Highlights & Basics
- Hemolytic anemia is characterized by the premature destruction of red blood cells.
- Anemia, reticulocytosis, low haptoglobin, high lactate dehydrogenase, and high indirect bilirubin suggest hemolysis.
- Direct antiglobulin test (Coombs) is important for differentiating immune from nonimmune etiologies. Peripheral smear review is important in identifying underlying cause.
- Corticosteroids are often first-line therapy in immune-mediated cases. Discontinuation of offending agents (e.g., suspected drugs) and supportive care are the mainstay of treatment for many subtypes.
- Early vaccination against encapsulated organisms is important in cases that may be treated with splenectomy.
Quick Reference
History & Exam
Key Factors
pallor
jaundice
Other Factors
fatigue
shortness of breath
dizziness
splenomegaly
active infections
episodic dark urine (hemoglobinuria)
triggered by exposure to cold
Diagnostics Tests
1st Tests to Order
CBC
MCHC
reticulocyte count
peripheral smear
unconjugated (indirect) bilirubin
LDH
haptoglobin
urinalysis
Other Tests to consider
direct antiglobulin test (Coombs)
creatinine, BUN
LFTs
Donath-Landsteiner antibody
Hb electrophoresis
flow cytometry for CD55/CD59
glucose-6-phosphate dehydrogenase (G6PD) fluorescent spot test and spectrophotometry
antinuclear antibody
Treatment Options
acute
acquired: direct antiglobulin test (Coombs) positive
autoimmune hemolytic anemia (AIHA)
AIHA: hematologic malignancy
AIHA: infection
AIHA: drug-induced
acquired: direct antiglobulin test (Coombs) negative
acquired: direct antiglobulin test (Coombs) negative
with liver disease
with worsening prosthetic valve hemolysis
with thrombotic thrombocytopenic purpura
with paroxysmal nocturnal hemoglobinuria
Definition
Classifications
Acquired hemolytic anemia: immune or nonimmune
- Warm antibody autoimmune hemolytic anemia: antibody (usually IgG) binds most avidly at core body temperature. Associated with underlying diseases such as systemic lupus erythematosus, lymphoma, and chronic lymphocytic leukemia.
- Cold antibody autoimmune hemolytic anemia: antibody binds red blood cell at temperature below body temperature (often IgM, but may be IgG). Can be idiopathic, or associated with infection or malignancy.
- Drug-induced immune hemolytic anemia.
- Alloimmune hemolytic anemia: hemolytic disease of the newborn or transfusion reaction.
- Infection: malaria, babesiosis, bartonellosis.
- Bacterial toxins: Clostridium perfringens infection.
- Drug-induced (by nonimmune mechanism).
- Trauma: microangiopathic hemolysis such as disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, eclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count) in pregnancy; mechanical prosthetic heart valve; march hemolysis.
- Membrane disorder (acquired): paroxysmal nocturnal hemoglobinuria, liver disease.
- Thermal injury.
- Osmotic lysis.
- Hypersplenism.
Congenital hemolytic anemia
- Hereditary spherocytosis
- Elliptocytosis
- Pyropoikilocytosis
- Glucose-6-phosphate dehydrogenase deficiency
- Pyruvate kinase deficiency
- Sickle cell anemia
- Thalassemia
Vignette
Common Vignette
Other Presentations
Epidemiology
Etiology
- Inherited red blood cell (RBC) defects (membrane defects) - hereditary spherocytosis, elliptocytosis, pyropoikilocytosis
- Enzyme deficiencies - glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency
- Abnormal Hb production - sickle cell anemia, thalassemia.
- Acquired hemolytic anemia can be subdivided into immune and nonimmune etiologies:
- Autoantibodies - the cause of immune-mediated hemolytic anemias, most often as part of other autoimmune conditions (e.g., systemic lupus erythematosus, rheumatoid arthritis, scleroderma) or related to a lymphoproliferative disorder (non-Hodgkin lymphoma, chronic lymphocytic leukemia).
