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SARS-CoV-2 receptor binding domain-specific antibodies activate platelets with features resembling the pathogenic antibodies in heparin-induced thrombocytopenia.

ABSTRACT: Severe COVID-19 is associated with unprecedented thromboembolic complications. We found that hospitalized COVID-19 patients develop immunoglobulin Gs (IgGs) that recognize a complex consisting of platelet factor 4 and heparin similar to those developed in heparin-induced thrombocytopenia and thrombosis (HIT), however, independent of heparin exposure. These antibodies activate platelets in the presence of TLR9 stimuli, stimuli that are prominent in COVID-19. Strikingly, 4 out of 42 antibodies cloned from IgG1 + RBD-binding B cells could activate platelets. These antibodies possessed, in the heavy-chain complementarity-determining region 3, an RKH or Y 5 motif that we recently described among platelet-activating antibodies cloned from HIT patients. RKH and Y 5 motifs were prevalent among published RBD-specific antibodies, and 3 out of 6 such antibodies tested could activate platelets. Features of platelet activation by these antibodies resemble those by pathogenic HIT antibodies. B cells with an RKH or Y 5 motif were robustly expanded in COVID-19 patients. Our study demonstrates that SARS-CoV-2 infection drives the development of a subset of RBD-specific antibodies that can activate platelets and have activation properties and structural features similar to those of the pathogenic HIT antibodies.

SUBMITTER: Zhu W

PROVIDER: S-EPMC8132233 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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SARS-CoV-2 receptor binding domain-specific antibodies activate platelets with features resembling the pathogenic antibodies in heparin-induced thrombocytopenia.

Zhu Wen W Zheng Yongwei Y Yu Mei M Wei Jianhui J Zhang Yongguang Y Topchyan Paytsar P Nguyen Christine C Janecke Rae R Kreuziger Lisa Baumann LB White Gilbert C GC Hari Parameswaran P Aster Richard R Cui Weiguo W Jobe Shawn S Graham Mary Beth MB Wang Demin D Wen Renren R

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Severe COVID-19 is associated with unprecedented thromboembolic complications. We found that hospitalized COVID-19 patients develop immunoglobulin Gs (IgGs) that recognize a complex consisting of platelet factor 4 and heparin similar to those developed in heparin-induced thrombocytopenia and thrombosis (HIT), however, independent of heparin exposure. These antibodies activate platelets in the presence of TLR9 stimuli, stimuli that are prominent in COVID-19. Strikingly, 4 out of 42 antibodies clo ...[more]

PMID: 34013243

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Project description:BackgroundHeparin-induced thrombocytopenia (HIT) is a prothrombotic, immune-mediated adverse drug reaction associated with high rates of thrombosis-related morbidity and mortality caused by FcγRIIa-activating pathogenic antibodies to PF4-heparin. Procoagulant platelets are a platelet subset that promote thrombin generation, are clinically relevant in prothrombotic diseases, and are formed when platelet G-protein-coupled receptor (GPCR) and ITAM-linked receptors are co-stimulated.ObjectivesWe examined the procoagulant platelet response of healthy donors to platelet agonists in the presence of HIT plasma and determined the contribution of FcγRIIa.Patients/methodsOur previously established flow cytometry-based procoagulant platelet assay was modified to incorporate plasma samples, performed using FcγRIIa-responsive donor platelets. Plasma samples were serotonin-release assay-confirmed HIT (HIT+), or negative on HIT screening.ResultsIn response to GPCR stimulation, only HIT+ plasma produced a heparin-dependent sensitization that required active FcγRIIa. As a potential diagnostic tool, the procoagulant platelet assay achieved 98% accuracy in identifying clinically verified HIT when performed blinded to the diagnoses of a validation cohort. Samples inducing a higher procoagulant platelet response were more likely from patients with thrombotic complications. Thrombin stimulation markedly increased the procoagulant platelet response with HIT+ plasma that was heparin independent and only partially reversed by FcγRIIa blockade, possibly reflecting ongoing thrombotic risk after heparin cessation.ConclusionsWe demonstrate that HIT plasma together with platelet agonists increased the procoagulant platelet proportions, which may contribute to thrombotic risk in HIT. Targeting procoagulant platelet activation may represent a novel treatment strategy. This assay may be a rapid, clinically relevant functional assay for accurately detecting pathological HIT antibodies.

Dataset Information

SARS-CoV-2 receptor binding domain-specific antibodies activate platelets with features resembling the pathogenic antibodies in heparin-induced thrombocytopenia.

Publications

SARS-CoV-2 receptor binding domain-specific antibodies activate platelets with features resembling the pathogenic antibodies in heparin-induced thrombocytopenia.

Similar Datasets

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