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

Michael B Boffa,Tanya T Marar,Calvin Yeang,Nicholas J Viney,Shuting Xia,Joseph L Witztum,Marlys L Koschinsky,Sotirios Tsimikas

doi:10.1194/jlr.p094763

Abstract

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.

Highlights

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
We evaluated whether substantial lowering of elevated Lp(a) results in an improvement in fibrinolytic potential using ex vivo clot lysis assays and measuring coagulation/fibrinolysis biomarkers
This study demonstrates that potent reductions in Lp(a) in patients with elevated Lp(a) did not result in significant changes in ex vivo clot lysis or in biomarkers of coagulation and fibrinolysis

Summary

Introduction

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. 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. Lp(a) has high homology (75–99%) to plasminogen but lacks protease activity and has been hypothesized to inhibit fibrinolysis and mediate prothrombotic potential This hypothesis has been supported by in vitro/ex vivo studies primarily using free apo(a), of which little if any is present in plasma in vivo, rather than purified Lp(a) [7,8,9,10,11,12]. Several association studies using genetic instruments related to LPA, the gene encoding apo(a), have suggested elevated Lp(a) levels are not associated with deep venous thrombosis [13, 14]. Whether Lp(a) might directly contribute to the thrombotic sequelae of arterial plaque rupture has been difficult to assess because of the inability to disentangle such effects from underlying atherosclerotic disease

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Conclusion