Thromb Haemost 2020; 120(04): 538-564
DOI: 10.1055/s-0040-1708035
Position Paper
Georg Thieme Verlag KG Stuttgart · New York

Thrombo-Inflammation in Cardiovascular Disease: An Expert Consensus Document from the Third Maastricht Consensus Conference on Thrombosis

Elisa d’Alessandro
1   Laboratory for Clinical Thrombosis and Hemostasis, Department of Biochemistry and Internal Medicine and Thrombosis Expert Center, Maastricht University Medical Center and CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
,
Christian Becker
2   Department of Dermatology, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany
,
Wolfgang Bergmeier
3   Department of Biochemistry and Biophysics, McAllister Heart Institute, University of North Carolina, Chapel Hill, United States
,
Christoph Bode
4   Department of Cardiology and Angiology I, Medical Center - University of Freiburg, University Heart Center Freiburg, Bad Krozingen, Germany
,
Joshua H. Bourne
5   Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
,
Helena Brown
6   Rudolf-Virchov-Zentrum, DFG Forschungszentrum fur Experimentelle Biomedizin, Wurzburg, Germany
,
Harry R. Buller
7   Department of Vascular Medicine, Amsterdam University Medical Center, Amsterdam, The Netherlands
,
Arina J. ten Cate-Hoek
1   Laboratory for Clinical Thrombosis and Hemostasis, Department of Biochemistry and Internal Medicine and Thrombosis Expert Center, Maastricht University Medical Center and CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
,
Vincent ten Cate
8   Clinical Epidemiology and Systems Medicine, Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
,
Yvonne J. M. van Cauteren
9   Department of Cardiology, Maastricht University Medical Center and CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
,
Yam F. H. Cheung
10   Leibniz-Institut für Analytische Wissenschaften – ISAS, Dortmund, Germany
,
Audrey Cleuren
11   Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, United States
,
Danielle Coenen
12   Department of Biochemistry, Maastricht University and CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
,
Harry J. G. M. Crijns
9   Department of Cardiology, Maastricht University Medical Center and CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
,
Ilaria de Simone
12   Department of Biochemistry, Maastricht University and CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
,
Sophie C. Dolleman
13   Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Experimental Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
,
Christine Espinola Klein
14   Center of Cardiology/Cardiology I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
,
Delia I. Fernandez
12   Department of Biochemistry, Maastricht University and CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
,
Lianne Granneman
15   Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands
,
Arnoud van t Hof
9   Department of Cardiology, Maastricht University Medical Center and CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
,
Peter Henke
16   Michigan Medicine Vascular Surgery Clinic, Cardiovascular Center, Ann Arbor, Michigan, United States
,
Yvonne M. C. Henskens
17   Central Diagnostic Laboratory, Maastricht University Medical Center and CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
,
Jingnan Huang
12   Department of Biochemistry, Maastricht University and CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
,
Lisa K. Jennings
18   CirQuest Labs, LLC and the University of Tennessee Health Science Center, Memphis, Tennessee, United States
,
Natalie Jooss
12   Department of Biochemistry, Maastricht University and CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
,
Mieke Karel
12   Department of Biochemistry, Maastricht University and CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
,
Danique van den Kerkhof
12   Department of Biochemistry, Maastricht University and CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
,
Frederik A. Klok
19   Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands
,
Bram Kremers
1   Laboratory for Clinical Thrombosis and Hemostasis, Department of Biochemistry and Internal Medicine and Thrombosis Expert Center, Maastricht University Medical Center and CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
,
Bernhard Lämmle
20   Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany; Haemostasis Research Unit, University College London, London, United Kingdom
,
Avi Leader
1   Laboratory for Clinical Thrombosis and Hemostasis, Department of Biochemistry and Internal Medicine and Thrombosis Expert Center, Maastricht University Medical Center and CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
21   Department of Hematology, Rabin Medical Center, Petah Tikva, Israel
,
Annika Lundstrom
22   Division of Internal Medicine, Department of Clinical Sciences, Karolinska Institute, Danderyd Hospital, Stockholm, Sweden
,
Nigel Mackman
23   Department of Medicine, UNC McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina, United States
,
Pier M. Mannucci
24   Scientific Direction, IRCCS Ca' Granda Maggiore Policlinico Hospital Foundation, Milano, Italy
,
Zahra Maqsood
6   Rudolf-Virchov-Zentrum, DFG Forschungszentrum fur Experimentelle Biomedizin, Wurzburg, Germany
,
Paola E. J. van der Meijden
1   Laboratory for Clinical Thrombosis and Hemostasis, Department of Biochemistry and Internal Medicine and Thrombosis Expert Center, Maastricht University Medical Center and CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
12   Department of Biochemistry, Maastricht University and CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
,
Marc van Moorsel
15   Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands
,
Luis A. Moran
25   CiMUS, University of Santiago de Compostela, Santiago de Compostela, Spain
,
John Morser
26   Division of Hematology, Stanford University School of Medicine and Palo Alto Veterans Administration Health Care System, California, United States
,
Manouk van Mourik
9   Department of Cardiology, Maastricht University Medical Center and CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
,
Stefano Navarro
6   Rudolf-Virchov-Zentrum, DFG Forschungszentrum fur Experimentelle Biomedizin, Wurzburg, Germany
,
Raluca A. I. Neagoe
5   Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
,
Renske H. Olie
1   Laboratory for Clinical Thrombosis and Hemostasis, Department of Biochemistry and Internal Medicine and Thrombosis Expert Center, Maastricht University Medical Center and CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
,
Pauline van Paridon
1   Laboratory for Clinical Thrombosis and Hemostasis, Department of Biochemistry and Internal Medicine and Thrombosis Expert Center, Maastricht University Medical Center and CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
,
Jens Posma
1   Laboratory for Clinical Thrombosis and Hemostasis, Department of Biochemistry and Internal Medicine and Thrombosis Expert Center, Maastricht University Medical Center and CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
,
Isabella Provenzale
12   Department of Biochemistry, Maastricht University and CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
,
Pieter H. Reitsma
13   Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Experimental Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
,
Billy Scaf
1   Laboratory for Clinical Thrombosis and Hemostasis, Department of Biochemistry and Internal Medicine and Thrombosis Expert Center, Maastricht University Medical Center and CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
,
Leon Schurgers
12   Department of Biochemistry, Maastricht University and CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
,
Jaap Seelig
1   Laboratory for Clinical Thrombosis and Hemostasis, Department of Biochemistry and Internal Medicine and Thrombosis Expert Center, Maastricht University Medical Center and CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
27   Department of Cardiology, Rijnstate ziekenhuis, Arnhem, The Netherlands
,
Agneta Siegbahn
28   Department of Medical Sciences, Clinical Chemistry and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
,
Bob Siegerink
29   Center for Stroke research Berlin, Charité Universitätamedizin, Berlin, Germany
,
Oliver Soehnlein
30   Institute for Cardiovascular Prevention, Ludwig Maximilian University Munich, Munich, Germany
,
Eva Maria Soriano
31   Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading, United Kingdom
,
Marcin A. Sowa
31   Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading, United Kingdom
,
Henri M. H. Spronk
1   Laboratory for Clinical Thrombosis and Hemostasis, Department of Biochemistry and Internal Medicine and Thrombosis Expert Center, Maastricht University Medical Center and CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
,
Robert F. Storey
32   Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
,
Chukiat Tantiwong
12   Department of Biochemistry, Maastricht University and CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
,
Alicia Veninga
12   Department of Biochemistry, Maastricht University and CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
,
Xueqing Wang
5   Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
,
Steve P. Watson
5   Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
,
Jeff Weitz
33   Division of Hematology and Thromboembolism, Department of Medicine and Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
,
Sacha S. Zeerleder
34   Department of Haematology and Central Haematology Laboratory, Inselspital, Bern University Hospital, University of Bern, and Department for BioMedical Research, University of Bern, Bern, Switzerland
,
Hugo ten Cate
1   Laboratory for Clinical Thrombosis and Hemostasis, Department of Biochemistry and Internal Medicine and Thrombosis Expert Center, Maastricht University Medical Center and CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
,
Scientific Reviewer Committee
› Author Affiliations
Funding This project has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement number 766118.” E.D., S.C.D., and B.S. are supported by a grant from the Netherlands Heart Foundation (CVON2014–09, RACE V, reappraisal of AF: interaction between hypercoagulability, electrical remodeling, and vascular destabilization in the progression of AF).
