Apolipoprotein(a) Enhances Platelet Responses to the Thrombin Receptor–Activating Peptide SFLLRN

From the Department of Biochemistry, University of Toronto, Toronto (M.L.R., D.M.T., M.A.P.), and the Department of Biochemistry, Queen's University, Kingston (W.S., M.A.H., M.L.K.), Ontario, Canada; and Northwest Lipid Research Laboratories, University of Washington (S.M.M.), Seattle, Wash.

Correspondence to Dr M.L. Rand, Division of Haematology/Oncology, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8. E-mail margaret.rand{at}sickkids.on.ca

Abstract—Elevated levels of lipoprotein(a) [Lp(a)] are correlated with an increased risk of atherosclerotic disease. We examined the effect of recombinant apolipoprotein(a) [r-apo(a)] and Lp(a) on responses of washed human platelets, prelabeled in the dense granules with [¹⁴C]serotonin and suspended in Tyrode's solution, to ADP and the thrombin receptor–activating peptide SFLLRN. No effect of the 17 kringle (K), 12K, or 6K r-apo(a) derivatives (at concentrations of 0.35 and 0.7 µmol/L) or Lp(a) (up to 0.1 µmol/L) on primary ADP-induced platelet aggregation was observed. In contrast, weak platelet responses stimulated by 7.5 µmol/L SFLLRN were significantly enhanced by the r-apo(a) derivatives; eg, 0.7 µmol/L 17K r-apo(a) increased aggregation from 15±4% to 58±6%, release of [¹⁴C]serotonin from 9±3% to 36±6%, and formation of thromboxane A₂, measured as its stable metabolite thromboxane B₂, from 7±1 to 29±5 ng/10⁹ platelets (n=3; P<0.04 to 0.015). Significant enhancement of aggregation and release of granule contents was observed at a concentration of 17K r-apo(a) as low as 0.175 µmol/L. Purified Lp(a) (0.25 to 0.1 µmol/L) also enhanced SFLLRN-induced aggregation and release in a dose-dependent manner. Although plasminogen (0.7 and 1.5 µmol/L) and low density lipoprotein (0.025 to 0.1 µmol/L) both exhibited potentiating effects on SFLLRN-mediated platelet aggregation, the magnitude of the responses was less than that observed with either the r-apo(a) derivatives or Lp(a). The enhanced responses of platelets via the protease-activated receptor-1 thrombin receptor in the presence of Lp(a) may contribute to the increased risk of thromboembolic complications of atherosclerosis associated with this lipoprotein.

Key Words: lipoprotein(a) • apolipoprotein(a) • platelet function • thrombin receptor–activating peptide • SFLLRN

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