Fadraersada Jaka, Alva-Gallegos Raúl, Skořepa Pavel, Musil František, Mrštná Kristýna, Javorská Lenka, Matoušová Kateřina, Krčmová Lenka Kujovská, Paclíková Markéta, Carazo Alejandro, Bláha Milan, Blaha Vladimír, Mladěnka Přemysl
Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic.
3rd Department of Internal Medicine-Metabolic Care and Gerontology, University Hospital and Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Jan 3. doi: 10.1007/s00210-024-03740-1.
Familial hypercholesterolemia (FH) is a relatively rare genetic disease associated with high serum cholesterol levels but also with abnormalities in blood coagulation. Novel pharmacotherapeutic approaches in FH including proprotein convertase subtilisin/kexin type 9 antibodies (PCSK9Ab) are very efficient in decreasing cholesterol levels but their impact on coagulation in FH is not yet established. Therefore, we hypothesized that these novel antidyslipidemic drugs can positively impact blood coagulation due to their more potent effect on cholesterol. A total of 15 healthy volunteers and all 15 available patients with severe FH treated at the University Hospital Hradec Králové were enrolled, coagulation was assessed by mechanic coagulometer, and the impact of four clinically used direct anticoagulants was analyzed ex vivo. FH patients were treated effectively as their total cholesterol was 4.11 ± 1.57 mM and LDL cholesterol was 2.44 ± 1.46 mM, which were even lower values than detected in our generally healthy controls. Twelve from the 15 FH patients were finally analyzed as 3 were treated with anticoagulants. Coagulation in FH patients was prolonged more extensively by dabigatran and rivaroxaban, when compared to healthy controls. Treatment with PCSK9Ab or lipid apheresis did not seem to have a significant effect on coagulation. The latter procedure however significantly decreased serum levels of one vitamin K form, MK4. Shorter coagulation time was associated with higher levels of LDL, non-HDL, and total cholesterol. Current treatment of FH seems to improve the effects of direct anticoagulants beyond known effects on LDL cholesterol levels.
家族性高胆固醇血症（FH）是一种相对罕见的遗传性疾病，与高血清胆固醇水平相关，但也与血液凝固异常有关。FH的新型药物治疗方法，包括前蛋白转化酶枯草杆菌蛋白酶/kexin 9型抗体（PCSK9Ab），在降低胆固醇水平方面非常有效，但它们对FH患者凝血功能的影响尚未明确。因此，我们推测这些新型降脂药物因其对胆固醇的更强作用，可能会对血液凝固产生积极影响。我们招募了15名健康志愿者以及在赫拉德茨克拉洛韦大学医院接受治疗的所有15名重度FH患者，使用机械凝血仪评估凝血功能，并在体外分析了四种临床常用直接抗凝剂的影响。FH患者得到了有效治疗，他们的总胆固醇为4.11±1.57 mM，低密度脂蛋白胆固醇为2.44±1.46 mM，这些值甚至低于我们的一般健康对照组。由于3名FH患者接受了抗凝治疗，最终对15名患者中的12名进行了分析。与健康对照组相比，达比加群和利伐沙班使FH患者的凝血时间延长得更明显。使用PCSK9Ab或血脂分离术治疗似乎对凝血功能没有显著影响。然而，后者显著降低了一种维生素K形式（MK4）的血清水平。较短的凝血时间与较高的低密度脂蛋白、非高密度脂蛋白和总胆固醇水平相关。目前对FH的治疗似乎除了对低密度脂蛋白胆固醇水平有已知影响外，还改善了直接抗凝剂的效果。
