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DOI: 10.1055/s-0038-1676794
Platelet Glycoprotein VI Haplotypes and the Presentation of Paediatric Sepsis
Funding Financial support by NIH R21AR061991 (to J.W.) and Arkansas Children's Hospital Research Institute and the Children's University Medical Group (to A.A.) is acknowledged.Publication History
18 July 2018
23 November 2018
Publication Date:
31 December 2018 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/201903/lookinside/thumbnails/10-1055-s-0038-1676794_180510-1.jpg)
Abstract
Sepsis triggers a complex series of pathophysiologic events involving inflammatory responses and coagulation abnormalities. While circulating blood platelets are well-characterized for their contributions to coagulation, increasingly platelet-dependent effects on inflammation are being recognized. Here, we focus on the platelet membrane receptor, glycoprotein VI (GPVI), and its role in platelet microparticle (pMP) release. The GPVI receptor is a platelet-specific collagen membrane receptor that, upon ligand binding, facilitates the release of pMPs. As membrane-bound platelet fragments of less than 1 μm, pMPs are known to have both pro-inflammatory and pro-coagulant properties. Thus, pMPs are potentially impacting sepsis at multiple stages of the inflammatory response. Studies are presented documenting the impact of the most common GPVI haplotypes, GPVIa and GPVIb, on pMP levels and release in healthy individuals (n = 49). The GPVIa haplotype corresponds to an approximately twofold increase in circulating pMPs as a percentage of total microparticles in healthy individuals along with a heightened in vitro release of pMPs. Additionally, patients admitted to a paediatric intensive care unit (ICU) (n = 73) with an initial diagnosis of sepsis were recruited and their GPVI haplotypes determined. Septic patients of the GPVIa haplotype (n = 59) were statistically more likely to present with a diagnosis of severe sepsis or septic shock, as compared with GPVIb individuals (n = 14). Independent disease classification via PELOD-2 and Pediatric Risk of Mortality III scores confirmed individuals with the GPVIa haplotype were more likely to have significant organ failure. Thus, GPVI haplotypes influence pMP levels in the circulation and are predictive of sepsis severity when presenting to the ICU.
Keywords
blood platelets - platelet glycoproteins - platelet microparticles - sepsis - genetic polymorphisms-
References
- 1 Leslie M. Cell biology. Beyond clotting: the powers of platelets. Science 2010; 328 (5978): 562-564
- 2 Zimmerman GA, Weyrich AS. Immunology. Arsonists in rheumatoid arthritis. Science 2010; 327 (5965): 528-529
- 3 Boilard E, Nigrovic PA, Larabee K. , et al. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 2010; 327 (5965): 580-583
- 4 Jain S, Russell S, Ware J. Platelet glycoprotein VI facilitates experimental lung metastasis in syngenic mouse models. J Thromb Haemost 2009; 7 (10) 1713-1717
- 5 Kehrel B, Wierwille S, Clemetson KJ. , et al. Glycoprotein VI is a major collagen receptor for platelet activation: it recognizes the platelet-activating quaternary structure of collagen, whereas CD36, glycoprotein IIb/IIIa, and von Willebrand factor do not. Blood 1998; 91 (02) 491-499
- 6 Inoue O, Suzuki-Inoue K, McCarty OJ. , et al. Laminin stimulates spreading of platelets through integrin alpha6beta1-dependent activation of GPVI. Blood 2006; 107 (04) 1405-1412
- 7 Mammadova-Bach E, Ollivier V, Loyau S. , et al. Platelet glycoprotein VI binds to polymerized fibrin and promotes thrombin generation. Blood 2015; 126 (05) 683-691
- 8 Induruwa I, Moroi M, Bonna A. , et al. Platelet collagen receptor glycoprotein VI-dimer recognizes fibrinogen and fibrin through their D-domains, contributing to platelet adhesion and activation during thrombus formation. J Thromb Haemost 2018; 16 (02) 389-404
