Konieczyńska Małgorzata, Natorska Joanna, Ząbczyk Michał, Undas Anetta
Department of Thromboembolic Disorders, Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland.
The John Paul II Hospital, Krakow, Poland.
Arch Med Sci. 2024 Dec 13;20(6):1770-1783. doi: 10.5114/aoms/197357. eCollection 2024.
Lipoprotein(a) [Lp(a)], a low-density lipoprotein-like particle containing a highly polymorphic apolipoprotein(a) [apo(a)] homologous in > 80% to plasminogen, was identified as a genetically determined independent risk factor for cardiovascular disease. Elevated Lp(a) levels, found in about 20% of Europeans, are strongly linked to higher rates of myocardial infarction, major adverse cardiac events, accelerated plaque progression, ischemic stroke (especially in younger adults), and calcific aortic valve disease. However, its role in venous thromboembolism, including atypical locations like cerebral and retinal vein thrombosis, remains controversial despite several shared mechanisms underlying arterial and venous thromboembolism. The most robust evidence supports antifibrinolytic properties of elevated Lp(a), particularly smaller apo(a) isoforms, which inhibit plasminogen activation mainly by interacting with the tissue-type plasminogen activator, plasminogen, and fibrin. Other prothrombotic mechanisms include increased synthesis of plasminogen activator inhibitor (PAI-1), formation of denser fibrin networks composed of thinner fibers, less susceptible to lysis, increased platelet activation, enhanced oxidation of phospholipids leading to a low-grade proinflammatory state, upregulated tissue factor expression, and suppression of tissue factor pathway inhibitor. Targeted Lp(a) lowering therapies are currently being tested in randomized clinical trials and could potentially have clinically relevant antithrombotic effects, evidenced by the reduced risk of thromboembolism. This review summarizes the available data on the prothrombotic and antifibrinolytic actions of Lp(a), along with clinical evidence for the increased risk of thromboembolic events related to elevated Lp(a). It also introduces new concepts to explain discrepant clinical results regarding venous events, highlighting the impact of oxidized phospholipids on a prothrombotic state under conditions of high Lp(a).
脂蛋白(a)[Lp(a)]是一种低密度脂蛋白样颗粒，含有一种高度多态的载脂蛋白(a)[apo(a)]，与纤溶酶原的同源性超过80%，被确定为心血管疾病的遗传决定独立危险因素。在约20%的欧洲人中发现Lp(a)水平升高，这与心肌梗死、主要不良心脏事件、斑块进展加速、缺血性中风（尤其是在年轻人中）以及钙化性主动脉瓣疾病的发生率较高密切相关。然而，尽管动脉和静脉血栓栓塞有几种共同机制，但其在静脉血栓栓塞（包括脑和视网膜静脉血栓形成等非典型部位）中的作用仍存在争议。最有力的证据支持升高的Lp(a)，特别是较小的apo(a)异构体的抗纤溶特性，其主要通过与组织型纤溶酶原激活物、纤溶酶原和纤维蛋白相互作用来抑制纤溶酶原激活。其他促血栓形成机制包括纤溶酶原激活物抑制剂(PAI-1)合成增加、由更细纤维组成的更致密纤维蛋白网络的形成、不易溶解、血小板激活增加、磷脂氧化增强导致低度促炎状态、组织因子表达上调以及组织因子途径抑制剂的抑制。目前正在随机临床试验中测试靶向降低Lp(a)的疗法，这些疗法可能具有临床相关的抗血栓作用，血栓栓塞风险降低证明了这一点。本综述总结了关于Lp(a)的促血栓形成和抗纤溶作用的现有数据，以及与Lp(a)升高相关的血栓栓塞事件风险增加的临床证据。它还引入了新的概念来解释关于静脉事件的不一致临床结果，强调了氧化磷脂在高Lp(a)条件下对促血栓形成状态的影响。
