Clinical and laboratory tests for the diagnosis of heparin-induced thrombocytopenia

Michael Nagler; Tamam Bakchoul

doi:10.1160/TH16-03-0240

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2016; 116(05): 823-834
DOI: 10.1160/TH16-03-0240

Theme Issue Article

Schattauer GmbH

Clinical and laboratory tests for the diagnosis of heparin-induced thrombocytopenia

Authors

Michael Nagler

¹Department of Haematology, Inselspital, Bern University Hospital, Bern, Switzerland

²Department of Clinical Research, University of Bern, Bern, Switzerland
Tamam Bakchoul

³Center for Clinical Transfusion Medicine, University Hospital of Tübingen, Tübingen, Germany

⁴Institute for Immunology and Transfusionsmedizin, Universitätsmedizin Greifswald, Germany

Abstract

Summary

A rapid diagnostic work-up is required in patients with suspected heparin-induced thrombocytopenia (HIT). However, diagnosis of HIT is challenging due to a number of practical issues and methodological limitations. Many laboratory tests and a few clinical scoring systems are available but the individual characteristics and the diagnostic accuracy of these are hard to appraise. The 4Ts score is a well evaluated clinical assessment tool with the potential to rule out HIT in many patients. Still, it requires experience and is subject to a relevant inter-observer variability. Immunoassays such as enzyme-linked immunosorbent assays or recently developed rapid assays are able to exclude HIT in a number of patients. But, accuracy of immunoassays differs depending on type of assay, threshold, antibody specificity and even manufacturer. Due to a comparatively low positive predictive value, HIT cannot be confirmed by immunoassays alone. In addition, only some of them are immediately accessible, particularly in small laboratories. While functional assays such as the serotonin release assay (SRA) and the heparin-induced platelet activation assay (HIPA) are considered as gold standard for diagnosis of HIT, they require a highly specialised laboratory. In addition, some of them are not adequately evaluated. In clinical practice, we recommend an integrated diagnostic approach combining not only clinical assessment (the 4Ts score) but immunoassays and functional assays as well. We propose a clear diagnostic algorithm supporting clinical decision-making. Furthermore, we provide an overview of all current laboratory techniques for HIT and discuss diagnostic pathways and strategies to reduce diagnostic errors, and future perspectives.

Keywords

Heparin/adverse effects - immunoassay/methods - thrombocytopenia/chemically induced - thrombocytopenia/diagnosis

