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: For example, sickle cell disease, 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 transplant or allogeneic hematopoietic stem cell transplant [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.
c) Posttransfusion hemolytic reactions.
d) Hemolytic disease of the fetus or newborn.
2) Nonimmune HA:
a) RBC destruction (mechanical; because 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 (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 may suggest an 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 (~50%) due to increased heme catabolism.
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.
4) Thalassemia syndromes: Spleen enlargement is typically observed. Severe HA develops in homozygotes or double heterozygotes and presents in the first year of life.
5) 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.
6) Cold agglutinin disease (incidence, ~1/1,000,000 per year): Symptoms of underlying lymphoma, infectious mononucleosis, or pneumonia are typically present. Acrocyanosis (purple discoloration of distal body parts on exposure to cold) and livedo reticularis may occur.
7) 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. Genetic testing: A variety of techniques can detect specific single gene abnormalities associated with specific forms of HA. They are useful if there is a common mutation known to be associated with a specific characteristic of the anemia. Next-generation sequencing or other techniques that can examine multiple genes simultaneously have become widely used in patients with hemolytic anemia, either in the case where a morphologic abnormality may be due to multiple mutations or as a second-line test replacing more complex chemical tests, such as the G6PD screen.
3. Biochemical tests: Elevated lactate dehydrogenase (LDH) levels, decreased (or undetectable) haptoglobin levels, elevated serum unconjugated bilirubin levels (usually <4 mg/dL).
4. Urinalysis: Elevated urobilinogen levels, hemoglobinuria (positive dipstick test).
5. Other studies specific for individual types of HA:
4) 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.
5) 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.
6) Warm antibody AIHA: Positive direct antiglobulin test (with anti-IgG or anti-C3d antibodies).
7) 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.
8) PNH: Deficiency of glycosylphosphatidylinositol-associated proteins (GPI-AP) in granulocytes and RBCs observed on flow cytometry.
6. Bone marrow examination: Increased erythropoiesis, frequently with megaloblastic features.
7. 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 often increased reticulocyte count.
Other types of anemia.
1. Secondary HA: Treat the underlying condition. Discontinue the drugs that may cause hemolysis.
2. Severe symptomatic anemia: Transfusion with the least incompatible PRBCs.
3. Chronic HA: Lifelong administration of folic acid 1 mg/d and oral vitamin B12 1000 microg daily to support ongoing erythropoiesis. 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 severe hemolysis, consider high-dose IV methylprednisolone. In steroid-resistant, steroid-intolerant, or steroid-dependent (>15 mg/d after a few months of therapy) individuals, consider IV rituximab 375 mg/m2 once a week for 4 consecutive weeks (most commonly used; sometimes in conjunction with glucocorticoids as a first-line therapy) or consider splenectomy 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 IV rituximab (375 mg/m2 on day 1) with IV bendamustine (90 mg/m2 on days 1 and 2) for 4 cycles given every 28 days; or alternatively rituximab with fludarabine (a less effective and more toxic treatment). Consider IV rituximab as monotherapy, 375 mg/m2 on days 1, 8, 15, and 22 in patients not eligible for the abovementioned combination therapy. 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. Thalassemia syndromes (see Thalassemia).
4. Sickle cell disease (see Sickle Cell Disease).
5. 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 or ravulizumab is the therapy 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; in situations with increased thrombotic risk use 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).