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  • Autoimmune Hemolytic Anemia

    Young Rok Do, M.D., Ph.DDivision of HematoOncology,

    Department of Internal Medicine,

    Keimyung University, Dongsan Medical Center

  • Contents

    Case Approach to Hemolytic Anemia Classification of Hemolytic Anemia AutoImmune Hemolytic Anemia

    -Warm Ab-Cold Ab,-Paroxysmal Cold Hemoglobinuria-Drug Induced

    Summary

  • 69, ,

    HgB 9.2 g/dL Ref) 12-18

    WBC 6.25 x103/u Ref) 5.2-12.4

    MCV 97.5 fl Ref) 80-99

    Platelet 226 x103/u Ref) 130-400

    Bilirubin(T/D) 2.5/0.5mg/dL Ref) (0.2-1.2/0.0-0.4)

  • ;

    ?

    1) Serum folate

    2) Serum ferritin

    3) Reticulocyte count

    4) ABO, Rh typing

    5) Electrophoresis

  • Direct Coombs test (+)

    Indirect Coombs test(-)

    LDH; 565.4mg/dL Ref) 50-320

    Haptoglobin;

  • ?

    1) Hereditary Spherocytosis

    2) Immune Hemolytic Anemia

    3) ABO incompatibility

    4) Severe Burn

    5) Heinz Body Anemia

  • ?

    1) Steroid

    2) Azathioprine

    3) Rituximab

    4) ImmuneGlobulin

    5) Chlorambucil

  • 66, ,

    HgB 7.2 g/dL Ref) 12-18

    WBC 5.48 x103/u Ref) 5.2-12.4

    MCV 95.1 fl Ref) 80-99

    Platelet 226 x103/u Ref) 130-400

    Reticulocyte 7.5% Ref) 0.5-1.5

  • Direct Coombs test (+) Indirect Coombs test(-) LDH; 701.2mg/dL Ref) 50-320 Haptoglobin; 7.5mg/dL Ref) 50-320 Bilirubin T/D; 3.5/0.5mg/dL Ref)-1.2/-0.4 C3; 64.4mg/dL Ref) 90-180 C4;

  • ?I

  • ?

    1) cold agglutinin .

    2) IgM.

    3) .

    4) .

    5) Steroid .

  • Approach to Hemolytic Anemia

    History Age; AIHA usually middle aged or older Sex; not specific, AIHA sl more in Symptom

    Pallor, fatigue, dizznessPiemented gall stoneSplenomegalyAcute pain in bone and chest

  • Family historyPositive Medical history

    Drug history; analgesicsanti-malaria antibacterial

  • Exam

    Pallor Jaundice Tachycardia, murmur Sign of CHF Splenomegaly Cholelithiasis

  • Investigation

    CBC; Red cell index, Reticulocyte Coombs test(DAT) Serum level; bilirubin, haptoglobin,

    plasma hemoglobin, LDH, u hemosiderin BM exam; erythroid hyperplasia Other test; Osmotic Fragility, enzyme

    assay, Hb electrophoresis

  • Treatment

    Transfusion; if neededSlowly transfuse to prevent destruction

    Discontinue offending agent Supply folic acid during active hemolysis Corticosteroid in AIHA IVIG; a few pt respond

  • Surgical Care

    Splenectomy; Hereditary Spherocytosis

    in AIHA other measures failed

    not indicated in cold agglutinin HARBC lysed in liver

    Immunization against H.influenzae, S.pneumoniae in advance of procedure

  • Hemolytic Anemia

    Anemia of increased destruction

    -Shortened RBC survival

    -Reticulocytosis: response to increased RBC destruction

    -Increased indirect bilirubin

    -Increased LDH

  • Classification of Hemolytic Anemia

    Drug-Related Hemolysis

    Alloimmune Hemolysis

    -Hemolytic Transfusion Reaction

    -Hemolytic Disease of the Newborn

    Autoimmune Hemolysis

    -Warm autoimmune hemolysis

    -Cold autoimmune hemolysis

    II

  • Hemolysis

    Acquired

    Inherited/

    Congenital

    Immune hemolysis

    Autoimmune

    Drug

    Alloimmune

    Traumatic

    (micro and macro)

    TTP/HUS/HELLP

    DIC

    Vasculitis

    Eclampsia

    Malignant HTN

    Prosthetic heart valve

    Arterial grafts

    Hypersplenism

    Membrane abnormalities

    Acanthocytes(spur cells)

    Echinocytes (burr cells)

    PNH

    Thermal injury (burns)

    RBC

    membranopthies

    RBC

    enzymopathies

    Hemoglobinopathy

  • # ::

    Extravascular

    Hematologic

    PBS

    reticulocyte count

    BM exam

    Plasma or serum

    bilirubin

    haptoglobin#

    plasma hemoglobin

    LDH

    Urine

    bilirubin

    hemosiderin

    hemoglobin

    Intravascular

    Polychromatophilia

    Erythroid hyperplasia

    Unconjugated

    , Absent

    N -

    (variable)

    0

    0

    0

    Polychromatophilia

    Erythroid hyperplasia

    Unconjugated

    Absent

    (variable)

    0

    +

    + in severe disease

    Classification of HA

  • -MAHA-Valve hemolysis-Chemical agents-Osmotic lysis-Infections-PNH-Cold agglutinin ds-Venoms

