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Semin Thromb Hemost 2021; 47(05): 480-489
DOI: 10.1055/s-0041-1725094
DOI: 10.1055/s-0041-1725094
Review Article
Fibrinolysis in Venous Thromboembolism
Funding The study was supported by a grant of Jagiellonian University Medical College (N41/DBS/000184).![](https://www.thieme-connect.de/media/sth/202105/lookinside/thumbnails/10-1055-s-0041-1725094_02823-1.jpg)
Abstract
Fibrinolysis is of paramount importance in maintaining or regaining the patency of veins and pulmonary arteries obstructed by thrombi. Growing experimental and clinical evidence indicates that impaired fibrinolysis mediated by multiple complex mechanisms is involved in venous thromboembolism (VTE). Global plasma fibrin clot lysis markers, especially clot lysis time, have been reported to predict recurrent deep-vein thrombosis and pulmonary embolism. The current overview summarizes available data linking fibrinolysis to VTE and its long-term sequelae.
Publication History
Article published online:
20 April 2021
© 2021. Thieme. All rights reserved.
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References
- 1 Heit JA, Spencer FA, White RH. The epidemiology of venous thromboembolism. J Thromb Thrombolysis 2016; 41 (01) 3-14
- 2 Cohen AT, Agnelli G, Anderson FA. et al; VTE Impact Assessment Group in Europe (VITAE). Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost 2007; 98 (04) 756-764
- 3 Konstantinides SV, Meyer G, Becattini C. et al; ESC Scientific Document Group. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J 2020; 41 (04) 543-603
- 4 Cushman M. Epidemiology and risk factors for venous thrombosis. Semin Hematol 2007; 44 (02) 62-69
- 5 Wendelboe AM, Raskob GE. Global burden of thrombosis: epidemiologic aspects. Circ Res 2016; 118 (09) 1340-1347
- 6 Huisman MV, Barco S, Cannegieter SC. et al. Pulmonary embolism. Nat Rev Dis Primers 2018; 4: 18028
- 7 Di Nisio M, van Es N, Büller HR. Deep vein thrombosis and pulmonary embolism. Lancet 2016; 388 (10063): 3060-3073
- 8 Puurunen MK, Gona PN, Larson MG, Murabito JM, Magnani JW, O'Donnell CJ. Epidemiology of venous thromboembolism in the Framingham Heart Study. Thromb Res 2016; 145: 27-33
- 9 Iorio A, Kearon C, Filippucci E. et al. Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review. Arch Intern Med 2010; 170 (19) 1710-1716
- 10 Khan F, Rahman A, Carrier M. et al; MARVELOUS Collaborators. Long term risk of symptomatic recurrent venous thromboembolism after discontinuation of anticoagulant treatment for first unprovoked venous thromboembolism event: systematic review and meta-analysis. BMJ 2019; 366: l4363
- 11 Hansson PO, Sörbo J, Eriksson H. Recurrent venous thromboembolism after deep vein thrombosis: incidence and risk factors. Arch Intern Med 2000; 160 (06) 769-774
- 12 Prandoni P, Noventa F, Ghirarduzzi A. et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica 2007; 92 (02) 199-205
- 13 Kyrle PA, Kammer M, Eischer L. et al. The long-term recurrence risk of patients with unprovoked venous thromboembolism: an observational cohort study. J Thromb Haemost 2016; 14 (12) 2402-2409
- 14 Kyrle PA, Rosendaal FR, Eichinger S. Risk assessment for recurrent venous thrombosis. Lancet 2010; 376 (9757): 2032-2039
- 15 Sundquist K, Sundquist J, Svensson PJ, Zöller B, Memon AA. Role of family history of venous thromboembolism and thrombophilia as predictors of recurrence: a prospective follow-up study. J Thromb Haemost 2015; 13 (12) 2180-2186
- 16 Marti C, John G, Konstantinides S. et al. Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis. Eur Heart J 2015; 36 (10) 605-614
