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Thromb Haemost 2020; 120(01): 075-082
DOI: 10.1055/s-0039-1700873
Coagulation and Fibrinolysis
Georg Thieme Verlag KG Stuttgart · New York

Imbalance between Fibrin Clot Formation and Fibrinolysis Predicts Cardiovascular Events in Patients with Stable Coronary Artery Disease

Søs Neergaard-Petersen
1   Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus N, Denmark
2   Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark
,
Sanne B. Larsen
2   Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark
,
Erik L. Grove 
2   Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark
3   Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
,
Steen D. Kristensen
2   Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark
3   Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
,
Ramzi A. Ajjan
4   Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom
,
Anne-Mette Hvas 
1   Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus N, Denmark
3   Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
› Author Affiliations Funding This work was supported by the Danish Agency for Science Technology and Innovation (grant no. 2101–05–0052 to S.D.K.); Novo-Nordic Foundation (grant no. NNF14OC0008817 to S.D.K.); Faculty of Health Sciences, Aarhus University, Denmark; The Danish Heart Foundation; A.P. Møller Foundation; Department of Clinical Medicine, Aarhus University; The Eva and Henry Fraenkel Foundation; The Aase and Ejnar Danielsen Foundation; The Korning Foundation; The Physician's assurance association anno 1891, and The Sophus Jacobsen and Spouse Astrid Jacobsen Foundation. The funding sources had no influence on the study design, collection, analysis or interpretation of the data, writing of the article, or the decision to submit the article for publication.
Further Information

Publication History

13 May 2019

21 September 2019

Publication Date:
16 November 2019 (online)

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Abstract

Background Despite long-term antiplatelet therapy with aspirin, recurrent cardiovascular events remain common in patients with coronary artery disease (CAD).

Objective We aimed to determine whether fibrin network characteristics are predictive of vascular events in patients with stable CAD treated with aspirin monotherapy.

Methods We included 786 patients with angiographically documented CAD and either prior myocardial infarction, type 2 diabetes mellitus, or both. Median follow-up time was 3 years. At inclusion, fibrin clot properties were evaluated using a turbidimetric assay and the following clot parameters were studied: (1) maximum absorbance, a measure of clot density and fiber thickness; (2) lysis time, assessing fibrinolysis potential; and (3) area under the curve (AUC), a measure of clot formation and lysis. The primary endpoint was the composite of nonfatal myocardial infarction, ischemic stroke, and cardiovascular death. Hazard ratios (HRs) were estimated using multivariable Cox proportional hazards regression.

Results A total of 70 primary endpoints occurred. The primary endpoint occurred more frequently in CAD patients with increased clot AUC (crude HR for first vs. fourth quartile: 2.4 [95% confidence interval 1.2–4.6], p = 0.01). This finding remained significant after adjusting for potential confounders (adjusted HR: 2.4 [1.2–4.8], p = 0.01). Neither clot maximum absorbance nor lysis time showed significant association with future vascular events (adjusted HR for maximum absorbance 1.8 [0.9–3.7]; p = 0.09) and lysis time (1.6 [0.8–3.0]; p = 0.18).

Conclusion We demonstrate that increased clot AUC predicts future cardiovascular events in stable CAD patients receiving aspirin monotherapy.

Keywords

aspirin - blood coagulation - fibrin clot - fibrinolysis - coronary artery disease
 

