Transcript Ina AIHA
AUTOIMMUNE HAEMOLYTIC
ANAEMIA
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
PATHOGENESIS
•Degree of haemolysis depends on :
1.
Characteristic of antibodyquantity
specificity
T
ability to fix C
ability to bind to tissue machrophage.
2. target ag –
density
expression
age of pt
cont
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
cont
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
cont
REC
have receptor for rbc bound C3b
and iC3b resulting fr C activation
Spleen – site for Ig G ass e/v hemolysis
Liver (kupper cell) – site for Ig M ass e/v
CLASSIFICATION OF AIHA
1.
1.
1.
1.
Warm AIHA
Idiopathic
Secondary (LPD, A/ Immune)
Cold AIHA
Cold Agglutinin syndrome
PCH
Mixed AIHA
Idiopathic
secondary
Drug induced
Autoimmune type
Drug adsorption type
Neoantigen type
cont
Classification
according to T reactivity of
a/b
Warm react strongly near 37 c
Cold bind rbc strongly near 0-4 c
d/o – about half of
cases of secondary cold and warm AIHA
Idiopathic more in female, peak at 4 and 5
decade
Lymphoproliferative
LAB EVALUATION
criteria to dx AIHA – serologic
evidence and clinical or lab evidence
2
WARM AIHA
Intro
48% - 70% of AIHA
incidence increase around 40 y/o
children peak incidence at first 4 years
of life
cont
variable clinical presentation
fulminant hemolysis – jaundice, pallor, edema,
dark urine, hepatosplenomrgaly
pregnancy – 5x risk of dev auto a/b
Lab 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.
WBC – mild leucocytosis
FBP – Polychromasis, macrocytosis, NRBC
Erythrophagocytosis, microspherocytes – a/I
hemolysis
BM – erythriod hyperplasis,
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.
DAT – neg in small percentage
A/b – in lower quantity than the detectable
threshold Ig A or Ig M
Warm auto a/b - panagglutination
cont
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.
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
–
Treatment
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.
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.
IVIG
Danazol, vincristine
PC transfusion
o Limited to life threatening anaemia
o Least incompatible
o Slow infusion
cont
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
(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 Evaluation
FBP – rbc clumping, polychromasia,
anisopoikilocytosis, occ spherocytes
MCV – increase
HB, HCT – mildly reduced
Retic – mildly increased
cont
• 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
cont
Pathological cold – large thermal amplitude with
high titre ( > 1: 1000 at o-4 c)
Primary CAS and CAS 2 t0 LPD has higher titre
Pathophysiology
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
cont
C cascade progress to MAC—i/v hemolysis
Rbc bound C3d – E/V hemolysis
90% directed to I ag and remaining to i. Ag
Treatment
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
cont
pc transfusion should be limited d/t 2 reason
o least incompatible have higher risk if contain
undetected allo a/b
o most cold directed toward I ag, I ag neg donor –
extremely rare
o exogenous donor plasma can exacerbate
hemolysis
cont
wash rbc – reduced exogenous C load
use in line blood warmer
keep pt warm
PCH
Intro
un common
2-10% of AIHA
acute cases predom in children, secondary to
infection
clinically presented with constitutional sx,
hemoglobinuria, cold urticaria and raynoud’s
phenomenon
Lab Evaluation
HCT,Hb – low
Reticulocytopenia in acute phase later
reticulocytosis
FBP – agglutination, polychromasia, NRBC,
Spherocytes, erythrophagocytosis
Increased IB ,LDH
cont
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)
cont
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 AIHA
Intro
~Idiopathic or secondary to LPD or SLE
~Some pt with warm AIHA also possess cold
agglutinin but not clinically significant
Lab 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 AIHA
Intro
Produced hemolysis by immune or non immune
mechanism
3 mech
~ induction of auto a/b
~ neoantigen ( i/c formation)
~ drug adsorption auto rbc
cont
Neoantigen formation
~ Drug bind weakly to normal rbc
~ Immune system perceive drug and rbc complex or
conformational altered rbc as foreign
cont
Drug adsorption
~Drug strongly bound to rbc
~A/b directed against the drug interact
with rbc
Lab 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
cont
drug induced IHA – serum and eluate a/b react
with rbc panel even if drug absent
Methyldopa
o Induce auto a/b
o Positive DAT 11%-36% of pt within 3-6
month of initiation
o Positive DAT d/t bound Ig G
cont
Other drugs : lenodopa, mefenamic, diclofenac etc
Treatment
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 AIHA
Ig type
DAT
Rbc eluate Specificity
Warm
Ig G
(+A/M)
Ig G+/M
Ig G
Panreactiv
e
CAS
Ig M
C3
NR
I>i>>Pr
PCH
Ig G
C3
NR
P
Mixed
Ig G,M
Ig G = C3
Ig G
Panreactiv
e
Drug
Ig G
Ig +/C3
Ig G
Often Rh
related
Thank You