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Hemolytic anemia

Last updated: September 14, 2021

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Hemolytic anemia is characterized by the breakdown of red blood cells (RBCs). Hemolysis can either be caused by abnormalities in RBCs (hemoglobin, the RBC membrane, or intracellular enzymes), which is called intrinsic hemolytic anemia, or by external causes (immune-mediated or mechanical damage), which is called extrinsic hemolytic anemia. Hemolysis can be further categorized depending on whether it occurs inside the blood vessels (intravascular hemolysis), in the reticuloendothelial system (extravascular hemolysis), or both. Hemolytic anemias cause varying degrees of fatigue, pallor, and weakness, ranging from asymptomatic disease to life-threatening hemolytic crisis; although, some hemolytic anemias have more specific findings (e.g., thrombosis in paroxysmal nocturnal hemoglobinuria). Hemolytic anemia should be suspected in patients with anemia and laboratory findings of hemolysis (e.g., elevated indirect bilirubin and lactate dehydrogenase, reticulocytosis, and decreased haptoglobin levels). The Coombs test helps to distinguish between antibody-mediated (positive direct Coombs test) and nonantibody-mediated (negative direct Coombs test) anemias. Further tests should be performed to investigate the underlying etiology. Treatment involves RBC transfusions as required. Additional treatment is based on the type of hemolytic anemia and its cause.

Types and etiologies of hemolytic anemia

Hemolytic anemias are characterized by an excessive breakdown of red blood cells (RBCs). They can be classified according to the cause of hemolysis (intrinsic or extrinsic) and by the location of hemolysis (intravascular or extravascular).

Type Definition Causes
By RBC pathology
Intrinsic hemolytic anemia
  • Increased destruction of RBCs due to a defect within the RBC
Extrinsic hemolytic anemia
  • Abnormal breakdown of normal RBCs
By location of RBC breakdown
Intravascular hemolytic anemia
  • Increased destruction of RBCs within the blood vessels
Extravascular hemolytic anemia

References: [3][4]

Consider hemolysis in patients with acute or chronic anemia in whom an obvious cause (e.g., bleeding) is not apparent. See “Diagnosis of anemia” for details on the general approach for a patient with anemia. [5]

Approach [5][6]

  1. Perform initial laboratory studies to confirm anemia and hemolysis and classify anemia by morphology.
  2. Obtain a direct Coombs test (i.e., DAT) to narrow the differential:
  3. Consider further investigations of the underlying etiology based on clinical suspicion and DAT results.

Rule out hemolysis in any patient with unexplained anemia, even if the urine dipstick test is negative for blood and jaundice is not evident on physical examination.

If the patient has severe symptoms of anemia or a life-threatening cause is suspected (i.e., TTP/HUS, disseminated intravascular coagulation, HELLP syndrome, acute hemolytic transfusion reaction), proceed directly to treatment in parallel with diagnostic evaluation.

Routine laboratory studies [5][6]

Iron studies are usually normal in hemolytic anemia, however, iron deficiency can be seen in chronic intravascular hemolysis [9]

While no single test can be used to confirm hemolysis, the finding of anemia in the presence of accelerated erythropoiesis (i.e., reticulocytosis) in addition to evidence of RBC destruction in serum and/or urine studies is highly suggestive of hemolytic anemia.

Typical biochemical findings in hemolysis include haptoglobin, LDH concentration, indirect bilirubin concentration, peripheral blood smear abnormalities (e.g., reticulocytes, schistocytes, spherocytes, polychromasia), and urinalysis abnormalities (e.g., hemoglobinuria, hemosiderinuria, and urobilinogen).

