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A brief look at the various types
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IMMUNE HAEMOLYTIC ANAEMIAS
Dr Brian Mitchelson
IMMUNE HAEMOLYTIC ANAEMIAGeneral Principles
All require antigen-antibody reactions
Types of reactions dependent on:– Availability of complement
– Environmental Temperature
– Functional status of reticuloendothelial system
Manifestations– Intravascular haemolysis
– Extravascular haemolysis
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IMMUNE HAEMOLYTIC ANAEMIAGeneral Principles - 2
Antibodies combine with RBC, and either:
1. Activate complement cascade, &/or
2. Opsonize RBC for immune system
If 1: if all of complement cascade is fixed to red cell, intravascular cell lysis occurs
If 2: &/or if complement is only partially fixed, macrophages recognize Fc receptor of Ig &/or C3b of complement & phagocytize RBC, causing extravascular RBC destruction
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IMMUNE HAEMOLYTIC ANAEMIACoombs Test - Direct
Looks for immunoglobulin &/or complement of
surface of red blood cell (normally neither found
on RBC surface)
Coombs reagent - combination of anti-human
immunoglobulin & anti-human complement
Mixed with patient’s red cells; if immunoglobulin or
complement are on surface, Coombs reagent will
link cells together and cause agglutination of
RBCs
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IMMUNE HAEMOLYTIC ANAEMIACoombs Test - Indirect
Looks for anti-red blood cell antibodies in the patient’s serum, using a panel of red cells with known surface antigens
Combine patient’s serum with cells from a panel of RBC’s with known antigens
Add Coombs’ reagent to this mixture
If anti-RBC antigens are in serum, agglutination occurs
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HAEMOLYTIC ANAEMIA - IMMUNE
Autoimmune Haemolysis -2 types:
– Warm autoimmune haemolysis
– Cold autoimmune haemolysis
Alloimmune Haemolysis
– Haemolytic Transfusion Reaction
– Haemolytic Disease of the Newborn
Drug-Related Haemolysis
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Autoimmune Haemolytic Anaemia
(AHA)
Autoimmune haemolytic anaemia (AHA)
is characterized by shortened red blood
cell (RBC) survival and the presence of
autoantibodies directed against
autologous RBCs.
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AUTOIMMUNE HAEMOLYSIS
Due to formation of autoantibodies that
attack patient’s own RBC’s
Type characterized by ability of
autoantibodies to fix complement & site of
RBC destruction
Often associated with either
lymphoproliferative disease or collagen
vascular disease
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Autoimmune Haemolytic Anaemia
Classified by thermal reactivity – Warm reacts near 37 o C, Cold at 0-4 o C
Serologic evidence is positive DAT (direct Coomb’s test) with IgG or C3d present
Indirect Coomb’s test and specificity (serum / eluate)
Diagnostic Criteria-– serologic evidence and laboratory or clinical haemolysis
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AIHA Classification
Warm autoimmune haemolytic anaemia– Idiopathic, Secondary
• (Lymphoproliferative disorders, autoimmune diseases)
Cold autoimmune haemolytic anaemia– Cold agglutinin syndrome
• (Idiopathic, Secondary- mycoplasma, infectious mono, LPD)
– Paroxysmal cold haemoglobinuria• (Idiopathic, Secondary- measles, mumps, syphilis)
Drug-induced IHA – (Autoimmune, Drug adsorption, Neoantigen)
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AUTOIMMUNE HAEMOLYSISWarm Type
Usually IgG antibodies
Fix complement only to level of C3,if at all
Immunoglobulin binding occurs at all temps
Fc receptors/C3b recognized by macrophages
Haemolysis primarily extravascular
70% associated with other illnesses
Responsive to steroids/splenectomy
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Diagnosis
Anaemia.
Spherocytes in peripheral blood film.
Reticulocytes are increased.
Neutrophilia common.
RBC coated with IgG, complement or both
(detect using DAT).
Autoantibody —often pan-reacting but specificity
in 10–15% (Rh: mainly anti-e, anti-D or anti-c).
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Diagnosis
LDH increased.
Serum haptoglobin decreased.
Exclude underlying lymphoma (BM, blood
and marrow cell markers).
Autoimmune profile—to exclude SLE or
other connective tissue disorder.
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AUTOIMMUNE HAEMOLYSISCold Type
Most commonly IgM mediated
Antibodies bind best at 30º or lower
Fix entire complement cascade
Leads to formation of membrane attack complex, which leads to RBC lysis in vasculature
90% associated with other illnesses
Poorly responsive to steroids, splenectomy
Responsive to plasmapheresis
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Diagnosis
Anaemia.
Reticulocytes are increased.
Neutrophilia common.
Positive DAT—C3 only.
± Autoantibodies —IgG or IgM
– Monoclonal in NHL.
– Polyclonal in infection-related CHAD.
IgM antibodies react best at 4°C (thermal amplitude 4–
32°C).
Specificity
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Diagnosis
Anti-I (Mycoplasma).
Anti-i (infectious mononucleosis)—causes little
haemolysis in adults
Since RBCs have little anti-i (cf. newborn i >> I).
LDH increased.