Further Information

Publication History

25 September 2019

22 January 2020

Publication Date:
14 April 2020 (online)

Abstract

Thrombo-inflammation describes the complex interplay between blood coagulation and inflammation that plays a critical role in cardiovascular diseases. The third Maastricht Consensus Conference on Thrombosis assembled basic, translational, and clinical scientists to discuss the origin and potential consequences of thrombo-inflammation in the etiology, diagnostics, and management of patients with cardiovascular disease, including myocardial infarction, stroke, and peripheral artery disease. This article presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following topics: (1) challenges of the endothelial cell barrier; (2) circulating cells and thrombo-inflammation, focused on platelets, neutrophils, and neutrophil extracellular traps; (3) procoagulant mechanisms; (4) arterial vascular changes in atherogenesis; attenuating atherosclerosis and ischemia/reperfusion injury; (5) management of patients with arterial vascular disease; and (6) pathogenesis of venous thrombosis and late consequences of venous thromboembolism.

 
  • References

  • 1 Jackson SP, Darbousset R, Schoenwaelder SM. Thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms. Blood 2019; 133 (09) 906-918
  • 2 Spronk HMH, Padro T, Siland JE. , et al. Atherothrombosis and thromboembolism: position paper from the Second Maastricht Consensus Conference on Thrombosis. Thromb Haemost 2018; 118 (02) 229-250
  • 3 Mozaffarian D, Wilson PW, Kannel WB. Beyond established and novel risk factors: lifestyle risk factors for cardiovascular disease. Circulation 2008; 117 (23) 3031-3038
  • 4 Lelieveld J, Münzel T. Air pollution, chronic smoking, and mortality. Eur Heart J 2019; 40 (38) 3204
  • 5 Mannucci PM, Harari S, Franchini M. Novel evidence for a greater burden of ambient air pollution on cardiovascular disease. Haematologica 2019; 104 (12) 2349-2357
  • 6 Finch J, Conklin DJ. Air pollution-induced vascular dysfunction: potential role of endothelin-1 (ET-1) system. Cardiovasc Toxicol 2016; 16 (03) 260-275
  • 7 Rudez G, Janssen NA, Kilinc E. , et al. Effects of ambient air pollution on hemostasis and inflammation. Environ Health Perspect 2009; 117 (06) 995-1001
  • 8 Varela-Carver A, Parker H, Kleinert C, Rimoldi O. Adverse effects of cigarette smoke and induction of oxidative stress in cardiomyocytes and vascular endothelium. Curr Pharm Des 2010; 16 (23) 2551-2558
  • 9 Miller MR, Shaw CA, Langrish JP. From particles to patients: oxidative stress and the cardiovascular effects of air pollution. Future Cardiol 2012; 8 (04) 577-602
  • 10 Kilinç E, Van Oerle R, Borissoff JI. , et al. Factor XII activation is essential to sustain the procoagulant effects of particulate matter. J Thromb Haemost 2011; 9 (07) 1359-1367
  • 11 Shapiro NI, Aird WC. Sepsis and the broken endothelium. Crit Care 2011; 15 (02) 135
  • 12 Sanz E, Yang L, Su T, Morris DR, McKnight GS, Amieux PS. Cell-type-specific isolation of ribosome-associated mRNA from complex tissues. Proc Natl Acad Sci U S A 2009; 106 (33) 13939-13944
  • 13 Everett LA, Cleuren AC, Khoriaty RN, Ginsburg D. Murine coagulation factor VIII is synthesized in endothelial cells. Blood 2014; 123 (24) 3697-3705
  • 14 Cleuren ACA, van der Ent MA, Jiang H. , et al. The in vivo endothelial cell translatome is highly heterogeneous across vascular beds. Proc Natl Acad Sci U S A 2019; 116 (47) 23618-23624
  • 15 von Drygalski A, Furlan-Freguia C, Ruf W, Griffin JH, Mosnier LO. Organ-specific protection against lipopolysaccharide-induced vascular leak is dependent on the endothelial protein C receptor. Arterioscler Thromb Vasc Biol 2013; 33 (04) 769-776
  • 16 Ziedins K, Mann K. Molecular Basis of Blood Coagulation. 2018: 1885-1905.e8 . Available at: https://www.ncbi.nlm.nih.gov/pubmed/3286010 . Accessed February 14, 2020
  • 17 Fujiwara A, Taguchi O, Takagi T. , et al. Role of thrombi n-activatable fibrinolysis inhibitor in allergic bronchial asthma. Lung 2012; 190 (02) 189-198
  • 18 Morser J, Gabazza EC, Myles T, Leung LL. What has been learnt from the thrombin-activatable fibrinolysis inhibitor-deficient mouse?. J Thromb Haemost 2010; 8 (05) 868-876
  • 19 Myles T, Nishimura T, Yun TH. , et al. Thrombin activatable fibrinolysis inhibitor, a potential regulator of vascular inflammation. J Biol Chem 2003; 278 (51) 51059-51067
  • 20 Shao Z, Nishimura T, Leung LL, Morser J. Carboxypeptidase B2 deficiency reveals opposite effects of complement C3a and C5a in a murine polymicrobial sepsis model. J Thromb Haemost 2015; 13 (06) 1090-1102
  • 21 Naito M, Taguchi O, Kobayashi T. , et al. Thrombin-activatable fibrinolysis inhibitor protects against acute lung injury by inhibiting the complement system. Am J Respir Cell Mol Biol 2013; 49 (04) 646-653
  • 22 Nishimura T, Myles T, Piliponsky AM, Kao PN, Berry GJ, Leung LL. Thrombin-activatable procarboxypeptidase B regulates activated complement C5a in vivo. Blood 2007; 109 (05) 1992-1997
  • 23 Relja B, Lustenberger T, Puttkammer B. , et al. Thrombin-activatable fibrinolysis inhibitor (TAFI) is enhanced in major trauma patients without infectious complications. Immunobiology 2013; 218 (04) 470-476
  • 24 Renckens R, Roelofs JJ, ter Horst SA. , et al. Absence of thrombin-activatable fibrinolysis inhibitor protects against sepsis-induced liver injury in mice. J Immunol 2005; 175 (10) 6764-6771
  • 25 Satoh T, Satoh K, Yaoita N. , et al. Activated TAFI promotes the development of chronic thromboembolic pulmonary hypertension: a possible novel therapeutic target. Circ Res 2017; 120 (08) 1246-1262
  • 26 Song JJ, Hwang I, Cho KH. , et al; Consortium for the Longitudinal Evaluation of African Americans with Early Rheumatoid Arthritis (CLEAR) Registry. Plasma carboxypeptidase B downregulates inflammatory responses in autoimmune arthritis. J Clin Invest 2011; 121 (09) 3517-3527
  • 27 Ono N, Nakashima K, Rittling SR. , et al. Osteopontin negatively regulates parathyroid hormone receptor signaling in osteoblasts. J Biol Chem 2008; 283 (28) 19400-19409
  • 28 Shao Z, Morser J, Leung LL. Thrombin cleavage of osteopontin disrupts a pro-chemotactic sequence for dendritic cells, which is compensated by the release of its pro-chemotactic C-terminal fragment. J Biol Chem 2014; 289 (39) 27146-27158
  • 29 Ge X, Yamaguchi Y, Zhao L. , et al. Prochemerin cleavage by factor XIa links coagulation and inflammation. Blood 2018; 131 (03) 353-364
  • 30 Du XY, Zabel BA, Myles T. , et al. Regulation of chemerin bioactivity by plasma carboxypeptidase N, carboxypeptidase B (activated thrombin-activable fibrinolysis inhibitor), and platelets. J Biol Chem 2009; 284 (02) 751-758
  • 31 Leung LLK, Morser J. Carboxypeptidase B2 and carboxypeptidase N in the crosstalk between coagulation, thrombosis, inflammation, and innate immunity. J Thromb Haemost 2018 Doi: 10.1111/jth.14199
  • 32 Kremer Hovinga JA, Coppo P, Lämmle B, Moake JL, Miyata T, Vanhoorelbeke K. Thrombotic thrombocytopenic purpura. Nat Rev Dis Primers 2017; 3: 17020