Serum studies

Evidence of hemolysis in serum studies [5][6]
Parameter Description Features of intravascular hemolysis Features of extravascular hemolysis
Haptoglobin [10][11]
Lactate dehydrogenase
  • ↑↑
Indirect (unconjugated) bilirubin
  • Can be normal or slightly elevated

Haptoglobin levels can be low in both intravascular hemolysis and extravascular hemolysis and, therefore, should not be used to differentiate between the two. [10]

Urine studies

Evidence of hemolysis in urine studies [5][6]
Parameter Description Findings
Intravascular hemolysis Extravascular hemolysis [13]
Hemoglobinuria [14]
  • Present
  • Usually absent
Hemosiderinuria [7]
  • Present
  • Usually absent
Urobilinogen [15]
  • Usually absent
  • Present

  • Description: A special reagent is added to patients' blood samples: Coombs serum, which contains antihuman globulins (AHGs) that detect and adhere (with 2 binding sites) to immune proteins that mediate hemolysis, i.e., antibodies (IgG) and/or complement
    • If these proteins are coating the RBC surface when the serum is added, AHGs will cause multiple RBCs to adhere to each other in a process called agglutination.
    • If no such proteins are present, AHGs will not bind to anything.
    • RBC agglutination is considered a positive result, while the absence of RBC agglutination is considered a negative result.

Direct Coombs test (DAT) [16]

This is a key test in the workup of hemolytic anemia.

Indirect Coombs test [18]

Differences between the Coombs tests

Key differences between direct and indirect Coombs testing
Direct Coombs test [16] Indirect Coombs test [18]
Clinical applications
Location of antibodies detected
  • Serum
Coombs serum added to:
  • The patient's purified RBCs
  • The patient's purified serum which has been mixed with test RBCs
AHGs in Coombs serum bind to:

The direct Coombs test detects antibodies that are directly attached to the RBC surface. The indirect (or not direct) Coombs test detects serum antibodies that are not bound to RBCs.

Perform further diagnostic workup according to the suspected etiology; specialist consultation is advised. [17][19]

Antibody-mediated hemolysis (DAT positive)

Laboratory investigations for antibody-mediated hemolysis [5]
Concerning initial features Suggested additional investigations
Laboratory studies PBS
AIHA [20] Warm AIHA
  • RBC agglutination

Hemolytic transfusion reactions [21]

Nonantibody-mediated hemolysis (DAT negative)

Laboratory investigations for nonantibody-mediated hemolysis [5]
Concerning initial features Suggested additional investigations
Laboratory studies PBS
Intrinsic hemolytic anemia Hereditary spherocytosis
Hereditary elliptocytosis
Paroxysmal nocturnal hemoglobinuria [17]
Pyruvate kinase deficiency
G6PD deficiency
Extrinsic hemolytic anemia

Microangiopathic hemolysis

Macroangiopathic hemolysis
Intracellular pathogens
  • Intracellular organisms

Hemolytic anemia that is caused by structural or functional RBC abnormalities can be further classified as one of the following based on pathogenesis:

Definition [22]

An acquired genetic defect of the hematopoietic stem cell characterized by a triad of hemolytic anemia, pancytopenia, and thrombosis

Epidemiology [23]

  • Median age of onset: approx. 35–40 years.
  • =

Pathophysiology [24]

Clinical features

Diagnostics [28][29]

CATCH PNH by testing patients with any of the following: Cytopenias, Aplastic anemia/MDS, Thrombosis, Coombs-negative hemolysis, and/or Hemoglobinuria. [30]

Management [17][28][30]

Consider eculizumab in patients with PNH and thromboembolism, as it is thought to prevent thrombus propagation and protect patients from further thromboembolic events. [28]

Complications [28]

References [32][33][34]


Pathophysiology [35]

Glutamic acid can also be replaced with a lysine, creating hemoglobin C.

In hemoglobin C disease, lyCine (lysine) replaces the amino acid glutamic acid.

Clinical features [35]


Characteristic findings in hemoglobin C disease compared with hemoglobin C trait [36]
Hemoglobin C disease (HbCC) Hemoglobin C trait (HbAC)
PBS [37]
  • Usually normal
Hemolysis workup
Hb electrophoresis

Treatment [38]

References: [39]

Hemolytic anemia that is caused by the destruction of functionally and structurally normal RBCs can be further classified as one of the following based on the mechanism of RBC destruction:

Cold agglutinin hemolytic anemia [20][40][41]


Background [41]

Cold weather is MMMMiserable: Cold (IgM) AIHA is seen in Malignancy (CLL), Mycoplasma pneumonia, and Mononucleosis.

