Lp(a) is not associated with diabetes but affects fibrinolysis and clot structure ex vivo

Månsson, Marianne; Kalies, I.; Bergström, Göran; Schmidt, Caroline; Legnehed, A.; Hultén, Lillemor Mattsson; Amrot-Fors, Lena; Gustafsson, David; Knecht, Wolfgang

doi:10.1038/srep05318

Cited by 13 publications

(9 citation statements)

References 53 publications

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“…correlations between Lp(a) levels and the inhibition of plasma clot lysis in vitro with Lp(a)-lowering hormone replacement therapy (30) or in the setting of disorders such as residual vein obstruction and cerebral venous sinus thrombosis (31), or myocardial infarction (32). In another study, it was found that patients with type 2 diabetes mellitus had longer clot lysis times than healthy control subjects, although no difference in lysis time by quartile of Lp(a) levels was found in either group (33). Our study has an The lack of effect of purified Lp(a) on clot lysis is surprising in light of an extensive body of evidence that apo(a) itself inhibits fibrinolysis and plasminogen activation (6).…”

Section: Discussionmentioning

confidence: 99%

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

Boffa

Marar

Yeang

et al. 2019

Journal of Lipid Research

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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.

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Section: Discussionmentioning

confidence: 99%

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

Boffa

Marar

Yeang

et al. 2019

Journal of Lipid Research

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“…Apo(a) by its similarity to plasminogen can competitively inhibit the functioning of this zymogen and hence increase the risk of atherosclerotic vascular disease. The similarity of Lp(a) to LDL and its ability to undergo oxidation are another reason why it has been implicated in atheroma development and has been suggested to be involved in foam cell formation, smooth cell proliferation, endothelial dysfunction, and vascular inflammation [9, 10]. Several epidemiological studies have found clear association between Lp(a) and CVD and have suggested Lp(a) to be an independent risk factor for CVD [11, 12].…”

Section: Introductionmentioning

confidence: 99%

Serum Lipoprotein (a) Levels in Black South African Type 2 Diabetes Mellitus Patients

Joseph

Ganjifrockwala

George

2016

Oxidative Medicine and Cellular Longevity

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Lipoprotein (a) (Lp(a)) which is a low-density lipoprotein-like particle containing apo(a) is considered as an emergent cardiovascular risk factor. Type 2 diabetes mellitus (T2DM) is associated with a two- to threefold increase in the risk of cardiovascular disease (CVD). The aim of this study was to investigate the levels of Lp(a) in Black South African T2DM patients and its association with other metabolic factors. 67 T2DM patients and 48 healthy control participants were recruited for the cross-sectional study. The Lp(a) level was determined by ELISA and the result was analyzed using SPSS. The Lp(a) level in diabetics was found to be significantly increased (P = 0.001) when compared to the normal healthy group. In the diabetic group, the Lp(a) levels correlated significantly with the duration of diabetes (P = 0.008) and oxidized LDL (ox-LDL) levels (P = 0.03) and decreased total antioxidant capacity (P = 0.001). The third tertile of Lp(a) was significantly correlated with increased ox-LDL, C-reactive protein, and triglycerides and decreased total antioxidant capacity.

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“…Recently, Rowland et al found that the LPA genetic variant rs3798220 was associated with decreased clot permeability and longer clot lysis time among Caucasians, but was associated with increased clot permeability and shorter clot lysis among non-Caucasians (Rowland et al 2014). Mansson et al however, reported that Lp(a) plasma levels had no effect on clot lysis time in diabetic subjects and normal controls (Mansson et al 2014). These discordant results may be caused by: (1) differing study designs; (2) different measure methods; (3) small sample size; and/or (4) differences in population characteristics.…”

Section: Discussionmentioning

confidence: 99%

Effect of Two Lipoprotein (a)-Associated Genetic Variants on Plasminogen Levels and Fibrinolysis

Wang

Hong

Lewis

et al. 2016

G3 Genes|Genomes|Genetics

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Two genetic variants (rs3798220 and rs10455872) in the apolipoprotein (a) gene (LPA) have been implicated in cardiovascular disease (CVD), presumably through their association with lipoprotein (a) [Lp(a)] levels. While Lp(a) is recognized as a lipoprotein with atherogenic and thrombogenic characteristics, it is unclear whether or not the two Lp(a)-associated genetic variants are also associated with markers of thrombosis (i.e., plasminogen levels and fibrinolysis). In the present study, we genotyped the two genetic variants in 2919 subjects of the Old Order Amish (OOA) and recruited 146 subjects according to the carrier and noncarrier status for rs3798220 and rs10455872, and also matched for gender and age. We measured plasma Lp(a) and plasminogen levels in these subjects, and found that the concentrations of plasma Lp(a) were 2.62- and 1.73-fold higher in minor allele carriers of rs3798220 and rs10455872, respectively, compared with noncarriers (P = 2.04 × 10−17 and P = 1.64 × 10−6, respectively). By contrast, there was no difference in plasminogen concentrations between carriers and noncarriers of rs3798220 and rs10455872. Furthermore, we observed no association between carrier status of rs3798220 or rs10455872 with clot lysis time. Finally, plasminogen mRNA expression in liver samples derived from 76 Caucasian subjects was not significantly different between carriers and noncarriers of these two genetic variants. Our results provide further insight into the mechanism of action behind two genetic variants previously implicated in CVD risk and show that these polymorphisms are not major modulating factors for plasma plasminogen levels and fibrinolysis.

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Lp(a) is not associated with diabetes but affects fibrinolysis and clot structure ex vivo

Cited by 13 publications

References 53 publications

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

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

Serum Lipoprotein (a) Levels in Black South African Type 2 Diabetes Mellitus Patients

Effect of Two Lipoprotein (a)-Associated Genetic Variants on Plasminogen Levels and Fibrinolysis

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