Retinal vein occlusion (RVO) is the most common retinal vascular disorder second to diabetic retinopathy. The main risk factors in patients with RVO are hypertension, diabetes, hyperlipidemia, increased blood viscosity and glaucoma. The pathogenesis of RVO has not yet been clarified. In these events platelets could play a very important role. In the present study the platelet response to collagen was deeply investigated. Experiments were carried out on a selected group of RVO patients, which were compared to a group of healthy subjects matched for age, sex, clinical and metabolic characteristics. In resting and activated platelets of both groups of subjects p72syk phosphorylation, phospholipase Cγ 2 phosphorylation, protein kinase C activation, intracellular calcium levels and nitric oxide formation were measured. Results show that platelets of patients were more responsive to collagen or ADP than healthy subjects and that the response was significantly different (p < 0.0005) at low concentrations of these agonists. In platelets of patients stimulated with collagen increased phosphorylation of p72syk and phospholipase C γ 2 was found. Also protein kinase C was more activated in patients. In addition intracellular calcium rise induced by collagen was significantly higher in patients than in healthy subjects. RVO patients showed a lower basal level of nitric oxide both in resting and stimulated platelets compared to healthy subjects. Altogether these results suggest that the platelet hyperaggregability described in patients might be an important factor in the development of RVO contributing to the thrombogenic effects.
Keywords
Collagen -
human platelets -
retinal vein occlusion
References
1
David R,
Zangwill L,
Badarna M.
et al. Epidemiology of retinal vein occlusion and its association with glaucoma and increased intraocular pressure. Ophthalmologica 1988; 197: 69-74.
2
Prisco D,
Marcucci R,
Bertini L.
et al. Cardiovascular and thrombophilic risk factors for central retinal vein occlusion. Eur J Intern Med 2002; 13: 163-169.
4
Sperduto RD,
Hiller R,
Chew E.
et al. Risk factors for hemiretinal vein occlusion: comparison with risk factors for central and branch retinal vein occlusion: the eye disease case-control study. Ophthalmology 1998; 105: 765-771.
11
Gibbins J,
Asselin J,
Farndale R.
et al. Tyrosine phosphorylation of the Fc receptor gamma-chain in collagen-stimulated platelets. J Biol Chem 1996; 271: 18095-18099.
12
Poole A,
Gibbins JM,
Turner M.
et al. The Fc receptor gamma-chain and the tyrosine kinase Syk are essential for activation of mouse platelets by collagen. EMBO J 1997; 16: 2333-2341.
13
Leoncini G,
Maresca M,
Buzzi E.
et al. Platelets of patients affected with Essential Thrombocythemia are abnormal in plasma membrane and adenine nucleotide content. Eur J Haematol 1990; 44: 116-120.
15
Rotondo S,
Evangelista V,
Manarini S.
et al. Different requirement of intracellular calcium and protein kinase C for arachidonic acid release and serotonin secretion in cathepsin G-activated platelets. Thromb Haemost 1997; 78: 919-925.
17
Granger DL,
Taintor RR,
Boockvar KS.
et al. Measurement of nitrate and nitrite in biological samples using nitrate reductase and Griess reaction. Methods Enzymol 1996; 268: 142-151.
18
Keely PJ,
Parise LV.
The alpha2beta1 integrin is a necessary co-receptor for collagen-induced activation of Syk and the subsequent phosphorylation of phospholipase Cgamma2 in platelets. J Biol Chem 1996; 271: 26668-26676.
19
Blake RA,
Schieven GL,
Watson SP.
Collagen stimulates tyrosine phosphorylation of phospholipase C-gamma 2 but not phospholipase C-gamma 1 in human platelets. FEBS Lett 1994; 353: 212-216.
21
Leoncini G,
Bruzzese D,
Signorello MG.
The L-arginine/ NO pathway in the early phases of platelet stimulation by collagen. Biochem Pharmacol 2005; 69: 289-296.
23
Leoncini G,
Signorello MG,
Piana A.
et al. Hyperactivity and increased hydrogen peroxide formation in platelets of NIDDM patients. Thromb Res 1997; 86: 153-160.
26
Hayreh SS,
Zimmerman B,
McCarthy MJ et al.
Systemic diseases associated with various types of retinal vein occlusions. Am J Ophthalmol 2001; 131: 61-77.
27
Janssen MC,
den Heijer M,
Cruysberg JR.
et al. Retinal vein occlusion: a form of venous thrombosis or a complication of atherosclerosis? A meta-analysis of thrombophilic factors. Thromb Haemost 2005; 93: 1021-1026.
31
Houtsmuller AJ,
Vermeulen JACM,
Klompe M.
et al. The influence of ticlopidine on the natural course of the retinal venal occlusion. Agents Actions Suppl. 1984; 15: 219-229.
32
Dodson PM,
Westwick J,
Marks G.
et al. Betathromboglogulin and platelet factor 4 levels in retinal vein occlusion. Br J Ophthalmol 1983; 67: 143-146.
33
Yamamoto T,
Kamei M,
Yokoi N et al.
Comparative effect of antiplatelet therapy in retinal vein occlusion evaluated by the particle-counting method using light scattering. Am J Ophthalmol 2004; 138: 809-817.
34
Cahill M,
Karabatzaki M,
Meleady R.
et al. Raised plasma homocysteine as a risk factor for retinal vascular occlusive disease. Br J Ophthalmol 2000; 84: 154-157.
37
Marcucci R,
Giusti B,
Betti I.
et al. Genetic determinants of fasting and post-methionine hyperhomocysteinemia in patients with retinal vein occlusion. Thromb Res 2003; 110: 7-12.
41
Leoncini G,
Pascale R,
Signorello MG.
Effects of homocysteine on l-arginine transport and nitric oxide formation in human platelets. Eur J Clin Invest 2003; 33: 713-719.
42
Menys VC,
Bhatnagar D,
Mackness MI.
et al. Spontaneous platelet aggregation in whole blood is increased in non-insulin-dependent diabetes mellitus and in female but not male patients with primary dyslipidemia. Atherosclerosis 1995; 112: 115-122.
43
Davì G,
Catalano I,
Averna M.
et al. Thromboxane biosynthesis and platelet function in type II diabetes mellitus. N Engl J Med 1990; 322: 1769-1774.
44
Leoncini G,
Signorello MG,
Piana A.
et al. Hydrogen peroxide formation in platelets in patients with non-insulin dependent diabetes. Platelets 1998; 9: 213-217.
45
Fusegawa Y,
Hashizume H,
Okumura T et al.
Hypertensive patients with carotid artery plaque exhibit increased platelet aggregability. Thromb Res 2006; 117: 615-622.
46
Loschiavo C,
Valvo E,
Bedogna V.
et al. Effects of ketanserin administration on lipid metabolism and platelet aggregation in hypertensive patients. Int J Clin Pharmacol Ther Toxicol 1990; 28: 455-457.