Original Articles
Vol. 4 No. 3 (2025)
Persistence of functional anti-PF4 antibodies and neutrophil activation in 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.
Published: 18 November 2025
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Background: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is characterized by thrombosis in unusual sites triggered by anti-PF4 antibodies. To the best of our knowledge, no studies with very long follow-up on anti-PF4 antibodies persistence have been reported.
Methods: We carried out a multicenter study in 16 VITT patients studied at T0 (acute episode), T1 and T2 (after 6 and 29 months) assessing the persistence of anti-PF4/heparin antibodies and of neutrophil activation.
Results: At T0 80%, at T1 75%, and at T2 11% of VITT patients were positive for anti-PF4/heparin antibodies by ELISA, while 75% at T0, 56% at T1, and 0% at T2 had a positive platelet activation assay. Plasmatic MMP-9 and MMP-9/NGAL were strikingly elevated at diagnosis, but they normalized at T1. No clinical relapses were observed.
Conclusions: Although anti-PF4 antibodies may persist for a long-time following an acute VITT episode, they seem to be clinically irrelevant.
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Citations
Greinacher A, Thiele T, Warkentin TE, et al. Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination. N Engl J Med 2021;384:2092-101. DOI: https://doi.org/10.1056/NEJMoa2104840 DOI: https://doi.org/10.1056/NEJMoa2104840
Petito E, Gresele P. Vaccine-induced immune thrombotic thrombocytopenia two years later: should it still be on the scientific agenda? Thromb Haemost 2025;125:97-107. DOI: https://doi.org/10.1055/a-2107-0891 DOI: https://doi.org/10.1055/a-2107-0891
Donadini MP, Tarasconi E, Bertù L, et al. Thrombotic events after vaccination for covid-19 in Italy: a report from the Italian society on thrombosis and haemostasis registry. Intern Emerg Med 2025;20:2065-77. DOI: https://doi.org/10.1007/s11739-025-04054-7 DOI: https://doi.org/10.1007/s11739-025-04054-7
Leung HHL, Perdomo J, Ahmadi Z, et al. NETosis and thrombosis in vaccine-induced immune thrombotic thrombocytopenia. Nat Commun 2022;13:5206. DOI: https://doi.org/10.1038/s41467-022-32946-1 DOI: https://doi.org/10.1038/s41467-022-32946-1
Petito E, Gresele P. VITT Pathophysiology: an update. Vaccines 2025;13:650. DOI: https://doi.org/10.3390/vaccines13060650 DOI: https://doi.org/10.3390/vaccines13060650
Napolitano A, Spiezia L, Biolo M, et al. Anti-platelet factor 4 antibody-mediated disorders: an updated narrative review. Semin Thromb Hemost 2025;51:578-93. DOI: https://doi.org/10.1055/a-2528-5425 DOI: https://doi.org/10.1055/a-2528-5425
Favaloro EJ, Clifford J, Leitinger E, et al. Assessment of immunological anti-platelet factor 4 antibodies for vaccine-induced thrombotic thrombocytopenia (VITT) in a large Australian cohort: A multicenter study comprising 1284 patients. J Thromb Haemost 2022;20:2896-908. DOI: https://doi.org/10.1111/jth.15881 DOI: https://doi.org/10.1111/jth.15881
Craven B, Lester W, Boyce S, et al. Natural history of PF4 antibodies in vaccine-induced immune thrombocytopenia and thrombosis. Blood 2022;139:2553-60. DOI: https://doi.org/10.1182/blood.2021014684 DOI: https://doi.org/10.1182/blood.2021014684
Schönborn L, Thiele T, Kaderali L, Greinacher A. Decline in pathogenic antibodies over time in VITT. N Engl J Med 2021;385:1815-6. DOI: https://doi.org/10.1056/NEJMc2112760 DOI: https://doi.org/10.1056/NEJMc2112760
Schönborn 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 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 DOI: https://doi.org/10.1002/ajh.26488
Montague SJ, Smith CW, Lodwick CS, et al. Anti-platelet factor 4 immunoglobulin G levels in vaccine-induced immune thrombocytopenia and thrombosis: Persistent positivity through 7 months. Res Pract Thromb Haemost 2022;6:e12707. DOI: https://doi.org/10.1002/rth2.12707 DOI: https://doi.org/10.1002/rth2.12707
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 DOI: https://doi.org/10.1016/j.jtha.2023.06.027
Nicolai L, Leunig A, Pekayvaz K, et al. Thrombocytopenia and splenic platelet-directed immune responses after IV ChAdOx1 nCov-19 administration. Blood 2022;140:478-90. DOI: https://doi.org/10.1182/blood.2021014712 DOI: https://doi.org/10.1182/blood.2021014712
