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When Selfies Go Bad!Decoding Autoantibodies and Autoimmune
Hemolytic Anemia
D. Joe Chaffin, MDJanuary 21, 2017
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Outline
• Background
• Warm autoantibodies and WAIHA
• Cold autoantibodies and CAD
• Paroxysmal Cold Hemoglobinuria
• Mixed Warm and Cold AIHA
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Note
• Hemolytic anemia categories:
- Autoimmune Hemolytic Anemia
- Alloimmune Hemolytic Anemia
- Drug-induced Hemolytic Anemia
Autoimmune:
Antibodies produced against substances
present in the person’s own body
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WAIHA CAD PCH Mixed
Frequency 70-80% 18% <2% Rare
Peak Age 60’s 60’s Children Older
DAT (poly) Positive Positive Us. Positive Positive
DAT (IgG) Pos (90%) Negative Negative Positive
DAT (C3) +/– Pos. (90%) Positive Positive
Antibody IgG IgM IgG IgG & IgM
Temp. 37oC 4oC 4oC 37oC 4-37oC
Target Rh-related I (rarely i) P Rh and I
TransfusionAuto/allo adsorp,
Matching
Autoadsorb,
prewarm
P-neg not
necessary
Avoid if possible;
As for WAIHA
CauseMalignancy,
Autoimmune, HIVLymphoprolif. d/o, Infx
Mono, Mycoplasma Viral infx, syphilis SLE, drugs
TreatmentBlock spleen (steroids,
drugs, surgery) Symptomatic Supportive Steroids
BBGuy AIHA Chart(inspired by D. Ambruso MD)
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Direct Antiglobulin Test
Credit: A. Rad 2006
Wash
DAT: In-vivo coating of RBCs
C
C
C
CC
C
C
C
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DAT Pos = AIHA
• VERY nonspecific
• 15+% of hospital pts have + DAT
• Only important with hemolysis
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Antibodies = AIHA
• WAAs not uncommon
• WAA + hemolysis IS uncommon!
• With evidence and +DAT, may mean AIHA
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Warm Autoantibodies
• React best at 37oC
• Almost always IgG
- Uncommonly IgA or IgM
• Ab binds but doesn’t fully fix complement
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Extravascular Hemolysis
Fc
Images courtesy Dr. Kristine Krafts (pathologystudent.com)
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Image courtesy Dr. Kristine Krafts (pathologystudent.com)
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WAIHA
• Older patients (7th-8th decade)
- 50% idiopathic / 50% secondary
✓Malignancies (esp. lymphoprolif)
✓Autoimmune disorders (SLE, RA)
✓May precede diagnosis (esp.
SLE)
✓HIV
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Why?
• Theories abound:
- Altered inflammatory pathways (decreased tolerance)
- Pathogens induce x-reacting Abs
- Immune complexes; RBCs bystanders
• NOT malignant clone from CLL/lymphoma
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DAT in WAIHA
• Pattern:
- Poly: 90+%
- IgG + C3: 67%
- IgG only: 20%
- C3 only 13%
DAT Polyspecific Anti-IgG Anti-C3
WAIHA POS POS NEG
Most common DAT result in WAIHA
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DAT in WAIHA
• DAT negative: Up to 10%
- Low antibody coating (<100/cell)
- Other antibodies (IgA, IgM)
DAT Polyspecific Anti-IgG Anti-C3
WAIHA NEG NEG NEG
DAT-negative result in WAIHA
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WAIHA Findings
• Pallor, weakness, fatigue, dyspnea
• Lab evidence of hemolysis:
• IgG antibody with broad reactivity
- May show “relative specificity”
✓Commonly e, c, or E
Bilirubin
LDH
Hemoglobin
Haptoglobin
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Things to Know
• Get on the phone!!!
- Has patient been transfused?
✓If yes, how long ago?
- Is transfusion necessary?
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Warm Auto AppearanceGenerally, ABO/RhD testing are fine, but…
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Warm Auto Appearance
1+ 1+
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Warm Auto ClinicalPossible appearance WITH Hemolysis
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Warm Auto ClinicalPossible appearance with NO Hemolysis
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Captain Obvious Says…
“They look exactly the same!”
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Elution
Not terribly helpful in most WAA workups
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The Big Question:
2+
2+
2+
2+
2+
0
0
0
0
0
0
If we get rid of THIS
Will we see THIS?
