Potent reduction of plasma lipoprotein (a) with an antisense oligonucleotide in human subjects does not affect ex vivo fibrinolysis[S]

被引:46
作者
Boffa, Michael B. [1 ]
Marar, Tanya T. [1 ]
Yeang, Calvin [3 ]
Viney, Nicholas J. [4 ]
Xia, Shuting [4 ]
Witztum, Joseph L. [3 ]
Koschinsky, Marlys L. [2 ]
Tsimikas, Sotirios [3 ,4 ]
机构
[1] Univ Western Ontario, Schulich Sch Med & Dent, Dept Biochem, London, ON, Canada
[2] Univ Western Ontario, Schulich Sch Med & Dent, Robarts Res Inst, London, ON, Canada
[3] Univ Calif San Diego, Div Endocrinol & Metab, La Jolla, CA 92093 USA
[4] Ionis Pharmaceut, Carlsbad, CA 92008 USA
关键词
apolipoprotein(a); thrombosis; atherosclerotic cardiovascular disease; CORONARY-ARTERY-DISEASE; OXIDIZED PHOSPHOLIPIDS; TARGETING APOLIPOPROTEIN(A); PLASMINOGEN-ACTIVATOR; GLU-PLASMINOGEN; DOUBLE-BLIND; IN-VITRO; FIBRIN; RISK; INFLAMMATION;
D O I
10.1194/jlr.P094763
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:2082 / 2089
页数:8
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