Treatment algorithm

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

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

Back
ACUTE
|
acquired: direct antiglobulin test (Coombs') positive
|
autoimmune haemolytic anaemia (AIHA)
1st line – 

removal of insult or treatment of underlying condition

A haematological consultation is warranted once haemolytic anaemia 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 pharmacological management in addition to removal of the insult.[10][37][46]

Plus – supportive care

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ACUTE
|
acquired: direct antiglobulin test (Coombs') positive
|
autoimmune haemolytic anaemia (AIHA)
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

All aetiologies of haemolytic anaemia 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 anaemia is life-threatening; uncertainty regarding matching should not delay transfusion.[37][38] Plasmapheresis may be considered in severe haemolysis requiring repeated transfusions, but its effects are transient. Plasmapheresis may serve as bridging therapy while immunotherapy is instituted.

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

Primary options

folic acid: 1 mg orally once daily

Plus – corticosteroid

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ACUTE
|
acquired: direct antiglobulin test (Coombs') positive
|
autoimmune haemolytic anaemia (AIHA)
Plus – 

corticosteroid

Treatment recommended for ALL patients in selected patient group

Corticosteroid use is intended to achieve reduction in antibody production. Oral prednisolone or, in some cases, oral dexamethasone may be used.[69]

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 haemolysis 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

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

OR

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

Consider – rituximab

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ACUTE
|
acquired: direct antiglobulin test (Coombs') positive
|
autoimmune haemolytic anaemia (AIHA)
Consider – 

rituximab

Additional 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.[50] Approximately 50% of patients received concomitant corticosteroids. A subsequent meta-analysis of two randomised controlled trials concluded that combination therapy with rituximab and corticosteroid may increase the rate of complete haematological response compared with corticosteroid alone (very low-certainty evidence) in patients with newly diagnosed warm AIHA.[51]

Infusion-related reactions and infections have been reported in patients with AIHA receiving rituximab therapy.[50][52]

Primary options

rituximab: consult specialist for guidance on dose

1st line – consider sutimlimab (cold AIHA only)

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ACUTE
|
acquired: direct antiglobulin test (Coombs') positive
|
autoimmune haemolytic anaemia (AIHA)
1st line – 

consider sutimlimab (cold AIHA only)

A haematological consultation is warranted once haemolytic anaemia is diagnosed.

Sutimlimab, a humanised monoclonal antibody that selectively targets and inhibits complement component 1 (C1)-activated haemolysis, 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.​[46][47]

Treatment with sutimlimab for up to 2 years resulted in sustained improvements in anaemia and haemolysis, although markers of anaemia and haemolysis returned to close to baseline after discontinuation of sutimlimab.[48][49]​​ Sutimlimab increases susceptibility to serious infections; patients prescribed sutimlimab must be immunised against encapsulated bacteria (e.g., Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae) at least 2 weeks before beginning treatment.

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

Sutimlimab is approved by the US Food and Drug Administration (USFDA) as the first treatment for use in patients with cold agglutinin disease to decrease the need for red blood cell transfusion due to haemolysis. Sutimlimab is approved by the European Medicines Agency (EMA) for the treatment of haemolytic anaemia 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
ACUTE
|
acquired: direct antiglobulin test (Coombs') positive
|
autoimmune haemolytic anaemia (AIHA)
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 pharmacological management in addition to removal of the insult.[10][37][46]

Plus – supportive care

Back
ACUTE
|
acquired: direct antiglobulin test (Coombs') positive
|
autoimmune haemolytic anaemia (AIHA)
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

All aetiologies of haemolytic anaemia 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 anaemia is life-threatening; uncertainty regarding matching should not delay transfusion.[37][38]​ Plasmapheresis may be considered in severe haemolysis 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: 1 mg orally once daily

2nd line – splenectomy

Back
ACUTE
|
acquired: direct antiglobulin test (Coombs') positive
|
autoimmune haemolytic anaemia (AIHA)
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 haemolysis occurs in the liver.[37][38][46]​​

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

Plus – supportive care

Back
ACUTE
|
acquired: direct antiglobulin test (Coombs') positive
|
autoimmune haemolytic anaemia (AIHA)
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

All aetiologies of haemolytic anaemia 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: 1 mg orally once daily

3rd line – immunosuppressant

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ACUTE
|
acquired: direct antiglobulin test (Coombs') positive
|
autoimmune haemolytic anaemia (AIHA)
3rd line – 

immunosuppressant

Following splenectomy, refractory or relapsing patients often require immunosuppression.

