AUTOIMMUNE HAEMOLYTIC ANAEMIA American Journal of Hematology 69:258-271 (2002) Bradley C. Gehrs and Richard C. Friedberg University of Alabama, Birmingham.

AUTOIMMUNE HAEMOLYTIC AUTOIMMUNE HAEMOLYTIC ANAEMIAANAEMIA

American Journal of Hematology

69:258-271 (2002)

Bradley C. Gehrs and Richard C. Friedberg

University of Alabama, Birmingham

INTRODUCTION

•Ig G and/or Ig M bind to rbc surface ag – initiate rbc destruction via C system and RES

•IHA – classification – autoimmune, alloimmune, drug induced

•AIHA – a/b directed against self rbc

cont

•AIHA – incidence 1-3 cases/100,000 per year

•Auto a/b usually reacted against high frequency ag – exhibit reactivity against allogeneic rbc as well

•Degree of haemolysis depends on :

1.      Characteristic of antibody- quantityspecificity Tability to fix C

ability to bind to tissue machrophage.

PATHOGENESIS

2.      target ag – densityexpressionage of pt

contcont

  Ig G a poor activator for classical C p/way

  Generally Ig G sensitized rbc are eliminated by phagocyte of RES

  RES also have receptor for C3b and iC3b – can potentiate e/v hemolysis

  Ig M -- sensitized rbc ass with e/v and i/v hemolysis

contcont

  I/v – Ig M readily activated by classical C p/way

  Regulatory rbc protein DAF and MIRL – overwhelming C activation is req. to produce clinically evident i/v hemolysis

  More common Ig M sensitized rbc u/go e/v hemolysis

contcont

REC have receptor for rbc bound C3b and iC3b resulting fr C activationSpleen – site for Ig G ass e/v hemolysisLiver (kupper cell) – site for Ig M ass e/v

CLASSIFICATION OF AIHA

1. Warm AIHA Idiopathic Secondary (LPD, A/ Immune)

1. Cold AIHA Cold Agglutinin syndrome PCH

1. Mixed AIHA Idiopathic secondary

1. Drug induced Autoimmune type Drug adsorption type Neoantigen type

contcontClassification according to T reactivity of a/bWarm react strongly near 37 cCold bind rbc strongly near 0-4 c

Lymphoproliferative d/o – about half of cases of secondary cold and warm AIHAIdiopathic more in female, peak at 4 and 5 decade

LAB EVALUATIONLAB EVALUATION

2 criteria to dx AIHA – serologic evidence and clinical or lab evidence

WARM AIHAWARM AIHA

Intro

     48% - 70% of AIHA

     incidence increase around 40 y/o

     children peak incidence at first 4 years of life

contcont

    variable clinical presentation     fulminant hemolysis – jaundice, pallor, edema,

dark urine, hepatosplenomrgaly      pregnancy – 5x risk of dev auto a/b

Lab EvaluationLab Evaluation

Hb, HCT – N in pt with indolent hemolysis

Low in pt wt fulminant hem. Reticulocytosis Reticulocytopenia – early in d/o, secondary to a/I

d/o, inadequate BM response

Cont.Cont.

WBC – mild leucocytosis FBP – Polychromasis, macrocytosis, NRBC

Erythrophagocytosis, microspherocytes – a/I hemolysis

BM – erythriod hyperplasis,

Cont.Cont.

IB – increase LDH – Increased Se haptoglobin – reduced Positive urine Hb and hemosiderin DAT – positive in 95% cases of WAIHA

Ig G (20-66%

Ig G + C3 (24 – 63%)

C3 ( 7-14%)

Cont.Cont.

DAT – neg in small percentage

A/b – in lower quantity than the detectable threshold Ig A or Ig M

Warm auto a/b - panagglutination

contcont

Risk of hemolysis:     Presence of bound Ig G1, Ig G3

     Presence of concomitantly bound Ig A and/or Ig M

     Quality of bound rbc auto a/b

     Strength of DAT

Cont.Cont.

     Quantity of bound C

     Characteristic of boubd rbc ag

     Affinity of auto a/b to these ag

     No of Ig G fc and c receptor on machrophage

     Functional status of phagocyte system–  

TreatmentTreatment

If Bm can compensate – monitor Anaemia develop – steroids – first line of tx.

70 – 80% improve within 3 mo Splenectomy –fail steroid, second line of tx

Removal primary site of e/v hem and site of a/b production. Response rate 60 – 75%

Cont.Cont.

Cytotoxic drug - fail steroid and splenectomy

Response rate 40 – 60% Recently reported cases fail to steroid and chemo

response to Rituximab ( anti CD 20) Plasma pheresis benefit in fulminant hemolysis

Cont.Cont.

