DIC and Hemolysis after WinRho Treatment for ITP

Abstract & Commentary

By Andrew S. Artz, MD, Section of Hematology/Oncology, University of Chicago. Dr. Artz reports no financial relationships with this field of study.

Synopsis: Summarizing adverse events reported to the FDA, 6 definite cases of intravascular hemolysis (hemoglobinuria/hemoglobinemia and/or DIC) are detailed after administration of anti-D IGIV (WinRho). Several patients developed intravascular hemolysis after previously uncomplicated anti-D IGIV. Five patients were adults and all died. This study not only demonstrates that potentially fatal acute intravascular hemolysis may occur after anti-D IGIV and the importance of post-marketing surveillance.

Source: Gaines AR. Disseminated intravascular coagulation associated with acute hemoglobinemia or hemoglobinuria following Rh(0)(D) immune globulin intravenous administration for immune thrombocytopenic purpura. Blood. 2005. 106:1532-1537.

The wide clinical spectrum of idiopathic or immune thrombocytopenic purpura (ITP) presents a challenge in determining the need and type of treatment. Although steroids are most commonly used, IVIG and Rho(D) immune globulin intravenous (anti-D IGIV, WinRho SDF), are often used solely, or in combination, with steroids. The mechanism of anti-D IGIV involves clearance by splenic macrophages of sensitized D antigen positive erythrocytes.1 Although the mechanism of action presumably leads to some degree of extravascular hemolysis, in the initial clinical trials, 2 cases of hemoglobinemia or hemoglobinuria were noted and subsequent review summarized 15 cases, suggesting the possibility of intravascular hemolysis as well.

Gaines summarizes the adverse events leading to intravascular hemolysis evidenced by hemoglobinemia, hemoglobinuria or disseminated intravascular coagulation reported to the Food and Drug Administration (FDA) of anti-D IGIV after licensure in 1995. Six cases meeting the defined case definition were received between 1999 and 2004. Five additional cases were received, but inadequate data led to exclusion. Among the 6 patients, all 5 adults died within 3 to 10 days of receiving therapy. The only child in the series survived. The mean decrease in hemoglobin from baseline was 5.8 g/dL, not accounting for possible red cell transfusions. Several patients previously received anti-D IGIV safely before developing severe intravascular hemolysis, indicating prior treatment does not ensure safe retreatment.

Commentary

ITP is frequently treated by hematologists and oncologists. In light of the chronic relapsing nature of ITP, complications of therapy may hold equal weight to efficacy in treatment decisions.

Two important implications arise from this study. First, treatment with anti-D IGIV may lead to intravascular hemolysis and death. Clearly, adverse events reported to the FDA under represent the actual frequency but also may be biased in reporting only the most severe cases. Another problem may be that cases of ITP could actually represent occult TTP/HUS or DIC, which are at least predisposed to this complication. Nevertheless, this study and the prior work confirm this potential complication of anti-D IGIV. More problematic, several patients developed intravascular hemolysis after prior treatment, which suggests close monitoring, may be needed after each treatment. Since the hemolysis was very acute, it would be reasonable to consider reevaluating the patient the same day or the following day of therapy. Despite the uncommon but serious problems with anti-D IGIV, the attendant complications of corticosteroids and IGIV suggest they do necessarily represent safer alternatives.

A second important implication involves reporting adverse events to the FDA. Increasingly, post-marketing reports, typically from community practicing physicians, alert physicians to unexpected but serious complications. We should all have familiarity with using the MedWatch system from the FDA (www.fda.gov/medwatch).

References

1. Ware RE, Zimmerman SA. Anti-D: mechanisms of action. Semin Hematol. 1998;35(1 Suppl 1):14-22.