Full Text

References

References
1 Bakchoul T. Current insight in the laboratory diagnosis of hit. Intern J Lab Hematol 2014; 36: 16.
2 Cuker A. Clinical and laboratory diagnosis of heparin-induced thrombocytopenia: an integrated approach. Semin Thromb Hemost 2014; 40: 106-114.
3 Warkentin TE. et al. Laboratory testing for heparin-induced thrombocytopenia: a conceptual framework and implications for diagnosis. J Thromb Haemost 2011; 09: 2498-2500.
4 Otis SA, Zehnder JL. Heparin-induced thrombocytopenia: current status and diagnostic challenges. Am J Hematol 2010; 85: 700-706.
5 Cuker A, Cines DB. How I treat heparin-induced thrombocytopenia. Blood 2012; 119: 2209-2218.
6 Price EA. 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.
7 Greinacher A. Heparin-induced thrombocytopenia. J Thromb Haemost 2009; 07 (Suppl. 01) 9-12.
8 Greinacher A. CLINICAL PRACTICE. Heparin-Induced Thrombocytopenia. N Engl J Med 2015; 373: 252-261.
9 Linkins LA. 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. Chest 2012; 141 (02) Suppl e495S-530S.
10 Warkentin TE. How I diagnose and manage HIT. Hematology 2011; 2011: 143-149.
11 Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med 1996; 101: 502-507.
12 Tardy B. et al. Predictive factors for thrombosis and major bleeding in an observational study in 181 patients with heparininduced thrombocytopenia treated with lepirudin. Blood 2006; 108: 1492-1496.
13 Greinacher A. et al. Anaphylactic and anaphylactoid reactions associated with lepirudin in patients with heparin-induced thrombocytopenia. Circulation 2003; 108: 2062-2065.
14 Cuker A. Heparin-induced thrombocytopenia (HIT) in 2011: an epidemic of overdiagnosis. Thromb Haemost 2011; 106: 993-994.
15 Warkentin TE, Linkins LA. Immunoassays are not created equal. J Thromb Haemost 2009; 07: 1256-1259.
16 Alatri A. et al. Results of a consensus meeting on the use of argatroban in patients with heparin-induced thrombocytopenia requiring antithrombotic therapy - a European Perspective. Thromb Res 2012; 129: 426-433.
17 Watson H. et al. Guidelines on the diagnosis and management of heparin-induced thrombocytopenia: second edition. Br J Haematol 2012; 159: 528-540.
18 Lo GK. et al. Evaluation of pretest clinical score (4 T’s) for the diagnosis of hepa-rin-induced thrombocytopenia in two clinical settings. J Thromb Haemost 2006; 04: 759-765.
19 Cuker A. et al. Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and metaanalysis. Blood 2012; 120: 4160-4167.
20 Lillo-Le Louet A. et al. Diagnostic score for heparin-induced thrombocytopenia after cardiopulmonary bypass. J Thromb Haemost 2004; 02: 1882-1888.
21 Pouplard C. 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; 05: 1373-1379.
22 Bryant A. et al. Timely diagnosis and management of heparin-induced throm-bocytopenia in a frequent request, low incidence single centre using clinical 4T’s score and particle gel immunoassay. Br J Haematol 2008; 143: 721-726.
23 Bakchoul T. et al. Prospective evaluation of PF4/heparin immunoassays for the diagnosis of heparin-induced thrombocytopenia. J Thromb Haemost 2009; 07: 1260-1265.
24 Nellen V. et al. Rapid exclusion or confirmation of heparin-induced thrombocytopenia: A single-center experience with 1,291 patients. Haematologica 2012; 97: 89-97.
25 Tawfik NM. et al. Egyptian experience of reliability of 4T’s score in diagnosis of heparin induced thrombocytopenia syndrome. Blood Coagulation and Fibrinolysis 2011; 22: 701-705.
26 Denys B. et al. A clinical-laboratory approach contributing to a rapid and reliable diagnosis of heparin-induced thrombocytopenia. Thromb Res 2008; 123: 137-145.
27 Crowther MA. et al. The 4Ts scoring system for heparin-induced thrombocytopenia in medical-surgical intensive care unit patients. J Crit Care 2010; 25: 287-293.
28 Berry C. et al. Overdiagnosis of heparin-induced thrombocytopenia in surgical ICU patients. J Am Coll Surg 2011; 213: 10-17.
29 Cuker A. et al. The HIT Expert Probability (HEP) Score: A novel pre-test probability model for heparin-induced thrombocytopenia based on broad expert opinion. J Thromb Haemost 2010; 08: 2642-2650.
