PB0518 - Novel insights into antifibrinolytic and prothrombotic functions of lipoprotein(a)

Background: Elevated levels of lipoprotein(a) (Lp(a)) are an independent and likely causal risk factor for atherothrombotic events. However, the impact of Lp(a) on thrombosis and fibrinolysis remains controversial. Although the apo(a) component of Lp(a) appears to have consistently strong antifibrinolytic effects in vitro, the effect of Lp(a) on fibrinolysis in whole blood thrombi is unknown. Additionally, a possible prothrombotic role for Lp(a) has not been assessed directly.

Aims: Evaluate the effects of Lp(a) on fibrinolysis and thrombosis under conditions more closely resembling those in vivo.

Methods: (i) Lp(a)-deficient human blood was rotated in a Chandler loop and supplemented with 250 nmol/L plasma-derived Lp(a), 17-kringle (17K) recombinant apo(a) or a variant (17KΔP) lacking the protease-like domain. Lysis of the resultant thrombi by tPA was measured by release of fluorescent fibrin degradation products. (ii) Ten-week-old transgenic mice expressing human apo(a) and apoB100 (i.e., Lp(a)) and littermate controls expressing only human apoB100 were anesthetized and intravenously injected with fluorescent antibodies against platelets and fibrin. After laser injury of mesenteric vessels, intravital video microscopy of the resultant thrombi was performed to quantify platelet and fibrin volumes.

Results: In the Chandler loop studies, Lp(a) significantly decreased clot lysis (up to 15% reduction versus control; p< 0.05), while 17K apo(a) had a much more marked effect (up to 48% reduction; p< 0.01). The 17KΔP variant, which notably cannot bind to plasminogen, had no effect on lysis. Following laser injury, thrombi in male Lp(a) mice (n=5) had significantly larger platelet (up to 49%; p< 0.01) and fibrin (up to 54%; p< 0.05) volumes than controls (n=5). Thrombi formed in female Lp(a) mice (n=5) had significantly increased fibrin volumes (up to 46%, p< 0.05) versus controls (n=5), without significant differences in platelet volumes.

Conclusion(s): Elevated plasma Lp(a) levels may confer both antifibrinolytic and prothrombotic properties, potentially contributing to atherothrombotic events in vivo.