Go RS, Winters JL, Kay NE. How I treat autoimmune hemolytic anemia. Blood. 2017 Jun 1;129(22):2971-2979. doi: 10.1182/blood-2016-11-693689. Epub 2017 Mar 30. Review. PubMed PMID: 28360039.
Also see Anemia: General Considerations.
Definition, Etiology, Pathogenesis Top
Hemolytic anemia (HA) refers to a heterogeneous group of diseases characterized by an abnormal, premature destruction of red blood cells (RBCs). Hemolysis may be either intravascular or extravascular (in the spleen and/or the liver).
1. Hereditary HAs are caused by primary intracorpuscular defects:
1) Membrane defects: For example, hereditary spherocytosis and hereditary elliptocytosis.
2) Enzymopathies: Glucose-6-phosphate dehydrogenase (G6PD) deficiency, pyruvate kinase (PK) deficiency.
3) Hemoglobinopathies: Some forms, for example, sickle cell disease, methemoglobinemia, HbC.
4) Thalassemia syndromes: Quantitative abnormalities of globin chain synthesis (most frequently affecting beta-globin).
2. In acquired HAs, RBCs are constitutively normal, and hemolysis is caused by extracorpuscular factors (except for paroxysmal nocturnal hemoglobinuria [PNH], which is acquired and intracorpuscular):
1) Immune HA (with antibodies against red cell antigens; in some cases, only complement may be detected on the RBC surface):
a) Warm antibody autoimmune HA (AIHA) (idiopathic or associated with other conditions [including systemic lupus erythematosus, chronic lymphocytic leukemia, non-Hodgkin lymphoma, immunodeficiency syndromes], drug-induced [methyldopa, cephalosporins, purine analogues], after solid organ transplantation or allogeneic hematopoietic stem cell transplantation [in the case of blood group mismatch of the donor and the host], after packed red blood cell [PRBC] transfusions). A variant of AIHA is seen in patients with common variable immunodeficiency.
b) Cold agglutinin disease (idiopathic or associated with infection [mycoplasma, Epstein-Barr virus] or lymphomas).
c) Posttransfusion hemolytic reactions.
d) Neonatal alloimmune hemolysis.
2) Nonimmune HA:
a) RBC destruction (mechanical due to the effect of fibrin deposition, artificial valves or native valvular disease, stents, “march hemoglobinuria,” thrombotic thrombocytopenic purpura [TTP], hemolytic-uremic syndrome [HUS], disseminated intravascular coagulation [DIC]).
b) Infections (malaria, babesiosis, toxoplasmosis, leishmaniasis, Clostridium perfringens).
c) Chemical or physical factors (methemoglobinemia, drugs [mitomycin C; cyclosporine, or INN ciclosporin; tacrolimus; ticlopidine; sulfonamides; sulfasalazine; dapsone; platinum analogues], drugs of abuse [cocaine], metals [lead, copper], venoms [Loxosceles spiders, bee, wasp, cobra, viper], severe burns).
Clinical Features and Natural HistoryTop
Patients with low-grade hemolysis, particularly chronic hemolysis, usually reveal no symptoms of HA. General symptoms of anemia are usually observed in patients with a hemoglobin (Hb) level <8 g/dL or rapidly progressive anemia. Jaundice is observed in the periods of increased RBC destruction but is frequently absent in patients with chronic hemolysis. An enlarged spleen (in some patients accompanied by an enlarged liver) is observed only in some types of HA and usually suggests a systemic underlying condition (lymphoproliferative or autoimmune disorders).
Characteristic clinical features of selected types of HA:
1) Hereditary spherocytosis (HS) is the most frequent hereditary HA in white patients; it typically involves an enlarged spleen, hemolytic and/or aplastic crises, and cholelithiasis due to increased heme catabolism (affects ~50% of adult patients).
2) G6PD deficiency: Men are more frequently affected than women. Acute attacks of hemolysis (acute jaundice, dark urine, abdominal pain) are triggered by certain drugs (see www.g6pd.org and www.g6pddeficiency.org) and foods (fava beans). No spleen enlargement is observed.
3) PK deficiency: Typically presents in early childhood, or in adulthood in heterozygous individuals.
4) Methemoglobinemia may be hereditary (HbM) or acquired (much more frequent); the latter is caused by agents that oxidize heme iron (sodium nitroprusside, phenacetin, sulfonamides, lidocaine, benzocaine, dapsone, rasburicase, nitrates, nitroglycerin, nitric oxide, nitrites, aniline, chlorites). Cyanosis is observed at methemoglobin levels >1.5 g/dL.
