Lipoprotein(a) promotes thrombosis through platelet activation and promotion of a lysis-resistant thrombus architecture

Abstract

Elevated levels of lipoprotein(a) (Lp(a)) are an independent risk factor for the development of atherothrombotic diseases. However, it is unknown if Lp(a) directly promotes thrombus formation, inhibits thrombus clearance, or merely accelerates the underlying atherosclerotic processes that culminate in plaque rupture. While numerous studies indicate that the apolipoprotein(a) (apo(a)) component of Lp(a) can inhibit plasminogen activation and fibrinolysis, recent evidence suggests that these effects may not be retained in Lp(a). An alternative mechanism through which Lp(a) may promote atherothrombotic events is by impacting platelet function. However, the effects of Lp(a) on platelet function and thrombosis have never been directly assessed in blood clots formed from flowing whole blood. Using a transgenic mouse model expressing high plasma concentrations of apo(a), we showed using a laser-induced mesenteric vessel injury model employing intravital microscopy that apo(a) increased platelet and fibrin volumes in the thrombi without affecting fibrinolysis. In a ferric chloride-induced mouse carotid artery thrombosis model, we found that apo(a) substantially reduced occlusion times and led to more stable thrombi; importantly, we also demonstrated that the effects of Lp(a) could be mitigated by low-dose aspirin therapy. We evaluated the prothrombotic potential of Lp(a) in human blood clots formed under arterial flow conditions using a Chandler loop apparatus. In these studies, we showed that the presence of Lp(a) during thrombogenesis inhibited lysis of the thrombi, without directly impacting fibrinolysis. Lp(a) promoted platelet accumulation in the Chandler thrombi and facilitated the development of fibrin networks that displayed features of fibrinolysis resistance. In an analysis of the UK Biobank, participants with Lp(a) [≥]125 nmol/L had a higher risk for arterial thrombosis of non-atherosclerotic etiology but not a higher risk for venous thromboembolism. Collectively, these findings demonstrate that Lp(a) is inherently prothrombotic and likely promotes arterial thrombosis in vivo in part through promoting platelet activation. These findings explain how elevated Lp(a) is an important risk factor for arterial thrombosis either with or without an atherosclerotic etiology as well as observational primary prevention data suggesting that aspirin reduces atherothrombotic risk specifically in patients with elevated Lp(a).