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DOI: 10.1055/s-0040-1718923
Fibrinolysis in Acute and Chronic Cardiovascular Disease
Funding This work received no specific funding. N.K. was funded by the Faculty of Medicine, Prince of Songkla University, Thailand. R.A.A.'s research work was supported by grants from the NIHR, Diabetes UK, the British Heart Foundation, Avacta Life Sciences, and Abbott Diabetes Care. R.A.S.A. was supported by the British Heart Foundation (RG/18/11/34036) and the Wellcome Trust (204951/B/16/Z).![](https://www.thieme-connect.de/media/sth/202105/lookinside/thumbnails/10-1055-s-0040-1718923_02798-1.jpg)
Abstract
The formation of an obstructive thrombus within an artery remains a major cause of mortality and morbidity worldwide. Despite effective inhibition of platelet function by modern antiplatelet therapies, these agents fail to fully eliminate atherothrombotic risk. This may well be related to extensive vascular disease, beyond the protective abilities of the treatment agents used. However, recent evidence suggests that residual vascular risk in those treated with modern antiplatelet therapies is related, at least in part, to impaired fibrin clot lysis. In this review, we attempt to shed more light on the role of hypofibrinolysis in predisposition to arterial vascular events. We provide a brief overview of the coagulation system followed by addressing the role of impaired fibrin clot lysis in acute and chronic vascular conditions, including coronary artery, cerebrovascular, and peripheral vascular disease. We also discuss the role of combined anticoagulant and antiplatelet therapies to reduce the risk of arterial thrombotic events, addressing both efficacy and safety of such an approach. We conclude that impaired fibrin clot lysis appears to contribute to residual thrombosis risk in individuals with arterial disease on antiplatelet therapy, and targeting proteins in the fibrinolytic system represents a viable strategy to improve outcome in this population. Future work is required to refine the antithrombotic approach by modulating pathological abnormalities in the fibrinolytic system and tailoring therapy according to the need of each individual.
Authors' Contributions
N.K. was responsible for drafting and writing of the manuscript, searching of literature, and interpreting of data. R.A.S.A. and R.A.A. were responsible for the drafting and writing of the manuscript and critical revision of important intellectual content. All authors approved the version to be published.
Publication History
Article published online:
20 April 2021
© 2021. Thieme. All rights reserved.
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References
- 1 Roth GA, Johnson C, Abajobir A. et al. Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015. J Am Coll Cardiol 2017; 70 (01) 1-25
- 2 Reininger AJ, Bernlochner I, Penz SM. et al. A 2-step mechanism of arterial thrombus formation induced by human atherosclerotic plaques. J Am Coll Cardiol 2010; 55 (11) 1147-1158
- 3 Versteeg HH, Heemskerk JW, Levi M, Reitsma PH. New fundamentals in hemostasis. Physiol Rev 2013; 93 (01) 327-358
- 4 Okafor ON, Gorog DA. Endogenous fibrinolysis: an important mediator of thrombus formation and cardiovascular risk. J Am Coll Cardiol 2015; 65 (16) 1683-1699
- 5 Longstaff C, Kolev K. Basic mechanisms and regulation of fibrinolysis. J Thromb Haemost 2015; 13 (Suppl. 01) S98-S105
- 6 Hethershaw EL, Cilia La Corte AL, Duval C. et al. The effect of blood coagulation factor XIII on fibrin clot structure and fibrinolysis. J Thromb Haemost 2014; 12 (02) 197-205
- 7 Stegner D, Nieswandt B. Platelet receptor signaling in thrombus formation. J Mol Med (Berl) 2011; 89 (02) 109-121
- 8 Medved L, Nieuwenhuizen W. Molecular mechanisms of initiation of fibrinolysis by fibrin. Thromb Haemost 2003; 89 (03) 409-419
