Hemolytic anemia

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

acquired: direct antiglobulin test (Coombs) positive

autoimmune hemolytic anemia (AIHA)

1st line – removal of insult or treatment of underlying condition

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1st line –

removal of insult or treatment of underlying condition

A hematology consultation is warranted once hemolytic anemia is diagnosed.

Initial management of AIHA includes the removal of the insult, if present. Management of an underlying condition may include treating infection in warm AIHA or treating lymphoma in cold AIHA.

Patients with warm AIHA, and most patients with cold AIHA, will also require pharmacologic management in addition to removal of the insult.[10][37][47]

Plus – supportive care

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Plus –

supportive care

Treatment recommended for ALL patients in selected patient group

All etiologies of hemolytic anemia require some degree of supportive care.

Supportive therapies include cold avoidance in patients with cold AIHA; avoid active cooling for fever.[37][38] Consideration should be given to the use of a blood warmer in patients with cold AIHA.[37]

Blood transfusion and plasmapheresis are considered to be rescue (emergency) therapies in patients with AIHA. Transfusion may be considered if anemia is life-threatening; uncertainty regarding matching should not delay transfusion.[37][38] Plasmapheresis may be considered in severe hemolysis requiring repeated transfusions, but its effects are transient. Plasmapheresis may serve as bridging therapy while immunotherapy is instituted.

Folic acid supplementation is widely practiced, and is recommended in some guidelines.[37][38] Folic acid is required to supply increased red blood cell production.

Primary options

folic acid (vitamin B9): 1 mg orally once daily

Plus – corticosteroid

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Plus –

corticosteroid

Treatment recommended for ALL patients in selected patient group

Corticosteroid use is intended to achieve reduction in antibody production. Oral prednisone or, in some cases, oral dexamethasone may be used.[70]

Corticosteroids may be used in warm or cold AIHA. Warm AIHA is much more likely to respond to corticosteroids than cold AIHA, although some cold antibody cases will improve.[38] Remission can be seen in 1-3 weeks. Once the hemolysis is corrected, corticosteroids must then be tapered. Absence of response by 21 days should be considered a corticosteroid failure.[37][38] Taper corticosteroid in unresponsive patients at 21 days.[38]

Close monitoring for relapses is required for a few weeks, with slowing of corticosteroid taper if signs of possible relapse develop.

Adverse effects are generally manageable during a short course of therapy but are not well tolerated with chronic therapy.

Primary options

prednisone: 1 mg/kg/day orally until response, followed by a slow taper over 1-2 months

dexamethasone: 40 mg orally once daily for 4 days, repeated monthly for 6 months

Consider – rituximab

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Consider –

rituximab

Treatment recommended for SOME patients in selected patient group

Rituximab should be considered for patients with warm or cold AIHA who are refractory to 3 weeks of corticosteroid therapy, and for those patients who relapse during or after corticosteroid tapering.[37][38]

One meta-analysis of observational studies reported overall response rates of 79% for warm AIHA and 57% for cold agglutinin disease.[51] Approximately 50% of patients received concomitant corticosteroids. A subsequent meta-analysis of two randomized controlled trials concluded that combination therapy with rituximab and corticosteroid may increase the rate of complete hematologic response compared with corticosteroid alone (very low-certainty evidence) in patients with newly diagnosed warm AIHA.[52]

Infusion-related reactions and infections have been reported in patients with AIHA receiving rituximab therapy.[51][53]

Primary options

rituximab: consult specialist for guidance on dose

1st line – consider sutimlimab (cold AIHA only)

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1st line –

consider sutimlimab (cold AIHA only)

A hematology consultation is warranted once hemolytic anemia is diagnosed.

