A PSGL-1 Glycomimetic Reduces Thrombus Burden Without Affecting Hemostasis

Citation:

Chaikof EL, Wong DJ, Park DD, Park SS, Haller C, Chen J, Dai E, Liu L, Mandhapati AR, Eradi P, et al. A PSGL-1 Glycomimetic Reduces Thrombus Burden Without Affecting Hemostasis. Blood. 2021.

Date Published:

May 4

Abstract:

Events mediated by the P-selectin/PSGL-1 pathway play a critical role in the initiation and propagation of venous thrombosis by facilitating the accumulation of leukocytes and platelets within the growing thrombus. Activated platelets and endothelium both express P-selectin, which binds PSGL-1 expressed on the surface of all leukocytes. We developed a pegylated glycomimetic of the N-terminus of PSGL-1, PEG40-GSnP-6 (P-G6), which proved to be a highly potent P-selectin inhibitor with a favorable pharmacokinetic profile for clinical translation. P-G6 inhibits human and mouse platelet-monocyte and platelet-neutrophil aggregation in vitro and blocks microcirculatory platelet-leukocyte interactions in vivo. Administration of P-G6 reduces thrombus formation in a non-occlusive model of deep vein thrombosis with a commensurate reduction in leukocyte accumulation, but without disruption of hemostasis. P-G6 potently inhibits the P-selectin/PSGL-1 pathway and represents a promising drug candidate for the prevention of venous thrombosis without increased bleeding risk.

Notes:

Chaikof, Elliot LWong, Daniel JamesPark, Diane DPark, Simon SHaller, CarolynChen, JiaxuanDai, ErbinLiu, LiyingMandhapati, Appi ReddyEradi, PradheepDhakal, BibekWever, WalterHanes, MelindaSun, LijunCummings, Richard DengBlood. 2021 May 4. pii: 475901. doi: 10.1182/blood.2020009428.