Highlights
- •The clinical significance of coagulation biomarkers in CAD remains elusive so far.
- •The association between D-Dimer and CAD may be mediated by low-grade inflammation.
- •An increased plasma thrombin potential is characteristic in patients with stable CAD.
- •Plasma thrombin potential is similar in CAD patients with or without prior MI.
Abstract
Introduction
Coagulation plays a crucial role in coronary artery disease (CAD) contributing to
both atherosclerotic plaque development and acute thrombotic complications, like myocardial
infarction (MI). Coagulation biomarkers have been linked with ischemic heart disease,
but results are still controversial.
Materials and methods
D-dimer and thrombin generation, two “overall” coagulation assays, were evaluated
in 775 subjects with or without angiographically-proven CAD (170 CAD-free and 605
CAD, 355 of whom with history of previous MI). Subjects taking anticoagulant drugs
or with any acute illness were excluded. D-dimer plasma concentration was determined
by an immuno-turbidimetric assay. Thrombin generation was assessed as the ability
of plasma to generate thrombin triggered by the addition of tissue factor ex-vivo by means of a chromogenic method.
Results
Both D-dimer and thrombin generation parameters were associated with several traditional
cardiovascular risk factors. Lag-time, time-to-peak, peak height, and Endogenous Thrombin
Potential (ETP), as well as D-dimer levels, were higher in CAD patients than in CAD-free
subjects. After adjustment for all the traditional risk factors, only ETP levels remained
significantly associated with CAD (the highest versus the lowest tertile: OR 2.61 with 95%CI 1.14–5.99), but without improvement of C-statistic.
The association of D-dimer vanished after adjustment for inflammatory markers. No
difference of either D-dimer or thrombin generation parameters was found between CAD
patients with or without previous MI history.
Conclusions
Our results suggest that an increased plasma thrombin potential is characteristic
in patients with clinically stable CAD, irrespective of previous MI history and independent
of traditional cardiovascular risk factors.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Thrombosis ResearchAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Heart disease and stroke statistics 2011 update: a report from the American Heart Association.Circulation. 2011; 123: e18-e209
- Thrombosing arteriosclerosis; result of long-term anticoagulant therapy.Br. Med. J. 1956; 2: 1038-1039
- The hemostatic system as a modulator of atherosclerosis.N. Engl. J. Med. 2011; 364: 1746-1760
- Role of the intrinsic coagulation pathway in atherogenesis assessed in hemophilic apolipoprotein E knockout mice.Arterioscler. Thromb. Vasc. Biol. 2005; 25: e123-e126
- Homozygosity for factor V Leiden leads to enhanced thrombosis and atherosclerosis in mice.Circulation. 2005 Apr 12; 111: 1822-1825
- Decreased coagulability has no clinically relevant effect on atherogenesis: observations in individuals with a hereditary bleeding tendency.Circulation. 2001 Aug 14; 104: 762-767
- Coronary atherosclerosis and cardiovascular mortality in hemophilia.J. Thromb. Haemost. 2010 Jan; 8: 208-211https://doi.org/10.1111/j.1538-7836.2009.03669
- Prognostic value of plasma fibrinolysis activation markers in cardiovascular disease.J. Am. Coll. Cardiol. 2010 Jun 15; 55: 2701-2709https://doi.org/10.1016/j.jacc.2009.11.095
- Can haemostatic factors predict atherothrombosis?.Intern. Emerg. Med. 2010; November; 28: 1739-1743https://doi.org/10.1007/s11739-011-0536-4
- D-dimer testing in laboratory practice.Clin. Chem. 2011; 57: 1256-1262https://doi.org/10.1373/clinchem.2011.166249
- Thrombin generation, a function test of the haemostatic-thrombotic system.Thromb. Haemost. 2006; 96: 553-561
- Thrombin generation in clinical conditions.Thromb. Res. 2012 Mar; 129: 367-370https://doi.org/10.1016/j.thromres.2011.10.017
- Polymorphisms at LDLR locus may be associated with coronary artery disease through modulation of coagulation factor VIII activity and independently from lipid profile.Blood. 2010 Dec 16; 116: 5688-5697https://doi.org/10.1182/blood-2010-03-277079
- Activated factor VII-antithrombin complex predicts mortality in patients with stable coronary artery disease: a cohort study.J. Thromb. Haemost. 2016 Apr; 14: 655-666https://doi.org/10.1111/jth.13274
- A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group.Ann. Intern. Med. 1999; 130: 461-470
- In vitro assessment, using thrombin generation, of the applicability of prothrombin complex concentrate as an antidote for Rivaroxaban.J. Thromb. Haemost. 2013; 11: 1111-1118https://doi.org/10.1111/jth.12236
- Statistics and ethics in medical research: how large a sample?.Br. Med. J. 1980 Nov 15; 281: 1336-1338
- Flexible Imputation of Missing Data.Chapman and Hall/CRC, Boca Raton, FL2012
- Multiple imputation using chained equations: issues and guidance for practice.Stat. Med. 2011; 30: 377-399
- Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach.Biometrics. 1988; 44: 837-845
- pROC: an open-source package for R and S+ to analyze and compare ROC curves.BMC Bioinf. 2011; 12: 77
