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• W2890343981 abstract "HomeCirculationVol. 138, No. 7D-Dimer for Long-Term Risk Prediction in Patients After Acute Coronary Syndrome Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBD-Dimer for Long-Term Risk Prediction in Patients After Acute Coronary SyndromeJack of All Trades, or Master of None? Paul A. Kyrle, MD and Sabine Eichinger, MD Paul A. KyrlePaul A. Kyrle Paul A. Kyrle, MD, Department of Medicine I, Medical University of Vienna, Austria, Waehringer Guertel 18–20, 1090 Vienna, Austria. E-mail E-mail Address: [email protected] Department of Medicine I, Medical University of Vienna, Austria (P.A.K., S.E.) Karl Landsteiner-Institute of Clinical Thrombosis Research, Vienna, Austria (P.A.K., S.E.). Search for more papers by this author and Sabine EichingerSabine Eichinger Department of Medicine I, Medical University of Vienna, Austria (P.A.K., S.E.) Karl Landsteiner-Institute of Clinical Thrombosis Research, Vienna, Austria (P.A.K., S.E.). Search for more papers by this author Originally published13 Aug 2018https://doi.org/10.1161/CIRCULATIONAHA.118.033670Circulation. 2018;138:724–726Article, see p 712The generation of D-dimer is illustrated in the Figure. Thrombin converts fibrinogen to fibrin monomers that are composed of a central E-domain and 2 peripheral D-domains. Fibrin monomers spontaneously polymerize, thereby forming an unstable fibrin network. Factor XIII, activated by thrombin, then cross-links the D-domains of adjacent fibrin monomers, which strengthens the fibrin mesh. Fibrin-bound plasmin degrades the fibrin network into soluble fragments: D-dimers and E fragments. Plasma levels of D-dimer, therefore, reflect the extent of coagulation and fibrinolysis activation and are elevated in hypercoagulable states.Download figureDownload PowerPointFigure. Simplified illustration of D-dimer generation. Temporary conditions of thrombus formation as, for instance, surgery, trauma, or pregnancy, and persistent risk factors, as well, including ageing, inflammation, cancer, or atrial fibrillation, exert a hypercoagulable state as reflected by enhanced thrombin generation by the coagulation system. Thrombin converts fibrinogen to fibrin monomers that are composed of a central E-domain and 2 peripheral D-domains. Fibrin monomers polymerize, thereby forming an unstable fibrin network. Activated factor XIII cross-links the D-domains, which strengthens the fibrin mesh. Fibrin-bound plasmin degrades the fibrin network into soluble fragments: D-dimers and E fragments. DIC indicates disseminated intravascular coagulation; and FXIII, factor XIII.D-Dimer was discovered in the 1970s, and it was first introduced into clinical practice for diagnosing venous thromboembolism (VTE) or disseminated intravascular coagulation. Later, several clinical studies found D-dimer to be associated with the occurrence of arterial or venous thrombosis, and with cancer development, as well. In 2 prospective studies, for instance, patients with a high D-dimer at enrollment and proven coronary artery disease or with a history of myocardial infarction were at high risk of cardiovascular death or occurrence of recurrent coronary events during a follow-up of >6 years or during a 26-month observation period, respectively.1,2 Abundant evidence suggests that patients with elevated D-dimer have an increased risk of recurrent VTE,3 and D-dimer has been successfully integrated into several risk assessment models of venous thrombosis.4–6 A high D-dimer was reported to be independently associated with the likelihood of occult cancer among patients with unprovoked VTE.7In the LIPID study (Long-Term Intervention with Pravastatin in Ischemic Disease), patients with myocardial infarction or unstable angina who were randomly assigned to pravastatin treatment had a reduced mortality from coronary heart disease, had a lower overall mortality, and fewer cardiovascular events than patients randomly assigned to placebo.8 In this issue of Circulation, Simes and colleagues