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DOI: 10.1055/s-0042-1758057
Fibrinolysis Shutdown and Hypofibrinolysis Are Not Synonymous Terms: The Clinical Significance of Differentiating Low Fibrinolytic States
Funding This research is supported in part by the American Society of Transplant Surgeons Veloxis Fellowship Grant and National Heart Lung and Blood Institute Grant R00-HL151887.![](https://www.thieme-connect.de/media/sth/202305/lookinside/thumbnails/10-1055-s-0042-1758057_03060-1.jpg)
Abstract
Low fibrinolytic activity has been associated with pathologic thrombosis and multiple-organ failure. Low fibrinolytic activity has two commonly associated terms, hypofibrinolysis and fibrinolysis shutdown. Hypofibrinolysis is a chronic state of lack of ability to generate an appropriate fibrinolytic response when anticipated. Fibrinolysis shutdown is the shutdown of fibrinolysis after systemic activation of the fibrinolytic system. There has been interchanging of these terms to describe critically ill patients in multiple settings. This is problematic in understanding the pathophysiology of disease processes related to these conditions. There is also a lack of research on the cellular mediators of these processes. The purpose of this article is to review the on and off mechanisms of fibrinolysis in the context of low fibrinolytic states to define the importance in differentiating hypofibrinolysis from fibrinolysis shutdown. In many clinical scenarios, the etiology of a low fibrinolytic state cannot be determined due to ambiguity if a preceding fibrinolytic activation event occurred. In this scenario, the term “low fibrinolytic activity” or “fibrinolysis resistance” is a more appropriate descriptor, rather than using assumptive of hypofibrinolysis and fibrinolysis shutdown, particularly in the acute setting of infection, injury, and surgery.
Publication History
Article published online:
01 November 2022
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References
- 1 Tillett WS, Sherry S. The effect in patients of streptococcal fibrinolysin (streptokinase) and streptococcal desoxyribonuclease on fibrinous, purulent, and sanguinous pleural exudations. J Clin Invest 1949; 28 (01) 173-190
- 2 Collins R, Peto R, Baigent C, Sleight P. Aspirin, heparin, and fibrinolytic therapy in suspected acute myocardial infarction. N Engl J Med 1997; 336 (12) 847-860
- 3 Wells PS, Forgie MA, Rodger MA. Treatment of venous thromboembolism. JAMA 2014; 311 (07) 717-728
- 4 Wechsler LR. Intravenous thrombolytic therapy for acute ischemic stroke. N Engl J Med 2011; 364 (22) 2138-2146
- 5 Von Kaulla KN, Kaye H, von Kaulla E, Marchioro TL, Starzl TE. Changes in blood coagulation. Arch Surg 1966; 92 (01) 71-79
- 6 Attar S, Boyd D, Layne E, McLaughlin J, Mansberger AR, Cowley RA. Alterations in coagulation and fibrinolytic mechanisms in acute trauma. J Trauma 1969; 9 (11) 939-965
- 7 Lijnen HR, Collen D. Fibrinolytic agents: mechanisms of activity and pharmacology. Thromb Haemost 1995; 74 (01) 387-390
- 8 Stein PD, Hull RD, Raskob G. Risks for major bleeding from thrombolytic therapy in patients with acute pulmonary embolism. Consideration of noninvasive management. Ann Intern Med 1994; 121 (05) 313-317
- 9 van Hinsbergh VW, Kooistra T, Emeis JJ, Koolwijk P. Regulation of plasminogen activator production by endothelial cells: role in fibrinolysis and local proteolysis. Int J Radiat Biol 1991; 60 (1-2): 261-272
- 10 O'Rourke J, Jiang X, Hao Z, Cone RE, Hand AR. Distribution of sympathetic tissue plasminogen activator (tPA) to a distant microvasculature. J Neurosci Res 2005; 79 (06) 727-733