- 17 Hao Q, Dong BR, Yue J, Wu T, Liu GJ. Thrombolytic therapy for pulmonary embolism. Cochrane Database Syst Rev 2018; 12: CD004437
- 18 Watson L, Broderick C, Armon MP. Thrombolysis for acute deep vein thrombosis. Cochrane Database Syst Rev 2016; 11: CD002783
- 19 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
- 20 Chandrashekar A, Singh G, Garry J, Sikalas N, Labropoulos N. Mechanical and biochemical role of fibrin within a venous thrombus. Eur J Vasc Endovasc Surg 2018; 55 (03) 417-424
- 21 Grau E, Moroz LA. Fibrinolytic activity of normal human blood monocytes. Thromb Res 1989; 53 (02) 145-162
- 22 Adams SA, Kelly SL, Kirsch RE, Robson SC, Shephard EG. Role of neutrophil membrane proteases in fibrin degradation. Blood Coagul Fibrinolysis 1995; 6 (08) 693-702
- 23 Webster NL, Crowe SM. Matrix metalloproteinases, their production by monocytes and macrophages and their potential role in HIV-related diseases. J Leukoc Biol 2006; 80 (05) 1052-1066
- 24 Ardi VC, Kupriyanova TA, Deryugina EI, Quigley JP. Human neutrophils uniquely release TIMP-free MMP-9 to provide a potent catalytic stimulator of angiogenesis. Proc Natl Acad Sci U S A 2007; 104 (51) 20262-20267
- 25 Wakefield TW, Myers DD, Henke PK. Mechanisms of venous thrombosis and resolution. Arterioscler Thromb Vasc Biol 2008; 28 (03) 387-391
- 26 Stachowicz A, Siudut J, Suski M. et al. Optimization of quantitative proteomic analysis of clots generated from plasma of patients with venous thromboembolism. Clin Proteomics 2017; 14: 38
- 27 Stachowicz A, Zabczyk M, Natorska J. et al. Differences in plasma fibrin clot composition in patients with thrombotic antiphospholipid syndrome compared with venous thromboembolism. Sci Rep 2018; 8 (01) 17301
- 28 Lord ST. Molecular mechanisms affecting fibrin structure and stability. Arterioscler Thromb Vasc Biol 2011; 31 (03) 494-499
- 29 Samson AL, Alwis I, Maclean JAA. et al. Endogenous fibrinolysis facilitates clot retraction in vivo. Blood 2017; 130 (23) 2453-2462
- 30 Cines DB, Lebedeva T, Nagaswami C. et al. Clot contraction: compression of erythrocytes into tightly packed polyhedra and redistribution of platelets and fibrin. Blood 2014; 123 (10) 1596-1603
- 31 Aleman MM, Walton BL, Byrnes JR, Wolberg AS. Fibrinogen and red blood cells in venous thrombosis. Thromb Res 2014; 133 (Suppl. 01) S38-S40
- 32 Longstaff C, Kolev K. Basic mechanisms and regulation of fibrinolysis. J Thromb Haemost 2015; 13 (Suppl. 01) S98-S105
- 33 Varjú I, Longstaff C, Szabó L. et al. DNA, histones and neutrophil extracellular traps exert anti-fibrinolytic effects in a plasma environment. Thromb Haemost 2015; 113 (06) 1289-1298
- 34 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
- 35 Nicklas JM, Gordon AE, Henke PK. Resolution of deep venous thrombosis: proposed immune paradigms. Int J Mol Sci 2020; 21 (06) E2080
- 36 Chapin JC, Hajjar KA. Fibrinolysis and the control of blood coagulation. Blood Rev 2015; 29 (01) 17-24
- 37 Reed GL, Houng AK. The contribution of activated factor XIII to fibrinolytic resistance in experimental pulmonary embolism. Circulation 1999; 99 (02) 299-304
- 38 Shaya SA, Gani DM, Weitz JI, Kim PY, Gross PL. Factor XIII prevents pulmonary emboli in mice by stabilizing deep vein thrombi. Thromb Haemost 2019; 119 (06) 992-999
- 39 Matsuno H, Okada K, Ueshima S, Matsuo O, Kozawa O. Alpha2-antiplasmin plays a significant role in acute pulmonary embolism. J Thromb Haemost 2003; 1 (08) 1734-1739
- 40 Potter van Loon BJ, Rijken DC, Brommer EJ, van der Maas AP. The amount of plasminogen, tissue-type plasminogen activator and plasminogen activator inhibitor type 1 in human thrombi and the relation to ex-vivo lysability. Thromb Haemost 1992; 67 (01) 101-105
