The Food and Drug Administration (FDA) initially licensed Rho(D) immune globulin intravenous (human; anti-D IGIV) as a lyophilized formulation (then WinRho, currently WinRho SDF;1
Cangene Corporation, Winnipeg, Manitoba, Canada) in March 1995 and as a liquid formulation (WinRho SDF Liquid1
) in March 2005. Both formulations (hereinafter referred to as WinRho unless otherwise noted) are approved for treatment of immune thrombocytopenic purpura (ITP) in Rho(D)-positive, nonsplenectomized children with acute ITP, children and adults with chronic ITP, and children and adults with ITP secondary to human immunodeficiency virus (HIV) infection as well as for suppression of Rh isoimmunization.1
WinRho is also used “off-label” to an unknown extent for treatment of secondary thrombocytopenia. The presumed mechanism of action of WinRho in ITP involves extravascular hemolysis of anti-D–sensitized red blood cells (RBCs) by splenic macrophages.1
In patients who respond therapeutically, this mechanism results in decreased splenic sequestration of autoantibody-sensitized platelets (PLTs), which results in an increased PLT count.1
In what appears contradictory to the presumed extravascular hemolysis mechanism of action and its typical clinical and laboratory findings, two cases of “acute-onset hemoglobinuria consistent with intravascular hemolysis” were observed during the WinRho ITP clinical trials.2
After licensure, additional reports of acute hemolysis after WinRho administration for ITP or secondary thrombocytopenia were (and continue to be) submitted to the FDA.
Most patients treated with WinRho for ITP or secondary thrombocytopenia do not experience signs/symptoms of acute hemolysis,1,3–13
and not all who experience signs/symptoms of acute hemolysis experience hemolysis-related complications14
or require medical intervention for any complications experienced.13 –16
Nonetheless, the acute hemolysis–associated complications that have been reported to date include clinically significant anemia, the need for RBC transfusion(s), acute or exacerbated renal failure, the need for dialysis, disseminated intravascular coagulation, and death secondary to these complications.14,17
The complications may occur singly or in combination,14,17
were previously reported in two case series of patients,14,17
and are listed in the WinRho professional package insert.1
If the acute hemolysis that occurs in some patients treated with WinRho for ITP or secondary thrombocytopenia is consistent with the acute hemolytic transfusion reaction (AHTR) mechanism and could be detected in vitro with a hemolysin assay, this assay could conceivably be used to identify patients at risk for acute hemolysis with specific WinRho lots. For such patients, those lots might be contraindicated. The hemolysin assay might also allow identification of WinRho lots that appear to pose no risk of acute hemolysis and could presumably be safely administered.
Such testing could be performed prior to administration of WinRho, borrowing from the historical precedent for the manufacture and distribution of two-vial packaging of an FDA-licensed Rho(D) immune globulin for intramuscular administration—one vial for preadministration testing of product and patient RBCs and one vial for subsequent patient administration (RhoGAM, then Ortho Diagnostic Systems, now Ortho-Clinical Diagnostics, Raritan, NJ18
). Although what prompted the two-vial packaging that was previously used with RhoGAM was unrelated to either acute hemolysis or ITP, we recognized that this packaging precedent could apply to the performance of a hemolysin assay as a screening procedure before administration of anti-D IGIV for treatment of ITP or secondary thrombocytopenia.
We report the results of a hemolysin assay study that we designed to evaluate whether the acute hemolysis associated with WinRho administration for treatment of ITP is consistent with the AHTR model. We also report an additional case of WinRho-associated acute hemolysis in a patient with a history of ITP.