Abstract
Purpose We determined the seroprevalence of platelet factor 4 (PF4)/heparin antibodies in healthy subjects. Methods A literature search identified studies in which healthy subjects were evaluated using commercial immunoassays for PF4/heparin antibody (IgG/M/A). Proportions of test-positive subjects were calculated, by assay. Results Across 11 eligible studies, 860 healthy subjects were tested using the Stago enzyme-linked immunosorbent assay (ELISA) (nine studies), GTI ELISA (three studies), and/or DiaMed particle gel immunoassay (PGIA) (three studies). Seropositivity occurred in 17 of 790 (2.2%, 95% CI, 1.1–3.2%) subjects by Stago ELISA, one of 100 (1.0%, 95% CI, 0–3.0%) subjects by GTI ELISA, and three of 70 (4.3%, 95% CI, 0–9.0%) subjects by PGIA (P > 0.20). Of seven seropositive subjects tested further, none had platelet-activating antibodies. Conclusion Commercial immunoassays detect PF4/heparin antibody in 1.0–4.3% of healthy subjects. Because this “background” prevalence overlaps seropositivity rates in heparin-treated patients in various clinical settings, normality cut-offs may require refinement.
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References
Horsewood P, Warkentin TE, Hayward CPM et al (1996) The epitope specificity of heparin-induced thrombocytopenia. Br J Haematol 95:161–167
Jang IK, Hursting MJ (2005) When heparins promote thrombosis: review of heparin-induced thrombocytopenia. Circulation 111:2671–2683
Arepally GM, Ortel TL (2006) Heparin-induced thrombocytopenia. N Engl J Med 355:809–817
Warkentin TE, Sheppard JA, Horsewood P et al (2000) Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood 96:1703–1708
Warkentin TE, Cook RJ, Marder VJ et al (2005) Anti-platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin. Blood 106:3791–3796
Levy JH, Hursting MJ (2007) Heparin-induced thrombocytopenia, a prothrombotic disease. Hematol Oncol Clin N Am 21:65–88
Stribling WK, Slaughter TF, Houle TT et al (2007) Beyond the platelet count: heparin antibodies as independent risk predictors. Am Heart J 153:900–906
Matsuo T, Suzuki S, Matsuo M et al (2005) Preexisting antibodies to platelet factor 4-heparin complexes in patients with acute coronary syndrome who have no history of heparin exposure. Pathophysiol Haemost Thromb 34:18–22
Warkentin TE, Jay RM, Makris M et al (2006) Platelet-activating anti-platelet factor 4/polyanion antibodies without preceding heparin therapy: a transient autoimmune disorder resembling heparin-induced thrombocytopenia (“spontaneous HIT”). Blood 108:311a–312a
de Larranaga G, Martinuzzo M, Bocassi A et al (2002) Heparin-platelet factor 4 induced antibodies in patients with either autoimmune or alloimmune antiphospholipid antibodies. Thromb Haemost 88:371–373
Martin-Toutain I, Piette JC, Diemert MC et al (2007) High prevalence of antibodies to platelet factor 4 heparin in patients with antiphospholipid antibodies in absence of heparin-induced thrombocytopenia. Lupus 16:79–83
Amiral J, Bridey F, Dreyfus M et al (1992) Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia. Thromb Haemost 68:95–96
Amiral J, Bridey F, Wolf M et al (1995) Antibodies to macromolecular platelet factor 4-heparin complexes in heparin-induced thrombocytopenia: a study of 44 cases. Thromb Haemost 73:21–28
Visentin GP, Ford SE, Scott JP et al (1994) Antibodies from patients with heparin-induced thrombocytopenia/thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells. J Clin Invest 93:81–88
Visentin GP, Moghaddam M, Beery SE et al (2001) Heparin is not required for detection of antibodies associated with heparin-induced thrombocytopenia/thrombosis. J Lab Clin Med 138:22–31
Newman PM, Swanson RL, Chong BH (1998) Heparin-induced thrombocytopenia: IgG binding to PF4-heparin complexes in the fluid phase and cross-reactivity with low molecular weight heparin and heparinoid. Thromb Haemost 80:2892–2897
Eichler P, Raschke R, Lubenow N et al (2002) The new ID-heparin/PF4 antibody test for rapid detection of heparin-induced antibodies in comparison with functional and antigenic assays. Br J Haematol 116:887–891
Meyer O, Salama A, Pittet N et al (1999) Rapid detection of heparin-induced platelet antibodies with particle gel immunoassay (ID-HPF4). Lancet 354:1525–1526