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Alloantibody Evaluation
• Dilution approach (Yikes!)
• Warm autoadsorption
• Allogeneic adsorption
• Phenotypically matched
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Dilution Approach (1:5)
• Dilute the auto-, leave the alloantibody
- Dangerous assumption!
• Unreliable (Leger/Garratty, Transf. 1999)
- 27% of alloabs missed
• Emergency strategy
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Alloantibody Evaluation
• Dilution approach (unreliable)
• Warm autoadsorption
• Allogeneic adsorption
• Phenotypically matched
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DAT 3+ Poly/IgG, No recent transfusions
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Warm Autoadsorption
Patient
Patient
Patient
AutoAb
AutoAb
AutoAb
AlloAb?
Patient
RBCs
“Adsorbed Serum”
1. Present?
2. What is it?
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Pre-adsorption
Post-adsorptionA
lloA
b?
1. Warm Autoantibody2. Allo-anti-K
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Ruling Out Alloantibodies
• Dilution approach (unreliable)
• Warm autoadsorption
• Allogeneic adsorption
• Phenotypically matched
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DAT 3+ Poly/IgG, Transfused 2 U RBC elsewhere last week
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Adsorption Problems
Patient
K+ RBC
Patient
K+ RBC
Patient
AutoAb
AutoAb
AutoAb
Anti-K
Recently
transfused
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Adsorption Problems
Patient
AutoAb
AutoAb
AutoAb
Anti-K
Severely
Anemic
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Allogeneic Adsorption
• Non-self RBCs of various phenotypes
Anti-K Anti-KK–
K–
K–
K–
K–
+
“Adsorbed Serum”
AutoAb
Classic series: R1R1, R2R2, rr (“triple adsorption”)
AutoAb
AutoAb An
ti-K
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Alloadsorption Issues
• Time and energy-intensive
• Choosing RBCs can be tough
• With high frequency antibody, may be impossible to get antigen-neg RBCs
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Ruling Out Alloantibodies
• Dilution approach (unreliable)
• Warm autoadsorption
• Allogeneic adsorption
• Phenotypically matched
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Phenotype Matching
• “What alloantibodies COULD this patient make?”
• Preventative and prophylactic
• Serologic (meh) vs molecular (yay)
- More on that shortly…
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Matching
• How far to go?
• WAA? 32% chance of alloimmunization
• Comparable to risk in sickle cell!
• These patients deserve special attention
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-Match all WAA for C, c, E, e, K, Jka, Jkb, Fya, Fyb, S, and s
-Accompanying editorial by Dr. Garratty (nice idea)
2002
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My Beliefs
Urgent patient need “trumps” all rules
Urgent patient need “trumps” all rules
No AlloantibodiesNo Alloantibodies
Full Phenotype or Genotype before TxFull Phenotype or
Genotype before Tx
Match for Rh and KMatch for Rh and K
AlloantibodiesAlloantibodiesMatch for
Rh, K, Jk, Fy, SsMatch for
Rh, K, Jk, Fy, Ss
Appropriate test for alloantibodies
Appropriate test for alloantibodies
-Ignore relatives
-Honor absolutes
-Avoid silly risk…
-Auto-anti-e in D neg
“Specificities”
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Let’s Talk About…
Least Incompatible!
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Even if you do it right…
1 3+
2 3+
3 2+
4 1+
BUT, is number 4
REALLY safer?
“And, doctor, we will choose the LEAST INCOMPATIBLE unit!”
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Talk to your Docs
• If not, you’re doing it wrong
• Huge gap in non-Heme-Onc docs
• Don’t bludgeon them with info
• “Appropriately tested blood”
• “Will my patient hemolyze the blood?”
• “Can I really give incompatible blood?”