30 Demma LJ. et al. A diagnosis of heparin-induced thrombocytopenia with combined clinical and laboratory methods in cardiothoracic surgical intensive care unit patients. Anesth Analg 2011; 113: 697-702.
31 Nagler M. et al. Prospective evaluation of the interobserver reliability of the 4Ts score in patients with suspected heparininduced thrombocytopenia. J Thromb Haemost 2012; 10: 151-152.
32 Nagler M. et al. Diagnostic value of the 4Ts score for heparin-induced throm-bocytopenia in the critically ill. J Crit Care 2014; 29: 1126-1127.
33 Linkins LA, Bates SM, Lee AY. et al. Combination of 4Ts score and PF4/H-PaGIA for diagnosis and management of heparin-induced thrombocy-topenia: prospective cohort study. Blood 2015; 126 (05) 597-603.
34 Favaloro EJ. Toward improved diagnosis of HIT. Blood 2015; 126: 563-564.
35 Messmore HL. et al. Simple scoring system for early management of heparin-induced thrombocytopenia. Clin Appl Thromb Hemost 2011; 17: 197-201.
36 Piednoir P. et al. Heparin-induced thrombocytopenia after cardiac surgery: an observational study of 1,722 patients. J Cardiothor Vasc Anesth 2012; 26: 585-590.
37 Amiral J. et al. Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia. Thromb Haemost 1992; 68: 95-96.
38 Greinacher A. 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. Transfusion 1994; 34: 381-385.
39 Arepally G. et al. Comparison of PF4/heparin ELISA assay with the ¹⁴C-serotonin release assay in the diagnosis of heparin-induced thrombocytopenia. Am J Clin Pathol 1995; 104: 648-654.
40 Shelat SG. et al. Serologic results in >1000 patients with suspected heparin-induced thrombocytopenia. Clin Appl Thromb Hemost 2008; 14: 410-414.
41 Morel-Kopp MC. et al. Heparin-induced thrombocytopenia: Evaluation of IgG and IgGAM ELISA assays. Intern J Lab Hematol 2011; 33: 245-250.
42 Greinacher A. 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. J Thromb Haemost 2007; 05: 1666-1673.
43 Warkentin TE. et al. Quantitative interpretation of optical density measurements using PF4-dependent enzyme-immunoassays. J Thromb Haemost 2008; 06: 1304-1312.
44 Vitale M. et al. Comparison between different laboratory tests for the detection and prevention of heparin-induced thrombocytopenia. Cytometry 2001; 46: 290-295.
45 Nasr R, Owaidah T. Validation of monospecific elisa test as a screening test for heparin indused thrombocytopenia compare to other immunological and functional assays. J Thromb Haemost 2011; 09: 333.
46 Schwarz N. et al. Performance of anti-heparin/platelet factor 4-assays in the diagnosis of heparin-induced thrombocytopenia (HIT) defined by clinical criteria. J Thromb Haemost 2009; 07 (Suppl. 02) 869.
47 Andrews DM. 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.
48 Pouplard C. et al. Effectiveness of a new immuno-assay for the diagnosis of heparin-induced thrombocytopenia and improved specificity when detecting IgG antibodies. Thromb Haemost 2010; 103: 145-150.
49 Juhl D. 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.
50 Farahani N. et al. Cost-effective HIT diagnosis: Utilizing IgG-specific PF4 assays reduces the number of confirmatory serotonin release assays without missing true HIT. J Thromb Haemost 2013; 11: 937.
51 Haouach K. et al. Contributions of biological tests and the 4 Ts score in the diagnosis of heparin induced thrombocytopenia. Pan Afr Med J 2012; 13: 9.
52 Eichler P. et al. The new ID-heparin/PF4 antibody test for rapid detection of heparin-induced antibodies in comparison with functional and antigenic assays. Br J Haematol 2002; 116: 887-891.
53 Izban KF. et al. Comparison of two PF4/heparin ELISA assays for the laboratory diagnosis of heparin-lnduced thrombocytopenia. Semin Thromb Hemost 1999; 25 (02) (Suppl. 01) 51-56.
54 Kapadia FN. et al. Evaluation of various laboratory assays in detection of hepa-rin-induced thrombocytopenia in an adult general ICU. Intern J Lab Hematol 2013; 35: 137-143.
55 Tazzari PL. et al. Heparin-induced thrombocytopenia: Detection of antiheparin/PF4 antibodies by means of heparin/PF4-coated beads and flow cytometry. Transf Med 2002; 12: 193-198.
