Increased soluble GPVI levels in cirrhosis: evidence for early in vivo platelet activation
Cirrhosis is a consequence of prolonged liver injury and is characterised by extensive tissue fibrosis: the deposition of collagen-rich extracellular matrix. The haemostatic balance is disordered in cirrhosis and coagulation activation appears to promote fibrosis. In spite of recent studies demonstrating a role for anticoagulant therapy in preventing cirrhosis progression, there has not been a change in clinical practice, suggesting that physicians are reluctant to anticoagulate patients with cirrhosis due to bleeding risks. Platelets play an important role in facilitating coagulation. Glycoprotein VI (GPVI) is a platelet-specific collagen receptor that is shed from the platelet surface in a metalloproteinase-dependent manner in response to GPVI ligation and coagulation activation. Our aim was to use soluble GPVI levels to determine whether there was evidence for collagen and coagulation-induced platelet activation in early, well-compensated cirrhosis. Plasma soluble GPVI levels were quantified in 46 patients with mixed aetiology cirrhosis and 55 healthy controls using an immunoassay. In the cirrhosis group, soluble GPVI levels were significantly increased (5.8 ± 4.4 ng/ml, n = 46) compared to healthy controls (3.3 ± 3.4 ng/ml, n = 55, p < 0.05). This increase in soluble GPVI levels was still evident when levels were adjusted for platelet count (Healthy controls; 0.015 ± 0.018 ng/106 platelets/ml vs. cirrhosis; 0.048 ± 0.04 ng/106 platelets/ml, p < 0.0001). This study provides evidence for early platelet activation in patients with well-compensated cirrhosis. This may have translational implications for prognosis, treatment, and risk stratification.
KeywordsCirrhosis Collagen Glycoprotein VI Platelet activation Shedding
Body mass index
Soluble glycoprotein VI
Low molecular weight heparin
Liver stiffness measurement
Model for end-stage liver disease
Alcoholic liver disease
Hepatitis C virus
Non alcoholic fatty liver disease
Primary biliary cholangitis
Protease activated receptor 1
Hepatitic stellate cells
This work was supported by the ‘Friends of the Rotunda’, the Health Research Board of Ireland (Health Research Award R13728), and by Science Foundation Ireland under Grant No 10/CE/B1821.
KE, SS, and FNA designed the study. AD, ED, BK, and ZG collected the samples. KE, ED, and BK performed the experiments. KE, AD, and ED analysed the data. KE, AD, PM, DK, SS, and FNA prepared and edited the manuscript.
Compliance with ethical standards
Conflict of Interest
The authors declare no conflict of interest.
- 5.Villa E, Cammà C, Marietta M, Luongo M, Critelli R, Colopi S, Tata C, Zecchini R, Gitto S, Petta S, Lei B, Bernabucci V, Vukotic R, De Maria N, Schepis F, Karampatou A, Caporali C, Simoni L, Del Buono M, Zambotto B et al (2012) Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterology 143:1253 e1–1260 e4CrossRefGoogle Scholar
- 8.Al-Tamimi M, Tan CW, Qiao J, Pennings GJ, Javadzadegan A, Yong ASC, Arthur JF, Davis AK, Jing J, Mu F-T, Hamilton JR, Jackson SP, Ludwig A, Berndt MC, Ward CM, Kritharides L, Andrews RK, Gardiner EE (2012) Pathologic shear triggers shedding of vascular receptors: a novel mechanism for down-regulation of platelet glycoprotein VI in stenosed coronary vessels. Blood 119:4311–4320CrossRefPubMedGoogle Scholar
- 12.Zaldivar MM, Pauels K, von Hundelshausen P, Berres M-L, Schmitz P, Bornemann J, Kowalska MA, Gassler N, Streetz KL, Weiskirchen R, Trautwein C, Weber C, Wasmuth HE (2010) CXC chemokine ligand 4 (Cxcl4) is a platelet-derived mediator of experimental liver fibrosis. Hepatology 51:1345–1353CrossRefPubMedGoogle Scholar
- 21.Panasiuk A, Prokopowicz D, Zak J, Matowicka-Karna J, Osada J, Wysocka J (2000) Activation of blood platelets in chronic hepatitis and liver cirrhosis P-selectin expression on blood platelets and secretory activity of beta-thromboglobulin and platelet factor-4. Hepatogastroenterology 48:818–822Google Scholar