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Thromb Haemost 2021; 121(05): 584-593
DOI: 10.1055/s-0040-1721146
Coagulation and Fibrinolysis

High Thrombin Generation after Acute Ischemic Stroke or Transient Ischemic Attack Is Associated with a Reduced Risk of Recurrence: An Observational Cohort Study

Annika Lundström
1   Division of Neurology, Department of Clinical Sciences, Danderyd University Hospital, Karolinska Institutet, Stockholm, Sweden
,
Elisabeth Änggårdh-Rooth
1   Division of Neurology, Department of Clinical Sciences, Danderyd University Hospital, Karolinska Institutet, Stockholm, Sweden
,
Fariborz Mobarrez
2   Department of Medical Sciences, Uppsala University, Uppsala, Sweden
,
Charlotte Thålin
3   Division of Internal Medicine, Department of Clinical Sciences, Danderyd University Hospital, Karolinska Institutet, Stockholm, Sweden
,
Bruna Gigante
4   Division of Cardiovascular Medicine, Department of Clinical Sciences, Danderyd University Hospital, Karolinska Institutet, Stockholm, Sweden
5   Division of Cardiovascular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
,
Ann Charlotte Laska
1   Division of Neurology, Department of Clinical Sciences, Danderyd University Hospital, Karolinska Institutet, Stockholm, Sweden
,
Håkan Wallén
4   Division of Cardiovascular Medicine, Department of Clinical Sciences, Danderyd University Hospital, Karolinska Institutet, Stockholm, Sweden
› Author Affiliations Funding This work was partly funded by the Swedish Stroke Association, Karolinska Institutet Coagulation Fund, and the Stockholm Regional Fund for Research, Development, and Education, which is gratefully acknowledged.
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Abstract

Thrombin is increasingly recognized to be of importance for cardiovascular disease. The aim of this study was to investigate the prognostic value of thrombin generation variables in a cohort of patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA). Thrombin generation potential measured by calibrated automated thrombogram (CAT) and prothrombin fragment F1 + 2 was determined in the acute and convalescent phases for a cohort of 190 patients with AIS/TIA. Microvesicle (MV)-induced thrombin generation potential was determined for a subset of patients using modified CAT. Primary outcome was a composite of fatal and nonfatal AIS or myocardial infarction as documented in Swedish registers during a total follow-up of 986 patient-years. Hazard ratios (HRs) were calculated using Cox regression based on variable median split. Peak thrombin and endogenous thrombin potential (ETP) above median in the acute phase were associated with a reduced risk of primary outcome after adjustment for cardiovascular risk factors, HR: 0.50 (0.27–0.92), p = 0.026 and HR: 0.53 (0.28–0.99), p = 0.048, respectively. F1 + 2 was lower in patients than in healthy controls but not associated with outcome. MV-induced peak thrombin above median in the acute phase was associated with recurrent AIS, unadjusted HR: 2.65 (1.03–6.44), p = 0.044. Contrary to expectation, high thrombin generation potential is associated with a reduced risk of recurrent ischemic event in patients with AIS/TIA. Low ETP/peak thrombin combined with high MV-induced peak thrombin can potentially identify patients at high risk of recurrence.

Keywords

thrombin - stroke - prevention

Supplementary Material



Publication History

Received: 10 June 2020

Accepted: 15 October 2020

Article published online:
12 December 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
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  • References

