A rapid test (STic Expert® ) for the diagnosis of heparin-induced thrombocytopenia--response to De Cooman and Devreese.

Abstract

The letter by de Cooman and Devreese is interesting as these authors have evaluated the clinical pre-test 4T's score combined with the STic Expert® HIT (Diagnostica Stago, Asnières sur Seine, France) in a retrospective cohort of 153 patients to exclude the diagnosis of heparin-induced thrombocytopenia (HIT). The authors compared their data to those we recently published (Leroux et al, 2014), and found a false negative result using this rapid nano-particle flow immunoassay in one patient. Briefly, the pre-test probability of HIT evaluated with the 4Ts score system in this patient was low (score = 3), and the STic Expert® HIT was negative, suggesting that HIT was unlikely. However, an IgG-specific immunoassay (Asserachrom® HPIA IgG, Diagnostica Stago) was positive, although a relatively low optical density (OD) value (0·725, cut-off = 0·251) was measured. Finally, the investigators confirmed the diagnosis of HIT in this patient based on the results of a flow cytometric CD62p functional assay, and concluded that caution was appropriate when the STic Expert® HIT was used with the possibility of false negative results. Several points about the methods that were applied, which may limit the clinical impact of this study, have to be discussed. First, the performances of STic Expert® HIT were evaluated retrospectively by testing frozen plasma samples collected over an 8-year period. However, this rapid assay is a screening test primarily designed for testing fresh plasma or serum in emergency conditions, and the evaluation of frozen samples has therefore not been recommended. Also, the definite diagnosis of HIT used by De Cooman and Devreese was based on the detection of platelet activation by a flow cytometric method that has been mainly used in few laboratories and remains to be validated prospectively in a large cohort of patients, compared with a validated and highly sensitive/specific functional assay, such as the serotonin release assay (SRA). In addition, the authors did not define the percentage of positive CD62p (p-selectin; SELP) platelets measured with their assay in the presence of patient plasma and heparin, and this result could be critical due to the apparent low level of anti-platelet factor 4 (PF4) antibodies detected by Asserachrom® HPIA IgG. Recently, we also recorded a false negative result with the STic Expert® HIT used on a fresh plasma sample, associated with a low OD value (0·77) measured by a PF4-specific enzyme immunoassay (EIA) (HAT® 45, Genetic Testing Institute Diagnostics, Waukesha, WI, USA). However, the pre-test probability of HIT was high in our patient (4T score = 7) and the SRA was strongly positive (maximum release 66%). We therefore agree that in practice, clinicians and biologists have to be very careful regarding the diagnosis and management of HIT given that most assays or scoring systems exhibit a negative predictive value not equal to 100%. The clinical features used to calculate clinical scores, such as the 4Ts or the HIT Expert Probability score (Cuker et al, 2010) have to be rigorously recorded. Furthermore, the interpretation of HIT laboratory tests has to take into account the clinical history, the OD value measured with EIA (as recently outlined by Cuker, 2014) and the extent of heparin-dependent platelet activation measured with functional assays. As recommended by the Platelet Immunology Working Group on HIT for the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (Warkentin et al, 2011), ‘the diagnosis of HIT requires a clinical scenario in which HIT is judged to be the most plausible diagnosis, generally meeting at least an intermediate probability for HIT (judged by a clinical scoring system), plus either a strong positive EIA-IgG or, preferably, a positive test for platelet-activating antibodies’. However, an improvement in the standardization of HIT immunoassays allowing a more precise quantification of pathogenic IgG antibodies to modified PF4 would be very helpful for the diagnosis of HIT in suspected patients.