- 11 Peng T, Jiang X, Wang Y. et al. Sympathectomy decreases and adrenergic stimulation increases the release of tissue plasminogen activator (t-PA) from blood vessels: functional evidence for a neurologic regulation of plasmin production within vessel walls and other tissue matrices. J Neurosci Res 1999; 57 (05) 680-692
- 12 Astrup T, Permin PM. Fibrinolysis in the animal organism. Nature 1947; 159 (4046): 681
- 13 Astrup T. Fibrinolysis in the organism. Blood 1956; 11 (09) 781-806
- 14 Fuhrman B. The urokinase system in the pathogenesis of atherosclerosis. Atherosclerosis 2012; 222 (01) 8-14
- 15 Cohen MJ, Call M, Nelson M. et al. Critical role of activated protein C in early coagulopathy and later organ failure, infection and death in trauma patients. Ann Surg 2012; 255 (02) 379-385
- 16 Johansson PI, Haase N, Perner A, Ostrowski SR. Association between sympathoadrenal activation, fibrinolysis, and endothelial damage in septic patients: a prospective study. J Crit Care 2014; 29 (03) 327-333
- 17 Chapman MP, Moore EE, Moore HB. et al. Overwhelming tPA release, not PAI-1 degradation, is responsible for hyperfibrinolysis in severely injured trauma patients. J Trauma Acute Care Surg 2016; 80 (01) 16-23 , discussion 23–25
- 18 Pannell R, Li S, Gurewich V. Fibrin-specific and effective clot lysis requires both plasminogen activators and for them to be in a sequential rather than simultaneous combination. J Thromb Thrombolysis 2017; 44 (02) 210-215
- 19 Falcone DJ, McCaffrey TA, Haimovitz-Friedman A, Garcia M. Transforming growth factor-beta 1 stimulates macrophage urokinase expression and release of matrix-bound basic fibroblast growth factor. J Cell Physiol 1993; 155 (03) 595-605
- 20 Cook AD, Vlahos R, Massa CM. et al. The effect of tissue type-plasminogen activator deletion and associated fibrin(ogen) deposition on macrophage localization in peritoneal inflammation. Thromb Haemost 2006; 95 (04) 659-667
- 21 Smith HW, Marshall CJ. Regulation of cell signalling by uPAR. Nat Rev Mol Cell Biol 2010; 11 (01) 23-36
- 22 Mahmood N, Mihalcioiu C, Rabbani SA. Multifaceted role of the urokinase-type plasminogen activator (uPA) and its receptor (uPAR): diagnostic, prognostic, and therapeutic applications. Front Oncol 2018; 8: 24
- 23 Kwaan HC, Lindholm PF. Fibrin and fibrinolysis in cancer. Semin Thromb Hemost 2019; 45 (04) 413-422
- 24 Ismail AA, Shaker BT, Bajou K. The plasminogen-activator plasmin system in physiological and pathophysiological angiogenesis. Int J Mol Sci 2021; 23 (01) 337
- 25 Breuss JM, Uhrin P. VEGF-initiated angiogenesis and the uPA/uPAR system. Cell Adhes Migr 2012; 6 (06) 535-615
- 26 Lacroix R, Sabatier F, Mialhe A. et al. Activation of plasminogen into plasmin at the surface of endothelial microparticles: a mechanism that modulates angiogenic properties of endothelial progenitor cells in vitro. Blood 2007; 110 (07) 2432-2439
- 27 Plesner T, Behrendt N, Ploug M. Structure, function and expression on blood and bone marrow cells of the urokinase-type plasminogen activator receptor, uPAR. Stem Cells 1997; 15 (06) 398-408
- 28 Plow EF, Doeuvre L, Das R. So many plasminogen receptors: why?. J Biomed Biotechnol 2012; 2012: 141806
- 29 Carmeliet P, Schoonjans L, Kieckens L. et al. Physiological consequences of loss of plasminogen activator gene function in mice. Nature 1994; 368 (6470): 419-424
- 30 Astrup T. The biological significance of fibrinolysis. Lancet 1956; 271 (6942): 565-568
- 31 Rijken DC, Sakharov DV. Basic principles in thrombolysis: regulatory role of plasminogen. Thromb Res 2001; 103 (Suppl. 01) S41-S49
- 32 Urano T, Suzuki Y, Iwaki T, Sano H, Honkura N, Castellino FJ. Recognition of plasminogen activator inhibitor type 1 as the primary regulator of fibrinolysis. Curr Drug Targets 2019; 20 (16) 1695-1701