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WAIHA Treatment
• “Block the Spleen”
- Corticosteroids
- Stronger immunosuppressants
- Splenectomy if necessary
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WAIHA CAD PCH Mixed
Frequency 70-80% 18% <2% Rare
Peak Age 60’s 60’s Children Older
DAT (poly) Positive Positive Us. Positive Positive
DAT (IgG) Pos (90%) Negative Negative Positive
DAT (C3) +/– Pos. (90%) Positive Positive
Antibody IgG IgM IgG IgG & IgM
Temp. 37oC 4oC 4oC 37oC 4-37oC
Target Rh-related I (rarely i) P Rh and I
TransfusionAuto/allo adsorp,
Matching
Autoadsorb,
prewarm
P-neg not
necessary
Avoid if possible;
As for WAIHA
CauseMalignancy,
Autoimmune, HIVLymphoprolif. d/o, Infx
Mono, Mycoplasma Viral infx, syphilis SLE, drugs
TreatmentBlock spleen (steroids,
drugs, surgery) Symptomatic Supportive Steroids
BBGuy AIHA Chart(inspired by D. Ambruso MD)
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Cold Autoantibodies
• Antibodies against self antigens that react best at 4oC (def. < 30oC)
• MUCH more common than WAA!
• Appearances matter!
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N 2 4 8 16 32 64 128 256 512102
4204
8409
6
37C 0 0 0 0 0 0 0 0 0 0 0 0 0
20C 1+ 0 0 0 0 0 0 0 0 0 0 0 0
4C 4+ 4+ 3+ 1+ 0 0 0 0 0 0 0 0 0
N 2 4 8 16 32 64 128 256 512102
4204
8409
6
37C 1+ 0 0 0 0 0 0 0 0 0 0 0 0
20C 2+ 2+ 1+ 1+ 1+ 1+ 0 0 0 0 0 0 0
4C 4+ 4+ 4+ 4+ 4+ 4+ 3+ 3+ 3+ 2+ 1+ 1+ 1+
Low Titer, Low Thermal Amplitude = Benign Cold Autoantibody
High Titer, High T.A = Pathologic Cold Autoantibody
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Cold Autoantibodies
• A real nuisance
• Cold “agglutinin” due to in-vitro effect
- Routine lab testing
- ABO discrepancies
• DAT+ with anti-C3 not anti-IgG
DAT Polyspecific Anti-IgG Anti-C3
POS NEG POS
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GlcNAcGal
GlcNAcGal
GlcNAcGal R
Type 2 chain
I product is enzyme
i
I
I i
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Dealing with CAAs
• Unhappy cold often happier warm
• Cold adsorption may be needed with stronger antibodies
- RESt
- Cold autoadsorption
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“What About Pre-
Warm?”• Reduces or eliminates reactions of
benign cold autoantibodies
- Can then detect alloantibodies
• BUT, it CAN make significant antibodies undetectable (e.g., anti-Vel)
• Only use if workup is thorough
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CAIHA
• Hemolysis with cold-reactive autoantibody
• Similar lab findings to WAIHA
- May see schistocytes
• Less common than WAIHA (18%)
• Types:
- Idiopathic
- Secondary
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Idiopathic CAIHA
• Older, female patients
• Chronic hemolysis worse in cold
- Extremity temp drops to 28oC!
• Antibody is IgM vs. I
• Transfusion: r/o allos; blood warmer
• Treat supportively (avoid cold, move to San Bernardino)
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Secondary AIHA
• Mycoplasma pneumonia infection
- IgM auto-anti-I (high titer)
- Intravascular hemolysis, substantial
- Resolves after infection
• Infectious mononucleosis
- IgM auto-anti-i (may be high titer)
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WAIHA CAD PCH Mixed
Frequency 70-80% 18% <2% Rare
Peak Age 60’s 60’s Children Older
DAT (poly) Positive Positive Us. Positive Positive
DAT (IgG) Pos (90%) Negative Negative Positive
DAT (C3) +/– Pos. (90%) Positive Positive
Antibody IgG IgM IgG IgG & IgM
Temp. 37oC 4oC 4oC 37oC 4-37oC
Target Rh-related I (rarely i) P Rh and I
TransfusionAuto/allo adsorp,
Matching
Autoadsorb,
prewarm
P-neg not
necessary
Avoid if possible;
As for WAIHA
CauseMalignancy,
Autoimmune, HIVLymphoprolif. d/o, Infx
Mono, Mycoplasma Viral infx, syphilis SLE, drugs
TreatmentBlock spleen (steroids,
drugs, surgery) Symptomatic Supportive Steroids
BBGuy AIHA Chart(inspired by D. Ambruso MD)
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PCH
• Paroxysmal Cold Hemoglobinuria
• Very uncommon (~2% of AIHA)
• Children post upper resp. infection
- Also viral exanthems, mono
• Acute severe intravascular hemolysis
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PCH Antibody
• Biphasic autoantibody (IgG) vs. P
- P antigen is very high frequency
- Biphasic:
✓Binds in cold
✓Hemolyzes in warm
• “Donath-Landsteiner biphasic hemolysin”
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P1PK/GLOB Systems
Pheno-type
P1 P Pk CaucasiansAfrican-
Americans
P1 + + – 79% 94%
P2 – + – 21% 6%
(little) p – – – rare rare
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Donath-Landsteiner
A: 4C to 37CB: 4C onlyC: 37C only
1: 10 ml patient serum2: 5 ml pt/5 ml fresh donor serum3: 10 ml fresh donor serum
Sanford KW and Roseff SD_Detection and significance of Donath-Landsteiner antibodies in a 5 year old female presenting with hemolytic anemia_Lab Medicine_0410
4 to 37 4 to 37 4 to 37 4 4 4 37 37 37
* *
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PCH
• Supportive treatment
• Transfusion often IS necessary…
• Uh-oh! What about P?
