HIT or miss? A comprehensive contemporary investigation of laboratory tests for heparin induced thrombocytopenia

Favaloro, Emmanuel J.; McCaughan, Georgia; Mohammed, Soma; Lau, Kun Kan Edwin; Gemmell, Rosalie; Cavanaugh, Lauren; Donikian, Dea; Kondo, Mayuko; Brighton, Timothy; Pasalic, Leonardo

doi:10.1016/j.pathol.2017.11.089

Cited by 37 publications

(58 citation statements)

References 25 publications

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“…Interestingly, initial reports around laboratory testing for HIT mostly comprised functional assays performed to assess platelet aggregation in response to patient sera in the presence of heparin . Experience from my own laboratory suggests that using standard light transmission aggregometry (LTA) to assess functional HIT reflects perhaps the least sensitive approach among current technologies . Many different immunological and functional assays have been developed from the first reports.…”

Section: Background and Historical Perspectivementioning

confidence: 99%

“…The most common contemporary immunological assays comprise enzyme‐linked immunosorbent assay [ELISA], chemiluminescence, lateral flow and particle gel techniques . The most common functional assays still comprise platelet aggregation or platelet activation, but for the former, whole blood aggregation (WBA), for example using the Multiplate system, seems more sensitive to pathological HIT than classical LTA . However, assays that assess platelet activation events, which precedes platelet aggregation, as theoretically measured by release of internalized platelet components (e.g., serotonin release assay; SRA) or exposure of external platelet receptors (typically by flow cytometry), are even more potentially sensitive than aggregation assays .…”

Section: Background and Historical Perspectivementioning

confidence: 99%

“…In general, immunological assays are more sensitive to HIT than functional assays, but functional assays are much more specific for pathological HIT. In our experience, ELISA was found to be more sensitive, for example, than either lateral flow or chemiluminescence, but chemiluminescence yielded fewer “false positives” than ELISA, and thus expressed greater potential specificity for pathological HIT . On the other hand, the ELISA procedure was less prone to missing HIT than either lateral flow or chemiluminescence .…”

Section: Preanalytical and Analytical Considerationsmentioning

confidence: 99%

“…In our experience, ELISA was found to be more sensitive, for example, than either lateral flow or chemiluminescence, but chemiluminescence yielded fewer “false positives” than ELISA, and thus expressed greater potential specificity for pathological HIT . On the other hand, the ELISA procedure was less prone to missing HIT than either lateral flow or chemiluminescence . Analogously, LTA showed poorer sensitivity and specificity compared to the Multiplate system, but seemed less prone to false positives .…”

Section: Preanalytical and Analytical Considerationsmentioning

confidence: 99%

“…On the other hand, the ELISA procedure was less prone to missing HIT than either lateral flow or chemiluminescence . Analogously, LTA showed poorer sensitivity and specificity compared to the Multiplate system, but seemed less prone to false positives . However, our laboratory's experience with HIT testing may or may not reflect the experience of other workers in the field; such is the complicated landscape which HIT testing reflects.…”

Section: Preanalytical and Analytical Considerationsmentioning

confidence: 99%

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Laboratory tests for identification or exclusion of heparin induced thrombocytopenia: HIT or miss?

Favaloro

2017

American J Hematol

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Heparin induced thrombocytopenia (HIT) is a potentially fatal condition that arises subsequent to formation of antibodies against complexes containing heparin, usually platelet-factor 4-heparin ("anti-PF4-heparin"). Assessment for HIT involves both clinical evaluation and, if indicated, laboratory testing for confirmation or exclusion, typically using an initial immunological assay ("screening"), and only if positive, a secondary functional assay for confirmation. Many different immunological and functional assays have been developed. The most common contemporary immunological assays comprise enzyme-linked immunosorbent assay [ELISA], chemiluminescence, lateral flow, and particle gel techniques. The most common functional assays measure platelet aggregation or platelet activation events (e.g., serotonin release assay; heparin-induced platelet activation (HIPA); flow cytometry). All assays have some sensitivity and specificity to HIT antibodies, but differ in terms of relative sensitivity and specificity for pathological HIT, as well as false negative and false positive error rate. This brief article overviews the different available laboratory methods, as well as providing a suggested approach to diagnosis or exclusion of HIT.

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Section: Background and Historical Perspectivementioning

confidence: 99%

Section: Background and Historical Perspectivementioning

confidence: 99%

Section: Preanalytical and Analytical Considerationsmentioning

confidence: 99%

Section: Preanalytical and Analytical Considerationsmentioning

confidence: 99%

Section: Preanalytical and Analytical Considerationsmentioning

confidence: 99%

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Laboratory tests for identification or exclusion of heparin induced thrombocytopenia: HIT or miss?

Favaloro

2017

American J Hematol

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Serotonin‐release assay‐positive but platelet factor 4‐dependent enzyme‐immunoassay negative: HIT or not HIT?

et al. 2020

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IgG‐specific and polyspecific PF4‐dependent enzyme‐immunoassays (EIAs) have exceptionally high sensitivity (≥99%) for diagnosis of heparin‐induced thrombocytopenia (HIT), a drug reaction caused by platelet‐activating antibodies detectable by serotonin‐release assay (SRA). The IgG‐specific EIAs are recommended for screening, as their high sensitivity is accompanied by relatively high specificity vis‐à‐vis polyspecific EIAs. We investigated the frequency of SRA‐positive/EIA‐negative (SRA+/EIA−) HIT, prompted by referral to our reference HIT laboratory of serial blood samples from a patient (“index case”) with false‐negative IgG‐specific EIAs. Despite initial clinical suspicion for HIT, repeat negative IgG‐specific EIAs prompted heparin resumption, which triggered recurrent thrombocytopenia and near‐fatal cardiac arrest, indicating likely post‐heparin HIT‐associated anaphylactoid reaction. Further investigations revealed a strong‐positive SRA, whether performed with heparin alone, PF4 alone, or PF4/heparin, with inhibition by Fc receptor‐blocking monoclonal antibody (indicating IgG‐mediated platelet activation); however, five different IgG‐specific immunoassays yielded primarily negative (or weak‐positive) results. To investigate the frequency of SRA+/EIA− HIT, we reviewed the laboratory and clinical features of patients with this serological profile during a 6‐year period in which our reference laboratory investigated for HIT using both SRA and IgG‐specific EIA. Although ~0.2% of 8546 patients had an SRA+/EIA− profile, further review of 15 such cases indicated clerical/laboratory misclassification or false‐positive SRA in all, with no SRA+/EIA− HIT case identified. We conclude that while SRA+/EIA− HIT is possible—as shown by our index case—this clinical picture is exceptionally uncommon. Moreover, the requirement for a positive EIA is a useful quality control maneuver that reduces risk of reporting a false‐positive SRA result.

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Heparin-Induced Thrombotic Thrombocytopenia (HITT) and Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT): Similar but Different

Favaloro

Pasalic

2023

Methods in Molecular Biology

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HIT or miss? A comprehensive contemporary investigation of laboratory tests for heparin induced thrombocytopenia

Cited by 37 publications

References 25 publications

Laboratory tests for identification or exclusion of heparin induced thrombocytopenia: HIT or miss?

Laboratory tests for identification or exclusion of heparin induced thrombocytopenia: HIT or miss?

Serotonin‐release assay‐positive but platelet factor 4‐dependent enzyme‐immunoassay negative: HIT or not HIT?

Heparin-Induced Thrombotic Thrombocytopenia (HITT) and Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT): Similar but Different

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