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Hematology: Autoimmune hemolytic anemia in adult: warm agglutinin, Causes, Types, Symptoms, Diagnosis and Therapy

HEM_direct_coombs_test
Source: www.msdmanuals.com


    Definition

    Autoimmune disease characterized through the existence of antibodies again antigens at the surface of the RBCs, which lead to its agglutinating and hemolysis in body temperatures

    Etiology

    -        Viral infections (usually in children)
    -        Autoimmune and connective tissue diseases (particularly systemic lupus erythematosus, till 10% of patients).
    -        Immune deficiency diseases.
    -        Malignancies of the immune system (eg, non-Hodgkin lymphoma, chronic lymphocytic leukemia (CLL) (till 11% of patients), with a higher incidence in those treated with purine analogs
    -        Prior allogeneic blood transfusion, hematopoietic cell transplantation, or solid organ transplantation.
    -        Drugs (penicillin, methyldopa)
    -        Evans-Syndrom: the occurrence of two or more hematologic immune cytopenia’s: most common: AIHA + Thrombocytopenia

    Clinical manifestation

    Signs and symptoms of anemia:
    -        exertional dyspnea, dyspnea at rest
    -        varying degrees of fatigue
    -        signs and symptoms of the hyperdynamic state, such as bounding pulses, palpitations, and "roaring in the ears”.
    -        By severe anemia lethargy, confusion and tachycardia
    Clinical examination may reveal:
    -        Pallor
    -        Jaundice
    -        Moderate Splenomegaly
    -        Signs of cardiac decompensation by severe anemia

    Diagnosis

    -        HGB is reduced: usually between 7 and 10 g/dl
    MCHC is elevated due to the presence of spherocytes
    MCV is elevated due to reticulocytes
    -        Reticulocytes count is elevated usually above 4-5%: may be absent (20-37%) by bone marrow suppression by viral infections B19, medications and malignancies, or due to antibodies attacking the RBCs normoblasts in bone marrow!
    -        LDH elevated
    -        Haptoglobin in reduced
    (LDH elevation + Haptoglobin reduction is 90% specific for AIHA, while normal LDH and Haptoglobin is 92% sensitive to ruling out AIHA)
    -        peripheral blood smear shows the presence of spherocytes, usually with an increased number of polychromatophilic red cells (reticulocytes)

    -        Direct Coombs' test: it detects the antibodies attached to the RBCs. Usually positive with anti-IgG, anti-C3, or both (positive in 99% in patients with AIHA)
    -        Indirect Coombs' test: it detects the antibodies in the plasma is generally of little value in this concern.

    Differential Diagnosis

    Hemolytic anemia of another causes:
    -        Drugs: drug history
    -        AIHA due to cold agglutinins: relationship between anemia and exposure to cold, Direct coombs test usually positive with anti-c3 and negative with anti-IgG, indirect coombs test reveals the presence of IgM autoantibodies in Serum (cold agglutinins)
      

    Therapy

    Goal of the therapy is to control of the degree of anemia enough for most activities without excessive compromise of immunologic responsiveness.
    The therapy aims to either reducing the amount of antibody being produced or reducing its efficiency in destruction of the red cells:
    Reducing the amount of antibody:
    1-     Steroids:
    -        prednisolone 1 mg/kg
    -        remission accrues in 60-70% of patients
    -        remission is to be seen within 1-3 weeks
    -        signs of benefit are the elevation of HGB.
    -        Tapering steroid should take place once remission has been established (HGB> 10g/dl): Tapering-Schema:

    Once HGB >10 g/dl
    Maintain Prednisolone 60 mg/day
    For one week
    If remission persistent
    Rapidly reduce the dose to 20 mg/day
    Over 2 weeks
    If remission persistent
    Maintain 20 mg/day
    For 4 weeks
    If remission persistent
    20 mg/day in alternation with 10 mg/day  
    For 4 weeks
    If remission persistent
    20 mg/day every other day

    If remission persistent
    Reduce to 10 mg/day every other day


    Stop steroid when
    HGB, LDH, Haptoglobin, absolute reticulocytes within the normal
    Control for recurrence for a number of months after stopping steroids

    If at any step the remission cannot be maintained other approaches should be considered:

    2-     Immunosuppressive and cytotoxic agents:
    Indications:
    - lack of response to steroids
    - Need of maintenance dose of steroids to maintain remission higher than 15-20
      mg/day
    - inability to tolerate steroids
    Azathioprine: 100-150 m/day, dose should be adjusted to produce a fall in WBC to 3000/µl. Response begins after 1 month, when 4 months without sufficient response then further therapy will be with no effect. Relapse after dose reduction would be seen after 3-4 months
    Cyclophosphamide: 100 mg/day p.o. or 500-700 mg/ 3-4 weeks i.v.
    Common SE: hair loss, gonadal toxicity, bone marrow suppression, bladder irritation with hematuria, and development of myelodysplastic syndrome or leukemia
    Cyclosporine: 5-10 mg/Kg/day divided on 2 Doses/ mycophenolate mofetil: 500-1000 mg/day divided on 2 doses with increase to 1000-2000 mg: these agents can be used in resistant cases of AIHA
    3-     Monoclonal Antibodies:
    Rituximab, Alemtuzumab: experience is limited

    Reducing the Effectiviness of antibodies:
    Splenectomy: remission in 60-70 %.
    Intravenous gamma globulin: remission in only 40%, and after high doses: 1000 mg/kg/ day i.v. for 5 days, to be used in very severe disease to establish control  
    RBCs- transfusion: by severe anemia: full compatible blood is difficult to find since the autoantibody will react with the antigen on the surface of RBCs in almost all individuals.
    “No patient with AIHA should die because of difficulties in finding blood for transfusion”.
    In general: consider steroids, then when no sufficient response splenectomy, and at least when splenectomy unable, not helpful then consider immunosuppressive agents

    Complications

    -        development of a lymphoproliferative disorder
    -        development of venous thromboembolic disease

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