Sutimlimab, a humanized monoclonal antibody that selectively targets and inhibits complement component 1 (C1)-activated hemolysis, can be considered as an alternative to corticosteroids in patients with cold AIHA to reduce the need for transfusion. Patients with cold AIHA often do not respond to corticosteroids, and so sutimlimab may be preferred as first-line treatment for cold AIHA.[47][48]

Treatment with sutimlimab for up to 2 years resulted in sustained improvements in anemia and hemolysis, although markers of anemia and hemolysis returned to close to baseline after discontinuation of sutimlimab.[49][50] Sutimlimab increases susceptibility to serious infections; patients prescribed sutimlimab must be immunized against encapsulated bacteria (e.g., Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae) at least 2 weeks before beginning treatment.

Respiratory tract infection, viral infection, diarrhea, dyspepsia, cough, arthralgia, arthritis, and peripheral edema are common with sutimlimab.

Sutimlimab is approved by the Food and Drug Administration (FDA) as the first treatment for use in patients with cold agglutinin disease to decrease the need for red blood cell transfusion due to hemolysis. Sutimlimab is approved by the European Medicines Agency (EMA) for the treatment of hemolytic anemia in adult patients with cold agglutinin disease.

Primary options

sutimlimab: 39 to <75 kg body weight: 6500 mg intravenously once weekly for 2 doses, followed by 6500 mg every 2 weeks thereafter; ≥75 kg body weight: 7500 mg intravenously once weekly for 2 doses, followed by 7500 mg every 2 weeks thereafter

Plus – removal of insult or treatment of underlying condition

Back

Plus –

removal of insult or treatment of underlying condition

Treatment recommended for ALL patients in selected patient group

Initial management of AIHA includes the removal of the insult, if present.

Management of an underlying condition may include treating lymphoma in cold AIHA.

Most patients with cold AIHA will also require pharmacologic management in addition to removal of the insult.[10][37][47]

Plus – supportive care

Back

Plus –

supportive care

Treatment recommended for ALL patients in selected patient group

All etiologies of hemolytic anemia require some degree of supportive care.

Folic acid supplementation is widely practiced, and is recommended in some guidelines.[37][38] Folic acid is required to supply increased red blood cell production.

Primary options

folic acid (vitamin B9): 1 mg orally once daily

2nd line – splenectomy

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2nd line –

splenectomy

Splenectomy removes the site of significant antibody production and the predominant site of red blood cell destruction, if patients do not respond to initial therapies.[37][38]

Splenectomy is typically not effective in cold AIHA because extravascular hemolysis occurs in the liver.[37][38][47]

Approximately one third of patients may relapse after splenectomy.[37][38]

Plus – supportive care

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Plus –

supportive care

Treatment recommended for ALL patients in selected patient group

All etiologies of hemolytic anemia require some degree of supportive care.

Supportive care including packed red blood cell transfusion and folic acid supplementation may possibly still be needed post-splenectomy.

Primary options

folic acid (vitamin B9): 1 mg orally once daily

3rd line – immunosuppressant

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3rd line –

immunosuppressant

Following splenectomy, refractory or relapsing patients often require immunosuppression.

Azathioprine, cyclosporine, danazol, and mycophenolate have been used in the management of warm AIHA. Evidence to support their use is largely derived from case reports and small retrospective series.[37][38] These agents may be used with or without corticosteroids.

Consult specialist for guidance on choice of an appropriate regimen.

Primary options

azathioprine: consult specialist for guidance on dose

cyclosporine modified: consult specialist for guidance on dose

danazol: consult specialist for guidance on dose

mycophenolate mofetil: consult specialist for guidance on dose

Plus – supportive care

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Plus –

supportive care

Treatment recommended for ALL patients in selected patient group

All etiologies of hemolytic anemia require some degree of supportive care. Supportive care includes folic acid supplementation.

Folic acid is useful for patients with a high reticulocyte count, as it is rapidly depleted in the setting of increased red cell production.

Primary options

folic acid (vitamin B9): 1 mg orally once daily

AIHA: hematologic malignancy

1st line – treatment of underlying malignancy

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1st line –

treatment of underlying malignancy

A hematologic consultation is warranted once hemolytic anemia is diagnosed.