present a subanalysis of the LIPID study.9 In 7863 patients, they evaluated the long-term relationship between D-dimer and vascular outcomes, cause-specific mortality, and new cancers. During a median follow-up of 6 years, risks of major coronary events, major cardiovascular events, and VTE increased with increasing D-dimer levels with adjusted hazard ratios of 1.45 (95% confidence interval, 1.21–1.74), 1.45 (95% confidence interval, 1.23–1.71), and 4.03 (95% confidence interval, 2.13–7.03), respectively, for patients in the highest quartile in comparison with patients in the lowest quartile. During a follow-up of 16 years, a high D-dimer was an independent predictor of all-cause mortality, cardiovascular disease mortality, cancer incidence and mortality, and noncardiovascular disease noncancer mortality. It is interesting to note that pravastatin reduced D-dimer levels significantly, but its benefits for coronary heart disease events could not be explained by changes in D-dimer levels.Some intriguing questions arise from these study results. What is a low and a high D-dimer? In the study, patients were grouped according to quartiles of D-dimer with corresponding mean levels of 80.7, 141.7, 217.4, and 613.8 ng/mL. This means that the majority of patients had D-dimer levels that were well below 500 ng/mL, which is the cutoff used for diagnosing acute VTE. Admittedly, D-dimer levels may have been lowered by antithrombotic treatment. Nevertheless, these data indicate that D-dimer levels are low in the majority of patients even after myocardial infarction or unstable angina, but that levels perceived as low and regarded as inconspicuous in daily clinical practice are associated with a high risk of clinical outcomes. There are 2 other noteworthy aspects. First, D-dimer levels in the study by Simes and colleagues were in a range similar to that found to be predictive for recurrent VTE.10 Second, some patients had values well above the 500 ng/mL cutoff. These patients may belong to a distinct high-risk subgroup, which deserves further attention. Of note, the cumulative all-cause mortality after 16 years among patients with D-dimer levels in the highest quartile exceeded 50%.Another important question is, “What drives D-dimer generation in these patients?” Formation of D-dimer is the consequence of thrombin generation, and D-dimer is, therefore, a global marker of coagulation activation. The triggers behind thrombin generation are manifold, they may interact, and they are either present over a long period of time (persistent) or only briefly (temporary) (Figure). In the study by Simes and colleagues, the concept of a multifactorial mechanism behind D-dimer generation is well reflected: D-dimer was predictive not only for cardiovascular outcomes, but also for cancer incidence, cancer mortality, and all-cause mortality. Along these lines goes the observation that D-dimer levels relate to numerous other biomarkers, including white blood cell count, C-reactive protein, sensitive troponin I, lipoprotein (a), and B-type natriuretic peptide, and clinical risk factors, as well, in particular, advanced age. In the LIPID study, D-dimer levels were measured shortly after the acute event and were related to outcome events that occurred many years later. This indicates that D-dimer generation is most likely driven by persistent risk factors linked to states of hypercoagulability, such as ageing, chronic inflammation, cancer, atrial fibrillation, or a genetic predisposition.11,12 The question therefore arises whether D-dimer is a jack of all trades as a useful predictor of several seemingly unrelated disease states, or a master of none, because it is very unspecific.How can the data be transferred into clinical practice? In comparison with placebo, pravastatin was particularly effective in reducing the incidence of recurrent cardiovascular events among patients belonging to the highest D-dimer quartile. From this finding, one may deduce that, in patients with a history of cardiovascular