Ferri – Anemia, Autoimmune Hemolytic

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Anemia, Autoimmune Hemolytic

  • Andre Luiz De Souza, M.D.
  • Bharti Rathore, M.D.

 Basic Information

Definition

Autoimmune hemolytic anemia (AIHA) is anemia secondary to premature clearance of red blood cells (RBCs) caused by binding of autoantibodies and/or complement to RBCs. The classification of the hemolytic anemias is described in Table 1.

TABLE1 Classification of the Hemolytic AnemiasFrom Goldman L, Schafer AI: Goldman’s Cecil medicine, ed 24, Philadelphia, 2012, Saunders.
Acquired
Environmental factors

  1. •

    Antibody: immunohemolytic anemias

  2. •

    Mechanical trauma: TTP, HUS, heart valve

  3. •

    Toxins, infectious agents: malaria, etc.
Membrane defects

  1. •

    Paroxysmal nocturnal hemoglobinuria

  2. •

    Spur cell anemia

  3. Hereditary spherocytosis, etc.
Congenital
Defects of cell interior

  1. •

    Hemoglobinopathies: sickle cell, thalassemia

  2. •

    Enzymopathies: G6PD deficiency, etc.

G6PD, Glucose-6-phosphate dehydrogenase; HUS, hemolytic-uremic syndrome; TTP, thrombotic thrombocytopenic purpura.

Synonyms

  1. Autoimmune hemolytic anemia

  2. Cold agglutinin disease

  3. Drug-induced hemolytic anemia

  4. Warm autoimmune hemolytic anemia

ICD-10CM CODES
D59.0 Drug-induced autoimmune hemolytic anemia
D59.1 Other autoimmune hemolytic anemias

Epidemiology & Demographics

The annual incidence is 3 cases per 100,000 persons, with 10% mortality; most common in women <50 years.

Physical Findings & Clinical Presentation

  1. •

    Most common presentation is dyspnea and fatigue.

  2. •

    Pallor, jaundice may be present.

  3. •

    Tachycardia with a flow murmur may be present if anemia is pronounced.

  4. •

    Patients with intravascular hemolysis may present with dark urine and back pain.

  5. •

    The presence of hepatomegaly and/or lymphadenopathy suggests an underlying lymphoproliferative disorder or malignancy; splenomegaly may indicate hypersplenism as a cause of hemolysis.

Etiology

  1. •

    Warm antibody mediated: IgG only (often idiopathic or associated with leukemia, lymphoma, thymoma, myeloma, viral infections, babesiosis, and collagen-vascular disease)

  2. •

    Cold antibody mediated: IgM and complement in majority of cases (often idiopathic; at times associated with infections, lymphoma, or cold agglutinin disease)

  3. •

    Il-33 may have a role in promoting increasing RBC autoantibodies in AIHA.

  4. •

    Drug induced (Table 2): three major mechanisms:

    TABLE2 Drug-Induced Autoimmune Hemolytic AnemiaFrom Hoffman R: Hematology, basic principles and practice, 6th ed, Philadelphia, 2013, Saunders.
    Drug Risk Factors AIHA Onset Type of AIHA Response to Treatment Diseases Treated
    Methyldopa Not known Delayed WAIHA Resolution after withdrawal Hypertension
    INF-α Pretherapeutic positive DAT Delayed (8-11 mo) WAIHA Resolution spontaneous or after steroids Hepatitis C
    Hematologic malignancies
    Efazulimab Not known Many months WAIHA Resolution after withdrawal Arthritis (rare)
    Etanercept Not known Delayed CAIHA Resolution after rituximab Rheumatoid arthritis (rare)
    Fludarabine
    Cladribine
    Pentostatin    		 CLL
    Pretherapeutic positive DAT result    		 Early (median, 3-4 cycle) or delayed WAIHA Mixed AIHA Half of AIHA resolve after steroids CLL
    Lymphomas∗
    AML∗
    Bendamustine CLL No or only very low risk of AIHA CLL
    Lymphomas
    Chlorambucil CLL Delayed onset WAIHA CLL
    Eculizumab Patients with incomplete response After treatment CAIHA PNH
    Lenalidomide During treatment WAIHA Resolution after withdrawal One case treated for lymphoma

    AML, Acute myeloid leukemia; CAIHA, cold autoimmune hemolytic anemia; CLL, chronic lymphocytic leukemia; INF, interferon; PNH, paroxysmal nocturnal hemoglobinuria; WAIHA, warm autoimmune hemolytic anemia.
    1. 1.

