It is postulated that lipoprotein (a) [Lp(a)] inhibits fibrinolysis, but this hypothesis has not been tested in humans due to the lack of specific Lp(a) lowering agents. Patients with elevated Lp(a) were randomized to antisense oligonucleotide [IONIS-APO(a)_Rx] directed to apo(a) (n = 7) or placebo (n = 10). Ex vivo plasma lysis times and antigen concentrations of plasminogen, factor XI, plasminogen activator inhibitor 1, thrombin activatable fibrinolysis inhibitor, and fibrinogen at baseline, day 85/92/99 (peak drug effect), and day 190 (3 months off drug) were measured. The mean ± SD baseline Lp(a) levels were 477.3 ± 55.9 nmol/l in IONIS-APO(a)_Rx and 362.1 ± 89.9 nmol/l in placebo. The mean± SD percentage change in Lp(a) for IONIS-APO(a)_Rx was -69.3 ± 12.2% versus -5.4 ± 6.9% placebo (P < 0.0010) at day 85/92/99 and -15.6 ± 8.9% versus 3.2 ± 12.2% (P = 0.003) at day 190. Clot lysis times and coagulation/fibrinolysis-related biomarkers showed no significant differences between IONIS-APO(a)_Rx and placebo at all time points. Clot lysis times were not affected by exogenously added Lp(a) at concentrations up to 200 nmol/l to plasma with very low (12.5 nmol/l) Lp(a) levels, whereas recombinant apo(a) had a potent antifibrinolytic effect. In conclusion, potent reductions of Lp(a) in patients with highly elevated Lp(a) levels do not affect ex vivo measures of fibrinolysis; the relevance of any putative antifibrinolytic effects of Lp(a) in vivo needs further study.

中文翻译：

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在人类受试者中用反义寡核苷酸有效降低血浆脂蛋白（a）不会影响离体纤维蛋白溶解。

假定脂蛋白（a）[Lp（a）]抑制纤维蛋白溶解，但是由于缺乏特定的Lp（a）降低剂，这一假说尚未在人类中得到验证。Lp（a）升高的患者被随机分配至针对apo（a）（n = 7）或安慰剂（n = 10）的反义寡核苷酸[IONIS-APO（a）_Rx ] 。基线，第85/92/99天（峰值药物作用）和第190天（停药3个月）的血浆纤溶酶原，因子XI，纤溶酶原激活物抑制剂1，凝血酶可激活的纤溶酶抑制剂和纤维蛋白原的离体血浆裂解时间和抗原浓度被测量。IONIS-APO（a）_Rx中的平均±SD基线Lp（a）水平为477.3±55.9 nmol / l安慰剂中为362.1±89.9 nmol / l。IONIS-APO（a）_Rx的Lp（a）的平均值±SD百分比变化在8.5 / 92/99天和-15.6±8.9％分别为-69.3±12.2％和-5.4±6.9％安慰剂（P <0.0010）对比第190天时的3.2±12.2％（P = 0.003）。凝块裂解时间和与凝血/纤维蛋白溶解相关的生物标记显示IONIS-APO（a）_Rx之间无显着差异和所有时间的安慰剂。血浆裂解时间不受浓度高达200 nmol / l的血浆中Lp（a）水平极低（12.5 nmol / l）的血浆外源添加Lp（a）的影响，而重组apo（a）具有强大的抗纤维蛋白溶解作用。总之，在高度升高的Lp（a）患者中有效降低Lp（a）不会影响离体的纤维蛋白溶解指标；Lp（a）体内任何可能的抗纤维蛋白溶解作用的相关性需要进一步研究。