Azathioprine, ciclosporin, 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

OR

ciclosporin: consult specialist for guidance on dose

OR

danazol: consult specialist for guidance on dose

OR

mycophenolate mofetil: consult specialist for guidance on dose

Plus – supportive care

Back
ACUTE
|
acquired: direct antiglobulin test (Coombs') positive
|
autoimmune haemolytic anaemia (AIHA)
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

All aetiologies of haemolytic anaemia 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: 1 mg orally once daily

1st line – treatment of underlying malignancy

Back
ACUTE
|
acquired: direct antiglobulin test (Coombs') positive
|
AIHA: haematological malignancy
1st line – 

treatment of underlying malignancy

A haematological consultation is warranted once haemolytic anaemia is diagnosed.

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

For patients with non-Hodgkin's lymphoma, lymphoma type and remission status will influence the decision to direct therapy towards the malignancy or to AIHA.[53] See Non-Hodgkin's lymphoma.

Plus – supportive care

Back
ACUTE
|
acquired: direct antiglobulin test (Coombs') positive
|
AIHA: haematological malignancy
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

All aetiologies of haemolytic anaemia 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: 1 mg orally once daily

1st line – treatment of underlying infection

Back
ACUTE
|
acquired: direct antiglobulin test (Coombs') positive
|
AIHA: infection
1st line – 

treatment of underlying infection

A haematological consultation is warranted once haemolytic anemia is diagnosed.

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

Plus – supportive care

Back
ACUTE
|
acquired: direct antiglobulin test (Coombs') positive
|
AIHA: infection
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

All aetiologies of haemolytic anaemia 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: 1 mg orally once daily

Consider – corticosteroid

Back
ACUTE
|
acquired: direct antiglobulin test (Coombs') positive
|
AIHA: infection
Consider – 

corticosteroid

Additional treatment recommended for SOME patients in selected patient group

May be indicated in specific circumstances (e.g., patients with severe and persistent cold haemagglutinin disease secondary to atypical and mycoplasma pneumonia).[53]

Primary options

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

OR

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

1st line – discontinuation of offending medication

Back
ACUTE
|
acquired: direct antiglobulin test (Coombs') positive
|
AIHA: drug-induced
1st line – 

discontinuation of offending medication

A haematological consultation is warranted once haemolytic anaemia is diagnosed.

The inciting drug should be discontinued. Haematological improvement may be evident within 1-2 weeks.[53]

Offending drugs affect the immune system, resulting in the production of red blood cell autoantibodies.[12] The most commonly implicated drugs include cephalosporins, diclofenac, rifampicin, oxaliplatin, and fludarabine.[12][54] 

Plus – supportive care

Back
ACUTE
|
acquired: direct antiglobulin test (Coombs') positive
|
AIHA: drug-induced
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

All aetiologies of haemolytic anaemia 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: 1 mg orally once daily

Consider – corticosteroid

Back
ACUTE
|
acquired: direct antiglobulin test (Coombs') positive
|
AIHA: drug-induced
Consider – 

corticosteroid

Additional treatment recommended for SOME patients in selected patient group

It is unclear whether corticosteroids are of benefit.[53] 

The decision to prescribe a corticosteroid will be informed by severity of haemolysis and strength of clinical suspicion that haemolysis is drug-induced.[53]

Primary options

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

OR

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
ACUTE
|
acquired: direct antiglobulin test (Coombs') negative
1st line – 

treat underlying cause

A haematological consultation is warranted once haemolytic anaemia is diagnosed.

A negative direct antiglobulin test suggests a non-immune disease mechanism. Non-immune haemolysis will not respond to immune suppression; therefore, corticosteroids are not indicated in most of these subtypes.

Treatment for non-immune aetiologies consists primarily of supportive care, along with removal of an offending agent if present.

