Diagnostic value of immunoassays for heparin-induced thrombocytopenia: a systematic review and meta-analysis.

Immunoassays are essential in the workup of patients with suspected heparin-induced thrombocytopenia. However, the diagnostic accuracy is uncertain with regard to different classes of assays, antibody specificities, thresholds, test variations, and manufacturers. We aimed to assess diagnostic accuracy measures of available immunoassays and to explore sources of heterogeneity. We performed comprehensive literature searches and applied strict inclusion criteria. Finally, 49 publications comprising 128 test evaluations in 15 199 patients were included in the analysis. Methodological quality according to the revised tool for quality assessment of diagnostic accuracy studies was moderate. Diagnostic accuracy measures were calculated with the unified model (comprising a bivariate random-effects model and a hierarchical summary receiver operating characteristics model). Important differences were observed between classes of immunoassays, type of antibody specificity, thresholds, application of confirmation step, and manufacturers. Combination of high sensitivity (>95%) and high specificity (>90%) was found in 5 tests only: polyspecific enzyme-linked immunosorbent assay (ELISA) with intermediate threshold (Genetic Testing Institute, Asserachrom), particle gel immunoassay, lateral flow immunoassay, polyspecific chemiluminescent immunoassay (CLIA) with a high threshold, and immunoglobulin G (IgG)-specific CLIA with low threshold. Borderline results (sensitivity, 99.6%; specificity, 89.9%) were observed for IgG-specific Genetic Testing Institute-ELISA with low threshold. Diagnostic accuracy appears to be inadequate in tests with high thresholds (ELISA; IgG-specific CLIA), combination of IgG specificity and intermediate thresholds (ELISA, CLIA), high-dose heparin confirmation step (ELISA), and particle immunofiltration assay. When making treatment decisions, clinicians should be a aware of diagnostic characteristics of the tests used and it is recommended they estimate posttest probabilities according to likelihood ratios as well as pretest probabilities using clinical scoring tools.

[1]  Johannes B Reitsma,et al.  Evidence of bias and variation in diagnostic accuracy studies , 2006, Canadian Medical Association Journal.

[2]  G. Kershaw,et al.  The Diamed assay has a poor positive predictive value for HIT in a tertiary hospital referral setting , 2007, International journal of laboratory hematology.

[3]  J. Dogné,et al.  Rapid exclusion of the diagnosis of immune HIT by AcuStar HIT and heparin-induced multiple electrode aggregometry. , 2014, Thrombosis research.

[4]  A. Greinacher.  CLINICAL PRACTICE. Heparin-Induced Thrombocytopenia. , 2015, The New England journal of medicine.

[5]  T. Warkentin,et al.  Immunoassays are not created equal , 2009, Journal of thrombosis and haemostasis : JTH.

[6]  A. Greinacher,et al.  Combined use of the high heparin step and optical density to optimize diagnostic sensitivity and specificity of an anti-PF4/heparin enzyme-immunoassay. , 2011, Thrombosis research.

[7]  J. Moran,et al.  Failure of early heparin cessation as treatment for heparin-induced thrombocytopenia. , 1999, The American journal of medicine.

[8]  Johannes B Reitsma,et al.  Bivariate analysis of sensitivity and specificity produces informative summary measures in diagnostic reviews. , 2005, Journal of clinical epidemiology.

[9]  Brahim Admou,et al.  Contributions of biological tests and the 4 Ts score in the diagnosis of Heparin Induced Thrombocytopenia , 2012, The Pan African medical journal.

[10]  Y. Gruel,et al.  Prospective evaluation of the ‘4Ts’ score and particle gel immunoassay specific to heparin/PF4 for the diagnosis of heparin‐induced thrombocytopenia , 2007, Journal of thrombosis and haemostasis : JTH.

[11]  A. Dans,et al.  Treatment and Prevention of Heparin-Induced Thrombocytopenia Antithrombotic Therapy and Prevention of Thrombosis , 9 th ed : American College of Chest Physicians Evidence-Based Clinical Practice Guidelines , 2011 .

[12]  J. Dogné,et al.  Assessment of the performances of AcuStar HIT and the combination with heparin-induced multiple electrode aggregometry: a retrospective study. , 2013, Thrombosis research.

[13]  G. Raskob,et al.  Heparin-Induced Thrombocytopenia , 2013, Thrombosis and Haemostasis.

[14]  T. Warkentin,et al.  Testing for heparin-induced thrombocytopenia antibodies. , 2006, Transfusion medicine reviews.

[15]  J. Kelton,et al.  Quantitative interpretation of optical density measurements using PF4‐dependent enzyme‐immunoassays , 2008, Journal of thrombosis and haemostasis : JTH.

[16]  J. Mazur,et al.  Evaluation of heparin-induced thrombocytopenia (HIT) laboratory testing and the 4Ts scoring system in the intensive care unit. , 2013, Annals of clinical and laboratory science.

