Effects of Magnesium on Platelet Aggregation and Adhesion

Summary

Magnesium deficiency and its association with platelet hyperreactivity has been well recognised in a variety of diseases including myocardial infarction, preeclampsia, and diabetes. In order to investigate potential effects of intravenous Mg²⁺ supplementation, platelet function was studied by measurements of in vitro bleeding time (BT) and of fibrinogen (Fg)-mediated aggregation of washed platelets. In addition, the effect of Mg²⁺ on platelet adhesion onto immobilised Fg, on Fg binding to activated platelets, and on surface expression of GMP-140 or GP53 was evaluated. Mg²⁺(4 mM) prolonged in vitro BT by 30% and inhibited Fg-mediated aggregation significantly, independent of the agonist used to initiate platelet aggregation (ADP, collagen, epinephrine, thrombin, phorbol ester). Adhesion of resting platelets to immobilised Fg was reduced by 50% in the presence of 2 mM Mg²⁺. Moreover, Mg²⁺ reduced Fg binding to ADP- or collagen-stimulated platelets as well as surface expression of GMP-140 with an IC50 of approximately 3 mM. Intravenous administration of Mg²⁺ to healthy volunteers inhibited both ADP-induced platelet aggregation (p <0.05) by 40% and binding of Fg or surface expression of GMP-140 by 30% (p <0.05). Thus, pharmacological concentrations of Mg²⁺ effectively inhibit platelet function in vitro and ex vivo.

