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Inhibitory Fab fragments against GPVI provide robust protection in mouse models of arterial thrombosis and ischemic stroke without impairing hemostasis in mice or humans. However, their short in vivo half-life limits their suitability for long-term therapy. In contrast, GPVI-targeting IgGs (e.g., JAQ1-3) induce complete receptor depletion and a GPVI-knockout-like (GPVI\n                    <jats:sup>KO-like<\/jats:sup>\n                    ) phenotype in mice, a mechanism also observed in humans with anti-GPVI autoantibodies. While GPVI deficiency causes only moderate hemostatic defects, bleeding risk increases when combined with high-dose aspirin (100\u2009mg\/kg). Using a humanized GPVI (\n                    <jats:italic>hGP6<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>tg\/tg<\/jats:italic>\n                    <\/jats:sup>\n                    ) mouse model, we show that high-affinity anti-human GPVI IgGs (Emf1 K\n                    <jats:sub>D<\/jats:sub>\n                    0.490\u2009nM, Emf2) induce a GPVI\n                    <jats:sup>KO-like<\/jats:sup>\n                    phenotype with antithrombotic efficacy. In contrast, JAQ1 IgG, which binds hGPVI with low affinity (K\n                    <jats:sub>D<\/jats:sub>\n                    : 9.6\u2009nM), induces only partial (~50%) GPVI downregulation, generating a stable low-density GPVI (GPVI\n                    <jats:sup>LO<\/jats:sup>\n                    ) phenotype lasting up to 10 days. GPVI\n                    <jats:sup>LO<\/jats:sup>\n                    platelets showed impaired aggregation, abolished procoagulant activity, and\u2014similar to Fab-mediated inhibition\u2014conferred protection from arterial thrombosis and LPS-induced thrombo-inflammation without increasing bleeding, even when combined with high-dose aspirin. The low-affinity anti-mouse GPVI antibody JAQ4 (K\n                    <jats:sub>D<\/jats:sub>\n                    \u2009=\u200921\u2009nM) induced a comparable GPVI\n                    <jats:sup>LO<\/jats:sup>\n                    phenotype in wild-type mice. Transfusion of human platelets in NOD\/SCID mice showed that complete and partial GPVI depletion, respectively, also occurs in human platelets in vivo. These findings establish that partial, affinity-dependent GPVI downregulation can provide sustained antithrombotic protection while preserving hemostasis, offering a promising strategy for long-term platelet inhibition.\n                  <\/jats:p>","DOI":"10.1038\/s41392-026-02864-5","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T16:14:29Z","timestamp":1782922469000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Partial downregulation of platelet glycoprotein VI by low affinity antibodies confers sustained and safe antithrombotic protection"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1112-8400","authenticated-orcid":false,"given":"Stefano","family":"Navarro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Beck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina I.","family":"Bonfiglio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernesto J.","family":"Cuenca-Zamora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas J.","family":"Wei\u00df","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marijke","family":"Kuijpers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"Heemskerk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Stegner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard","family":"Nieswandt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"2864_CR1","unstructured":"Michelson, A. 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