      Antibody directed against Rh complex (e.g., methyldopa)

    2. 2.

      Antibody directed against RBC-drug complex (hapten induced; e.g., penicillin)

    3. 3.

      Antibody directed against complex formed by drug and plasma proteins; the drug-plasma protein-antibody complex causes destruction of RBCs (innocent bystander; e.g., quinidine)

Diagnosis

Differential Diagnosis

  1. •

    Hemolytic anemia caused by membrane defects (acquired: paroxysmal nocturnal hemoglobinuria, spur cell anemia, Wilson disease; inherited: spherocytosis, elliptosis), hemoglobinopathies, and enzyme deficiencies (G6PD, pyruvate kinase)

  2. •

    Non–immune mediated (microangiopathic hemolytic anemias, hypersplenism, cardiac valve prosthesis, giant cavernous hemangiomas, march hemoglobinuria, physical agents, infections, heavy metals, certain drugs [nitrofurantoin, sulfonamides, ribavirin])

  3. •

    Chronic lymphocytic leukemia (CLL) can be a cause of direct antiglobulin test (DAT) positivity (15% of CLL cases) without AIHA. In a series of patients treated with fludarabine and cyclophosphamide, only 30% of patients with DAT+ disease developed AIHA after therapy; conversely, 85% of patients with AIHA were previously positive for DAT.

Workup

Evaluation consists primarily of laboratory evaluation to confirm hemolysis and exclude other causes of the anemia. Although most cases of AIHA are idiopathic, potential causes should always be sought.

Laboratory Tests

  1. •

    The basic features of hemolytic anemia are reticulocytosis (if no concurrent bone marrow suppression), low haptoglobin levels, elevated indirect bilirubin, and elevated LDH.

  2. •

    Initial laboratory tests: complete blood count (anemia), reticulocyte count (elevated; Fig. E1 describes the evaluation of anemia with increased reticulocytes), liver function studies (elevated indirect bilirubin, LDH), evaluation of peripheral smear (Fig. E2).

FIG.E1 

Anemia with elevated reticulocytes and increased unconjugated bilirubin.
DAT, Direct antiglobulin test; EB, Epstein-Barr; G6PD, glucose-6-phosphate dehydrogenase; PCH, paroxysmal cold hemoglobinuria; PNH, paroxysmal nocturnal hemoglobinuria.
From Young NS, et al. [eds]: Clinical hematology, St Louis, 2006, Mosby.
FIG.E2 

In warm antibody hemolytic anemia, numerous spherocytes are seen.
From Jaffe ES et al.: Hematopathology, Philadelphia, 2011, Saunders.
  1. •

    A direct antiglobulin test (DAT, Coombs test) is initially performed with a polyspecific antibody to detect IgG or complement C3d bound to RBCs. If the DAT is positive, the diagnosis of autoimmune hemolytic anemia (AIHA) is confirmed. A positive direct Coombs test indicates presence of antibodies or complement on the surface of RBCs; positive indirect Coombs test implies presence of anti-RBC antibodies freely circulating in the patient’s serum. Positive DAT findings and characteristic features of autoantibody in AIHA are summarized in Table 3. Typical serologic features of the different types of drug-induced hemolytic anemia of immunologic origin are summarized in Table 4.

    TABLE3 Positive DAT Findings, Characteristic Features of Autoantibody in AIHA
    Warm AIHA CHAD Mixed-AIHA PCH IgA
    AIHA
    DAT IgG or IgG + C3 or
    IgG + C3 + IgM    		 C3 or C3 + IgM IgG + C3 + IgM C3 Neg with polyspecific reagent
    Pos with anti-IgA
    Antibody characteristic
    1. 1)

      Antibody subclass

    		 IgG IgM IgG + IgM IgG IgA
    1. 2)

      Specificity

    		 Apparent Rh specificity (common) I, i, Pr P
    1. 3)

      Thermal reactivity

    (in vitro)

    		 Optimal at 37°C by IAT 0-30°C by saline agglutination Combined 0-24°C, biphasic in nature
    1. 4)

