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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