elevated reticulocyte counts, low or absent haptoglobin levels and variable presence of hemosiderin in urine
Peripheral blood smear demonstrates evidence of RBC fragmentation, including spherocytes, target cells and Howell Jolly bodies

Clinical Presentation

Symptoms include splenomegaly, anemia and jaundice

Specific Hemolytic Disorders

Cell membrane disorders
- Hereditary spherocytosis
  - Incidence – 1/2000 in Caucasians
  - Inheritance
    - Autosomal dominant trait
  - Clinical Presentation
    - Range of severity from asymptomatic to severe disease
    - Anemia, splenomegaly and jaundice
  - Diagnosis
    - Laboratory testing
      - Cell abnormality is a spherocyte
        
        Immune-mediated hemolytic anemias may also have spherocytes
      - Abnormal osmotic fragility test and spherocytes on peripheral blood smear
- Hereditary elliptocytosis
  - Incidence – 1-2/10,000 in Caucasians
  - Inheritance
    - Autosomal dominant trait
  - Clinical Presentation
    - Usually no significant hemolysis, may be asymptomatic
  - Diagnosis
    - Laboratory testing
      - Blood smear with ovalocytes
- Hereditary stomatocytosis
  - Incidence – 1/50,000
  - Inheritance
    - Autosomal dominant
  - Clinical Presentation
    - Asymptomatic to moderately severe disease
  - Diagnosis
    - Laboratory testing
      - Blood smear – may show stomatocytes; easy to confuse this disease with hereditary elliptocytosis
      - Osmotic fragility – increased
RBC enzyme defects
- G-6-PD deficiency
  - Incidence
    - Over 400 million people worldwide have this defect
  - Inheritance
    - Sex linked
    - Over 50 variants
    - Mutation protects against malaria
  - Clinical Presentation
    - Most patients are asymptomatic
    - Patients may present with fatigue, back pain, anemia and jaundice as an indicator of hemolysis
      - Hemolysis occurs when patient is exposed to environmental stressors – viral and bacterial infections or oxidative stress
        
        Some drugs cause hemolysis – sulfa, nitrofurantoin, antimalarials
  - Diagnosis
    - Laboratory testing
      - Heinz bodies present in acute hemolysis
      - G-6-PD enzyme activity testing
      - G-6-PD mutation testing if deficiency determined by enzymatic testing
- Pyruvate kinase (PK) deficiency
  - Incidence
    - 1/20,000 in Caucasians
    - The most common causes of congenital non-spherocytic hemolytic anemia
  - Inheritance
    - Autosomal recessive
    - More common in the Mediterranean population
    - Carriers are recognized by their erythrocytes which contain about 50% of the normal PK activity
    - Over 180 different mutations
  - Clinical Presentation
    - Degree of hemolysis varies from mild to life-threatening neonatal anemia and jaundice, necessitating exchange transfusion
  - Diagnosis
    - Laboratory testing
      - PK enzyme activity testing
Acquired hemolytic anemias – immune-mediated
- Warm antibody disease and cold reactive antibody disease
- Usually caused by IgG or IgM antibodies reacting to red blood cells
- Clinical Presentation
  - Warm antibody
    - Symptoms usually a result of the anemia
    - Slow, insidious onset
    - May have jaundice
  - Cold agglutinin hemolysis
    - Episodic acute hemolysis with hemoglobinuria
    - In some patients acrocyanosis and vasoocclusive phenomena of the fingers, toes, ears and nose
  - Drug immune – mediated
    - Severity depends on the drug
    - Varies from mild to severe hemolysis
    - Most common drugs implicated – cephalosporins, NSAIDs
- Diagnosis
  - Laboratory testing
    - Coombs test used for diagnosis
      - Direct positive Coombs detects IgG or C3 on the patient’s RBC
      - Cold agglutinins testing
      - RBC antibody detection
Paroxysmal cold hemoglobinuria
- Incidence – rare
- Median age – 5 years
- Caused by a biphasic antibody (Donath Landsteiner antibody)
- Clinical Presentation
  - Pallor, hemoglobinuria and mild jaundice
  - Usually have a history of recent viral infection
- Diagnosis
  - Laboratory testing
    - Direct Coombs testing
    - Donath Landsteiner antibody – positive

Indications for Ordering

Tests generally appear in the order most useful for common clinical situations
Click on number for test-specific information in the ARUP Laboratory Test Directory

