Aster, Richard
Mayo Clinic
Versiti Blood Research Institute, Milwaukee, WI.
Citations 1
Prothrombotic antibodies targeting the spike protein's receptor-binding domain in severe COVID-19
Zhu, Wen , Zheng, Yongwei , Yu, Mei , Witman, Nathan , Zhou, Lu , Wei, Jianhui, Zhang, Yongguang , Nguyen, Christine , Wang, David , Janecke, Rae , Padmanabhan, Anand , White, Gilbert, Fields, Alexander T. , Kornblith, Lucy Z. , Aster, Richard H. , Zhu, Jieqing , Jobe, Shawn M. , Graham, Mary Beth, Wang, Demin , Wen, Renren , Topchyan, Paytsar , Nguyen, Christine , Wang, David , Janecke, Rae , Padmanabhan, Anand , Baumann Kreuziger, Lisa , Hari, Parameswaran , Gu, Tongjun , Kornblith, Lucy Z , Aster, Richard , Zhu, Jieqing , Cui, Weiguo , Jobe, Shawn , Graham, Mary Beth , Wang, Demin , Wen, Renren , Zhou, Lu , Kreuziger, Lisa Baumann , White, Gilbert C., Hari, Parameswaran , Cui, Weiguo
Blood | November 22, 2024 | Volume: 145 | Issue: 6 | Pages: 635-647
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.