56 Van Hoecke F, Devreese K. Evaluation of two new automated chemiluminescent assays (HemosILAcuStar HIT-IgG and HemosILAcuStar HIT-Ab) for the detection of heparin-induced antibodies in the diagnosis of heparin-induced thrombocytopenia. Intern J Lab Hematol 2012; 34: 410-416.
57 Javela K, Koskinen S. Comparison of a heparin-platelet factor 4 (PF4)-ELISA IgG/M/A and the heparin-induced platelet activation assay (HIPA) with a PF4-ELISA IgG. Vox Sang 2010; 99: 27-28.
58 Minet V. 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.
59 Kiefel V. et al. Lateral flow immunoassay-a useful tool for detection of PF4/heparin antibodies in HIT?. Hamostaseologie 2012; 32: A83-A4.
60 Look KA. et al. Heparin-induced platelet aggregation vs platelet factor 4 enzyme-linked immunosorbent assay in the diagnosis of heparin-induced thrombocytopenia- thrombosis. Am J Clin Pathol 1997; 108: 78-82.
61 Pierce W. et al. Evaluation of heparin-induced thrombocytopenia (HIT) laboratory testing and the 4Ts scoring system in the intensive care unit. Ann Clin Lab Sci 2013; 43: 429-435.
62 Verma AK. et al. Frequency of heparin-induced thrombocytopenia in critical care patients. Pharmacotherapy 2003; 23: 745-753.
63 Shaheed G. et al. PF4 ENHANCED assay for the diagnosis of heparin-induced thrombocytopenia in complex medical and surgical patients. Crit Care Med 2007; 35: 1691-1695.
64 Nagler M. et al. Diagnostic value of immunoassays for heparin-induced throm-bocytopenia: a systematic review and metaanalysis. Blood 2016; 127: 546-557.
65 Smock KJ. et al. Proficiency testing results for heparin-induced thrombocytopenia in north america. Semin Thromb Hemost 2014; 40: 254-260.
66 Althaus K. et al. Combined use of the high heparin step and optical density to optimize diagnostic sensitivity and specificity of an anti-PF4/heparin enzymeimmunoassay. Thromb Res 2011; 128: 256-260.
67 Bakchoul T. et al. Performance characteristics of two commercially available IgG-specific immunoassays in the assessment of heparin-induced thrombocytopenia (HIT). Thromb Res 2011; 127: 345-348.
68 Denys B, Devreese K. A clinical-laboratory approach contributing to a rapid and reliable diagnosis of heparin-induced thrombocytopenia: An update. Thromb Res 2009; 124: 642-643.
69 Kolde HJ. et al. Rapid and simple IgG specific test for the exclusion of heparin induced thrombocytopenia (HIT). Clin Chem Lab Med 2011; 49: 2065-2068.
70 Novelli C. et al. Evaluation of a new rapid test for detection of anti PF4-heparin antibodies in hit diagnosis. Blood Transfus 2012; 10: s69.
71 Sachs UJ. 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.
72 Seidel H. et al. Laboratory and clinical performance of rapid immunoassays in diagnosis of heparin induced thrombocytopenia: Comparison of lateral flow and gel centrifugation with ELISA technique. Hamostaseologie 2013; 33: A71.
73 Alhaliq AR. et al. The Diamed assay has a poor positive predictive value for HIT in a tertiary hospital referral setting [1]. Intern J Lab Hematol 2007; 29: 69-70.
74 Leroux D. et al. Prospective evaluation of a rapid nanoparticle-based lateral flow immunoassay (STic Expert((R)) HIT) for the diagnosis of heparin-induced thrombocytopenia. Br J Haematol 2014; 166: 774-782.
75 Kolde HJ. et al. Multicentric validation of a rapid assay for heparin-induced thrombocytopenia with different specimen types. Blood Coagul Fibrinol 2014; 25: 6-9.
76 Warkentin TE. et al. Performance characteristics of a rapid assay for anti-PF4/heparin antibodies: The particle immunofiltration assay [5]. J Thromb Haemost 2007; 05: 2308-2310.
77 Legnani 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.
78 Archambault AJ. et al. Comparison of the hemosil HIT-AB1 to the standard ELISA assay for heparin-induced thrombocytopenia (HIT) antibody. Am J Hematol 2012; 87: S184.
79 Althaus K. et al. Evaluation of automated immunoassays in the diagnosis of heparin induced thrombocytopenia. Thromb Res 2013; 131: e85-e90.
80 Minet V. et al. Rapid exclusion of the diagnosis of immune HIT by AcuStar HIT and heparin-induced multiple electrode aggregometry. Thromb Res 2014; 133: 1074-1078.
