Relevance of anti-platelet factor 4/heparin antibodies and platelet activation in systemic inflammatory diseases and thrombosis disorders: insight from the COVID-19 pandemic

Nicolas Gendron; Dominique Helley; Johannes Thaler; Dorothée Faille; Christine Le Beller; Maxime Gruest; Jérôme Hadjadj; Aurélien Philippe; Faris Zeco; Marie Courbebaisse; Luc Darnige; Wafa Amara; Leyla Calmette; Beatrice Parfait; Claire Auditeau; Richard Chocron; Lina Khider; Laetitia Mauge; Olivier Espitia; Gérard Friedlander; Nadine Ajzenberg; David Lebeaux; Benjamin Planquette; Olivier Sanchez; Jean-Luc Diehl; COVID-HOP Study Group; Agnès Lillo-Le Louet; Benjamin Terrier; David M Smadja

doi:10.1016/j.rpth.2025.102701

Relevance of anti-platelet factor 4/heparin antibodies and platelet activation in systemic inflammatory diseases and thrombosis disorders: insight from the COVID-19 pandemic

Res Pract Thromb Haemost. 2025 Feb 9;9(1):102701. doi: 10.1016/j.rpth.2025.102701. eCollection 2025 Jan.

Authors

Nicolas Gendron^{1

2

3}, Dominique Helley^{1

3}, Johannes Thaler⁴, Dorothée Faille⁵, Christine Le Beller^{3

6}, Maxime Gruest^{1

3}, Jérôme Hadjadj⁷, Aurélien Philippe^{1

3}, Faris Zeco^{1

3}, Marie Courbebaisse⁸, Luc Darnige^{1

3}, Wafa Amara¹, Leyla Calmette⁹, Beatrice Parfait¹⁰, Claire Auditeau¹, Richard Chocron¹¹, Lina Khider^{3

12}, Laetitia Mauge^{1

3}, Olivier Espitia¹³, Gérard Friedlander¹⁴, Nadine Ajzenberg⁵, David Lebeaux^{15

16}, Benjamin Planquette^{2

3

17}, Olivier Sanchez^{2

3

17}, Jean-Luc Diehl^{3

18}; COVID-HOP Study Group; Agnès Lillo-Le Louet^{3

6}, Benjamin Terrier¹⁹, David M Smadja^{1

2

3}

Affiliations

¹ Hematology department, Assistance Publique Hôpitaux de Paris, Centre-Université de Paris (APHP-CUP), Paris, France.
² F-CRIN INNOVTE, Saint-Étienne, France.
³ Paris Cité University, INSERM, Paris Cardiovascular Research Centre, Team Endotheliopathy and Hemostasis Disorders, Paris, France.
⁴ Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
⁵ Paris Cité University, INSERM UMR 1144 Optimisation Thérapeutique en Neuropsychopharmacologie, Paris, France, Laboratoire d'Hématologie, AP-HP, Bichat-Claude Bernard Hospital, Paris, France.
⁶ Département de Pharmacovigilance, Assistance Publique Hôpitaux de Paris.Centre-Université de Paris (APHP-CUP), Paris, France.
⁷ Sorbonne Université, Service de Médecine interne, Hôpital Saint-Antoine, AP-HP, Imagine Institute, Laboratory for Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, Paris, France.
⁸ Université Paris Cité, Physiology Department, European Georges-Pompidou Hospital, APHP, INSERM U1151, Paris, France.
⁹ Hematology-Immunology-Transfusion Department, Hôpitaux Universitaires Paris Ile De France Ouest, Université Versailles Saint Quentin, Boulogne, France.
¹⁰ Centre de Ressources Biologiques de l'Hôpital Cochin, AP-HP.Centre-Université Paris Cité, Paris, France.
¹¹ Paris Cité University, INSERM, Paris Cardiovascular Research Centre, F-75015 Paris, France, and Emergency department, Assistance Publique Hôpitaux de Paris-Centre (APHP-CUP), Paris, France.
¹² Vascular Medicine Department, Assistance Publique Hôpitaux de Paris-Centre (APHP-CUP), Paris, France.
¹³ Nantes Université, CHU Nantes, Department of Internal and Vascular Medicine, l'institut du thorax, INSERM UMR1087/CNRS UMR 6291, Team III Vascular & Pulmonary diseases, Nantes, France.
¹⁴ Fondation Université Paris Cité, Paris, France.
¹⁵ Institut Pasteur, Université Paris Cité, CNRS UMR 6047, Genetics of Biofilms Laboratory, Paris, France.
¹⁶ Service de Microbiologie, Unité Mobile d'Infectiologie, Assistance Publique Hôpitaux de Paris-Centre (APHP-CUP), Hôpital Européen Georges Pompidou, Paris, France.
¹⁷ Respiratory Medicine Department, Assistance Publique - Hôpitaux de Paris-Centre (APHP-CUP), Paris, France.
¹⁸ Intensive care medicine, Assistance Publique Hôpitaux de Paris.Centre-Université de Paris (APHP-CUP), Paris, France.
¹⁹ Paris Cité University, INSERM, Paris Cardiovascular Research Centre, F-75015 Paris, France, Department of Internal Medicine, National Referral Center for Rare Systemic Autoimmune Diseases, Assistance Publique Hôpitaux de Paris-Centre (APHP-CUP), Paris, France.

Abstract

Background: The increased interest in anti-platelet factor 4 (PF4)-heparin complex (anti-PF4/H) antibodies following the COVID-19 pandemic has established them as crucial players in immunothrombosis.

Objectives: We aimed to investigate the involvement of anti-PF4/H antibodies during COVID-19 and after vaccination, particularly in patients with systemic inflammatory disease (SID).

Methods: This retrospective study analyzed the presence of anti-PF4/H antibodies and their ability to induce platelet activation in COVID-19 patients with and without suspected heparin-induced thrombocytopenia (HIT), vaccine-induced immune thrombotic thrombocytopenia (VITT) patients, and in controls and SID patients following COVID-19 vaccination.

Results: No significant increase in anti-PF4/H antibody levels was observed during COVID-19 regardless of disease severity. Despite a 2-fold increase in HIT suspicion observed during the pandemic, there was no corresponding increase in HIT diagnoses. Additionally, no significant increase in anti-PF4/H levels was noted after vaccination, even in SID patients. None of the positive anti-PF4/H antibodies detected in COVID-19 or vaccination cohorts induced platelet activation, measured by soluble P-selectin levels and flow cytometry-based on platelet microvesicle generation. Finally, in VITT patients, unlike in HIT patients, anti-PF4/H levels were strongly associated with platelet microvesicle assay and moderately with soluble P-selectin levels.

Conclusion: Our study found no significant increase in anti-PF4/H antibodies in COVID-19 or after vaccination, including in SID patients. However, in VITT patients, but not in HIT patients, these antibodies were correlated with platelet activation. This finding suggests that anti-PF4/H antibodies play a different role in the pathophysiology of VITT but that their interest is limited outside clear contexts of HIT/VITT suspicion.

Keywords: COVID-19; antibodies; connectivite tissue disease; thrombocytopenia; vaccine; vasculitis.