Ceftriaxone-Induced Hemolytic Anemia in a Jehovah’s Witness

Background

Drug-induced immune hemolytic anemia (DIIHA) is a rare but potentially life-threatening disorder that should be considered if a patient develops hemolysis under drug treatment [1]. DIIHA occurs in approximately 1 in 1 million people, but is likely underdiagnosed despite its potential lethality [2]. Second- and third-generation cephalosporins, especially cefotetan and ceftriaxone, are increasingly associated with severe, sometimes fatal, immune hemolytic anemia [3]. The first case of fatal ceftriaxone-induced immune hemolytic anemia (CIIHA) was reported by Garratty et al. in 1991 [4,5]. Estimates of fatality in CIIHA are reported as high as 40% [5–7]. DIIHA should be classified as involving either drug-dependent (DDAB) or drug-independent antibodies (DIAB) to more appropriately treat the condition. When involving DDAB, hemolysis typically appears within 2 weeks of starting the causative drug with the patient developing a progressive anemia [2]. Cessation of the offending agent is standard treatment, along with blood product transfusions for symptomatic anemia.

Case Report

OUTCOME AND FOLLOW-UP:

Figure 3 shows the gradual improvement in hemoglobin (Hgb) throughout the second hospital stay and post-hospital stay. The patient’s severe anemia was successfully treated conservatively and she was safely discharged to home with assistance from family. The patient finished her outpatient antibiotic course of intravenous vancomycin and continues to follow up on a routine basis. The multiple episodes of transient vision loss, which the patient suffered prior to admission, never returned and were explained as being directly related to her severe anemia; i.e., ischemic optic neuropathy.

Discussion

The patient was determined to have a subacute, progressive hemolytic anemia due to her infusions of ceftriaxone. It was concluded that her type of anemia was due to an extravascular hemolysis due to the presence of spherocytes/lack of red blood cell fragments on smear, positive DAT, increase in serum LDH, and absence of urine hemoglobin. The patient’s normal haptoglobin points away from an intravascular hemolysis and may be due to the progressive nature of the anemia. Normal haptoglobin levels may be present in extravascular hemolysis. In the United States, ceftriaxone appears to be the second most common drug causing DIIHA [6,8]. A positive DAT is the most reliable laboratory finding in DIIHA [2].

For clinical management of a DIIHA, it is useful to categorize the involved antibody as drug-dependent (DDAB) or drug-independent (DIAB) [2]. Ceftriaxone, along with other cephalosporin antibiotics, are most commonly associated with DDAB formation [2,9]. Extravascular hemolysis may result from the production of non-complement-activating, drug-dependent antibodies (DDAB) [10]. DDAB-related hemolysis usually demonstrates a positive DAT and a negative elution, which may be performed to characterize the antibody coating the RBCs [2]. The DAT was positive in our patient, with both IgG and C3d positivity. Unfortunately, there was no elution completed on our patient, which in retrospect may have been helpful in clarifying the final diagnosis. Another possibility would have been to have an immunohematology laboratory, which specializes in DDAB detection, confirm the presence or absence of specific anti-ceftriaxone antibodies.

For drug-dependent hemolysis, cessation of the drug (usually cefotetan, ceftriaxone, or piperacillin) is critical and this is equally true for drug-independent hemolysis, but because of the true autoantibody in drug-independent hemolysis, patients should additionally be treated as for warm antibody autoimmune hemolytic anemia (WAIHA) (i.e., with steroids, IVIG, and/ or plasma exchange) [2,8]. It was decided to initiate intravenous steroids in the patient due to the lack of contraindication and possibility of benefit in that WAIHA could not be ruled out secondary to the lack of antibody analysis. Differentiation between DIIHA and WAIHA can be fairly challenging. The only reliable confirmation of DDAB-mediated DIIHA over WAIHA requires testing the patient’s serum after drug cessation and clearance of any circulating drug or drug-antibody complexes, indicated by a clear decrease in serologic reactivity [2]. There is no need at the present time for this continued testing in the patient due to the lack of DDAB verification during the acute event. Retrospectively, confirmation of the presence of DDAB should be been sought.

Most cases of WAIHA are idiopathic, with no direct cause found. It is usually associated with splenomegaly, severe anemia, fever, and jaundice, and is mostly associated with extravascular hemolysis [11]. Our patient did not have splenomegaly, fever, or jaundice, but did have spherocytes and polychromatophilicred cells on the repeat blood smear completed on hospital day 4. Hemolysis associated with ceftriaxone typically appears within 2 weeks of starting the drug and presents with progressive anemia [2], which exactly fits the clinical picture of our patient, leading to the conclusion that this case was likely a DIIHA, specifically a CIIHA. This again can only be concluded with a relative amount of certainty in that the serological evaluation was limited and therefore not allowing for a definitive diagnosis.

The differential diagnosis initially included G6PD deficiency, which was deemed doubtful due to the standard timing of G6PD presentation being 2–4 days after initial drug ingestion, as well as the lack of red blood cells fragments or “bite” cells on peripheral smear. Acute transfusion reaction could easily have been eliminated from the list of differential diagnosis in our patient. Infectious etiology, with the patient’s recent (3 weeks prior) endocarditis history, was initially debated as the cause of the acute hemolysis. It is important to mention that the only positive blood cultures documented were the initial set during the initial hospitalization, which grew group B streptococcus. The presence of fragmented erythrocytes (on smear) suggests mechanical destruction of the RBCs [12], even regarding a native heart valve. There were no RBC fragments seen on smear, and with the clinical picture pointing toward an extravascular hemolysis, an infectious cause was considered unlikely.

Conclusions

The presented case highlights the importance of close vigilance while prescribing drugs known to cause hemolytic anemia. Most published cases to date involving CIIHA are in children [13] and most include blood product transfusions as the standard of treatment. The presented case is very unique in that this patient with severe hemolytic anemia was a Jehovah’s Witness and was able to be successfully treated without blood product transfusion. In retrospect, further antibody evaluation should have been sought, which would have eliminated the need to speculate on the definitive diagnosis.