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. 2021 Feb 25;137(8):1082-1089.
doi: 10.1182/blood.2020008195.

A prospective, blinded study of a PF4-dependent assay for HIT diagnosis

Bethany Samuelson Bannow  1 , Deepti M Warad  2   3 , Curtis G Jones  4 , Shannon M Pechauer  5 , Brian R Curtis  6 , Daniel W Bougie  5 , Ruchika Sharma  6 , Diane E Grill  7 , Mary W Redman  8 , Parisa R Khalighi  9 , Rachel R Leger  3 , Rajiv K Pruthi  3   10 , Dong Chen  3 , Daniel E Sabath  11   12 , Richard H Aster  5 , David A Garcia  12 , Anand Padmanabhan  3
Affiliations

A prospective, blinded study of a PF4-dependent assay for HIT diagnosis

Bethany Samuelson Bannow et al. Blood. .

Abstract

Heparin-induced thrombocytopenia (HIT) is a life-threatening, prothrombotic, antibody-mediated disorder. To maximize the likelihood of recovery, early and accurate diagnosis is critical. Widely available HIT assays, such as the platelet factor 4 (PF4) heparin enzyme-linked immunosorbent assay (ELISA) lack specificity, and the gold-standard carbon 14-labeled serotonin release assay (SRA) is of limited value for early patient management because it is available only through reference laboratories. Recent studies have demonstrated that pathogenic HIT antibodies selectively activate PF4-treated platelets and that a technically simpler assay, the PF4-dependent P-selectin expression assay (PEA), may provide an option for rapid and conclusive results. Based upon predefined criteria that combined 4Ts scores and HIT ELISA results, 409 consecutive adults suspected of having HIT were classified as disease positive, negative, or indeterminate. Patients deemed HIT indeterminate were considered disease negative in the primary analysis and disease positive in a sensitivity analysis. The ability of PEA and SRA to identify patients judged to have HIT was compared using receiver operating characteristic curve statistics. Using these predefined criteria, the diagnostic accuracy of PEA was high (area under the curve [AUC], 0.94; 95% confidence interval [CI], 0.87-1.0) and similar to that of SRA (AUC, 0.91; 95% CI, 0.82-1.0). In sensitivity analysis, the AUCs of PEA and SRA were also similar at 0.88 (95% CI, 0.78-0.98) and 0.86 (95% CI, 0.77-0.96), respectively. The PEA, a technically simple nonradioactive assay that uses ∼20-fold fewer platelets compared with the SRA, had high accuracy for diagnosing HIT. Widespread use of the PEA may facilitate timely and more effective management of patients with suspected HIT.

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Conflict of interest statement

Conflict-of-interest disclosure: C.G.J. reports issued patents on HIT diagnosis, with patents assigned to Versiti, Inc., and equity ownership and employment in Retham Technologies. B.R.C. reports personal fees from Ionis Pharmaceuticals and RallyBio, outside the submitted work, and an issued patent on HIT diagnosis, with the patent assigned to Versiti, Inc., outside the submitted work. D.W.B. reports issued patents on HIT diagnosis, with patents assigned to Versiti, Inc. R.K.P. reports honoraria for advisory board participation from CSL Behring, Genentech, Bayer Healthcare AG, HEMA Biologics, Instrumentation Laboratory, and Merck, outside the submitted work. R.H.A. reports issued patents on HIT diagnosis, with patents assigned to Versiti, Inc., and reports serving on the advisory board of Retham Technologies. D.A.G. reports grants from Incyte, personal fees and nonfinancial support from Janssen, personal fees from Seattle Genetics, and grants from Daiichi Sankyo, outside the submitted work. A.P. reports issued patents on HIT diagnosis, with patents assigned to Versiti, Inc., reports consulting fees and equity ownership in Retham Technologies, and reports serving on the advisory board of Veralox Therapeutics and as a consultant for Terumo BCT, outside the submitted work. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Study design. Consecutive samples suspected of HIT from two large tertiary care centers were evaluated in the PEA and SRA as shown. The central laboratory was blinded to clinical histories and HIT ELISA results. Disease state (HIT-positive) was pre-defined by clinico-pathologic diagnostic criteria.
Figure 2.
Figure 2.
Test results and accuracy. PEA and SRA test results for HIT+ (A), HIT-indeterminate (B), and HIT− (C) samples are shown. Open circles and triangles refer to SRA and PEA test results, respectively. Median results are listed above each data set. (D) ROC testing for SRA and PEA and AUC estimates with CIs are presented.
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Comment in

References

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