Chronic lymphocytic leukemia treatment options include a conservative (watch and wait) approach, chemoimmunotherapy, targeted therapies, and stem cell transplant. See Chronic lymphocytic leukemia.

For patients with non-Hodgkin lymphoma, lymphoma type and remission status will influence the decision to direct therapy towards the malignancy or to AIHA.[54] See Non-Hodgkin lymphoma.

Plus – supportive care

Back

Plus –

supportive care

Treatment recommended for ALL patients in selected patient group

All etiologies of hemolytic anemia require some degree of supportive care. Supportive care includes folic acid supplementation.

Folic acid is useful for patients with a high reticulocyte count, as it is rapidly depleted in the setting of increased red cell production.

Primary options

folic acid (vitamin B9): 1 mg orally once daily

AIHA: infection

1st line – treatment of underlying infection

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1st line –

treatment of underlying infection

A hematologic consultation is warranted once hemolytic anemia is diagnosed.

Treatment for the infection is used to address the cause of hemolysis. See Malaria infection, Babesiosis, Bartonella infection, Leishmaniasis, Bacterial meningitis, and Atypical pneumonia (non-COVID-19).

Plus – supportive care

Back

Plus –

supportive care

Treatment recommended for ALL patients in selected patient group

All etiologies of hemolytic anemia require some degree of supportive care. Supportive care includes folic acid supplementation.

Folic acid is useful for patients with a high reticulocyte count, as it is rapidly depleted in the setting of increased red cell production.

Primary options

folic acid (vitamin B9): 1 mg orally once daily

Consider – corticosteroid

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Consider –

corticosteroid

Treatment recommended for SOME patients in selected patient group

May be indicated in specific circumstances (e.g., patients with severe and persistent cold hemagglutinin disease secondary to atypical and mycoplasma pneumonia).[54]

Primary options

prednisone: 1 mg/kg/day orally until response, followed by a slow taper over 1-2 months

dexamethasone: 40 mg orally once daily for 4 days, repeated monthly for 6 months

AIHA: drug-induced

1st line – discontinuation of offending medication

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1st line –

discontinuation of offending medication

A hematologic consultation is warranted once hemolytic anemia is diagnosed.

The inciting drug should be discontinued. Hematologic improvement may be evident within 1-2 weeks.[54]

Offending drugs affect the immune system, resulting in the production of red blood cell autoantibodies.[12] The most commonly implicated drugs include cephalosporins, diclofenac, rifampin, oxaliplatin, and fludarabine.[12][55]

Plus – supportive care

Back

Plus –

supportive care

Treatment recommended for ALL patients in selected patient group

All etiologies of hemolytic anemia require some degree of supportive care. Supportive care includes folic acid supplementation.

Folic acid is useful for patients with a high reticulocyte count, as it is rapidly depleted in the setting of increased red cell production.

Primary options

folic acid (vitamin B9): 1 mg orally once daily

Consider – corticosteroid

Back

Consider –

corticosteroid

Treatment recommended for SOME patients in selected patient group

It is unclear whether corticosteroids are of benefit.[54]

The decision to prescribe a corticosteroid will be informed by severity of hemolysis and strength of clinical suspicion that hemolysis is drug-induced.[54]

Primary options

prednisone: 1 mg/kg/day orally until response, followed by a slow taper over 1-2 months

dexamethasone: 40 mg orally once daily for 4 days, repeated monthly for 6 months

acquired: direct antiglobulin test (Coombs) negative

1st line – treat underlying cause

Back

1st line –

treat underlying cause

A hematologic consultation is warranted once hemolytic anemia is diagnosed.

A negative direct antiglobulin test suggests a nonimmune disease mechanism. Nonimmune hemolysis will not respond to immune suppression; therefore, corticosteroids are not indicated in most of these subtypes.

Treatment for nonimmune etiologies consists primarily of supportive care, along with removal of an offending agent if present.

