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Potent reduction of plasma lipoprotein (a) with an antisense oligonucleotide in human subjects does not affect ex vivo fibrinolysis
- Source :
- Journal of Lipid Research, Vol 60, Iss 12, Pp 2082-2089 (2019), J Lipid Res, Journal of lipid research, vol 60, iss 12
- Publication Year :
- 2019
- Publisher :
- Elsevier, 2019.
-
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.
- Subjects :
- 0301 basic medicine
Male
medicine.medical_treatment
Oligonucleotides
030204 cardiovascular system & hematology
Medical Biochemistry and Metabolomics
Fibrinogen
Biochemistry
chemistry.chemical_compound
0302 clinical medicine
Endocrinology
Fibrinolysis
atherosclerotic cardiovascular disease
Hematology
Middle Aged
Plasminogen activator inhibitor-1
6.1 Pharmaceuticals
apolipoprotein(a)
Female
medicine.drug
Adult
medicine.medical_specialty
Biochemistry & Molecular Biology
Antifibrinolytic
Adolescent
medicine.drug_class
Clinical Trials and Supportive Activities
QD415-436
Placebo
03 medical and health sciences
Young Adult
In vivo
Clinical Research
Internal medicine
medicine
Humans
Antisense
thrombosis
Aged
business.industry
Evaluation of treatments and therapeutic interventions
Cell Biology
Oligonucleotides, Antisense
030104 developmental biology
chemistry
Biochemistry and Cell Biology
business
Patient-Oriented and Epidemiological Research
Ex vivo
Lipoprotein
Lipoprotein(a)
Subjects
Details
- Language :
- English
- ISSN :
- 00222275
- Volume :
- 60
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- Journal of Lipid Research
- Accession number :
- edsair.doi.dedup.....abbda1348c600143a43a2831df9abfd3