Journal of Preventive Medicine & Infectious Diseases

Abstract

Background and Objective: Innocent bystander haemolysis (IBH) is an immune-mediated destruction of red blood cells (RBCs) in which antigen-negative erythrocytes are lysed as collateral casualties of complement activation triggered elsewhere. It is encountered in three principal clinical settings in transfusion medicine: drug-induced immune haemolytic anaemia (DIIHA), delayed haemolytic transfusion reaction (DHTR) with hyperhaemolysis syndrome (HHS) in sickle cell disease (SCD), and passenger lymphocyte syndrome (PLS) following transplantation. Despite its clinical importance, IBH is frequently underdiagnosed owing to atypical serological findings. This review examines the historical evolution, immunological basis, clinical mechanisms, laboratory diagnosis, and therapeutic management of IBH.

Methods: PubMed, Google Scholar, and reference-list searching were used to identify peer-reviewed literature on IBH, DIIHA, HHS, DHTR, PLS, and complement-mediated haemolysis published between 1965 and 2025.

Key Content and Findings: IBH arises through classical pathway complement activation, with secondary amplification via the alternative pathway. Key presentations include DIIHA (16–18% of acquired immune haemolytic anaemia), HHS complicating approximately 4% of transfusions in SCD, and PLS in up to 18% of minor ABO-incompatible transplants. Diagnosis relies on a complement-only or complement-predominant direct antiglobulin test (DAT), biochemical haemolysis markers, and drug or transfusion history, but is frequently delayed because routine alloantibody screening is negative. Management centres on removing the precipitating cause, first-line immunosuppression with corticosteroids and intravenous immunoglobulin (IVIG), avoidance of further transfusion in HHS, and escalation to targeted biologics — eculizumab, rituximab, and tocilizumab — in refractory cases. Extended RBC genotyping and complement inhibitor therapies represent the frontiers of prevention and treatment.

Conclusions: IBH spans multiple haematological and transplant settings and demands a high index of clinical suspicion, especially when haemolysis occurs despite a compatible crossmatch. Expanding access to extended RBC genotyping, standardised diagnostic protocols, and complement inhibitor therapies is central to improving outcomes in affected patients.