Increased von Willebrand factor, P-selectin and fibrin content in occlusive thrombus resistant to lytic therapy

Antonia Sambola; Bruno García Del Blanco; Marisol Ruiz-Meana; Jaume Francisco; José A. Barrabés; Jaume Figueras; Jordi Bañeras; Imanol Otaegui; Angeles Rojas; Úrsula Vilardosa; Joan Montaner; David García-Dorado

doi:10.1160/TH15-12-0985

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2016; 115(06): 1129-1137
DOI: 10.1160/TH15-12-0985

Coagulation and Fibrinolysis

Schattauer GmbH

Increased von Willebrand factor, P-selectin and fibrin content in occlusive thrombus resistant to lytic therapy

Antonia Sambola

¹Department of Cardiology, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

,

Bruno García Del Blanco

¹Department of Cardiology, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

,

Marisol Ruiz-Meana

²Experimental Cardiocirculatory Pathology Laboratory, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

,

Jaume Francisco

¹Department of Cardiology, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

,

José A. Barrabés

¹Department of Cardiology, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

,

Jaume Figueras

¹Department of Cardiology, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

,

Jordi Bañeras

¹Department of Cardiology, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

,

Imanol Otaegui

¹Department of Cardiology, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

,

Angeles Rojas

²Experimental Cardiocirculatory Pathology Laboratory, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

,

Úrsula Vilardosa

²Experimental Cardiocirculatory Pathology Laboratory, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

,

Joan Montaner

³Neurovascular Research Laboratory, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

,

David García-Dorado

¹Department of Cardiology, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

²Experimental Cardiocirculatory Pathology Laboratory, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

› Author Affiliations

Abstract

Summary

Therapeutic fibrinolysis is ineffective in 40 % of ST-segment elevation acute myocardial infarction (STEMI) patients, but understanding of the mechanisms is incomplete. It was our aim to compare the composition of coronary thrombus in lysis-resistant STEMI patients with that of lysis-sensitive patients. Intracoronary thrombi (n=64) were obtained by aspiration in consecutive STEMI patients. Of them, 20 had received fibrinolysis and underwent rescue percutaneous coronary intervention (r-PCI, lysis-resistant patients) and 44 underwent primary PCI (p-PCI). Lysis-sensitivity was determined in vitro by clot permeability measurements and turbidimetric lysis in plasma of 44 patients undergoing p-PCI and 20 healthy donors. Clot-lysis sensitivity was defined as a clot-lysis time not greater than 1 SD over the mean of healthy donors. Coronary thrombus composition in 20 lysis-resistant and in 20 lysissensitive patients was analysed by immunofluorescence with confocal microscopy. Plasma biomarkers (P-selectin, VWF, PAI-1, t-PA, D-dimer, TF pathway markers, plasmin and CD34⁺) were measured simultaneously on peripheral blood. Lysis-resistant clots had higher levels of fibrin (p=0.02), P-selectin (p=0.03) and VWF (p=0.01) than lysis-sensitive clots. Among thrombi obtained ≤ 6 hours after onset of symptoms, those from lysis-resistant patients showed a higher content in fibrin than those from p-PCI patients (p=0.01). Plasma PAI-1 (p=0.02) and D-dimer levels were significantly higher (p=0.003) in lysis-resistant patients, whereas plasmin levels were lower (p=0.03). Multivariate analysis showed the content of fibrin and VWF within thrombus as predictors of thrombolysis resistance. In conclusion, coronary thrombi in STEMI patients resistant to fibrinolysis are characterised by higher fibrin, P-selectin and VWF content than lysis-sensitive thrombi.