- 9 Yakovlev S, Makogonenko E, Kurochkina N, Nieuwenhuizen W, Ingham K, Medved L. Conversion of fibrinogen to fibrin: mechanism of exposure of tPA- and plasminogen-binding sites. Biochemistry 2000; 39 (51) 15730-15741
- 10 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
- 11 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
- 12 Cieslik J, Mrozinska S, Broniatowska E, Undas A. Altered plasma clot properties increase the risk of recurrent deep vein thrombosis: a cohort study. Blood 2018; 131 (07) 797-807
- 13 Carr Jr ME, Alving BM. Effect of fibrin structure on plasmin-mediated dissolution of plasma clots. Blood Coagul Fibrinolysis 1995; 6 (06) 567-573
- 14 Collet JP, Park D, Lesty C. et al. Influence of fibrin network conformation and fibrin fiber diameter on fibrinolysis speed: dynamic and structural approaches by confocal microscopy. Arterioscler Thromb Vasc Biol 2000; 20 (05) 1354-1361
- 15 Gabriel DA, Muga K, Boothroyd EM. The effect of fibrin structure on fibrinolysis. J Biol Chem 1992; 267 (34) 24259-24263
- 16 Undas A, Plicner D, Stepień E, Drwiła R, Sadowski J. Altered fibrin clot structure in patients with advanced coronary artery disease: a role of C-reactive protein, lipoprotein(a) and homocysteine. J Thromb Haemost 2007; 5 (09) 1988-1990
- 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
- 18 Wolberg AS, Monroe DM, Roberts HR, Hoffman M. Elevated prothrombin results in clots with an altered fiber structure: a possible mechanism of the increased thrombotic risk. Blood 2003; 101 (08) 3008-3013
- 19 He S, Blombäck M, Bark N, Johnsson H, Wallén NH. The direct thrombin inhibitors (argatroban, bivalirudin and lepirudin) and the indirect Xa-inhibitor (danaparoid) increase fibrin network porosity and thus facilitate fibrinolysis. Thromb Haemost 2010; 103 (05) 1076-1084
- 20 Ariëns RA. Fibrin(ogen) and thrombotic disease. J Thromb Haemost 2013; 11 (Suppl. 01) 294-305
- 21 de Vries JJ, Snoek CJM, Rijken DC, de Maat MPM. Effects of post-translational modifications of fibrinogen on clot formation, clot structure, and fibrinolysis: a systematic review. Arterioscler Thromb Vasc Biol 2020; 40 (03) 554-569
- 22 Ariëns RA, Lai TS, Weisel JW, Greenberg CS, Grant PJ. Role of factor XIII in fibrin clot formation and effects of genetic polymorphisms. Blood 2002; 100 (03) 743-754
- 23 Aoki N. Discovery of alpha2-plasmin inhibitor and its congenital deficiency. J Thromb Haemost 2005; 3 (04) 623-631
- 24 Meltzer ME, Doggen CJ, de Groot PG, Rosendaal FR, Lisman T. Plasma levels of fibrinolytic proteins and the risk of myocardial infarction in men. Blood 2010; 116 (04) 529-536
- 25 Cushman M, Lemaitre RN, Kuller LH. et al. Fibrinolytic activation markers predict myocardial infarction in the elderly. The Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 1999; 19 (03) 493-498
- 26 Folsom AR, Delaney JA, Lutsey PL. et al; Multiethnic Study of Atherosclerosis Investigators. Associations of factor VIIIc, D-dimer, and plasmin-antiplasmin with incident cardiovascular disease and all-cause mortality. Am J Hematol 2009; 84 (06) 349-353
- 27 Morange PE, Bickel C, Nicaud V. et al; AtheroGene Investigators. Haemostatic factors and the risk of cardiovascular death in patients with coronary artery disease: the AtheroGene study. Arterioscler Thromb Vasc Biol 2006; 26 (12) 2793-2799
- 28 Redondo M, Carroll VA, Mauron T. et al. Hemostatic and fibrinolytic parameters in survivors of myocardial infarction: a low plasma level of plasmin-alpha2-antiplasmin complex is an independent predictor of coronary re-events. Blood Coagul Fibrinolysis 2001; 12 (01) 17-24
- 29 Dunn EJ, Philippou H, Ariëns RA, Grant PJ. Molecular mechanisms involved in the resistance of fibrin to clot lysis by plasmin in subjects with type 2 diabetes mellitus. Diabetologia 2006; 49 (05) 1071-1080
- 30 Agren A, Jörneskog G, Elgue G, Henriksson P, Wallen H, Wiman B. Increased incorporation of antiplasmin into the fibrin network in patients with type 1 diabetes. Diabetes Care 2014; 37 (07) 2007-2014