5) Thalassemia syndromes: Spleen enlargement is typically observed. Severe HA develops in homozygotes or double heterozygotes and presents in the first year of life.
6) Sickle cell disease: Recurrent severe pain of hands and feet, jaundice, spleen enlargement, cholelithiasis, ankle ulcers, and a tendency to thromboembolism causing ischemia and functional impairment of various organs, including cerebral ischemia.
7) Cold agglutinin disease (incidence, ~1/1,000,000 per year): Symptoms of lymphoma, infectious mononucleosis, or pneumonia are typically present. Acrocyanosis (purple discoloration of distal body parts on exposure to cold) and livedo reticularis may occur.
8) PNH (incidence, ~1/1,000,000 per year): Hemolytic anemia, thrombosis in an atypical location (~50%), pancytopenia in patients with overlapping bone marrow failure (aplastic anemia or myelodysplastic syndrome).
1. Complete blood count (CBC): Anemia is typically normocytic and normochromic, although in some patients it may be macrocytic due to reticulocytosis. Reticulocyte counts are usually increased (typically 5%-20%). In patients with thalassemia, microcytic and hypochromic anemia is observed. Spherocytes and elliptocytes may be observed in HS and AIHA, sickled RBCs are present in sickle cell disease, acanthocytes in PK deficiency, target cells in thalassemia syndromes, and RBC fragments in DIC, HUS, and TTP. Erythroblasts may be present in severe anemia associated with increased erythropoiesis. Elevated mean corpuscular hemoglobin concentration (MCHC) is observed in HS.
2. Biochemical tests: Elevated lactate dehydrogenase (LDH) levels, decreased (or undetectable) haptoglobin levels, elevated serum unconjugated bilirubin levels (usually <4 mg/dL).
3. Urinalysis: Elevated urobilinogen levels, hemoglobinuria (positive dipstick test).
4. Other studies specific for individual types of HA:
1) HS: Positive acidified glycerol lysis test (AGLT) and/or positive eosin-5-maleimide (EMA) binding test on immunohistochemical analysis.
2) G6PD deficiency: Heinz bodies in RBC cytoplasm, decreased G6PD activity in RBCs (the measurements should not be performed in periods of acute hemolysis).
3) PK deficiency: Decreased PK activity in RBCs.
4) Methemoglobinemia: Elevated methemoglobin levels.
5) Beta-thalassemia syndromes: Absence of hemoglobin A (HbA) and elevated hemoglobin F (HbF) levels in Hb electrophoresis in homozygotes. Heterozygotes may produce small amounts of HbA and in 50% of cases have increased HbF; all have increased hemoglobin A2 (HbA2) fractions.
6) Sickle cell disease: Howell-Jolly bodies in RBCs, absence of HbA, increased sickle hemoglobin (HbS) and HbF levels in Hb electrophoresis, presence of sickle cells.
7) Warm antibody AIHA: Positive direct antiglobulin test (with anti-IgG or anti-C3d antibodies).
8) Cold agglutinin disease: Positive direct antiglobulin test (with anti-C3d antibodies), RBC agglutination observed by light microscopy, increased mean corpuscular volume (MCV) (apparent macrocytosis caused by RBC aggregates), monoclonal protein testing.
9) PNH: Deficiency of glycosylphosphatidylinositol-associated proteins (GPI-AP) in granulocytes and RBCs observed on flow cytometry.
5. Bone marrow examination: Increased erythropoiesis, frequently with megaloblastic features.
6. Imaging studies: Spleen enlargement and/or cholelithiasis are observed on ultrasonography in some types of hemolytic anemia.
Anemia of varying severity, typically normocytic and normochromic (exceptions: above), with increased serum LDH and unconjugated bilirubin levels, decreased haptoglobin levels, and increased reticulocyte counts.
Anemia of chronic disease.
1. Secondary HA: Treat the underlying condition. Discontinue the drugs that may cause hemolysis.
2. Severe symptomatic anemia: Transfusion of PRBCs.
3. Chronic HA: Lifelong administration of folic acid 1 mg/d. Iron therapy only in patients with a documented absolute iron deficiency (see Iron Deficiency Anemia) (however, it is contraindicated in the majority of cases).