- 9 Watson SP, Herbert JM, Pollitt AY. GPVI and CLEC-2 in hemostasis and vascular integrity. J Thromb Haemost 2010; 8 (07) 1456-1467
- 10 Li Z, Delaney MK, O'Brien KA, Du X. Signaling during platelet adhesion and activation. Arterioscler Thromb Vasc Biol 2010; 30 (12) 2341-2349
- 11 Ardoin SP, Shanahan JC, Pisetsky DS. The role of microparticles in inflammation and thrombosis. Scand J Immunol 2007; 66 (2-3): 159-165
- 12 Flaumenhaft R, Mairuhu AT, Italiano JE. Platelet- and megakaryocyte-derived microparticles. Semin Thromb Hemost 2010; 36 (08) 881-887
- 13 Pisetsky DS. Platelet microparticles: making blood a bad humor. J Rheumatol 2011; 38 (04) 590-592
- 14 Trifiro E, Williams SA, Cheli Y. , et al. The low-frequency isoform of platelet glycoprotein VIb attenuates ligand-mediated signal transduction but not receptor expression or ligand binding. Blood 2009; 114 (09) 1893-1899
- 15 Snoep JD, Gaussem P, Eikenboom JC. , et al. The minor allele of GP6 T13254C is associated with decreased platelet activation and a reduced risk of recurrent cardiovascular events and mortality: results from the SMILE-Platelets project. J Thromb Haemost 2010; 8 (11) 2377-2384
- 16 Bigalke B, Haap M, Stellos K. , et al. Platelet glycoprotein VI (GPVI) for early identification of acute coronary syndrome in patients with chest pain. Thromb Res 2010; 125 (05) e184-e189
- 17 Bigalke B, Stellos K, Geisler T. , et al. Expression of platelet glycoprotein VI is associated with transient ischemic attack and stroke. Eur J Neurol 2010; 17 (01) 111-117
- 18 Calandra T, Cohen J. ; International Sepsis Forum Definition of Infection in the ICU Consensus Conference. The international sepsis forum consensus conference on definitions of infection in the intensive care unit. Crit Care Med 2005; 33 (07) 1538-1548
- 19 Leteurtre S, Martinot A, Duhamel A. , et al. Validation of the paediatric logistic organ dysfunction (PELOD) score: prospective, observational, multicentre study. Lancet 2003; 362 (9379): 192-197
- 20 Gonçalves JP, Severo M, Rocha C, Jardim J, Mota T, Ribeiro A. Performance of PRISM III and PELOD-2 scores in a pediatric intensive care unit. Eur J Pediatr 2015; 174 (10) 1305-1310
- 21 Weyrich AS, Zimmerman GA. Platelets: signaling cells in the immune continuum. Trends Immunol 2004; 25 (09) 489-495
- 22 von Hundelshausen P, Weber C. Platelets as immune cells: bridging inflammation and cardiovascular disease. Circ Res 2007; 100 (01) 27-40
- 23 Semple JW, Italiano Jr JE, Freedman J. Platelets and the immune continuum. Nat Rev Immunol 2011; 11 (04) 264-274
- 24 Huang HS, Chang HH. Platelets in inflammation and immune modulations: functions beyond hemostasis. Arch Immunol Ther Exp (Warsz) 2012; 60 (06) 443-451
- 25 Jenne CN, Urrutia R, Kubes P. Platelets: bridging hemostasis, inflammation, and immunity. Int J Lab Hematol 2013; 35 (03) 254-261
- 26 Corken A, Russell S, Dent J, Post SR, Ware J. Platelet glycoprotein Ib-IX as a regulator of systemic inflammation. Arterioscler Thromb Vasc Biol 2014; 34 (05) 996-1001
- 27 Morrell CN, Aggrey AA, Chapman LM, Modjeski KL. Emerging roles for platelets as immune and inflammatory cells. Blood 2014; 123 (18) 2759-2767
- 28 Ho-Tin-Noé B, Demers M, Wagner DD. How platelets safeguard vascular integrity. J Thromb Haemost 2011; 9 (Suppl. 01) 56-65
- 29 Mueller K. Inflammation. Inflammation's yin-yang. Introduction. Science 2013; 339 (6116): 155
- 30 Hartman ME, Linde-Zwirble WT, Angus DC, Watson RS. Trends in the epidemiology of pediatric severe sepsis*. Pediatr Crit Care Med 2013; 14 (07) 686-693
- 31 Michou L, Cornélis F, Baron M. , et al. Association study of the platelet collagen receptor glycoprotein VI gene with rheumatoid arthritis. Clin Exp Rheumatol 2013; 31 (05) 770-772