Test Name and Number	Recommended Use	Limitations
CBC with Platelet Count & Automated Differential 0040003 Method: Automated Cell Count with Flow Cell Differential	Identify the presence of hemolysis and anemia
Reticulocytes, Percent & Number 0040022 Method: Flow Cytometry	Identify increased RBC production suggestive of increased loss
Osmotic Fragility, Erythrocyte 0049015 Method: Spectrophotometry	Assess presence or absence of spherocytes (which have very little redundant membrane) and roughly gauge quantity in RBC population Use in conjunction with Wright stain Diagnose hereditary spherocytosis	For patients with acute hemolysis, a normal red cell osmotic fragility test result cannot exclude an osmotic fragility abnormality since the osmotically labile cells may be hemolyzed and not present Recommend testing during a state of prolonged homeostasis with stable hematocrit For patients with acute hemolysis, a normal test result cannot exclude an abnormality since osmotically labile cells may be hemolyzed and not present Does not distinguish between spherocytes in hereditary spherocytosis and acquired autoimmune hemolytic anemia
Heinz Body Stain 0049090 Method: Supravital Stain	Use as a nonspecific screen for inherited disorders in conjunction with clinical information Detect unstable hemoglobins or inherited defects in erythrocyte oxidative pathways (e.g., G-6-PD deficiency) If patient is known not to have an inherited disorder (e.g., G-6-PD deficiency), Heinz bodies may implicate a toxin or drug	Test results are unreliable in infants < 6 months of age
Glucose-6-Phosphate Dehydrogenase 0080135 Method: Enzymatic	Confirm etiology of congenital non-spherocytic hemolytic anemia Determine safety of anti-malarial drugs prior to use	Patients who have recently received transfusions have normal donor cells that may mask G-6-PD deficient erythrocytes
Glucose-6-Phosphate Dehydrogenase, G6PD Mutations, African Alleles 0051684 Method: Polymerase Chain Reaction/TaqMAN®	Use to determine if deficiency due to mutation
Pyruvate Kinase 0080290 Method: Enzymatic	Determine levels of pyruvate kinase in suspected anemia Screen for carriers of hemolytic anemia	Elevated serum PK levels may be seen in disorders of shortened erythrocyte survival Patients who have recently received transfusions have normal donor cells that may mask pyruvate kinase deficient erythrocytes
Direct Coombs (Anti-Human Globulin) 0013008 Method: Hemagglutination	Identify antibodies as cause of hemolysis
Donath Landsteiner 0013039 Method: Hemolysis	Determine if Donath Landsteiner antibodies are present Diagnose paroxysmal cold hemoglobinuria
Cold Agglutinins 0050175 Method: Hemagglutination	Identify antibodies as cause of hemolysis
Antibody Detection, RBC 0010004 Method: Hemagglutination	Identify antibodies as cause of hemolysis

Additional Tests Available

Click on number for test-specific information in the ARUP Laboratory Test Directory

Test Name and Number	Comments
Haptoglobin 0050280 Method: Immunoturbidimetric	Assess the presence of intravascular hemolysis
Hemoglobin, Plasma 0020058 Method: Spectrophotometry
Hemosiderin, Urine 0020222 Method: Microscopic Stain	Order for suspected intravascular hemolysis within the past week

General References

Delaunay J. The molecular basis of hereditary red cell membrane disorders. Blood Rev. 2007;21(1):1-20. (Link to PubMed)

Dhaliwal G, Cornett PA, Tierney LM Jr. Hemolytic anemia. Am Fam Physician. 2004;69(11):2599-2606. (Link to PubMed)

Gallagher PG. Red cell membrane disorders. Hematology (Am Soc Hematol Educ Program ). 2005;13-18. (Link to PubMed)

Garratty G. Immune hemolytic anemia-a primer. Semin Hematol. 2005;42(3):119-121. (Link to PubMed)

Meremikwu M. Sickle cell disease. Clin Evid. 2005;(14):15-28. (Link to PubMed)

Rosse WF, Hillmen P, Schreiber AD. Immune-mediated hemolytic anemia. Hematology (Am Soc Hematol Educ Program ). 2004;48-62. (Link to PubMed)

Semple JW, Freedman J. Autoimmune pathogenesis and autoimmune hemolytic anemia. Semin Hematol. 2005;42(3):122-130. (Link to PubMed)

References from the ARUP Institute for Clinical and Experimental Pathology®

Prchal JT, Gregg XT. Red cell enzymes. Hematology Am Soc Hematol Educ Program. 2005;19-23. (Link to PubMed)

Reviewed by

Blaylock, Robert C. , M.D. Medical Director, Transfusion Services at ARUP Laboratories; Director of Hospital Clinical Laboratories at University Hospital, Associate Professor, Clinical Pathology, University of Utah

Grenache, David G., Ph.D. Medical Director, Special Chemistry at ARUP Laboratories; Assistant Professor, Clinical Pathology, University of Utah

Lehman, Christopher M., M.D. Co-Medical Director, University Hospital Clinical Laboratory; Associate Professor, Clinical Pathology, University of Utah

Litwin, Christine, M.D. Medical Director, Immunology at ARUP Laboratories; Professor, Clinical Pathology, University of Utah

Perkins, Sherrie L. , M.D., Ph.D. Medical Director, Hematopathology at ARUP Laboratories; Professor, Anatomic Pathology, University of Utah

Roberts, William L. , M.D., Ph.D. Medical Director, Automated Core Laboratory at ARUP Laboratories; Professor, Pathology, University of Utah

Comprehensive Review: July 2008
Last Update: July 2008