- 41 Carmeliet P, Stassen JM, Schoonjans L. et al. Plasminogen activator inhibitor-1 gene-deficient mice. II. Effects on hemostasis, thrombosis, and thrombolysis. J Clin Invest 1993; 92 (06) 2756-2760
- 42 Eitzman DT, Westrick RJ, Nabel EG, Ginsburg D. Plasminogen activator inhibitor-1 and vitronectin promote vascular thrombosis in mice. Blood 2000; 95 (02) 577-580
- 43 Hennan JK, Morgan GA, Swillo RE. et al. Effect of tiplaxtinin (PAI-039), an orally bioavailable PAI-1 antagonist, in a rat model of thrombosis. J Thromb Haemost 2008; 6 (09) 1558-1564
- 44 Diaz JA, Hawley AE, Alvarado CM. et al. Thrombogenesis with continuous blood flow in the inferior vena cava. A novel mouse model. Thromb Haemost 2010; 104 (02) 366-375
- 45 Diaz JA, Ballard-Lipka NE, Farris DM. et al. Impaired fibrinolytic system in ApoE gene-deleted mice with hyperlipidemia augments deep vein thrombosis. J Vasc Surg 2012; 55 (03) 815-822
- 46 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
- 47 Siefert SA, Chabasse C, Mukhopadhyay S. et al. Enhanced venous thrombus resolution in plasminogen activator inhibitor type-2 deficient mice. J Thromb Haemost 2014; 12 (10) 1706-1716
- 48 Martinez MR, Cuker A, Mills AM. et al. Enhanced lysis and accelerated establishment of viscoelastic properties of fibrin clots are associated with pulmonary embolism. Am J Physiol Lung Cell Mol Physiol 2014; 306 (05) L397-L404
- 49 Stubblefield WB, Alves NJ, Rondina MT, Kline JA. Variable resistance to plasminogen activator initiated fibrinolysis for intermediate-risk pulmonary embolism. PLoS One 2016; 11 (02) e0148747
- 50 Ząbczyk M, Natorska J, Janion-Sadowska A. et al. Prothrombotic fibrin clot properties associated with NETs formation characterize acute pulmonary embolism patients with higher mortality risk. Sci Rep 2020; 10 (01) 11433
- 51 Ząbczyk M, Natorska J, Janion-Sadowska A, Malinowski KP, Janion M, Undas A. Elevated lactate levels in acute pulmonary embolism are associated with prothrombotic fibrin clot properties: contribution of NETs formation. J Clin Med 2020; 9 (04) E953
- 52 Lisman T, de Groot PG, Meijers JCM, Rosendaal FR. Reduced plasma fibrinolytic potential is a risk factor for venous thrombosis. Blood 2005; 105 (03) 1102-1105
- 53 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 (01) 113-121
- 54 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 (05) e97
- 55 Lisman T. Decreased plasma fibrinolytic potential as a risk for venous and arterial thrombosis. Semin Thromb Hemost 2017; 43 (02) 178-184
- 56 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
- 57 Xu S, Xu Z, Kim OV, Litvinov RI, Weisel JW, Alber M. Model predictions of deformation, embolization and permeability of partially obstructive blood clots under variable shear flow. J R Soc Interface 2017; 14 (136) 0170441
- 58 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
- 59 Zabczyk M, Plens K, Wojtowicz W, Undas A. Prothrombotic fibrin clot phenotype is associated with recurrent pulmonary embolism after discontinuation of anticoagulant therapy. Arterioscler Thromb Vasc Biol 2017; 37 (02) 365-373
- 60 Kupis RW, Goldman-Mazur S, Polak M, Ząbczyk M, Undas A. Faster fibrin clot degradation characterizes patients with central pulmonary embolism at a low risk of recurrent peripheral embolism. Sci Rep 2019; 9 (01) 72
- 61 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
- 62 Bagoly Z. Altered fibrin clot phenotype as predictor of the risk of recurrent venous thromboembolism: evidence is growing. Pol Arch Intern Med 2018; 128 (10) 569-571
