Haemostatic biomarkers are associated with long-term recurrent vascular events after ischaemic stroke

Annie Pedersen; Petra Redfors; Linnea Lundberg; Ann Gils; Paul J. Declerck; Staffan Nilsson; Katarina Jood; Christina Jern

doi:10.1160/TH15-12-0938

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2016; 116(03): 537-543
DOI: 10.1160/TH15-12-0938

Stroke, Systemic or Venous Thromboembolism

Schattauer GmbH

Haemostatic biomarkers are associated with long-term recurrent vascular events after ischaemic stroke

Authors

Annie Pedersen

¹Institute of Biomedicine, the Sahlgrenska Academy at University of Gothenburg, Sweden
Petra Redfors

²Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Sweden
Linnea Lundberg

¹Institute of Biomedicine, the Sahlgrenska Academy at University of Gothenburg, Sweden
Ann Gils

³Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
Paul J. Declerck

³Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
Staffan Nilsson

⁴Department of Mathematical Statistics, Chalmers Univeristy of Technology, Gothenburg, Sweden
Katarina Jood

²Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Sweden
Christina Jern

¹Institute of Biomedicine, the Sahlgrenska Academy at University of Gothenburg, Sweden

Abstract

Summary

Ischaemic stroke patients continue to be at risk for recurrent vascular events for many years. Predictors of long-term prognosis are needed. It was the objective of this study to investigate levels of four haemostatic proteins as long-term predictors of recurrent vascular events after ischaemic stroke. We prospectively followed 548 ischaemic stroke patients, 18–69 years, and registered recurrent vascular events. Plasma levels of tissue-type plasminogen activator (t-PA), von Willebrand factor (VWF), fibrinogen and thrombin activatable fibrinolysis inhibitor activation peptide (TAFI-AP) were measured three months after index stroke. Cox regression models were used to assess associations to outcomes for single biomarkers and for a combined biomarker measure. For single biomarkers significantly associated with any of the outcomes, we performed subanalyses stratified for age, sex, diabetes and atherosclerosis. During 5,637 person-years of follow-up, we registered 74 vascular deaths, 90 recurrent strokes and 62 coronary events. Levels of t-PA, VWF and fibrinogen were significantly associated with vascular death and coronary events. After adjustment, the association between t-PA and vascular death remained (HR per 1 SD increase in plasma level 1.27, 95 % CI 1.00–1.61, p=0.047). The combined effect of t-PA, VWF and fibrinogen was associated with coronary events (adjusted HR 1.35, 1.02–1.80, p=0.04). In non-diabetic patients, an association with coronary events was seen for VWF levels (adjusted HR 2.23, 1.45–3.43, p<0.01). In conclusion, plasma levels of haemostatic factors were associated with vascular death and coronary events, but not with recurrent stroke. Our results suggest that the predictive value of biomarkers differ by specific outcome measure and subgroup of patients.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Cardiovascular diseases - disease-free survival - haemostasis - prognosis - stroke