- 33 Reilly TM, Mousa SA, Seetharam R, Racanelli AL. Recombinant plasminogen activator inhibitor type 1: a review of structural, functional, and biological aspects. Blood Coagul Fibrinolysis 1994; 5 (01) 73-81
- 34 Kluft C, Verheijen JH, Jie AF. et al. The postoperative fibrinolytic shutdown: a rapidly reverting acute phase pattern for the fast-acting inhibitor of tissue-type plasminogen activator after trauma. Scand J Clin Lab Invest 1985; 45 (07) 605-610
- 35 Otter M, Kuiper J, van Berkel TJ, Rijken DC. Mechanisms of tissue-type plasminogen activator (tPA) clearance by the liver. Ann N Y Acad Sci 1992; 667: 431-442
- 36 Porte RJ, Bontempo FA, Knot EA, Lewis JH, Kang YG, Starzl TE. Systemic effects of tissue plasminogen activator-associated fibrinolysis and its relation to thrombin generation in orthotopic liver transplantation. Transplantation 1989; 47 (06) 978-984
- 37 Hoylaerts M, Rijken DC, Lijnen HR, Collen D. Kinetics of the activation of plasminogen by human tissue plasminogen activator. Role of fibrin. J Biol Chem 1982; 257 (06) 2912-2919
- 38 Bouma BN, Mosnier LO. Thrombin activatable fibrinolysis inhibitor (TAFI)–how does thrombin regulate fibrinolysis?. Ann Med 2006; 38 (06) 378-388
- 39 Rijken DC, Uitte de Willige S. Inhibition of fibrinolysis by coagulation factor XIII. BioMed Res Int 2017; 2017: 1209676
- 40 Lee KN, Lee CS, Tae WC, Jackson KW, Christiansen VJ, McKee PA. Crosslinking of alpha 2-antiplasmin to fibrin. Ann N Y Acad Sci 2001; 936: 335-339
- 41 Collen D. Natural inhibitors of fibrinolysis. J Clin Pathol Suppl (R Coll Pathol) 1980; 14: 24-30
- 42 Booth NA. Fibrinolysis and thrombosis. Best Pract Res Clin Haematol 1999; 12 (03) 423-433
- 43 Mutch NJ, Thomas L, Moore NR, Lisiak KM, Booth NA. TAFIa, PAI-1 and alpha-antiplasmin: complementary roles in regulating lysis of thrombi and plasma clots. J Thromb Haemost 2007; 5 (04) 812-817
- 44 Egeblad K, Astrup T. Effects of human plasma on thrombelastographic patterns produced by fibrinolytic agents in fibrin clots. Br J Haematol 1967; 13 (01) 10-13
- 45 Moore HB, Moore EE, Chapman MP. et al. Viscoelastic measurements of platelet function, not fibrinogen function, predicts sensitivity to tissue-type plasminogen activator in trauma patients. J Thromb Haemost 2015; 13 (10) 1878-1887
- 46 Brass LF, Diamond SL, Stalker TJ. Platelets and hemostasis: a new perspective on an old subject. Blood Adv 2016; 1 (01) 5-9
- 47 Brass LF, Stalker TJ. Minding the gaps – and the junctions, too. Circulation 2012; 125 (20) 2414-2416
- 48 Huebner BR, Moore EE, Moore HB. et al. Thrombin provokes degranulation of platelet α-granules leading to the release of active plasminogen activator inhibitor-1 (PAI-1). Shock 2018; 50 (06) 671-676
- 49 Mosnier LO, Buijtenhuijs P, Marx PF, Meijers JC, Bouma BN. Identification of thrombin activatable fibrinolysis inhibitor (TAFI) in human platelets. Blood 2003; 101 (12) 4844-4846
- 50 Moore HB, Moore EE, Gonzalez E. et al. Hemolysis exacerbates hyperfibrinolysis, whereas platelolysis shuts down fibrinolysis: evolving concepts of the spectrum of fibrinolysis in response to severe injury. Shock 2015; 43 (01) 39-46
- 51 Sakharov DV, Nagelkerke JF, Rijken DC. Rearrangements of the fibrin network and spatial distribution of fibrinolytic components during plasma clot lysis. Study with confocal microscopy. J Biol Chem 1996; 271 (04) 2133-2138
- 52 Mutch NJ, Koikkalainen JS, Fraser SR. et al. Model thrombi formed under flow reveal the role of factor XIII-mediated cross-linking in resistance to fibrinolysis. J Thromb Haemost 2010; 8 (09) 2017-2024
- 53 Zubairova LD, Nabiullina RM, Nagaswami C. et al. Circulating microparticles alter formation, structure, and properties of fibrin clots. Sci Rep 2015; 5: 17611