    Intravascular hemolysis

  • Causes of Acquired Hemolytic Anemia

    I. Entrapment

    II. Immune

    A. Warm-reactive (IgG) Ab.

    B. Cold-reactive IgM Ab. (cold agglutinin ds.)

    C. Cold-reactive IgG Ab. (Paroxysmal cold hemoglobinuria)

    D. Drug-dependent ab

    1. Autoimmune

    2. Haptene

    III. Paroxymal nocturnal hemoglobinuria

  • IV. Traumatic hemolytic anemia

    A. Impact hemolysis

    B. Macrovascular defects-prostheses

    C. Microvascular causes

    1. TTP/HUS

    2. Other causes of microvascular abnormalities

    3. DIC

    V. Hemolytic anemia d/t toxic effects on the membrane

    A. Spur cell anemia

    B. Metals (ex. Copper)

    C. Organic compounds

  • Reticulocyte countnot elevated

    Hemolysis or Blood loss

    no sx. or signs of

    blood loss

    Hemolysis

    Acquired Inherited/Congenital

    elevated

    Approach to Hemolytic Anemia

  • Classification-Immune Hemolytic Anemia

    Autoantibodies

    Induced by IgG or IgM antibodies with specific

    for antigens associated with patients RBC

    Alloantibodies

    Transfused RBC may be hemolyzed by

    alloantibodies directed against foreign antigens

    on those cells

  • Hemolysis due to Antibodies

    Warm-Ab Immnehemolytic AnemiaIdiopathic

    Lymphoma: CLL, NHL, HD (infrequent)

    SLE & other collagen-vascular ds.

    Drugs

    a. -Methyldopa type (autoab. to Rh ag.)

    b. Penicillin type (stable hapten)

    c. Quinidine type (unstable hapten)

    Postviral infections

    Other tumors (rare)

    Cold-Ab Immunehemolytic AnemiaCold agglutinin ds.

    a. Acute: Mycoplasma infection, infectious mononucleosis

    b. Chronic: idiopathic, lymphoma

    c. PCH (paroxysmal cold hemoglobinuria)

  • Cold-reacting antibodies

    (agglutinins or Donath-Landsteiner antibody),

    Most drug-related antibodies, IgM antibodies,

    IgG antibodies of low affinity,

    Activation of complement immune complexes

    YesNo

    Antibodies to glycoprotein antigens, SLEYesYes

    Antibodies to Rh proteins,

    Hemolysis caused by -methyldopa or penicillin:

    Not seen in SLE

    NoYes

    CausesAnti-C3Anti-IgG

    Coombs test

  • AutoImmune Hemolytic Anemia

    A. Warm-reactive (IgG) Ab.

    B. Cold-reactive IgM Ab. (cold agglutinin ds.)

    C. Cold-reactive IgG Ab. (Paroxysmal cold hemoglobinuria)

    D. Drug-dependent ab

    1. Autoimmune

    2. Haptene

    III

  • AIHA-Warm Ab

    Autoantibody: IgG,

    react at body temperature (370C)

    Pathophysiology

    1. Immune adherence

    : Ab+C` on RBC Fc Rc on phagocyte of RES

    2. Complement activation->RBC mb. destruction

  • Clinical ManifestationCommon in adults, women-25%: underlying disease affecting immune system-Presentation and course: variable anemia, spherocytosis, splenomegaly

    Evans syndrome: immune thrombocytopenia + im. Hem. anemia: separate antibodies against platelets and RBC

    AHA + ITP

  • Spherocytosis Loss of membrane Hereditary

    spherocytosis,

    immunehemolytic A.

    Morphology Cause Syndromes

    RBC Morphology in HA

  • Nature Reviews Rheumatology 8, 458-468 (August 2012)

  • Prednisone 40 mg/m2 (60-100 mg/d)

    7 days

    Response

    Folic acid (1-5 mg/d)

    Continue until normal ofHb & hematocrit

    Increase dose to60 mg/m2

    ResponseSlow dose reduction(6-8 wks)

    Hemolysis PRD maintenance10-20 mg/d

    Withdraw PRDin 3-6 ms (30%)

    splenectomy

    RemissionIVIG,

    yes no

    3 wksyes

    yes

    no

    no

    no

    no25-30%

    60-70%

    10-15%

    50-70%

    Transfusion: Hb < 4 g/dL or Sx(+) --- 0.5 1U PRC

    Treatment of AIHA

  • Prognosis

    1. In most patients, controlled by glucocorticoid, splenectomy or combination

    2. Fatal courses

    overwhelming hemolysis

    impared host defenses by steroid, splenectomy

    immunosuppressive agents

    rarely major thrombotic events may occur

  • AIHA-Cold Ab

    Cold reactive antibody

    -IgM, react at lower than 370C (0-100C)

    -monoclonal Ab: lymphocytic neoplasm, paraneoplasm

    -polyclonal Ab: infection

    transient cold agglutinin: Mycoplasma pn. infection,

    infectious mononucleosis

  • Specificity of Ab

    Anti-I : cold agglutinin reacting more strongly to adult RBC

    than fetal (cord) RBC

    : benign lymphoproliferation

    Anti-i : reacting more strongly with cord RBC

    : aggressive lymphoma and inf. mononucleosis

  • Clinical Manifestations

    -intravascular agglutination (acrocyanosis),

    -hemolysis d/t complement

    Diagnosis

    Direct Coombs test

    -IgM cold agglutin: low affinity for RBC memb. at 370C

    -C3: stable at 370C, C3

    IV

  • Morphology Cause Syndromes

    Agglutinated cells IgM ab (+) Cold agglutinin ds.

  • (Cold agglutinin test)

    -: At 00C, normal RBC pt plasmaplasma

    -: Mycoplasma pneumoniae , cold agglutinin

    -: Cold agglutinin autohemagglutinin 020(, 303

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