Keywords

Clot structure - coronary syndrome - fibrin - fibrinolytic disorders - von Willebrand factor

Full Text

References

References
1 O’Gara PT, Kushner FG, Ascheim DD. et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013; 127: e362-425.
2 Windecker S, Kolh P, Alfonso F. et al. 2014 ESC/EACTS Guidelines on myocardial revascularisation: The Task Force on Myocardial Revascularisation of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014; 35: 2541-2619.
3 Eagle KA, Goodman SG, Avezum A. et al. Practice variation and missed opportunities for reperfusion in ST-segment-elevation myocardial infarction: findings from the Global Registry of Acute Coronary Events (GRACE). Lancet 2002; 359: 373-377.
4 Gershlick AH, Stephens-Lloyd A, Hughes S. et al. REACT Trial Investigators. Rescue angioplasty after failed thrombolytic therapy for acute myocardial infarction. N Engl J Med 2005; 353: 2758-2768.
5 Svilaas T, Vlaar PJ, van der Horst IC. et al. Clot aspiration during primary percutaneous coronary intervention. N Engl J Med 2008; 358: 557-567.
6 Fuster V, Badimon L, Badimon JJ. et al. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992; 326: 242-250.
7 Savage B, Jacobs F, Ruggeri F. Specific synergy of multiple substrate-receptor interactions in platelet clot formation under flow. Cell 1998; 94: 657-666.
8 Carter A, Cymbalista Ch, Spector T. et al. Grant, on behalf of the EuroCLOT Investigators. Heritability of Clot Formation, Morphology, and Fibrinolysis The EuroCLOT Study. Arterioscler Thromb Vasc Biol 2007; 27: 2783-2789.
9 Thygesen K, Alpert JS, Jaffe AS. et al. Third universal definition of myocardial infarction. Circulation 2012; 126: 2020-2035.
10 Sambola A, García Del Blanco B, Francisco J. et al. Prognostic impact of tissue factor pathway on long-term ischemic events of ST-elevated myocardial infarction treated with a primary percutaneous coronary intervention. Int J Cardiol 2013; 168: 2916-2918.
11 Monasterio J, Bermúdez P, Quiroga D. et al. Plasma thrombin-activable fibrinolytic inhibitor (TAFI) among healthy subjects and patients with vascular diseases: a validation study. Pathophysiol Haemost Thromb 2004; 33: 382-387.
12 Cocho D, Borrell M, Martí-Fàbregas J. et al. Pretreatment Hemostatic Markers of Symptomatic Intracerebral Hemorrhage in Patients Treated With Tissue Plasminogen Activator. Stroke 2006; 37: 996-999.
13 Kristensen SD, Laut KG, Fajadet J. et al. Reperfusion therapy for ST elevation acute myocardial infarction. 2010/2011: current status in 37 ESC countries. Eur Heart J 2014; 35: 1957-1970.
14 Yamashita A, Sumi T, Goto S. et al. Detection of Von Willebrand factor and tissue factor in platelets-fibrin rich coronary thrombi in acute myocardial infarction. Am J Cardiol 2006; 97: 26-28.
15 Hoshiba Y, Hatakeyama K, Tanabe T. et al. Co-localisation of von Willebrand factor with platelet thrombi, tissue factor and platelets with fibrin, and consistent presence of inflammatory cells in coronary thrombi obtained by an aspiration device from patients with acute myocardial infarction. J Thromb Haemost 2006; 04: 114-120.
16 Sato Y, Hatakeyama K, Yamashita A. et al. Proportion of fibrin and platelets differs in thrombi on ruptured and eroded coronary atherosclerotic plaques in humans. Heart 2005; 91: 526-530.
17 Zalewski J, Undas A, Godlewski J. et al. No-Reflow Phenomenon After Acute Myocardial Infarction Is Associated With Reduced Clot Permeability and Susceptibility to Lysis. Arterioscler Thromb Vasc Biol 2007; 27: 2258-2265.
18 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: 278-282.