[17]  D. Altman,et al.  Diagnostic tests 4: likelihood ratios , 2004, BMJ : British Medical Journal.

[18]  J. Philippé,et al.  A clinical-laboratory approach contributing to a rapid and reliable diagnosis of heparin-induced thrombocytopenia. , 2008, Thrombosis research.

[19]  R. Abbate,et al.  Evaluation of automated immunoassays in the diagnosis of heparin induced thrombocytopenia. , 2013, Thrombosis research.

[20]  C M Rutter,et al.  A hierarchical regression approach to meta‐analysis of diagnostic test accuracy evaluations , 2001, Statistics in medicine.

[21]  G. Bein,et al.  Prospective evaluation of PF4/heparin immunoassays for the diagnosis of heparin‐induced thrombocytopenia , 2009, Journal of thrombosis and haemostasis : JTH.

[22]  A. Greinacher,et al.  The new ID‐heparin/PF4 antibody test for rapid detection of heparin‐induced antibodies in comparison with functional and antigenic assays , 2002, British journal of haematology.

[23]  R. Gerkin,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. , 2013, Chest.

[24]  D. Hoppensteadt,et al.  Pharmacokinetics of low molecular weight heparins in animal models. , 1999, Seminars in thrombosis and hemostasis.

[25]  A. Angelillo-Scherrer,et al.  Diagnostic value of the 4Ts score for heparin-induced thrombocytopenia in the critically ill. , 2014, Journal of critical care.

[26]  G. Bein,et al.  Performance characteristics of two commercially available IgG-specific immunoassays in the assessment of heparin-induced thrombocytopenia (HIT). , 2011, Thrombosis research.

[27]  Roger M Harbord,et al.  A unification of models for meta-analysis of diagnostic accuracy studies. , 2007, Biostatistics.

[28]  S. Koskinen,et al.  Significance of quantitative measurement of heparin‐induced platelet antibodies , 2010, European journal of haematology.

[29]  T. Bakchoul,et al.  Multicentric validation of a rapid assay for heparin-induced thrombocytopenia with different specimen types , 2014, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[30]  Constantine Gatsonis,et al.  Analysing and Presenting Results , 2010 .

[31]  M. Morel-Kopp,et al.  Heparin‐induced thrombocytopenia: evaluation of IgG and IgGAM ELISA assays , 2011, International journal of laboratory hematology.

[32]  F. Kapadia,et al.  Evaluation of various laboratory assays in detection of heparin‐induced thrombocytopenia in an adult general ICU , 2013, International journal of laboratory hematology.

[33]  K. Devreese,et al.  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 , 2012, International journal of laboratory hematology.

[34]  G. Guyatt,et al.  Physicians Evidence-Based Clinical Practice Development : American College of Chest Thrombolytic Therapy Guideline Methodology for Antithrombotic and , 2008 .

[35]  W. Wuillemin,et al.  Prospective evaluation of the interobserver reliability of the 4Ts score in patients with suspected heparin‐induced thrombocytopenia , 2012, Journal of thrombosis and haemostasis : JTH.

[36]  A. Jawad,et al.  Comparison of PF4/heparin ELISA assay with the 14C-serotonin release assay in the diagnosis of heparin-induced thrombocytopenia. , 1995, American journal of clinical pathology.

[37]  J. Kelton,et al.  A 14-year study of heparin-induced thrombocytopenia. , 1996, The American journal of medicine.

[38]  Y. Gruel,et al.  Effectiveness of a new immuno-assay for the diagnosis of heparin-induced thrombocytopenia and improved specificity when detecting IgG antibodies , 2009, Thrombosis and Haemostasis.

[39]  E. Pollak,et al.  Serologic Results in >1000 Patients With Suspected Heparin-Induced Thrombocytopenia , 2008, Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis.

[40]  T. Ittermann,et al.  Heparin‐induced thrombocytopenia: towards standardization of platelet factor 4/heparin antigen tests , 2010, Journal of thrombosis and haemostasis : JTH.

[41]  A. Greinacher,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 , 2006, European journal of haematology.

[42]  J. Francis.  A critical evaluation of assays for detecting antibodies to the heparin-PF4 complex. , 2004, Seminars in thrombosis and hemostasis.

[43]  T. Warkentin.  How I diagnose and manage HIT. , 2011, Hematology. American Society of Hematology. Education Program.

[44]  M. Carr,et al.  Recombinant human factor VIIa (rFVIIa) cleared principally by antithrombin following intravenous administration in hemophilia patients , 2011, Journal of thrombosis and haemostasis : JTH.

[45]  K. F. Izban,et al.  Comparison of two PF4/heparin ELISA assays for the laboratory diagnosis of heparin-induced thrombocytopenia. , 1999, Seminars in thrombosis and hemostasis.

