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1004 The Role of PF4 Antibodies in Pediatric Sars-Cov-2 Infections

Program: Oral and Poster Abstracts
Session: 301. Vasculature, Endothelial Cells and Platelets: Basic and Translational: Poster I
Hematology Disease Topics & Pathways:
Bleeding and Clotting, autoimmune disorders, Viral, Clinical Practice (Health Services and Quality), platelet disorders, Diversity, Equity, Inclusion, and Accessibility (DEI/DEIA) , Diseases, thrombocytopenias, Immune Disorders, SARS-CoV-2/COVID-19, immune mechanism, Pediatric, Infectious Diseases, Biological Processes, multi-systemic interactions, Study Population, pathogenesis
Saturday, December 11, 2021, 5:30 PM-7:30 PM

Meady Chiem1*, Lubica Rauova, MD, PhD2*, Caroline Diorio, MD3,4, Kevin O McNerney, MD, MSTR5*, Hamid Bassiri, MD/PhD6,7*, Kathleen Sullivan, MD, PhD8,9*, Edward M Behrens, MD10*, David T. Teachey, MD5,6 and Michele P. Lambert, MD6,11,12

1Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA
2Children's Hospital of Philadelphia, Philadelphia, PA
3Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA
4Immune Dysregulation Fronteir Program, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA
5Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA
6Immune Dysregulation Frontier Program, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA
7Division of Infectious Diseases, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA
8Immune Dysregulation Frontier Program, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA
9Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA
10Division of Rheumatology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA
11Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA
12Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA

Background The ChAdOx1 nCoV-19 vaccine has been shown to induce Vaccine-induced Immune Thrombotic Thrombocytopenia (VITT), a syndrome that shares clinical features with heparin-induced thrombocytopenia (HIT). The mechanism of thrombocytopenia and thrombosis in these disorders appears to be related to the development of pathologic anti-PF4/heparin antibodies, some of which could activate complement. Interestingly, we and others have found that complement activation is vital when both pediatric and adult patients have severe respiratory illness from SARS-CoV-2 virus (COVID-19) or in the post-infectious multisystem inflammatory syndrome in children (MIS-C). We hypothesized that patients with severe COVID-19 or MIS-C develop similar anti-PF4/heparin antibodies, which lead to endothelial complement activation that drive the inflammatory responses seen in these diseases.

Methods Our cohort included 30 pediatric patients with positive SARS-CoV-2 RT-PCRs: 10 each of severe COVID-19 (“Severe”, MIS-C, and mild/asymptomatic (“Mild”) infection. Using ELISA, we evaluated the levels of antibodies to various platelet-related proteins including PF4, PF4-heparin, and NAP2; in addition, we examined the ability of plasma from each patient to activate complement. The antibody levels were compared to control samples including samples from adult patients with VITT and HIT. Statistical analyses with ANOVA were performed to evaluate differences.

Results Patients with MIS-C have a significantly higher anti-PF4 antibody concentration (as measured by mean optical density [OD]) than patients with either mild/asymptomatic disease, or severe COVID-19: Severe 0.5 +/- 0.14; Mild 0.3 +/- 0.12; MIS-C 0.77 +/- 0.35, p=0.003 MIS-C vs. Mild); Similar results were seen for anti-PF4/heparin antibodies: Severe 0.4 +/- 0.14; Mild 0.35 +/- 0.12; MIS-C 0.64 +/- 0.3, p=0.003 MIS-C vs. Mild; p=0.034 MIS-C vs. Severe). These were similar to values obtained for the HIT sample (Figure).

Conclusion Patients with MIS-C and severe COVID19 have significant detectable anti-PF4 and PF4/heparin antibodies in contrast to those patients with mild/asymptomatic disease. Our previous studies have shown that patients with MIS-C and COVID-19 have evidence of endovascular complement activation in the form of elevated soluble membrane attack complex (sC5-b9). We have also previously demonstrated that VITT anti-PF4 and anti-PF4/heparin antibodies activate complement and result in endothelial cell activation. These antibodies in pediatric SARS-CoV-2 infection may be involved in the development of more severe disease manifestations. Ongoing investigations will identify if this is due to endothelial complement activation and inflammatory responses that accompany severe disease. This is the first demonstration of the role of anti-PF4 and PF4/heparin antibodies in pediatric SARS-CoV-2.

Disclosures: Bassiri: Guidepoint Global: Consultancy; Kriya Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company. Teachey: Janssen: Consultancy; NeoImmune Tech: Research Funding; Sobi: Consultancy; BEAM Therapeutics: Consultancy, Research Funding. Lambert: Novartis, shionogi, argenx, Rigel, octapharma: Consultancy; Rigel, Novartis, Sysmex, octapharma: Research Funding.

*signifies non-member of ASH