  • 33 Saha M, McDaniel JK, Zheng XL. Thrombotic thrombocytopenic purpura: pathogenesis, diagnosis and potential novel therapeutics. J Thromb Haemost 2017; 15 (10) 1889-1900
  • 34 Rock GA, Shumak KH, Buskard NA. , et al; Canadian Apheresis Study Group. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. N Engl J Med 1991; 325 (06) 393-397
  • 35 Fuchs TA, Kremer Hovinga JA, Schatzberg D, Wagner DD, Lämmle B. Circulating DNA and myeloperoxidase indicate disease activity in patients with thrombotic microangiopathies. Blood 2012; 120 (06) 1157-1164
  • 36 Deford CC, Reese JA, Schwartz LH. , et al. Multiple major morbidities and increased mortality during long-term follow-up after recovery from thrombotic thrombocytopenic purpura. Blood 2013; 122 (12) 2023-2029
  • 37 Falter T, Schmitt V, Herold S. , et al. Depression and cognitive deficits as long-term consequences of thrombotic thrombocytopenic purpura. Transfusion 2017; 57 (05) 1152-1162
  • 38 Roose E, Schelpe AS, Joly BS. , et al. An open conformation of ADAMTS-13 is a hallmark of acute acquired thrombotic thrombocytopenic purpura. J Thromb Haemost 2018; 16 (02) 378-388
  • 39 Masias C, Cataland SR. Novel therapies in thrombotic thrombocytopenic purpura. Res Pract Thromb Haemost 2017; 2 (01) 19-26
  • 40 Scully M, Cataland SR, Peyvandi F. , et al. Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura. New Engl J Med 2019; 380 (04) 335-346
  • 41 Coppo P, Froissart A. ; French Reference Center for Thrombotic Microangiopathies. Treatment of thrombotic thrombocytopenic purpura beyond therapeutic plasma exchange. Hematology (Am Soc Hematol Educ Program) 2015; 2015: 637-643
  • 42 Scully M, Knöbl P, Kentouche K. , et al. Recombinant ADAMTS-13: first-in-human pharmacokinetics and safety in congenital thrombotic thrombocytopenic purpura. Blood 2017; 130 (19) 2055-2063
  • 43 Alshehri OM, Hughes CE, Montague S. , et al. Fibrin activates GPVI in human and mouse platelets. Blood 2015; 126 (13) 1601-1608
  • 44 Mammadova-Bach E, Ollivier V, Loyau S. , et al. Platelet glycoprotein VI binds to polymerized fibrin and promotes thrombin generation. Blood 2015; 126 (05) 683-691
  • 45 Onselaer MB, Hardy AT, Wilson C. , et al. Fibrin and D-dimer bind to monomeric GPVI. Blood Adv 2017; 1 (19) 1495-1504
  • 46 Slater A, Perrella G, Onselaer MB. , et al. Does fibrin(ogen) bind to monomeric or dimeric GPVI, or not at all?. Platelets 2019; 30 (03) 281-289
  • 47 Voors-Pette C, Lebozec K, Dogterom P. , et al. Safety and tolerability, pharmacokinetics, and pharmacodynamics of ACT017, an antiplatelet GPVI (glycoprotein VI) Fab. Arterioscler Thromb Vasc Biol 2019; 39 (05) 956-964
  • 48 Bergmeier W, Stefanini L. Platelets at the vascular interface. Res Pract Thromb Haemost 2018; 2 (01) 27-33
  • 49 Stefanini L, Bergmeier W. RAP GTPases and platelet integrin signaling. Platelets 2019; 30 (01) 41-47
  • 50 Cook AA, Deng W, Ren J, Li R, Sondek J, Bergmeier W. Calcium-induced structural rearrangements release autoinhibition in the Rap-GEF CalDAG-GEFI. J Biol Chem 2018; 293 (22) 8521-8529
  • 51 Stefanini L, Paul DS, Robledo RF. , et al. RASA3 is a critical inhibitor of RAP1-dependent platelet activation. J Clin Invest 2015; 125 (04) 1419-1432
  • 52 Su W, Wynne J, Pinheiro EM. , et al. Rap1 and its effector RIAM are required for lymphocyte trafficking. Blood 2015; 126 (25) 2695-2703
  • 53 Stritt S, Wolf K, Lorenz V. , et al. Rap1-GTP-interacting adaptor molecule (RIAM) is dispensable for platelet integrin activation and function in mice. Blood 2015; 125 (02) 219-222
  • 54 Lagarrigue F, Gingras AR, Paul DS. , et al. Rap1 binding to the talin 1 F0 domain makes a minimal contribution to murine platelet GPIIb-IIIa activation. Blood Adv 2018; 2 (18) 2358-2368
  • 55 Gingras AR, Lagarrigue F, Cuevas MN. , et al. Rap1 binding and a lipid-dependent helix in talin F1 domain promote integrin activation in tandem. J Cell Biol 2019; 218 (06) 1799-1809
  • 56 Bromberger T, Klapproth S, Rohwedder I. , et al. Direct Rap1/Talin1 interaction regulates platelet and neutrophil integrin activity in mice. Blood 2018; 132 (26) 2754-2762
  • 57 Soehnlein O, Steffens S, Hidalgo A, Weber C. Neutrophils as protagonists and targets in chronic inflammation. Nat Rev Immunol 2017; 17 (04) 248-261
  • 58 Drechsler M, Megens RT, van Zandvoort M, Weber C, Soehnlein O. Hyperlipidemia-triggered neutrophilia promotes early atherosclerosis. Circulation 2010; 122 (18) 1837-1845
  • 59 Döring Y, Drechsler M, Wantha S. , et al. Lack of neutrophil-derived CRAMP reduces atherosclerosis in mice. Circ Res 2012; 110 (08) 1052-1056
  • 60 Koenen RR, von Hundelshausen P, Nesmelova IV. , et al. Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice. Nat Med 2009; 15 (01) 97-103
  • 61 von Hundelshausen P, Agten SM, Eckardt V. , et al. Chemokine interactome mapping enables tailored intervention in acute and chronic inflammation. Sci Transl Med 2017; 9 (384) eaah6650
  • 62 Alard JE, Ortega-Gomez A, Wichapong K. , et al. Recruitment of classical monocytes can be inhibited by disturbing heteromers of neutrophil HNP1 and platelet CCL5. Sci Transl Med 2015; 7 (317) 317ra196
  • 63 Ortega-Gomez A, Salvermoser M, Rossaint J. , et al. Cathepsin G controls arterial but not venular myeloid cell recruitment. Circulation 2016; 134 (16) 1176-1188
  • 64 Scheiermann C, Gibbs J, Ince L, Loudon A. Clocking in to immunity. Nat Rev Immunol 2018; 18 (07) 423-437
  • 65 Winter C, Silvestre-Roig C, Ortega-Gomez A. , et al. Chrono-pharmacological targeting of the CCL2-CCR2 axis ameliorates atherosclerosis. Cell Metab 2018; 28 (01) 175-182
  • 66 Scheiermann C, Kunisaki Y, Lucas D. , et al. Adrenergic nerves govern circadian leukocyte recruitment to tissues. Immunity 2012; 37 (02) 290-301
  • 67 He W, Holtkamp S, Hergenhan SM. , et al. Circadian expression of migratory factors establishes lineage-specific signatures that guide the homing of leukocyte subsets to tissues. Immunity 2018; 49 (06) 1175-1190.e7
  • 68 Angkananard T, Anothaisintawee T, McEvoy M, Attia J, Thakkinstian A. Neutrophil lymphocyte ratio and cardiovascular disease risk: a systematic review and meta-analysis. BioMed Res Int 2018; 2018: 2703518
  • 69 Gaul DS, Stein S, Matter CM. Neutrophils in cardiovascular disease. Eur Heart J 2017; 38 (22) 1702-1704
  • 70 Megens RT, Vijayan S, Lievens D. , et al. Presence of luminal neutrophil extracellular traps in atherosclerosis. Thromb Haemost 2012; 107 (03) 597-598
  • 71 Quillard T, Araújo HA, Franck G, Shvartz E, Sukhova G, Libby P. TLR2 and neutrophils potentiate endothelial stress, apoptosis and detachment: implications for superficial erosion. Eur Heart J 2015; 36 (22) 1394-1404
  • 72 Franck G, Mawson T, Sausen G. , et al. Flow perturbation mediates neutrophil recruitment and potentiates endothelial injury via TLR2 in mice: implications for superficial erosion. Circ Res 2017; 121 (01) 31-42
  • 73 Franck G, Mawson TL, Folco EJ. , et al. Roles of PAD4 and NETosis in experimental atherosclerosis and arterial injury: implications for superficial erosion. Circ Res 2018; 123 (01) 33-42
