Potent reduction of plasma lipoprotein (a) with an antisense oligonucleotide in human subjects does not affect ex vivo fibrinolysis[S]
Potent reduction of plasma lipoprotein (a) with an antisense oligonucleotide in human subjects does not affect ex vivo fibrinolysis[S]
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DOI：
10.1194/jlr.p094763
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发表时间：
2019-12-01
影响因子：
6.5
通讯作者：
Tsimikas, Sotirios
中科院分区：
文献类型：
--
作者：
Boffa, Michael B.;Marar, Tanya T.;Tsimikas, Sotirios
假设脂蛋白（a）[Lp（a）]抑制纤维蛋白溶解，但由于缺乏特异性Lp（a）降低剂，该假设尚未在人体中进行测试。Lp（a）升高的患者随机接受针对apo（a）的反义寡核苷酸[IONIS-APO（a）（Rx）]（n = 7）或安慰剂（n = 10）。测量基线、第85/92/99天（药物作用峰值）和第190天（停药3个月）时纤溶酶原、因子XI、纤溶酶原激活物抑制物1、凝血酶可激活的纤溶抑制物和纤维蛋白原的离体血浆溶解时间和抗原浓度。IONIS-APO（a）（Rx）组的平均+/- SD基线Lp（a）水平为477.3 +/- 55.9 nmol/l，安慰剂组为362.1 +/- 89.9 nmol/l。在第85/92/99天，IONIS-APO（a）（Rx）组Lp（a）的平均+/- SD百分比变化为-69.3 +/- 12.2% vs安慰剂组-5.4 +/- 6.9%（P < 0.0010），在第190天为-15.6 +/- 8.9% vs 3.2 +/- 12.2%（P = 0.003）。在所有时间点，IONIS-APO（a）（Rx）和安慰剂之间的凝块溶解时间和凝血/纤溶相关生物标志物均无显著差异。血浆中加入浓度高达200 nmol/l的Lp（a），且Lp（a）水平极低（12.5 nmol/l），凝块溶解时间不受影响，而重组apo（a）具有强效抗纤维蛋白溶解作用。总之，在Lp（a）水平高度升高的患者中，Lp（a）的有效降低不影响纤溶的离体测量; Lp（a）体内任何推定的抗纤溶作用的相关性需要进一步研究。
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.