thrombosis, lipid-lowering strategies can be adjusted according to the D-dimer level. Consequent lowering of lipids, however, benefits all patients with coronary artery disease; therefore, additional risk stratification according to D-dimer levels is most likely futile. In contrast to VTE, D-dimer has not been incorporated in assessment models for recurrent arterial disease. The data presented in this study are convincing enough to consider adding D-dimer to already existing risk scores. This could improve risk stratification of these patients, possibly allowing a better targeted treatment strategy. One has to keep in mind, however, that this approach is time consuming and costly, because it necessitates prospective validation and management studies in many patients.DisclosuresNone.Footnoteshttps://www.ahajournals.org/journal/circThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Paul A. Kyrle, MD, Department of Medicine I, Medical University of Vienna, Austria, Waehringer Guertel 18–20, 1090 Vienna, Austria. E-mail paul.[email protected]ac.atReferences1. Morange PE, Bickel C, Nicaud V, Schnabel R, Rupprecht HJ, Peetz D, Lackner KJ, Cambien F, Blankenberg S, Tiret L; AtheroGene Investigators. Haemostatic factors and the risk of cardiovascular death in patients with coronary artery disease: the AtheroGene study.Arterioscler Thromb Vasc Biol. 2006; 26:2793–2799. doi: 10.1161/01.ATV.0000249406.92992.0d.LinkGoogle Scholar2. Moss AJ, Goldstein RE, Marder VJ, Sparks CE, Oakes D, Greenberg H, Weiss HJ, Zareba W, Brown MW, Liang CS, Lichstein E, Little WC, Gillespie JA, Van Voorhees L, Krone RJ, Bodenheimer MM, Hochman J, Dwyer EM, Arora R, Marcus FI, Watelet LF, Case RB. Thrombogenic factors and recurrent coronary events.Circulation. 1999; 99:2517–2522.LinkGoogle Scholar3. Marcucci M, Smith CT, Douketis JD, Tosetto A, Baglin T, Cushman M, Eichinger S, Palareti G, Poli D, Tait RC, Iorio A. Patient-level compared with study-level meta-analyses demonstrate consistency of D-dimer as predictor of venous thromboembolic recurrences.J Clin Epidemiol. 2013; 66:415–425. doi: 10.1016/j.jclinepi.2012.08.007.CrossrefMedlineGoogle Scholar4. Rodger MA, Kahn SR, Wells PS, Anderson DA, Chagnon I, Le Gal G, Solymoss S, Crowther M, Perrier A, White R, Vickars L, Ramsay T, Betancourt MT, Kovacs MJ.I dentifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy.CMAJ. 2008; 179:417–426.CrossrefMedlineGoogle Scholar5. Eichinger S, Heinze G, Jandeck LM, Kyrle PA. Risk assessment of recurrence in patients with unprovoked deep vein thrombosis or pulmonary embolism: the Vienna prediction model.Circulation. 2010; 121:1630–1636. doi: 10.1161/CIRCULATIONAHA.109.925214.LinkGoogle Scholar6. Tosetto A, Iorio A, Marcucci M, Baglin T, Cushman M, Eichinger S, Palareti G, Poli D, Tait RC, Douketis J. Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH).J Thromb Haemost. 2012; 10:1019–1025. doi: 10.1111/j.1538-7836.2012.04735.x.CrossrefMedlineGoogle Scholar7. Han D, ó Hartaigh B, Lee JH, Cho IJ, Shim CY, Chang HJ, Hong GR, Ha JW, Chung N. Impact of D-dimer for prediction of incident occult cancer in patients with unprovoked venous thromboembolism.PLoS One. 2016; 11:e0153514. doi: 10.1371/journal.pone.0153514.MedlineGoogle Scholar8. Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.N Engl J Med. 1998; 339:1349–1357.CrossrefMedlineGoogle Scholar9. Simes J, Robledo KP, White HD, Espinoza D, Stewart RA, Sullivan DR, Zeller T, Hague W, Nestel PJ, Glasziou PP, Keech AC, Elliott J, Blankenberg S, Tonkin AM; for the LIPID study investigators. D-dimer predicts long-term cause-specific mortality, cardiovascular events, and cancer in patients with stable coronary heart disease patients.Circulation. 2018; 138:712–723. doi: 10.1161/CIRCULATIONAHA.117.029901.LinkGoogle Scholar10. Eichinger S, Minar E, Bialonczyk C, Hirschl M, Quehenberger P, Schneider B, Weltermann A, Wagner O, Kyrle PA. D-dimer levels and risk of recurrent venous thromboembolism.JAMA. 2003; 290:1071–1074. doi: 10.1001/jama.290.8.1071.CrossrefMedlineGoogle Scholar11. Weitz JI, Fredenburgh JC, Eikelboom JW. A test in context: D-dimer.J Am Coll Cardiol. 