Department of Biochemistry and Robarts Research Institute, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada.
Atherosclerosis. 2022 May;349:72-81. doi: 10.1016/j.atherosclerosis.2022.04.009.
Elevated plasma concentrations of lipoprotein(a) (Lp(a)) are a causal risk factor for the development of atherothrombotic disorders including coronary heart disease. However, the pathological mechanisms underlying this causal relationship remain incompletely defined. Lp(a) consists of a lipoprotein particle in which apolipoproteinB100 is covalently linked to the unique glycoprotein apolipoprotein(a) (apo(a)). The remarkable homology between apo(a) and the fibrinolytic proenzyme plasminogen strongly suggests an antifibrinolytic role: apo(a) contains a strong lysine binding site and can block the sites on fibrin and cellular receptors required for plasminogen activation, but itself lacks proteolytic activity. While numerous in vitro and animal model studies indicate that apo(a) can inhibit plasminogen activation and fibrinolysis, this activity may not be preserved in Lp(a). Moreover, elevated Lp(a) does not reduce the efficacy of thrombolytic therapy and is not a risk factor for some non-atherosclerotic thrombotic disorders such as venous thromboembolism. Accordingly, different prothrombotic mechanisms for Lp(a) must be contemplated. Evidence exists that Lp(a) binds to and inactivates tissue factor pathway inhibitor and stimulates expression of tissue factor by monocytes. Moreover, some studies have shown that Lp(a) promotes platelet activation and aggregation, at least in response to some agonists. Lp(a) alters the structure of the fibrin network to make it less permeable and more resistant to lysis. Finally, Lp(a) may promote the development of a vulnerable plaque phenotype that is more prone to rupture and hence the precipitation of atherothrombotic events. Further study, especially in animal models of thrombosis, is required to clarify the prothrombotic effects of Lp(a).
脂蛋白(a)（Lp(a)）的血浆浓度升高是动脉粥样血栓形成疾病（包括冠心病）发展的一个因果危险因素。然而，这种因果关系的病理机制仍不完全明确。Lp(a)由脂蛋白颗粒组成，其中载脂蛋白 B100 与独特的糖蛋白载脂蛋白(a)（apo(a)）共价连接。apo(a)与纤维蛋白溶酶原之间的显著同源性强烈提示其具有抗纤维蛋白溶解作用：apo(a)含有一个强赖氨酸结合位点，可以阻断纤维蛋白和细胞受体上纤维蛋白溶酶原激活所需的位点，但自身缺乏蛋白水解活性。虽然大量的体外和动物模型研究表明 apo(a)可以抑制纤维蛋白溶酶原的激活和纤维蛋白溶解，但这种活性可能在 Lp(a)中并不存在。此外，升高的 Lp(a)并不能降低溶栓治疗的疗效，也不是某些非动脉粥样硬化血栓形成疾病（如静脉血栓栓塞症）的危险因素。因此，必须考虑 Lp(a)的不同促血栓形成机制。有证据表明，Lp(a)可以结合并失活组织因子途径抑制剂，刺激单核细胞表达组织因子。此外，一些研究表明，Lp(a)至少可以促进血小板的激活和聚集，至少对一些激动剂是如此。Lp(a)改变纤维蛋白网络的结构，使其更不易渗透且更不易溶解。最后，Lp(a)可能促进易损斑块表型的发展，这种表型更容易破裂，从而导致动脉粥样血栓形成事件的发生。需要进一步的研究，特别是在血栓形成的动物模型中，以阐明 Lp(a 的促血栓形成作用。
