By: Samad Tirmizi, PharmD Candidate c/o 2014

–

Hemolytic anemia (HA) is a type of anemia that occurs due to the breakdown of red blood cells. It is classified as intrinsic and extrinsic according to causative factors. Medication induced hemolytic anemia is an example of extrinsic, while genetic predisposition is an intrinsic factor. Drug induced hemolytic anemia can be further broken down into either nonimmune-mediated or immune-mediated.¹ In the case of nonimmune-mediated HA, hemolysis results from oxidant injury. Ceftriaxone-induced HA is an example of immune-mediated hemolytic anemia, since the etiology involves an antigen-antibody reaction. The anemia results when red blood cells are perceived by the body as antigens and subsequently destroyed. Antibodies are formed against the drug-membrane complex (neoantigen). Erythrocyte injury is primarily mediated by the compliment system, a system derived from innate immunity. To test this occurrence the Direct Coombs Test, also known as a direct antiglobulin test (DAT) is implemented in such patients. This is used to test if complement system factors or antibodies are bound to the surface of an RBC.²

Patients with drug-induced hemolytic anemia may present immediately upon initiation of therapy or several weeks to months after. Patients with hemolytic anemia often present with dark urine, general weakness, low hemoglobin, dizziness, and renal failure.³ Reports of pediatric patients show that they present with hemoglobin levels under 5 g/dL, potential renal failure, and intravascular hemolysis.³ Tests for antibodies are performed to see whether the anemia is drug induced or secondary to other causes.⁴

Ceftriaxone-induced hemolytic anemia was first reported in 1987 in southern California.⁵ The laboratory found extravascular red cell destruction associated with IgG-mediated antibodies. Ceftriaxone has become the second most prevalent cause of drug-induced immune hemolytic anemia (DIIHA), superseded only by cefotetan. According to a report published by the American Society of Hematology, there were 99 reported cases of DIIHA associated with cephalosporin from 1971 to 2008.⁵ Ceftriaxone accounted for 29 of these cases, ten of which resulted in death. Five of the 47 cases of cefotetan-induced DIIHA resulted in death. This implicates ceftriaxone in causing the highest rate of fatality amongst cephalosporins and drugs in general.^6,7

Hemolytic anemia is often resolved soon after the implicated drug is discontinued, and in most cases steroids are not required.⁵ However, cefotetan is an exception, as hemolytic anemia in these patients continues for a longer than expected duration even after drug discontinuation. Cefotetan binds strongly to red blood cells and this complex can be detected in the serum for up to 98 days.Serology testing is conducted to test for ceftriaxone-mediated immune response by detecting immune complexes.^8,9

The clinical and laboratory findings in ceftriaxone DIIHA differ dramatically from other associated drugs, such as cefotetan. The American Red Cross Blood Services studied blood samples from 53 patients with IHA and/or a positive DAT due to second- and third-generation cephalosporins from 1984 to 1999. Of the 53 patients, 43 were due to cefotetan, eight due to ceftriaxone, one due to cefotaxime, and one due to cefoxitin. Table 1 shows that among the patients with ceftriaxone-induced hemolytic anemia, five were tested, and none had antibodies for IgA & IgM.⁸ Of the eight ceftriaxone induced hemolytic anemia patients tested for IgG antibodies, six were shown to be positive. However, among those with cefotetan induced hemolytic anemia, two out of 27 patients had IgM antibodies, 12 out of 27 patients had IgA antibodies, and 43 out of 43 tested for IgG had positive antibodies.⁸ It is noteworthy that the study did not list in their methods why certain patients received some antibody tests and not others.

      It is also unusual that ceftriaxone antibodies do not react with drug-treated RBCs and are only detected via the immune-complex method, which includes the serum, the drug, and RBCs. Furthermore, RBC-bound complement was detected in all patients with DIIHA caused by ceftriaxone.⁸ It is also significant that children afflicted with hemolytic anemia have a higher fatality rate (58%) than adults (27%). They suffer immediate hemolysis within a 5 to 30 minute time frame compared to an onset of days in adults.¹⁰

In summary, ceftriaxone has been implicated in numerous cases of DIIHA, and it appears to be the second most common drug to cause DIIHA after cefotetan.⁹ Children have a higher mortality rate than adults. Though there have been in vitro tests that recommend avoiding a cephalosporin in such patients, it unknown if the in vitro data correlates to in vivo reactivity.¹¹ More studies need to be conducted regarding cephalosporin induced hemolytic anemia, and care should be taken when prescribing certain cephalosporins to the pediatric population. Most importantly, patients with a history of DIIHA to one cephalosporin should avoid cephalosporins altogether as there is potential for cross-reactivity, even if minimal.

SOURCES:

1. Dipiro JT, Talbert RL, Yee GC et al. Pharmacotherapy: A Pathophysiologic Approach. 8^th ed. New York, NY: McGraw-Hill; 2008: 1737-8
2. Sattar H. Fundamentals of Pathology. Pathoma LLC.; 2013
3. Laber DA, Martin ME. Cefotetan-Induced Hemolytic Anemia After Perioperative Prophylaxis. American Journal of Hematology. 2006; 81: 186-188.
4. Miller DA, Tisdale JE. Drug-Induced Diseases. 2^nd ed. American Society of Health-System Pharmacists, Inc.; 2010.
5. Garratty G. Drug-induced immune hemolytic anemia. Hematology. 2009;73-9
6. Arndt PA, Leger RM, and Garratty G. Serologic characteristics of ceftriaxone antibodies in 25 patients with drug-induced immune hemolytic anemia. Transfusion. 2012;52:602-12
7. Garratty G. Immune hemolytic anemia associated with drug therapy. Blood Reviews. 2010;24:143-150
8. Arndt PA, Leger RM, and Garratty G. Serology of antibodies to second- and third-generation cephalosporins associated with immune hemolytic anemia and/or positive direct antiglobulin tests. Transfusion. 1999;39:1239-46
9. Pierce A and Nester T. Pathology Consultation on Drug-induced hemolytic anemia. Am J Clin Pathol. 2011;136:7-12
10. Arndt PA, Garratty G. The changing spectrum of drug-induced immune hemolytic anemia. Hematology. 2009;42:137-144
11. Arndt PA, Garratty G. Cross-Reactivity of Cefotetan and Ceftriaxone Antibodies Associated with Hemolytic Anemia, with Other Cephalosporins and Penicillin. Am J Clin Pathol. 2002;118:256-262

Published by Rho Chi Post