- 54 Cockell KA, Ren S, Sun J, Angel A, Shen GX. Effect of thrombin on release of plasminogen activator inhibitor-1 from cultured primate arterial smooth muscle cells. Thromb Res 1995; 77 (02) 119-131
- 55 Longstaff C, Varjú I, Sótonyi P. et al. Mechanical stability and fibrinolytic resistance of clots containing fibrin, DNA, and histones. J Biol Chem 2013; 288 (10) 6946-6956
- 56 Gould TJ, Lysov Z, Liaw PC. Extracellular DNA and histones: double-edged swords in immunothrombosis. J Thromb Haemost 2015; 13 (Suppl. 01) S82-S91
- 57 Xie F, Tan Q, Yu A. et al. The role of cell-free DNA in fibrinolysis for intraventricular hemorrhage. J Neurosurg 2021; doi: 10.3171/2020.7.JNS201429
- 58 Mosesson MW. Fibrinogen and fibrin structure and functions. J Thromb Haemost 2005; 3 (08) 1894-1904
- 59 Mangin PH, Neeves KB, Lam WA. et al; Subcommittee on Biorheology. In vitro flow-based assay: from simple toward more sophisticated models for mimicking hemostasis and thrombosis. J Thromb Haemost 2021; 19 (02) 582-587
- 60 Hoffman M, Monroe III DM. A cell-based model of hemostasis. Thromb Haemost 2001; 85 (06) 958-965
- 61 Kwaan HC. Fibrinolysis – a perspective. Prog Cardiovasc Dis 1979; 21 (05) 397-403
- 62 Sherry S, Lindemeyer RI, Fletcher AP, Alkjaersig N. Studies on enhanced fibrinolytic activity in man. J Clin Invest 1959; 38 (05) 810-822
- 63 Kjaeldgaard A, Kjaeldgaard M. In vitro stimulation of plasminogen activator release from vein walls by adrenaline. J Clin Pathol 1986; 39 (11) 1241-1244
- 64 Keber D, Stegnar M, Kluft C. Different tissue plasminogen activator release in the arm and leg during venous occlusion is equalized after DDAVP infusion. Thromb Haemost 1990; 63 (01) 72-75
- 65 Urano T, Malyszko J, Takada Y, Takada A. Close relationships between serotonergic and fibrinolytic systems revealed by a monoamine oxidase inhibitor treatment in rats. Haemostasis 1995; 25 (06) 277-282
- 66 Kwaan HC, Lo R, McFadzean AJ. The production of plasma fibrinolytic activity in vivo by serotonin (5-hydroxytryptamine) creatinine sulphate. Clin Sci 1957; 16 (02) 255-259
- 67 Holemans R, Langdell RD. Histamine-induced increase in fibrinolytic activity. Proc Soc Exp Biol Med 1964; 115: 584-587
- 68 Brown NJ, Gainer JV, Murphey LJ, Vaughan DE. Bradykinin stimulates tissue plasminogen activator release from human forearm vasculature through B(2) receptor-dependent, NO synthase-independent, and cyclooxygenase-independent pathway. Circulation 2000; 102 (18) 2190-2196
- 69 Andreotti L, Nuzzaci G. Paneraia. [Fibrinolytic effect of acetylcholine administered by intra-arterial route. Preliminary note]. Boll Soc Ital Biol Sper 1961; 37: 1273-1274
- 70 Vervloet MG, Thijs LG, Hack CE. Derangements of coagulation and fibrinolysis in critically ill patients with sepsis and septic shock. Semin Thromb Hemost 1998; 24 (01) 33-44
- 71 Gando S. Disseminated intravascular coagulation in trauma patients. Semin Thromb Hemost 2001; 27 (06) 585-592
- 72 Hardaway RM. Trauma, sepsis, and disseminated intravascular coagulation. J Intensive Care Med 1995; 10 (03) 145-152
- 73 Levi M, van der Poll T. A short contemporary history of disseminated intravascular coagulation. Semin Thromb Hemost 2014; 40 (08) 874-880
- 74 Innes D, Sevitt S. Coagulation and fibrinolysis in injured patients. J Clin Pathol 1964; 17: 1-13
- 75 Moore HB, Moore EE. Temporal changes in fibrinolysis following injury. Semin Thromb Hemost 2020; 46 (02) 189-198
- 76 Biemond BJ, Levi M, Ten Cate H. et al. Plasminogen activator and plasminogen activator inhibitor I release during experimental endotoxaemia in chimpanzees: effect of interventions in the cytokine and coagulation cascades. Clin Sci (Lond) 1995; 88 (05) 587-594
