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DOI: 10.1055/s-0036-1585081
Decreased Plasma Fibrinolytic Potential As a Risk for Venous and Arterial Thrombosis
Publikationsverlauf
Publikationsdatum:
29. Juli 2016 (online)
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Abstract
It has been well established that inherited or acquired hypercoagulability is a risk factor for venous thrombosis. In addition, hypercoagulability may contribute to the risk of arterial events. Much less is known regarding the role of the fibrinolytic system in the risk of thrombotic disease, which partly relates to the lack of validated assays. A plasma-based global fibrinolysis assay, which is sensitive to plasma levels of plasminogen, regulators of fibrinolysis, and proteins involved in coagulation, has been used in large epidemiological studies to assess the role of fibrinolysis in thrombosis. It has been demonstrated that a hypofibrinolytic state increases the risk of a first venous thrombosis, but not of a recurrence. This increased risk of venous thrombosis associated with plasma hypofibrinolysis appears primarily driven by elevated plasma levels of thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor type 1. The combination of hypercoagulability and hypofibrinolysis synergistically enhances the risk of a first venous event. Plasma hypofibrinolysis may constitute a risk factor for the postthrombotic syndrome. Decreased fibrinolytic potential is also associated with an increased risk of arterial thrombosis, but only in individuals younger than 55 years. The association between hypofibrinolysis and myocardial infarction appears primarily driven by elevated levels of α2-antiplasmin. Although recent studies have clearly demonstrated a role of the fibrinolytic system in thrombotic disease, the clinical utility of plasma-based clot lysis assays is probably limited.
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References
- 1 Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353 (9159): 1167-1173
- 2 Ye Z, Liu EH, Higgins JP , et al. Seven haemostatic gene polymorphisms in coronary disease: meta-analysis of 66,155 cases and 91,307 controls. Lancet 2006; 367 (9511): 651-658
- 3 Boekholdt SM, Kramer MH. Arterial thrombosis and the role of thrombophilia. Semin Thromb Hemost 2007; 33 (6) 588-596
- 4 de Moerloose P, Boehlen F. Inherited thrombophilia in arterial disease: a selective review. Semin Hematol 2007; 44 (2) 106-113
- 5 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 (8) e0133523
- 6 Schwarz T, Siegert G, Oettler W , et al. Venous thrombosis after long-haul flights. Arch Intern Med 2003; 163 (22) 2759-2764
- 7 Mehta R, Shapiro AD. Plasminogen deficiency. Haemophilia 2008; 14 (6) 1261-1268
- 8 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 (6) 736-742
- 9 Prins MH, Hirsh J. A critical review of the evidence supporting a relationship between impaired fibrinolytic activity and venous thromboembolism. Arch Intern Med 1991; 151 (9) 1721-1731
- 10 Prins MH, Hirsh J. A critical review of the relationship between impaired fibrinolysis and myocardial infarction. Am Heart J 1991; 122 (2) 545-551
- 11 Fay WP, Eitzman DT, Shapiro AD, Madison EL, Ginsburg D. Platelets inhibit fibrinolysis in vitro by both plasminogen activator inhibitor-1-dependent and -independent mechanisms. Blood 1994; 83 (2) 351-356
- 12 Wohner N, Sótonyi P, Machovich R , et al. Lytic resistance of fibrin containing red blood cells. Arterioscler Thromb Vasc Biol 2011; 31 (10) 2306-2313
- 13 Burnand KG, Gaffney PJ, McGuinness CL, Humphries J, Quarmby JW, Smith A. The role of the monocyte in the generation and dissolution of arterial and venous thrombi. Cardiovasc Surg 1998; 6 (2) 119-125
- 14 Zubairova LD, Nabiullina RM, Nagaswami C , et al. Circulating microparticles alter formation, structure, and properties of fibrin clots. Sci Rep 2015; 5: 17611
- 15 Rijken DC, Hoegee-de Nobel E, Jie AF, Atsma DE, Schalij MJ, Nieuwenhuizen W. Development of a new test for the global fibrinolytic capacity in whole blood. J Thromb Haemost 2008; 6 (1) 151-157
- 16 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
- 17 Sharma S, Farrington K, Kozarski R , et al. Impaired thrombolysis: a novel cardiovascular risk factor in end-stage renal disease. Eur Heart J 2013; 34 (5) 354-363
- 18 Kuiper GJ, Kleinegris MC, van Oerle R , et al. Validation of a modified thromboelastometry approach to detect changes in fibrinolytic activity. Thromb J 2016; 14: 1