  • 74 Silvestre-Roig C, Braster Q, Wichapong K. , et al. Externalized histone H4 orchestrates chronic inflammation by inducing lytic cell death. Nature 2019; 569 (7755): 236-240
  • 75 Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013; 13 (01) 34-45
  • 76 Brinkmann V, Reichard U, Goosmann C. , et al. Neutrophil extracellular traps kill bacteria. Science 2004; 303 (5663): 1532-1535
  • 77 Marsman G, Zeerleder S, Luken BM. Extracellular histones, cell-free DNA, or nucleosomes: differences in immunostimulation. Cell Death Dis 2016; 7 (12) e2518
  • 78 Marsman G, von Richthofen H, Bulder I. , et al. DNA and factor VII-activating protease protect against the cytotoxicity of histones. Blood Adv 2017; 1 (26) 2491-2502
  • 79 Xu J, Zhang X, Pelayo R. , et al. Extracellular histones are major mediators of death in sepsis. Nat Med 2009; 15 (11) 1318-1321
  • 80 Chaaban H, Keshari RS, Silasi-Mansat R. , et al. Inter-α inhibitor protein and its associated glycosaminoglycans protect against histone-induced injury. Blood 2015; 125 (14) 2286-2296
  • 81 Lee KH, Cavanaugh L, Leung H. , et al. Quantification of NETs-associated markers by flow cytometry and serum assays in patients with thrombosis and sepsis. Int J Lab Hematol 2018; 40 (04) 392-399
  • 82 de Buhr N, von Köckritz-Blickwede M. Detection, visualization, and quantification of neutrophil extracellular traps (NETs) and NET markers. Methods Mol Biol 2020; 2087: 425-442
  • 83 Yousefi S, Simon HU. NETosis - does it really represent nature's “suicide bomber”?. Front Immunol 2016; 7: 328
  • 84 Yipp BG, Petri B, Salina D. , et al. Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo. Nat Med 2012; 18 (09) 1386-1393
  • 85 Buchanan JT, Simpson AJ, Aziz RK. , et al. DNase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps. Curr Biol 2006; 16 (04) 396-400
  • 86 Li P, Li M, Lindberg MR, Kennett MJ, Xiong N, Wang Y. PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J Exp Med 2010; 207 (09) 1853-1862
  • 87 Martinod K, Demers M, Fuchs TA. , et al. Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice. Proc Natl Acad Sci U S A 2013; 110 (21) 8674-8679
  • 88 Martinod K, Fuchs TA, Zitomersky NL. , et al. PAD4-deficiency does not affect bacteremia in polymicrobial sepsis and ameliorates endotoxemic shock. Blood 2015; 125 (12) 1948-1956
  • 89 Biron BM, Chung CS, O'Brien XM, Chen Y, Reichner JS, Ayala A. Cl-amidine prevents histone 3 citrullination and neutrophil extracellular trap formation, and improves survival in a murine sepsis model. J Innate Immun 2017; 9 (01) 22-32
  • 90 Liang Y, Pan B, Alam HB. , et al. Inhibition of peptidylarginine deiminase alleviates LPS-induced pulmonary dysfunction and improves survival in a mouse model of lethal endotoxemia. Eur J Pharmacol 2018; 833: 432-440
  • 91 Mackman N. The role of tissue factor and factor VIIa in hemostasis. Anesth Analg 2009; 108 (05) 1447-1452
  • 92 Chen VM, Hogg PJ. Encryption and decryption of tissue factor. J Thromb Haemost 2013; 11 (Suppl. 01) 277-284
  • 93 Ansari SA, Pendurthi UR, Rao LVM. Role of cell surface lipids and thiol-disulphide exchange pathways in regulating the encryption and decryption of tissue factor. Thromb Haemost 2019; 119 (06) 860-870
  • 94 Mackman N. Triggers, targets and treatments for thrombosis. Nature 2008; 451 (7181): 914-918
  • 95 van der Pol E, Böing AN, Harrison P, Sturk A, Nieuwland R. Classification, functions, and clinical relevance of extracellular vesicles. Pharmacol Rev 2012; 64 (03) 676-705
  • 96 Hisada Y, Alexander W, Kasthuri R. , et al. Measurement of microparticle tissue factor activity in clinical samples: a summary of two tissue factor-dependent FXa generation assays. Thromb Res 2016; 139: 90-97
  • 97 Key NS, Mackman N. Tissue factor and its measurement in whole blood, plasma, and microparticles. Semin Thromb Hemost 2010; 36 (08) 865-875
  • 98 Kuijpers MJ, van der Meijden PE, Feijge MA. , et al. Factor XII regulates the pathological process of thrombus formation on ruptured plaques. Arterioscler Thromb Vasc Biol 2014; 34 (08) 1674-1680
  • 99 Wolberg AS, Rosendaal FR, Weitz JI. , et al. Venous thrombosis. Nat Rev Dis Primers 2015; 1: 15006
  • 100 Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood 2013; 122 (10) 1712-1723
  • 101 Khorana AA, Francis CW, Menzies KE. , et al. Plasma tissue factor may be predictive of venous thromboembolism in pancreatic cancer. J Thromb Haemost 2008; 6 (11) 1983-1985
  • 102 Hisada Y, Ay C, Auriemma AC, Cooley BC, Mackman N. Human pancreatic tumors grown in mice release tissue factor-positive microvesicles that increase venous clot size. J Thromb Haemost 2017; 15 (11) 2208-2217
  • 103 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
  • 104 Johnston SC, Amarenco P, Albers GW. , et al; SOCRATES Steering Committee and Investigators. Ticagrelor versus aspirin in acute stroke or transient ischemic attack. N Engl J Med 2016; 375 (01) 35-43
  • 105 Ornello R, Degan D, Tiseo C. , et al. Distribution and temporal trends from 1993 to 2015 of ischemic stroke subtypes: a systematic review and meta-analysis. Stroke 2018; 49 (04) 814-819
  • 106 Diener HC, Bogousslavsky J, Brass LM. , et al; MATCH investigators. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004; 364 (9431): 331-337
  • 107 Benavente OR, Hart RG, McClure LA, Szychowski JM, Coffey CS, Pearce LA. ; SPS3 Investigators. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med 2012; 367 (09) 817-825
  • 108 Bath PM, Woodhouse LJ, Appleton JP. , et al; TARDIS Investigators. Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial. Lancet 2018; 391 (10123): 850-859
  • 109 Wang Y, Wang Y, Zhao X. , et al; CHANCE Investigators. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med 2013; 369 (01) 11-19
  • 110 Johnston SC, Easton JD, Farrant M. , et al; Clinical Research Collaboration, Neurological Emergencies Treatment Trials Network, and the POINT Investigators. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med 2018; 379 (03) 215-225
  • 111 Donkel SJ, Benaddi B, Dippel DWJ, Ten Cate H, de Maat MPM. Prognostic hemostasis biomarkers in acute ischemic stroke. Arterioscler Thromb Vasc Biol 2019; 39 (03) 360-372
  • 112 A L. Platelet function and thrombin generation in ischemic stroke – clinical correlates and prognostic importance' Dissertation 2018. Available at: https://openarchive.ki.se/xmlui/bitstream/handle/10616/46302/Thesis_%20Annika_Lundstr%c3%b6m.pdf?sequence=3&isAllowed=y . Accessed February 14, 2020
  • 113 De Luca C, Virtuoso A, Maggio N, Papa M. Neuro-coagulopathy: blood coagulation factors in central nervous system diseases. Int J Mol Sci 2017; 18 (10) E2128
  • 114 Aikawa E, Nahrendorf M, Figueiredo JL. , et al. Osteogenesis associates with inflammation in early-stage atherosclerosis evaluated by molecular imaging in vivo. Circulation 2007; 116 (24) 2841-2850
  • 115 Wasilewski GB, Vervloet MG, Schurgers LJ. The bone-vasculature axis: calcium supplementation and the role of vitamin K. Front Cardiovasc Med 2019; 6: 6
  • 116 Vajen T, Benedikter BJ, Heinzmann ACA. , et al. Platelet extracellular vesicles induce a pro-inflammatory smooth muscle cell phenotype. J Extracell Vesicles 2017; 6 (01) 1322454
