Reviews
Vol. 3 No. 2 (2024)
Recent advances in classic heparin-induced thrombocytopenia (HIT), autoimmune HIT, spontaneous HIT, and vaccine-induced immune thrombotic thrombocytopenia
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Received: 2 March 2024
Accepted: 9 June 2024
Accepted: 9 June 2024
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Anti-platelet factor 4 (PF4) disorders are a group of platelet-consumptive disorders characterized by platelet-activating antibodies against PF4, thrombocytopenia and an increased risk of thrombosis. PF4 is a chemokine released by platelet alpha granules upon activation, which can form immune complexes with negatively charged substances, such as heparin, cartilage components, nucleic acids, and viral and bacterial agents. Antibodies formed in response to PF4-polyanion complexes may display platelet-activating properties and cause pan-cellular activation, leading to the marked prothrombotic state of anti-PF4 disorders. In recent years, the landscape of anti-PF4 disorders has evolved to include classic heparin-induced thrombocytopenia (cHIT), autoimmune HIT (aHIT), spontaneous HIT (SpHIT), vaccine-induced immune thrombotic thrombocytopenia (VITT), and the newly recognized spontaneous VITT (SpVITT). These disorders have garnered increased attention due to their association with severe clinical outcomes. Recent discoveries have expanded the understanding of these conditions, highlighting the role of various triggers, such as upper respiratory tract infections and monoclonal gammopathy of undetermined significance, in their development. Compared to cHIT, the less common anti-PF4 disorders VITT, aHIT, SpHIT and SpVITT generally appear more severe, with aggressive disease courses, more severe thrombocytopenia and a higher frequency of bleeding, thrombosis at unusual sites, involvement of the central nervous system and of multiple vascular beds. Clinical suspicion and knowledge of the less well-known triggers of anti-PF4 disorders are pivotal to ordering the appropriate laboratory tests and initiating the necessary treatments. Herein, we will review cHIT, aHIT, SpHIT and VITT, focusing on their clinical presentation and therapeutic management.
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Warkentin TE, Arnold DM, Sheppard JAI, et al. Investigation of anti-PF4 versus anti-PF4/heparin reactivity using fluid-phase enzyme immunoassay for 4 anti-PF4 disorders: classic heparin-induced thrombocytopenia (HIT), autoimmune HIT, vaccine-induced immune thrombotic thrombocytopenia, and spontaneous HIT. J Thromb Haemost 2023;21:2268-76. DOI: https://doi.org/10.1016/j.jtha.2023.04.034
Schönborn L, Esteban O, Wesche J, et al. Anti-PF4 immunothrombosis without proximate heparin or adenovirus vector vaccine exposure. Blood 2023;142:2305-14. DOI: https://doi.org/10.1182/blood.2023022136
Hursting MJ, Pai PJ, McCracken JE, et al. Platelet factor 4/heparin antibodies in blood bank donors. Am J Clin Pathol 2010;134:774-80. DOI: https://doi.org/10.1309/AJCPG0MNR5NGKNFX
Clerici B, Scavone M, Birocchi S, et al. Prevalence of anti-platelet factor 4 antibodies in healthy vaccinees with adenoviral vector vaccines - A systematic review and meta-analysis. Br J Haematol 2023;200:821-3. DOI: https://doi.org/10.1111/bjh.18635
Marcucci R, Berteotti M, Gori AM, et al. Heparin induced thrombocytopenia: position paper from the Italian Society on Thrombosis and Haemostasis (SISET). Blood Transf 2021;19:14-23.