- 31 Foley JH, Kim PY, Mutch NJ, Gils A. Insights into thrombin activatable fibrinolysis inhibitor function and regulation. J Thromb Haemost 2013; 11 (Suppl. 01) 306-315
- 32 Schroeder V, Chatterjee T, Mehta H. et al. Thrombin activatable fibrinolysis inhibitor (TAFI) levels in patients with coronary artery disease investigated by angiography. Thromb Haemost 2002; 88 (06) 1020-1025
- 33 de Bruijne EL, Gils A, Rijken DC. et al. High thrombin activatable fibrinolysis inhibitor levels are associated with an increased risk of premature peripheral arterial disease. Thromb Res 2011; 127 (03) 254-258
- 34 de Bruijne EL, Gils A, Guimarães AH. et al. The role of thrombin activatable fibrinolysis inhibitor in arterial thrombosis at a young age: the ATTAC study. J Thromb Haemost 2009; 7 (06) 919-927
- 35 Meltzer ME, Doggen CJ, de Groot PG, Meijers JC, Rosendaal FR, Lisman T. Low thrombin activatable fibrinolysis inhibitor activity levels are associated with an increased risk of a first myocardial infarction in men. Haematologica 2009; 94 (06) 811-818
- 36 Juhan-Vague I, Morange PE, Aubert H. et al; HIFMECH Study Group. Plasma thrombin-activatable fibrinolysis inhibitor antigen concentration and genotype in relation to myocardial infarction in the north and south of Europe. Arterioscler Thromb Vasc Biol 2002; 22 (05) 867-873
- 37 Juhan-Vague I, Morange PE. PRIME Study Group. Very high TAFI antigen levels are associated with a lower risk of hard coronary events: the PRIME Study. J Thromb Haemost 2003; 1 (10) 2243-2244
- 38 Tregouet DA, Schnabel R, Alessi MC. et al; AtheroGene Investigators. Activated thrombin activatable fibrinolysis inhibitor levels are associated with the risk of cardiovascular death in patients with coronary artery disease: the AtheroGene study. J Thromb Haemost 2009; 7 (01) 49-57
- 39 Robbie LA, Bennett B, Croll AM, Brown PA, Booth NA. Proteins of the fibrinolytic system in human thrombi. Thromb Haemost 1996; 75 (01) 127-133
- 40 Kohler HP, Grant PJ. Plasminogen-activator inhibitor type 1 and coronary artery disease. N Engl J Med 2000; 342 (24) 1792-1801
- 41 Jung RG, Simard T, Labinaz A. et al. Role of plasminogen activator inhibitor-1 in coronary pathophysiology. Thromb Res 2018; 164: 54-62
- 42 Urano T, Sakakibara K, Rydzewski A, Urano S, Takada Y, Takada A. Relationships between euglobulin clot lysis time and the plasma levels of tissue plasminogen activator and plasminogen activator inhibitor 1. Thromb Haemost 1990; 63 (01) 82-86
- 43 Hess K, Alzahrani SH, Price JF. et al. Hypofibrinolysis in type 2 diabetes: the role of the inflammatory pathway and complement C3. Diabetologia 2014; 57 (08) 1737-1741
- 44 Levi M, Biemond BJ, van Zonneveld AJ, ten Cate JW, Pannekoek H. Inhibition of plasminogen activator inhibitor-1 activity results in promotion of endogenous thrombolysis and inhibition of thrombus extension in models of experimental thrombosis. Circulation 1992; 85 (01) 305-312
- 45 Gorog DA. Prognostic value of plasma fibrinolysis activation markers in cardiovascular disease. J Am Coll Cardiol 2010; 55 (24) 2701-2709
- 46 Song C, Burgess S, Eicher JD, O'Donnell CJ, Johnson AD. Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease. J Am Heart Assoc 2017; 6 (06) 6
- 47 Barthel D, Schindler S, Zipfel PF. Plasminogen is a complement inhibitor. J Biol Chem 2012; 287 (22) 18831-18842
- 48 Hess K, Alzahrani SH, Mathai M. et al. A novel mechanism for hypofibrinolysis in diabetes: the role of complement C3. Diabetologia 2012; 55 (04) 1103-1113
- 49 Schutt KA, Maxeiner S, Lysaja K. et al. Complement activation leads to C3 and C5 dependent prothrombotic alterations of fibrin clots. Eur Heart J 2019; 40 (supplement): 1948
- 50 Ajjan R, Grant PJ, Futers TS. et al. Complement C3 and C-reactive protein levels in patients with stable coronary artery disease. Thromb Haemost 2005; 94 (05) 1048-1053