  • 117 Petsophonsakul P, Furmanik M, Forsythe R. , et al. Role of vascular smooth muscle cell phenotypic switching and calcification in aortic aneurysm formation. Arterioscler Thromb Vasc Biol 2019; 39 (07) 1351-1368
  • 118 Kapustin AN, Schoppet M, Schurgers LJ. , et al. prothrombin loading of vascular smooth muscle cell-derived exosomes regulates coagulation and calcification. Arterioscler Thromb Vasc Biol 2017; 37 (03) e22-e32
  • 119 Brandenburg VM, Schurgers LJ, Kaesler N. , et al. Prevention of vasculopathy by vitamin K supplementation: can we turn fiction into fact?. Atherosclerosis 2015; 240 (01) 10-16
  • 120 Borissoff JI, Spronk HM, ten Cate H. The hemostatic system as a modulator of atherosclerosis. N Engl J Med 2011; 364 (18) 1746-1760
  • 121 Posma JJ, Posthuma JJ, Spronk HM. Coagulation and non-coagulation effects of thrombin. J Thromb Haemost 2016; 14 (10) 1908-1916
  • 122 Griffin JH, Zlokovic BV, Mosnier LO. Activated protein C: biased for translation. Blood 2015; 125 (19) 2898-2907
  • 123 Sinha RK, Wang Y, Zhao Z. , et al. PAR1 biased signaling is required for activated protein C in vivo benefits in sepsis and stroke. Blood 2018; 131 (11) 1163-1171
  • 124 Borissoff JI, Heeneman S, Kilinç E. , et al. Early atherosclerosis exhibits an enhanced procoagulant state. Circulation 2010; 122 (08) 821-830
  • 125 Quillard T, Franck G, Mawson T, Folco E, Libby P. Mechanisms of erosion of atherosclerotic plaques. Curr Opin Lipidol 2017; 28 (05) 434-441
  • 126 Libby P, Pasterkamp G, Crea F, Jang IK. Reassessing the mechanisms of acute coronary syndromes. Circ Res 2019; 124 (01) 150-160
  • 127 Saia F, Komukai K, Capodanno D. , et al; OCTAVIA Investigators. Eroded versus ruptured plaques at the culprit site of STEMI: in vivo pathophysiological features and response to primary PCI. JACC Cardiovasc Imaging 2015; 8 (05) 566-575
  • 128 Wang Z, Jia H, Tian J. , et al. Computer-aided image analysis algorithm to enhance in vivo diagnosis of plaque erosion by intravascular optical coherence tomography. Circ Cardiovasc Imaging 2014; 7 (05) 805-810
  • 129 Marchesseau S, Seneviratna A, Sjöholm AT. , et al. Hybrid PET/CT and PET/MRI imaging of vulnerable coronary plaque and myocardial scar tissue in acute myocardial infarction. J Nucl Cardiol 2018; 25 (06) 2001-2011
  • 130 Ten Cate H, Meade T. The Northwick Park Heart Study: evidence from the laboratory. J Thromb Haemost 2014; 12 (05) 587-592
  • 131 Lowe G, Rumley A. The relevance of coagulation in cardiovascular disease: what do the biomarkers tell us?. Thromb Haemost 2014; 112 (05) 860-867
  • 132 Mackman N, Spronk HMH, Stouffer GA, Ten Cate H. Dual anticoagulant and antiplatelet therapy for coronary artery disease and peripheral artery disease patients. Arterioscler Thromb Vasc Biol 2018; 38 (04) 726-732
  • 133 Posthuma JJ, Posma JJN, van Oerle R. , et al. Targeting coagulation factor Xa promotes regression of advanced atherosclerosis in apolipoprotein-e deficient mice. Sci Rep 2019; 9 (01) 3909
  • 134 Gurbel PA, Fox KAA, Tantry US, Ten Cate H, Weitz JI. Combination antiplatelet and oral anticoagulant therapy in patients with coronary and peripheral artery disease. Circulation 2019; 139 (18) 2170-2185
  • 135 Griffin JH, Zlokovic BV, Mosnier LO. Activated protein C, protease activated receptor 1, and neuroprotection. Blood 2018; 132 (02) 159-169
  • 136 Lyden P, Pryor KE, Coffey CS. , et al; NeuroNEXT Clinical Trials Network NN104 Investigators. Final results of the RHAPSODY trial: a multi-center, phase 2 trial using a continual reassessment method to determine the safety and tolerability of 3K3A-APC, a recombinant variant of human activated protein C, in combination with tissue plasminogen activator, mechanical thrombectomy or both in moderate to severe acute ischemic stroke. Ann Neurol 2019; 85 (01) 125-136
  • 137 Jennings RB. Historical perspective on the pathology of myocardial ischemia/reperfusion injury. Circ Res 2013; 113 (04) 428-438
  • 138 Wu MY, Yiang GT, Liao WT. , et al. Current mechanistic concepts in ischemia and reperfusion injury. Cell Physiol Biochem 2018; 46 (04) 1650-1667
  • 139 Hausenloy DJ, Yellon DM. Myocardial ischemia-reperfusion injury: a neglected therapeutic target. J Clin Invest 2013; 123 (01) 92-100
  • 140 Russo I, Penna C, Musso T. , et al. Platelets, diabetes and myocardial ischemia/reperfusion injury. Cardiovasc Diabetol 2017; 16 (01) 71
  • 141 Warner TD, Nylander S, Whatling C. Anti-platelet therapy: cyclo-oxygenase inhibition and the use of aspirin with particular regard to dual anti-platelet therapy. Br J Clin Pharmacol 2011; 72 (04) 619-633
  • 142 Ye Y, Long B, Qian J, Perez-Polo JR, Birnbaum Y. Dipyridamole with low-dose aspirin augments the infarct size-limiting effects of simvastatin. Cardiovasc Drugs Ther 2010; 24 (5-6): 391-399
  • 143 Birnbaum Y, Lin Y, Ye Y. , et al. Aspirin before reperfusion blunts the infarct size limiting effect of atorvastatin. Am J Physiol Heart Circ Physiol 2007; 292 (06) H2891-H2897
  • 144 Yang XM, Liu Y, Cui L. , et al. Two classes of anti-platelet drugs reduce anatomical infarct size in monkey hearts. Cardiovasc Drugs Ther 2013; 27 (02) 109-115
  • 145 Wallentin L, Becker RC, Budaj A. , et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361 (11) 1045-1057
  • 146 Ye Y, Perez-Polo JR, Birnbaum Y. Protecting against ischemia-reperfusion injury: antiplatelet drugs, statins, and their potential interactions. Ann N Y Acad Sci 2010; 1207: 76-82
  • 147 Kingma JG. Inhibition of Na+/H+ exchanger with EMD 87580 does not confer greater cardioprotection beyond preconditioning on ischemia-reperfusion injury in normal dogs. J Cardiovasc Pharmacol Ther 2018; 23 (03) 254-269
  • 148 Yang XM, Cui L, White J. , et al. Mitochondrially targeted endonuclease III has a powerful anti-infarct effect in an in vivo rat model of myocardial ischemia/reperfusion. Basic Res Cardiol 2015; 110 (02) 3
  • 149 Sivaraman V, Yellon DM. Pharmacologic therapy that simulates conditioning for cardiac ischemic/reperfusion injury. J Cardiovasc Pharmacol Ther 2014; 19 (01) 83-96
  • 150 Ras M, Reitsma JB, Hoes AW, Six AJ, Poldervaart JM. Secondary analysis of frequency, circumstances and consequences of calculation errors of the HEART (history, ECG, age, risk factors and troponin) score at the emergency departments of nine hospitals in the Netherlands. BMJ Open 2017; 7 (10) e017259
  • 151 Ma H, Campbell BCV, Parsons MW. , et al; EXTEND Investigators. Thrombolysis guided by perfusion imaging up to 9 hours after onset of stroke. N Engl J Med 2019; 380 (19) 1795-1803
  • 152 Schellinger PD, Demaerschalk BM. Endovascular stroke therapy in the late time window. Stroke 2018; 49 (10) 2559-2561
  • 153 Ebinger M, Winter B, Wendt M. , et al; STEMO Consortium. Effect of the use of ambulance-based thrombolysis on time to thrombolysis in acute ischemic stroke: a randomized clinical trial. JAMA 2014; 311 (16) 1622-1631
  • 154 Calderon VJ, Kasturiarachi BM, Lin E, Bansal V, Zaidat OO. Review of the mobile stroke unit experience worldwide. Intervent Neurol 2018; 7 (06) 347-358