Warkentin TE. Laboratory diagnosis of heparin-induced thrombocytopenia. Int J Lab Hematol 2019;41:15-25. DOI: https://doi.org/10.1111/ijlh.12993
Greinacher A. Clinical practice. Heparin-Induced Thrombocytopenia. N Engl J Med 2015;373:252-61. DOI: https://doi.org/10.1056/NEJMcp1411910
Toh CH, Wang G, Parker AL. The aetiopathogenesis of vaccine-induced immune thrombotic thrombocytopenia. Clin Med 2022;22:140-4. DOI: https://doi.org/10.7861/clinmed.2022-0006
Klok FA, Pai M, Huisman MV, Makris M. Vaccine-induced immune thrombotic thrombocytopenia. Lancet Haematol 2022;9:e73-80. DOI: https://doi.org/10.1016/S2352-3026(21)00306-9
Vaccine-induced immune thrombotic thrombocytopenia, version 1.9. 2022. Available from: https://www.hematology.org/covid-19/vaccine-induced-immune-thrombotic-thrombocytopenia (accessed on 27th April 2023) DOI: https://doi.org/10.23880/oajmb-16000233
May J, Westbrook B, Cuker A. Heparin-induced thrombocytopenia: an illustrated review. Res Pract Thromb Haemost 2023;7:100283. DOI: https://doi.org/10.1016/j.rpth.2023.100283
Warkentin TE, Sheppard JA, Horsewood P, et al. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood 2000;96:1703-8. DOI: https://doi.org/10.1182/blood.V96.5.1703.h8001703_1703_1708
Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. New Eng J Med 1995;332:1330-6. DOI: https://doi.org/10.1056/NEJM199505183322003
Warkentin TE, Sheppard JAI, Sigouin CS, et al. Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. Blood. 2006 Nov 1;108(9):2937–41. DOI: https://doi.org/10.1182/blood-2005-11-012450
Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 2005;106:2710-5. DOI: https://doi.org/10.1182/blood-2005-04-1546
Pavord S, Makris M. Second-dose VITT: rare but real. Blood 2022;139:2581-3. DOI: https://doi.org/10.1182/blood.2022016118
Mendes-de-Almeida DP, Mouta Nunes de Oliveira P, Bertollo Gomes Porto V, et al. Vaccine-induced immune thrombotic thrombocytopenia post COVID-19 booster vaccination in Brazil: a case series. Res Pract Thromb Haemost 2023;7:102243. DOI: https://doi.org/10.1016/j.rpth.2023.102243
Warkentin TE. Platelet-activating anti-PF4 disorders: an overview. Semin Hematol 2022;59:59-71. DOI: https://doi.org/10.1053/j.seminhematol.2022.02.005
Warkentin TE. Autoimmune heparin-induced thrombocytopenia. J Clin Med 2023;12:6921. DOI: https://doi.org/10.3390/jcm12216921
Warkentin TE, Baskin-Miller J, Raybould AL, et al. Adenovirus-associated thrombocytopenia, thrombosis, and VITT-like antibodies. New Eng J Med 2023;389:574-7. DOI: https://doi.org/10.1056/NEJMc2307721
Campello E, Biolo M, Simioni P. More on adenovirus-associated thrombocytopenia, thrombosis, and VITT-like antibodies. New Engl J Med 2023;389:1729-31. DOI: https://doi.org/10.1056/NEJMc2310644
Uzun G, Zlamal J, Althaus K, et al. Cerebral venous sinus thrombosis and thrombocytopenia due to heparin-independent anti-PF4 antibodies after adenovirus infection. Haematologica 2023;109:2010-5. DOI: https://doi.org/10.3324/haematol.2023.284127
Wang JJ, Schönborn L, Warkentin TE, et al. Antibody fingerprints linking adenoviral anti-PF4 disorders. New Engl J Med 2024;390:1827-9. DOI: https://doi.org/10.1056/NEJMc2402592
Kanack AJ, Bayas A, George G, et al. Monoclonal and oligoclonal anti-platelet factor 4 antibodies mediate VITT. Blood 2022;140:73-7. DOI: https://doi.org/10.1182/blood.2021014588
Cuker A, Cines DB, Arepally G. Autoantibodies in heparin-induced thrombocytopenia. in: autoantibodies. Elsevier 2014;511-8. DOI: https://doi.org/10.1016/B978-0-444-56378-1.00060-5
