{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nStudies on the platelet glycoprotein Ib‐IX complex have highlighted critical functions of its β‐subunit in modulating platelet adhesion and activation. For instance, one study used a monoclonal antibody directed at a cysteine loop in the carboxy‐terminal leucine‐rich region of GPIbβ to demonstrate that interference with this subunit abrogates ristocetin‐ and botrocetin‐mediated interactions with von Willebrand factor (vWF), thus directly modulating the adhesive properties of the receptor complex."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional investigations have shown that the GPIb‐IX complex is implicated in the pathophysiology of sepsis. In models of lipopolysaccharide‐induced endotoxemia, the adhesive receptor mediates platelet interactions with the inflammatory vascular endothelium and exposed subendothelium, contributing to microvascular thrombosis and thrombocytopenia."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurther evidence of the importance of this receptor comes from studies of platelet‐type von Willebrand disease, where mutations that enhance the affinity of GPIb for vWF result in aberrant receptor–ligand binding. Such alterations lead to impaired thrombus formation in vivo and a concomitant reduction in agonist‐induced fibrinogen binding despite focal VWF accumulation on the platelet surface."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, research into the role of Reelin—a secreted glycoprotein—has uncovered that it serves as a physiological ligand for platelet receptors, including GPIb. Reelin engages signaling pathways via GPIb, the amyloid precursor protein (APP), and ApoER2 to trigger downstream activators such as Akt and Erk, thereby promoting integrin activation and arterial thrombus formation without affecting normal hemostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn vivo genetic rescue experiments have further underscored the significance of the intracellular domains of GPIbβ. Targeted re-expression in knockout mice corrected several defects associated with GPIb‐IX deficiency, while deletion of specific intracellular segments resulted in opposite hemostatic outcomes—ranging from increased thrombosis to prolonged bleeding—thus supporting a signaling role for GPIbβ."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, studies in megakaryocytes have linked the proper trafficking of GPIbβ to membrane dynamics during proplatelet formation. Activation of the GTPase Rab5, which governs early endosomal function, was shown to regulate the distribution of GPIbβ between the plasma membrane and intracellular vesicles. Enhanced Rab5 activity led to its increased incorporation into the proplatelet membranes, thereby coupling endosomal maturation to efficient receptor presentation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "C Perrault, S Moog, E Rubinstein, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A novel monoclonal antibody against the extracellular domain of GPIbbeta modulates vWF mediated platelet adhesion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Thromb Haemost (2001)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11816713"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11816713"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Hong Yin, Aleksandra Stojanovic-Terpo, Weidong Xu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role for platelet glycoprotein Ib-IX and effects of its inhibition in endotoxemia-induced thrombosis, thrombocytopenia, and mortality."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arterioscler Thromb Vasc Biol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/ATVBAHA.113.302339"}], "href": "https://doi.org/10.1161/ATVBAHA.113.302339"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24051142"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24051142"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Jose A Guerrero, Mark Kyei, Susan Russell, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Visualizing the von Willebrand factor/glycoprotein Ib-IX axis with a platelet-type von Willebrand disease mutation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2009-03-210823"}], "href": "https://doi.org/10.1182/blood-2009-03-210823"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19808696"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19808696"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Nina Sarah Gowert, Irena Krüger, Meike Klier, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss of Reelin protects mice against arterial thrombosis by impairing integrin activation and thrombus formation under high shear conditions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Signal (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cellsig.2017.09.016"}], "href": "https://doi.org/10.1016/j.cellsig.2017.09.016"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28943410"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28943410"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "C Strassel, A Bull, S Moog, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Lentiviral gene rescue of a Bernard-Soulier mouse model to study platelet glycoprotein Ibβ function."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Thromb Haemost (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jth.13355"}], "href": "https://doi.org/10.1111/jth.13355"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27148783"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27148783"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Ivana Bertović, Roberta Kurelić, Hana Mahmutefendić Lučin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Early Endosomal GTPase Rab5 (Ras-Related Protein in Brain 5) Regulates GPIbβ (Glycoprotein Ib Subunit β) Trafficking and Platelet Production In Vitro."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arterioscler Thromb Vasc Biol (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/ATVBAHA.121.316552"}], "href": "https://doi.org/10.1161/ATVBAHA.121.316552"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34732055"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34732055"}]}]}]}