• References

• 1 Rasmussen HS, McNair P, Goransson L, Balslov S, Larsen OG, Aurup P. Magnesium deficiency in patients with and without acute myocardialinfarction uncovered by an intravenous loading test. Arch Intern Med 1988; 148: 329-332
• 2 Rector WG, De Wood MA, Williams RV, Sullivan JF. Serum magnesium and copper levels in myocardial infarction. Am J Med Sci 1981; 281: 25-29
• 3 Briel RC, Lippert TH, Zahradnik HP. Changes in blood coagulation, thrombocyte function and vascular prostacyclin synthesis induced by magnesium sulphate. Geburth Frauenheilk 1987; 47: 332-336
• 4 Nadler J, Malayan S, Luong H. Evidence that intracellular free magnesium deficiency plays a key role in increased platelet reactivity in type II diabetes mellitus. Diabetes Care 1992; 15: 835-841
• 5 Trip MD, Cats VM, Van Capelle FJL, Vreeken J. Platelet hyperreactivity and prognosis in survivors of myocardial infarction. N Engl J Med 1990; 322: 1549-1554
• 6 Siess W. Molecular mechanisms of platelet activation. Physiol Reviews 1990; 69: 58-178
• 7 Leung L, Nachman R. Molecular mechanisms of platelet aggregation. Ann Rev Med 1986; 37: 179-186
• 8 Phillips DR, Charo IF, Prise LV, Fitzgerald LA. The platelet membrane glycoprotein Ilb-IIIa complex. Blood 1988; 71: 831-843
• 9 Plow EF, Ginsberg MH. Cellular adhesion: GPIIb-IIIa as a prototypic adhesion receptor. In: Progress in Hemostasis and Thrombosis. Coller BS. editor WB Saunders Co; Philadelphia: 1989: 117-156
• 10 Gawaz MP, Loftus JC, Bajt ML, Frojmovic MM, Plow EF, Ginsberg MH. Ligand binding mediates integrin allbb3 (glycoprotein GPIIb-IIIa) dependent homotypic and heterotypiccell-cell interaction. J Clin Invest 1991; 88: 1128-1134
• 11 Stenberg DE, McEver RP, Shuman MA, Jacques ZV, Bainton DF. A platelet membrane glycoprotein (GMP-140) is expressed on the plasma membrane after activation. J Cell Biol 1985; 101: 880-885
• 12 Nieuwenhuis HK, Oosterhoutvon JJG, Rosemuller E, Iwaarden van F, Sixma JJ. Studies with a monoclonal antibody against activated platelets. Evidence that a secreted Mw 53,000 lysosome-like granule protein is exposed on the surface of activated platelets in the circulation. Blood 1987; 70: 838-845
• 13 Nishibori M, Cham B, McNicol A, Shalev A, Jain N, Gerrard JM. The protein CD63 is in plateletdense granules, is deficient in a patient with Hermansky-Pudlak syndrome, and appears identical to granulophysin. J Clin Invest 1993; 91: 1775-1782
• 14 Anstall HB, Huntsman RG, Lehmann H, Hayward GH, Weitzman D. The effect of magnesium on blood coagulation in human subjects. Lancet 1959; 1: 814-815
• 15 Adams JH, Mitchell JRA. The effects of agents which modify platelet behaviour and of magnesium ions on thrombus formation in vivo. Thromb Haemost 1979; 42: 603-609
• 16 Bom GVR, Cross GP. Effect of inorganic ions and ofplasma proteins on the aggregation of blood platelets by adenosine diphosphate. J Physiol 1964; 170: 397-414
• 17 Herrmann RG, Lacefield WB, Crowe VG. Effect of ionic calcium and magnesium on human platelet aggregation. Proc Soc Exp Biol Med 1970; 135: 100-103
• 18 Heptinstall S, Taylor PM. The effects of citrate and extracellular calcium ions on the platelet release reaction induced by adenosine disphosphate and collagen. Thromb Haemost 1979; 42: 778-793
• 19 Gertz SD, Wajnberg RS, Kurgan A, Uretzky G. Effect of magnesium sulfate on thrombus formation following partial arterial constriction: implications for coronary vasospasm. Magnesium 1987; 6: 225-235
• 20 Hwang DL, Yen CF, Nadler JL. Effect of extracellular magnesium on platelet activation and intracellular calcium mobilization. Am J Hypertens 1992; 5: 700-706
• 21 Watson KV, Moldow CF, Ogburn PL, Jacob HS. Magnesium sulfate: rationale for its use in preeclampsia. Proc Natl Acad Sci USA 1986; 83: 1075-1078
• 22 Nadler JL, Goodson S, Rude RK. Evidence that prostacyclin mediates the vascular action of magnesium in humans. Hypertension 1987; 9: 379-383
• 23 Kratzer MAA, Bom GVR. Simulation of primary haemostasis in vitro. Haemostasis 1985; 15: 357-362
• 24 Gawaz M, Mayinger P, Neumann FJ. Effects of adenosine-5′-triphosphate (ATP) on ligand recognition of platelet fibrinogen receptor on GPIIb-IIIa. Am J Physiol 1994; 267 H 1098-1106
• 25 Gawaz MP, Ward RA. Effects of hemodialysis on platelet-derived throm-bospondin. Kidney Intern 1991; 40: 257-265
• 26 Ginsberg MH, Frelinger AL, Lam SCT, Forsyth J, McMillan R, Plow EF, Shattil SJ. Analysis of platelet aggregation disorders based on flow cytometric analysis of platelet membrane glycoprotein Ilb-IIIa with conformation specific monoclonal antibodies. Blood 1990; 76: 2017-2023
• 27 Gawaz MP, Dobos G, Spath M, Mujais SK. Platelet membrane glcoprotein IIb-IIIIa function is impaired in end-stage renal failure (ESRF). J Am Soc Nephrol 1994; 5: 36-46
• 28 Gawaz M, Mujais SK, Schmid B, Gurland HJ. Platelet-leukocyte aggregation during hemodialysis. Kidney Int 1994; 46: 489-495
• 29 Gawaz M, Fateh-Moghadam S, Pilz G, Gurland HJ, Werdan K. Increased platelet aggregation in patients with sepsis and multiple organ failure (MOF) - severity of multiple organ failure but not of sepsis correlates with irreversible platelet degranulation. Infection (in press)
• 30 Heinzmann U, Hofler H. EGF-receptor immunolabeling as shown by LM and SEM. Prog Histochem Cytoc 1992; 26: 88-94
• 31 Niewiarowski S, Budzynski AZ, Morinelli TA, Brudzynski TM, Stewart GJ. Exposure of fibrinogen receptor on human platelets by proteolytic enzymes. J Biol Chem 1981; 256: 917-925
• 32 Pidard D, Frelinger AL, Bouillot C, Nurden AT. Activation of the fibrinogen receptor on human platelets exposed to alpha chymotrypsin. Eur J Biochem 1991; 437: 447
• 33 Coller BS. Interaction of normal, thrombasthenic, and Bernard-Soulier platelets with immobilized fibrinogen. Defective platelet-fibrinogen interaction in thrombasthenia. Blood 1980; 55: 169-178
• 34 Savage B, Ruggeri ZM. Selective recognition of adhesive sites in surface-bound fibrinogen by glycoprotein Ilb-IIIa on nonactivated platelets. J Biol Chem 991 266: 11227-11233
• 35 Gulino D, Boudignon C, Zhang L, Concord E, Rabiet MJ, Marguerie G. Ca²⁺-binding properties of the platelet glycoprotein lib ligand-interacting domain. J Biol Chem 1992; 267: 11001-11007
• 36 Fitzgerald DJ, Roy L, Catella F, Fitzgerald GA. Platelet activation in unstable coronary disease. N Engl J Med 1986; 315: 983-989
• 37 Hamm CW, Lorenz RL, Bleifeld W, Kupper W, Wober W, Weber PC. Biochemical evidence of platelet activation in patients with persistent unstable angina. J Am Coll Cardiol 1987; 10: 998-1006
• 38 Woods KL, Fletcher S, Roffe C, Haider Y. Intravenous magnesium sulfate in suspected acute myocardial infarction: results of the second Leicester intravenous magnesium intervention trial (LIMIT-II). Lancet 1992; 339: 1553-1558