IVIG Danazol, vincristine PC transfusion

o Limited to life threatening anaemiao Least incompatibleo Slow infusion

contcont

Donor rbs are destroyed at same rate as auto rbc Exhibit specificity – ag neg unit should be

transfused Transfusion may induce further auto a/b formation

COLD AGGLITININ SYNDROME COLD AGGLITININ SYNDROME (CAS)(CAS)

Intro• 16 – 32% of AIHA• primary – older, peak incidence 70 y/o, >

female• secondary – lymphoproliferative and inf

cold env may exacerbate the condition pt may present with acryocyanosis, raynoud’s

phenomenon

Lab EvaluationLab Evaluation

FBP – rbc clumping, polychromasia, anisopoikilocytosis, occ spherocytes

MCV – increase HB, HCT – mildly reduced Retic – mildly increased

contcont

• IB,LDH – increased• Reduced se haptoglobin with

hemoglobinuria – in severe exacerbation• DAT – positive for C3 and neg for Ig G• Majority of auto a/b are benign

contcont

Pathological cold – large thermal amplitude with high titre ( > 1: 1000 at o-4 c)

Primary CAS and CAS 2 t0 LPD has higher titre

PathophysiologyPathophysiology

Ig M auto a/b fix C1 – then initiate C cascade Warmer T ( at central circulation) – maximize C

fixation and activation – facilitate hemolysis Dissociate cold agglutinin and allow them to bind

back to rbc and rpt the cycle

contcont

C cascade progress to MAC—i/v hemolysis Rbc bound C3d – E/V hemolysis 90% directed to I ag and remaining to i. Ag

TreatmentTreatment

avoid cold T and tx primary ds severe hemolysis- immunosupressant steroid – rarely helpful for CAS splenectomy only benefit for pt wt Ig G cold

agglutinin plasma pheresis severe hemolysis

contcont

pc transfusion should be limited d/t 2 reasono least incompatible have higher risk if contain

undetected allo a/bo most cold directed toward I ag, I ag neg donor –

extremely rareo exogenous donor plasma can exacerbate

hemolysis

contcont

wash rbc – reduced exogenous C load use in line blood warmer keep pt warm

PCHPCH

Introun common2-10% of AIHAacute cases predom in children, secondary to

infectionclinically presented with constitutional sx,

hemoglobinuria, cold urticaria and raynoud’s phenomenon

Lab EvaluationLab Evaluation

HCT,Hb – low Reticulocytopenia in acute phase later

reticulocytosis FBP – agglutination, polychromasia, NRBC,

Spherocytes, erythrophagocytosis Increased IB ,LDH

contcont

Reduced se Haptoglobin Positive urine HB, hemosiderinuria ARF PCH – caused by biphasic Ig G auto a/b ( fix C at

cold T and dissociate at higher T) ( Donath Landsteiner a/b)

contcont

A/b are potent , small titre can cause hemolysis DAT – positive anti C3 , Ig G positive if

performed at cold T Biphasic Ig G exhibit specificity against P ag DL test to detect biphasic auto a/b

MIXED TYPE AIHAMIXED TYPE AIHA

Intro 

~Idiopathic or secondary to LPD or SLE

~Some pt with warm AIHA also possess cold agglutinin but not clinically significant

Lab EvaluationLab Evaluation

DAT positive IgG,C3 Rbc eluate – panreactive warm Ig G auto a/b. Cold auto a/b usually exhibit specificity against I

ag

DRUG INDUCED AIHADRUG INDUCED AIHA

IntroIntro

Produced hemolysis by immune or non immune mechanism

3 mech

~ induction of auto a/b

~ neoantigen ( i/c formation)

~ drug adsorption auto rbc

contcont

Neoantigen formation

~ Drug bind weakly to normal rbc

~ Immune system perceive drug and rbc complex or conformational altered rbc as foreign

contcont

Drug adsorption

~Drug strongly bound to rbc

~A/b directed against the drug interact with rbc

Lab EvaluationLab Evaluation

3 mech can be distinguished from the reaction of serum and eluate

drug induced IHA 2 neoag formation or drugb adsorption has positive DAT

require exogenous drug to detect the a/b

contcont

drug induced IHA – serum and eluate a/b react with rbc panel even if drug absent

Methyldopao Induce auto a/bo Positive DAT 11%-36% of pt within 3-6

month of initiationo Positive DAT d/t bound Ig G

contcont

Other drugs : lenodopa, mefenamic, diclofenac etc

TreatmentTreatment  

Auto a/b result in hemolysis anaemia < 1% Positive DAT alone is not indicated to stop the

drugs If significant hemolysis – stop the drugs

SEROLOGIC CHARACTERISTIC OF AIHASEROLOGIC CHARACTERISTIC OF AIHA

Ig type DAT Rbc eluate Specificity

Warm Ig G (+A/M)

Ig G+/M Ig G Panreactive

CAS Ig M C3 NR I>i>>Pr

PCH Ig G C3 NR P

Mixed Ig G,M Ig G = C3 Ig G Panreactive

Drug Ig G Ig +/C3 Ig G Often Rh related

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