Antithrombotic effects of saratin on human atherosclerotic plaques

Gemma Vilahur; Xavier Duran; Oriol Juan-Babot; Laura Casaní; Lina Badimon

doi:10.1160/TH03-11-0687

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2004; 92(01): 191-200
DOI: 10.1160/TH03-11-0687

New Technologies and Diagnostic Tools

Schattauer GmbH

Antithrombotic effects of saratin on human atherosclerotic plaques

Gemma Vilahur

¹Cardiovascular Research Center, ICCC-CSIC, Hospital de la Santa Creu i Sant Pau (U.A.B), Barcelona, Spain

,

Xavier Duran

¹Cardiovascular Research Center, ICCC-CSIC, Hospital de la Santa Creu i Sant Pau (U.A.B), Barcelona, Spain

,

Oriol Juan-Babot

¹Cardiovascular Research Center, ICCC-CSIC, Hospital de la Santa Creu i Sant Pau (U.A.B), Barcelona, Spain

,

Laura Casaní

¹Cardiovascular Research Center, ICCC-CSIC, Hospital de la Santa Creu i Sant Pau (U.A.B), Barcelona, Spain

,

Lina Badimon

¹Cardiovascular Research Center, ICCC-CSIC, Hospital de la Santa Creu i Sant Pau (U.A.B), Barcelona, Spain

› Author Affiliations

Abstract

Summary

Platelets play a primary role in thrombus formation after plaque rupture. Platelets recognize the exposed collagen via Von Willebrand factor (VWF) and become activated. Saratin, an inhibitor of the VWF-dependent binding of platelets to collagen, may reduce the thrombotic risk associated to atherosclerosis. Our objective was to evaluate the antithrombotic effects of local treatment with saratin on human atherosclerotic lesions. Thrombus formation was assessed by the deposition of ¹¹¹Inplatelets on different human atherosclerotic lesions under three local shear conditions (800,1700 and 3400/s) with blood derived from catheterized pigs. Human atherosclerotic lesions were locally treated with saratin (30 µg/ml) at 37ºC for 5 min and placed in the chamber. Under stenotic shear conditions of 800/s, saratin significantly (p<0.05) reduced platelet deposition triggered by human denuded vessel wall (44%), fatty streaks (47%), severely damaged vessel (50%) and atherosclerotic plaque (57%). Thrombus characterization by immunohistochemistry showed also a reduction in fibrin deposition in treated vessels. These results suggest that the local site-specific treatment with saratin inhibits atherosclerotic plaque thrombogenicity at haemodynamic conditions typical of moderately stenotic coronary arteries.

