title: Inverse association of the endogenous thrombin potential (ETP) with cardiovascular death: the Ludwigshafen Risk and Cardiovascular Health (LURIC) study.
abstract: BACKGROUND
  Coagulation and prothrombotic potential have genuinely been associated with increased cardiovascular risk. However, not all studies in this regard are conclusive. Some clinical trials have shown an increased frequency of cardiovascular complications in patients receiving direct thrombin inhibitors. Previous data from human subjects after acute cardiovascular events showed an inverse association between the thrombin generation marker F1+2 and cardiovascular endpoints indicating that not the lowest, but a slightly elevated propensity for thrombin generation is associated with a lower risk of cardiovascular events. This observation has been supported by findings in animal models of atherosclerosis. Hence, we evaluated the association between the endogenous thrombin potential (ETP) and cardiovascular death (CVD) and markers of vascular dysfunction in a large prospective study with long-term follow up.
  
  
  METHODS
  After excluding patients receiving anticoagulants we tested ETP in 2196 participants (median follow-up 10 years) for its ability to predict vascular death (CVD). In addition, the association between ETP and sVCAM-1, sICAM-1, LpPLA2, hsCRP and SAA was determined.
  
  
  RESULTS
  We observed an inverse association between ETP and CVD with the lowest hazard ratio in the 4th ETP quartile. The nadirs of sICAM-1 or sVCAM-1 were observed in the 3rd, for LpPLA2 in the 4th ETP quartile. Conversely, hsCRP and SAA were highest in the 4th quartile.
  
  
  CONCLUSIONS
  These results demonstrate that not the lowest ETP possible, but slightly higher levels are associated with a reduced risk of CVD and lower markers of endothelial dysfunction, suggesting a more complex role of thrombin in cardiovascular disease.
authors.affiliation: Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Luxembourg; Department of Internal Medicine II, Saarland University Medical Center at Homburg/Saar, Germany. Electronic address: jg.schneider@outlook.com.
authors.forename: Jochen G
authors.initials: JG
authors.lastname: Schneider
authors.affiliation: Department of Clinical Pathology and Pathobiochemistry, Otto-von-Guericke University, Magdeburg, Germany. Electronic address: berend.isermann@med.ovgu.de.
authors.forename: Berend
authors.initials: B
authors.lastname: Isermann
authors.affiliation: Medical Clinic V (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany; LURIC Study nonprofit LLC, Freiburg, Germany. Electronic address: Marcus.Kleber@medma.uni-heidelberg.de.
authors.forename: Marcus E
authors.initials: ME
authors.lastname: Kleber
authors.affiliation: Department of Clinical Pathology and Pathobiochemistry, Otto-von-Guericke University, Magdeburg, Germany. Electronic address: hongjie.wang@med.ovgu.de.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Wang
authors.affiliation: Immuno-Metabolism Laboratory, Nanyang University, Lee Kong Chian School of Medicine, Singapore, Singapore; Imperial College London, London, UK. Electronic address: Bernhard.boehm@ntu.edu.sg.
authors.forename: Bernhard O
authors.initials: BO
authors.lastname: Boehm
authors.affiliation: Medical Clinic V (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany. Electronic address: Tanja.Grammer@medma.uni-heidelberg.de.
authors.forename: Tanja B
authors.initials: TB
authors.lastname: Grammer
authors.affiliation: Medical University of Graz, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Graz, Austria. Electronic address: florian.prueller@klinikum-graz.at.
authors.forename: Florian
authors.initials: F
authors.lastname: Prueller
authors.affiliation: Department of Internal Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg Germany. Electronic address: peter.nawroth@med.uni-heidelberg.de.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Nawroth
authors.affiliation: Medical Clinic V (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany; Medical University of Graz, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Graz, Austria; Synlab Academy, Synlab Services GmbH, Mannheim, Germany. Electronic address: winfried.maerz@synlab.com.
authors.forename: Winfried
authors.initials: W
authors.lastname: Maerz
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood* / Q000175:diagnosis / Q000401:mortality*; D015331:Cohort Studies; D003643:Death; D005260:Female; D005500:Follow-Up Studies; D005858:Germany / Q000453:epidemiology; D006304:Health Status; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012307:Risk Factors; D013917:Thrombin / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D013917:Thrombin
keywords: Cardiovascular death; Endogenous thrombin potential; Thrombin