Prothrombotic Mechanisms of Lp(a)-Mediated Pathophysiology: Implications for Platelet Function, Fibrin Clot Architectures, and Atherothrombosis
Abstract
Elevated levels of lipoprotein(a) (Lp(a)) are an independent and causal 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. Similarities between the apolipoprotein(a) (apo(a)) component of Lp(a) with the fibrinolytic proenzyme plasminogen are strongly suggestive of antifibrinolytic activity. While numerous studies indicate that apo(a) can inhibit plasminogen activation and fibrinolysis, existing 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. Corroborating this notion, recent observational clinical studies demonstrated that individuals with high Lp(a) levels derive increased benefit from dual anti-platelet therapy. However, the effects of Lp(a) on platelet function and thrombosis have never been directly assessed in blood clots formed from flowing whole blood. In our first set of experiments, we used ex vivo plasma clot lysis assays to elucidate the previously reported disparities between the antifibrinolytic effects of Lp(a) and apo(a). In these studies, we showed that the residue in apo(a) responsible for mediating its antifibrinolytic effects appears to become functionally blocked during covalent Lp(a) assembly. Next, 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 promoted platelet accumulation and facilitated the development of fibrin networks that displayed features of fibrinolysis resistance. Finally, we examined the prothrombotic potential of Lp(a) in vivo using established murine models of thrombosis and hemostasis. In the absence of underlying cardiovascular disease, we showed that mice expressing human apo(a) had increased thrombus volumes, and accelerated rates of vessel occlusion and hemostasis. Importantly, we also demonstrated that the observed prothrombotic effects of Lp(a) could be mitigated by low-dose aspirin therapy. Collectively, this body of work offers novel insights into the pathophysiological mechanisms of Lp(a), and suggests that, rather than inhibiting plasminogen activation, Lp(a) contributes to atherothrombotic diseases by exerting direct prothrombotic effects on platelet function and developing fibrin networks.