Keywords

Von Willebrand Factor - collagen - saratin - platelets - thrombosis

Full Text

References

References
1 Fuster V, Badimon L, Badimon JJ. et al. The pathogenesis of coronary artery disease and the acute coronary syndromes (2). N Engl J Med 1992; 326: 310-8.
2 Muller JE, Kaufmann PG, Luepker RV. et al. Mechanisms precipitating acute cardiac events: review and recommendations of an NHLBI workshop. National Heart, Lung, and Blood Institute. Mechanisms Precipitating Acute Cardiac Events Participants. Circulation 1997; 96: 3233-9.
3 Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002; 08: 1227-34.
4 Dogne JM, Leval XXd, Benoit P. et al. Recent advances in antiplatelet agents. Curr Med Chem 2002; 09: 577-89.
5 Patrono C, Coller B, Dalen JE. et al. Plateletactive drugs : the relationships among dose, effectiveness, and side effects. Chest 2001; 119: 39S-63S.
6 Furlan M. Von Willebrand factor: molecular size and functional activity. Ann Hematol 1996; 72: 341-8.
7 Ruggeri ZM. Von Willebrand factor. J Clin Invest 1997; 99: 559-64.
8 Lankhof H, van Hoeij M, Schiphorst ME. et al. A3 domain is essential for interaction of von Willebrand factor with collagen type III. Thromb Haemost 1996; 75: 950-8.
9 Obert B, Houllier A, Meyer D. et al. Conformational changes in the A3 domain of von Willebrand factor modulate the interaction of the A1 domain with platelet glycoprotein Ib. Blood 1999; 93: 1959-68.
10 Watson S, Berlanga O, Best D. et al. Update on collagen receptor interactions in platelets: is the two-state model still valid?. Platelets 2000; 11: 252-8.
11 Adams PC, Badimon JJ, Badimon L. et al. Role of platelets in atherogenesis: relevance to coronary arterial restenosis after angioplasty. Cardiovasc Clin 1987; 18: 49-71.
12 Chandrasekar B, Tanguay JF. Platelets and restenosis. J Am Coll Cardiol 2000; 35: 555-62.
13 Barnes CS, Krafft B, Frech M. et al. Production and characterization of saratin, an inhibitor of von Willebrand factor-dependent platelet adhesion to collagen. Semin Thromb Hemost 2001; 27: 337-48.
14 Maurer T, Bonke J, Frech M. et al. Sequential assignment and secondary structure of saratin, an inhibitor of von Willebrand factor-dependent platelet adhesion to collagen. J Biomol NMR 2001; 21: 77-8.
15 Smith TP, Alshafie TA, Cruz CP. et al. Saratin, an inhibitor of collagen-platelet interaction, decreases venous anastomotic intimal hyperplasia in a canine dialysis access model. Vasc Endovascular Surg 2003; 37: 259-69.
16 Cruz CP, Eidt J, Drouilhet J. et al. Saratin, an inhibitor of von Willebrand factor-dependent platelet adhesion, decreases platelet aggregation and intimal hyperplasia in a rat carotid endarterectomy model. J Vasc Surg 2001; 34: 724-9.
17 Badimon L, Turitto V, Rosemark JA. et al. Characterization of a tubular flow chamber for studying platelet interaction with biologic and prosthetic materials: deposition of Indium 111-labeled platelets on collagen, subendothelium and expanded polytetrafluoroethylene. J Lab Clin Med 1987; 110: 706-18.
18 Gould KL, Lipscomb K, Calvert C. Compensatory changes of the distal coronary vascular bed during progressive coronary constriction. Circulation 1975; 51: 1085-94.
19 Badimon L, Badimon JJ. Mechanisms of arterial thrombosis in nonparallel streamlines: platelet thrombi grow on the apex of stenotic severely injured vessel wall. Experimental study in the pig model. J Clin Invest 1989; 84: 1134-44.
20 Alfon J, Royo T, Garcia-Moll X. et al. Platelet deposition on eroded vessel wall at a stenotic shear rate is inhibited by lipid-lowering treatment with atorvastatin. Arterioscler Thromb Vasc Biol 1999; 19: 1812-7.
21 Kauhanen P, Kovanen PT, Lassila R. Coimmobilized native macromolecular heparin proteoglycans strongly inhibit plateletcollagen interactions in flowing blood. Arterioscler Thromb Vasc Biol 2000; 20: E113-9.
22 Sakariassen KS, Baumgartner HR. Axial dependence of platelet-collagen interactions in flowing blood. Upstream thrombus growth impairs downstream platelet adhesion. Arteriosclerosis 1989; 09: 33-42.
23 Sambrano GR, Weiss EJ, Zheng YW. et al. Role of thrombin signalling in platelets in haemostasis and thrombosis. Nature 2001; 413: 74-8.
24 Cauwenberghs N, Meiring M, Vauterin S. et al. Antithrombotic effect of platelet glycoprotein Ib-blocking monoclonal antibody Fab fragments in nonhuman primates. Arterioscler Thromb Vasc Biol 2000; 20: 1347-53.
25 Cadroy Y, Hanson SR, Kelly AB. et al. Relative antithrombotic effects of monoclonal antibodies targeting different platelet glycoprotein-adhesive molecule interactions in nonhuman primates. Blood 1994; 83: 3218-24.
26 Wu D, Vanhoorelbeke K, Cauwenberghs N. et al. Inhibition of the von Willebrand (VWF)collagen interaction by an antihuman VWF monoclonal antibody results in abolition of in vivo arterial platelet thrombus formation in baboons. Blood 2002; 99: 3623-8.
27 Zahger D, Fishbein MC, Garfinkel LI. et al. VCL, an antagonist of the platelet GP1b receptor, markedly inhibits platelet adhesion and intimal thickening after balloon injury in the rat. Circulation 1995; 92: 1269-73.
28 Deckmyn H, Stassen JM, Vreys I. et al. Calin from Hirudo medicinalis, an inhibitor of platelet adhesion to collagen, prevents platelet-rich thrombosis in hamsters. Blood 1995; 85: 712-9.
29 Schaffer LW, Davidson JT, Siegl PK. et al. Recombinant leech antiplatelet protein prevents collagen-mediated platelet aggregation but not collagen graft thrombosis in baboons. Arterioscler Thromb 1993; 13: 1593-601.
30 Becker BH, Miller JL. Effects of an antiplatelet glycoprotein Ib antibody on hemostatic function in the guinea pig. Blood 1989; 74: 690-4.
31 McGhie AI, McNatt J, Ezov N. et al. Abolition of cyclic flow variations in stenosed, endothelium-injured coronary arteries in nonhuman primates with a peptide fragment (VCL) derived from human plasma von Willebrand factor-glycoprotein Ib binding domain. Circulation 1994; 90: 2976-81.
32 Badimon JJ, Lettino M, Toschi V. et al. Local inhibition of tissue factor reduces the thrombogenicity of disrupted human atherosclerotic plaques. Circulation 1999; 99: 1780-7.
33 Sugimoto M, Tsuji S, Kuwahara M. et al. Shear-dependent functions of the interaction between soluble von Willebrand factor and platelet glycoprotein Ib in mural thrombus formation on a collagen surface. Int J Hematol 1999; 69: 48-53.
34 Badimon L, Badimon JJ, Turitto VT. et al. Role of von Willebrand Factor in mediating platelet-vessel wall interaction at low shear rate; the importance of perfusion conditions. Blood 1989; 73: 961-7.
35 Fuster V, Stein B, Ambrose JA. et al. Atherosclerotic plaque rupture and thrombosis. Evolving concepts. Circulation 1990; 82: II47-59.