Lipoprotein(a) plasma levels and coagulation biomarkers: Results from a comprehensive laboratory assessment in an angiographically-controlled cardiovascular cohort.

Abstract Background: lipoprotein(a) [Lp(a)] is an established risk factor for cardiovascular disease. Among the molecular mechanisms underlying this association, beyond proatherogenic and proinflammatory properties, a prothrombotic diathesis has also been proposed, usually related to the homology between apolipoprotein(a) and plasminogen which supports a potential antifibrinolytic role. Moreover, other Lp(a)-related mechanisms of haemostatic imbalance have been advocated, from platelet activation to tissue factor (TF) expression. However, the link between Lp(a) and coagulation remains controversial so far. Aims: the aim of this study was to investigate the relationship of Lp(a) plasma levels with coagulation phenotype, evaluated by the assessment of both individual coagulation factors and global coagulation test such as thrombin generation assay (TGA), in a cardiovascular cohort of subjects with angiographic documentation of coronary artery vessels. Material and methods: plasma levels of Lp(a) and a large panel of coagulation biomarkers were assessed in clinically stable subjects undergoing elective coronary angiography. Subjects taking any anticoagulant therapy were excluded from this analysis. The coagulation panel included coagulant activities of factors II, V, VII, VIII, IX, X, XI and XII, as well as TGA, which explores the individual's overall plasma propensity to form a blood clot when triggered by TF exposure ex-vivo, and activated factor VII-antithrombin (FVIIa-AT) complex, which is considered an indirect marker of TF expression. Lp(a) threshold values were defined according to the European Atherosclerosis Society consensus statement: normal <30 mg/dL, intermediate 30-50 mg/dL, and high >50 mg/dL. Results: laboratory data were available for 384 subjects (males 75.3%; mean age 68.2±9.7 years): 65 subjects had normal coronary arteries (CAD-free), 52 subjects had coronary lesions with stenosis <50% (CAD-borderline), and 267 subjects had coronary lesions with stenosis ≥50% (CAD). Most of patients (87.0%) were taking lipid-lowering therapies. Subjects with intermediate-high Lp(a) plasma levels were more represented in CAD than in CAD-free (12.0%-24.0% versus 7.7%-18.5%, respectively). As regards the correlation with coagulation biomarkers, in the whole study population a progressive and mild increase in coagulant activity of FV (FV:C) from low to high Lp(a) plasma levels was found (84.3±18.7%, 88.8±18.3%, and 90.1±18.7%, P=0.010), while there was no difference for the other individual coagulant activities. No difference was detected for either FVIIa-AT plasma levels or TGA parameters. The association of Lp(a) levels with FV:C was confirmed by multiple linear regression models after adjustment for sex, age, CAD diagnosis, and renal function (standardized beta coefficient=0.101, P=0.047), plasma lipids, including LDL cholesterol and apolipoprotein B (standardized beta coefficient=0.107, P=0.046), and the other coagulant activities (standardized beta coefficient=0.133, P=0.004). Conclusions: in this pilot analysis within a cohort of cardiovascular patients we did not find a major contribution of Lp(a) plasma levels in modulating coagulation phenotype, which was assessed by means of different laboratory biomarkers. High Lp(a) plasma levels were associated only with a mild increase of FV:C. This association appears independent of some potential confounding factors but deserves further validation and elucidation by both larger epidemiological/clinical studies and more in-depth biological/biochemical investigations.