Download PDF
Semin Respir Crit Care Med 2021; 42(02): 218-232
DOI: 10.1055/s-0041-1723953
Review Article

Advances in the Management of Acute Venous Thromboembolism and New Therapeutic Agents

Hannah Stevens
1   Atherothrombosis and Vascular Biology Program, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
2   Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia
3   Department of Clinical Haematology, Alfred Hospital, Melbourne, Victoria, Australia
,
James McFadyen
1   Atherothrombosis and Vascular Biology Program, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
2   Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia
3   Department of Clinical Haematology, Alfred Hospital, Melbourne, Victoria, Australia
,
Noel Chan
4   Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
› Author Affiliations
› Further Information
    Permissions and Reprints

Abstract

Important advances in the understanding and management of venous thromboembolism (VTE) have enhanced our ability to diagnose, prevent, and treat VTE. In this narrative review, we discuss how recent advances in the understanding and management of VTE are changing practice, highlight ongoing unmet needs in VTE management, and outline how novel therapeutic targets with little or no influence on hemostasis may help address these unmet needs.

Keywords

venous thromboembolism - pulmonary embolism - deep vein thrombosis - direct oral anticoagulants - diagnosis


Publication History

Article published online:
18 February 2021

© 2021. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Raskob GE, Angchaisuksiri P, Blanco AN. et al; ISTH Steering Committee for World Thrombosis Day. Thrombosis: a major contributor to global disease burden. Arterioscler Thromb Vasc Biol 2014; 34 (11) 2363-2371
    CrossrefPubMedGoogle Scholar
  • 2 Wendelboe AM, Raskob GE. Global burden of thrombosis: epidemiologic aspects. Circ Res 2016; 118 (09) 1340-1347
    CrossrefPubMedGoogle Scholar
  • 3 Kearon C. Natural history of venous thromboembolism. Circulation 2003; 107 (23) (Suppl. 01) I22-I30
    PubMedGoogle Scholar
  • 4 Mackman N. New insights into the mechanisms of venous thrombosis. J Clin Invest 2012; 122 (07) 2331-2336
    CrossrefPubMedGoogle Scholar
  • 5 Budnik I, Brill A. Immune factors in deep vein thrombosis initiation. Trends Immunol 2018; 39 (08) 610-623
    CrossrefPubMedGoogle Scholar
  • 6 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
    CrossrefPubMedGoogle Scholar
  • 7 Wakefield TW, Myers DD, Henke PK. Mechanisms of venous thrombosis and resolution. Arterioscler Thromb Vasc Biol 2008; 28 (03) 387-391
    CrossrefPubMedGoogle Scholar
  • 8 Diamond MS, Staunton DE, de Fougerolles AR. et al. ICAM-1 (CD54): a counter-receptor for Mac-1 (CD11b/CD18). J Cell Biol 1990; 111 (6, Pt 2): 3129-3139
    CrossrefPubMedGoogle Scholar
  • 9 Pawlinski R, Pedersen B, Schabbauer G. et al. Role of tissue factor and protease-activated receptors in a mouse model of endotoxemia. Blood 2004; 103 (04) 1342-1347
    CrossrefPubMedGoogle Scholar
  • 10 Del Conde I, Shrimpton CN, Thiagarajan P, López JA. Tissue-factor-bearing microvesicles arise from lipid rafts and fuse with activated platelets to initiate coagulation. Blood 2005; 106 (05) 1604-1611
    CrossrefPubMedGoogle Scholar
  • 11 Martinod K, Wagner DD. Thrombosis: tangled up in NETs. Blood 2014; 123 (18) 2768-2776
    CrossrefPubMedGoogle Scholar
  • 12 Brill A, Fuchs TA, Savchenko AS. et al. Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Haemost 2012; 10 (01) 136-144
    CrossrefPubMedGoogle Scholar
  • 13 Reinhardt C, von Brühl ML, Manukyan D. et al. Protein disulfide isomerase acts as an injury response signal that enhances fibrin generation via tissue factor activation. J Clin Invest 2008; 118 (03) 1110-1122
    PubMedGoogle Scholar
  • 14 Cho J, Furie BC, Coughlin SR, Furie B. A critical role for extracellular protein disulfide isomerase during thrombus formation in mice. J Clin Invest 2008; 118 (03) 1123-1131
    PubMedGoogle Scholar
  • 15 Cho J. Protein disulfide isomerase in thrombosis and vascular inflammation. J Thromb Haemost 2013; 11 (12) 2084-2091
    CrossrefPubMedGoogle Scholar
  • 16 Morrissey JH, Smith SA. Polyphosphate as modulator of hemostasis, thrombosis, and inflammation. J Thromb Haemost 2015; 13 (Suppl. 01) S92-S97
    CrossrefPubMedGoogle Scholar
  • 17 Smith SA, Mutch NJ, Baskar D, Rohloff P, Docampo R, Morrissey JH. Polyphosphate modulates blood coagulation and fibrinolysis. Proc Natl Acad Sci U S A 2006; 103 (04) 903-908
    CrossrefPubMedGoogle Scholar
  • 18 Becattini C, Agnelli G, Lankeit M. et al. Acute pulmonary embolism: mortality prediction by the 2014 European Society of Cardiology risk stratification model. Eur Respir J 2016; 48 (03) 780-786
    CrossrefPubMedGoogle Scholar
  • 19 Riedel M, Stanek V, Widimsky J, Prerovsky I. Long term follow-up of patients with pulmonary thromboembolism. Late prognosis and evolution of hemodynamic and respiratory data. Chest 1982; 81 (02) 151-158