      Antibody titer at 4°C

    		 Not applicable ≥256 Usually <64 but can be >256 Usually <32
    Autoagglutination No Common Common Less common No

    AIHA, Autoimmune hemolytic anemia; C, complement; CHAD, cold hemagglutinin disease; DAT, direct antiglobulin test; Ig, immunoglobulin; Neg, negative; Pos, positive.
    The determination of autospecificity is not required for diagnosis of CHAD, but confirmation of high thermal amplitude (i.e., cold autoagglutinin reacting at or above 30°C) is essential.
    From Bain BJ, Bates I, Laffan MA: Dacie and Lewis practical haematology, ed 12, Philadelphia, 2017, Elsevier.
    TABLE4 Serologic Features of the Different Types of Drug-Induced Hemolytic Anemia of Immunologic OriginFrom Bain BJ, Bates I, Laffan MA: Dacie and Lewis practical haematology, ed 12, Philadelphia, 2017, Elsevier.
    Mechanism Prototype drug DAT IAT
    Drug-dependent antibody No drug Serum + drug Eluate + drug
    C′ activation Quin(id)ine C′∗ Neg C′∗ Neg
    No C′ activation Penicillin IgG Neg IgG IgG
    Autoantibody α-Methyldopa IgG IgG NA NA

    C´, Complement; NA, not applicable; Neg, negative.
  2. •

    If the DAT is positive with IgG alone or with IgG + C3d, the AIHA is most likely due to warm antibody (WAIHA), whereas if the DAT is positive with C3d only, it is most likely caused by a cold antibody (CAIHA).

  3. •

    Hepatitis serology, antinuclear antibody.

  4. •

    Urinary tests may reveal hemosiderinuria or hemoglobinuria (documenting intravascular hemolysis).

Imaging Studies

  1. •

    Chest x-ray

  2. •

    CT scan of chest, abdomen, and pelvis should be considered if underlying lymphoproliferative disorder is suspected

Treatment

Nonpharmacologic Therapy

  1. •

    Discontinuation of any potentially offensive drugs

  2. •

    Plasmapheresis exchange transfusion for severe life-threatening cases only

  3. •

    Avoid cold exposure in patients with cold antibody

Acute General Rx

  1. •

    Prednisone 1 to 2 mg/kg/day in divided doses initially in warm antibody AIHA. Corticosteroids are generally ineffective in cold antibody AIHA. In cold agglutinin disease treatment, modalities consist of cold avoidance, therapy of underlying lymphoproliferative disorder, and use of rituximab and plasmapheresis in severe cases.

  2. •

    Splenectomy is indicated in patients responding inadequately to corticosteroids when RBC sequestration studies indicate splenic sequestration.

  3. •

    Immunosuppressive drugs and/or immunoglobulins only after both corticosteroids and splenectomy (unless surgery is contraindicated) have failed to produce an adequate remission.

  4. •

    Danazol, typically used in conjunction with corticosteroids (may be useful in warm antibody AIHA).

  5. •

    Immunosuppressive drugs (azathioprine, cyclophosphamide) may be useful in warm antibody AIHA but are indicated only after both corticosteroids and splenectomy (unless surgery is contraindicated) have failed to produce an adequate remission.

  6. •

    Table 5 summarizes treatment options for primary and secondary warm autoimmune hemolytic anemia and cold autoimmune hemolytic anemia. Second-line treatment options after steroids are described in Table 6.

    TABLE5 Treatment Options for Primary and Secondary Warm Autoimmune Hemolytic Anemia and Cold Autoimmune Hemolytic AnemiaFrom Hoffman R: Hematology, basic principles and practice, 6th ed, Philadelphia, 2013, Saunders.
    Disease or Condition First Line Second Line Beyond Second Line Last Resort
    Primary AIHA Steroids Splenectomy
    Rituximab    		 Azathioprine, MMF, cyclosporine, cyclophosphamide High-dose cyclophosphamide, alemtuzumab
    B- and T-cell NHL Steroids Chemotherapy +/− rituximab (splenectomy in SMZL)
    Hodgkin’s lymphoma Steroids Chemotherapy
    Solid tumors Steroids
    Surgery
    Ovarian dermoid cyst Ovariectomy
    SLE Steroids Azathioprine MMF Rituximab
    Autologous SCT
    Ulcerative colitis Steroids Azathioprine Total colectomy
    CVID Steroids + IgG replacement
    ALPD Steroids MMF Sirolimus
    Wiskott-Aldrich syndrome Steroids Allogeneic SCT
    Allogeneic SCT Steroids Rituximab∗ Splenectomy
    T-cells infusion
    Organ transplantation Reduction of immune suppression, steroids
    Drug induced Withdrawal Steroids
    Primary CAD Protection from cold exposure Rituximab
    Chlorambucil    		 Fludarabine + rituximab Eculizumab,† bortezomib†
    PCH Supportive treatment (postinfectious) Rituximab∗ (chronic)