- P-neg blood extremely rare!
- P-pos RBCs usually survive well
- Consider plasma exchange if not
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WAIHA CAD PCH Mixed
Frequency 70-80% 18% <2% Rare
Peak Age 60’s 60’s Children Older
DAT (poly) Positive Positive Us. Positive Positive
DAT (IgG) Pos (90%) Negative Negative Positive
DAT (C3) +/– Pos. (90%) Positive Positive
Antibody IgG IgM IgG IgG & IgM
Temp. 37oC 4oC 4oC 37oC 4-37oC
Target Rh-related I (rarely i) P Rh and I
TransfusionAuto/allo adsorp,
Matching
Autoadsorb,
prewarm
P-neg not
necessary
Avoid if possible;
As for WAIHA
CauseMalignancy,
Autoimmune, HIVLymphoprolif. d/o, Infx
Mono, Mycoplasma Viral infx, syphilis SLE, drugs
TreatmentBlock spleen (steroids,
drugs, surgery) Symptomatic Supportive Steroids
BBGuy AIHA Chart(inspired by D. Ambruso MD)
![Page 65: When Selfies Go Bad! · WAIHA CAD PCH Mixed Frequency 70-80% 18%](https://reader034.vdocuments.net/reader034/viewer/2022050114/5f4b4638aaa2945f4a38c557/html5/thumbnails/65.jpg)
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Mixed AIHA
• Garratty: “WAIHA associated with IgM autoantibodies”
• Presence of IgM and IgG classic
• Severe hemolysis, with IgM mediated intravascular hemolysis
• May present with VERY low HGB
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Mixed AIHA
• Thankfully, often responds dramatically to corticosteroids
• Avoid transfusion if possible
- If needed, must use special techniques to r/o alloantibodies
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WAIHA CAD PCH Mixed
Frequency 70-80% 18% <2% Rare
Peak Age 60’s 60’s Children Older
DAT (poly) Positive Positive Us. Positive Positive
DAT (IgG) Pos (90%) Negative Negative Positive
DAT (C3) +/– Pos. (90%) Positive Positive
Antibody IgG IgM IgG IgG & IgM
Temp. 37oC 4oC 4oC 37oC 4-37oC
Target Rh-related I (rarely i) P Rh and I
TransfusionAuto/allo adsorp,
Matching
Autoadsorb,
prewarm
P-neg not
necessary
Avoid if possible;
As for WAIHA
CauseMalignancy,
Autoimmune, HIVLymphoprolif. d/o, Infx
Mono, Mycoplasma Viral infx, syphilis SLE, drugs
TreatmentBlock spleen (steroids,
drugs, surgery) Symptomatic Supportive Steroids
BBGuy AIHA Chart(inspired by D. Ambruso MD)
![Page 70: When Selfies Go Bad! · WAIHA CAD PCH Mixed Frequency 70-80% 18%](https://reader034.vdocuments.net/reader034/viewer/2022050114/5f4b4638aaa2945f4a38c557/html5/thumbnails/70.jpg)
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Take Homes
• CAA (IgM) >> WAA (IgG)
• WAIHA >> CAIHA
• Transfusion generally safe in WAIHA
• Always rule out alloantibodies
• “Least incompatible” is not a strategy
• Block spleen for WAIHA, not CAIHA
• PCH: Biphasic IgG auto-anti-P
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Thanks!