  • 155 Ebinger M, Harmel P, Nolte CH, Grittner U, Siegerink B, Audebert HJ. Berlin prehospital or usual delivery of acute stroke care - study protocol. Int J Stroke 2017; 12 (06) 653-658
  • 156 Harmel P, Ebinger M, Freitag E. , et al. Functional stroke outcomes after mobile stroke unit deployment – the revised protocol for the Berlin Prehospital Or Usual Delivery of acute stroke care (B_PROUD) part 2 study. Neurol Res Pract 2019; 1 (01) 18
  • 157 Klok FA, Barco S, Siegerink B. Measuring functional limitations after venous thromboembolism: A call to action. Thromb Res 2019; 178: 59-62
  • 158 Maino A, Rosendaal FR, Algra A, Peyvandi F, Siegerink B. Hypercoagulability is a stronger risk factor for ischaemic stroke than for myocardial infarction: a systematic review. PLoS One 2015; 10 (08) e0133523
  • 159 Siegerink B, Maino A, Algra A, Rosendaal FR. Hypercoagulability and the risk of myocardial infarction and ischemic stroke in young women. J Thromb Haemost 2015; 13 (09) 1568-1575
  • 160 Al-Horani RA, Desai UR. Factor XIa inhibitors: a review of the patent literature. Expert Opin Ther Pat 2016; 26 (03) 323-345
  • 161 Ducroux C, Di Meglio L, Loyau S. , et al. thrombus neutrophil extracellular traps content impair tpa-induced thrombolysis in acute ischemic stroke. Stroke 2018; 49 (03) 754-757
  • 162 Aboyans V, Ricco JB, Bartelink MEL. , et al; ESC Scientific Document Group. 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS): Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries Endorsed by: the European Stroke Organization (ESO)The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS). Eur Heart J 2018; 39 (09) 763-816
  • 163 Espinola-Klein C, Rupprecht HJ, Blankenberg S. , et al; AtheroGene Investigators. Impact of infectious burden on extent and long-term prognosis of atherosclerosis. Circulation 2002; 105 (01) 15-21
  • 164 CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348 (9038): 1329-1339
  • 165 Hiatt WR, Fowkes FG, Heizer G. , et al; EUCLID Trial Steering Committee and Investigators. Ticagrelor versus clopidogrel in symptomatic peripheral artery disease. N Engl J Med 2017; 376 (01) 32-40
  • 166 Fowkes FG, Price JF, Stewart MC. , et al; Aspirin for Asymptomatic Atherosclerosis Trialists. Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial. JAMA 2010; 303 (09) 841-848
  • 167 Hess CN, Norgren L, Ansel GM. , et al. A structured review of antithrombotic therapy in peripheral artery disease with a focus on revascularization: a TASC (InterSociety Consensus for the Management of Peripheral Artery Disease) initiative. Circulation 2017; 135 (25) 2534-2555
  • 168 Efficacy of oral anticoagulants compared with aspirin after infrainguinal bypass surgery (The Dutch Bypass Oral Anticoagulants or Aspirin Study): a randomised trial. Lancet 2000; 355 (9201): 346-351
  • 169 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
  • 170 Steven S, Daiber A, Dopheide JF, Münzel T, Espinola-Klein C. Peripheral artery disease, redox signaling, oxidative stress - Basic and clinical aspects. Redox Biol 2017; 12: 787-797
  • 171 Dopheide JF, Scheer M, Doppler C. , et al. Change of walking distance in intermittent claudication: impact on inflammation, oxidative stress and mononuclear cells: a pilot study. Clin Res Cardiol 2015; 104 (09) 751-763
  • 172 Kaptoge S, Seshasai SRK, Gao P. , et al. Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis. Eur Heart J 2014; 35 (09) 578-589
  • 173 Hagström E, Held C, Stewart RA. , et al; STABILITY Investigators. Growth differentiation factor 15 predicts all-cause morbidity and mortality in stable coronary heart disease. Clin Chem 2017; 63 (01) 325-333
  • 174 Held C, White HD, Stewart RAH. , et al; STABILITY Investigators. Inflammatory biomarkers interleukin-6 and C-reactive protein and outcomes in stable coronary heart disease: experiences from the STABILITY (stabilization of atherosclerotic plaque by initiation of darapladib therapy) trial. J Am Heart Assoc 2017; 6 (10) e005077
  • 175 Lindholm D, Lindbäck J, Armstrong PW. , et al. Biomarker-based risk model to predict cardiovascular mortality in patients with stable coronary disease. J Am Coll Cardiol 2017; 70 (07) 813-826
  • 176 Gold L, Ayers D, Bertino J. , et al. Aptamer-based multiplexed proteomic technology for biomarker discovery. PLoS One 2010; 5 (12) e15004
  • 177 Assarsson E, Lundberg M, Holmquist G. , et al. Homogenous 96-plex PEA immunoassay exhibiting high sensitivity, specificity, and excellent scalability. PLoS One 2014; 9 (04) e95192
  • 178 Ganz P, Heidecker B, Hveem K. , et al. Development and validation of a protein-based risk score for cardiovascular outcomes among patients with stable coronary heart disease. JAMA 2016; 315 (23) 2532-2541
  • 179 McCarthy CP, van Kimmenade RRJ, Gaggin HK. , et al. Usefulness of multiple biomarkers for predicting incident major adverse cardiac events in patients who underwent diagnostic coronary angiography (from the catheter sampled blood archive in cardiovascular diseases [CASABLANCA] STUDY). Am J Cardiol 2017; 120 (01) 25-32
  • 180 Ridker PM, Everett BM, Thuren T. , et al; CANTOS Trial Group. antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017; 377 (12) 1119-1131
  • 181 Aday AW, Ridker PM. Antiinflammatory therapy in clinical care: the CANTOS Trial and beyond. Front Cardiovasc Med 2018; 5: 62
  • 182 Ridker PM. Anticytokine agents: targeting interleukin signaling pathways for the treatment of atherothrombosis. Circ Res 2019; 124 (03) 437-450
  • 183 Tardif JC, Kouz S, Waters DD. , et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med 2019; 381 (26) 2497-2505
  • 184 Hijazi Z, Oldgren J, Siegbahn A, Wallentin L. Application of biomarkers for risk stratification in patients with atrial fibrillation. Clin Chem 2017; 63 (01) 152-164
  • 185 Hijazi Z, Aulin J, Andersson U. , et al; ARISTOTLE Investigators. Biomarkers of inflammation and risk of cardiovascular events in anticoagulated patients with atrial fibrillation. Heart 2016; 102 (07) 508-517
  • 186 Hijazi Z, Lindbäck J, Alexander JH. , et al; ARISTOTLE and STABILITY Investigators. The ABC (age, biomarkers, clinical history) stroke risk score: a biomarker-based risk score for predicting stroke in atrial fibrillation. Eur Heart J 2016; 37 (20) 1582-1590
  • 187 Hijazi Z, Oldgren J, Lindbäck J. , et al; ARISTOTLE and RE-LY Investigators. The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study. Lancet 2016; 387 (10035): 2302-2311
  • 188 Berg DD, Ruff CT, Jarolim P. , et al. Performance of the ABC scores for assessing the risk of stroke or systemic embolism and bleeding in patients with atrial fibrillation in ENGAGE AF-TIMI 48. Circulation 2019; 139 (06) 760-771
  • 189 Esteve-Pastor MA, Roldán V, Rivera-Caravaca JM, Ramírez-Macías I, Lip GYH, Marín F. The use of biomarkers in clinical management guidelines: a critical appraisal. Thromb Haemost 2019; 119 (12) 1901-1919
  • 190 Schwartz GG, Steg PG, Szarek M. , et al; ODYSSEY OUTCOMES Committees and Investigators. Alirocumab and cardiovascular outcomes after acute coronary syndrome. n engl j med 2018; 379 (22) 2097-2107