  • 1 Borissoff JI, Spronk HM, Heeneman S, ten Cate H. Is thrombin a key player in the ‘coagulation-atherogenesis’ maze?. Cardiovasc Res 2009; 82 (03) 392-403
    CrossrefPubMedGoogle Scholar
  • 2 Kalz J, ten Cate H, Spronk HM. Thrombin generation and atherosclerosis. J Thromb Thrombolysis 2014; 37 (01) 45-55
    CrossrefPubMedGoogle Scholar
  • 3 Hemker HC, Béguin S. Thrombin generation in plasma: its assessment via the endogenous thrombin potential. Thromb Haemost 1995; 74 (01) 134-138
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Hemker HC, Giesen P, AlDieri R. et al. The calibrated automated thrombogram (CAT): a universal routine test for hyper- and hypocoagulability. Pathophysiol Haemost Thromb 2002; 32 (5–6): 249-253
    CrossrefPubMedGoogle Scholar
  • 5 Ten Cate H, Hemker HC. Thrombin generation and atherothrombosis: what does the evidence indicate?. J Am Heart Assoc 2016; 5 (08) e003553
    CrossrefPubMedGoogle Scholar
  • 6 Sacco RL, Diener HC, Yusuf S. et al. PRoFESS Study Group. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med 2008; 359 (12) 1238-1251
    CrossrefPubMedGoogle Scholar
  • 7 Carcaillon L, Alhenc-Gelas M, Bejot Y. et al. 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; 31 (06) 1445-1451
    CrossrefPubMedGoogle Scholar
  • 8 Loeffen R, Winckers K, Ford I. et al. PROSPER Study Group. Associations between thrombin generation and the risk of cardiovascular disease in elderly patients: results from the PROSPER study. J Gerontol A Biol Sci Med Sci 2015; 70 (08) 982-988
    CrossrefPubMedGoogle Scholar
  • 9 Mohr JP, Thompson JL, Lazar RM. et al. Warfarin-Aspirin Recurrent Stroke Study Group. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001; 345 (20) 1444-1451
    CrossrefPubMedGoogle Scholar
  • 10 Sharma M, Hart RG, Connolly SJ. et al. Stroke outcomes in the COMPASS trial. Circulation 2019; 139 (09) 1134-1145
    CrossrefPubMedGoogle Scholar
  • 11 Rooth E, Sobocinski-Doliwa P, Antovic J. et al. Thrombin generation in acute cardioembolic and non-cardioembolic ischemic stroke. Scand J Clin Lab Invest 2013; 73 (07) 576-584
    CrossrefPubMedGoogle Scholar
  • 12 Doliwa Sobocinski P, Anggårdh Rooth E, Frykman Kull V, von Arbin M, Wallén H, Rosenqvist M. Improved screening for silent atrial fibrillation after ischaemic stroke. Europace 2012; 14 (08) 1112-1116
    CrossrefPubMedGoogle Scholar
  • 13 Lundström A, Mobarrez F, Rooth E. et al. Prognostic value of circulating microvesicle subpopulations in ischemic stroke and TIA. Transl Stroke Res 2020; 11 (04) 708-719
    CrossrefPubMedGoogle Scholar
  • 14 Mobarrez F, He S, Bröijersen A. et al. Atorvastatin reduces thrombin generation and expression of tissue factor, P-selectin and GPIIIa on platelet-derived microparticles in patients with peripheral arterial occlusive disease. Thromb Haemost 2011; 106 (02) 344-352
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Gremmel T, Koppensteiner R, Ay C, Panzer S. Residual thrombin generation potential is inversely linked to the occurrence of atherothrombotic events in patients with peripheral arterial disease. Eur J Clin Invest 2014; 44 (03) 319-324
    CrossrefPubMedGoogle Scholar
  • 16 Hansen CH, Ritschel V, Andersen GO. et al. Markers of thrombin generation are associated with long-term clinical outcome in patients with ST-segment elevation myocardial infarction. Clin Appl Thromb Hemost 2018; 24 (07) 1088-1094
    CrossrefPubMedGoogle Scholar
  • 17 Christersson C, Lindahl B, Berglund L, Siegbahn A, Oldgren J. The utility of coagulation activity for prediction of risk of mortality and cardiovascular events in guideline-treated myocardial infarction patients. Ups J Med Sci 2017; 122 (04) 224-233
    CrossrefPubMedGoogle Scholar
  • 18 Smid M, Dielis AW, Winkens M. et al. Thrombin generation in patients with a first acute myocardial infarction. J Thromb Haemost 2011; 9 (03) 450-456
    CrossrefPubMedGoogle Scholar
  • 19 Fisher MJ. Brain regulation of thrombosis and hemostasis: from theory to practice. Stroke 2013; 44 (11) 3275-3285
    CrossrefPubMedGoogle Scholar
  • 20 Badr Eslam R, Posch F, Lang IM. et al. Association of thrombin generation potential with platelet PAR-1 regulation and P-selectin expression in patients on dual antiplatelet therapy. J Cardiovasc Transl Res 2014; 7 (01) 126-132
    CrossrefPubMedGoogle Scholar
  • 21 Hellum M, Franco-Lie I, Øvstebø R, Hauge T, Henriksson CE. The effect of corn trypsin inhibitor, anti-tissue factor pathway inhibitor antibodies and phospholipids on microvesicle-associated thrombin generation in patients with pancreatic cancer and healthy controls. PLoS One 2017; 12 (09) e0184579
    CrossrefPubMedGoogle Scholar