Skip to main content
Log in

Heparin-induced thrombocytopenia with very high antibody titer is associated with slower platelet recovery and higher risk of thrombosis

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder mediated by platelet-activating antibodies targeting platelet factor 4 (PF4) and heparin complex. A higher antibody titer is reflected in a higher optical density (OD) by enzyme-linked immunosorbent assay for heparin–PF4 antibodies. This single-institution retrospective study of 116 HIT patients examined the effect of heparin–PF4 OD on time to platelet recovery, vascular thrombosis, and in-hospital mortality. Patients were divided into 3 cohorts based on heparin–PF4 OD: cohort 1 had an OD ≥ 2 and ≤ 2.4, cohort 2 had an OD > 2.4 and ≤ 2.8, and cohort 3 had an OD > 2.8. A higher OD titer was associated with significantly increased time to platelet recovery when compared between cohorts 1 versus 2 (HR = 0.599, p = 0.0221) and 1 versus 3 (HR = 0.515, p = 0.0014), as well as an increased risk of thrombosis (79.4%—cohort 3 vs 53.8%—cohort 2 vs 46.1%—cohort 1, p = 0.04), but had no impact on mortality (2.62—alive vs 2.65—deceased, p = 0.7432). A higher OD titer can inform risk assessment and support decision-making in HIT patients; however, prospective studies are needed to further clarify the impact of heparin–PF4 OD on outcomes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

References

  1. Warkentin TE, Sheppard JI, Moore JC, Sigouin CS, Kelton JG. Quantitative interpretation of optical density measurements using PF4-dependent enzyme-immunoassays. J Thromb Haemost. 2008;6(8):1304–12.

    Article  CAS  PubMed  Google Scholar 

  2. Warkentin TE, Sheppard JAI. Testing for heparin-induced thrombocytopenia antibodies. Transfus Med Rev. 2006;20(4):259–72.

    Article  PubMed  Google Scholar 

  3. Zwicker JI, Uhl L, Huang WY, Shaz BH, Bauer KA. Thrombosis and ELISA optical density values in hospitalized patients with heparin-induced thrombocytopenia. J Thromb Haemost. 2004;2(12):2133–7.

    Article  CAS  PubMed  Google Scholar 

  4. Wallis DE, Workman DL, Lewis BE, Steen L, Pifarre R, Moran JF. Failure of early heparin cessation as treatment for heparin-induced thrombocytopenia. Am J Med. 1999;106(6):629–35.

    Article  CAS  PubMed  Google Scholar 

  5. Rice L. Cases of heparin-induced thrombocytopenia elucidate the syndrome. Chest. 2005;127(2):21S-26S.

    Article  PubMed  Google Scholar 

  6. Visentin GP, Moghaddam M, Beery SE, McFarland JG, Aster RH. Heparin is not required for detection of antibodies associated with heparin-induced thrombocytopenia/thrombosis. J Lab Clin Med. 2001;138(1):22–31.

    Article  CAS  PubMed  Google Scholar 

  7. Eichler P, Raschke R, Lubenow N, Meyer O, Schwind P, Greinacher A. The new ID-heparin/PF4 antibody test for rapid detection of heparin-induced antibodies in comparison with functional and antigenic assays: ID-heparin/PF4 antibody test for detection of HIT antibodies. Br J Haematol. 2002;116(4):887–91.

    Article  CAS  PubMed  Google Scholar 

  8. Legnani C, Cini M, Pili C, Boggian O, Frascaro M, Palareti G. 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(08):402–9.

    Article  CAS  PubMed  Google Scholar 

  9. Juhl D, Eichler P, Lubenow N, Strobel U, Wessel A, Greinacher A. 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(5):420–6.

    Article  PubMed  Google Scholar 

  10. Francis J. A critical evaluation of assays for detecting antibodies to the heparin-PF4 complex. Semin Thromb Hemost. 2004;30(03):359–68.

    Article  CAS  PubMed  Google Scholar 

  11. Padmanabhan A, Jones C, Curtis BR, Bougie DW, Sullivan M, Peswani N, et al. A novel PF4-dependent platelet activation assay identifies patients likely to have heparin-induced thrombocytopenia/thrombosis (HIT). Blood. 2015;126(23):764–764.

    Article  Google Scholar 

  12. Marchetti M, Zermatten MG, Bertaggia Calderara D, Aliotta A, Alberio L. Heparin-induced thrombocytopenia: a review of new concepts in pathogenesis, diagnosis, and management. J Clin Med. 2021;10(4):683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Greinacher A. Heparin-induced thrombocytopenia. Solomon CG, editor. N Engl J Med. 2015;373(3):252–61.

    Article  CAS  PubMed  Google Scholar 

  14. Warkentin TE, Anderson JAM. How I treat patients with a history of heparin-induced thrombocytopenia. Blood. 2016;128(3):348–59.

    Article  CAS  PubMed  Google Scholar 

  15. Arepally GM, Ortel TL. Heparin-induced thrombocytopenia. Annu Rev Med. 2010;61(1):77–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cuker A, Cines DB. How I treat heparin-induced thrombocytopenia. Blood. 2012;119(10):2209–18.

    Article  CAS  PubMed  Google Scholar 

  17. Thorevska N, Amoateng-Adjepong Y, Sabahi R, Schiopescu I, Salloum A, Muralidharan V, et al. Anticoagulation in hospitalized patients with renal insufficiency. Chest. 2004;125(3):856–63.