  • References

  • 1 Montalescot G, Sechtem U, Achenbach S. , et al; Task Force Members; ESC Committee for Practice Guidelines; Document Reviewers. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013; 34 (38) 2949-3003
    CrossrefPubMedSearch in Google Scholar
  • 2 Fihn SD, Blankenship JC, Alexander KP. , et al. 2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 2014; 130 (19) 1749-1767
    CrossrefPubMedSearch in Google Scholar
  • 3 Bhatt DL, Eagle KA, Ohman EM. , et al; REACH Registry Investigators. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA 2010; 304 (12) 1350-1357
    CrossrefPubMedSearch in Google Scholar
  • 4 Jernberg T, Hasvold P, Henriksson M, Hjelm H, Thuresson M, Janzon M. Cardiovascular risk in post-myocardial infarction patients: nationwide real world data demonstrate the importance of a long-term perspective. Eur Heart J 2015; 36 (19) 1163-1170
    CrossrefPubMedSearch in Google Scholar
  • 5 Bhatt DL, Flather MD, Hacke W. , et al; CHARISMA Investigators. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol 2007; 49 (19) 1982-1988
    CrossrefPubMedSearch in Google Scholar
  • 6 Bonaca MP, Bhatt DL, Cohen M. , et al; PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015; 372 (19) 1791-1800
    CrossrefPubMedSearch in Google Scholar
  • 7 Rothberg MB, Celestin C, Fiore LD, Lawler E, Cook JR. Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit. Ann Intern Med 2005; 143 (04) 241-250
    PubMedSearch in Google Scholar
  • 8 van Es RF, Jonker JJ, Verheugt FW, Deckers JW, Grobbee DE. ; Antithrombotics in the Secondary Preventionof Events in Coronary Thrombosis-2 (ASPECT-2) Research Group. Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial. Lancet 2002; 360 (9327): 109-113
    CrossrefPubMedSearch in Google Scholar
  • 9 Eikelboom JW, Connolly SJ, Bosch J. , et al; COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017; 377 (14) 1319-1330
    CrossrefPubMedSearch in Google Scholar
  • 10 Fox KAA, Eikelboom JW, Anand SS. , et al. Anti-thrombotic options for secondary prevention in patients with chronic atherosclerotic vascular disease: what does COMPASS add?. Eur Heart J 2019; 40 (18) 1466-1471
    CrossrefPubMedSearch in Google Scholar
  • 11 Okafor ON, Gorog DA. Endogenous fibrinolysis: an important mediator of thrombus formation and cardiovascular risk. J Am Coll Cardiol 2015; 65 (16) 1683-1699
    CrossrefPubMedSearch in Google Scholar
  • 12 Leander K, Blombäck M, Wallén H, He S. Impaired fibrinolytic capacity and increased fibrin formation associate with myocardial infarction. Thromb Haemost 2012; 107 (06) 1092-1099
    Thieme ConnectPubMedSearch in Google Scholar
  • 13 Gremmel T, Ay C, Riedl J. , et al. Platelet-specific markers are associated with monocyte-platelet aggregate formation and thrombin generation potential in advanced atherosclerosis. Thromb Haemost 2016; 115 (03) 615-621
    Thieme ConnectPubMedSearch in Google Scholar
  • 14 Wolberg AS, Campbell RA. Thrombin generation, fibrin clot formation and hemostasis. Transfus Apheresis Sci 2008; 38 (01) 15-23
    CrossrefPubMedSearch in Google Scholar
  • 15 Neergaard-Petersen S, Ajjan R, Hvas AM. , et al. Fibrin clot structure and platelet aggregation in patients with aspirin treatment failure. PLoS One 2013; 8 (08) e71150
    CrossrefPubMedSearch in Google Scholar
  • 16 Undas A, Zalewski J, Krochin M. , et al. Altered plasma fibrin clot properties are associated with in-stent thrombosis. Arterioscler Thromb Vasc Biol 2010; 30 (02) 276-282
    CrossrefPubMedSearch in Google Scholar
  • 17 Collet JP, Allali Y, Lesty C. , et al. Altered fibrin architecture is associated with hypofibrinolysis and premature coronary atherothrombosis. Arterioscler Thromb Vasc Biol 2006; 26 (11) 2567-2573
    CrossrefPubMedSearch in Google Scholar
  • 18 Sumaya W, Wallentin L, James SK. , et al. Fibrin clot properties independently predict adverse clinical outcome following acute coronary syndrome: a PLATO substudy. Eur Heart J 2018; 39 (13) 1078-1085
    CrossrefPubMedSearch in Google Scholar
  • 19 Farag M, Spinthakis N, Gue YX. , et al. Impaired endogenous fibrinolysis in ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention is a predictor of recurrent cardiovascular events: the RISK PPCI study. Eur Heart J 2019; 40 (03) 295-305
