Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα

Caroline Kardeby, Knut Fälker, Elizabeth J Haining, Maarten Criel, Madelene Lindkvist, Ruben Barroso, Peter Påhlsson, Liza U Ljungberg, Mattias Tengdelius, G. Ed Rainger, Stephanie Watson, Johannes A. Eble, Marc F Hoylaerts, Jonas Emsley, Peter Konradsson, Steve P. Watson, Yi Sun, Magnus Grenegård

Research output: Contribution to journalArticlepeer-review


Fucoidans are sulfated fucose-based polysaccharides that activate platelets and have pro- and anticoagulant effects; thus, they may have therapeutic value. In the present study, we show that 2 synthetic sulfated α-l-fucoside-pendant glycopolymers (with average monomeric units of 13 and 329) and natural fucoidans activate human platelets through a Src- and phosphatidylinositol 3-kinase (PI3K)-dependent and Syk-independent signaling cascade downstream of the platelet endothelial aggregation receptor 1 (PEAR1). Synthetic glycopolymers and natural fucoidan stimulate marked phosphorylation of PEAR1 and Akt, but not Syk. Platelet aggregation and Akt phosphorylation induced by natural fucoidan and synthetic glycopolymers are blocked by a monoclonal antibody to PEAR1. Direct binding of sulfated glycopolymers to epidermal like growth factor (EGF)-like repeat 13 of PEAR1 was shown by avidity-based extracellular protein interaction screen technology. In contrast, synthetic glycopolymers and natural fucoidans activate mouse platelets through a Src- and Syk-dependent pathway regulated by C-type lectin-like receptor 2 (CLEC-2) with only a minor role for PEAR1. Mouse platelets lacking the extracellular domain of GPIbα and human platelets treated with GPIbα-blocking antibodies display a reduced aggregation response to synthetic glycopolymers. We found that synthetic sulfated glycopolymers bind directly to GPIbα, substantiating that GPIbα facilitates the interaction of synthetic glycopolymers with CLEC-2 or PEAR1. Our results establish PEAR1 as the major signaling receptor for natural fucose-based polysaccharides and synthetic glycopolymers in human, but not in mouse, platelets. Sulfated α-l-fucoside-pendant glycopolymers are unique tools for further investigation of the physiological role of PEAR1 in platelets and beyond.

Original languageEnglish
Pages (from-to)275-287
Number of pages12
JournalBlood advances
Issue number3
Early online date12 Feb 2019
Publication statusE-pub ahead of print - 12 Feb 2019

Bibliographical note

© 2019 by The American Society of Hematology


  • Animals
  • Biopolymers/pharmacology
  • Calcium/blood
  • Humans
  • Mice
  • Mice, Knockout
  • Platelet Aggregation/drug effects
  • Platelet Glycoprotein GPIb-IX Complex/metabolism
  • Polysaccharides/pharmacology
  • Receptors, Cell Surface/blood
  • Syk Kinase/blood


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