Download PDF
Thromb Haemost 2014; 112(05): 941-946
DOI: 10.1160/th14-04-0297
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Elevated levels of D-dimers increase the risk of ischaemic and haemorrhagic stroke

Findings from the EPICOR Study
Augusto Di Castelnuovo
1   Laboratory of Molecular and Nutritional Epidemiology, Department of Epidemiology and Prevention, IRCCS-Istituto Neurologico Mediterraneo Neuromed-Pozzilli, Italy
,
Claudia Agnoli
2   Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
,
Amalia de Curtis
1   Laboratory of Molecular and Nutritional Epidemiology, Department of Epidemiology and Prevention, IRCCS-Istituto Neurologico Mediterraneo Neuromed-Pozzilli, Italy
,
Maria Concetta Giurdanella
3   Cancer Registry ASP Ragusa, Italy
,
Sabina Sieri
2   Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
,
Amalia Mattiello
4   Dipartimento di Medicina Clinica e Chirurgia, University of Naples “Federico II”, Italy
,
Giuseppe Matullo
5   Department of Medical Sciences, University of Torino, Italy
6   Human Genetics Foundation, Torino, Italy
,
Salvatore Panico
4   Dipartimento di Medicina Clinica e Chirurgia, University of Naples “Federico II”, Italy
,
Carlotta Sacerdote
6   Human Genetics Foundation, Torino, Italy
7   Unit of Cancer Epidemiology, AO Città della Salute e della Scienza-University of Torino and Center for Cancer Prevention, Torino, Italy
,
Rosario Tumino
3   Cancer Registry ASP Ragusa, Italy
,
Paolo Vineis
7   Unit of Cancer Epidemiology, AO Città della Salute e della Scienza-University of Torino and Center for Cancer Prevention, Torino, Italy
8   Department of Epidemiology & Biostatistics, School of Public Health, Faculty of Medicine, Imperial College, London, UK
,
Giovanni de Gaetano
1   Laboratory of Molecular and Nutritional Epidemiology, Department of Epidemiology and Prevention, IRCCS-Istituto Neurologico Mediterraneo Neuromed-Pozzilli, Italy
,
Maria Benedetta Donati
1   Laboratory of Molecular and Nutritional Epidemiology, Department of Epidemiology and Prevention, IRCCS-Istituto Neurologico Mediterraneo Neuromed-Pozzilli, Italy
,
Licia Iacoviello
1   Laboratory of Molecular and Nutritional Epidemiology, Department of Epidemiology and Prevention, IRCCS-Istituto Neurologico Mediterraneo Neuromed-Pozzilli, Italy
› Author Affiliations Financial support: This work was supported by Compagnia di San Paolo for the EPIC, EPICOR and EPICOR2 projects and partially by Italian Ministry of Education, University and Research (MIUR) ex60% (2012).
Further Information

Publication History

Received: 03 April 2014

Accepted after minor revision: 30 May 2014

Publication Date:
20 November 2017 (online)

    Permissions and Reprints

Summary

Elevated D-dimer levels are reportedly associated with coronary artery disease. It was the study objective to investigate the association of baseline D-dimer levels with strokes that occurred in the European Prospective Investigation into Cancer and Nutrition-Italy cohort. Using a nested case-cohort design, a centre-–stratified sample of 832 subjects (66 % women, age 35–71) was selected as subcohort and compared with 289 strokes in a mean follow-up of nine years. D-dimers were measured by an automated latex-enhanced immunoassay (HemosIL-IL). The multivariable hazard ratios were estimated by a Cox regression model using Prentice method. Individuals with elevated D-dimer levels had significantly higher risk of incident stroke. It was evident from the second quartile (D-dimers > 100 ng/ml) and persisted almost unchanged for higher D-dimers (hazard ratio [HR] 2.10, 95 % confidence interval [CI]: 1.28–3.47; 2.42, 95 %CI: 1.44–4.09 and 2.10, 95 %CI: 1.27–3.48 for the second, third or fourth quartile compared with the lowest quartile, respectively). The association was independent of several confounders, including triglycerides and C-reactive protein. No differences were observed in men and women (P for interaction= 0.46), in hypertensive or non-hypertensive subjects (P for interaction= 0.88) or in subjects with low (< 1 mg/l) or elevated (≥ 1 mg/l) C-reactive protein (P for interaction=0.35). After stratification for stroke type, the hazard ratio for every standard deviation increase was statistically significant both for ischaemic (1.21; 95 %CI: 1.01 to 1.45) and haemorrhagic (1.24; 95 %CI: 1.00 to 1.65) strokes. In conclusion, our data provide clear evidence that elevated levels of D-dimers are potential risk factors not only for ischaemic but also for haemorrhagic strokes.