Rybak ME, Gimbrone MA, Davies PF, Handin RI. Interaction of platelet factor four with cultured vascular endothelial cells. Blood 1989;73:1534-9. DOI: https://doi.org/10.1182/blood.V73.6.1534.1534
Cines DB. Disorders associated with antibodies to endothelial cells. Rev Infect Dis 1989;11:S705-11. DOI: https://doi.org/10.1093/clinids/11.Supplement_4.S705
Sachais BS, Higazi AAR, Cines DB, et al. Interactions of platelet factor 4 with the vessel wall. Semin Thromb Hemost 2004;30:351-8. DOI: https://doi.org/10.1055/s-2004-831048
Lubenow N, Hinz P, Thomaschewski S, et al. The severity of trauma determines the immune response to PF4/heparin and the frequency of heparin-induced thrombocytopenia. Blood 2010;115:1797-803. DOI: https://doi.org/10.1182/blood-2009-07-231506
Nguyen TH, Greinacher A. Distinct binding characteristics of pathogenic anti-platelet factor-4/polyanion antibodies to antigens coated on different substrates: a perspective on clinical application. ACS Nano 2018;12:12030-41. DOI: https://doi.org/10.1021/acsnano.8b04487
Schönborn L, Thiele T, Kaderali L, Greinacher A. Decline in pathogenic antibodies over time in VITT. New Engl J Med 2021;385:1815-6. DOI: https://doi.org/10.1056/NEJMc2112760
Cuker A, Arepally GM, Chong BH, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia. Blood Adv 2018;2:3360-92. DOI: https://doi.org/10.1182/bloodadvances.2018024489
Madeeva D, Cines DB, Poncz M, Rauova L. Role of monocytes and endothelial cells in heparin-induced thrombocytopenia. Thromb Haemost 2016;116:806-12. DOI: https://doi.org/10.1160/TH16-02-0162
Huynh A, Arnold DM, Ivetic N, et al. Antibodies against platelet factor 4 and the risk of cerebral venous sinus thrombosis in patients with vaccine-induced immune thrombotic thrombocytopenia. J Thromb Haemost 2023;21:2833-43. DOI: https://doi.org/10.1016/j.jtha.2023.06.026
Zhang Y, Bissola AL, Treverton J, et al. Vaccine-induced immune thrombotic thrombocytopenia: clinicopathologic features and new perspectives on anti-pf4 antibody-mediated disorders. J Clin Med 2024;13:1012. DOI: https://doi.org/10.3390/jcm13041012
Huynh A, Kelton JG, Arnold DM, et al. Antibody epitopes in vaccine-induced immune thrombotic thrombocytopaenia. Nature 2021;596:565-9. DOI: https://doi.org/10.1038/s41586-021-03744-4
Schönborn L, Greinacher A. Longitudinal aspects of VITT. Semin Hematol 2022;59:108-14. DOI: https://doi.org/10.1053/j.seminhematol.2022.03.001
Schonborn L, Thiele T, Kaderali L, et al. Most anti-PF4 antibodies in vaccine-induced immune thrombotic thrombocytopenia are transient. Blood 2022;139:1903-7. DOI: https://doi.org/10.1182/blood.2021014214
Kanack AJ, Singh B, George G, et al. Persistence of Ad26.COV2.S‐associated vaccine‐induced immune thrombotic thrombocytopenia (VITT) and specific detection of VITT antibodies. Am J Hematol 2022;97:519-26. DOI: https://doi.org/10.1002/ajh.26488
Schönborn L, Seck SE, Thiele T, et al. Long-term outcome in vaccine-induced immune thrombocytopenia and thrombosis. J Thromb Haemost 2023;21:2519-27. DOI: https://doi.org/10.1016/j.jtha.2023.06.027
Faille D, Hurtado-Nedelec M, Ouedrani A, et al. Isolation of a monoclonal IgG kappa with functional autoantibody activity against platelet factor 4/heparin from a patient with a monoclonal gammopathy of undetermined significance and clinically overt heparin thrombocytopenia. Res Pract Thromb Haemost. 2017;1:1.