81 Sun L. et al. Diagnostic accuracy of rapid immunoassays for heparin-induced thrombocytopenia. A systematic review and meta-analysis. Thromb Haemost 2016; 115: 1044-1055.
82 Caton S. et al. Assessing the clinical and cost impact of on-demand immunoassay testing for the diagnosis of heparin induced thrombocytopenia. Thromb Res 2016; 140: 155-162.
83 Warkentin TE. PF4-dependent immunoassays and inferential detection of HIT antibodies. J Thromb Haemost 2007; 05: 232-234.
84 Bakchoul T. et al. Current insights into the laboratory diagnosis of HIT. Intern J Lab Hematol 2014; 36: 296-305.
85 Warkentin TE. et al. Laboratory testing for the antibodies that cause heparin-induced thrombocytopenia: How much class do we need?. J Lab Clin Med 2005; 146: 341-346.
86 Sheridan D. et al. A diagnostic test for heparin-induced thrombocytopenia. Blood 1986; 67: 27-30.
87 Greinacher A. et al. A rapid and sensitive test for diagnosing heparin-associated thrombocytopenia. Thrombosis and haemostasis 1991; 66 (06) 734-6.
88 Warkentin TE. HIT paradigms and paradoxes. J Thromb Haemost 2011; 09 (Suppl. 01) 105-117.
89 Favaloro EJ. et al. Heparin-induced thrombocytopenia: laboratory investigation and confirmation of diagnosis. Pathology 1992; 24: 177-183.
90 Warkentin TE. et al. The platelet serotonin-release assay. Am J Hematol 2015; 90: 564-572.
91 Morel-Kopp MC. et al. Whole blood impedance aggregometry detects heparin-induced thrombocytopenia antibodies. Thromb Res 2010; 125: e234-e239.
92 Stricker H. et al. Heparin-dependent in vitro aggregation of normal platelets by plasma of a patient with heparin-induced skin necrosis: specific diagnostic test for a rare side effect. Am J Med 1988; 85: 721-724.
93 Chong BH. et al. The clinical usefulness of the platelet aggregation test for the diagnosis of heparin-induced thrombocytopenia. Thromb Haemost 1993; 69: 344-350.
94 Tomer A. et al. Determination of heparin-induced thrombocytopenia: A rapid flow cytometric assay for direct demonstration of antibody-mediated platelet activation. Am J Hematol 1999; 61: 53-61.
95 Gobbi G. et al. New Laboratory Test in Flow Cytometry for the Combined Analysis of Serologic and Cellular Parameters in the Diagnosis of Heparin-Induced Thrombocytopenia. Cytometry B 2004; 58: 32-38.
96 Lee DH. et al. A diagnostic test for heparin-induced thrombocytopenia: Detection of platelet microparticles using flow cytometry. Br J Haematol 1996; 95: 724-731.
97 Mullier F. et al. Contribution of platelet microparticles generation assay to the diagnosis of type II heparin-induced thrombocytopenia. Thromb Haemost 2010; 103: 1277-1281.
98 Greinacher A. et al. Heparin-induced thrombocytopenia: towards standardization of platelet factor 4/heparin antigen tests. J Thromb Haemost 2010; 08: 2025-2031.
99 Lindhoff-Last E. et al. Determination of heparin-platelet factor 4-IgG antibodies improves diagnosis of heparin-induced thrombocytopenia. Br J Haematol 2001; 113: 886-890.
100 Warkentin TE, Sheppard JI. No significant improvement in diagnostic specificity of an anti-PF4/ polyanion immunoassay with use of high heparin confirmatory procedure [10]. J Thromb Haemost 2006; 04: 281-282.
101 McGowan KE. et al. Reducing the hospital burden of heparin-induced thrombocytopenia: impact of an avoid-heparin program. Blood 2016; 127: 1954-1959.
102 Wallis DE. et al. Failure of early heparin cessation as treatment for heparin-induced thrombocytopenia. Am J Med 1999; 106: 629-635.
103 Cuker A. Does my patient have HIT? There should be an app for that. Blood 2016; 127: 522-524.
104 Raschke RA. et al. Improving clinical interpretation of the anti-platelet factor 4/heparin enzyme-linked immunosorbent assay for the diagnosis of heparininduced thrombocytopenia through the use of receiver operating characteristic analysis, stratum-specific likelihood ratios, and Bayes theorem. Chest 2013; 144: 1269-1275.
105 Morel-Kopp MC. et al. Validation of whole blood impedance aggregometry as a new diagnostic tool for HIT: results of a large Australian study. Thromb Haemost 2012; 107: 575-583.