- Immune hemolytic anemias - divided into warm- or cold-reacting antibodies, depending on the temperature at which the antibody binds most avidly to the RBCs.
- Alloimmune hemolytic anemias - include hemolytic disease of the newborn or transfusion reaction.
- Drugs - some through immune-mediated mechanisms and others through nonimmune-mediated mechanisms.
- Other nonimmune-mediated causes - include infection, trauma in various forms (microangiopathic hemolysis such as disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, malignant hypertension, eclampsia, HELLP syndrome [hemolysis, elevated liver enzymes, low platelet count] in pregnancy, mechanical prosthetic heart valves, march hemolysis, thermal injury, osmotic lysis), hypersplenism, and liver disease.
- Paroxysmal nocturnal hemoglobinuria - a rare disorder resulting in an acquired RBC membrane defect and subsequent hemolysis.
Pathophysiology
Images
Peripheral blood smear with spherocytes, reticulocytes, and a nucleated red blood cell
Peripheral blood smear with red blood cell fragments, or schistocytes (arrow)
Digitally-colorized scanning electron micrograph showing normal red blood cells (RBCs) and a sickle cell RBC (left) in a blood specimen of patient with sickle cell anemia
A photomicrograph of a blood smear showing erythrocytes containing developing Plasmodium vivax parasites
Photomicrograph revealing the presence of what were determined to be numbers of intraerythrocytic Babesia sp. ring-form parasites
Diagnostic Approach
History
Physical exam
Laboratory tests to determine the presence of hemolysis
Subsequent testing for specific cause
- Antinuclear antibody should be requested to evaluate for SLE.
- Hb electrophoresis detects hemoglobinopathy.
- Testing for glucose-6-phosphate dehydrogenase deficiency includes a fluorescent spot test followed by definitive assay of glucose-6-phosphate dehydrogenase activity by spectrophotometry.
- Paroxysmal nocturnal hemoglobinuria is evaluated by flow cytometry for CD55/CD59.
- Abnormal renal function in the presence of hemolysis suggests hemolytic uremic syndrome or thrombotic thrombocytopenic purpura.
- Elevated liver function tests may indicate liver disease.
Risk Factors
History & Exam
Tests
Differential Diagnosis
Anemia due to blood loss
Differentiating Signs/Symptoms
- History and physical exam will often identify source of blood loss.
Differentiating Tests
- Normal haptoglobin, bilirubin, and LDH.
- Microcytic anemia. Iron deficiency.
- Fecal occult blood test may be positive.
Underproduction anemia
Differentiating Signs/Symptoms
- Due to decreased red blood cell production from multiple causes, such as bone marrow failure (myelofibrosis, myelodysplastic syndrome, myelosuppression, aplastic anemia), anemia of chronic disease, and deficiency states (iron, vitamin B12, folate). Clinical evaluation depends on underlying cause.
Differentiating Tests
- Reticulocyte count is low, signs of hemolysis typically absent.
Transfusion reaction
Differentiating Signs/Symptoms
- Acute reactions occur during or immediately following blood transfusion.
- Symptoms of acute reactions may include: chills; fever; headache; pallor; pain along the infusion site; abdomen, back or chest pain. Signs of acute reactions may include: pruritus; flushing; dyspnea; urticaria; hypotension; hemoglobinuria; wheezing; and stridor.
- There may be a history of prior exposures to foreign red-cell antigen following pregnancy, previous transfusion, or organ transplantation with delayed hemolytic transfusion reactions. Symptoms and signs occur days to weeks following a transfusion, and include: pallor; jaundice; hemoglobinuria; purpura; bleeding (disseminated intravascular coagulation).
Differentiating Tests
- Direct antiglobulin test (Coombs) may be positive and serum haptoglobin low, as for hemolysis generally.
- Visual inspection of post-transfusion sample may show pink-to-red color.
