Hemolytic Anemias

Algorithm(s)

PDF algorithm(s) available at www.arupconsult.com.

Hemolytic Anemias Testing Algorithm

Clinical Background

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
  Hereditary elliptocytosis
  - Incidence - 1-2/10,000 in Caucasians
  - Inheritance
    - Autosomal dominant trait
  - Clinical Presentation
    - Usually no significant hemolysis, may be asymptomatic
  Hereditary stomatocytosis
  - Incidence - 1/50,000
  - Inheritance
    - Autosomal dominant
  - Clinical Presentation
    - Asymptomatic to moderately severe disease
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
  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
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
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

See Also

Babesia microti

Cold Agglutinin Disease

Epstein-Barr Virus - EBV

HELLP Syndrome

Hemoglobinopathies

Hemolytic Disease of the Newborn - Rh Disease

Mycoplasma pneumoniae

Paroxysmal Nocturnal Hemoglobinuria - PNH

Parvovirus B 19 - Parvo

Thalassemias

Unstable Hemoglobinopathies

Algorithm(s)

PDF algorithm(s) available at www.arupconsult.com.

Hemolytic Anemias Testing Algorithm

Tests

Tests generally appear in the order most useful for common clinical situations

Test name: CBC with Platelet Count & Automated Differential

ARUP #: 0040003

Methodology: Automated Cell Count with Flow Cell Differential

Use:

Identify the presence of hemolysis and anemia

Test name: Reticulocytes, Percent & Number

ARUP #: 0040022

Methodology: Flow Cytometry

Use:

Identify increased RBC production suggestive of increased loss

Limitations:

Follow-up:

Test name: Osmotic Fragility, Erythrocyte

ARUP #: 0049015

Methodology: Spectrophotometry

Use:

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

Limitations:

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

Follow-up:

Test name: Heinz Body Stain

ARUP #: 0049090

Methodology: Supravital Stain

Use:

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

Limitations:

Test results are unreliable in infants < 6 months of age

Follow-up:

Test name: Glucose-6-Phosphate Dehydrogenase

ARUP #: 0080135

Methodology: Enzymatic

Use:

Confirm etiology of congenital non-spherocytic hemolytic anemia

Determine safety of anti-malarial drugs prior to use

Limitations:

Patients who have recently received transfusions have normal donor cells that may mask G-6-PD deficient erythrocytes

Follow-up:

Test name: Glucose-6-Phosphate Dehydrogenase, G6PD Mutations, African Alleles

ARUP #: 0051684

Methodology: Polymerase Chain Reaction/TaqMAN®

Use:

Use to determine if deficiency due to mutation

Test name: Pyruvate Kinase

ARUP #: 0080290

Methodology: Enzymatic

Use:

Determine levels of pyruvate kinase in suspected anemia

Screen for carriers of hemolytic anemia

Limitations:

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

Follow-up:

Test name: Direct Coombs (Anti-Human Globulin)

ARUP #: 0013008

Methodology: Hemagglutination

Use:

Identify antibodies as cause of hemolysis

Limitations:

Follow-up:

Test name: Donath Landsteiner

ARUP #: 0013039

Methodology: Hemolysis

Use:

Determine if Donath Landsteiner antibodies are present

Diagnose paroxysmal cold hemoglobinuria

Limitations:

Follow-up:

Test name: Cold Agglutinins

ARUP #: 0050175

Methodology: Hemagglutination

Use:

Identify antibodies as cause of hemolysis

Test name: Antibody Detection, RBC

ARUP #: 0010004

Methodology: Hemagglutination

Use:

Identify antibodies as cause of hemolysis

Limitations:

Follow-up:

Additional Tests Available

Test name: Haptoglobin

ARUP #: 0050280

Methodology: Immunoturbidimetric

Comments: Assess the presence of intravascular hemolysis

Test name: Hemoglobin, Plasma

ARUP #: 0020058

Methodology: Spectrophotometry

Comments:

Test name: Hemosiderin, Urine

ARUP #: 0020222

Methodology: Microscopic Stain

Comments: Order for suspected intravascular hemolysis within the past week