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

Plus – supportive care

Back
ACUTE
|
acquired: direct antiglobulin test (Coombs') negative
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

All aetiologies of haemolytic anaemia 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: 1 mg orally once daily

Consider – splenectomy

Back
ACUTE
|
acquired: direct antiglobulin test (Coombs') negative
|
with liver disease
Consider – 

splenectomy

Additional treatment recommended for SOME patients in selected patient group

Consider splenectomy in patients with liver disease. Liver disease may cause haemolysis 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.[55][56][57] Consult local guidance.

Plus – cardiology evaluation

Back
ACUTE
|
acquired: direct antiglobulin test (Coombs') negative
|
with worsening prosthetic valve haemolysis
Plus – 

cardiology evaluation

Treatment recommended for ALL patients in selected patient group

Subclinical haemolysis 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 haemolysis.[22]​ Patients with severe symptomatic haemolysis despite maximal medical therapy require invasive treatment informed by the type of prosthesis and the haemolytic mechanism.[22] 

Plus – plasma exchange and corticosteroid

Back
ACUTE
|
acquired: direct antiglobulin test (Coombs') negative
|
with thrombotic thrombocytopenic purpura
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.[59] See Thrombotic thrombocytopenic purpura.

Plus – complement inhibitor

Back
ACUTE
|
acquired: direct antiglobulin test (Coombs') negative
|
with paroxysmal nocturnal haemoglobinuria
Plus – 

complement inhibitor

Treatment recommended for ALL patients in selected patient group

First-line therapies for paroxysmal nocturnal haemoglobinuria (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.[60][61]​ 

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

inherited disorders

1st line – splenectomy

Back
ACUTE
|
inherited disorders
|
red cell membrane disorders
1st line – 

splenectomy

A haematology consultation is warranted once haemolytic anaemia is diagnosed.

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

Splenectomy will often result in significant decrease in haemolysis.[62]

Indications for splenectomy in patients with hereditary spherocytosis include severe anaemia/transfusion dependence. The decision will be premised upon quality of life issues and spleen size in patients with moderate hereditary spherocytosis.[62] 

Plus – supportive care

Back
ACUTE
|
inherited disorders
|
red cell membrane disorders
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

All aetiologies of haemolytic anaemia 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: 1 mg orally once daily

1st line – avoidance of triggers

Back
ACUTE
|
inherited disorders
|
glucose-6-phosphate dehydrogenase deficiency
1st line – 

avoidance of triggers

A haematology consultation is warranted once haemolytic anaemia is diagnosed.

Common inciting drugs are sulfa drugs, nitrofurantoin, and salicylates.[63] These should be pre-emptively avoided and discontinued if in use. Other possible triggers include naphthalene, fava beans, nitrites, dapsone, ribavirin, phenazopyridine, or paraquat.[28][64] See Glucose-6-phosphate dehydrogenase deficiency.

Plus – supportive care

Back
ACUTE
|
inherited disorders
|
glucose-6-phosphate dehydrogenase deficiency
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

All etiologies of haemolytic anaemia 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: 1 mg orally once daily

1st line – transfusion plus consideration of splenectomy

Back
ACUTE
|
inherited disorders
|
pyruvate kinase deficiency
1st line – 

transfusion plus consideration of splenectomy

A haematological consultation is warranted once haemolytic anaemia is diagnosed.

Therapy is primarily supportive, including transfusions. Splenectomy may be considered for severe cases.[65]

Plus – supportive care

Back
ACUTE
|
inherited disorders
|
pyruvate kinase deficiency
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

All aetiologies of haemolytic anaemia 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: 1 mg orally once daily

2nd line – mitapivat

Back
ACUTE
|
inherited disorders
|
pyruvate kinase deficiency
2nd line – 

mitapivat

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

Approval was based on results from phase 3 trials that demonstrated, respectively: improved haemoglobin response in 16 (40%) participants receiving mitapivat compared with placebo; and a reduction in transfusion burden by at least 33% in 10 (37%) participants.[66][67]

Common adverse reactions include decreases in oestrone and oestradiol in men, increased urate, back pain, and arthralgia.

Primary options

mitapivat: consult specialist for guidance on dose

Plus – supportive care

Back
ACUTE
|
inherited disorders
|
pyruvate kinase deficiency
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

All aetiologies of haemolytic anaemia 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: 1 mg orally once daily

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

Back
ACUTE
|
inherited disorders
|
haemoglobinopathies
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 anaemia.

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: 1 mg orally once daily

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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

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