- 51 Wilson DP, Jacobson TA, Jones PH. et al. Use of lipoprotein(a) in clinical practice: a biomarker whose time has come. A scientific statement from the National Lipid Association. J Clin Lipidol 2019; 13 (03) 374-392
- 52 Boffa MB, Koschinsky ML. Lipoprotein (a): truly a direct prothrombotic factor in cardiovascular disease?. J Lipid Res 2016; 57 (05) 745-757
- 53 Undas A, Stepien E, Tracz W, Szczeklik A. Lipoprotein(a) as a modifier of fibrin clot permeability and susceptibility to lysis. J Thromb Haemost 2006; 4 (05) 973-975
- 54 Etingin OR, Hajjar DP, Hajjar KA, Harpel PC, Nachman RL. Lipoprotein (a) regulates plasminogen activator inhibitor-1 expression in endothelial cells. A potential mechanism in thrombogenesis. J Biol Chem 1991; 266 (04) 2459-2465
- 55 Ren S, Man RY, Angel A, Shen GX. Oxidative modification enhances lipoprotein(a)-induced overproduction of plasminogen activator inhibitor-1 in cultured vascular endothelial cells. Atherosclerosis 1997; 128 (01) 1-10
- 56 Boffa MB, Marar TT, Yeang C. et al. Potent reduction of plasma lipoprotein (a) with an antisense oligonucleotide in human subjects does not affect ex vivo fibrinolysis. J Lipid Res 2019; 60 (12) 2082-2089
- 57 Ilich A, Bokarev I, Key NS. Global assays of fibrinolysis. Int J Lab Hematol 2017; 39 (05) 441-447
- 58 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
- 59 Kreutz RP, Schmeisser G, Maatman B. et al. Fibrin clot strength measured by thrombelastography and outcomes after percutaneous coronary intervention. Thromb Haemost 2017; 117 (02) 426-428
- 60 Christopoulos C, Farag M, Sullivan K, Wellsted D, Gorog DA. Impaired thrombolytic status predicts adverse cardiac events in patients undergoing primary percutaneous coronary intervention. Thromb Haemost 2017; 117 (03) 457-470
- 61 Saraf S, Christopoulos C, Salha IB, Stott DJ, Gorog DA. Impaired endogenous thrombolysis in acute coronary syndrome patients predicts cardiovascular death and nonfatal myocardial infarction. J Am Coll Cardiol 2010; 55 (19) 2107-2115
- 62 Undas A, Slowik A, Wolkow P, Szczudlik A, Tracz W. Fibrin clot properties in acute ischemic stroke: relation to neurological deficit. Thromb Res 2010; 125 (04) 357-361
- 63 Bembenek JP, Niewada M, Siudut J, Plens K, Członkowska A, Undas A. Fibrin clot characteristics in acute ischaemic stroke patients treated with thrombolysis: the impact on clinical outcome. Thromb Haemost 2017; 117 (07) 1440-1447
- 64 Karpińska IA, Nowakowski T, Wypasek E, Plens K, Undas A. A prothrombotic state and denser clot formation in patients following acute limb ischemia of unknown cause. Thromb Res 2020; 187: 32-38
- 65 Nowakowski T, Malinowski KP, Niżankowski R, Iwaniec T, Undas A. Restenosis is associated with prothrombotic plasma fibrin clot characteristics in endovascularly treated patients with critical limb ischemia. J Thromb Thrombolysis 2019; 47 (04) 540-549
- 66 Reddel CJ, Curnow JL, Voitl J. et al. Detection of hypofibrinolysis in stable coronary artery disease using the overall haemostatic potential assay. Thromb Res 2013; 131 (05) 457-462
- 67 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
- 68 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
- 69 Tantry US, Bliden KP, Suarez TA, Kreutz RP, Dichiara J, Gurbel PA. Hypercoagulability, platelet function, inflammation and coronary artery disease acuity: results of the Thrombotic RIsk Progression (TRIP) study. Platelets 2010; 21 (05) 360-367
- 70 Gurbel PA, Bliden KP, Kreutz RP, Dichiara J, Antonino MJ, Tantry US. The link between heightened thrombogenicity and inflammation: pre-procedure characterization of the patient at high risk for recurrent events after stenting. Platelets 2009; 20 (02) 97-104
- 71 Hou X, Han W, Gan Q, Liu Y, Fang W. Relationship between thromboelastography and long-term ischemic events as gauged by the response to clopidogrel in patients undergoing elective percutaneous coronary intervention. Biosci Trends 2017; 11 (02) 209-213
