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To describe the prevalence of heparin-induced thrombocytopenia (HIT) in patients on extracorporeal membrane oxygenation (ECMO) and to explore ways to improve the diagnostic accuracy of the HIT enzyme-linked immunosorbent assay (ELISA). Retrospective review of all patients needing ECMO between September 2011 and September 2020 who underwent evaluation for HIT while on ECMO. The diagnosis of HIT required a confirmatory serotonin release assay (SRA). Various break points for the optical density (OD) that defines a positive HIT ELISA were examined to estimate their utility as screening tests for HIT. Patient outcomes served as a secondary endpoint. Among 417 ECMO patients, 162 (38.8%) had a HIT ELISA. Of these, 114 (70.4%) had a subsequent SRA. Although the HIT ELISA was positive at an OD ≥ 0.4 in 1/3 rd of subjects, only 15 subjects met criteria for HIT by SRA. Hence, the prevalence of HIT equaled 3.6%. At an OD ≥ 0.4 the ELISA had both poor specificity (71.7%) and accuracy (74.6%). Changing the definition of the ELISA to an OD ≥ 1.2 improved both specificity and accuracy with only a limited impact on sensitivity. Nearly 60% of those with HIT developing during ECMO died. HIT is infrequent in persons requiring ECMO. However, HIT remains associated with substantial mortality. The HIT ELISA as currently implemented performs poorly as a screening test and likely results in the unnecessary overuse of alternatives to unfractionated heparin. Altering the definition of a positive OD improves the HIT ELISA's accuracy., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)