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

Abstract

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 [ 14 C]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 mol/L) or Lp(a) (up to 0.1 mol/L) on primary ADP-induced platelet aggregation was observed. In contrast, weak platelet responses stimulated by 7.5 mol/L SFLLRN were significantly enhanced by the r-apo(a) derivatives; eg, 0.7 mol/L 17K r-apo(a) increased aggregation from 15Ϯ4% to 58Ϯ6%, release of [14 C]serotonin from 9Ϯ3% to 36Ϯ6%, and formation of thromboxane A 2 , measured as its stable metabolite thromboxane B 2 , from 7Ϯ1 to 29Ϯ5 ng/10 9 platelets (nϭ3; PϽ0.04 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 mol/L. Purified Lp(a) (0.25 to 0.1 mol/L) also enhanced SFLLRN-induced aggregation and release in a dose-dependent manner. Although plasminogen (0.7 and 1.5 mol/L) and low density lipoprotein (0.025 to 0.1 mol/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 prospective study of lipoprotein(a) and risk of coronary heart disease among women with type 2 diabetes

“…In addition to its role as a cholesterol carrier, Lp(a) has a thrombogenic effect because of the structural homology of apo(a) and plasminogen [27]. Lp(a) enhances platelet aggregation [28], modulates vascular endothelial , alcohol intake (less than or more than 5 g/day), physical activity (0-0.9, 1-1.9, 2-3.9, 4+ h/week), postmenopausal hormone use (premenopausal, current, past, never, missing), aspirin use (non-daily, daily), parental history of MI, history of hypertension, and levels of HbA 1 c (quintiles), LDL-c (quintiles) and HDL-c (quintiles) cell function [29] and is considered an acute-phase reactant [30]. It is not clear whether the mechanisms by which Lp(a) is involved in atherosclerosis progression in the diabetic population is identical to that in the non-diabetic population.…”

The Mechanism by Which Flaxseed Oil Consumption Increases Bleeding Time in Patients with Type 2 Diabetes in Cape Breton, Nova Scotia, Canada is Independent of Lipoprotein(a) Concentration

“…However, previous studies (34)(35)(36)(37)(38) have suggested that there is a negative correlation between platelet reactivity in vitro and Lp(a) concentrations based on competitive displacement of fibrinogen from the IIb protein on the fibrinogen (GPIIb/IIIa) receptor on agonist-stimulated platelets and manipulation of platelet c-AMP concentrations by Lp(a). On the contrary, a number of authors have shown an increase (39,40) or no change (41) in in vitro platelet reactivity upon incubation with increasing concentration of Lp(a). It was hypothesized that while elevated Lp(a) concentrations would present an enhanced risk of atherosclerosis in terms of increased lipid influx into the arterial wall and potential interference with plasmin activity, they also may modify platelet reactivity in vivo in patients with type 2 diabetes.…”

Lipoprotein (a) – An Overview

“…On the other hand there are studies reporting an apparent proaggregatory action of Lp(a) possibly mediated by the apo-a subunit. While no effect of recombinant apo-a [r-apoa] derivatives on primary ADP-induced platelet aggregation was observed weak platelet responses stimulated by the thrombin receptor-activating peptide SFLLRN were significantly enhanced by the r-apo-a derivatives accompanied by a significant enhancement of [ 14 C]serotonin release of the dense granules [53]. Further investigations showed that r-apo-a isoforms and Lp(a) do not cause platelet aggregation by themselves but preincubation of platelets with r-apo-a derivatives promotes an aggregation response to otherwise subaggregant doses of thrombin receptor activation peptide (TRAP) and arachidonic acid while inversely platelet stimulation with arachidonic acid enhanced platelet binding of apo-a [54].…”

“…Summarizing, in vitro studies indicate that Lp(a) induced decreases, increases or no change at all in platelet aggregation [43,45,50,51,53,54]. In all cases the mechanisms involved are quite unclear and only speculative.…”