    Article  CAS  PubMed  Google Scholar 

  18. Hughes S, Szeki I, Nash MJ, Thachil J. Anticoagulation in chronic kidney disease patients—the practical aspects. Clin Kidney J. 2014;7(5):442–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Warkentin TE, Pai M, Linkins LA. Direct oral anticoagulants for treatment of HIT: update of Hamilton experience and literature review. Blood. 2017;130(9):1104–13.

    Article  CAS  PubMed  Google Scholar 

  20. Tardy-Poncet B, Piot M, Montmartin A, Burdier A, Chalayer E, Tardy B. Delayed-onset heparin-induced thrombocytopenia without thrombosis in a patient receiving postoperative thromboprophylaxis with rivaroxaban. Thromb Haemost. 2015;114(09):652–4.

    Article  PubMed  Google Scholar 

  21. Linkins LA, Warkentin TE, Pai M, Shivakumar S, Manji RA, Wells PS, et al. Rivaroxaban for treatment of suspected or confirmed heparin-induced thrombocytopenia study. J Thromb Haemost. 2016;14(6):1206–10.

    Article  CAS  PubMed  Google Scholar 

  22. Sharifi M, Bay C, Vajo Z, Freeman W, Sharifi M, Schwartz F. New oral anticoagulants in the treatment of heparin-induced thrombocytopenia. Thromb Res. 2015;135(4):607–9.

    Article  CAS  PubMed  Google Scholar 

  23. Larsen PB, Jørgensen M, Friis-Hansen L, Ingeberg S. Apixaban used for the management of heparin-induced thrombocytopenia in a 72-year-old woman with lung cancer. Clin Case Rep. 2015;3(12):987–9.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Delgado-García G, Monreal-Robles R. Acute apixaban treatment of heparin-induced thrombocytopenia. J Thromb Thrombolysis. 2017;43(3):289–90.

    Article  PubMed  Google Scholar 

  25. Anniccherico FJ, Alonso JL. Dabigatran for heparin-induced thrombocytopenia. Mayo Clin Proc. 2013;88(9):1036.

    Article  PubMed  Google Scholar 

  26. Noel E, Abbas N, Skaradinskiy Y, Schreiber Z. Heparin-induced thrombocytopenia in a patient with essential thrombocythemia: a case based update. Case Rep Hematol. 2015;2015:1–5.

    Article  Google Scholar 

  27. Cuker A, Arepally GM, Chong BH, Cines DB, Greinacher A, Gruel Y, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia. Blood Adv. 2018;2(22):3360–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Altuntas F, Matevosyan K, Burner J, Shen YM, Sarode R. Higher optical density of an antigen assay predicts thrombosis in patients with heparin-induced thrombocytopenia. Eur J Haematol. 2008;80(5):429–35.

    Article  PubMed  Google Scholar 

  29. Baroletti S, Hurwitz S, Conti NAS, Fanikos J, Piazza G, Goldhaber SZ. Thrombosis in suspected heparin-induced thrombocytopenia occurs more often with high antibody levels. Am J Med. 2012;125(1):44–9.

    Article  CAS  PubMed  Google Scholar 

  30. Warkentin T, Hayward C, Boshkov L, Santos A, Sheppard J, Bode A, et al. Sera from patients with heparin-induced thrombocytopenia generate platelet-derived microparticles with procoagulant activity: an explanation for the thrombotic complications of heparin-induced thrombocytopenia. Blood. 1994;84(11):3691–9.

    Article  CAS  PubMed  Google Scholar 

  31. Arman M, Krauel K. Human platelet IgG Fc receptor FcγRIIA in immunity and thrombosis. J Thromb Haemost. 2015;13(6):893–908.

    Article  CAS  PubMed  Google Scholar 

  32. Rauova L, Hirsch JD, Greene TK, Zhai L, Hayes VM, Kowalska MA, et al. Monocyte-bound PF4 in the pathogenesis of heparin-induced thrombocytopenia. Blood. 2010;116(23):5021–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kasthuri RS, Glover SL, Jonas W, McEachron T, Pawlinski R, Arepally GM, et al. PF4/heparin-antibody complex induces monocyte tissue factor expression and release of tissue factor positive microparticles by activation of FcγRI. Blood. 2012;119(22):5285–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Cines DB, Tomaski A, Tannenbaum S. Immune endothelial-cell injury in heparin-associated thrombocytopenia. N Engl J Med. 1987;316(10):581–9.

    Article  CAS  PubMed  Google Scholar 

  35. Brandt S, Krauel K, Gottschalk KE, Renné T, Helm CA, Greinacher A, et al. Characterisation of the conformational changes in platelet factor 4 induced by polyanions: towards in vitro prediction of antigenicity. Thromb Haemost. 2014;112(07):53–64.

    Article  CAS  PubMed  Google Scholar 

  36. Ziporen L, Li ZQ, Park KS, Sabnekar P, Liu WY, Arepally G, et al. Defining an antigenic epitope on platelet factor 4 associated with heparin-induced thrombocytopenia. Blood. 1998;92(9):3250–9.

    Article  CAS  PubMed  Google Scholar 

  37. Zheng Y, Yu M, Podd A, Yuan L, Newman DK, Wen R, et al. Critical role for mouse marginal zone B cells in PF4/heparin antibody production. Blood. 2013;121(17):3484–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

None

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Cesar Gentille.

Ethics declarations

Conflict of interest

No conflict of interest noted for any authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mukherjee, A., Gentille, C., Patel, A. et al. Heparin-induced thrombocytopenia with very high antibody titer is associated with slower platelet recovery and higher risk of thrombosis. Int J Hematol (2024). https://doi.org/10.1007/s12185-024-03811-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12185-024-03811-2

Keywords

Navigation