Clinical features

Diagnostics [41][42][45]

Spherocytes may be seen in both cold AIHA and warm AIHA. However, abundant spherocytosis is characteristic of warm AIHA.

Management [20][45][46]

Hematology consult is advised.

  • Goal: Reduce cold-induced symptoms, control hemolysis, and improve anemia.
  • Approach
    • Compensated hemolysis and mild or absent circulatory symptoms : close surveillance
    • Significant clinical manifestations: Start acute therapy.
    • CAS: Treat the underlying condition
    • CAD: Consider chronic therapy (systemic immunomodulatory).
    • Advise all patients to avoid exposure to the cold.
    • Consider folic acid supplementation in all patients.
    • Manage disease complications: Venous thromboembolism (VTE) [47]
  • Prognosis: Spontaneous remission is rare in CAD but is common in CAS secondary to infection (e.g., Mycoplasma) and typically occurs within a few weeks of onset. [41][42]
Treatment of cold AIHA
Indications Description
Acute therapy
Chronic therapy

Splenectomy is not an effective treatment in cold agglutinin hemolytic anemia, as most extravascular hemolysis occurs in the liver.

Warm agglutinin hemolytic anemia [20][43][48][49][50]


Warm weather is Great”: Warm AIHA is IgG mediated.

Clinical features

Diagnosis [46]

Consider warm AIHA in patients with severe anemia for whom the blood bank is unable to find crossmatch-compatible blood units.

Management [20][46][53]

Early specialist consultation is advised (e.g., hematology, intensive care).

  • Goal: control hemolysis and improve anemia.
  • Approach
    • Provide acute management for severe disease.
    • Address potential secondary causes (see “Etiology”). [54]
      • Hold any potentially causative medications.
      • Identify and manage underlying conditions.
    • Consider the need for chronic systemic immunomodulators.
    • Observation without immunosuppressive interventions may be appropriate for patients with mild asymptomatic anemia.
    • Manage disease complications: VTE
  • Prognosis: The disease course is often chronic with recurrent relapses, which require close monitoring and repeated therapeutic intervention.
Management of warm agglutinin hemolytic anemia [46][53]
Indications Description
Acute management
Chronic management
  • Consider in most patients to reduce autoantibody production.

Do not delay a potentially life-saving blood transfusion in unstable patients with severe anemia, even if crossmatched blood is unavailable. Use type-specific uncrossmatched blood in close consultation with the blood bank. [53]

Microangiopathic hemolytic anemia [5][56]


Clinical features


Workup for underlying causes of MAHA
Suspected etiology Supportive clinical features Diagnostic testing and characteristic findings
Primary thrombotic microangiopathy TTP
  • Fever
  • Neurological features
  • Young age
  • Impaired renal function
  • Recent gastrointestinal illness, typically with bloody diarrhea
Atypical HUS
  • Consider the following tests: [58]
    • Extended plasma complement levels
    • Genetic testing for complement mutations
Drug-induced thrombotic microangiopathy [59][60]
  • History of exposure to a typical culprit drug
  • Acute onset when immune mediated (e.g., from quinine exposure)
  • Gradual, dose-dependent onset when caused by a toxic effect (e.g., from cyclosporine or tacrolimus exposure)
  • Improvement after drug discontinuation
  • Test for drug-dependent antibodies.
Malignant hypertension
HELLP syndrome [61]
Disseminated intravascular coagulation
Autoimmune disease (e.g., SLE)
  • History of an autoimmune disease
  • Features of a systemic autoimmune disease
  • Any of the following:
  • Positive findings on infection-specific testing [62]

Management [57][60]

MAHA is a medical emergency. Consult hematology urgently, especially if there is no immediately evident cause (e.g., hypertensive emergency, preeclampsia).

Consider urgent initiation of plasma exchange for suspected TTP while waiting for ADAMTS13 test results.

Macroangiopathic hemolytic anemia

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