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Original Research: Critical Care |

A Novel PF4-Dependent Platelet Activation Assay Identifies Patients Likely to Have Heparin-Induced Thrombocytopenia/Thrombosis

Anand Padmanabhan, MD, PhD; Curtis G. Jones, BS; Brian R. Curtis, PhD; Daniel W. Bougie, PhD; Mia J. Sullivan, BS; Namrata Peswani, MD; Janice G. McFarland, MD; Daniel Eastwood, MS; Demin Wang, PhD; Richard H. Aster, MD
Author and Funding Information

FUNDING/SUPPORT: This study was supported in part by funds from the National Blood Foundation, American Heart Association, CTSI of Southeastern Wisconsin (A. P.), and by National Institutes of Health [grant HL-13629 (R. H. A.)].

aMedical Sciences Institute, BloodCenter of Wisconsin, Milwaukee, WI

bBlood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI

cPlatelet and Neutrophil Immunology Laboratory, BloodCenter of Wisconsin, Milwaukee, WI

dDepartment of Pathology, Medical College of Wisconsin, Milwaukee, WI

eDepartment of Medicine, Medical College of Wisconsin, Milwaukee, WI

fDepartment of Biostatistics, Medical College of Wisconsin, Milwaukee, WI

gDepartment of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI

CORRESPONDENCE TO: Anand Padmanabhan, MD, PhD, BloodCenter of Wisconsin, 8733 Watertown Plank Rd, Milwaukee, WI 53226-3548


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;150(3):506-515. doi:10.1016/j.chest.2016.02.641
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Background  Almost without exception, patients with heparin-induced thrombocytopenia/thrombosis (HIT) have antibodies that recognize platelet factor 4 (PF4) in a complex with heparin; however, many heparin-treated patients without HIT are also antibody-positive. A platelet activation test, the serotonin release assay (SRA), is useful for identifying a subset of antibodies that are platelet-activating and most likely to cause HIT. However, this “gold standard” assay for HIT diagnosis is technically demanding and is routinely available only through referral laboratories, limiting its availability for timely diagnosis and management.

Methods  We compared the diagnostic performance of the SRA with that of a technically simple platelet activation assay, the PF4-dependent P-selectin expression assay (PEA), which uses platelets pretreated with PF4 as targets for antibody detection. Archived serum samples from 91 patients for whom clinical information (HIT 4Ts [thrombocytopenia, timing of platelet count fall, thrombosis, and other causes of thrombocytopenia] score) was available were used. Patients with an intermediate 4Ts score and a PF4 ELISA (enzyme-linked immunosorbent assay) optical density ≥ 2.0, or a high 4Ts score and a PF4 ELISA optical density ≥ 1.0, were considered HIT positive; others were designated HIT negative.

Results  The PEA had higher diagnostic accuracy (area under the curve, 0.92 vs 0.82; P = .02) than the SRA, using this definition of HIT. Eleven of 16 serum samples that were PEA positive and SRA negative were HIT positive. Studies done with identical target platelets and serially diluted samples from patients with HIT showed that the PEA is inherently more sensitive than the SRA for the detection of platelet-activating antibodies.

Conclusions  The PEA is technically less demanding than the SRA and may be more accurate for the diagnosis of HIT.

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