- Trunk weighted obesity, cholesterol levels and low grade inflammation are main determinants for enhanced thrombin generation.Atherosclerosis. 2012 Jan; 220: 215-218https://doi.org/10.1016/j.atherosclerosis.2011.09.035
- Hemostatic factors and risk of coronary heart disease in general populations: new prospective study and updated meta-analyses.PLoS One. 2013; 8e55175https://doi.org/10.1371/journal.pone.0055175
- Thrombin generation in the Glasgow Myocardial Infarction Study.PLoS One. 2013 Jun 24; 8e66977https://doi.org/10.1371/journal.pone.0066977
- Phospholipids and blood coagulation.Am. J. Clin. Nutr. 1958; 6: 681-687
- Cardiovascular risk factors: interactive effects of lipids, coagulation and fibrinolysis.Scand. J. Clin. Lab. Investig. Suppl. 1993; 215: 19-27
- Diet modulates endogenous thrombin generation, a biological estimate of thrombosis risk, independently of the metabolic status.Arterioscler. Thromb. Vasc. Biol. 2012 Oct; 32: 2394-2404https://doi.org/10.1161/ATVBAHA.112.250332
- Apolipoprotein C-III predicts cardiovascular mortality in severe coronary artery disease and is associated with an enhanced plasma thrombin generation.J. Thromb. Haemost. 2010; 8: 463-471
- Factor II activity is similarly increased in patients with elevated apolipoprotein CIII and in carriers of the factor II 20210A allele.J. Am. Heart Assoc. 2013; 2e000440
- C-reactive protein, fibrin D-dimer, and incident ischemic heart disease in the Speedwell study: are inflammation and fibrin turnover linked in pathogenesis?.Arterioscler. Thromb. Vasc. Biol. 2001 Apr; 21: 603-610
- The prognostic utility of D-dimer and fibrin monomer at long-term follow-up after hospitalization with coronary chest pain.Blood Coagul. Fibrinolysis. 2008; 19: 701-707https://doi.org/10.1097/MBC.0b013e32830b1512
- Associations of factor VIIIc, D-dimer, and plasmin–antiplasmin with incident cardiovascular disease and all-cause mortality.Am. J. Hematol. 2009; 84: 349-353https://doi.org/10.1002/ajh.21429
- C-reactive protein, fibrin D-dimer, and risk of ischemic heart disease: the Caerphilly and Speedwell studies.Arterioscler. Thromb. Vasc. Biol. 2004 Oct; 24: 1957-1962
- Plasma fibrin D-dimer level and risk of stable coronary artery disease. Results of a large case-control study.Arterioscler. Thromb. Vasc. Biol. 2001; 21: 1701-1705
- A comparison of the associations between seven hemostatic or inflammatory variables and coronary heart disease.J. Thromb. Haemost. 2007; 5: 1795-1800
- Haemostatic and inflammatory markers are independently associated with myocardial infarction in men and women.Thromb. Res. 2012 Jan; 129: 68-73https://doi.org/10.1016/j.thromres.2011.05.015
- Haemostatic factors and the risk of cardiovascular death in patients with coronary artery disease: the AtheroGene study.Arterioscler. Thromb. Vasc. Biol. 2006 Dec; 26: 2793-2799
- Thrombin generation in patients with a first acute myocardial infarction.J. Thromb. Haemost. 2011 Mar; 9: 450-456https://doi.org/10.1111/j.1538-7836.2010.04162
- Increased tissue factor pathway inhibitor activity is associated with myocardial infarction in young women: results from the RATIO study.J. Thromb. Haemost. 2011 Nov; 9: 2243-2250https://doi.org/10.1111/j.1538-7836.2011.04497
- Regulation of thrombin generation by TFPI in plasma without and with heparin.Transl. Res. 2009 Mar; 153: 124-131https://doi.org/10.1016/j.trsl.2008.12.004
- Detection of hypofibrinolysis in stable coronary artery disease using the overall haemostatic potential assay.Thromb. Res. 2013 May; 131: 457-462https://doi.org/10.1016/j.thromres.2013.03.015
- Accelerated in vivo thrombin formation independently predicts the presence and severity of CT angiographic coronary atherosclerosis.JACC Cardiovasc. Imaging. 2012 Dec; 5: 1201-1210https://doi.org/10.1016/j.jcmg.2012.01.02
- Relationship between thrombin generation and carotid intima-media thickness.Hamostaseologie. 2010 Nov; 30: S168-S171
- Increased thrombin generation in persons with echogenic carotid plaques.Thromb. Haemost. 2008 Mar; 99: 602-608https://doi.org/10.1160/TH07-08-0493
- Increased thrombin generation is associated with acute ischemic stroke but not with coronary heart disease in the elderly: the Three-City cohort study.Arterioscler. Thromb. Vasc. Biol. 2011 Jun; 31: 1445-1451https://doi.org/10.1161/ATVBAHA.111.223453
- Increased thrombin generation after acute versus chronic coronary disease as assessed by the thrombin generation test.Thromb. Haemost. 2008; 99: 382-387
- Thrombin generation in acute coronary syndrome and stable coronary artery disease: dependence on plasma factor composition.J. Thromb. Haemost. 2008 Jan; 6: 104-110
- Systemic blood coagulation activation in acute coronary syndromes.Blood. 2009 Feb 26; 113: 2070-2078https://doi.org/10.1182/blood-2008-07-167411
- Stability of prothrombin and factor VII in freeze-dried plasma.J. Clin. Pathol. 1971 Nov; 24: 690-693
- Stability of blood coagulation factors in deep frozen fresh plasma by storage at −20 degrees C and −40 degrees C.Infusionsther. Klin. Ernahr. 1984 Feb; 11: 46-50
Article info
Publication history
Published online: April 28, 2017
Accepted:
April 21,
2017
Received in revised form:
March 25,
2017
Received:
July 31,
2016
Identification
Copyright
© 2017 Elsevier Ltd. All rights reserved.