    AIHA, Autoimmune hemolytic anemia; ALPD, autoimmune lymphoproliferative disorders; CAD, cold agglutinin disease; CVID, common variable immune deficiency; IgG, immunoglobulin G; MMF, mycophenolate mofetil; NHL, non-Hodgkin lymphoma; PCH, paroxysmal cold hemoglobinuria; SCT, stem cell transplantation; SLE, systemic lupus erythematosus; SMZL, splenic marginal zone lymphoma.
    TABLE6 Second-Line Treatment Options After SteroidsFrom Hoffman R: Hematology, basic principles and practice, 6th ed, Philadelphia, 2013, Saunders.
    Treatment Dosing and Application Side Effects Precautions
    Splenectomy (acute) Preferentially laparoscopic Infections, thrombosis Postoperative thromboprophylaxis
    Splenectomy (long term) — Infections
    Venous thrombosis    		 Vaccination, patient information
    Rituximab 375 mg/m2 on days 1, 8, 15, and 22 IV Infusional reactions
    Infections    		 Premedication with antihistamines (and steroids)
    Danazol 200-400/day PO Hepatotoxicity None
    Cyclophosphamide PO or IV
    Dose adjusted to neutrophil count    		 Neutropenia
    Mutagenesis    		 Neutrophil count monitoring, bladder protection after high doses
    Azathioprine 2.0-3.mg/kg/day PO
    Dose adjusted to neutrophil count    		 Neutropenia Neutrophil count monitoring; avoid interaction with other drugs (e.g., allopurinol)
    Mycophenolate mofetil 1-2 × 1 g/d PO Gastrointestinal
    Cyclosporine PO
    Dose adjusted to blood levels of CyA
    Target level, 200-400 ng/mL    		 Nephrotoxicity
    Gum hyperplasia    		 Monitoring of CyA levels and creatinine
    Alemtuzumab SC (variable doses) Neutropenia Anti-infectious prophylaxis

    CyA, Cyclosporine A; IV, intravenous; PO, oral; SC, subcutaneous.

Disposition

Prognosis is generally good unless anemia is associated with underlying disorder with a poor prognosis (e.g., leukemia, myeloma).

Referral

  1. •

    Hematology referral in all cases of AIHA

  2. •

    Surgical referral for splenectomy in refractory cases

Pearls & Considerations

Comments

  1. •

    The direct antiglobulin test demonstrates the presence of antibodies or complement on the surface of RBCs and is the hallmark of autoimmune hemolysis.

  2. •

    Warm AIHA is often associated with autoimmune diseases, whereas cold AIHA often follows viral infections (e.g., mononucleosis) and Mycoplasma pneumoniae infections.

  3. •

    HIV can induce both warm and cold AIHA.

  4. •

    Hemolytic anemia is a common autoimmune complication of hematopoietic stem cell transplantation occurring in up to 6% of patients as a late complication (median 202 days); it presents as either warm or cold AIHA.

Suggested Readings

  • X. Bu, et al.: IL-33 reflects dynamics of disease activity in patients with autoimmune hemolytic anemia by regulating autoantibody production. J Transl Med. 13:381 2015 26675669

  • M. Wang, et al.: Autoimmune hemolytic anemia after allogeneic hematopoietic stem cell transplantation: analysis of 533 adult patients who underwent transplantation at King’s College Hospital. Biol Blood Marrow Transplant. 21 (1):60–66 2015 25262883

  • AE. Wooley, et al.: Post-babesiosis warm autoimmune hemolytic anemia. N Engl J Med. 376:939–946 2017 28273010

  • A. Zanella, W. Barcellini: Treatment of autoimmune hemolytic anemias. Haematologica. 99 (10):1547–1554 2014 25271314

 

 

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