Two roads diverged: Emerging lessons from IVIG about hemolysis

See article on page 1053–1063, in this issue Hemolysis is an important adverse event of transfusion, perhaps most notably exemplified by the acute hemolytic transfusion reaction. This classically arises from major ABO incompatibility, where patient with ABO-incompatible RBCs leads to opsonization circulating complement-fixing immunoglobulin (Ig) M and intravascular hemolysis.1 Acute hemolysis can lead devastating outcomes, including disseminated coagulation, endothelial dysfunction, death. Therefore, prevention incompatibility a RBC top priority.2 The number Food Drug Administration (FDA)-reported fatalities due transfusions has decreased substantially over last decade, 1 per 2 million units transfused 2000–2009 7.14 2010–2019.3 Today, mismatch-related reactions are clerical errors sample collection (e.g., wrong blood tube).3 In contrast minor much more commonly encountered clinically, for example, products containing antibodies, such as platelets plasma-derived products. generally acceptable practice United States except neonates. Non-ABO-matched well-tolerated, pointing relative safety low doses incompatible antibodies. One study estimated overall rate plasma-incompatible platelet be 0.12%.4 A 2005 survey North American laboratories found that 83% responding institutions had policy use plasma products, although specifics differed greatly, highlighting absence formal consensus.5 Another source intravenous (IVIG). IVIG antibody-containing fraction prepared pooled donor includes used at two dosing regimens: low-dose replete humoral immunity immunodeficient individuals, while high-dose attenuate inflammation autoimmune diseases chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, immune thrombocytopenic purpura, Kawasaki disease. 2008 retrospective 1000 patients IVIG-related reaction 1.6%.6 Despite efforts limit anti-ABO titers IVIG, IVIG-mediated reported FDA increased since 2011, even warranting workshop convened 2014.7 good understanding scale mechanistic drivers remains elusive. Confounding factors include (i) paucity data type recipient patients, (ii) variable product used, (iii) different regimens, (iv) criteria define hemolysis, (v) surveillance regimens.8-10 It critical clarify contribution product- patient-specific develop effective precise mitigating strategies. review 263 cases between 2003 2014 risk (≥2 g/kg) non-group O recipients.10 Interestingly, median anti-A anti-B implicated were 16 8, respectively, well within limits recommended European Pharmacopoeia. These findings raise questions about whether stringent might value which benefit them. regard, reflect not just complement-driven proportionate antibody dose but also accelerated destruction opsonized extravascular hemolysis.11, 12 Extravascular regulated only isoagglutinins poorly understood factors, underlying state.7 Understanding role could provide insight into underpinnings hemolysis. TRANSFUSION, Pendergrast et al. performed prospective incidence IVIG-induced Guided their pilot data, they focused treated IVIG. They demonstrated high (32%) after therapy, grade 4 representing 22% those cases, all clinically stable throughout. Median interval treatment testing revealing was 7 days. slightly longer than previous studies 0–4 days post-IVIG infusion, may have enhanced detection.10, 13 No clear product-associated emerged analysis. Patient associated included AB nonconcurrent immunosuppressants. 88% positive direct antiglobulin test (DAT), sufficient explain 49% nonhemolytic infusions DAT. DAT strength does complete unifying explanation; 19% showed >1+, 57% suggesting importance ABO-independent factors. evaluated several particularly regulate High-risk Fc receptor (FcR)polymorphisms Of particular interest, using monocyte monolayer assay (MMA) monocytes who (“hemolyzers”) uptake drawn hemolyzers infusion. Supporting hypothesis necessary, did show hemolyzer-derived before Demonstrating impact facet function, healthy control individuals Together, these results suggest MMA reveals dysregulation function predisposes individual efficient clearance RBCs. related immunosuppressants prior Although find clinical markers hemolyzers, exclude specific mechanistically dysregulation. For recent driven TLR7 signaling drive development hemophagocytes.14 exemplify how pathways modulate innate cells essential Taken together, demonstrates help predict complexity limited availability confound widespread application stratify patients. However, point interrogating other phagocytes identify better biomarkers pathophysiologic pathways, potential therapies. Indeed, relatively controlled setting understand broader implications settings alloimmunization, anemia, others. None.