  • 191 Zinman B, Wanner C, Lachin JM. , et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373 (22) 2117-2128
  • 192 Bauer T, Bouman HJ, van Werkum JW, Ford NF, ten Berg JM, Taubert D. Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis. BMJ 2011; 343: d4588
  • 193 Claassens DMF, Vos GJA, Bergmeijer TO. , et al. A genotype-guided strategy for oral P2Y12 inhibitors in primary PCI. N Engl J Med 2019; 381 (17) 1621-1631
  • 194 Makkar RR, Fontana G, Jilaihawi H. , et al. Possible subclinical leaflet thrombosis in bioprosthetic aortic valves. N Engl J Med 2015; 373 (21) 2015-2024
  • 195 Yanagisawa R, Fetterly KA, Johnson GB. , et al. Integrated use of perfusion SPECT/CTA fusion imaging and pulmonary balloon angioplasty for chronic pulmonary thromboembolism. JACC Cardiovasc Interv 2017; 10 (05) 532-534
  • 196 Ruile P, Jander N, Blanke P. , et al. Course of early subclinical leaflet thrombosis after transcatheter aortic valve implantation with or without oral anticoagulation. Clin Res Cardiol 2017; 106 (02) 85-95
  • 197 Chakravarty T, Søndergaard L, Friedman J. , et al; RESOLVE; SAVORY Investigators. Subclinical leaflet thrombosis in surgical and transcatheter bioprosthetic aortic valves: an observational study. Lancet 2017; 389 (10087): 2383-2392
  • 198 Dangas GD, Tijssen JGP, Wöhrle J. , et al; GALILEO Investigators. A controlled trial of rivaroxaban after transcatheter aortic-valve replacement. N Engl J Med 2020; 382 (02) 120-129
  • 199 Büller HR, Bethune C, Bhanot S. , et al; FXI-ASO TKA Investigators. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med 2015; 372 (03) 232-240
  • 200 Povsic TJ, Vavalle JP, Aberle LH. , et al; RADAR Investigators. A Phase 2, randomized, partially blinded, active-controlled study assessing the efficacy and safety of variable anticoagulation reversal using the REG1 system in patients with acute coronary syndromes: results of the RADAR trial. Eur Heart J 2013; 34 (31) 2481-2489
  • 201 Peeters A, Mamun AA, Willekens F, Bonneux L. A cardiovascular life history. A life course analysis of the original Framingham Heart Study cohort. Eur Heart J 2002; 23 (06) 458-466
  • 202 Rioufol G, Finet G, Ginon I. , et al. Multiple atherosclerotic plaque rupture in acute coronary syndrome: a three-vessel intravascular ultrasound study. Circulation 2002; 106 (07) 804-808
  • 203 Storey RF, Parker WA. Choices for potent platelet inhibition in patients with diabetes mellitus. Circulation 2016; 134 (11) 793-796
  • 204 Storey RF, Angiolillo DJ, Bonaca MP. , et al. Platelet inhibition with ticagrelor 60 mg versus 90 mg twice daily in the PEGASUS-TIMI 54 trial. J Am Coll Cardiol 2016; 67 (10) 1145-1154
  • 205 Orme RC, Parker WAE, Thomas MR. , et al. Study of two dose regimens of ticagrelor compared with clopidogrel in patients undergoing percutaneous coronary intervention for stable coronary artery disease (STEEL-PCI). Circulation 2018; CIRCULATIONAHA.118.034790
  • 206 Steg PG, Harrington RA, Emanuelsson H. , et al; PLATO Study Group. Stent thrombosis with ticagrelor versus clopidogrel in patients with acute coronary syndromes: an analysis from the prospective, randomized PLATO trial. Circulation 2013; 128 (10) 1055-1065
  • 207 Gosling R, Yazdani M, Parviz Y. , et al. Comparison of P2Y12 inhibitors for mortality and stent thrombosis in patients with acute coronary syndromes: Single center study of 10 793 consecutive ‘real-world’ patients. Platelets 2017; 28 (08) 767-773
  • 208 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
  • 209 Sumaya W, Geisler T, Kristensen SD, Storey RF. Dual antiplatelet or dual antithrombotic therapy for secondary prevention in high-risk patients with stable coronary artery disease?. Thromb Haemost 2019; 19 (10) 1583-1589
  • 210 Hagström E, James SK, Bertilsson M. , et al; PLATO Investigators. Growth differentiation factor-15 level predicts major bleeding and cardiovascular events in patients with acute coronary syndromes: results from the PLATO study. Eur Heart J 2016; 37 (16) 1325-1333
  • 211 Bhatt DL, Bonaca MP, Bansilal S. , et al. Reduction in ischemic events with ticagrelor in diabetic patients with prior myocardial infarction in PEGASUS-TIMI 54. J Am Coll Cardiol 2016; 67 (23) 2732-2740
  • 212 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
  • 213 Storey RF, James SK, Siegbahn A. , et al. Lower mortality following pulmonary adverse events and sepsis with ticagrelor compared to clopidogrel in the PLATO study. Platelets 2014; 25 (07) 517-525
  • 214 Thomas MR, Outteridge SN, Ajjan RA. , et al. Platelet P2Y12 inhibitors reduce systemic inflammation and its prothrombotic effects in an experimental human model. Arterioscler Thromb Vasc Biol 2015; 35 (12) 2562-2570
  • 215 Kiers D, van der Heijden WA, van Ede L. , et al. A randomised trial on the effect of anti-platelet therapy on the systemic inflammatory response in human endotoxaemia. Thromb Haemost 2017; 117 (09) 1798-1807
  • 216 Weitz JI. Insights into the role of thrombin in the pathogenesis of recurrent ischaemia after acute coronary syndrome. Thromb Haemost 2014; 112 (05) 924-931
  • 217 Tello-Montoliu A, Tomasello SD, Ueno M, Angiolillo DJ. Antiplatelet therapy: thrombin receptor antagonists. Br J Clin Pharmacol 2011; 72 (04) 658-671
  • 218 Franchi F, Angiolillo DJ. Novel antiplatelet agents in acute coronary syndrome. Nat Rev Cardiol 2015; 12 (01) 30-47
  • 219 Mega JL, Braunwald E, Wiviott SD. , et al; ATLAS ACS 2–TIMI 51 Investigators. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012; 366 (01) 9-19
  • 220 Alexander JH, Lopes RD, James S. , et al; APPRAISE-2 Investigators. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011; 365 (08) 699-708
  • 221 Ridker PM, Everett BM, Pradhan A. , et al; CIRT Investigators. Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med 2019; 380 (08) 752-762
  • 222 DeLoughery EP, Olson SR, Puy C, McCarty OJT, Shatzel JJ. The safety and efficacy of novel agents targeting factors XI and XII in early phase human trials. Semin Thromb Hemost 2019; 45 (05) 502-508
  • 223 Chan NC, Weitz JI. Antithrombotic agents. Circ Res 2019; 124 (03) 426-436
  • 224 von Brühl ML, Stark K, Steinhart A. , et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 2012; 209 (04) 819-835
  • 225 Ponomaryov T, Payne H, Fabritz L, Wagner DD, Brill A. Mast cells granular contents are crucial for deep vein thrombosis in mice. Circ Res 2017; 121 (08) 941-950
  • 226 Bertin FR, Rys RN, Mathieu C, Laurance S, Lemarié CA, Blostein MD. Natural killer cells induce neutrophil extracellular trap formation in venous thrombosis. J Thromb Haemost 2019; 17 (02) 403-414
  • 227 Penn MS, Igwe C. Role of inflammation in modulating thrombotic-fibrinolytic balance in venous thrombosis. Circ Res 2016; 119 (12) 1256-1257
  • 228 Luther N, Shahneh F, Brähler M. , et al. Innate effector-memory T-cell activation regulates post-thrombotic vein wall inflammation and thrombus resolution. Circ Res 2016; 119 (12) 1286-1295
  • 229 Heestermans M, Salloum-Asfar S, Streef T. , et al. Mouse venous thrombosis upon silencing of anticoagulants depends on tissue factor and platelets, not FXII or neutrophils. Blood 2019; 133 (19) 2090-2099