Keywords

Stroke / prevention - cerebrovascular disease - coagulation factors - epidemiological studies - risk factors
 

  • References

  • 1 Feigin VL. et al. Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurol 2003; 2: 43-53.
    CrossrefPubMedGoogle Scholar
  • 2 van Holten TC. et al. Circulating biomarkers for predicting cardiovascular disease risk; a systematic review and comprehensive overview of meta-analyses. PLoS One 2013; 22: e62080.
    PubMedGoogle Scholar
  • 3 Meade TW. et al. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet 1986; ii: 533-537.
    PubMedGoogle Scholar
  • 4 Gorog DA. Prognostic value of plasma fibrinolysis activation markers in cardiovascular disease. J Am Coll Cardiol 2010; 55: 2701-2709.
    CrossrefPubMedGoogle Scholar
  • 5 Cushman M. et al. Fibrin fragment D-dimer and the risk of future venous thrombosis. Blood 2003; 101: 1243-1248.
    CrossrefPubMedGoogle Scholar
  • 6 Huisman MV, Klok FA. How I diagnose acute pulmonary embolism. Blood 2013; 121: 4443-4448.
    CrossrefPubMedGoogle Scholar
  • 7 Bates SM. D-dimer assays in diagnosis and management of thrombotic and bleeding disorders. Semin Thromb Haemost 2012; 38: 673-682.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Danesh J. et al. Fibrin D-dimer and coronary heart disease: prospective study and meta-analysis. Circulation 2001; 103: 2323-2327.
    CrossrefPubMedGoogle Scholar
  • 9 Lowe GDO, Rumley A. Use of fibrinogen and fibrin D-dimer in prediction of arterial thrombotic events. Thromb Haemost 1999; 82: 667-672.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Fowkes FGR. et al. Cross-linked fibrin degradation products, risk of coronary heart disease, and progression of peripheral arterial disease. Lancet 1993; 342: 84-86.
    CrossrefPubMedGoogle Scholar
  • 11 Ridker PM. et al. Plasma concentration of cross-linked fibrin degradation products (D-dimer) and the risk of future myocardial infarction among apparently healthy men. Circulation 1994; 90: 2236-2240.
    CrossrefPubMedGoogle Scholar
  • 12 Moss AJ. et al. Thrombogenic factors and recurrent coronary events. Circulation 1999; 99: 2517-2522.
    CrossrefPubMedGoogle Scholar
  • 13 Cortellaro M. et al. Increased fibrin turnover and high PAI-1 activity as predictors of ischaemic events in atherosclerotic patients. A case-control study. The PLAT Group. Arterioscler Thromb 1993; 13: 1412-1417.
    CrossrefPubMedGoogle Scholar
  • 14 Cushman M. et al. Fibrinolytic activation markers predict myocardial infarction in the elderly: the Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 1999; 19: 493-498.
    CrossrefPubMedGoogle Scholar
  • 15 Lowe GD. et al. C-reactive protein, fibrin D-dimer, and incident ischaemic heart disease in the Speedwell study: are inflammation and fibrin turnover linked in pathogenesis?. Arterioscler Thromb Vasc Biol 2001; 21: 603-610.
    CrossrefPubMedGoogle Scholar
  • 16 Lowe GDO. et al. Fibrin D-dimer, tissue plasminogen activator, tissue plasminogen activator inhibitor, and the risk of major ischaemic heart disease in the Caerphilly Study. Thromb Haemost 1998; 79: 129-133.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Di Castelnuovo A. et al. Association of D-dimer levels with all-cause mortality in a healthy adult population: findings from the MOLI-SANI study. Haematologica 2013; 98: 1476-1480.
    CrossrefPubMedGoogle Scholar
  • 18 Folsom AR. et al. Multiethnic Study of Atherosclerosis Investigators. Associations of factor VIIIc, D-dimer, and plasmin-antiplasmin with incident cardiovascular disease and all-cause mortality. Am J Hematol 2009; 84: 349-353.
    CrossrefPubMedGoogle Scholar
  • 19 Ay C. et al. High D-dimer levels are associated with poor prognosis in cancer patients. Haematologica 2012; 97: 1158-1164.
    CrossrefPubMedGoogle Scholar
  • 20 Donati MB. Thrombosis and cancer: a personal view. Thromb Haemost 2007; 98: 126-128.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Hasan N. et al. Towards the identification of blood biomarkers for acute stroke in humans: a comprehensive systematic review. Br J Clin Pharmacol 2012; 74: 230-240.
