1. Cold Agglutinin Disease

2. Patient History
62 year old female who presented to clinic with a one month history of worsening fatigue and subjective fevers.

3. Physical Exam/Labs Jaundice and scleral icterus Labs: Date Hgb
Haptoglobin
LDH
TBili
CBili
10/30/13
6.1
1151
5.9
<8
847
4.9
0.4
10/31/13
5.7
717
3.9

4. Labs - Previous
4/2012
Presented with exertional fatigue, jaundice, and dark urine and laboratory evidence of hemolysis
Antibody screen (pre-warmed): negative
Antibody screen (room temperature): positive
Direct antiglobulin test (Coomb’s) was positive (+4) for complement fixation and negative for IgG
The cold agglutinin titer at 4C is 1:512.
The thermal amplitude is 30 C
The specificity of the cold agglutinin is anti I.

5. Labs- Previous
12/2012
Antibody screen was performed on prewarmed plamsa was negative
A cold agglutinin titer showed:
anti-I titer at 37 degrees C is 0
anti-I titer at 30 degrees C is 1:256
the anti-I titer at 4 degrees C is 1:32768
A DAT was perfomed and was positive for complement (4+) and negative for IgG.

6. Labs - Current Cold (IgM) antibody at a titer of 1:4096
The patient's blood type is B positive.
The reverse type is discrepant, likely due to high cold agglutinin titer.
Antibody screen was negative
A direct antiglobulin test (DAT) was negative for IgG and positive for complement (4+).

7. Cold Agglutinin Disease
15% of AIHAs
Usually presents in 7th decade of life, F>M
90% of cases - IgM antibodies react with RBC antigens at temperatures below core body temperature
IgM can span the distance between RBCs, thus producing in vitro agglutination

8. Diagnosis Signs/symptoms of hemolysis DAT: Titer and thermal activity
+C3d, - IgG (classically)
Both C3d and IgG in ~20%
Titer and thermal activity
>512 is clinically significant, but hemolysis can occur in lower titers

9. CAD, hemolysis Once IgM binds to RBC, complement activation occurs
C3b binds to cell surface in periphery RBC travels to body coreIgM dissociates
Can lead to extravascular or intravascular hemolysis
Can be polyclonal or monoclonal
Polyclonal – postinfectious (Mycoplasma, EBV, legionella)
Monoclonal – underlying lymphoproliferative d/o (clonal light chain predominance in 90%, trisomies 3, 12 and t(8:22); )

12. Monoclonal
Those that bind to the I/i antigens have heavy chains encoded by V4.34 gene segment
10% of all mature B cells use this gene segmentwhy normal subjects can have low-titers

13. Treatment Supportive Corticosteroids, cytotoxic agents, purine analogs
Rituximab
Plasmapheresis

14. References
Swiecicki PL, Hegerova LT, and Gertz MA. Cold Agglutinin Disease. BLOOD, 15 AUGUST 2013 x VOLUME 122, NUMBER 7
Gertz MA. Cold Hemolytic Syndrome. Hematology 2006