Faculty Collaboration Database

Prothrombotic antibodies targeting the spike protein's receptor-binding domain in severe COVID-19. Blood 2025 Feb 06;145(6):635-647

Date

11/22/2024

Pubmed ID

39576992

Pubmed Central ID

PMC11811936

DOI

10.1182/blood.2024025010

Scopus ID

2-s2.0-85214228692 (requires institutional sign-in at Scopus site)   1 Citation

Abstract

Thromboembolic complication is common in severe coronavirus disease 2019 (COVID-19), leading to an investigation into the presence of prothrombotic antibodies akin to those found in heparin-induced thrombocytopenia (HIT). In a study of samples from 130 hospitalized patients, collected 3.6 days after COVID-19 diagnosis, 80% had immunoglobulin G (IgG) antibodies recognizing complexes of heparin and platelet factor 4 (PF4; PF4/H), and 41% had antibodies inducing PF4-dependent P-selectin expression in CpG oligodeoxynucleotide-treated normal platelets. Unlike HIT, both PF4/H-reactive and platelet-activating antibodies were found in patients with COVID-19 regardless of recent heparin exposure. Notably, PF4/H-reactive IgG antibodies correlated with those targeting the receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 spike protein. Moreover, introducing exogenous RBD to or removing RBD-reactive IgG from COVID-19 plasma or IgG purified from COVID-19 plasma significantly reduced their ability to activate platelets. RBD-specific antibodies capable of platelet activation were cloned from peripheral blood B cells of patients with COVID-19. These antibodies possessed sequence motifs in the heavy-chain complementarity-determining region 3 (HCDR3), resembling those identified in pathogenic HIT antibodies. Furthermore, IgG+ B cells having these HCDR3 signatures were markedly expanded in patients with severe COVID-19. Importantly, platelet-activating antibodies present in patients with COVID-19 were associated with a specific elevation of platelet α-granule proteins in the plasma and showed a positive correlation with markers for inflammation and tissue damage, suggesting a functionality of these antibodies in patients. The demonstration of functional and structural similarities between certain RBD-specific antibodies in patients with COVID-19 and pathogenic antibodies typical of HIT suggests a novel mechanism by which RBD-specific antibodies might contribute to thrombosis in COVID-19.

Author List

Zhu W, Zheng Y, Yu M, Witman N, Zhou L, Wei J, Zhang Y, Topchyan P, Nguyen C, Wang D, Janecke R, Padmanabhan A, Baumann Kreuziger L, White GC, Hari P, Gu T, Fields AT, Kornblith LZ, Aster R, Zhu J, Cui W, Jobe S, Graham MB, Wang D, Wen R

Authors

Lisa M. Baumann Kreuziger MD Professor in the Medicine department at Medical College of Wisconsin
Mary Beth Graham MD Associate Chief, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Aged
Antibodies, Viral
Blood Platelets
Female
Humans
Immunoglobulin G
Male
Middle Aged
Platelet Activation
Platelet Factor 4
Protein Domains
Spike Glycoprotein, Coronavirus
Thrombocytopenia