This approach applies to the following subtypes: drug-induced nonimmune hemolytic anemia (discontinuation of the offending drug); infection or bacterial toxin (treat infection); footstrike (march) hemolysis (resolves when exceptional physical exertion stops); thermal injury (removal of thermal insult); and osmotic lysis (removal of osmotic insult).

Plus – supportive care

Back

Plus –

supportive care

Treatment recommended for ALL patients in selected patient group

All etiologies of hemolytic anemia require some degree of supportive care. Supportive care includes folic acid supplementation. Folic acid is useful for patients with a high reticulocyte count, as it is rapidly depleted in the setting of increased red cell production.

Primary options

folic acid (vitamin B9): 1 mg orally once daily

with liver disease

Consider – splenectomy

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Consider –

splenectomy

Treatment recommended for SOME patients in selected patient group

Consider splenectomy in patients with liver disease. Liver disease may cause hemolysis through acquired membrane defect or splenomegaly. Consensus guidelines have considered portal hypertension to be a contraindication to laparoscopic splenectomy, but there is some evidence to suggest that this may no longer be the case.[56][57][58] Consult local guidance.

with worsening prosthetic valve hemolysis

Plus – cardiology evaluation

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Plus –

cardiology evaluation

Treatment recommended for ALL patients in selected patient group

Subclinical hemolysis is not uncommon, even with more contemporary prostheses (≥5% in some studies).[22] It is generally well tolerated, so significant worsening suggests possible valve dysfunction requiring urgent evaluation by a cardiologist.

Medical and supportive therapy is usually appropriate for patients with mild prosthesis-related hemolysis.[22] Patients with severe symptomatic hemolysis despite maximal medical therapy require invasive treatment informed by the type of prosthesis and the hemolytic mechanism.[22]

with thrombotic thrombocytopenic purpura

Plus – plasma exchange and corticosteroid

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Plus –

plasma exchange and corticosteroid

Treatment recommended for ALL patients in selected patient group

A combination of plasma exchange therapy, with the intent of stopping the causative process, and corticosteroids is the mainstay of treatment.[60] See Thrombotic thrombocytopenic purpura.

with paroxysmal nocturnal hemoglobinuria

Plus – complement inhibitor

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Plus –

complement inhibitor

Treatment recommended for ALL patients in selected patient group

First-line therapies for paroxysmal nocturnal hemoglobinuria (PNH), eculizumab and ravulizumab are monoclonal antibodies to the fifth component of complement. Eculizumab and ravulizumab improve health-related quality of life and increase transfusion independence.[61][62]

The complement C3 inhibitor iptacopan and complement factor B inhibitor pegcetacoplan are also first-line options for PNH. See Paroxysmal nocturnal hemoglobinuria.

inherited disorders

red cell membrane disorders

1st line – splenectomy

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1st line –

splenectomy

A hematology consultation is warranted once hemolytic anemia is diagnosed.

Includes hereditary spherocytosis, elliptocytosis, and pyropoikilocytosis. See Hereditary spherocytosis.

Splenectomy will often result in significant decrease in hemolysis.[63]

Indications for splenectomy in patients with hereditary spherocytosis include severe anemia/transfusion dependence. The decision will be premised upon quality of life issues and spleen size in patients with moderate hereditary spherocytosis.[63]

Plus – supportive care

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Plus –

supportive care

Treatment recommended for ALL patients in selected patient group

All etiologies of hemolytic anemia require some degree of supportive care. Supportive care includes folic acid supplementation.

Folic acid is useful for patients with a high reticulocyte count, as it is rapidly depleted in the setting of increased red cell production.

Primary options

folic acid (vitamin B9): 1 mg orally once daily

glucose-6-phosphate dehydrogenase deficiency

1st line – avoidance of triggers

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1st line –

avoidance of triggers

A hematology consultation is warranted once hemolytic anemia is diagnosed.

Common inciting drugs are sulfa drugs, nitrofurantoin, and salicylates.[64] These should be preemptively avoided and discontinued if in use. Other possible triggers include naphthalene, fava beans, nitrites, dapsone, ribavirin, phenazopyridine, or paraquat.[28][65] See Glucose-6-phosphate dehydrogenase deficiency.

