Download PDF
Thromb Haemost 2016; 115(05): 1044-1055
DOI: 10.1160/TH15-06-0523
New Technologies, Diagnostic Tools and Drugs
Schattauer GmbH

Diagnostic accuracy of rapid immunoassays for heparin-induced thrombocytopenia

A systematic review and meta-analysis
Lova Sun
1   Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
,
Phyllis A. Gimotty
2   Department of Biostatistics & Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
,
Suvasini Lakshmanan
3   Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
,
Adam Cuker
1   Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
4   Department of Pathology & Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
› Author Affiliations Financial Support: This work was supported by K23 HL112903 from the National Institutes of Health to AC.
Further Information

Publication History

Received: 30 June 2015

Accepted after major revision: 03 January 2015

Publication Date:
06 December 2017 (online)

    Permissions and Reprints

Summary

The platelet factor 4/heparin ELISA has limited specificity for heparininduced thrombocytopenia (HIT) and frequently does not provide same-day results. Rapid immunoassays (RIs) have been developed which provide results in 30 minutes or less. We conducted a systematic review and meta-analysis to evaluate the diagnostic accuracy of RIs for HIT. We searched the literature for studies in which samples from patients with suspected HIT were tested using a RI and a functional assay against which the performance of the RI could be measured. We performed sensitivity analyses of studies that directly compared different RIs with each other and with ELISAs. Estimates of sensitivity and specificity for each RI were calculated. Twenty-three articles, collectively involving six different RIs, met eligibility criteria. All RIs exhibited high sensitivity (0.96 to 1.00); there was wider variability in specificity (0.68 to 0.94). Specificity of the IgG-specific chemiluminescent assay (IgG-CA) was greater than the polyspecific chemiluminescent assay [0.94 (95 %CI 0.89–0.99) vs 0.82 (0.77–0.87)]. The particle gel immunoassay demonstrated greater specificity than the polyspecific ELISA [0.96 (0.95–0.97) vs 0.91 (0.89–0.92)]. The IgG-CA and lateral flow immunoassay [0.94 (0.91–0.97)] exhibited greater specificity than the IgG-specific ELISA [0.86 (0.82–0.90)]. Given their high sensitivity and rapid turnaround time, RIs are a reliable means of excluding HIT at the point-of-care in patients with low or intermediate clinical probability. Additionally, some RIs have greater specificity than HIT ELISAs. In summary, IgG-specific RIs appear to have improved diagnostic accuracy compared with ELISAs in patients with suspected HIT and may reduce misdiagnosis and overtreatment.