- 19 Meltzer ME, Doggen CJ, de Groot PG, Rosendaal FR, Lisman T. Fibrinolysis and the risk of venous and arterial thrombosis. Curr Opin Hematol 2007; 14 (3) 242-248
- 20 Meltzer ME, Doggen CJ, de Groot PG, Rosendaal FR, Lisman T. The impact of the fibrinolytic system on the risk of venous and arterial thrombosis. Semin Thromb Hemost 2009; 35 (5) 468-477
- 21 Okafor ON, Gorog DA. Endogenous fibrinolysis: an important mediator of thrombus formation and cardiovascular risk. J Am Coll Cardiol 2015; 65 (16) 1683-1699
- 22 Chapin JC, Hajjar KA. Fibrinolysis and the control of blood coagulation. Blood Rev 2015; 29 (1) 17-24
- 23 von dem Borne PA, Meijers JC, Bouma BN. Feedback activation of factor XI by thrombin in plasma results in additional formation of thrombin that protects fibrin clots from fibrinolysis. Blood 1995; 86 (8) 3035-3042
- 24 Von dem Borne PA, Bajzar L, Meijers JC, Nesheim ME, Bouma BN. Thrombin-mediated activation of factor XI results in a thrombin-activatable fibrinolysis inhibitor-dependent inhibition of fibrinolysis. J Clin Invest 1997; 99 (10) 2323-2327
- 25 Mosnier LO, von dem Borne PA, Meijers JC, Bouma BN. Plasma TAFI levels influence the clot lysis time in healthy individuals in the presence of an intact intrinsic pathway of coagulation. Thromb Haemost 1998; 80 (5) 829-835
- 26 Lisman T, Leebeek FW, Mosnier LO , et al. Thrombin-activatable fibrinolysis inhibitor deficiency in cirrhosis is not associated with increased plasma fibrinolysis. Gastroenterology 2001; 121 (1) 131-139
- 27 Colucci M, Binetti BM, Tripodi A, Chantarangkul V, Semeraro N. Hyperprothrombinemia associated with prothrombin G20210A mutation inhibits plasma fibrinolysis through a TAFI-mediated mechanism. Blood 2004; 103 (6) 2157-2161
- 28 Lisman T, de Groot PG, Meijers JC, Rosendaal FR. Reduced plasma fibrinolytic potential is a risk factor for venous thrombosis. Blood 2005; 105 (3) 1102-1105
- 29 Undas A, Celinska-Löwenhoff M, Löwenhoff T, Szczeklik A. Statins, fenofibrate, and quinapril increase clot permeability and enhance fibrinolysis in patients with coronary artery disease. J Thromb Haemost 2006; 4 (5) 1029-1036
- 30 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 (5) 1071-1080
- 31 Silva MM, Thelwell C, Williams SC, Longstaff C. Regulation of fibrinolysis by C-terminal lysines operates through plasminogen and plasmin but not tissue-type plasminogen activator. J Thromb Haemost 2012; 10 (11) 2354-2360
- 32 Foley JH, Nesheim ME. Soluble thrombomodulin partially corrects the premature lysis defect in FVIII-deficient plasma by stimulating the activation of thrombin activatable fibrinolysis inhibitor. J Thromb Haemost 2009; 7 (3) 453-459
- 33 Colucci M, Binetti BM, Branca MG , et al. Deficiency of thrombin activatable fibrinolysis inhibitor in cirrhosis is associated with increased plasma fibrinolysis. Hepatology 2003; 38 (1) 230-237
- 34 Zucker M, Seligsohn U, Salomon O, Wolberg AS. Abnormal plasma clot structure and stability distinguish bleeding risk in patients with severe factor XI deficiency. J Thromb Haemost 2014; 12 (7) 1121-1130
- 35 He S, Antovic A, Blombäck M. A simple and rapid laboratory method for determination of haemostasis potential in plasma. II. Modifications for use in routine laboratories and research work. Thromb Res 2001; 103 (5) 355-361
- 36 Longstaff C. Shiny app for calculating clot lysis times. https://Drclongstaff.shinyapps.io/clotlysisCL/ . Accessed April 1, 2016
- 37 Meltzer ME, Lisman T, de Groot PG , et al. Venous thrombosis risk associated with plasma hypofibrinolysis is explained by elevated plasma levels of TAFI and PAI-1. Blood 2010; 116 (1) 113-121
- 38 Meltzer ME, Hasstedt SJ, Vossen CY , et al. Genome scan of clot lysis time and its association with thrombosis in a protein C-deficient kindred. J Thromb Haemost 2011; 9 (7) 1383-1390
- 39 Kadomatsu K, Muramatsu T. Midkine and pleiotrophin in neural development and cancer. Cancer Lett 2004; 204 (2) 127-143
- 40 Muramatsu T. Midkine, a heparin-binding cytokine with multiple roles in development, repair and diseases. Proc Jpn Acad, Ser B, Phys Biol Sci 2010; 86 (4) 410-425
- 41 Kojima S, Muramatsu H, Amanuma H, Muramatsu T. Midkine enhances fibrinolytic activity of bovine endothelial cells. J Biol Chem 1995; 270 (16) 9590-9596
- 42 Lisman T, Meltzer ME, Cannegieter SC, Rosendaal FR. Plasma levels of midkine (neurite growth-promoting factor 2) are not associated with plasma fibrinolytic potential or risk of venous thrombosis. J Thromb Haemost 2012; 10 (5) 964-966
