Autoimmune hemolytic anemiaKaipol Takpradit

Topic

PathophysiologyPresentationTreatment

AIHA pathophysiology

● Caused by autoantibody to self RBC● Divided into

○ Primary AIHA: without obvious cause○ Secondary AIHA: precipitated by some

condition■ mainstay of treatment is removal of etiology

IgG autoantibody

● Bind to RBC and cause hemophagocytosis in spleen

● Partial phagocytosis render RBC loss its membrane and produce microspherocyte

IgM autoantibody

● Fix complement on RBC cause intravascular hemolysis

● After fixation and lysis, C3b also cause destruction of RBC in liver (Kupffer cells)

Cause of secondary AIHA

● Drug: penicillin, fludarabine, methyldopa● Infection: mycoplasma● Tumor: lymphoma, ovarian dermal cyst,

renal CA● Other autoimmune disease: SLE

Antibody in AIHA

● Warm type○ increase activity when near 37 c○ usually IgG

● Cold type○ increase activity when near 4c○ usually IgM○ cause auto-agglutination○ fixed complement

● Mixed type

Agglutination in AIHA

IgM antibody can cause auto-agglutination due to its large size

While IgG need Coomb reagent to extend its size

Coomb test

● Coomb reagent is anti-human Fc portion of IgG immunoglobulin derived from rabbit

● Also called antiglobulin test

Coomb test

● Most commercial Coomb reagent is comprised of polyspecific antiglobulin antibody

● Monospecific antibody for IgG, C3d, etc. are available to identify type of AIHA

Coomb test

Coomb test

● Direct antiglobulin test (DAT)○ detect IgG attached on patient's RBC○ use in AIHA

● Indirect antiglobulin test (IAT)○ detect IgG in patient's serum○ the IgG must be lured to attach to control

RBC before perform DAT on the control RBC○ use in cross-matching

Coomb test false positivity

● Poor technique (over centrifuged, dirty test tube)

● Septicemia● Drug induced non specific protein

adsorption (cephalosporin, clavulanic acid)

● Wharton's jelly (non-specific adsorption)● High paraproteinemia● Alloantibody from transfused plasma

Coomb test false negativity

● Poor technique (incubation, cell washing, centrifusion)

● IgA, IgM autoantibody● Low-affinity antibody● Too few antibody presence● Prozone reaction from unlicensed product

(too many target antigen)● Forget to apply antiglobulin reagent

Guideline for Coomb positivity

Wintrobe's ed. 12th

Presentation of AIHA

● Acute anemia● Increased reticulocyte count● May have jaundice (indirect

hyperbilirubinemia; rarely > 5 mg/dL)● Hepatosplenomegaly and

lymphadenopathy may present● Other symptoms include edema, dark

urine, dizziness, confusion,

Other associated disease

Should aware of..● Thrombocytopenia -> Evans syndrome● Other autoimmune feature -> SLE● Markedly large splenomegaly or

lymphadenopathy may indicate NHL● Recently used drugs● Patient may have increased risk of VTE

especially in association with lupus anticoagulant or S/P splenectomy

Treatment of AIHA

● There is conflicting goal of treatment of AIHA

● Generally accepted aim of treatment is Hb 10/dL

● Treatment goal must be weighted with their side effect and cost

Treatment of warm/mixed type AIHAFirst line therapy is steroid● Prednisolone 1 mkd (Pred)● CR is achieved if Hb > 10 g/dL● After CR reduce Pred by 50% (to 20-30

mg/day)● Then reduce by 2.5-5 mg/day every

month● Continue Pred 5 mg/day for 3-4 month

then stop if can remain in CR

Treatment of warm/mixed type AIHA

Supportive treatment● Folate supplement● Antacid● Calcium supplement● Vitamin D supplement● Bisphosphonate● Monitor blood sugar (2-3 wk after Pred)● Aware of VTE especially in association with

lupus anticoagulant or S/P splenectomy

Second line treatment

Indicate if● Can not maintain acceptable Hb level● Required Pred more than 15 mg/d● Required Pred between 5-15 mg /d may

indicate second line treatment

Second line treatment

● Splenectomy○ Response 38-82% (around 2/3)○ Long term response vary around 50%○ Pneumococcal vaccine is required 2 wk

before procedure and every 5 years● Rituximab

○ Off label use○ Dose 375 mg/m2 weekly x 4 doses○ Response about 82%○ But seem to relapse in 1 -3 years

Other second line therapy

● Azathioprine● Cyclophosphamide● Cyclosporine● Mycophenolate mofetil● Danazol

All treatment may be combined with low dose steroid (Pred < 15 mg/day)

Treatment of cold type AIHA

● In most case associated with lymphoproliferative disease

● Less common ass. with autoimmune, infection, drugs (rarely)

Primary chronic cold agglutinin disease (PAD)● Have IgM monoclonal gammopathy or

lymphoma in marrow without overt clinical sign

● Anemia is mild● Treatment is usually not required● Usually steroid and splenectomy resistant● Most evidence of response are from

rituximab, though only in PR

Treatment of secondary AIHA

● SLE○ Treatment is the same as primary AIHA

● CLL○ Pred is the first-line (also in fludarabine asso.) ○ In active CLL case add chemo (chlorambucil,

R-CVP, etc.)○ In refractory case rituximab and splenectomy

are indicated● NHL

○ Treatment of NHL give a sustained response

FIN