Adam J. Kanack, Noah P. Splinter, Emily Mauch, Leben Tefera, Morayma Reyes Gil, Sakshi Jasra, Andrew Goodwin, Kristi J. Smock, Hadiyah Ahmad, Aneel A. Ashrani, Nathaniel L. Robinson, Ana I. Casanegra, Curtis G. Jones, Shannon M. Pechauer, erin yttre, Richard H. Aster, Mindy Kohlhagen, Rachel Leger, Gretchen Johns, David Murray, Lu Zhou, Demin Wang, Renren Wen, Dong Chen, Rajiv K. Pruthi, Anand Padmanabhan
BACKGROUND: Platelet factor 4-polyanion enzyme-linked immunosorbent assays (ELISAs) are considered highly sensitive for diagnosing heparin-induced thrombocytopenia (HIT), such that current practice guidelines recommend use of ELISA-negative results to exclude HIT. Once HIT is ruled out, alternative, non-heparin-based anticoagulant treatments are ceased, and heparin reintroduction frequently occurs. METHODS: Antigen-based and PF4-dependent functional testing were used to study PF4/polyvinylsulfonate ELISA-negative platelet-activating antibodies in HIT-suspected patients. RESULTS: Three patients with clinical presentations consistent with HIT tested negative in an ELISA using PF4-polyvinylsulfonate (PF4/PVS), an antigenic target very commonly used for HIT antibody screening. All three patients demonstrated PF4-dependent platelet activation in functional testing that was sensitive to blockade of platelet FcγRIIa receptors and inhibited by high concentrations of heparin, consistent with pathogenic HIT antibodies. Functional testing-based screening of 500 ELISA-negative patients identified three additional patients whose sera activated platelets in a PF4- and FcγRIIa-dependent manner and had clinical histories consistent with HIT. Five of the six ELISA-negative HIT patients were re-exposed to heparin, which precipitated a decrease in platelet counts in all re-exposed patients, and one patient developed a new thrombus. CONCLUSIONS: Recognition of ELISA-negative HIT is critical to avoid harm due to the cessation of alternative anticoagulation therapy and re-exposure of these patients to heparin.