19 Neergaard-Petersen S, Ajjan R, Hvas AM. et al. Fibrin clot structure and platelet aggregation in patients with aspirin treatment failure. PloS One 2013; 08: e71150.
20 Lu D, Owens J, Kreutz RP. Plasma and whole blood clot strength measured by thrombelastography in patients treated with clopidogrel during acute coronary syndromes. Thromb Res 2013; 132: e94-98.
21 Patel R, Li Q, Ghasemzadeh N. et al. Circulating CD34+ Progenitor Cells and Risk of Mortality in a Population with Coronary Artery Disease. Circ Research 2016; 116: 289-297.
22 Barba I, Garcia del Blanco B, Abdul-Jawad O. et al. MRI discriminates thrombus composition and ST resolution after percutaneous coronary intervention in patients with ST-elevation myocardial infarction. PLoS One 2011; 06: e18459.
23 Silvain J, Collet JP, Nagaswami C. et al. Composition of coronary thrombus in acute myocardial infarction. J Am Coll Cardiol 2011; 22: 1359-1367.
24 Ramaiola I, Padro T, Peña E. et al. Changes in clot composition and profilin-1 release in acute myocardial infarction. Eur Heart J 2015; 36: 965-975.
25 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: 551-557.
26 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: 2567-2573.
27 Undas A, Podolec P, Zawilska K. et al. Altered fibrin clot structure/function in patients with cryptogenic ischemic stroke. Stroke 2009; 40: 1499-501. 28. Empana JP, Canoui-Poitrine F, Luc G, et al. PRIME Study Group. Contribution of novel biomarkers to incident stable angina and acute coronary syndrome: the PRIME study. Eur Heart J 2008; 29: 1966–1974.
28 Gorog D. Prognostic Value of Plasma fibrinolysis Activation Markers in Cardiovascular Disease. J Am Coll Cardiol 2010; 55: 2701-2709.
29 May M, Lawlor DA, Patel R. et al. Associations of von Willebrand factor, fibrin, D-dimer and tissue plasminogen activator with incident coronary heart disease: British Women’s Heart and Health cohort study. Eur J Cardiovasc Prev Rehabil 2007; 14: 638-645.
30 Mutch NJ, Thomas L, Moore NR. et al. TAFIa, PAI-1 and alpha-antiplasmin: complementary roles in regulating fibrinolysis of thrombi and plasma clots. J Thromb Haemost 2007; 05: 812-817.
31 Sambola A, Francisco J, García-Del Blanco B. et al. Tissue factor pathway inhibitor is an early biomarker of myocardial injury in patients with ST-segment elevation acute myocardial infarction. Int J Cardiol 2014; 172: 279-281.
32 Sgueglia GA, Niccoli G, Spaziani C. et al. Baseline von Willebrand factor plasma levels and no-reflow phenomenon after primary percutaneous coronary intervention for ST segment elevation myocardial infarction. Int J Cardiol 2010; 145: 230-232.
33 Lee KW, Blann AD, Lip G. Plasma markers of endothelial damage/dysfunction, inflammation and thrombogenesis in relation to TIMI risk stratification in acute coronary syndromes. Thromb Haemost 2005; 94: 1077-1083.
34 Hunt J, Petteway Jr S, Scuderi Ph. et al. Simplified recombinant plasmin: Production and functional comparison of a novel thrombolytic molecule with plasma-derived plasmin. Thromb Haemost 2008; 100: 413-419.
35 Leander K, Blombäck K, Wallén H. et al. Impaired fibrinolytic capacity and increased fibrin formation associate with myocardial infarction. Thromb Haemost 2012; 107: 1092-1099.
36 Ribo M, Montaner J, Molina C. et al. Admission fibrinolytic profile predicts clot lysis resistance in stroke patients treated with tissue plasminogen activator. Thromb Haemost 2004; 91: 1146-1151.
37 Georgieva AM, Cate HT, Keulen ET. et al. Prothrombotic markers in familial combined hyperlipidemia: evidence of endothelial cell activation and relation to metabolic syndrome. Atherosclerosis 2004; 175: 345-351.