Plus – supportive care

Back

Plus –

supportive care

Treatment recommended for ALL patients in selected patient group

All etiologies of hemolytic anemia require some degree of supportive care. Supportive care includes folic acid supplementation.

Folic acid is useful for patients with a high reticulocyte count, as it is rapidly depleted in the setting of increased red cell production.

Primary options

folic acid (vitamin B9): 1 mg orally once daily

pyruvate kinase deficiency

1st line – transfusion plus consideration of splenectomy

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1st line –

transfusion plus consideration of splenectomy

A hematologic consultation is warranted once hemolytic anemia is diagnosed.

Therapy is primarily supportive, including transfusions. Splenectomy may be considered for severe cases.[66]

Plus – supportive care

Back

Plus –

supportive care

Treatment recommended for ALL patients in selected patient group

All etiologies of hemolytic anemia require some degree of supportive care. Supportive care includes folic acid supplementation.

Folic acid is useful for patients with a high reticulocyte count, as it is rapidly depleted in the setting of increased red cell production.

Primary options

folic acid (vitamin B9): 1 mg orally once daily

2nd line – mitapivat

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2nd line –

mitapivat

Mitapivat, an oral pyruvate kinase activator, is the first disease-modifying therapy approved by the Food and Drug Administration for the treatment of hemolytic anemia in adults with pyruvate kinase deficiency.

Approval was based on results from phase 3 trials that demonstrated, respectively: improved hemoglobin response in 16 (40%) participants receiving mitapivat compared with placebo; and a reduction in transfusion burden by at least 33% in 10 (37%) participants.[67][68]

Common adverse reactions include decreases in estrone and estradiol in men, increased urate, back pain, and arthralgia.

Primary options

mitapivat: consult specialist for guidance on dose

Plus – supportive care

Back

Plus –

supportive care

Treatment recommended for ALL patients in selected patient group

All etiologies of hemolytic anemia require some degree of supportive care. Supportive care includes folic acid supplementation.

Folic acid is useful for patients with a high reticulocyte count, as it is rapidly depleted in the setting of increased red cell production.

Primary options

folic acid (vitamin B9): 1 mg orally once daily

hemoglobinopathies

1st line – disease-specific specialist care and supportive care

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1st line –

disease-specific specialist care and supportive care

Supportive care is the primary therapy, alongside reducing the threat of infection.

Adjunctive therapies in sickle cell crises can include oxygen, pain control, aggressive hydration, and treatment of any concurrent stressors (e.g., infection). See Sickle cell anemia.

Folic acid is useful for patients with a high reticulocyte count, as it is rapidly depleted in the setting of increased red cell production.

Primary options

folic acid (vitamin B9): 1 mg orally once daily

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Hemolytic anemia

Treatment algorithm

acquired: direct antiglobulin test (Coombs) positive

removal of insult or treatment of underlying condition

supportive care

Primary options

corticosteroid

Primary options

rituximab

Primary options

consider sutimlimab (cold AIHA only)

Primary options

removal of insult or treatment of underlying condition

supportive care

Primary options

splenectomy

supportive care

Primary options

immunosuppressant

Primary options

supportive care

Primary options

treatment of underlying malignancy

supportive care

Primary options

treatment of underlying infection

supportive care

Primary options

corticosteroid

Primary options

discontinuation of offending medication

supportive care

Primary options

corticosteroid

Primary options

acquired: direct antiglobulin test (Coombs) negative

treat underlying cause

supportive care

Primary options

splenectomy

cardiology evaluation

plasma exchange and corticosteroid

complement inhibitor

inherited disorders

splenectomy

supportive care

Primary options

avoidance of triggers

supportive care

Primary options

transfusion plus consideration of splenectomy

supportive care

Primary options

mitapivat

Primary options

supportive care

Primary options

disease-specific specialist care and supportive care

Primary options