    CrossrefPubMedGoogle Scholar
  • 22 Smith FB. et al. Haemostatic factors as predictors of ischaemic heart disease and stroke in the Edinburgh Artery Study. Arterioscler Thromb Vasc Biol 1997; 17: 3321-3325.
    CrossrefPubMedGoogle Scholar
  • 23 Smith FB. et al. Haemostatic factors and prediction of ischaemic heart disease and stroke in claudicants. Br J Haematol 1998; 100: 758-763.
    CrossrefPubMedGoogle Scholar
  • 24 Smith A. et al. Which haemostatic markers add to the predictive value of conventional risk factors for coronary heart disease and ischaemic stroke? The Caerphilly Study. Circulation 2005; 112: 3080-3087.
    CrossrefPubMedGoogle Scholar
  • 25 Riboli E, Kaaks R. The EPIC Project: rationale and study design. European Prospective Investigation into Cancer and Nutrition. Int J Epidemiol 1997; 26 (Suppl. 01) S6-14.
    CrossrefPubMedGoogle Scholar
  • 26 Palli D. et al. A molecular epidemiology project on diet and cancer: the EPIC-Italy Prospective Study. Design and baseline characteristics of participants. Tumori 2003; 89: 586-593.
    PubMedGoogle Scholar
  • 27 Juhan-Vague I, Alessi MC. PAI-1, obesity, insulin resistance and risk of cardiovascular events. Thromb Haemost 1997; 78: 656-660.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Pala V. et al. Diet in the Italian EPIC cohorts: presentation of data and methodological issues. Tumori 2003; 89: 594-607.
    PubMedGoogle Scholar
  • 29 Le Polain de Waroux O. et al. The case-cohort design in outbreak investigations. Euro Surveill 2012; 17: 1-5.
    CrossrefPubMedGoogle Scholar
  • 30 Prentice RL. A case-cohort design for epidemiologic cohort studies and disease prevention trials. Biometrika 1986; 73: 1-11.
    CrossrefPubMedGoogle Scholar
  • 31 Wareham NJ. et al. Validity and repeatability of a simple index derived from the short physical activity questionnaire used in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Public Health Nutr 2003; 6: 407-413.
    PubMedGoogle Scholar
  • 32 Matijevic N, Wu KK. Hypercoagulable states and strokes. Curr Atheroscler Rep 2006; 8: 324-329.
    CrossrefPubMedGoogle Scholar
  • 33 Stott DJ. et al. Haemostasis in ischaemic stroke and vascular dementia. Blood Coagul Fibrinol 2001; 12: 651-657.
    CrossrefPubMedGoogle Scholar
  • 34 Whiteley W. et al. Blood biomarkers for the diagnosis of acute cerebrovascular diseases: a prospective cohort study. Cerebrovasc Dis 2011; 32: 141-147.
    CrossrefPubMedGoogle Scholar
  • 35 Carcaillon L. et al. Elevated plasma fibrin D-dimer as a risk factor for vascular dementia: the Three-City cohort Study. J Thromb Haemost 2009; 1972-1978.
    PubMedGoogle Scholar
  • 36 Wannamethee SG. et al. Fibrin D-dimer, tissue-type plasminogen activator, von Willebrand factor, and risk of incident stroke in older men. Stroke 2012; 43: 1206-1211.
    CrossrefPubMedGoogle Scholar
  • 37 Fujii Y. et al. Haemostatic activation in spontaneous intracerebral haemorrhage. Stroke 2001; 32: 883-890.
    CrossrefPubMedGoogle Scholar
  • 38 Delgado P. et al. Plasma d-dimer predicts poor outcome after acute intracerebral haemorrhage. Neurology 2006; 67: 94-98.
    CrossrefPubMedGoogle Scholar
  • 39 Varoglu AO. et al. Prognostic values of lesion volume and biochemical markers in ischaemic and haemorrhagic stroke: a stereological and clinical study. Int J Neurosci 2009; 119: 2206-2218.
    CrossrefPubMedGoogle Scholar
  • 40 Ariëns RA. et al. Activation markers of coagulation and fibrinolysis in twins: heritability of the prethrombotic state. Lancet 2002; 359: 667-671.
    CrossrefPubMedGoogle Scholar
  • 41 Lip GY. et al. Plasma fibrinogen and fibrin D-dimer in patients with atrial fibrillation. Int J Cardiol 1995; 51: 245-251.
    CrossrefPubMedGoogle Scholar
  • 42 Lip GY. et al. Fibrin D-dimer and b-thromboglobulin as markers of thrombo-genesis and platelet activation in atrial fibrillation: effects of introducing ultra-low-dose warfarin and aspirin. Circulation 1996; 94: 425-431.
    CrossrefPubMedGoogle Scholar