Glycans and glycosylation of platelets: current concepts and implications for transfusion

Sørensen, Anne Louise; Hoffmeister, Karin M.; Wandall, Hans H.

doi:10.1097/moh.0b013e328313e3bd

Cited by 12 publications

(10 citation statements)

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“…With the aim of using glycoengineering to prevent clearance of cold-stored platelets, we have shown that addition of the donor substrate UDP-Gal causes glycosylation of exposed GlcNAc residues on GPIb␣, preventing recognition of cold-stored platelets by the hepatic macrophage ␣M␤2 clearance system. 11,15,48 The present study demonstrates that platelet sialyltransferases transfer fluorescently labeled CMP-SA to specific platelet surface proteins, capping exposed galactose and preventing the clearance of platelets mediated by the hepatic asialoglycoprotein receptor. 29 These findings suggest that glycoengineering could prevent the recognition of cold-stored platelets using a combination of galactosylation and sialylation.…”

Section: Platelets Have Glycan Biosynthesis Capacity 633mentioning

confidence: 99%

“…29 These findings suggest that glycoengineering could prevent the recognition of cold-stored platelets using a combination of galactosylation and sialylation. 48 Immature glycans could also represent essential clearance signals on activated circulating platelets, and it is tempting to speculate that reglycosylation of exposed immature glycans could prolong platelet survival. In support of this notion, desialylated GPIb␣ was shown previously to be a target for TACE (ADAM17), which inactivates VWF receptor function.…”

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The origin and function of platelet glycosyltransferases

Wandall

Rumjantseva

Sørensen

et al. 2012

Blood

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Platelets are megakaryocyte subfragments that participate in hemostatic and host defense reactions and deliver proand antiangiogenic factors throughout the vascular system. Although they are anucleated cells that lack a complex secretory apparatus with distinct Golgi/ endoplasmic reticulum compartments, past studies have shown that platelets have glycosyltransferase activities. In the present study, we show that members of 3 distinct glycosyltransferase families are found within and on the surface of platelets. Immunocytology and flow cytometry results indicated that megakaryocytes package these Golgi-derived glycosyltransferases into vesicles that are sent via proplatelets to nascent platelets, where they accumulate. These glycosyltransferases are active, and intact platelets glycosylate large exogenous substrates. Furthermore, we show that activation of platelets results in the release of soluble glycosyltransferase activities and that platelets contain sufficient levels of sugar nucleotides for detection of glycosylation of exogenously added substrates. Therefore, the results of the present study show that blood platelets are a rich source of both glycosyltransferases and donor sugar substrates that can be released to function in the extracellular space. This plateletglycosylation machinery offers a pathway to a simple glycoengineering strategy improving storage of platelets and may serve hitherto unknown biologic functions. (Blood. 2012;120(3):626-635) IntroductionGlycosylation of proteins and lipids has a wide range of biologic functions. 1 The glycosylation apparatus of nucleated cells is primarily located in the secretory pathway throughout the endoplasmic reticulum-Golgi stacks and consists of more than 200 glycosyltransferases, most of which are type II transmembrane-anchored proteins with distinct localization. Their topology within these compartments is directed by signal motifs contained in their stem, transmembrane, and cytoplasmic domains. 2,3 Golgi-located membrane-bound glycosyltransferases are believed to be retained in the appropriate compartments by coat protein I-mediated retrograde transport 3 and to be released and secreted only after proteolytic cleavage in their stalk regions to yield soluble, catalytically active truncated enzymes lacking their N-terminal transmembrane segment. 4 Several previous studies have described unusual subcellular localization of glycosyltransferases outside of their normal confinement to the endoplasmic reticulum-Golgi (referred to herein as ectopic localization). Methodologic ambiguities, however, have cast doubt on these findings. 5 One notable exception concerns reports of glycosyltransferase activities associated with blood platelets. [6][7][8][9][10][11] Platelets are anucleated megakaryocyte subfragments that participate in hemostatic, inflammatory, and host defense reactions. 12 Moreover, platelets deliver pro-and antiangiogenic factors throughout the vascular system. 12 Glycosyltransferase activities in platelets were described 30 years ago and are propo...

