Laura Verbree-Willemsen1, Ya-Nan Zhang2, Crystel M Gijsberts3, Arjan H Schoneveld4, Jiong-Wei Wang2, Carolyn S P Lam5, Floor Vernooij2, Michiel L Bots1, Linda M Peelen6, Diederick E Grobbee1, Joel S Raichlen7, Dominique P V de Kleijn8. 1. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, The Netherlands. 2. Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore & Cardiovascular Research Institute, National University Heart Centre Singapore, Singapore. 3. Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht University, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht University, The Netherlands. 4. Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht University, The Netherlands. 5. National Heart Centre Singapore, Duke-NUS Graduate Medical School, Singapore & Cardiology, University Medical Center Groningen, Groningen, The Netherlands. 6. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, The Netherlands; Department of Anesthesiology, University Medical Center Utrecht, Utrecht University, the Netherlands. 7. Clinical Department, AstraZeneca, Wilmington, DE, USA. 8. Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore & Cardiovascular Research Institute, National University Heart Centre Singapore, Singapore; Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht University, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht University, The Netherlands; Department of Vascular Surgery, University Medical Center Utrecht, Utrecht University, The Netherlands. Electronic address: dkleijn@umcutrecht.nl.
Abstract
BACKGROUND: Statins are thought to have pleiotropic properties, including anticoagulant effects, in addition to reducing lipoprotein (LDL) levels. Plasma extracellular vesicles (EVs) are small bilayer membrane vesicles involved in various biological processes including coagulation. Since subsets of EVs in the LDL plasma fraction (LDL-EVs) correlate with thrombin activity, we hypothesized that changes in LDL-EVs after statin therapy may differ from that of serum levels of coagulation proteins, providing insight into the effects of statins on coagulation. METHODS: The study was conducted in 666 subjects with available serum from the METEOR trial, a trial of the effect of rosuvastatin versus placebo in patients with subclinical atherosclerosis. Changes in protein levels of von Willebrand Factor (VWF), SerpinC1 and plasminogen were measured in serum and in LDL-EVs, and were compared between the rosuvastatin and placebo groups. RESULTS:LDL-EV levels of plasminogen and VWF increased with rosuvastatin treatment compared to placebo (mean change of 126 ± 8 versus 17 ± 12 μg/mL for plasminogen (p < 0.001) and 310 ± 60 versus 64 ± 55 μg/mL for VWF (p = 0.015)). There was no difference between groups for change in LDL-EV-SerpinC1. In contrast, serum plasminogen levels increased to a lesser extent with rosuvastatin compared to placebo (23 ± 29 versus 67 ± 17 μg/mL, p = 0.024) and serum VWF levels showed no significant difference between both groups. CONCLUSIONS:Rosuvastatin increases LDL-EV coagulation proteins plasminogen and VWF in patients with subclinical atherosclerosis, an effect that is different from the effect of rosuvastatin on the same proteins in serum. This identifies LDL-EVs as a newly detected possible intermediate between statin therapy and coagulation.
RCT Entities:
BACKGROUND: Statins are thought to have pleiotropic properties, including anticoagulant effects, in addition to reducing lipoprotein (LDL) levels. Plasma extracellular vesicles (EVs) are small bilayer membrane vesicles involved in various biological processes including coagulation. Since subsets of EVs in the LDL plasma fraction (LDL-EVs) correlate with thrombin activity, we hypothesized that changes in LDL-EVs after statin therapy may differ from that of serum levels of coagulation proteins, providing insight into the effects of statins on coagulation. METHODS: The study was conducted in 666 subjects with available serum from the METEOR trial, a trial of the effect of rosuvastatin versus placebo in patients with subclinical atherosclerosis. Changes in protein levels of von Willebrand Factor (VWF), SerpinC1 and plasminogen were measured in serum and in LDL-EVs, and were compared between the rosuvastatin and placebo groups. RESULTS: LDL-EV levels of plasminogen and VWF increased with rosuvastatin treatment compared to placebo (mean change of 126 ± 8 versus 17 ± 12 μg/mL for plasminogen (p < 0.001) and 310 ± 60 versus 64 ± 55 μg/mL for VWF (p = 0.015)). There was no difference between groups for change in LDL-EV-SerpinC1. In contrast, serum plasminogen levels increased to a lesser extent with rosuvastatin compared to placebo (23 ± 29 versus 67 ± 17 μg/mL, p = 0.024) and serum VWF levels showed no significant difference between both groups. CONCLUSIONS:Rosuvastatin increases LDL-EV coagulation proteins plasminogen and VWF in patients with subclinical atherosclerosis, an effect that is different from the effect of rosuvastatin on the same proteins in serum. This identifies LDL-EVs as a newly detected possible intermediate between statin therapy and coagulation.
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