- 77 Kwaan HC, Lindholm PF. The central role of fibrinolytic response in COVID-19 - a hematologist's perspective. Int J Mol Sci 2021; 22 (03) 1283
- 78 Meizoso JP, Moore HB, Moore EE. Fibrinolysis shutdown in COVID-19: clinical manifestations, molecular mechanisms, and therapeutic implications. J Am Coll Surg 2021; 232 (06) 995-1003
- 79 Tillett WS, Edwards LB, Garner RL. Fibrinolytic activity of hemolytic streptococci. The development of resistance to fibrinolysis following acute hemolytic streptococcus infections. J Clin Invest 1934; 13 (01) 47-78
- 80 Bennett B, Croll A, Ferguson K, Booth NA. Complexing of tissue plasminogen activator with PAI-1, alpha 2-macroglobulin, and C1-inhibitor: studies in patients with defibrination and a fibrinolytic state after electroshock or complicated labor. Blood 1990; 75 (03) 671-676
- 81 Moore HB, Moore ME, Gonzalez E, Huebner BJ. et al. Reperfusion shutdown: delayed onset of fibrinolysis resistance after resuscitation from hemorrhagic shock is associated with increased circulating levels of plasminogen activator inhibitor-1 and postinjury complications. Blood 2016; 128: 206
- 82 Moore HB, Moore EE, Huebner BR. et al. Fibrinolysis shutdown is associated with a fivefold increase in mortality in trauma patients lacking hypersensitivity to tissue plasminogen activator. J Trauma Acute Care Surg 2017; 83 (06) 1014-1022
- 83 Cardenas JC, Wade CE, Cotton BA. et al; PROPPR Study Group. TEG lysis shutdown represents coagulopathy in bleeding trauma patients: analysis of the PROPPR cohort. Shock 2019; 51 (03) 273-283
- 84 Gall LS, Vulliamy P, Gillespie S. et al. The S100A10 pathway mediates an occult hyperfibrinolytic subtype in trauma patients. Ann Surg 2018; 229: 92-101
- 85 Moore HB, Moore EE, Chapman MP. et al. Does tranexamic acid improve clot strength in severely injured patients who have elevated fibrin degradation products and low fibrinolytic activity, measured by thrombelastography?. J Am Coll Surg 2019; 229 (01) 92-101
- 86 Shakur H, Roberts I, Bautista R. et al; CRASH-2 Trial Collaborators. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet 2010; 376 (9734): 23-32
- 87 Moore HB, Yaffe H, Pomposelli JJ. et al. Detection of early allograft dysfunction at 30 min of reperfusion in liver transplantation: an intraoperative diagnostic tool with real time assessment of graft function. Am J Surg 2020; 220 (06) 1518-1525
- 88 de Boer A, Kluft C, Kroon JM. et al. Liver blood flow as a major determinant of the clearance of recombinant human tissue-type plasminogen activator. Thromb Haemost 1992; 67 (01) 83-87
- 89 van Griensven JM, Koster RW, Burggraaf J. et al. Effects of liver blood flow on the pharmacokinetics of tissue-type plasminogen activator (alteplase) during thrombolysis in patients with acute myocardial infarction. Clin Pharmacol Ther 1998; 63 (01) 39-47
- 90 van der Kaaden ME, Rijken DC, Kruijt JK, van Berkel TJ, Kuiper J. The role of the low-density lipoprotein receptor-related protein (LRP) in the plasma clearance and liver uptake of recombinant single-chain urokinase-type plasminogen activator in rats. Thromb Haemost 1997; 77 (04) 710-717
- 91 Biessen EA, van Teijlingen M, Vietsch H. et al. Antagonists of the mannose receptor and the LDL receptor-related protein dramatically delay the clearance of tissue plasminogen activator. Circulation 1997; 95 (01) 46-52
- 92 Narita M, Bu G, Herz J, Schwartz AL. Two receptor systems are involved in the plasma clearance of tissue-type plasminogen activator (t-PA) in vivo. J Clin Invest 1995; 96 (02) 1164-1168
- 93 Kuiper J, Otter M, Voorschuur AH, van Zonneveld AJ, Rijken DC, van Berkel TJ. Characterization of the interaction of a complex of tissue-type plasminogen activator and plasminogen activator inhibitor type 1 with rat liver cells. Thromb Haemost 1995; 74 (05) 1298-1304
