Incidence and Risk Factors for IVIG-Mediated Hemolysis

INTRODUCTION: Hemolysis is a recognized complication of high-dose IVIG infusion, but as the majority of case reports are retrospective the actual incidence and risk factors for its occurrence are poorly understood. METHODS: Between November 2012 and October 2016, recipients of high-dose IVIG in Toronto (Canada) were prospectively monitored for hemolysis using a panel of investigations performed pre- and post-infusion and then 5-10 days later. Hemolysis was defined and graded as per the Canadian IVIG Hemolysis Pharmacovigilance Group, with both patient and product risk factors analyzed for correlation. RESULTS: After a preliminary analysis revealed a strong association with ABO group and dose, enrollment was restricted to patients with non-O blood group receiving doses ≥ 2 g/kg, adjusted for lean body mass. Within this cohort, 99 infusions to 78 patients completed the follow-up protocol, with hemolysis observed in 32 (32%) and 28 (36%) of cases, respectively. Hemolytic anemia of Grades 1, 2, 3 and 4 were observed in 10, 9, 2 and 7 patients, respectively, and an additional 4 patients hemolyzed but maintained a stable hemoglobin via reticulocytosis. Although the initial fall in hemoglobin was slightly larger in hemolytic than non-hemolytic reactions (-14.9 vs -11.1 g/L, p = 0.0091), in 84% of cases laboratory confirmation of hemolysis only manifested 5-10 days after the infusion. In contrast, while 88% of hemolyzers had a positive DAT immediately post-IVIG, this proportion had fallen to 38% by day 5-10. Amongst 49 infusions evaluated by day 5-10 monocyte monolayer assay, there was 69% correlation between the development of hemolysis and the presence of heightened phagocytic activity in patient monocytes, vs 43% correlation when testing was performed with monocytes from healthy controls. Further supporting a state of increased macrophage activation, the proportional increase in serum ferritin was greater in hemolyzers than non-hemolyzers (5.1-fold vs 2.1-fold, p = 0.033). Conversely, all positive DAT test results were for IgG only, with no evidence of complement deposition. In regards to predictors of hemolysis, univariate analysis identified a higher incidence with group AB than with other blood groups (90% vs 26%, p = 0.0001), in first-time compared to repeat recipients (50% vs 20%, p = 0.002), in patients not taking immunosuppressant medications (43% vs 23%, p = 0.0316), and in patients whose post-infusion DAT was 1+ or stronger as compared to weak or by eluate only (57% vs 19%, p = 0.0001). One of three manufacturers had a lower rate of hemolysis (0% vs 35%, p = 0.009) but was also more likely than the other two manufacturers to be given to patients on immunosuppressant medications (83% vs 24%, p=0.0001). No correlation was observed with year of treatment, patient age, sex, BMI, diagnosis, rate of infusion, steroid pre-medication, subjective symptoms or pre-infusion levels of CRP or IL1-RA. CONCLUSION: Amongst non-O blood group recipients of high-dose IVIG, hemolysis is common and appears to occur via delayed-onset phagocytosis by activated patient monocytes. The highest risk appears to be in patients with blood group AB, those who are receiving IVIG for the first time, who are not taking immunosuppressive medications, or who have a 1+ or stronger DAT immediately post-infusion. Whether specific IVIG products carry higher risk requires further study.