Full Text

References

References
1 Rutten-Jacobs LC, Maaijwee NA, Arntz RM. et al. Long-term risk of recurrent vascular events after young stroke: The FUTURE study. Ann Neurol 2013; 74: 592-601.
2 Ntaios G, Papavasileiou V, Makaritsis K. et al. Association of ischaemic stroke subtype with long-term cardiovascular events. Eur J Neurol 2014; 21: 1108-1114.
3 Rutten-Jacobs LC, Arntz RM, Maaijwee NA. et al. Cardiovascular disease is the main cause of long-term excess mortality after ischaemic stroke in young adults. Hypertension 2015; 65: 670-675.
4 Rosengren A, Giang KW, Lappas G. et al. Twenty-four-year trends in the incidence of ischaemic stroke in Sweden from 1987 to 2010. Stroke 2013; 44: 2388-2393.
5 Kissela BM, Khoury JC, Alwell K. et al. Age at stroke: temporal trends in stroke incidence in a large, biracial population. Neurology 2012; 79: 1781-1787.
6 Whiteley W, Jackson C, Lewis S. et al. Association of circulating inflammatory markers with recurrent vascular events after stroke: a prospective cohort study. Stroke 2011; 42: 10-16.
7 Di Napoli M, Papa F.. Inflammation, haemostatic markers, and antithrombotic agents in relation to long-term risk of new cardiovascular events in first-ever ischaemic stroke patients. Stroke 2002; 33: 1763-1771.
8 Segal HC, Burgess AI, Poole DL. et al. Population-based study of blood biomarkers in prediction of subacute recurrent stroke. Stroke 2014; 45: 2912-2917.
9 Ridker PM, Hennekens CH, Stampfer MJ. et al. Prospective study of endogenous tissue plasminogen activator and risk of stroke. Lancet 1994; 343: 940-943.
10 Tzoulaki I, Murray GD, Lee AJ. et al. Relative value of inflammatory, haemostatic, and rheological factors for incident myocardial infarction and stroke: the Edinburgh Artery Study. Circulation 2007; 115: 2119-2127.
11 Willeit P, Thompson A, Aspelund T. et al. Haemostatic factors and risk of coronary heart disease in general populations: new prospective study and updated meta-analyses. PloS one 2013; 8: e55175.
12 Danesh J, Lewington S, Thompson SG. et al. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. J Am Med Assoc 2005; 294: 1799-1809.
13 Jood K, Redfors P, Gils A. et al. Convalescent plasma levels of TAFI activation peptide predict death and recurrent vascular events in ischaemic stroke survivors. J Thromb Haemost 2012; 10: 725-727.
14 Jood K, Ladenvall C, Rosengren A. et al. Family history in ischaemic stroke before 70 years of age: The Sahlgrenska academy study on ischaemic stroke. Stroke 2005; 36: 1383-1387.
15 Adams Jr. HP, Bendixen BH, Kappelle LJ. et al. Classification of subtype of acute ischaemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993; 24: 35-41.
16 Jern C, Blomstrand C, Westerlind A.. Evidence of a net release of tissue-type plasminogen activator across the human cerebral vasculature. Thromb Haemost 2004; 91: 1019-1025.
17 Hanson E, Jood K, Karlsson S. et al. Plasma levels of von Willebrand factor in the etiologic subtypes of ischaemic stroke. J Thromb Haemost 2011; 9: 275-281.
18 Ladenvall C, Gils A, Jood K. et al. Thrombin activatable fibrinolysis inhibitor activation peptide shows association with all major subtypes of ischaemic stroke and with TAFI gene variation. Arterioscl Thromb Vasc Biol 2007; 27: 955-962.
19 Jood K, Danielson J, Ladenvall C. et al. Fibrinogen gene variation and ischaemic stroke. J Thromb Haemost 2008; 6: 897-904.
20 Grambsch P, Therneau T.. Proportional hazards tests and diagnostics based on weighted residuals. Biometrika 1994; 81: 515-526.
21 Uno H, Cai T, Pencina MJ. et al. On the C-statistics for evaluating overall adequacy of risk prediction procedures with censored survival data. Stat Med 2011; 30: 1105-1117.
22 Ladenvall C, Jood K, Blomstrand C. et al. Serum C-reactive protein concentration and genotype in relation to ischaemic stroke subtype. Stroke 2006; 37: 2018-2023.
23 Carter AM, Catto AJ, Mansfield MW. et al. Predictive variables for mortality after acute ischaemic stroke. Stroke 2007; 38: 1873-1880.
24 Greisenegger S, Segal HC, Burgess AI. et al. Biomarkers and mortality after transient ischaemic attack and minor ischaemic stroke: population-based study. Stroke 2015; 46: 659-666.
25 Woodward M, Lowe GD, Campbell DJ. et al. Associations of inflammatory and haemostatic variables with the risk of recurrent stroke. Stroke 2005; 36: 2143-2147.
26 Spiel AO, Gilbert JC, Jilma B.. von Willebrand factor in cardiovascular disease: focus on acute coronary syndromes. Circulation 2008; 117: 1449-1459.
27 Rothwell PM, Howard SC, Power DA. et al. Fibrinogen concentration and risk of ischaemic stroke and acute coronary events in 5113 patients with transient ischaemic attack and minor ischaemic stroke. Stroke 2004; 35: 2300-2305.
28 Stegmayr B, Asplund K.. Measuring stroke in the population: quality of routine statistics in comparison with a population-based stroke registry. Neuroepidemiology 1992; 11: 204-213.
29 Hirano K, Takashima S, Dougu N. et al. Study of haemostatic biomarkers in acute ischaemic stroke by clinical subtype. J Stroke Cerebrovasc Dis 2012; 21: 404-410.
30 Jood K, Ladenvall P, Tjarnlund-Wolf A. et al. Fibrinolytic gene polymorphism and ischaemic stroke. Stroke 2005; 36: 2077-2081.
31 Putaala J, Haapaniemi E, Metso AJ. et al. Recurrent ischaemic events in young adults after first-ever ischaemic stroke. Ann Neurol 2010; 68: 661-671.
32 Redfors P, Jood K, Holmegaard L. et al. Stroke subtype predicts outcome in young and middle-aged stroke sufferers. Acta Neurol Scand 2012; 126: 329-335.

Supplementary Material

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