Amiral J, Marfaing-Koka A, Wolf M et al (1996) Presence of autoantibodies to interleukin-8 or neutrophil-activating peptide-2 in patients with heparin-associated thrombocytopenia. Blood 88:410–416
Arepally G, Reynolds C, Tomaski A et al (1995) Comparison of PF4/heparin ELISA assay with the 14C-serotonin release assay in the diagnosis of heparin-induced thrombocytopenia. Am J Clin Pathol 104:648–654
Bachelot-Loza C, Saffroy R, Lasne D et al (1998) Importance of the FcγRIIa-Arg/His-131 polymorphism in heparin-induced thrombocytopenia diagnosis. Thromb Haemost 79:523–528
Walenga JM, Jeske WP, Fasanella AR et al (1999) Laboratory tests for the diagnosis of heparin-induced thrombocytopenia. Semin Thromb Hemost 25(Suppl 1):43–49
Woodhams BJ, Grimaux M (1999) Detection of PF4-heparin auto-antibodies by ELISA. Thromb Haemost 82:157–158
Tazzari PL, Ricci F, Vitale M et al (2002) Heparin-induced thrombocytopenia: detection of antiheparin/PF4 antibodies by means of heparin/PF4-coated beads and flow cytometry. Transfus Med 12:193–198
Untch B, Ahmad S, Jeske WP et al (2002) Prevalence, isotype, and functionality of antiheparin-platelet factor 4 antibodies in patients treated with heparin and clinically suspected for heparin-induced thrombocytopenia. The pathogenic role of IgG. Thromb Res 105:117–123
Lee EY, Hwang KY, Yang JO et al (2003) Anti-heparin platelet factor 4 antibody is a risk factor for vascular access obstruction in patients undergoing hemodialysis. J Korean Med Sci 18:69–72
Alberio L, Kimmerle S, Baumann A et al (2003) Rapid determination of anti-heparin/platelet factor 4 antibody titers in the diagnosis of heparin-induced thrombocytopenia. Am J Med 114:528–536
Krakow EF, Goudar R, Petzold E et al (2007) Influence of sample collection and storage on the detection of platelet factor 4-heparin antibodies. Am J Clin Pathol 128:150–156
Warkentin TE, Sheppard JI, Raschke R et al (2007) Performance characteristics of a rapid assay for anti-PF4/heparin antibodies, the particle immunofiltration assay. J Thromb Haemost 5:2308–2310
Zwicker JI, Uhl L, Huang WY, Shaz BH et al (2004) Thrombosis and ELISA optical density values in hospitalized patients with heparin-induced thrombocytopenia. J Thromb Haemost 2:2133–2137
Warkentin TE, Sheppard JA, Moore JC et al (2005) Laboratory testing for the antibodies that cause heparin-induced thrombocytopenia: how much class do we need? J Lab Clin Med 146:341–346
Lo GK, Sigouin CS, Warkentin TE (2007) What is the potential for overdiagnosis of heparin-induced thrombocytopenia? Am J Hematol 82:1037–1043
Keeling D, Davidson S, Watson H (2006) The management of heparin-induced thrombocytopenia. Br J Haematol 133:259–269
Refaai MA, Laposata M, Van Cott EM (2003) Clinical significance of a borderline titer in a negative ELISA for heparin-induced thrombocytopenia. Am J Clin Pathol 119:61–65
Guilbert B, Dighiero G, Avrameas S (1982) Naturally occurring antibodies against nine common antigens in human sera. I. Detection, isolation and characterization. J Immunol 128:2779–2787
Palinski W, Witztum JL (2000) Immune responses to oxidative neoepitopes on LDL and phospholipids modulate the development of atherosclerosis. J Intern Med 247:371–380
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The authors have full control of all primary data and agree to allow the journal to review their data if requested. Supported by the National Institutes of Health HL081395 (GMA).
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GMA has received research support from Amgen, GlaxoSmithKline, and Progen Industries; Marcie J. Hursting has received consultancy fees from GlaxoSmithKline.
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Frederick Spencer, MD served as the guest editor for the manuscript.
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Arepally, G.M., Hursting, M.J. Platelet factor 4/heparin antibody (IgG/M/A) in healthy subjects: a literature analysis of commercial immunoassay results. J Thromb Thrombolysis 26, 55–61 (2008). https://doi.org/10.1007/s11239-008-0217-y
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DOI: https://doi.org/10.1007/s11239-008-0217-y