Current insights into the laboratory diagnosis of HIT

Abstract

Summary Heparin‐induced thrombocytopenia (HIT) is an adverse drug reaction and prothrombotic disorder caused by immunization against platelet factor 4 (PF4) after complex formation with heparin or other polyanions. After antibody binding to PF4/heparin complexes, HIT antibodies are capable of intravascular platelet activation by cross‐linking Fc gamma receptor IIa (FcγRIIa) on the platelet surface leading to a platelet count decrease and/or thrombosis. In contrast to most other immune‐mediated disorders, the currently available laboratory tests for anti‐PF4/heparin antibodies show a high sensitivity also for clinically irrelevant antibodies. This makes the diagnosis of HIT challenging and bears the risk to substantially overdiagnose HIT. The strength of the antigen assays for HIT is in ruling out HIT when the test is negative. Functional assays have a higher specificity for clinically relevant antibodies, but they are restricted to specialized laboratories. Currently, a Bayesian approach combining the clinical likelihood estimation for HIT with laboratory tests is the most appropriate approach to diagnose HIT. In this review, we give an overview on currently available diagnostic procedures and discuss their limitations.

The new and the old of heparin-induced thrombocytopenia

“…First, the rate of 'true HIT' (defined as intermediate/ high 4Ts score and positive HIPA) in their cohort of consecutively referred patients was much higher (at 25.9%) than typically reported in the literature (10%-15%) [7]. This high rate might suggest a more stringent pre-selection criteria applied by physicians at the authors' institution.…”

“…When the authors used an optimized cut-off ( ≥ 0.92 OD) based on the receiver-operating characteristic (ROC) analysis, the specificity increased to 88%. The lateral-flow immunoassay for the detection of HIT antibodies (Stago LFI-STic Expert ® HIT) is designed to evaluate one patient sample within 15 min without the need for special equipment [7]. This assay classified correctly 103 out of 114 patients, which equates to PPV and NPV of 75% and 97%, respectively.…”

Current management of heparin-induced thrombocytopenia

“…As a result, functional assays are generally accepted as the reference standard assays. However, such tests require referral to specialized reference laboratories as they are technically demanding, require human platelets from known reactive donors, and, in the case of the SRA, require radiation as donor platelets are incubated with 14 C serotonin, which is then stored in dense granules and released on platelet activation [37].…”

“…Immunological assays can detect anti-PF4-heparin antibodies regardless of their ability to activate platelets and can be polyspecific or IgG specific. ELISA is very sensitive and therefore their negative predictive value is high, while their positive predictive value is low with high rate of false positives and low specificity [37]. There is a correlation between the strength of the reaction with an ELISA (measured using optical density units [OD]) and the likelihood of clinical HIT [22] and the combination of a threshold >1.0 OD with a high clinical suspicion for HIT (e.g., intermediate or high 4Ts score) may have a similar accuracy for diagnosing HIT as the reference standard [22] as shown by a recent prospective cohort study comparing a commercial ELISA test and SRA [38,39].…”

En kvinne i 60-årene med store trombemasser i aorta

“…Flere laboratorier gjør derimot immunologiske tester. Immunologiske tester for heparinindusert trombocytopeni har en sensitivitet på naer 100 %, men varierende spesifisitet (40 -80 %) (17). En positiv test betyr ikke at antistoffene er klinisk relevante, de trenger ikke medføre plateaggregering og trombosedanning in vivo.…”