APOLIPOPROTEIN(A) ENHANCES PLATELET RESPONSES TO THE THROMBIN RECEPTOR-ACTIVATING PEPTIDE SFLLRN

Elevated levels of lipoprotein(a) [Lp(a)] are correlated with an incre ased risk of atherosclerotic disease. We examined the effect of recomb inant apolipoprotein(a) [r-apo(a)] and Lp(a) on responses of washed hu man platelets, prelabeled in the dense granules with [C-14]serotonin a nd suspended in Tyrode's solution, to ADP and the thrombin receptor-ac tivating peptide SFLLRN. No effect of the 17 kringle (K), 12K, or 6K r -apo(a) derivatives (at concentrations of 0.35 and 0.7 mu mol/L) or Lp (a) (up to 0.1 mu mol/L) on primary ADP-induced platelet aggregation w as observed. In contrast, weak platelet responses stimulated by 7.5 mu mol/L SFLLRN were significantly enhanced by the r-apo(a) derivatives; eg, 0.7 mu mol/L 17K r-apo(a) increased aggregation from 15+/-4% to 5 8+/-6%, release of [C-14]serotonin from 9+/-3% to 36+/-6%, and formati on of thromboxane A,, measured as its stable metabolite thromboxane B- 2, from 7+/-1 to 29+/-5 ng/10(9) platelets (n=3; P<0.04 to 0.015). Sig nificant enhancement of aggregation and release of granule contents wa s observed at a concentration of 17K r-apo(a) as low as 0.175 mu mol/L . Purified Lp(a) (0.25 to 0.1 mu mol/L) also enhanced SFLLRN-induced a ggregation and release in a dose-dependent manner. Although plasminoge n (0.7 and 1.5 mu mol/L) and low density lipoprotein (0.025 to 0.1 mu mol/L) both exhibited potentiating effects on SFLLRN-mediated platelet aggregation, the magnitude of the responses was less than that observ ed with either the r-apo(a) derivatives or Lp(a). The enhanced respons es of platelets via the protease-activated receptor-1 thrombin recepto r in the presence of Lp(a) may contribute to the increased risk of thr omboembolic complications of atherosclerosis associated with this lipo protein.