- Testing may show ABO incompatibility between recipient and donor.
- In cases of anaphylactic reaction, serum IgA levels may be low and anti-IgA antibodies may be positive.
Screening
Treatment Approach
Acquired: direct antiglobulin test (Coombs) positive
Acquired: direct antiglobulin test (Coombs) negative
Inherited disorders
Treatment Options
acquired: direct antiglobulin test (Coombs) positive
autoimmune hemolytic anemia (AIHA)
removal of insult or treatment of underlying condition
Comments
- A hematology consultation is warranted once hemolytic anemia is diagnosed.
- Initial management of AIHA includes the removal of the insult, if any. Management of an underlying condition may include treating infection in warm AIHA or treating lymphoma in cold AIHA.
supportive care
Primary Options
folic acid (vitamin B9)
1 mg orally once daily
Comments
- All etiologies of hemolytic anemia require some degree of supportive care.
- 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.
corticosteroid
Primary Options
- prednisone
1 mg/kg/day orally until response, followed by a slow taper over 1-2 months
- prednisone
- dexamethasone
40 mg orally once daily for 4 days, repeated monthly for 6 months
- dexamethasone
Comments
- Corticosteroid use is intended to achieve reduction in antibody production. Oral prednisone or, in some cases, oral dexamethasone may be used.[64]
- 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.
rituximab
Primary Options
- rituximab
consult specialist for guidance on dose
- rituximab
Comments
- One meta-analysis of observational studies reported overall response rates of 79% for warm AIHA and 57% for cold agglutinin disease.[46] 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.[47]
supportive care
Primary Options
folic acid (vitamin B9)
1 mg orally once daily
Comments
- 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.
immunosuppressant
Primary Options
- azathioprine
consult specialist for guidance on dose
- azathioprine
- cyclosporine modified
consult specialist for guidance on dose
- cyclosporine modified
- danazol
consult specialist for guidance on dose
- danazol
- mycophenolate mofetil
consult specialist for guidance on dose
- mycophenolate mofetil
Comments
- 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.
supportive care
Primary Options
folic acid (vitamin B9)
1 mg orally once daily
Comments
- 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.
AIHA: hematologic malignancy
treatment of underlying malignancy
Comments
- 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.[49] See Non-Hodgkin lymphoma .
supportive care
Primary Options
folic acid (vitamin B9)
1 mg orally once daily
Comments
- 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.
AIHA: infection
treatment of underlying infection
Comments
- 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) .
supportive care
Primary Options
folic acid (vitamin B9)
1 mg orally once daily
Comments
- 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.
corticosteroid
Primary Options
- prednisone
1 mg/kg/day orally until response, followed by a slow taper over 1-2 months
- prednisone
- dexamethasone
40 mg orally once daily for 4 days, repeated monthly for 6 months
- dexamethasone
Comments
- May be indicated in specific circumstances (e.g., patients with severe and persistent cold hemagglutinin disease secondary to atypical and mycoplasma pneumonia).[49]
AIHA: drug-induced
discontinuation of offending medication
Comments
- 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.[49] 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] [50]
supportive care
Primary Options
folic acid (vitamin B9)
1 mg orally once daily
Comments
- 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.
corticosteroid
Primary Options
- prednisone
1 mg/kg/day orally until response, followed by a slow taper over 1-2 months
- prednisone
- dexamethasone
40 mg orally once daily for 4 days, repeated monthly for 6 months
- dexamethasone
Comments
acquired: direct antiglobulin test (Coombs) negative
treat underlying cause
Comments
- 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). More directed therapy exists for some etiologies.
supportive care
Primary Options
folic acid (vitamin B9)
1 mg orally once daily
Comments
- 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.
with liver disease
splenectomy
Comments
- 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.[54] [55] [56] Consult local guidance.
with worsening prosthetic valve hemolysis
cardiology evaluation
Comments
- 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.