    CrossrefPubMedSearch in Google Scholar
  • 20 Schmidt M, Maeng M, Jakobsen CJ. , et al. Existing data sources for clinical epidemiology: the Western Denmark Heart Registry. Clin Epidemiol 2010; 2: 137-144
    Search in Google Scholar
  • 21 Neergaard-Petersen S, Hvas AM, Kristensen SD. , et al. The influence of type 2 diabetes on fibrin clot properties in patients with coronary artery disease. Thromb Haemost 2014; 112 (06) 1142-1150
    Thieme ConnectPubMedSearch in Google Scholar
  • 22 Larsen SB, Grove EL, Neergaard-Petersen S, Würtz M, Hvas AM, Kristensen SD. Reduced antiplatelet effect of aspirin does not predict cardiovascular events in patients with stable coronary artery disease. J Am Heart Assoc 2017; 6 (08) e006050
    PubMedSearch in Google Scholar
  • 23 Carter AM, Cymbalista CM, Spector TD, Grant PJ. ; EuroCLOT Investigators. Heritability of clot formation, morphology, and lysis: the EuroCLOT study. Arterioscler Thromb Vasc Biol 2007; 27 (12) 2783-2789
    CrossrefPubMedSearch in Google Scholar
  • 24 Vibede E, Hvas CL, Tønnesen E, Hvas AM. The effect of fresh frozen plasma in critically ill patients. Acta Anaesthesiol Scand 2017; 61 (05) 492-501
    Search in Google Scholar
  • 25 Fatah K, Hamsten A, Blombäck B, Blombäck M. Fibrin gel network characteristics and coronary heart disease: relations to plasma fibrinogen concentration, acute phase protein, serum lipoproteins and coronary atherosclerosis. Thromb Haemost 1992; 68 (02) 130-135
    Thieme ConnectPubMedSearch in Google Scholar
  • 26 Undas A, Szułdrzynski K, Stepien E. , et al. Reduced clot permeability and susceptibility to lysis in patients with acute coronary syndrome: effects of inflammation and oxidative stress. Atherosclerosis 2008; 196 (02) 551-557
    CrossrefPubMedSearch in Google Scholar
  • 27 Undas A, Ariëns RA. Fibrin clot structure and function: a role in the pathophysiology of arterial and venous thromboembolic diseases. Arterioscler Thromb Vasc Biol 2011; 31 (12) e88-e99
    PubMedSearch in Google Scholar
  • 28 Cilia La Corte AL, Philippou H, Ariëns RA. Role of fibrin structure in thrombosis and vascular disease. Adv Protein Chem Struct Biol 2011; 83: 75-127
    PubMedSearch in Google Scholar
  • 29 Sumaya W, Parker WAE, Fretwell R. , et al. Pharmacodynamic effect of a 6-hour regimen of enoxaparin in patients undergoing primary percutaneous coronary intervention (PENNY PCI Study). Thromb Haemost 2018; 118 (07) 1250-1256
    Thieme ConnectPubMedSearch in Google Scholar
  • 30 Wolberg AS. Thrombin generation and fibrin clot structure. Blood Rev 2007; 21 (03) 131-142
    CrossrefPubMedSearch in Google Scholar
  • 31 Scott EM, Ariëns RA, Grant PJ. Genetic and environmental determinants of fibrin structure and function: relevance to clinical disease. Arterioscler Thromb Vasc Biol 2004; 24 (09) 1558-1566
    CrossrefPubMedSearch in Google Scholar
  • 32 Bochenek M, Zalewski J, Sadowski J, Undas A. Type 2 diabetes as a modifier of fibrin clot properties in patients with coronary artery disease. J Thromb Thrombolysis 2013; 35 (02) 264-270
    CrossrefPubMedSearch in Google Scholar
  • 33 Konieczyńska M, Bryk AH, Malinowski KP, Draga K, Undas A. Interplay between elevated cellular fibronectin and plasma fibrin clot properties in type 2 diabetes. Thromb Haemost 2017; 117 (09) 1671-1678
    Thieme ConnectPubMedSearch in Google Scholar
  • 34 Hvas AM, Favaloro EJ. Gender related issues in thrombosis and hemostasis. Expert Rev Hematol 2017; 10 (11) 941-949
    CrossrefPubMedSearch in Google Scholar
  • 35 Go AS, Mozaffarian D, Roger VL. , et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics--2013 update: a report from the American Heart Association. Circulation 2013; 127 (01) e6-e245
    PubMedSearch in Google Scholar
  • 36 Vaccarino V, Badimon L, Corti R. , et al. Presentation, management, and outcomes of ischaemic heart disease in women. Nat Rev Cardiol 2013; 10 (09) 508-518
    CrossrefPubMedSearch in Google Scholar
  • 37 Siegerink B, Meltzer ME, de Groot PG, Algra A, Lisman T, Rosendaal FR. Clot lysis time and the risk of myocardial infarction and ischaemic stroke in young women; results from the RATIO case-control study. Br J Haematol 2012; 156 (02) 252-258
    CrossrefPubMedSearch in Google Scholar