Greinacher A, Langer F, Schönborn L, et al. Platelet-activating anti-PF4 antibodies mimic VITT antibodies in an unvaccinated patient with monoclonal gammopathy. Haematologica 2022;107:1219-21. DOI: https://doi.org/10.3324/haematol.2021.280366
Kanack AJ, Schaefer JK, Sridharan M, et al. Monoclonal gammopathy of thrombotic/thrombocytopenic significance. Blood 2023;141:1772-6. DOI: https://doi.org/10.1182/blood.2022018797
Clerici B, Pontisso E, Aloise C, et al. Thrombosis and bleeding in patients with vaccine-induced immune thrombotic thrombocytopenia: a systematic review of published cases. Thromb Haemost 2023;124:423-31. DOI: https://doi.org/10.1055/s-0043-1777134
Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med 1996;101:502-7. DOI: https://doi.org/10.1016/S0002-9343(96)00258-6
Gruel Y, Vayne C, Rollin J, et al. Comparative analysis of a french prospective series of 144 patients with heparin-induced thrombocytopenia (FRIGTIH) and the literature. Thromb Haemost 2020;120:1096-107. DOI: https://doi.org/10.1055/s-0040-1712957
Goel R, Ness PM, Takemoto CM, et al. Platelet transfusions in platelet consumptive disorders are associated with arterial thrombosis and in-hospital mortality. Blood 2015;125:1470-6. DOI: https://doi.org/10.1182/blood-2014-10-605493
Salih F, Kohler S, Schönborn L, et al. Early recognition and treatment of pre-VITT syndrome after adenoviral vector-based SARS-CoV-2 vaccination may prevent from thrombotic complications: review of published cases and clinical pathway. Eur Heart J Open 2022;2. DOI: https://doi.org/10.1093/ehjopen/oeac036
Kim AY, Woo W, Yon DK, et al. Thrombosis patterns and clinical outcome of COVID-19 vaccine-induced immune thrombotic thrombocytopenia: a systematic review and meta-analysis. Int J Infect Dis 2022;119:130-9. DOI: https://doi.org/10.1016/j.ijid.2022.03.034
Kim AY, Woo W, Yon DK, et al. Thrombosis patterns and clinical outcome of COVID-19 vaccine-induced immune thrombotic thrombocytopenia: a systematic review and meta-analysis. Int J Infect Dis 2022;119:130-9. DOI: https://doi.org/10.1016/j.ijid.2022.03.034
Hwang J, Park SH, Lee SW, et al. Predictors of mortality in thrombotic thrombocytopenia after adenoviral COVID-19 vaccination: the FAPIC score. Eur Heart J 2021;42:4053-63. DOI: https://doi.org/10.1093/eurheartj/ehab592
Pavord S, Scully M, Hunt BJ, et al. Clinical features of vaccine-induced immune thrombocytopenia and thrombosis. New Engl J Med 2021;385:1680-9. DOI: https://doi.org/10.1056/NEJMoa2109908
Thrombosis Canada. Heparin-induced thrombocytopenia (HIT). 2023. Available from: https://thrombosiscanada.ca/wp-content/uploads/2021/11/27.-Heparin-Induced-Thrombocytopenia_23October2021-1.pdf (accessed on 1st March 2024)
Greinacher A, Selleng K, Warkentin TE. Autoimmune heparin-induced thrombocytopenia. J Thromb Haemost 2017;15:2099-114. DOI: https://doi.org/10.1111/jth.13813
Guidance from the Expert Hematology Panel (EHP) on COVID-19 vaccine-induced immune thrombocytopenia and thrombosis. Updated guidance on management. Version 2.2. 2021. Available from: https://b-s-h.org.uk/media/20499/guidance-version-22-20210903.pdf (accessed on 30th January 2024)
Thrombosis Canada. Vaccine-induced prothrombotic immune thrombocytopenia (VIPIT/VITT). 2021. Available from: https://thrombosiscanada.ca/wp-uploads/uploads/2021/04/51.-Vaccine-induced-prothrobotic-immune-thrombcytopenia_26Apr21-Final.pdf (accessed on 1st March 2024)
Warkentin TE, Anderson JAM. How I treat patients with a history of heparin-induced thrombocytopenia. Blood 2016;128:348-59. DOI: https://doi.org/10.1182/blood-2016-01-635003
Warkentin TE. Heparin-induced thrombocytopenia in critically ill patients. Semin Thromb Hemost 2015;41:49-60. DOI: https://doi.org/10.1055/s-0034-1398381
Warkentin TE. Limb ischemic necrosis secondary to microvascular thrombosis: a brief historical review. Semin Thromb Hemost 2024;50:760-72. DOI: https://doi.org/10.1055/s-0044-1786356
Scavone M, Clerici B, Birocchi S, et al. Platelet activation and modulation in thrombosis with thrombocytopenia syndrome associated with ChAdOx1 nCov-19 vaccine. Haematologica 2021;106:3228-31. DOI: https://doi.org/10.3324/haematol.2021.279345
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Clerici B, Scavone M, Podda GM. Recent advances in classic heparin-induced thrombocytopenia (HIT), autoimmune HIT, spontaneous HIT, and vaccine-induced immune thrombotic thrombocytopenia. Bleeding Thromb Vascul Biol [Internet]. 2024 Jun. 20 [cited 2025 Nov. 9];3(2). Available from: https://www.btvb.org/btvb/article/view/127
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