Petito E, Colonna E, Falcinelli E, et al. Anti-severe acute respiratory syndrome coronavirus-2 adenoviral-vector vaccines trigger subclinical antiplatelet autoimmunity and increase of soluble platelet activation markers. Br J Haematol 2022;198:257-66. DOI: https://doi.org/10.1111/bjh.18245 DOI: https://doi.org/10.1111/bjh.18245
Meier RT, Porcelijn L, Hofstede-van Egmond S, et al. Antibodies against platelet glycoproteins in clinically suspected VITT patients. Antibodies 2024;13:35. DOI: https://doi.org/10.3390/antib13020035 DOI: https://doi.org/10.3390/antib13020035
Nakamura T, Morodomi Y, Kanaji S, et al. Detection of anti-GPIbα autoantibodies in a case of immune thrombocytopenia following COVID-19 vaccination. Thromb Res 2022;209:80-3. DOI: https://doi.org/10.1016/j.thromres.2021.11.030 DOI: https://doi.org/10.1016/j.thromres.2021.11.030
Al-Samkari H, Leaf RK, Goodarzi K. Transient thrombocytopenia with glycoprotein-specific platelet autoantibodies after Ad26.COV2.S vaccination: A case report. Ann Intern Med 2021;174:1632-3. DOI: https://doi.org/10.7326/L21-0427 DOI: https://doi.org/10.7326/L21-0427
Shafqat A, Omer MH, Albalkhi I, et al. Neutrophil extracellular traps and long COVID. Front Immunol 2023;14:1254310. DOI: https://doi.org/10.3389/fimmu.2023.1254310 DOI: https://doi.org/10.3389/fimmu.2023.1254310
Kempuraj D, Tsilioni I, Aenlle KK, et al. Long COVID elevated MMP-9 and release from microglia by SARS-CoV-2 Spike protein. Transl Neurosci 2024;15:20220352. DOI: https://doi.org/10.1515/tnsci-2022-0352 DOI: https://doi.org/10.1515/tnsci-2022-0352
Petito E, Bury L, Antunes Heck L, et al. Association of human leucocyte antigen loci with vaccine-induced immune thrombotic thrombocytopenia: Potential role of the interaction between platelet factor 4-derived peptides and MHC-II. Br J Haematol 2025;206:290-5. DOI: https://doi.org/10.1111/bjh.19838 DOI: https://doi.org/10.1111/bjh.19838
Pavord S, Scully M, Hunt BJ, et al. Clinical features of vaccine-induced immune thrombocytopenia and thrombosis. N Engl J Med 2021;385:1680-9. DOI: https://doi.org/10.1056/NEJMoa2109908 DOI: https://doi.org/10.1056/NEJMoa2109908
Petito E, Franco L, Falcinelli E, et al. COVID-19 infection-associated platelet and neutrophil activation is blunted by previous anti-SARS-CoV-2 vaccination. Br J Haematol 2023;201:851-6. DOI: https://doi.org/10.1111/bjh.18726 DOI: https://doi.org/10.1111/bjh.18726
Petito E, Falcinelli E, Paliani U, et al. Association of neutrophil activation, more than platelet activation, with thrombotic complications in coronavirus disease 2019. J Infect Dis 2021;223:933-44. DOI: https://doi.org/10.1093/infdis/jiaa756 DOI: https://doi.org/10.1093/infdis/jiaa756
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 DOI: https://doi.org/10.3390/jcm13041012
Greinacher A, Selleng K, Palankar R, et al. Insights in ChAdOx1 nCoV-19 vaccine-induced immune thrombotic thrombocytopenia. Blood 2021;138:2256-68. DOI: https://doi.org/10.1182/blood.2021013231 DOI: https://doi.org/10.1182/blood.2021013231
Martins-Gonçalves R, Rozini SV, Mendes-de-Almeida DP, et al. Platelet-neutrophil aggregate formation induces NLRP3 inflammasome activation in vaccine-induced thrombotic thrombocytopenia. J Thromb Haemost 2025;23:1034-42. DOI: https://doi.org/10.1016/j.jtha.2024.12.012 DOI: https://doi.org/10.1016/j.jtha.2024.12.012
Panagiota V, Dobbelstein C, Werwitzke S, et al. Long-term outcomes after vaccine-induced thrombotic thrombocytopenia. Viruses 2022;14:1702. DOI: https://doi.org/10.3390/v14081702 DOI: https://doi.org/10.3390/v14081702
Gresele P, Marietta M, Ageno W, et al. Management of cerebral and splanchnic vein thrombosis associated with thrombocytopenia in subjects previously vaccinated with Vaxzevria (AstraZeneca): a position statement from the Italian Society for the Study of Haemostasis and Thrombosis (SISET). Blood Transfus 2021;19:281-3.
Ethics Approval
the study was approved by the local Ethics Committees (CER Umbria n. 3656/20) and the Bioethics Committee of University of Perugia (n. 222848)How to Cite
1.
Petito E, Mezzasoma AM, Falcinelli E, Conti C, De Candia E, De Cristofaro R, et al. Persistence of functional anti-PF4 antibodies and neutrophil activation in vaccine-induced immune thrombotic thrombocytopenia. Bleeding Thromb Vasc Biol [Internet]. 2025 Nov. 18 [cited 2026 May 5];4(3). Available from: https://www.btvb.org/btvb/article/view/400
Copyright (c) 2025 The Author(s)
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