- 72 Neergaard-Petersen S, Larsen SB, Grove EL, Kristensen SD, Ajjan RA, Hvas AM. Imbalance between fibrin clot formation and fibrinolysis predicts cardiovascular events in patients with stable coronary artery disease. Thromb Haemost 2020; 120 (01) 75-82
- 73 Anzej S, Bozic M, Antovic A. et al. Evidence of hypercoagulability and inflammation in young patients long after acute cerebral ischaemia. Thromb Res 2007; 120 (01) 39-46
- 74 Undas A, Podolec P, Zawilska K. et al. Altered fibrin clot structure/function in patients with cryptogenic ischemic stroke. Stroke 2009; 40 (04) 1499-1501
- 75 Vucković BA, Djerić MJ, Ilić TA. et al. Fibrinolytic parameters, lipid status and lipoprotein(a) in ischemic stroke patients. Srp Arh Celok Lek 2010; 138 (Suppl. 01) 12-17
- 76 Wang B, Li XQ, Ma N. et al. Association of thrombelastographic parameters with post-stenting ischemic events. J Neurointerv Surg 2017; 9 (02) 192-195
- 77 Undas A, Nowakowski T, Cieśla-Dul M, Sadowski J. Abnormal plasma fibrin clot characteristics are associated with worse clinical outcome in patients with peripheral arterial disease and thromboangiitis obliterans. Atherosclerosis 2011; 215 (02) 481-486
- 78 Okraska-Bylica A, Wilkosz T, Słowik L, Bazanek M, Konieczyńska M, Undas A. Altered fibrin clot properties in patients with premature peripheral artery disease. Pol Arch Med Wewn 2012; 122 (12) 608-615
- 79 Bhasin N, Ariëns RA, West RM, Parry DJ, Grant PJ, Scott DJ. Altered fibrin clot structure and function in the healthy first-degree relatives of subjects with intermittent claudication. J Vasc Surg 2008; 48 (06) 1497-1503 , 1503.e1
- 80 Bhasin N, Parry DJ, Scott DJ, Ariëns RA, Grant PJ, West RM. Regarding “Altered fibrin clot structure and function in individuals with intermittent claudication”. J Vasc Surg 2009; 49 (04) 1088-1089
- 81 Orfeo T, Gissel M, Butenas S, Undas A, Brummel-Ziedins KE, Mann KG. Anticoagulants and the propagation phase of thrombin generation. PLoS One 2011; 6 (11) e27852
- 82 Morishima Y, Honda Y. A direct oral anticoagulant edoxaban accelerated fibrinolysis via enhancement of plasmin generation in human plasma: dependent on thrombin-activatable fibrinolysis inhibitor. J Thromb Thrombolysis 2019; 48 (01) 103-110
- 83 Franchi F, Rollini F, Garcia E. et al. Effects of edoxaban on the cellular and protein phase of coagulation in patients with coronary artery disease on dual antiplatelet therapy with aspirin and clopidogrel: results of the EDOX-APT study. Thromb Haemost 2020; 120 (01) 83-93
- 84 Gue YX, Kanji R, Wellsted DM, Srinivasan M, Wyatt S, Gorog DA. Rationale and design of “Can Very Low Dose Rivaroxaban (VLDR) in addition to dual antiplatelet therapy improve thrombotic status in acute coronary syndrome (VaLiDate-R)” study: a randomised trial modulating endogenous fibrinolysis in patients with acute coronary syndrome. J Thromb Thrombolysis 2020; 49 (02) 192-198
- 85 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
- 86 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
- 87 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
- 88 Anand SS, Caron F, Eikelboom JW. et al. Major adverse limb events and mortality in patients with peripheral artery disease: the COMPASS trial. J Am Coll Cardiol 2018; 71 (20) 2306-2315
- 89 Coppens M, Weitz JI, Eikelboom JWA. Synergy of dual pathway inhibition in chronic cardiovascular disease. Circ Res 2019; 124 (03) 416-425
- 90 Ammollo CT, Semeraro F, Incampo F, Semeraro N, Colucci M. Dabigatran enhances clot susceptibility to fibrinolysis by mechanisms dependent on and independent of thrombin-activatable fibrinolysis inhibitor. J Thromb Haemost 2010; 8 (04) 790-798
- 91 Königsbrügge O, Weigel G, Quehenberger P, Pabinger I, Ay C. Plasma clot formation and clot lysis to compare effects of different anticoagulation treatments on hemostasis in patients with atrial fibrillation. Clin Exp Med 2018; 18 (03) 325-336