- 63 Pieters M, Philippou H, Undas A, de Lange Z, Rijken DC, Mutch NJ. Subcommittee on Factor XIII and Fibrinogen, and the Subcommittee on Fibrinolysis. An international study on the feasibility of a standardized combined plasma clot turbidity and lysis assay: communication from the SSC of the ISTH. J Thromb Haemost 2018; 16 (05) 1007-1012
- 64 Mrozińska S, Cieślik J, Broniatowska E, Undas A. Unfavorably altered plasma clot properties in women with a HERDOO2 score equal to or greater than 2 and prediction of recurrent venous thromboembolism. Pol Arch Intern Med 2018; 128 (10) 572-579
- 65 Medeiros SK, Emery B, Bhagirath V. et al. Does cell-free DNA promote coagulation and inhibit fibrinolysis in patients with unprovoked venous thromboembolism?. Thromb Res 2020; 186: 13-19
- 66 Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 2007; 5 (03) 632-634
- 67 Chao CH, Wang HY, Kao CH. Occult cancer and thromboembolism: current epidemiology and its practical implications. Pol Arch Intern Med 2018; 128 (09) 539-544
- 68 Mrozinska S, Cieslik J, Broniatowska E, Malinowski KP, Undas A. Prothrombotic fibrin clot properties associated with increased endogenous thrombin potential and soluble P-selectin predict occult cancer after unprovoked venous thromboembolism. J Thromb Haemost 2019; 17 (11) 1912-1922
- 69 Rabinovich A, Kahn SR. How I treat the postthrombotic syndrome. Blood 2018; 131 (20) 2215-2222
- 70 Meissner MH, Zierler BK, Bergelin RO, Chandler WL, Strandness Jr DE. Coagulation, fibrinolysis, and recanalization after acute deep venous thrombosis. J Vasc Surg 2002; 35 (02) 278-285
- 71 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 (04) 784-793
- 72 Undas A, Cieśla-Dul M, Drążkiewicz T, Sadowski J. Altered fibrin clot properties are associated with residual vein obstruction: effects of lipoprotein(a) and apolipoprotein(a) isoform. Thromb Res 2012; 130 (03) e184-e187
- 73 Polak MW, Siudut J, Plens K, Undas A. Prothrombotic clot properties can predict venous ulcers in patients following deep vein thrombosis: a cohort study. J Thromb Thrombolysis 2019; 48 (04) 603-609
- 74 Zhang M, Wang N, Zhai Z. et al. Incidence and risk factors of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism: a systematic review and meta-analysis of cohort studies. J Thorac Dis 2018; 10 (08) 4751-4763
- 75 Morris TA, Marsh JJ, Chiles PG, Auger WR, Fedullo PF, Woods Jr VL. Fibrin derived from patients with chronic thromboembolic pulmonary hypertension is resistant to lysis. Am J Respir Crit Care Med 2006; 173 (11) 1270-1275
- 76 Morris TA, Marsh JJ, Chiles PG. et al. High prevalence of dysfibrinogenemia among patients with chronic thromboembolic pulmonary hypertension. Blood 2009; 114 (09) 1929-1936
- 77 Marsh JJ, Chiles PG, Liang NC, Morris TA. Chronic thromboembolic pulmonary hypertension-associated dysfibrinogenemias exhibit disorganized fibrin structure. Thromb Res 2013; 132 (06) 729-734
- 78 Mannucci PM, Franchini M. Classic thrombophilic gene variants. Thromb Haemost 2015; 114 (05) 885-889
- 79 Krzek M, Ciesla-Dul M, Zabczyk M, Undas A. Fibrin clot properties in women heterozygous for factor V Leiden mutation: effects of oral contraceptives. Thromb Res 2012; 130 (04) e216-e221
- 80 Janion-Sadowska A, Natorska J, Siudut J, Ząbczyk M, Stanisz A, Undas A. Plasma fibrin clot properties in the G20210A prothrombin mutation carriers following venous thromboembolism: the effect of rivaroxaban. Thromb Haemost 2017; 117 (09) 1739-1749
- 81 Celinska-Lowenhoff M, Iwaniec T, Alhenc-Gelas M, Musial J, Undas A. Arterial and venous thrombosis and prothrombotic fibrin clot phenotype in a Polish family with type 1 antithrombin deficiency (antithrombin Krakow). Thromb Haemost 2011; 106 (02) 379-381
