When Selfies Go Bad! · WAIHA CAD PCH Mixed Frequency 70-80% 18%

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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)


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)




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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





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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





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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










Matching

Autoadsorb,

prewarm

P-neg not

necessary

Avoid if possible;

As for WAIHA

CauseMalignancy,






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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


POS NEG POS

www.bbguy.org Images courtesy Dr. Kristine Krafts (pathologystudent.com)

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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










Matching

Autoadsorb,

prewarm

P-neg not

necessary

Avoid if possible;

As for WAIHA

CauseMalignancy,






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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










Matching

Autoadsorb,

prewarm

P-neg not

necessary

Avoid if possible;

As for WAIHA

CauseMalignancy,






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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










Matching

Autoadsorb,

prewarm

P-neg not

necessary

Avoid if possible;

As for WAIHA

CauseMalignancy,






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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!

Documents

When Selfies Go Bad! · WAIHA CAD PCH Mixed Frequency 70-80% 18%