Hemolysis After High Dose IVIG In Blood Group A Women With Alloimmune Thrombocytopenia

Hemolysis after IVIG infusion has been observed in clinical trials and case reports. Certain factors seem to place a patient receiving IVIG at higher risk for hemolytic anemia: 1) having blood type A, B, or AB and 2) receiving high doses of IVIG (≥ 2g/kg).

IVIG contains isohemagglutinins that coat red blood cells and may cause red cell clearance by the RES (Table 1). Anti-A, Anti-B, and Anti-D titers have been detected in IVIG products at varying concentrations by different IVIG manufacturers. It has been suggested that Anti-A titers > 1:16 are more likely to cause clinically significant hemolysis and thus anemia in recipients.

15 summarized studies reported 63 patients who experienced hemolysis after IVIG infusion and showed the higher risk of non-group O recipients to hemolyze with IVIG:

In the current study, we sought to explore the degree of anemia as related to ABO blood types in mothers treated with IVIG for fetal alloimmune thrombocytopenia (AIT).

A retrospective chart review was conducted on 84 women who had received IVIG for AIT treatment during their pregnancy to increase the fetal platelet count. Women were randomized to receive IVIG 2g/kg/wk (arm A, n=43) or IVIG 1g/kg/wk + prednisone (arm B, n=41) starting at 20-30 weeks of gestation until delivery. One CBC per month was collected from each mother from the start of treatment until delivery. Hemoglobins and mean corpuscular volumes (MCVs) were tracked and development of anemia was compared among women with blood types (BT) A, B, AB and O in each treatment arm. Patients who non-randomly received IVIG 2g/kg/wk + prednisone together as rescuetreatment were excluded from this study.

36 of the 84 women had hemoglobins less than 10 on at least one CBC during IVIG treatment. All 36 had MCV values in the normocytic range (80-100). The degree of anemia was significantly greater in Arm A (IVIG 2g/kg) than Arm B (IVIG 1g/kg + pred) (Fisher's exact test, p=0.016; table 3).

Among women in arm A (IVIG 2g/kg), BT non-O had a significantly higher incidence of marked anemia (Hg<10) than those with BT O (Fisher's exact test, p=.001; table 4), with BT A having the highest number of women with Hg<10 (A=16, B=1, AB=1, O=4, unknown=2).

There was no significant difference among women by blood type O (n=4) versus non-O (A=4,B=2,AB=0,unknown=2) in the incidence of anemia in arm B (IVIG 1g/kg + pred); both BT groups showed a low incidence of hemolysis (table 5).

Patients who were on 2g/kg/wk IVIG became substantially more anemic than those on the 1g/kg/wk IVIG + prednisone dose, which supports reported findings that higher dose (HD) IVIG is associated with a greater risk of anemia. Note: receiving IVIG 2g/kg/wk for multiple weeks is very high dose IVIG. In particular, those patients receiving HD IVIG who were BT A had a greater risk of developing a greater extent of anemia than those of blood type O. This finding is consistent with the hypothesis that blood-group specific antibodies in IVIG result in immune hemolysis primarily in BT A recipients because of the higher anti-A titers. Furthermore, while 1 g/kg/wk of IVIG is not “low dose”, the concomitant use of prednisone 0.5mg/kg/d may protect against development of a greater degree of anemia in these patients.

IVIG is the standard of care treatment for AIT; however 1 g/kg/wk is known not sufficiently effective in severely thrombocytopenic fetuses (Berkowitz, OB-GYN 2006). Therefore we believe appropriate treatment of women whose previous babies did not have an ICH needs to be > 1g/kg/wk. Our study found that hemolytic anemia in non-O blood types may be an important side effect of 2g/kg/wk IVIG treatment, indicating that patient blood type should be considered when deciding which IVIG regimen to use.

Bussel:Shionogi: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Ligand: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; IgG of America: Research Funding; Genzyme: Research Funding; Cangene: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Amgen: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Symphogen: Membership on an entity’s Board of Directors or advisory committees.