- 82 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 (02) 287-296
- 83 Vikerfors A, Svenungsson E, Ågren A. et al. Studies of fibrin formation and fibrinolytic function in patients with the antiphospholipid syndrome. Thromb Res 2014; 133 (05) 936-944
- 84 Celinska-Löwenhoff M, Zabczyk M, Iwaniec T, Plens K, Musial J, Undas A. Reduced plasma fibrin clot permeability is associated with recurrent thromboembolic events in patients with antiphospholipid syndrome. Rheumatology (Oxford) 2018; 57 (08) 1340-1349
- 85 Ząbczyk M, Celińska-Löwenhoff M, Plens K, Iwaniec T, Musiał J, Undas A. Antiphosphatidylserine/prothrombin complex antibodies as a determinant of prothrombotic plasma fibrin clot properties in patients with antiphospholipid syndrome. J Thromb Haemost 2019; 17 (10) 1746-1755
- 86 Sidelmann JJ, Kluft C, Krug AH, Winkler U, Jespersen J, Gram JB. Fibrin clot structure - pro-fibrinolytic effect of oral contraceptives in apparently healthy women. Thromb Haemost 2017; 117 (04) 700-705
- 87 Piróg M, Piwowarczyk S, Undas A. Plasma fibrin clot properties are unfavorably altered in women following venous thromboembolism associated with combined hormonal contraception. Dis Markers 2019; 2019: 4923535
- 88 Wójcik M, Zaręba L, Undas A. Prothrombotic fibrin clot properties are associated with post-discharge venous thromboembolism in acutely ill medical patients. Thromb Res 2019; 182: 141-149
- 89 Goldman S, Frączek P, Szklanny K, Papuga-Szela E, Stanisz A, Undas A. Altered plasma clot properties and trauma-related venous thromboembolism despite thromboprophylaxis. Thromb Haemost 2018; 118 (04) 654-663
- 90 Ząbczyk M, Majewski J, Karkowski G, Malinowski KP, Undas A. Vitamin K antagonists favourably modulate fibrin clot properties in patients with atrial fibrillation as early as after 3days of treatment: relation to coagulation factors and thrombin generation. Thromb Res 2015; 136 (04) 832-838
- 91 Blombäck M, He S, Bark N, Wallen HN, Elg M. Effects on fibrin network porosity of anticoagulants with different modes of action and reversal by activated coagulation factor concentrate. Br J Haematol 2011; 152 (06) 758-765
- 92 van Es N, Coppens M, Schulman S, Middeldorp S, Büller HR. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood 2014; 124 (12) 1968-1975
- 93 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
- 94 Varin R, Mirshahi S, Mirshahi P. et al. Improvement of thrombolysis by rivaroxaban, an anti-Xa inhibitor. Potential therapeutic importance in patients with thrombosis. Blood 2008; 112: 3031
- 95 Frączek P, Krzysztofik M, Stanisz A, Undas A. Clinical outcomes and plasma clot permeability and lysability in patients with venous thromboembolism on rivaroxaban: a cohort study. Pol Arch Intern Med 2019; 129 (06) 377-385
- 96 Mirshahi S, Varin R, Soria J. Importance of clot permeability and clot degradability for determination of rivaroxaban efficacy. Pol Arch Intern Med 2019; 129 (06) 367-369
- 97 Carter RLR, Talbot K, Hur WS. et al. Rivaroxaban and apixaban induce clotting factor Xa fibrinolytic activity. J Thromb Haemost 2018; 16 (11) 2276-2288
- 98 Yeromonahos C, Marlu R, Polack B, Caton F. Antithrombin-independent effects of heparins on fibrin clot nanostructure. Arterioscler Thromb Vasc Biol 2012; 32 (05) 1320-1324
- 99 Undas A, Zabczyk M. Antithrombotic medications and their impact on fibrin clot structure and function. J Physiol Pharmacol 2018; 69 (04) DOI: 10.26402/jpp.2018.4.02.
- 100 Undas A, Natorska J. Improving fibrinolysis in venous thromboembolism: impact of fibrin structure. Expert Rev Hematol 2019; 12 (08) 597-607