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Section: Platelets Have Glycan Biosynthesis Capacity 633mentioning

confidence: 99%

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confidence: 99%

The origin and function of platelet glycosyltransferases

Wandall

Rumjantseva

Sørensen

et al. 2012

Blood

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“…4,10 As platelets lose sialic acid from membrane glycoproteins during aging and circulation, enhanced exposure of nonsialylated glycan chains may represent a physiologic phenomenon triggering clearance of senescent blood cells. [11][12][13] Observations that platelets with increased exposure of ␤Gal may serve as endogenous ligands for the ASGPR were recently substantiated in a study that demonstrated this clearance mechanism to induce thrombocytopenia during Streptococcus pneumoniae sepsis. 14 Sialyltransferases are a family of 21 characterized glycosyltransferases transferring sialic acid from the donor substrate CMP-sialic acid to acceptor oligosaccharide substrates.…”

Section: Introductionmentioning

confidence: 97%

Role of sialic acid for platelet life span: exposure of β-galactose results in the rapid clearance of platelets from the circulation by asialoglycoprotein receptor–expressing liver macrophages and hepatocytes

Sørensen

Rumjantseva

Nayeb-Hashemi

et al. 2009

Blood

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Although surface sialic acid is considered a key determinant for the survival of circulating blood cells and glycoproteins, its role in platelet circulation lifetime is not fully clarified. We show that thrombocytopenia in mice deficient in the St3gal4 sialyltransferase gene (St3Gal-IV ؊/؊ mice) is caused by the recognition of terminal galactose residues exposed on the platelet surface in the absence of sialylation. This results in accelerated platelet clearance by asialoglycoprotein receptorexpressing scavenger cells, a mechanism that was recently shown to induce thrombocytopenia during Streptococcus pneumoniae sepsis. We now identify platelet GPIb␣ as a major counterreceptor on ST3Gal-IV ؊/؊ platelets for asialoglycoprotein receptors. Moreover, we report data that establish the importance of sialylation of the von Willebrand factor in its function. (Blood. 2009;114:1645-1654)

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“…The major drawbacks of storage at room temperature are the growth of bacteria, which contaminate one in 2,000 platelet units 1 and the decline in platelet viability and function known as platelet storage lesion. 2 Lowering the temperature to 0-4°C may be a better alternative, but this approach introduces new problems as it affects glycoprotein (GP) Ibα. GPIbα is the major subunit of the receptor for von Willebrand factor (VWF), which traps platelets at sites of vessel damage enabling firm attachment by collagen receptors GPVI and integrin α2b1.…”

Section: Introductionmentioning

confidence: 99%

Improved platelet survival after cold storage by prevention of glycoprotein Ib clustering in lipid rafts

et al. 2012

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The online version of this article has a Supplementary Appendix. BackgroundStoring platelets for transfusion at room temperature increases the risk of microbial infection and decreases platelet functionality, leading to out-date discard rates of up to 20%. Cold storage may be a better alternative, but this treatment leads to rapid platelet clearance after transfusion, initiated by changes in glycoprotein Ibα, the receptor for von Willebrand factor. Design and MethodsWe examined the change in glycoprotein Ibα distribution using Förster resonance energy transfer by time-gated fluorescence lifetime imaging microscopy. ResultsCold storage induced deglycosylation of glycoprotein Ibα ectodomain, exposing N-acetyl-Dglucosamine residues, which sequestered with GM1 gangliosides in lipid rafts. Raft-associated glycoprotein Ibα formed clusters upon binding of 14-3-3ζ adaptor proteins to its cytoplasmic tail, a process accompanied by mitochondrial injury and phosphatidyl serine exposure. Cold storage left glycoprotein Ibα surface expression unchanged and although glycoprotein V decreased, the fall did not affect glycoprotein Ibα clustering. Prevention of glycoprotein Ibα clustering by blockade of deglycosylation and 14-3-3ζ translocation increased the survival of cold-stored platelets to above the levels of platelets stored at room temperature without compromising hemostatic functions. ConclusionsWe conclude that glycoprotein Ibα translocates to lipid rafts upon cold-induced deglycosylation and forms clusters by associating with 14-3-3ζ. Interference with these steps provides a means to enable cold storage of platelet concentrates in the near future.Key words: platelets, cold storage, glycoprotein Ibα, 14-3-3ζ, lipid raft, clustering. Ibα clustering in lipid rafts. Haematologica 2012;97(12):1873-1881. doi:10.3324/haematol.2012 This is an open-access paper. Citation: Gitz E, Koekman CA, van den Heuvel DJ, Deckmyn H, Akkerman JW, Gerritsen HC and Urbanus RT. Improved platelet survival after cold storage by prevention of glycoprotein Improved platelet survival after cold storage by prevention of glycoprotein Ibα clustering in lipid rafts ABSTRACT© F e r r a t a S t o r t i F o u n d a t i o n

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Glycans and glycosylation of platelets: current concepts and implications for transfusion

Cited by 12 publications

References 68 publications

The origin and function of platelet glycosyltransferases

The origin and function of platelet glycosyltransferases

Role of sialic acid for platelet life span: exposure of β-galactose results in the rapid clearance of platelets from the circulation by asialoglycoprotein receptor–expressing liver macrophages and hepatocytes

Improved platelet survival after cold storage by prevention of glycoprotein Ib clustering in lipid rafts

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