- 43 Meltzer ME, Lisman T, Doggen CJ, de Groot PG, Rosendaal FR. Synergistic effects of hypofibrinolysis and genetic and acquired risk factors on the risk of a first venous thrombosis. PLoS Med 2008; 5 (5) e97
- 44 Karasu A, Baglin TP, Luddington R, Baglin CA, van Hylckama Vlieg A. Prolonged clot lysis time increases the risk of a first but not recurrent venous thrombosis. Br J Haematol 2016; 172 (6) 947-953
- 45 Undas A, Zawilska K, Ciesla-Dul M , et al. Altered fibrin clot structure/function in patients with idiopathic venous thromboembolism and in their relatives. Blood 2009; 114 (19) 4272-4278
- 46 Meltzer ME, Bol L, Rosendaal FR, Lisman T, Cannegieter SC. Hypofibrinolysis as a risk factor for recurrent venous thrombosis; results of the LETS follow-up study. J Thromb Haemost 2010; 8 (3) 605-607
- 47 Christiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR. Thrombophilia, clinical factors, and recurrent venous thrombotic events. JAMA 2005; 293 (19) 2352-2361
- 48 Traby L, Kollars M, Eischer L, Eichinger S, Kyrle PA. Prediction of recurrent venous thromboembolism by clot lysis time: a prospective cohort study. PLoS ONE 2012; 7 (12) e51447
- 49 Ten Cate-Hoek AJ, Henke PK, Wakefield TW. The post thrombotic syndrome: ignore it and it will come back to bite you. Blood Rev 2016; 30 (2) 131-137
- 50 Siudut J, Grela M, Wypasek E, Plens K, Undas A. Reduced plasma fibrin clot permeability and susceptibility to lysis are associated with increased risk of postthrombotic syndrome. J Thromb Haemost 2016; 14 (4) 784-793
- 51 Bouman AC, McPherson H, Cheung YW , et al. Clot structure and fibrinolytic potential in patients with post thrombotic syndrome. Thromb Res 2016; 137: 85-91
- 52 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 (1) 121-127
- 53 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 (2) 252-258
- 54 Fredriksson L, Lawrence DA, Medcalf RL. tPA modulation of the blood-brain barrier: a unifying explanation for the pleiotropic effects of tPA in the CNS?. Semin Thromb Hemost 2017; 43 (2) 154-168
- 55 Guimarães AH, de Bruijne EL, Lisman T , et al. Hypofibrinolysis is a risk factor for arterial thrombosis at young age. Br J Haematol 2009; 145 (1) 115-120
- 56 Leebeek FW, Goor MP, Guimaraes AH , et al. High functional levels of thrombin-activatable fibrinolysis inhibitor are associated with an increased risk of first ischemic stroke. J Thromb Haemost 2005; 3 (10) 2211-2218
- 57 Undas A, Podolec P, Zawilska K , et al. Altered fibrin clot structure/function in patients with cryptogenic ischemic stroke. Stroke 2009; 40 (4) 1499-1501
- 58 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 (4) 357-361
- 59 Leander K, Blombäck M, Wallén H, He S. Impaired fibrinolytic capacity and increased fibrin formation associate with myocardial infarction. Thromb Haemost 2012; 107 (6) 1092-1099
- 60 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 (4) 529-536
- 61 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 (6) 811-818
- 62 Middeldorp S. Is thrombophilia testing useful?. Hematology (Am Soc Hematol Educ Program) 2011; 2011: 150-155
- 63 Lisman T, Bakhtiari K, Adelmeijer J, Meijers JC, Porte RJ, Stravitz RT. Intact thrombin generation and decreased fibrinolytic capacity in patients with acute liver injury or acute liver failure. J Thromb Haemost 2012; 10 (7) 1312-1319
- 64 Lisman T, Leuvenink HG, Porte RJ, Ploeg RJ. Activation of hemostasis in brain dead organ donors: an observational study. J Thromb Haemost 2011; 9 (10) 1959-1965
- 65 Kleiss SF, Adelmeijer J, Meijers JC, Porte RJ, Lisman T. A sustained decrease in plasma fibrinolytic potential following partial liver resection or pancreas resection. Thromb Res 2016; 140: 36-40
- 66 van Marion AM, Auwerda JJ, Minnema MC , et al. Hypofibrinolysis during induction treatment of multiple myeloma may increase the risk of venous thrombosis. Thromb Haemost 2005; 94 (6) 1341-1343
- 67 Celińska-Lowenhoff M, Iwaniec T, Padjas A, Musiał J, Undas A. Altered fibrin clot structure/function in patients with antiphospholipid syndrome: association with thrombotic manifestation. Thromb Haemost 2014; 112 (2) 287-296
- 68 Bollen L, Vande Casteele N, Peeters M , et al. The occurrence of thrombosis in inflammatory bowel disease is reflected in the clot lysis profile. Inflamm Bowel Dis 2015; 21 (11) 2540-2548
- 69 Konieczynska M, Fil K, Bazanek M, Undas A. Prolonged duration of type 2 diabetes is associated with increased thrombin generation, prothrombotic fibrin clot phenotype and impaired fibrinolysis. Thromb Haemost 2014; 111 (4) 685-693