Scientific Online Resource System

Scripta Scientifica Medica

Effects of Melatonin and Luzindole on plasma levels of tissue factor, tissue factor Pathway inhibitor and Von Willebrand factor in rats

Negrin Negrev, Yuri Nyagolov, Antoaneta Zarkova, Irina Ilieva Pashalieva, Emiliya Stancheva, Diana Radkova


Introduction: The role of melatonin in hemostasis is still poorly studied.

Purpose: The purpose of this study was to investigate the effects of melatonin and luzindole, inhibitor of the melatonin receptors - MT1 and MT2, on plasma levels of tissue factor, tissue factor pathway inhibitor and von Willebrand factor.

Material and methods: The study was performed on 52 male Wistar rats, kept at 12/12 h natural regimen dark/light. The daily doses of melatonin 0.2 mg/kg b.m. and luzindole 0.4 mg/kg b.m. were applied subcutaneously twice daily at intervals of 12h for three consecutive days. The rats were distributed into four equal groups (n = 13) and were treated as follows: the first group (control group) - by saline; the second group - by melatonin; the third group - by luzindole; and the fourth group - by luzindole and an hour later by melatonin.

Results: The results show that melatonin significantly increases the plasma levels of TF, reduces the values of free TFPI antigen and free TFPI activity, and increases the values of vWF antigen and vWF activity. Applied alone, luzindole lowers the plasma levels of TF, increases the values of free TFPI antigen and free TFPI activity; decreases the values of vWF antigen and vWF activity. Pretreatment with luzindole repeats the effect of self-administration. The received data show that melatonin induces a pronounced tendency to hypercoagulability in rats by a significant increase in TF, a decrease of free TFPI and free TFPI activity, as well as an increase in vWF antigen and vWF activity.

Conclusions: Lizindole self-administration and pretreatment show a decisive involvement of MT1 and MT2 receptors for accomplishing the effects of the hormone.


melatonin; luzindole; TF; TFPI; vWF; MT1 and MT2 receptors; hypercoagulability

Full Text


Kasthuri RS, Sam LG, Boles J, Mackman N. Tissue factor and tissue factor pathway inhibitor as key regulators of global hemostasis: measurement of their levels in coagulation assays. Semin Thromb Hemost. 2010;36:764-771.

Mackman N. Role of tissue factor in hemostasis, thrombosis, and vascular development. Arterioscler Thromb Vasc Biol. 2004;24(6):1015-1022.

Østerud B, Bjørklid E. Sources of tissue factor. Semin Thromb Hemost. 2006;32(1):11-23.

Schecter AD, Sprin B, Rossikhina M, Giesen PL, Bogdanov V, Fallon JT et al. Release of active tissue factor by human arterial smooth muscle cells. Circ Res. 2000;87(2):126-132.

Mumford AD, McVey JH. Tissue factor in the myocardium: evidence of roles in haemostasis and inflammation. Dis Markers. 2004;20(6):353-358.

Mann KG, Orfeo T, Butenas S, Undas A, Brummel-Ziedins K. Blood coagulation dynamics in haemostasis. Hamostaseologie. 2009;29(1):7-16.

Butenas S, Mann GK. Blood coagulation. Biochemistry 2002;67(1):3-12.

Ellery PE, Adams MJ. Tissue factor pathway inhibitor: then and now. Semin Thromb Hemost. 2014;40:881-886.

Wood JP, Ellery PE, Maroney SA, Mast AE. Biology of tissue factor pathway inhibitor. Blood 2014;123:2934-2943.

Bajaj MS, Kuppuswamy MN, Satio H, Spitzer SG, Bajaj SP. Cultured normal human hepatocytes do not synthesize lipoprotein-associated coagulation inhibitor: evidence that endothelium is the principal site of its synthesis. Proc Natl Acad Sci, USA 1990;87(22):8869-8873.

Mast AE, Acharya N, Malecha MJ, Hall CL, Dietzen DJ. Characterization of the association of tissue factor pathway inhibitor with human placenta. Arterioscler Thromb Vasc Biol. 2002;22(12):2099-2104.

Girard TJ, Warren LA, Novotny WF, Likert KM, Brown SG, Miletich JP et al. Functional significance of the Kunitz-type inhibitory domains of lipoprotein-associated coagulation inhibitor. Nature 1989;338(6215):518-520.

Petersen LC, Bjørn SE, Olsen OH, Nordfang O, Norris F, Norris K. Inhibitory properties of separate recombinant Kunitz-type-protease-inhibitor domains from tissue-factor-pathway inhibitor. Eur J Biochem. 1996;235(1-2):310-316.

Baugh RJ, Broze Gr Jr, Krishnaswamy S. Regulation of extrinsic pathway factor Xa formation by tissue factor pathway inhibitor. J Biol Chem. 1998;273(8):4378-4386.

Crawley JT, Lane DA. The haemostatic role of tissue factor pathway inhibitor. Arterioscler Thromb Vasc Biol. 2008;28(2):233-242.

Reininger AJ. Function of von Willebrand factor in haemostasis and thrombosis. Haemophilia. 2008;14 Suppl 5:11-26.

Szanto T, Joutsi-Korhonen L, Deckmyn H, Lassila R. New insights into von Willebrand disease and platelet function. Semin Thromb Hemost. 2012;38:55-63.

Vlot AJ, Koppelman SJ, Bouma BN, Sixma JJ. Factor VIII and von Willebrand factor. Thromb Haemost. 1998;79(3):456-465.

Mayadas TN, Wagner DD. von Willebrand factor biosynthesis and processing. Ann N Y Acad Sci. 1991;614:153-166.

McGrath RT, McRae E, Smith OP, OÍ´Donnel JS. Platelet von Willebrand factor-structure, function and biological importance. Br J Haematol. 2010; 148(6):834-843.

Mackman N. Role of tissue factor in hemostasis and thrombosis. Blood Cells Mol Dis. 2006;36(2):104-107.

Pashalieva I, Decheva L, Stancheva E, Nyagolov Y, Negrev N. Melatonin and luzindole - induced effects on integral blood coagulation parameters in rats. Comptes rendus de L`Academie bulgare des Sciences 2014;67:1269-1274.

Vischer UM. von Willebrand factor, endothelial dysfunction, and cardiovascular disease. J Thromb Haemost. 2006;4:1186-1193.

Pashalieva I, Stancheva E, Decheva L, Nyagolov Y, Negrev N. Experimental date about effect of melatonin on the count and functional activity of thrombocytes. Comptes rendus de L`Academie bulgare des Sciences 2012;65:855-860.

Nyagolov Y, Stancheva E, Decheva L, Pashalieva I, Negrev N. Melatonin and luzindole effects on the activity of plasma clotting factors V, XI, XII and XIII in rat. Comptes Rendus de L`Academie bulgare des Sciences 2012;65:1151-1156.

About The Authors

Negrin Negrev
Department of physiology and pathophysiology, Medical university of Varna

Yuri Nyagolov
Department of physiology, Medical university of Sofia

Antoaneta Zarkova
Specialized hospital for active treatment of hematological diseases of Sofia

Irina Ilieva Pashalieva
Department of physiology and pathophysiology, Medical university of Varna

Emiliya Stancheva
Department of physiology and pathophysiology, Medical university of Varna

Diana Radkova
Medical university of Varna

Department of infectious diseases

Font Size