  • 230 Simon MM, Greenaway S, White JK. , et al. A comparative phenotypic and genomic analysis of C57BL/6J and C57BL/6N mouse strains. Genome Biol 2013; 14 (07) R82
  • 231 Wilkerson WR, Sane DC. Aging and thrombosis. Semin Thromb Hemost 2002; 28 (06) 555-568
  • 232 Enden T, Haig Y, Kløw NE. , et al; CaVenT Study Group. Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial. Lancet 2012; 379 (9810): 31-38
  • 233 Vedantham S, Goldhaber SZ, Julian JA. , et al; ATTRACT Trial Investigators. Pharmacomechanical catheter-directed thrombolysis for deep-vein thrombosis. N Engl J Med 2017; 377 (23) 2240-2252
  • 234 Comerota AJ, Kearon C, Gu CS. , et al; ATTRACT Trial Investigators. Endovascular thrombus removal for acute iliofemoral deep vein thrombosis. Circulation 2019; 139 (09) 1162-1173
  • 235 Notten P, Ten Cate-Hoek AJ, Arnoldussen CWKP. , et al. Ultrasound-accelerated catheter-directed thrombolysis versus anticoagulation for the prevention of post-thrombotic syndrome (CAVA): a single-blind, multicentre, randomised trial. Lancet Haematol 2020; 7 (01) e40-e49
  • 236 Brill A, Fuchs TA, Chauhan AK. , et al. von Willebrand factor-mediated platelet adhesion is critical for deep vein thrombosis in mouse models. Blood 2011; 117 (04) 1400-1407
  • 237 Simes J, Becattini C, Agnelli G. , et al; INSPIRE Study Investigators (International Collaboration of Aspirin Trials for Recurrent Venous Thromboembolism). Aspirin for the prevention of recurrent venous thromboembolism: the INSPIRE collaboration. Circulation 2014; 130 (13) 1062-1071
  • 238 Becattini C, Agnelli G, Schenone A. , et al; WARFASA Investigators. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med 2012; 366 (21) 1959-1967
  • 239 Cheung YW, Middeldorp S, Prins MH. , et al; Einstein PTS Investigators Group. Post-thrombotic syndrome in patients treated with rivaroxaban or enoxaparin/vitamin K antagonists for acute deep-vein thrombosis. A post-hoc analysis. Thromb Haemost 2016; 116 (04) 733-738
  • 240 Prandoni P, Ageno W, Mumoli N. , et al. Recanalization rate in patients with proximal vein thrombosis treated with the direct oral anticoagulants. Thromb Res 2017; 153: 97-100
  • 241 Wik HS, Enden TR, Ghanima W, Engeseth M, Kahn SR, Sandset PM. Diagnostic scales for the post-thrombotic syndrome. Thromb Res 2018; 164: 110-115
  • 242 Myers Jr DD, Henke PK, Bedard PW. , et al. Treatment with an oral small molecule inhibitor of P selectin (PSI-697) decreases vein wall injury in a rat stenosis model of venous thrombosis. J Vasc Surg 2006; 44 (03) 625-632
  • 243 Hull RD, Pineo GF, Brant R. , et al; LITE Trial Investigators. Home therapy of venous thrombosis with long-term LMWH versus usual care: patient satisfaction and post-thrombotic syndrome. Am J Med 2009; 122 (08) 762-769.e3
  • 244 Chitsike RS, Rodger MA, Kovacs MJ. , et al. Risk of post-thrombotic syndrome after subtherapeutic warfarin anticoagulation for a first unprovoked deep vein thrombosis: results from the REVERSE study. J Thromb Haemost 2012; 10 (10) 2039-2044
  • 245 Ziegler S, Schillinger M, Maca TH, Minar E. Post-thrombotic syndrome after primary event of deep venous thrombosis 10 to 20 years ago. Thromb Res 2001; 101 (02) 23-33
  • 246 Diaz JA, Wrobleski SK, Alvarado CM. , et al. P-selectin inhibition therapeutically promotes thrombus resolution and prevents vein wall fibrosis better than enoxaparin and an inhibitor to von Willebrand factor. Arterioscler Thromb Vasc Biol 2015; 35 (04) 829-837
  • 247 Obi AT, Diaz JA, Ballard-Lipka NL. , et al. Plasminogen activator-1 overexpression decreases experimental postthrombotic vein wall fibrosis by a non-vitronectin-dependent mechanism. J Thromb Haemost 2014; 12 (08) 1353-1363
  • 248 Ripplinger CM, Kessinger CW, Li C. , et al. Inflammation modulates murine venous thrombosis resolution in vivo: assessment by multimodal fluorescence molecular imaging. Arterioscler Thromb Vasc Biol 2012; 32 (11) 2616-2624
  • 249 Deatrick KB, Luke CE, Elfline MA. , et al. The effect of matrix metalloproteinase 2 and matrix metalloproteinase 2/9 deletion in experimental post-thrombotic vein wall remodeling. J Vasc Surg 2013; 58 (05) 1375-1384.e2
  • 250 Metz AK, Diaz JA, Obi AT, Wakefield TW, Myers DD, Henke PK. Venous thrombosis and post-thrombotic syndrome: from novel biomarkers to biology. Methodist DeBakey Cardiovasc J 2018; 14 (03) 173-181
  • 251 Andraska EA, Luke CE, Elfline MA. , et al. Pre-clinical model to study recurrent venous thrombosis in the inferior vena cava. Thromb Haemost 2018; 118 (06) 1048-1057
  • 252 Mukhopadhyay S, Johnson TA, Duru N. , et al. Fibrinolysis and inflammation in venous thrombus resolution. Front Immunol 2019; 10: 1348
  • 253 Kimball AS, Obi AT, Luke CE. , et al. Ly6CLo monocyte/macrophages are essential for thrombus resolution in a murine model of venous thrombosis. Thromb Haemost 2019
  • 254 Appelen D, van Loo E, Prins MH, Neumann MH, Kolbach DN. Compression therapy for prevention of post-thrombotic syndrome. Cochrane Database Syst Rev 2017; 9: CD004174
  • 255 Klok FA, Zondag W, van Kralingen KW. , et al. Patient outcomes after acute pulmonary embolism. A pooled survival analysis of different adverse events. Am J Respir Crit Care Med 2010; 181 (05) 501-506
  • 256 Klok FA, van der Hulle T, den Exter PL, Lankeit M, Huisman MV, Konstantinides S. The post-PE syndrome: a new concept for chronic complications of pulmonary embolism. Blood Rev 2014; 28 (06) 221-226
  • 257 Sista AK, Miller LE, Kahn SR, Kline JA. Persistent right ventricular dysfunction, functional capacity limitation, exercise intolerance, and quality of life impairment following pulmonary embolism: Systematic review with meta-analysis. Vasc Med 2017; 22 (01) 37-43
  • 258 Sista AK, Klok FA. Late outcomes of pulmonary embolism: the post-PE syndrome. Thromb Res 2018; 164: 157-162
  • 259 Delcroix M, Lang I, Pepke-Zaba J. , et al. Long-term outcome of patients with chronic thromboembolic pulmonary hypertension: results from an international prospective registry. Circulation 2016; 133 (09) 859-871
  • 260 Pepke-Zaba J, Delcroix M, Lang I. , et al. Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry. Circulation 2011; 124 (18) 1973-1981
  • 261 Klok FA, Barco S, Konstantinides SV. , et al. Determinants of diagnostic delay in chronic thromboembolic pulmonary hypertension: results from the European CTEPH Registry. Eur Respir J 2018; 52 (06) 1801687
  • 262 Ende-Verhaar YM, Meijboom LJ, Kroft LJM. , et al. Usefulness of standard computed tomography pulmonary angiography performed for acute pulmonary embolism for identification of chronic thromboembolic pulmonary hypertension: results of the InShape III study. J Heart Lung Transplant 2019; 38 (07) 731-738
  • 263 Ende-Verhaar YM, van den Hout WB, Bogaard HJ. , et al. Healthcare utilization in chronic thromboembolic pulmonary hypertension after acute pulmonary embolism. J Thromb Haemost 2018; 16 (11) 2168-2174
  • 264 Klok FA, Delcroix M, Bogaard HJ. Chronic thromboembolic pulmonary hypertension from the perspective of patients with pulmonary embolism. J Thromb Haemost 2018; 16 (06) 1040-1051