Hemolysis after high‐dose intravenous immunoglobulin: An under‐appreciated sequelae
Authors: Donald R. Branch, Ruqayyah J. Almizraq, James B. Bussel
Journal: American Journal of Hematology (2022)

In 1981, intravenous immunoglobulin (IVIG) at 2 g/kg total dose was first infused to ameliorate immune thrombocytopenia (ITP)1, 2 with dramatic results leading to a substantial increase in IVIG use for ITP and subsequently many other indications. Clinically-relevant hemolysis was rarely seen; even though, recognition of a positive direct antiglobulin test (DAT), low haptoglobin, and other measures of hemolysis demonstrated that IVIG could induce hemolysis.2 Isoagglutinins, anti-A and anti-B, were strongly suspected as the causes of hemolysis and this hypothesis instigated development of IV anti-D (e.g., WinRho®/RhoGAM®) to treat ITP by causing hemolysis! Thus IVIG-induced hemolysis was thought of as interesting but almost always clinically unimportant.2-5 Initially IVIG was manufactured by Cohn-Oncley fractionation,6 a process involving precipitation and purification which results in an IgG product consisting almost entirely of monomers. Cohn-Oncley fractionation results in five fractions: fraction II contained most of the IgG while fraction III contained a proportion of IgG but also included anti-A and anti-B isoagglutinins and most of the IgM. Until 2007, fraction II was kept but fraction III was discarded; clinically-significant IVIG-associated hemolysis was virtually nonexistent.4-6 To increase yield, since IgG was lost when fraction III was discarded, ion-exchange chromatography was introduced to conserve fraction III. These more "inclusive" products began use around 20074; with inclusion of fraction III, not only were titers of IgG isoagglutinins higher but also reports of hemolysis became so frequent that in 2014, the FDA issued a black box warning for one manufacturer and organized a consensus workshop in partnership with the National Institutes of Health. The workshop conclusions were to develop strategies for removal of anti-A and anti-B isoagglutinins from IVIG to reduce hemolysis. Recent studies have confirmed that IVIG-induced hemolysis is related to administration of high doses of IVIG (1–2 g/kg) in recipients who are blood type A, B, or AB3-5 suggesting the culpability of passive infusion of anti-A/anti-B isoagglutinins. IVIG recipients at highest risk of IVIG-associated hemolysis are blood group AB followed by blood group A, presumably because there are higher levels of anti-A than anti-B in plasma, and thus in IVIG.3, 4 Additional studies identified a direct association between anti-A and anti-B titers in IVIG and hemolysis in patients.7, 8 In one study, only group A recipients receiving IVIG underwent hemolysis and those receiving IVIG 1 g/kg/wk had less hemolysis than those randomized to 2 g/kg/wk.3 A prospective study showed that 32% of IVIG infusions resulted in hemolysis with 19% clinically-significant, occasionally severe hemolysis.3-5 Many such examples suggesting the role of isoagglutinins to induce hemolysis exist.3-5, 7, 8 Overall, cases of hemolysis have increased substantially,3, 4 apparently directly attributable to the 2007 change in manufacturing. One mildly successful approach to reducing recipient hemolysis was removing donors with high titer isoagglutinins.8 However, making certain donors ineligible to donate was counter-productive at a time of IVIG shortage. Subsequent study demonstrated that immunoaffinity removal of anti-A/anti-B was more effective at reducing isoagglutinin titers; using this technique, certain manufacturers were able to reduce the final titers of isoagglutinins in their products9 and this had a greater effect in reducing recipient hemolysis. Despite the post-2007 increase in cases, IVIG-induced hemolysis remains under-appreciated. One reason for this is because IVIG is routinely given to so many patients. Another reason is its use by non-hematologists; that is, by neurologists, for treatment of neuropathies. Also, IVIG-hemolysis typically occurs after the patient has left the infusion site. When/if care is sought, the patient is seen by an emergency room physician who has not been involved with the preceding IVIG infusion. IVIG treatment often causes positive DAT3 which may instigate hemolysis. We have seen life-threatening instances following administration of IVIG where hemoglobin levels fell dramatically within 24 h.3, 5 In one case,5 a starting hemoglobin 12.9 g/dL, decreased to 8.4 g/dL 24 h after 2 g/kg IVIG for ITP, and nadired at 6.9 g/dL. This patient only returned to the hospital because of urinary discoloration and jaundice, and developed right-sided chest pain and dyspnea. The patient refused transfusion. The patient received oxygen for dyspnea but progressed to atrial fibrillation. By the end of the 10-day hospitalization, the hemoglobin had increased to 8.4 g/d. Of note, IVIG has beneficial effects in reducing the severity of COVID-1910 in adults, limiting cytokine storm, and in children, ameliorating multisystem inflammatory syndrome. This may further increase use of high dose IVIG which will likely increase hemolysis in vulnerable patients. Bottom line: greater attention is needed to anticipate, diagnose, and manage hemolysis to improve safety in patients receiving high IVIG doses for inflammatory diseases. In summary, increased awareness of hemolysis associated with IVIG is timely because this under-appreciated problem is surprisingly frequent and occasionally severe. Post-IVIG hemolysis can be anticipated based on recipient blood type, dose of IVIG, and ongoing inflammation. One manufacturer changed their IVIG processing to lower isoagglutinin titers, which resulted in less hemolysis.8, 9 DRB and JBB have been consultants for CSL Behring. JBB served on an unrelated DSMB for them. Data sharing not applicable to this article as no datasets were generated or analysed during the current study