- 94 Andreasen PA, Sottrup-Jensen L, Kjøller L. et al. Receptor-mediated endocytosis of plasminogen activators and activator/inhibitor complexes. FEBS Lett 1994; 338 (03) 239-245
- 95 Mantuano E, Azmoon P, Brifault C. et al. Tissue-type plasminogen activator regulates macrophage activation and innate immunity. Blood 2017; 130 (11) 1364-1374
- 96 Huebner BR, Moore EE, Moore HB. et al. Thrombin stimulates increased plasminogen activator inhibitor-1 release from liver compared to lung endothelium. J Surg Res 2018; 225: 1-5
- 97 Fearns C, Loskutoff DJ. Induction of plasminogen activator inhibitor 1 gene expression in murine liver by lipopolysaccharide. Cellular localization and role of endogenous tumor necrosis factor-alpha. Am J Pathol 1997; 150 (02) 579-590
- 98 Sugimoto MA, Ribeiro ALC, Costa BRC. et al. Plasmin and plasminogen induce macrophage reprogramming and regulate key steps of inflammation resolution via annexin A1. Blood 2017; 129 (21) 2896-2907
- 99 Barrett CD, Moore HB, Banerjee A, Silliman CC, Moore EE, Yaffe MB. Human neutrophil elastase mediates fibrinolysis shutdown through competitive degradation of plasminogen and generation of angiostatin. J Trauma Acute Care Surg 2017; 83 (06) 1053-1061
- 100 Roberts DJ, Kalkwarf KJ, Moore HB. et al. Time course and outcomes associated with transient versus persistent fibrinolytic phenotypes after injury: a nested, prospective, multicenter cohort study. J Trauma Acute Care Surg 2019; 86 (02) 206-213
- 101 Meizoso JP, Karcutskie CA, Ray JJ, Namias N, Schulman CI, Proctor KG. Persistent fibrinolysis shutdown is associated with increased mortality in severely injured trauma patients. J Am Coll Surg 2017; 224 (04) 575-582
- 102 Schmitt FCF, Manolov V, Morgenstern J. et al. Acute fibrinolysis shutdown occurs early in septic shock and is associated with increased morbidity and mortality: results of an observational pilot study. Ann Intensive Care 2019; 9 (01) 19
- 103 Blasi A, Patel VC, Adelmeijer J. et al. Mixed fibrinolytic phenotypes in decompensated cirrhosis and acute-on-chronic liver failure with hypofibrinolysis in those with complications and poor survival. Hepatology 2020; 71 (04) 1381-1390
- 104 Keber D, Blinc A, Fettich J. Increase of tissue plasminogen activator in limbs during venous occlusion: a simple haemodynamic model. Thromb Haemost 1990; 64 (03) 433-437
- 105 Katz J, Lurie A, Becker D, Metz J. The euglobulin lysis time test: an ineffectual monitor of the therapeutic inhibition of fibrinolysis. J Clin Pathol 1970; 23 (06) 529-532
- 106 Conard J, Veuillet-Duval A, Horellou MH, Samama M. [Study of coagulation and fibrinolysis in 131 cases of recurrent deep vein thrombosis]. Nouv Rev Fr Hematol (1978) 1982; 24 (03) 205-209
- 107 Nguyen G, Horellou MH, Kruithof EK, Conard J, Samama MM. Residual plasminogen activator inhibitor activity after venous stasis as a criterion for hypofibrinolysis: a study in 83 patients with confirmed deep vein thrombosis. Blood 1988; 72 (02) 601-605
- 108 Nilsson IM, Ljungnér H, Tengborn L. Two different mechanisms in patients with venous thrombosis and defective fibrinolysis: low concentration of plasminogen activator or increased concentration of plasminogen activator inhibitor. Br Med J (Clin Res Ed) 1985; 290 (6480): 1453-1456
- 109 Hrafnkelsdóttir T, Ottosson P, Gudnason T, Samuelsson O, Jern S. Impaired endothelial release of tissue-type plasminogen activator in patients with chronic kidney disease and hypertension. Hypertension 2004; 44 (03) 300-304
- 110 Newby DE, Wright RA, Labinjoh C. et al. Endothelial dysfunction, impaired endogenous fibrinolysis, and cigarette smoking: a mechanism for arterial thrombosis and myocardial infarction. Circulation 1999; 99 (11) 1411-1415