- 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
plasma exchange and corticosteroid
Comments
- A combination of plasma exchange therapy, with the intent of stopping the causative process, and corticosteroids is the mainstay of treatment.[52] See Thrombotic thrombocytopenic purpura .
with paroxysmal nocturnal hemoglobinuria
eculizumab
Comments
- First-line therapy for paroxysmal nocturnal hemoglobinuria, eculizumab is a monoclonal antibody to the fifth component of complement. Eculizumab increases health-related quality of life and increases transfusion independence.[53] See Paroxysmal nocturnal hemoglobinuria .
inherited disorders
red cell membrane disorders
splenectomy
Comments
- 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.[57]
- 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.[57]
supportive care
Primary Options
folic acid (vitamin B9)
1 mg orally once daily
Comments
- 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.
glucose-6-phosphate dehydrogenase deficiency
avoidance of triggers
Comments
- A hematology consultation is warranted once hemolytic anemia is diagnosed.
- Common inciting drugs are sulfa drugs, nitrofurantoin, and salicylates.[58] Other possible triggers include naphthalene, fava beans, nitrites, dapsone, ribavirin, phenazopyridine, or paraquat.[28] [59] These should be preemptively avoided and discontinued if in use. See Glucose-6-phosphate dehydrogenase deficiency .
supportive care
Primary Options
folic acid (vitamin B9)
1 mg orally once daily
Comments
- 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.
pyruvate kinase deficiency
transfusion plus consideration of splenectomy
Comments
- A hematologic consultation is warranted once hemolytic anemia is diagnosed.
- Therapy is primarily supportive, including transfusions. Splenectomy may be considered for severe cases.[60]
supportive care
Primary Options
folic acid (vitamin B9)
1 mg orally once daily
Comments
- 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.
mitapivat
Primary Options
- mitapivat
consult specialist for guidance on dose
- mitapivat
Comments
- 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 positive results from two phase 3 trials. In the ACTIVATE study, 40% of participants receiving mitapivat reported improved hemoglobin response (the primary end point) compared with participants receiving placebo.[61] In the ACTIVATE-T study, 33% of participants achieved a transfusion reduction response at the end of 24 weeks of treatment, while 22% were transfusion-free.[62]
- Common adverse reactions include decreases in estrone and estradiol in men, increased urate, back pain, and arthralgia.
supportive care
Primary Options
folic acid (vitamin B9)
1 mg orally once daily
Comments
- 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.
hemoglobinopathies
disease-specific specialist care and supportive care
Primary Options
folic acid (vitamin B9)
1 mg orally once daily
Comments
- 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.
Emerging Tx
Sutimlimab
Prevention
Secondary Prevention
Follow-Up Overview
Prognosis
Acquired disorders
Congenital disorders
Monitoring
Complications
Citations
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Hill QA, Stamps R, Massey E, et al. The diagnosis and management of primary autoimmune haemolytic anaemia. Br J Haematol. 2017 Feb;176(3):395-411.[Abstract][Full Text]
Hill QA, Stamps R, Massey E, et al. Guidelines on the management of drug-induced immune and secondary autoimmune, haemolytic anaemia. Br J Haematol. 2017 Apr;177(2):208-20.[Abstract][Full Text]
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Key Articles
Referenced Articles
Guidelines
Diagnostic
Summary
Consensus guidelines for the diagnosis of autoimmune hemolytic anemias.Published by
First International Consensus Group
Published
2020
Summary
Evidence-based diagnostic guidelines informed by a systematic review of the literature.Published by
British Society for Haematology
Published
2016
Treatment
Summary
Consensus recommendations for the management of autoimmune hemolytic anemias.Published by
First International Consensus Group
Published
2020
Summary
Recommendations regarding the efficacy of splenectomy in hereditary hemolytic anemias.Published by
Working Study Group on Red Cells and Iron of the EHA
Published
2017
Summary
Guidance on the management of patients with primary autoimmune hemolytic anemia.Published by
British Society for Haematology
Published
2016