[46]  D. Andrews,et al.  Prospective observational evaluation of the particle immunofiltration anti-platelet factor 4 rapid assay in MICU patients with thrombocytopenia , 2013, Critical Care.

[47]  D. Cines,et al.  How I treat heparin-induced thrombocytopenia. , 2012, Blood.

[48]  H. Kolde,et al.  Rapid and simple IgG specific test for the exclusion of heparin induced thrombocytopenia (HIT) , 2011, Clinical chemistry and laboratory medicine.

[49]  Patrick Bossuyt,et al.  Systematic Reviews of Diagnostic Test Accuracy , 2008, Annals of Internal Medicine.

[50]  A. Greinacher,et al.  Laboratory diagnosis of heparin‐associated thrombocytopenia and comparison of platelet aggregation test, heparin‐induced platelet activation test, and platelet factor 4/heparin enzyme‐linked immunosorbent assay , 1994, Transfusion.

[51]  A. Cuker.  Heparin-induced thrombocytopenia: present and future , 2011, Journal of Thrombosis and Thrombolysis.

[52]  R. Wesley,et al.  PF4 ENHANCED assay for the diagnosis of heparin-induced thrombocytopenia in complex medical and surgical patients* , 2007, Critical care medicine.

[53]  J. Amiral,et al.  Platelet Factor 4 Complexed to Heparin Is the Target for Antibodies Generated in Heparin-Induced Thrombocytopenia , 1992, Thrombosis and Haemostasis.

[54]  E. Ley,et al.  Overdiagnosis of heparin-induced thrombocytopenia in surgical ICU patients. , 2011, Journal of the American College of Surgeons.

[55]  Susan Mallett,et al.  QUADAS-2: A Revised Tool for the Quality Assessment of Diagnostic Accuracy Studies , 2011, Annals of Internal Medicine.

[56]  Peter Schlattmann,et al.  Use of 3×2 tables with an intention to diagnose approach to assess clinical performance of diagnostic tests: meta-analytical evaluation of coronary CT angiography studies , 2012, BMJ : British Medical Journal.

[57]  J. Zehnder,et al.  Heparin-induced platelet aggregation vs platelet factor 4 enzyme-linked immunosorbent assay in the diagnosis of heparin-induced thrombocytopenia-thrombosis. , 1997, American Journal of Clinical Pathology.

[58]  H. Watson,et al.  Guidelines on the diagnosis and management of heparin‐induced thrombocytopenia: second edition , 2012, British journal of haematology.

[59]  B. Lämmle,et al.  Rapid exclusion or confirmation of heparin-induced thrombocytopenia: a single-center experience with 1,291 patients , 2012, Haematologica.

[60]  Guido Knapp,et al.  Improved tests for a random effects meta‐regression with a single covariate , 2003, Statistics in medicine.

[61]  P. Boutouyrie,et al.  Diagnostic score for heparin‐induced thrombocytopenia after cardiopulmonary bypass , 2004, Journal of thrombosis and haemostasis : JTH.

[62]  M. Vitale,et al.  Comparison between different laboratory tests for the detection and prevention of heparin-induced thrombocytopenia. , 2001, Cytometry.

[63]  M. Vitale,et al.  Heparin‐induced thrombocytopenia: detection of antiheparin/PF4 antibodies by means of heparin/PF4‐coated beads and flow cytometry , 2002, Transfusion medicine.

[64]  J. Kelton,et al.  Frequency of Heparin‐Induced Thrombocytopenia in Critical Care Patients , 2003, Pharmacotherapy.

[65]  G. Guyatt,et al.  The 4Ts scoring system for heparin-induced thrombocytopenia in medical-surgical intensive care unit patients. , 2010, Journal of critical care.

[66]  J. Low,et al.  Timely diagnosis and management of heparin‐induced thrombocytopenia in a frequent request, low incidence single centre using clinical 4T’s score and particle gel immunoassay , 2008, British journal of haematology.

[67]  A. Greinacher,et al.  Heparin‐induced thrombocytopenia: a prospective study on the incidence, platelet‐activating capacity and clinical significance of antiplatelet factor 4/heparin antibodies of the IgG, IgM, and IgA classes , 2007, Journal of thrombosis and haemostasis : JTH.

[68]  C. Legnani,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 , 2010, Thrombosis and Haemostasis.

[69]  Navid Farahani,et al.  Cost-Effective HIT Diagnosis: Utilizing IgG-Specific PF4 Immunoassays Reduces the Number of Confirmatory Serotonin Release Assays without Missing True HIT , 2015 .

[70]  Adam Cuker,et al.  Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis. , 2012, Blood.

[71]  Paolo Prandoni,et al.  Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. , 2012, Chest.

[72]  A. Cuker.  Heparin-induced thrombocytopenia (HIT) in 2011: an epidemic of overdiagnosis. , 2011, Thrombosis and haemostasis.

[73]  A. Dans,et al.  Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. , 2012, Chest.