- 92 Salta S, Papageorgiou L, Larsen AK. et al. Comparison of antithrombin-dependent and direct inhibitors of factor Xa or thrombin on the kinetics and qualitative characteristics of blood clots. Res Pract Thromb Haemost 2018; 2 (04) 696-707
- 93 Franchi F, Rollini F, Cho JR. et al. Effects of dabigatran on the cellular and protein phase of coagulation in patients with coronary artery disease on dual antiplatelet therapy with aspirin and clopidogrel. Results from a prospective, randomised, double-blind, placebo-controlled study. Thromb Haemost 2016; 115 (03) 622-631
- 94 Connolly SJ, Ezekowitz MD, Yusuf S. et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12) 1139-1151
- 95 Oldgren J, Budaj A, Granger CB. et al; RE-DEEM Investigators. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. Eur Heart J 2011; 32 (22) 2781-2789
- 96 Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials. Arch Intern Med 2012; 172 (05) 397-402
- 97 Willemse JL, Heylen E, Nesheim ME, Hendriks DF. Carboxypeptidase U (TAFIa): a new drug target for fibrinolytic therapy? . J Thromb Haemost 2009; 7 (12) 1962-1971
- 98 Wyseure T, Declerck PJ. Novel or expanding current targets in fibrinolysis. Drug Discov Today 2014; 19 (09) 1476-1482
- 99 Kearney K, Tomlinson D, Smith K, Ajjan R. Hypofibrinolysis in diabetes: a therapeutic target for the reduction of cardiovascular risk. Cardiovasc Diabetol 2017; 16 (01) 34
- 100 Van De Craen B, Scroyen I, Vranckx C. et al. Maximal PAI-1 inhibition in vivo requires neutralizing antibodies that recognize and inhibit glycosylated PAI-1. Thromb Res 2012; 129 (04) e126-e133
- 101 Izuhara Y, Yamaoka N, Kodama H. et al. A novel inhibitor of plasminogen activator inhibitor-1 provides antithrombotic benefits devoid of bleeding effect in nonhuman primates. J Cereb Blood Flow Metab 2010; 30 (05) 904-912
- 102 Zhou X, Hendrickx ML, Hassanzadeh-Ghassabeh G, Muyldermans S, Declerck PJ. Generation and in vitro characterisation of inhibitory nanobodies towards plasminogen activator inhibitor 1. Thromb Haemost 2016; 116 (06) 1032-1040
- 103 Elokdah H, Abou-Gharbia M, Hennan JK. et al. Tiplaxtinin, a novel, orally efficacious inhibitor of plasminogen activator inhibitor-1: design, synthesis, and preclinical characterization. J Med Chem 2004; 47 (14) 3491-3494
- 104 Fortenberry YM. Plasminogen activator inhibitor-1 inhibitors: a patent review (2006-present). Expert Opin Ther Pat 2013; 23 (07) 801-815
- 105 Rouch A, Vanucci-Bacqué C, Bedos-Belval F, Baltas M. Small molecules inhibitors of plasminogen activator inhibitor-1 - an overview. Eur J Med Chem 2015; 92: 619-636
- 106 Wyseure T, Rubio M, Denorme F. et al. Innovative thrombolytic strategy using a heterodimer diabody against TAFI and PAI-1 in mouse models of thrombosis and stroke. Blood 2015; 125 (08) 1325-1332
- 107 Singh S, Houng A, Reed GL. Releasing the brakes on the fibrinolytic system in pulmonary emboli: unique effects of plasminogen activation and α2-antiplasmin inactivation. Circulation 2017; 135 (11) 1011-1020
- 108 Ricklin D, Lambris JD. Complement-targeted therapeutics. Nat Biotechnol 2007; 25 (11) 1265-1275
- 109 King R, Tiede C, Simmons K, Fishwick C, Tomlinson D, Ajjan R. Inhibition of complement C3 and fibrinogen interaction: a potential novel therapeutic target to reduce cardiovascular disease in diabetes. Lancet 2015; 385 (Suppl. 01) S57
- 110 Ajjan RA, Gamlen T, Standeven KF. et al. Diabetes is associated with posttranslational modifications in plasminogen resulting in reduced plasmin generation and enzyme-specific activity. Blood 2013; 122 (01) 134-142
- 111 Meltzer ME, Doggen CJ, de Groot PG, Rosendaal FR, Lisman T. Reduced plasma fibrinolytic capacity as a potential risk factor for a first myocardial infarction in young men. Br J Haematol 2009; 145 (01) 121-127