Pathology Consultation on Drug-Induced Hemolytic Anemia

Pathology Consultation / Special Article Pathology Consultation on Drug-Induced Hemolytic Anemia Arand Pierce, MD,1 and Theresa Nester, MD1,2; for the Education Committee of the Academy of Clinical Laboratory Physicians and Scientists Key Words: Pathology consultation; Drug-induced immune hemolytic anemia; Hemolytic anemia; Cephalosporins DOI: 10.1309/AJCPBVLJZH6W6RQM CME/SAM Upon completion of this activity you will be able to: • list the drugs most commonly implicated in drug-induced immune hemolytic anemia (DIIHA). • describe the mechanisms of DIIHA. • direct the appropriate laboratory and clinical evaluation of DIIHA. • provide clinically relevant recommendations for DIIHA management based on specific laboratory and clinical findings. The ASCP is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ASCP designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit ™ per article. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity qualifies as an American Board of Pathology Maintenance of Certification Part II Self-Assessment Module. The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. Questions appear on p 152. Exam is located at www.ascp.org/ajcpcme. Abstract Consult Drug-induced immune hemolytic anemia is considered to be rare but is likely underrecognized. The consulting pathologist plays a critical role in integrating serologic findings with the clinical history, as drug-induced antibodies should be distinguished as either drug-dependent or drug-independent for appropriate clinical management. Drug-dependent antibodies (DDABs) are most commonly associated with cefotetan, ceftriaxone, and piperacillin, whereas fludarabine, methyldopa, β-lactamase inhibitors, and platinum-based chemotherapeutics are frequent causes of drug-independent antibodies (DIABs). DDABs usually demonstrate a positive direct antiglobulin test and a negative elution, while DIABs are serologically indistinguishable from warm autoantibodies and are similarly steroid-responsive. Drug cessation is always recommended. Drug-induced immune hemolytic anemia (DIIHA) is an uncommon entity that is frequently mistaken for warm autoimmune hemolytic anemia (WAIHA). Providing diagnosis and guidance to the inpatient care team is paramount because failure to recognize DIIHA may result in death. Once recognized, treatment options differ based on the nature of the antibody. The condition of a 28-year-old man with cystic fibrosis (CF) and bilateral lung transplants who was hospitalized for fever, productive cough, and dyspnea progressed to respiratory failure requiring mechanical ventilation. Further investigations identified drug-resistant H1N1 viral infection, gram-negative bacteremia and pneumonia, fungal pneumonia, and systemic reactivation of cytomegalovirus. Therapy was immediately started with broad-spectrum antiviral and antimicrobial therapy, including piperacillin-tazobactam. Soon after initiation of therapy, a steady decrease in hemoglobin and hematocrit values (nadir, 5.2 g/dL [52 g/L] and 16% [0.16], respectively) was accompanied by elevations in lactate dehydrogenase and total bilirubin levels. Coagulation study results were normal. A WAIHA was suspected, and RBC transfusion was ordered. An antibody screen of patient plasma revealed 2+ reactions with both screening cells; an antibody identification panel disclosed positive agglutination of all cells with variable reactivity (2-3+) and a positive autologous control (2+). A direct antiglobulin test (DAT) was strongly (3+) reactive using polyspecific and anti-IgG antibody reagents but nonreactive with anti-C3. All controls reacted appropriately. However, acid elution showed no reactivity of the patient’s serum against any cells of the RBC test panel, in contrast with what is expected of a pan-agglutinating warm autoantibody. © American Society for Clinical Pathology Am J Clin Pathol 2011;136:7-12 7 DOI: 10.1309/AJCPBVLJZH6W6RQM 7 7 Pierce and Nester / Drug-Induced Hemolytic Anemia An underlying alloantibody was ruled out by autologous adsorptions. Compatible RBC units were allocated, and the transfusion physician made the inpatient care team aware of the possibility of DIIHA. The team then requested guidance on how best to support the patient given these findings. Questions DIIHA is a rare but serious complication that is often underdiagnosed. This consult will outline the current state of knowledge regarding DIIHA with the aim of answering the following: • What drugs are most commonly implicated in DIIHA? • What are the mechanisms of DIIHA? • How is DIIHA diagnosed? • What is the recommended management of DIIHA? Background DIIHA occurs in approximately 1 in 1 million people1 but is likely underdiagnosed despite its potential lethality. Reports of DIIHA first began in the 1950s.2 As the drug armamentarium has evolved, so have the drugs most commonly associated with DIIHA. Forty years ago, methyldopa and high-dose intravenous penicillin were most commonly associated with hemolytic anemias.3 Today, second- and third-generation cephalosporins are implicated in the vast majority of DIIHA cases. Other drugs commonly implicated are listed in ❚Table 1❚. However, myriad other drugs have been implicated, mostly in case reports, so any drug is a potential culprit. DIIHA antibodies should be classed as drug-dependent or drug-independent for the purposes of diagnosis and management. An antibody is drug-dependent if it demonstrates reactivity only in the presence of drug (in serum or added for in vitro testing). An antibody is drug-independent if it is capable of in vitro reactivity in the absence of drug. However, the in vivo mechanisms of most drug antibody-antigen interactions are poorly understood, and drug-associated hemolysis is likely mediated by more than 1 mechanism. Despite these limitations, a consistent serologic investigation coupled with a thorough clinical history is usually sufficient to arrive at the correct diagnosis. Discussion Drug-Dependent Antibodies Most drugs that cause hemolysis are mediated by DDABs. In the 30-year experience of 1 reference laboratory, cefotetan, ceftriaxone, and piperacillin were, in aggregate, responsible for 76% of all cases of DIIHA, with cefotetan accounting for the majority of cases.3 Hemolysis typically appears within 2 weeks after starting the drug, and the patient has progressive anemia or other evidence of hemolysis. There is often no clinical suspicion of drug-mediated hemolysis because a routine request for RBC transfusion or preoperative screen typically initiates the evaluation. A positive DAT is the most reliable laboratory finding in DIIHA; if the DAT is negative, the likelihood of DIIHA is exceedingly small. Fol (...truncated)