Anti-D immune globulin: protecting platelets at a cost

Comment on Gaines, page 1532

Six cases of disseminated intravascular coagulation after intravenous administration of anti-D immune globulin raise additional concern about intravascular hemolysis and demonstrate the importance of postmarketing drug surveillance.

Dr Frank Oski, a giant in the field of pediatric hematology, often advised that the best time to use a new drug was when it was first licensed, since that was when the drug worked the best and caused the fewest side effects. With his usual wit, he was warning us that the therapeutic bandwagon sometimes travels an unpredictable course. Now Gaines, in this issue of Blood, has added another agent, anti-Dimmune globulin for intravenous administration, to the list of drugs whose safety profile has become more completely defined only after widespread use. Gaines' description furthers our understanding of the consequences of hemoglobinemia and/or hemoglobinuria after intravenous administration of anti-D immuneglobulin, but perhaps even more importantly, the paper demonstrates the importance of postmarketing drug surveillance and regular reporting by physicians of drug-related adverse events.

Licensed in 1995 for the treatment of immune-mediated thrombocytopenic purpura in Rh-positive patients, anti-D immune globulin sends coated red cells to die at the hands of splenic macrophages so that their platelet brethren can live. Consequently, some degree of extravascular hemolysis is not unexpected and may even be essential for successful therapy. What came as a surprise after 2 or 3 years of clinical use of anti-D immune globulin was the rare but serious presentation of clinical findings suggestive of intravascular hemolysis. Red cell destruction in the relative safety of the spleen may cause anemia, but intravascular destruction may set off a horrific cascade of events that, in addition to anemia, includes renal failure, disseminated intravascular coagulation (DIC), and death, as classically demonstrated by severe, acute hemolytic transfusion reactions. By 2000, Gaines had identified 15 patients who developed hemoglobinemia and/or hemoglobinuria after intravenous administration of anti-D immune globulin.¹  Eight of these patients had evidence of related renal insufficiency. It was only a matter of time before the other shoe dropped and DIC was recognized as a consequence of intravascular hemolysis. In her current paper, Gaines identifies 6 patients with findings that are suggestive of DIC associated with hemoglobinemia and/or hemoglobinuria following intravenous administration of anti-D immune globulin. The 5 adults died; only the 12-year-old boy recovered. The usual problems associated with postmarketing surveillance, such as nonuniform data collection, variable consideration of comorbid conditions, and underreporting, may raise reasonable questions about some of the cases or the overall frequency of this adverse event, but the story becomes more convincing as the data accumulate.

The final paragraph of this paper, in which the author provides detailed and important information for reporting adverse events to the FDA, deserves particular attention. Well-publicized experience with several drugs has emphasized the critical role that clinicians play in identifying new toxicities after drugs emerge from clinical trials and enter widespread clinical use. The potentially lifesaving information that is provided by Gaines about anti-D immune globulin is available only because health care professionals recognized a possible drug reaction and took the time to report it. ▪