A 59-year-old woman presented with new-onset jaundice and anemia 10 days after undergoing surgery for uterine cancer. Laboratory workup found evidence of hemolysis including a positive direct Coombs test. Further testing revealed the patient's red blood cells were sensitizied to the antibiotic cefotetan, indicating drug-induced immune hemolytic anemia. She was treated with transfusions and the hemolysis resolved after discontinuing the offending drug. Drug-induced immune hemolytic anemia is a rare but serious complication that can be triggered by certain antibiotics like cefotetan through non-immune or immune mediated mechanisms.

1. Case DT:
“I’m turning yellow…”
October 8, 2015
Neha Mehta-Shah
Fellow, Department of Medicine
Memorial Sloan Kettering Cancer Center

2. Case DT
CC: Anemia
• 59 yo with recently diagnosed uterine serous cancer s/p robotically assisted
TAH/BSO, sentinel LN mapping and omental biopsy (POD 14)
• POD #2: discharged
• POD #10: notes dark urine and yellowing of her eyes

3. Case DT
PMH:
- Breast Cancer (stage II,T1cN1Mx ER+,
PR+, Her2 Neg; 2007;CMF completed
tamoxifenletrozole 2013),
- uterine CA
PSH: Bilateral Mastectomy with
Reconstruction (9/2007),
bunionectomy, ORIF
Medications: Lexapro 10mg, oxycodone
acetaminophen 5/325mg prn
All: NKDA
Social History: never smoker, social EtOH,
denies ilicits, lives inWestchester
FH: father (MI), paternal GM (kidney Ca in
90s), Mat Gm (LungCa 80s)
PHYSICAL EXAM
- General: well developed, well nourished,
KPS 90%
- HEENT: +scleral and sublingual icterus
- CV: RRR normal S1S2 no m/r/g
- Chest:CTAB no r/r/w
- Abd: well healing abdominal
laparoscopic incision sites, soft NT, ND
+BS, no HSM
- Extremities: no c/c/e

4. Laboratory Evaluation
9.7
6.5 292
28.5
140 101 15
3.9 28 1.16
11.9 at discharge (POD2)
7.9
5.3 272
23.2
POD 13
POD 14 Haptoglobin <1
LDH 388
Retic count 6.0% (Abs 145.4)
AST 58
ALT 133
ALK Phos 166
T Bili 10.4
Conj Bili 0.6 (6%)
LDH 388

5. Laboratory Evaluation
9.7
6.5 292
28.5
140 101 15
3.9 28 1.16
11.9 at discharge (POD2)
7.9
5.3 272
23.2
POD 13
POD 14 Haptoglobin <1
LDH 508
Retic count 6.0% (Abs 145.4)
Peripheral smear with spherocytes
AST 58
ALT 133
ALK Phos 166
T Bili 10.4
Conj Bili 0.6 (6%)
LDH 388

6. Diagnosis?

7. What was the culprit?

8. Drug Induced Hemolytic Anemia
• First described in 1950s
• Incidence: 1/1,000,000
– Drug induced neutropenia: 2-15/1,000,000
– Drug induced thrombocytopenia: 10-18/1,000,000

9. Drug Induce Hemolytic Anemia
Garraty G, Drug Induced Hemolytic Anemia. Hematology 2009

10. Evaluation
• Must show:
– Antibodies that reaction ONLY in presence of drug
• CoombsTest

11. CoombsTest
"Coombs test schematic” https://commons.wikimedia.org/wiki/

12. Evaluation
• Must show:
– Antibodies that reaction ONLY in presence of drug
CoombsTest Positive
Eluate
• RBCs washed of unbound antibody
• Bound antibodies stripped from RBCs (via acid)
• Resultant fluid = Eluate (contains antibodies from the RBCs)
• Eluate then tested against reagent RBCs
In drug induced hemolysis, eluant analysis is negative or weakly positive.

13. Evaluation
Pierce and Nester Am J Clin Pathol 2011

14. Mechanism
https://www.med-ed.virginia.edu/courses/path/innes/rcd/antibody.cfm/

15. Hapten Mechanism
• Drug binds covalently to proteins on RBC
membrane
• Antibody binds to drug-RBC membrane
complex
• Examples:
– Penicillin
– Cefotetan
• If high drug concentrations, RBCs can be
coated with drug and lead to Fc-mediated
destruction

16. Immune Complexes Mechanism
• Drug and carrier protein epitope form complex
• Complex then attaches to RBC membrane and
leads to complement mediated destruction
• Examples:
– Quinidine

17. Autoantibody Mechanism
• Drug induces warm autoimmune hemolytic
anemia
• Antibodies persist 2/2 uninhibited B-cell
antibody production
• Examples:
– Methyldopa

18. Nonimmune Mechanism
• Drug modifies RBC membrane
• Drug binds nonimmunologically to RBC
membrane
• Examples:
– Cefotetan
– Cephaolthin
– Cisplatin/oxaliplatin/carboplatin
– Diglycoaldehyde
– Suramin
– Sulbactam
– Clavulonate
– Tazobactam

19. Cefotetan Induced Hemolytic Anemia
• 1985-1997: 85 cases of cefotetan induced hemolytic anemia
– 15/85 (18%) fatalities
– Mean fall in Hgb 6.7 g/dL
• As high as 1.4%of cefotetan exposures
• Acute reaction can occur 7-21 days asfter exposure
• Cefotetan bound antibodies can be seen up to 98 days post drug
exposure
• Can be mistaken for transfusion reactions in perioperative setting
Viraghavan et al. Adv Drug ReactToxicol Re 2002
Davenport et alTransfusion 2004
Martin and Laber Am J Hematology 2006

20. Management
• Withhold drug
• Tends to be self limited
• Steroids have limited utility
• Support with transfusions

21. What Drugs Should I Avoid?

22. Our patient, DT
• DAT with polyspecific 3+, IgG 2+, C3 2+
• Initial eluate was negative
• Sent to NY Blood bank and performed testing with cefotetan and was
positive
• Required 1-2 transfusions per day for 48 hours
• Discharged 4 days after admission
• Repeat labs 2 weeks after discharge
– Hgb 13.0, LDH 271, Haptoglobin 32
– Direct cooombs: positive weak