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

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.

Association of lipoprotein(a) with intrinsic and on-clopidogrel platelet reactivity

“…Results of flow cytometry analyzing surface protein expression on platelets confirmed these results. These findings, along with similar data from coagulation studies [26] showing no effect on fibrinolysis parameters with potent Lp(a) lowering treatment, suggest that the risk for coronary vascular disease associated with levels of Lp(a) may be primarily mediated by pro-atherogenic and pro-inflammatory effects via its oxidized phospholipids rather [27] than by anti-fibrinolytic or anti-platelet effects. These findings may have implications in the mechanism of any potential benefit in an ongoing trial testing the "Lp(a) hypothesis" with Lp(a) lowering by an antisense oligonucleotide (ClinicalTrials.gov Identifier: NCT04023552).…”

Lipoprotein(a), venous thromboembolism and COVID-19: A pilot study

“…The pro-thrombotic effect of Lp(a) in clinical studies has been controversial, with substantiation in some observational studies with a preponderance of elevated Lp(a) levels in VTE patients compared with controls (Lp[a] elevation in 20% of VTE patients compared with 7% in controls; 95% 1.9–5.3, p < 0.001) [ 18 ]. However, genetic studies [ 19 ] and in vitro studies failed to support a causal role [ 20 ]. Lp(a) concentrations in the biobank were also not associated with thromboembolic events in COVID-19 patients [ 21 ].…”

Lipoprotein (a) and coronary artery calcification: prospective study assessing interactions with other risk factors

“…However, the underlying mechanism for such interaction effect between Lp (a) and fibrinogen level is not clear. In fact, a recent study has demonstrated that reduction in Lp(a) by antisense oligonucleotide in patients with very high Lp(a) levels does not affect the ex vivo fibrinolysis [53]. Further studies are therefore needed to assess whether Lp(a) interacts with IL-2 sRα, sTNF-R1 and fibrinogen in the association with clinical CVD outcome events.…”