2017; 70:2411–2420. doi: 10.1016/j.jacc.2017.09.024.CrossrefMedlineGoogle Scholar12. Ariëns RA, de Lange M, Snieder H, Boothby M, Spector TD, Grant PJ. Activation markers of coagulation and fibrinolysis in twins: heritability of the prethrombotic state.Lancet. 2002; 359:667–671. doi: 10.1016/S0140-6736(02)07813-3.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Li J, Yan S, Zhang X, Xiang M, Zhang C, Gu L, Wei X, You C, Chen S, Zeng D and Jiang J (2022) Circulating D-Dimers Increase the Risk of Mortality and Venous Thromboembolism in Patients With Lung Cancer: A Systematic Analysis Combined With External Validation, Frontiers in Medicine, 10.3389/fmed.2022.853941, 9 Ke J, Chen Y, Wang X, Wu Z, Zhang Q, Lian Y and Chen F (2022) Machine learning-based in-hospital mortality prediction models for patients with acute coronary syndrome, The American Journal of Emergency Medicine, 10.1016/j.ajem.2021.12.070, 53, (127-134), Online publication date: 1-Mar-2022. Chen R, Liu C, Zhou P, Li J, Zhou J, Song R, Liu W, Chen Y, Song L, Zhao H and Yan H (2022) Prognostic Value of Age-Adjusted D-Dimer Cutoff Thresholds in Patients with Acute Coronary Syndrome Treated by Percutaneous Coronary Intervention, Clinical Interventions in Aging, 10.2147/CIA.S347168, Volume 17, (117-128) Oikawa M, Yaegashi D, Yokokawa T, Misaka T, Sato T, Kaneshiro T, Kobayashi A, Yoshihisa A, Nakazato K, Ishida T and Takeishi Y (2022) D-Dimer Is a Predictive Factor of Cancer Therapeutics-Related Cardiac Dysfunction in Patients Treated With Cardiotoxic Chemotherapy, Frontiers in Cardiovascular Medicine, 10.3389/fcvm.2021.807754, 8 Chen R, Liu C, Zhou P, Tan Y, Sheng Z, Li J, Zhou J, Chen Y, Song L, Zhao H and Yan H (2021) Prognostic Value of D-dimer in patients with acute coronary syndrome treated by percutaneous coronary intervention: a retrospective cohort study, Thrombosis Journal, 10.1186/s12959-021-00281-y, 19:1, Online publication date: 1-Dec-2021. Zhi H, Zhang Z, Deng Y, Yan B, Li Z, Wu W, Feng Z, Lei M, Long H, Hou J, Guo D and Wu W (2021) Restoring perturbed oxylipins with Danqi Tongmai Tablet attenuates acute myocardial infarction, Phytomedicine, 10.1016/j.phymed.2021.153616, 90, (153616), Online publication date: 1-Sep-2021. Steinbrecher O, Šinkovec H, Eischer L, Kyrle P and Eichinger S (2021) D-dimer levels over time after anticoagulation and the association with recurrent venous thromboembolism, Thrombosis Research, 10.1016/j.thromres.2020.11.015, 197, (160-164), Online publication date: 1-Jan-2021. Chang D, Zhao P, Zhang D, Dong J, Xu Z, Yang G, Li B, Liu H, Li B, Qin C, Peng X, Wang F, Xie L, Chen Z, Dela Cruz C, Sharma L and Qin E (2020) Persistent Viral Presence Determines the Clinical Course of the Disease in COVID-19, The Journal of Allergy and Clinical Immunology: In Practice, 10.1016/j.jaip.2020.06.015, 8:8, (2585-2591.e1), Online publication date: 1-Sep-2020. Kyrle P, Eischer L, Šinkovec H and Eichinger S (2019) Factor XI and recurrent venous thrombosis: an observational cohort study , Journal of Thrombosis and Haemostasis, 10.1111/jth.14415, 17:5, (782-786), Online publication date: 1-May-2019. Zhi H, Deng Y, Yan B, Li Z, Han S, Zhang Y, Hou J, Wu W and Guo D (2019) Study on the herb-herb interaction of Danqi Tongmai Tablet based on the pharmacokinetics of twelve notoginsenoides in acute myocardial ischemia and sham rats, Journal of Pharmaceutical and Biomedical Analysis, 10.1016/j.jpba.2018.12.043, 166, (52-65), Online publication date: 1-Mar-2019. Zaha V, Hundley W and Hill J (2018) Cardio-Oncology, Circulation, 138:7, (663-665), Online publication date: 14-Aug-2018. August 14, 2018Vol 138, Issue 7 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.118.033670PMID: 30359138 Originally publishedAugust 13, 2018 KeywordsEditorialspredictive value of testsD-dimerrisk assessmentvenous thromboembolismmyocardial ischemiaPDF download Advertisement" @default.
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