Keywords

Heparin - immunoassay - meta-analysis - review - thrombocytopenia
 

  • References

  • 1 Amiral J, Bridey F, Dreyfus M. et al. Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia. Thromb Haemost 1992; 68: 95-96.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Greinacher A, Pötzsch B, Amiral J. et al. Heparin-associated thrombocytopenia: isolation of the antibody and characterization of a multimolecular PF4-heparin complex as the major antigen. Thromb Haemost 1994; 71: 247-251.
    PubMedGoogle Scholar
  • 3 Cuker A. Heparin-induced thrombocytopenia (HIT) in 2011: an epidemic of overdiagnosis. Thromb Haemost 2011; 106: 993-994.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Warkentin TE, Chong BH, Greinacher A. Heparin-induced thrombocytopenia: towards consensus. Thromb Haemost 1998; 79: 1-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Warkentin TE. Platelet count monitoring and laboratory testing for heparin-induced thrombocytopenia. Arch Pathol Lab Med 2002; 126: 1415-1423.
    PubMedGoogle Scholar
  • 6 Walenga JM, Jeske WP, Fasanella AR. et al. Laboratory diagnosis of heparin-induced thrombocytopenia. Clin Appl Thromb Hemost 1999; 5 (Suppl. 01) S21-27.
    CrossrefPubMedGoogle Scholar
  • 7 Warkentin TE, Sheppard JA. Testing for heparin-induced thrombocytopenia antibodies. Transfus Med Rev 2006; 20: 259-272.
    CrossrefPubMedGoogle Scholar
  • 8 Cuker A. Clinical and laboratory diagnosis of heparin-induced thrombocytopenia: an integrated approach. Semin Thromb Hemost 2014; 40: 106-114.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Whiting PF, Rutjes AW, Westwood ME. et al. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med 2011; 155: 529-536.
    CrossrefPubMedGoogle Scholar
  • 10 Chu HaNLaCSRaPC. Meta-analysis of diagnostic accuracy studies accounting for disease prevalence: Alternative parameterizations and model selection. Statistics Med 2009; 28: 2384-2399.
    CrossrefPubMedGoogle Scholar
  • 11 Borenstein M, Hedges LV, Higgins JP. et al. A basic introduction to fixed-effect and random-effects models for meta-analysis. Res Synth Methods 2010; 1: 97-111.
    CrossrefPubMedGoogle Scholar
  • 12 Moher D, Shamseer L, Clarke M. et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 2015; 4: 1.
    CrossrefPubMedGoogle Scholar
  • 13 Alberio L, Kimmerle S, Baumann A. et al. Rapid determination of anti-heparin/platelet factor 4 antibody titres in the diagnosis of heparin-induced thrombocytopenia. Am J Med 2003; 114: 528-536.
    CrossrefPubMedGoogle Scholar
  • 14 Althaus K, Hron G, Strobel U. et al. Evaluation of automated immunoassays in the diagnosis of heparin induced thrombocytopenia. Thromb Res 2013; 131: e85-e90.
    CrossrefPubMedGoogle Scholar
  • 15 Andrews DM, Cubillos GF, Paulino SK. et al. Prospective observational evaluation of the particle immunofiltration anti-platelet factor 4 rapid assay in MICU patients with thrombocytopenia. Crit Care 2013; 17: R143.
    CrossrefPubMedGoogle Scholar
  • 16 Bakchoul T, Giptner A, Najaoui A. et al. Prospective evaluation of PF4/heparin immunoassays for the diagnosis of heparin-induced thrombocytopenia. J Thromb Haemost 2009; 7: 1260-1265.
    CrossrefPubMedGoogle Scholar
  • 17 Bryant A, Low J, Austin S. et al. Timely diagnosis and management of heparininduced thrombocytopenia in a frequent request, low incidence single centre using clinical 4T’s score and particle gel immunoassay. Br J Haematol 2008; 143: 721-726.
    CrossrefPubMedGoogle Scholar
  • 18 De Cooman L, Devreese KM. A rapid test (STic Expert(®)) for the diagnosis of heparin-induced thrombocytopenia. Br J Haematol. 2015 Epub ahead of print.
    PubMedGoogle Scholar
  • 19 Denys B, Stove V, Philippé J. et al. A clinical-laboratory approach contributing to a rapid and reliable diagnosis of heparin-induced thrombocytopenia. Thromb Res 2008; 123: 137-145.
    CrossrefPubMedGoogle Scholar
  • 20 Jourdy Y, Nougier C, Rugeri L. et al. Prospective evaluation of automatized PF4/heparin immunoassays HemosIL HIT-ab (PF4-H) for the diagnosis of heparin-induced thrombocytopenia. Int J Lab Hematol 2015; 37: 244-252.
    CrossrefPubMedGoogle Scholar
  • 21 Kapadia FN, Ketkar AS, Deshpande AS. et al. Evaluation of various laboratory assays in detection of heparin-induced thrombocytopenia in an adult general ICU. Int J Lab Hematol 2013; 35: 137-143.
    CrossrefPubMedGoogle Scholar
  • 22 Kolde HJ, Dostatni R, Mauracher S. Rapid and simple IgG specific test for the exclusion of heparin induced thrombocytopenia (HIT). Clin Chem Lab Med 2011; 49: 2065-2068.
    PubMedGoogle Scholar
  • 23 Kolde HJ, Habrecht U, von Hesberg J. et al. Multicentric validation of a rapid assay for heparin-induced thrombocytopenia with different specimen types. Blood Coagul Fibrinolysis 2014; 25: 6-9.
    CrossrefPubMedGoogle Scholar
  • 24 Legnani C, Cini M, Pili C. et al. Evaluation of a new automated panel of assays for the detection of anti-PF4/heparin antibodies in patients suspected of having heparin-induced thrombocytopenia. Thromb Haemost 2010; 104: 402-409.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Leroux D, Hezard N, Lebreton A. et al. Prospective evaluation of a rapid nanoparticle- based lateral flow immunoassay (STic Expert(®) HIT) for the diagnosis of heparin-induced thrombocytopenia. Br J Haematol 2014; 166: 774-782.
    CrossrefPubMedGoogle Scholar