- 111 Van Guilder GP, Hoetzer GL, Smith DT. et al. Endothelial t-PA release is impaired in overweight and obese adults but can be improved with regular aerobic exercise. Am J Physiol Endocrinol Metab 2005; 289 (05) E807-E813
- 112 Brommer EJ, Verheijen JH, Chang GT, Rijken DC. Masking of fibrinolytic response to stimulation by an inhibitor of tissue-type plasminogen activator in plasma. Thromb Haemost 1984; 52 (02) 154-156
- 113 Petäjä J, Rasi V, Vahtera E, Myllylä G. Familial clustering of defective release of t-PA. Br J Haematol 1991; 79 (02) 291-295
- 114 Jern C, Selin L, Tengborn L, Jern S. Sympathoadrenal activation and muscarinic receptor stimulation induce acute release of tissue-type plasminogen activator but not von Willebrand factor across the human forearm. Thromb Haemost 1997; 78 (02) 887-891
- 115 Jern C, Seeman-Lodding H, Biber B, Winsö O, Jern S. An experimental multiple-organ model for the study of regional net release/uptake rates of tissue-type plasminogen activator in the intact pig. Thromb Haemost 1997; 78 (03) 1150-1156
- 116 Saternos HC, Almarghalani DA, Gibson HM. et al. Distribution and function of the muscarinic receptor subtypes in the cardiovascular system. Physiol Genomics 2018; 50 (01) 1-9
- 117 Gryglewski RJ, Uracz W, Chłopicki S, Marcinkiewicz E. Bradykinin as a major endogenous regulator of endothelial function. Pediatr Pathol Mol Med 2002; 21 (03) 279-290
- 118 Hu Y, Chen M, Wang M, Li X. Flow-mediated vasodilation through mechanosensitive G protein-coupled receptors in endothelial cells. Trends Cardiovasc Med 2022; 32 (02) 61-70
- 119 Juhan-Vague I, Alessi MC, Morange PE. Hypofibrinolysis and increased PAI-1 are linked to atherothrombosis via insulin resistance and obesity. Ann Med 2000; 32 (Suppl. 01) 78-84
- 120 Solá E, Vayá A, España F. et al. Plasminogen activator inhibitor-1 levels in severe and morbid obesity. Effect of weight loss and influence of 4G/5G polymorphism. Thromb Res 2008; 122 (03) 320-327
- 121 Vrij AA, Rijken J, van Wersch JW, Stockbrügger RW. Coagulation and fibrinolysis in inflammatory bowel disease and in giant cell arteritis. Pathophysiol Haemost Thromb 2003; 33 (02) 75-83
- 122 Tsantes AE, Nikolopoulos GK, Bagos PG, Bonovas S, Kopterides P, Vaiopoulos G. The effect of the plasminogen activator inhibitor-1 4G/5G polymorphism on the thrombotic risk. Thromb Res 2008; 122 (06) 736-742
- 123 Zheng Z, Nakamura K, Gershbaum S. et al. Interacting hepatic PAI-1/tPA gene regulatory pathways influence impaired fibrinolysis severity in obesity. J Clin Invest 2020; 130 (08) 4348-4359
- 124 Preidl RHM, Reuss S, Neukam FW, Kesting M, Wehrhan F. Endothelial inflammatory and thrombogenic expression changes in microvascular anastomoses - an immunohistochemical analysis. J Craniomaxillofac Surg 2021; 49 (05) 422-429
- 125 Lupu F, Bergonzelli GE, Heim DA. et al. Localization and production of plasminogen activator inhibitor-1 in human healthy and atherosclerotic arteries. Arterioscler Thromb 1993; 13 (07) 1090-1100
- 126 Whyte CS, Mitchell JL, Mutch NJ. Platelet-mediated modulation of fibrinolysis. Semin Thromb Hemost 2017; 43 (02) 115-128
- 127 Uchida Y, Takeshita K, Yamamoto K. et al. Stress augments insulin resistance and prothrombotic state: role of visceral adipose-derived monocyte chemoattractant protein-1. Diabetes 2012; 61 (06) 1552-1561
- 128 Morrow GB, Whyte CS, Mutch NJ. A serpin with a finger in many PAIs: PAI-1's central function in thromboinflammation and cardiovascular disease. Front Cardiovasc Med 2021; 8: 653655
- 129 Mohebi R, Chen C, Ibrahim NE. et al. Cardiovascular disease projections in the United States based on the 2020 census estimates. J Am Coll Cardiol 2022; 80 (06) 565-578