1. Warm antibody AIHA: Administer glucocorticoids (oral prednisone 1 mg/kg/d) for several weeks, then taper the dose down to the lowest level that maintains remission and negative antiglobulin test results. Hb levels usually increase after 1 to 3 weeks of treatment. In patients with a more severe hemolysis, initiate high-dose intravenous methylprednisolone. In steroid-resistant, steroid-intolerant, or steroid-dependent (>15 mg/d after a few months of therapy) individuals, consider splenectomy; in the case of contraindications to or ineffectiveness of splenectomy, consider IV rituximab 375 mg/m2 once a week for 4 consecutive weeks or a trial of another immunosuppressive agent (oral azathioprine 100-150 mg/d, oral cyclophosphamide 100 mg/d or 500-700 mg/d IV every 3-4 weeks, cyclosporine [INN ciclosporin] in doses adjusted to serum drug levels, oral mycophenolate mofetil 0.5-1 g bid). In steroid-resistant patients, particularly in the case of hemolytic crisis, plasmapheresis with intravenous immunoglobulin (IVIG) administration (1 g/kg for 2 days or 1 dose of 2 g/kg) may be used. Syk inhibitors may be effective in refractory cases.
2. Cold agglutinin disease: Treat the underlying condition. In the majority of patients avoidance of exposure to cold and wearing appropriately warm clothing is sufficient to prevent hemolysis. Warm PRBCs and IV fluids; avoid blood products with a high amount of complement (platelets, fresh-frozen plasma). In patients with severe disease consider a trial of immunosuppressive treatment with oral cyclophosphamide 100 mg/d, chlorambucil, IV rituximab 375 mg/m2 once a week for 4 consecutive weeks (this is most effective as monotherapy or in combination with fludarabine). If urgent suppression of antibody titers is necessary, perform plasmapheresis. IVIG may also reduce hemolysis in acute crises. Acute cold agglutinin disease due to mycoplasma infection usually responds promptly to glucocorticoids and/or IVIG and rarely produces long-lasting disease.
3. Methemoglobinemia: Discontinue the drugs that may have caused methemoglobinemia. In severe cases (>20% of total Hb) administer methylene blue 1 to 2 mg/kg (1% solution in 0.9% saline) in an IV infusion over 5 minutes and consider hyperbaric oxygen therapy. In patients with life-threatening methemoglobinemia (>50% of total Hb), perform exchange transfusion. In patients with chronic methemoglobinemia, administer oral ascorbic acid 0.3 to 1 g/d in divided doses and oral riboflavin 20 mg/d; in exacerbations use oral methylene blue 100 to 300 mg/d.
4. Thalassemia syndromes (see Thalassemia): In all patients with thalassemia major and some patients with thalassemia intermedia, chronic PRBC transfusions are usually necessary to eliminate symptomatic anemia. Monitor iron parameters and treat iron overload. Supplement with folic acid. Consider splenectomy in the case of >50% increase in PRBC transfusion requirements over a 1-year period. In selected cases, consider allogeneic hematopoietic stem cell transplantation (HSCT).
5. Sickle cell disease (see Sickle Cell Disease): In the majority of patients, treatment is symptomatic (analgesics, antithrombotic treatment, physiotherapy). PRBC transfusions are used in the case of aplastic crisis and in situations posing a risk of exacerbation (to achieve HbS levels ≤30% as a result of dilution). Monitor iron parameters and start appropriate treatment in case of absolute deficiency (see Iron Deficiency Anemia) or treat iron overload. Administer folic acid. Treatment with hydroxyurea (INN hydroxycarbamide) 15 to 20 mg/kg/d is recommended with dose increments until reduction in the white blood cell count is achieved. Chronic transfusion therapy may be indicated for prevention of cerebrovascular diseases. In selected cases consider allogeneic HSCT. Red cell exchange transfusion may be indicated in patients with acute severe complications of sickle cell disease.
6. PNH: In the classic form of the disease (GPI-AP absent in >50% of granulocytes; overt intravascular hemolysis) treatment is necessary in patients with clinically significant symptoms and complications. Eculizumab is the drug of choice. Allogeneic HSCT is the only “curative” treatment that can eradicate the PNH clone. In case of thromboembolic complications, use standard antithrombotic treatment, with secondary prophylaxis with a vitamin K antagonist and primary prophylaxis with heparin. In patients with moderate or severe anemia, consider danazol 200 to 600 mg/d in 3 divided doses. Supportive treatment includes PRBC transfusions, supplementation of iron and folic acid, and growth factors (erythropoietin and granulocyte colony-stimulating factor [G-CSF] in the case of bone marrow failure). In atypical forms of the disease treatment depends on the coexisting type of bone marrow failure (aplastic anemia, myelodysplastic syndrome).