  • 26 Linkins LA, Bates SM, Lee AY. et al. Combination of 4Ts score and PF4/H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia: prospective cohort study. Blood 2015; 126: 597-603.
    CrossrefPubMedGoogle Scholar
  • 27 Meyer O, Salama A, Pittet N. et al. Rapid detection of heparin-induced platelet antibodies with particle gel immunoassay (ID-HPF4). Lancet 1999; 354: 1525-1526.
    CrossrefPubMedGoogle Scholar
  • 28 Minet V, Bailly N, Douxfils J. et al. Assessment of the performances of AcuStar HIT and the combination with heparin-induced multiple electrode aggregometry: a retrospective study. Thromb Res 2013; 132: 352-359.
    CrossrefPubMedGoogle Scholar
  • 29 Nellen V, Sulzer I, Barizzi G. et al. Rapid exclusion or confirmation of heparininduced thrombocytopenia: a single-centre experience with 1,291 patients. Haematologica 2012; 97: 89-97.
    CrossrefPubMedGoogle Scholar
  • 30 Pouplard C, Gueret P, Fouassier M. et al. Prospective evaluation of the ‘4Ts’ score and particle gel immunoassay specific to heparin/PF4 for the diagnosis of heparin-induced thrombocytopenia. J Thromb Haemost 2007; 5: 1373-1379.
    CrossrefPubMedGoogle Scholar
  • 31 Sachs UJ, von Hesberg J, Santoso S. et al. Evaluation of a new nanoparticle-based lateral-flow immunoassay for the exclusion of heparin-induced thrombocytopenia (HIT). Thromb Haemost 2011; 106: 1197-1202.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 Solano C, Mutsando H, Self M. et al. Using HitAlert flow cytometry to detect heparin-induced thrombocytopenia antibodies in a tertiary care hospital. Blood Coagul Fibrinolysis 2013; 24: 365-370.
    CrossrefPubMedGoogle Scholar
  • 33 Tawfik NM, Hegazy MA, Hassan EA. et al. Egyptian experience of reliability of 4T’s score in diagnosis of heparin induced thrombocytopenia syndrome. Blood Coagul Fibrinolysis 2011; 22: 701-705.
    CrossrefPubMedGoogle Scholar
  • 34 Van Hoecke F, Devreese K. Evaluation of two new automated chemiluminescent assays (HemosIL® AcuStar HIT-IgG and HemosIL® AcuStar HIT-Ab) for the detection of heparin-induced antibodies in the diagnosis of heparin-induced thrombocytopenia. Int J Lab Hematol 2012; 34: 410-416.
    CrossrefPubMedGoogle Scholar
  • 35 Vianello F, Sambado L, Scarparo P. et al. Comparison of three different immunoassays in the diagnosis of heparin-induced thrombocytopenia. Clin Chem Lab Med 2015; 53: 257-263.
    PubMedGoogle Scholar
  • 36 Pauzner R, Greinacher A, Selleng K. et al. False-positive tests for heparin-induced thrombocytopenia in patients with antiphospholipid syndrome and systemic lupus erythematosus. J Thromb Haemost 2009; 7: 1070-1074.
    CrossrefPubMedGoogle Scholar
  • 37 Warkentin TE, Greinacher A, Gruel Y. et al. Laboratory testing for heparin-induced thrombocytopenia: a conceptual framework and implications for diagnosis. J Thromb Haemost 2011; 9: 2498-2500.
    CrossrefPubMedGoogle Scholar
  • 38 Amiral J, Marfaing-Koka A, Wolf M. et al. Presence of autoantibodies to interleukin- 8 or neutrophil-activating peptide-2 in patients with heparin-associated thrombocytopenia. Blood 1996; 88: 410-416.
    PubMedGoogle Scholar
  • 39 Amiral J. Antigens involved in heparin-induced thrombocytopenia. Semin Hematol 1999; 36 (01) (Suppl. 01) 7-11.
    PubMedGoogle Scholar
  • 40 Juhl D, Eichler P, Lubenow N. et al. Incidence and clinical significance of anti- PF4/heparin antibodies of the IgG, IgM, and IgA class in 755 consecutive patient samples referred for diagnostic testing for heparin-induced thrombocytopenia. Eur J Haematol 2006; 76: 420-426.
    CrossrefPubMedGoogle Scholar
  • 41 Schneiter S, Colucci G, Sulzer I. et al. Variability of anti-PF4/heparin antibody results obtained by the rapid testing system ID-H/PF4-PaGIA. J Thromb Haemost 2009; 7: 1649-1655.
    CrossrefPubMedGoogle Scholar
  • 42 Cuker A, Rux AH, Hinds JL. et al. Novel diagnostic assays for heparin-induced thrombocytopenia. Blood 2013; 121: 3727-3732.
    CrossrefPubMedGoogle Scholar
  • 43 Raschke RA, Curry SC, Warkentin TE. et al. Improving clinical interpretation of the anti-platelet factor 4/heparin enzyme-linked immunosorbent assay for the diagnosis of heparin-induced thrombocytopenia through the use of receiver operating characteristic analysis, stratum-specific likelihood ratios, and Bayes theorem. Chest 2013; 144: 1269-1275.
    CrossrefPubMedGoogle Scholar
  • 44 Zwicker JI, Uhl L, Huang WY. et al. Thrombosis and ELISA optical density values in hospitalized patients with heparin-induced thrombocytopenia. J Thromb Haemost 2004; 2: 2133-2137.
    CrossrefPubMedGoogle Scholar
  • 45 Warkentin TE, Sheppard JI, Moore JC. et al. Quantitative interpretation of optical density measurements using PF4-dependent enzyme-immunoassays. J Thromb Haemost 2008; 6: 1304-1312.
    CrossrefPubMedGoogle Scholar
  • 46 Price EA, Hayward CP, Moffat KA. et al. Laboratory testing for heparin-induced thrombocytopenia is inconsistent in North America: a survey of North American specialized coagulation laboratories. Thromb Haemost 2007; 98: 1357-1361.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 47 Nazi I, Arnold DM, Moore JC. et al. Pitfalls in the diagnosis of heparin-Induced thrombocytopenia: A 6-year experience from a reference laboratory. Am J Hematol 2015; 90: 629-633.
    CrossrefPubMedGoogle Scholar
  • 48 Warkentin TE. Scoring systems for heparin-induced thrombocytopenia (HIT): whither now?. Thromb Haemost 2015; 113: 437-438.
    Article in Thieme ConnectPubMedGoogle Scholar