Hemolytic anemia resulting from
IV Immunoglobulin (
IVIG) treatment can be a serious complication, especially for those with underlying conditions with a high level of
inflammation and after administration of high
IVIG dosages, such as
Kawasaki disease (KD), a multisystem
vasculitis affecting young children. This
hemolysis is caused by
antibodies against
blood groups A and B, but the precise mechanism for
hemolysis is not known. We performed a single center, partly retrospective, partly prospective study of a cohort of 581 patients who received
IVIG for treatment of KD from 2006 to 2013. Factors associated with
hemolysis were identified through univariable and multivariable logistic regression. Six
IVIG preparations were assayed for their hemolytic effect with serological and cellular assays to clarify the mechanism of red cell destruction. During the study period, a sudden increase in the incidence of
hemolysis was observed, which coincided with the introduction of new
IVIG preparations in North America that contained relatively high titers of anti-A and anti-B. These
blood-group-specific
antibodies were of the
immunoglobulin G2 (
IgG2) subclass and resulted in phagocytosis by monocyte-derived macrophages in an FcγRIIa-dependent manner. Phagocytosis was increased in the presence of proinflammatory mediators that mimicked the inflammatory state of KD. An increased frequency of severe
hemolysis following
IVIG administration was caused by
ABO blood-group-specific
IgG2 antibodies leading to FcγRIIa-dependent clearance of erythrocytes. This increase in adverse events necessitates a reconsideration of the criteria for maximum titer (1:64) of anti-A and anti-B in
IVIG preparations.