Serum haptoglobin decreased.
Exclude underlying lymphoma (BM, blood and marrow
cell markers).
Autoimmune profile to exclude SLE or other connective
tissue disorder.
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IMMUNE HAEMOLYSISDrug-Related
Immune Complex Mechanism
– Quinidine, Quinine, Isoniazid
“Haptenic” Immune Mechanism
– Penicillins, Cephalosporins
True Autoimmune Mechanism
– Methyldopa, L-DOPA, Procaineamide,
Ibuprofen
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DRUG-INDUCED HAEMOLYSISImmune Complex Mechanism
Drug & antibody bind in the plasma
Immune complexes either– Sit on red blood cell
Antigen-antibody complex recognized by RE system
Red cells lysed as “innocent bystander” of destruction of immune complex
REQUIRES DRUG IN SYSTEM
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DRUG-INDUCED HAEMOLYSISHaptenic Mechanism
Drug binds to & reacts with red cell
surface proteins
Antibodies recognize altered protein, ±drug, as foreign
Antibodies bind to altered protein & initiate
process leading to hemolysis
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DRUG-INDUCED HAEMOLYSISTrue Autoantibody Formation
Certain drugs appear to cause antibodies
that react with antigens normally found on
RBC surface, and do so even in the
absence of the drug
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Drug-Induced Autoimmune
Haemolytic Anaemia
Prototype Drugs Clinical Findings Detection of
Drug-Induced
Antibody
Proposed
Mechanism
Stibophen Acute
Intravascular
Haemolysis
Serum +
Drug + Red Cells
Neoantigen
Penicillins/
Cephalosporin
Subacute
Extravascular
Haemolysis
Serum + Drug-
Coated Red Cells
Drug Adsorption
α-methyldopa Warm antibody
autoimmune
haemolytic
anaemia
Serum + Normal
Red Cells
Autoimmune
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Drug-Induced Positive Antiglobulin Tests
Mechanism DAT Serum and Eluate
Neoantigen
-Drug +RBC complex
C3 (sometimes IgG also) Serum reacts with rbcs
only in the presence of
drug; eluate non-reactive
Drug Adsorption (DA)
-Drug binds to RBC
IgG (sometimes C3 also) React with drug-coated
RBCs but not untreated
RBCs- Ab to drug
Autoantibodies
-WAIHA
IgG (rarely C3 also)
11-36% of pts
React with normal RBCs in
absence of drug
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Treatment - AIHA
WAIHA CAD PCH Drug-IHA
Folate
Corticosteroids
20% complete
response
Folate
Avoid cold
Treat secondary cause
Folate
Avoid cold
Treat if haemolysis
present
Splenectomy
60-75% response rate
Chlorambucil
Cytoxan,
α-Interferon
Treat infection Folate
Stop drugs
Cytotoxic drugs-
Cytoxan, Rituxan
Plasmapheresis ? Plasmapheresis Corticosteroids-severe
cases
Transfuse –least
incompatible
Transfuse-I+, blood
warmer
Transfuse- P+, blood
warmer
Transfuse
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ALLOIMUNE HAEMOLYSISHaemolytic Transfusion Reaction
Caused by recognition of foreign antigens on transfused blood cells
Several types– Immediate Intravascular Haemolysis (Minutes) - Due to
preformed antibodies; life-threatening
– Slow extravascular haemolysis (Days) - Usually due to repeat exposure to a foreign antigen to which there was a previous exposure; usually only mild symptoms
– Delayed sensitization - (Weeks) - Usually due to 1st exposure to foreign antigen; asymptomatic
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ALLOIMMUNE HAEMOLYSISTesting Pre-transfusion
ABO & Rh Type of both donor & recipient
Antibody Screen of Donor & Recipient,
including indirect Coombs
Major cross-match by same procedure
(recipient serum & donor red cells)
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Manifestations of Delayed
Haemolytic Transfusion ReactionsClinical
– Fevers
– Chills
– Symptoms of anaemia
– Jaundice
– Oliguria or anuria (uncommon)
– Generalized Bleeding (Rare)
Laboratory
– Unexplained anaemia (or decrease in haemoglobin)
– Positive direct antiglobulin test
– Haemoglobinemia
– Haemoglobinuria (Uncommon)
– Haemosiderinuria
– Decreased haptoglobin
– Responsible antibody in post-transfusion RBC eluate
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ALLOIMMUNE HAEMOLYSISHaemolytic Disease of the Newborn
Due to incompatibility between mother negative
for an antigen & foetus/father positive for that
antigen.
Rh incompatibility, ABO incompatibility most
common causes
Usually occurs with 2nd or later pregnancies
Requires maternal IgG antibodies vs. RBC
antigens in foetus
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HYDROPS FETALIS
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ALLOIMMUNE HAEMOLYSISHaemolytic Disease of the Newborn - #2
Can cause severe anaemia in foetus, with
erythroblastosis and heart failure
Hyperbilirubinaemia can lead to severe brain
damage (kernicterus) if not promptly treated
HDN due to Rh incompatibility can be almost
totally prevented by administration of anti-Rh D
to Rh negative mothers after each pregnancy
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The EndThank you for your attention.
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