Drug-Induced Immune Hemolytic Anemia Caused by Postoperative Cefotetan Administration

Dear Editor:

Drugs can induce almost any hematologic disorder that affects white blood cells, red blood cells (RBCs), platelets, and the coagulation system. Although the clinical manifestation of drug-induced immune hemolytic anemia (DIIHA) is usually mild, it may progress to acute severe hemolytic anemia (HA) and death. There is an increasing number of reports of second and third-generation cephalosporins causing clinical hemolysis¹. Cefotetan is a second-generation cephalosporin used frequently in postoperative condition. Here, we report a case of cefotetan-induced immune hemolytic anemia in a Korean (CIIHA).

A 68-year-old male with a small nasal nodule was diagnosed as basal cell carcinoma was referred to our hospital for further treatment. We removed the remaining lesion and the defect was repaired with a nasolabial flap (Fig. 1). Intravenous cefotetan 2 g daily was administered to the patient postoperatively for 7 days. Before discharge, the patient developed sudden mild fever (37.8℃) and fell down due to dizziness. Other symptoms including nausea, weakness, dark urine color, drowsiness, and pale appeared successively. During his hospitalization, there were no symptoms other than stomach discomfort. His hemoglobin (Hb) and hematocrit were 3.5 g/dl and 12.8%, respectively. The total serum bilirubin was 6.86 mg/dl (Table 1). There was no evidence of internal bleeding upon physical examination. His reticulocyte and red cell production index were 2.93% (normal, 1%~2%) and 0.916. We excluded chronic anemia, and acute gastrointestinal bleeding as a possible diagnosis. Therefore, we doubted a drug-induced condition. The patient was transferred to the Medical Intensive Care Unit. The patient's serum did not react with the antibody-detection RBCs. The direct antiglobulin test was positive (polyspecific+ and anti-C3+) (Table 1). He was diagnosed with DIIHA due to cefotetan. His symptoms completely resolved after massive systemic steroid treatment and blood transfusion with 5 units of packed RBCs. The lactate dehydrogenase (LDH) level dropped from 3,005 to 1,003 U/L, and the Hb count was 9.6 g/dl at the time of discharge.

Fig. 1. A 1.0 cm×1.0 cm sized erythematous nodule with brown pigments on the nose (A) and at the 3 months follow-up (B). We received the patient's permission about publishing all photographic materials.

Table 1. Characteristics of laboratory results and direct antiglobulin test of the patient.

Hospital day		Hemoglobin (mg/dl)	WBC (×109/L)	MCV (fl)	Platelet (×109/L)	Total bilirubin (mg/dl)	AST (SGOT) (U/L)	ALT (SGPT) (U/L)	BUN (mg/dl)	Creatinine (mg/dl)	Iron (µg/dl)	Ferritin (ng/ml)	TIBC (U/L)	Haptoglobin	Creatinine (mg/dl)	LDH (U/L)	POLY	Anti-C3
Pre-surgery		10.7	7.66	77.0	420	0.46	18	20	13.2	0.65					0.65	Not tested	Not tested	Not tested
POD 8		3.9	22.98	80.5	262	6.86	247	22	88.6	1.6	283	>16,500	295		1.6	3,505	+	+
Post-intravenous systemic steroid
	POD 9	6.7	19.31	86.9	215	1.94	134	36	106.2	0.87				<20	0.87	1,207
	POD 13	7.9	16.02	92.5	196	0.55	32	30	34.5	0.68					0.68	1,147
	POD 15	9.4	10.21	92.4	147	0.46	18	27	18.8	0.65					0.65	1,003

POD: postoperative day, WBC: white blood cell, MCV: mean corpuscular volume, AST: aspartate transaminase, SGOT: serum glutamic oxaloacetic transaminase, ALT: alanine aminotransferase, SGPT: serum glutamate-pyruvate transaminase, BUN: blood urea nitrogen, TIBC: total iron-binding capacity, LDH: lactate dehydrogenase, POLY: polyspecific anti-human globulin.

The induction of HA can be explained by four hypothetical mechanisms: 1) drug-induced production of antibodies leading to hemolysis. 2) The drug binds to the homologous site on the RBC membrane to form an antigen-neocomplex. 3) The drug is absorbed into the cell membrane through direct covalent bonds. 4) The drug binds to the RBC membrane followed by the binding of proteins other than antibodies. In the case of cefotetan, hemolysis is most likely caused by 3) or 4).

Cefotetan accounts for 43% of all drugs which cause DIIHA over a 10 year period². The incidence of CIIHA was 1.4%³. The US FDA reported 18% fatalities and 8% renal failures³.

To our knowledge, this is the first reported case CIIHA in Korea. Prompt diagnosis, aggressive supportive measures, and appropriate treatments including systemic steroid treatment and blood transfusion are essential factors. Halting of the suspected drug is the first and most important step. The LDH level is a useful marker for the severity of hemolysis and for monitoring treatment responses⁴. Although DIIHA is rare, dermatologists should be aware of the causative drugs and clinical characteristics associated with severe HA.