Inhibition of Fibrinolytic Activity In-Vivo by Dexamethasone Is Counterbalanced by an Inhibition of Platelet Aggregation

Summary

Dexamethasone decreases the fibrinolytic activity in cultured medium of several cell types by an induction of PAI-1 synthesis. As a result of this enhanced PAI-1 synthesis a prothrombotic state is expected in patients treated with dexamethasone. However, such a prothrombotic state is not reported as a major adverse effect. We have studied the effects of dexamethasone (dose range: 0.1–3.0 mg/kg) on the fibrinolytic system of rats after a 5 day pretreatment period. It appeared that dexamethasone dose dependently decreased the fibrinolytic activity (a dose of 1 mg/kg showed a reduction of about 40%). This reduced fibrinolytic activity could be functionally translated into an increased thrombus size as measured with a venous thrombosis model: thrombus size was increased by 50% with 1 mg/kg dexamethasone. No effects could be measured on the coagulation system, but it appeared that ex-vivo measured platelet aggregation was dose dependently inhibited by dexamethasone treatment. This effect resulted in-vivo in prolonged obstruction times as measured with a modified aorta-loop model. These results indicate that the expected prothrombotic state due to a diminished fibrinolytic activity caused by dexamethasone is counterbalanced by an inhibition of platelet aggregation.

• References

• 1 Granelli-Piperno A, Reich E. Plasminogen activators of the pituitary gland enzymatic characterisation and hormonal modulation. J Cell Biol 1988; 97: 1029-1037
• 2 Medcalf RL, Van den Berg E, Schleuning WD. Glucocorticoid-modulated gene expression of tissue and urinary type plasminogen activator and plasminogen activator inhibitor 1 and 2. J Cell Biol 1988; 106: 971-978
• 3 Andreassen PA, Christensen TM, Huang JY, Wilson EL, Danø K. Hormonal regulation of extracellular plasminogen activators and Mw 54000 plasminogen activator inhibitor in human neoplastic cell-lines. Studies with monoclonal antibodies. Mol Cell Endocrinol 1986; 45: 137-147
• 4 Laug WE. Glucocorticoids inhibit plasminogen activator production by endothelial cells. Thromb Haemostas 1983; 50: 888-892
• 5 Gelehrter TD, Barouski-Miller PA, Coleman PL, Cwickel BJ. Hormonal regulation of plasminogen activator in rat hepatoma cells. Mol Cell Biochem 1983; 53/54: 11-21
• 6 Gelehrter TD, Sznycer-Lasuk R, Zeheb R, Cwickel BJ. Dexamethasone induced inhibition of tissue-type plasminogen activator (tPA) activity: paradoxical induction of both tPA antigen and plasminogen activator inhibitor. Mol Endocrinol 1987; 1: 97-101
• 7 Andreassen PA, Pyce C, Riccio A, Kristensen P, Nielsen LS, Lund LR, Blasi F, Danø K. Plasminogen activator inhibitor type-1 biosynthesis and mRNA level are increased by dexamethasone in human fibrosarcoma-cells. Mol Cell Biol 1987; 7: 3021-3025
• 8 Heaton JH, Nebes VL, O’Dell LG, Morris SM, Gelehrter TD. Glucocorticoid and cyclic nucleotide regulation of plasminogen activator and plasminogen activator inhibitor gene expression in primary cultures of rat hepatocytes. Mol Endocrinol 1989; 3: 185-192
• 9 Zonneveld AJ van, Curriden SA, Loskutoff DJ. Type 1 plasminogen activator inhibitor gene: Functional analysis and glucocorticoid regulation of its promotor. Proc Natl Acad Sci USA 1988; 85: 5525-5529
• 10 Oikarinen A, Höythyä M, Järvinen M. Dexamethasone induced plasminogen activator inhibitor: characterization, purification, and preparation of monoclonal antibodies. Arch Dermatol Res 1990; 282: 153-158
• 11 Fadul CE, Lemann W, Thaler HT, Posner JB. Perforation of the gastrointestinal tract in patients receiving steroids for neurologic disease. Neurology 1988; 38: 348-352
• 12 Friedenberg WR, Kyle RA, Knospe WH, Bennet JM, Tsiatis AA, Oken MM. High-dose dexamethasone for refractory or relapsing multiple myeloma. Am J Hematol 1991; 36: 171-175
• 13 Blombäck B, Blombäck M, Hessel B, Iwanaga S. Structure of N-terminal fragments of fibrinogen and specificity of thrombin. Nature 1967; 215: 1445-1448
• 14 Fearnley GR, Balmforth G, Fearnley E. Evidence of a diurnal fibrinolytic rhythm; with a simple method of measuring natural fibrinolysis. Clin Sci 1957; 16: 645-650
• 15 Verheijen JH, Mullaart E, Chang GTC, Kluft C, Wijngaards G. A simple sensitive spectrofotometric assay for extrinsic (tissue-type) plasminogen activator applicable to measurements in plasma. Thromb Haemostas 1982; 48: 266-269
• 16 Born GVR. Aggregation of blood platelets by adenosinediphosphate and its reversal. Nature 1962; 194: 927-929
• 17 Kumada T, Ishirara M, Ogowa H, Abiko Y. Experimental model of venous thrombosis in rats and effects of some agents. Thromb Res 1980; 18: 189-203
• 18 Lowry OH, Rosebourgh NJ, Farr AL, Randall RJ. Protein measurement with the folin phenol reagent. J Biol Chem 1951; 193: 265-275
• 19 Hornstra G, Vendelmans-Starrenburg A. Induction of experimental arterial occlusive thrombi in rats. Atherosclerosis 1973; 17: 369-382
• 20 Lesch KP, Lerer B. The 5-HT receptor G-protein effector system complex in depression. I. Effect of glucocorticoids. J Neural Transm Gen Sect 1991; 84: 3-18
• 21 Nilsson IM, Ljungner H, Tengborn L. Two different mechanisms in patients with venous thrombosis and defective fibrinolysis: low concentration of plasminogen activator or increased concentration of plasminogen activator inhibitor. Br Med J 1985; 290: 1453-1456
• 22 Wiman B, Ljungberg B, Chmielewska J, Urden G, Blombäck M, Johnsson H. The role of the fibrinolytic system in deep vein thrombosis. J Lab Clin Med 1985; 105: 265-270
• 23 Haigh RM, Jones CT, Milligan G. Glucocorticoids regulate the amount of G proteins in rat aorta. J Mol Endocrinol 1990; 5: 185-188
• 24 Brass LF, Laposata M, Banga HS, Rittenhouse S. Regulation of the phosphoinositide hydrolysis pathway in thrombin-stimulated platelets by a pertussis toxin-sensitive guanidine nucleotide-binding protein. J Biol Chem 1986; 261: 16838-16847
• 25 Colic M, Drabek D. Expression and function of intracellular adhesion molecule 1 (ICAM-1) on rat thymic macrophages in culture. Immunol Lett 1991; 28: 251-257