New insights into glycoprotein Ibα desialylation-mediated platelet clearance

The GPIb-IX complex on platelets: insight into its novel physiological functions affecting immune surveillance, hepatic thrombopoietin generation, platelet clearance and its relevance for cancer development and metastasis

“…The force-induced unfolding of the mechanosensitive domain and consequences for platelet signaling have recently been characterized in detail. In pulling-relaxation experiments the authors showed that refolding of the unfolded mechanosensitive domain occurs also under force and that the glycosylation status of the mechanosensitive domain has an impact on the required unfolding force, e.g., a non-glycosylated mechanosensitive domain needs a significantly weaker force to unfold than the glycosylated one [ 63 , 64 ]. Furthermore, a longer shear force exposure (up to 5 min) initiates an enhanced P-selectin, and phosphatidylserine exposition on platelet membranes than a 30 s force exposure.…”

“…Several billions of platelets are produced daily. To avoid spontaneous bleeding events or arterial or venous occlusions, the complex process of platelet production by megakaryocytes and clearance by hepatocytes, liver macrophages (Kupffer cells), or spleen macrophages is a sophisticated, balanced, and tightly regulated process [ 64 ]. During infection and sepsis, platelets are rapidly cleared from circulation to mitigate the risk of lethal coagulopathies [ 102 ].…”

“…The AMR exhibits a higher binding affinity and preference for tri- or tetra-antennary galactose-terminal oligosaccharides than for single galactose units [ 119 – 121 ]. Thus, it was supposed that galactose exposed by N -linked glycans is the major ligand for the AMR since O -linked glycans do not present a ternary complex [ 64 ]. Recently, Wang et al revealed that desialylation of O -glycans, instead of N -glycans, on GPIbα induces mechanosensitive domain unfolding, GPIb-IX signaling, and finally platelet clearance by the AMR [ 122 ].…”

“…Megakaryocytes are the largest cells in the bone marrow (50–100 µm) and responsible for the production and secretion of about 10 11 platelets per day [ 64 , 146 ]. Megakaryocytes develop from hematopoietic stem cells under the continuous supply with TPO and further regulatory proteins [ 136 , 138 , 147 , 148 ].…”