    CrossrefPubMedGoogle Scholar
  • 20 Stevens H, Fang W, Clements W, Bloom J, McFadyen J, Tran H. Risk stratification of acute pulmonary embolism and determining the effect on chronic cardiopulmonary complications: the REACH Study. TH Open 2020; 4 (01) e45-e50
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Dronkers CEA, van der Hulle T, Le Gal G. et al; Subcommittee on Predictive and Diagnostic Variables in Thrombotic Disease. Towards a tailored diagnostic standard for future diagnostic studies in pulmonary embolism: communication from the SSC of the ISTH. J Thromb Haemost 2017; 15 (05) 1040-1043
    CrossrefPubMedGoogle Scholar
  • 22 Mountain D, Keijzers G, Chu K. et al. RESPECT-ED: rates of pulmonary emboli (PE) and subsegmental PE with modern computed tomographic pulmonary angiograms in emergency departments: a multi-center observational study finds significant yield variation, uncorrelated with use or small PE Rates. PLoS One 2016; 11 (12) e0166483
    CrossrefPubMedGoogle Scholar
  • 23 Richardson S, Lucas E, Cohen SL. et al. Predictors of overtesting in pulmonary embolism diagnosis. Acad Radiol 2020; 27 (03) 404-408
    CrossrefPubMedGoogle Scholar
  • 24 Kelly J, Rudd A, Lewis RR, Hunt BJ. Plasma D-dimers in the diagnosis of venous thromboembolism. Arch Intern Med 2002; 162 (07) 747-756
    CrossrefPubMedGoogle Scholar
  • 25 Righini M, Goehring C, Bounameaux H, Perrier A. Effects of age on the performance of common diagnostic tests for pulmonary embolism. Am J Med 2000; 109 (05) 357-361
    CrossrefPubMedGoogle Scholar
  • 26 Tardy B, Tardy-Poncet B, Viallon A. et al. Evaluation of D-dimer ELISA test in elderly patients with suspected pulmonary embolism. Thromb Haemost 1998; 79 (01) 38-41
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Righini M, Van Es J, Den Exter PL. et al. Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study. JAMA 2014; 311 (11) 1117-1124
    CrossrefPubMedGoogle Scholar
  • 28 van der Hulle T, Cheung WY, Kooij S. et al; YEARS Study Group. Simplified diagnostic management of suspected pulmonary embolism (the YEARS study): a prospective, multicentre, cohort study. Lancet 2017; 390 (10091): 289-297
    CrossrefPubMedGoogle Scholar
  • 29 van der Pol LM, Tromeur C, Bistervels IM. et al; Artemis Study Investigators. Pregnancy-adapted YEARS algorithm for diagnosis of suspected pulmonary embolism. N Engl J Med 2019; 380 (12) 1139-1149
    CrossrefPubMedGoogle Scholar
  • 30 Kearon C, de Wit K, Parpia S. et al; PEGeD Study Investigators. Diagnosis of Pulmonary embolism with D-dimer adjusted to clinical probability. N Engl J Med 2019; 381 (22) 2125-2134
    CrossrefPubMedGoogle Scholar
  • 31 Kline JA, Mitchell AM, Kabrhel C, Richman PB, Courtney DM. Clinical criteria to prevent unnecessary diagnostic testing in emergency department patients with suspected pulmonary embolism. J Thromb Haemost 2004; 2 (08) 1247-1255
    CrossrefPubMedGoogle Scholar
  • 32 Penaloza A, Soulié C, Moumneh T. et al. Pulmonary Embolism Rule-Out Criteria (PERC) rule in European patients with low implicit clinical probability (PERCEPIC): a multicentre, prospective, observational study. Lancet Haematol 2017; 4 (12) e615-e621
    CrossrefPubMedGoogle Scholar
  • 33 Freund Y, Cachanado M, Aubry A. et al; PROPER Investigator Group. Effect of the pulmonary embolism rule-out criteria on subsequent thromboembolic events among low-risk emergency department patients: The PROPER Randomized Clinical Trial. JAMA 2018; 319 (06) 559-566
    CrossrefPubMedGoogle Scholar
  • 34 Saint CA, Castelli MR, Crannage AJ, Stacy ZA, Hennessey EK. Comparison of hospital length of stay in patients treated with non-vitamin K oral anticoagulants or parenteral agents plus warfarin for venous thromboembolism. SAGE Open Med 2017; 5: 2050312117719628
    CrossrefPubMedGoogle Scholar
  • 35 Tran H, Joseph J, Young L. et al; Australasian Society of Thrombosis and Haemostasis. New oral anticoagulants: a practical guide on prescription, laboratory testing and peri-procedural/bleeding management. Intern Med J 2014; 44 (06) 525-536
    CrossrefPubMedGoogle Scholar
  • 36 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
    CrossrefPubMedGoogle Scholar
  • 37 Brekelmans MP, Ageno W, Beenen LF. et al. Recurrent venous thromboembolism in patients with pulmonary embolism and right ventricular dysfunction: a post-hoc analysis of the Hokusai-VTE study. Lancet Haematol 2016; 3 (09) e437-e445
    CrossrefPubMedGoogle Scholar
  • 38 Groetzinger LM, Miller TJ, Rivosecchi RM, Smith RE, Gladwin MT, Rivera-Lebron BN. Apixaban or rivaroxaban versus warfarin for treatment of submassive pulmonary embolism after catheter-directed thrombolysis. Clin Appl Thromb Hemost 2018; 24 (06) 908-913
    CrossrefPubMedGoogle Scholar
  • 39 Prins MH, Lensing AW, Bauersachs R. et al; EINSTEIN Investigators. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J 2013; 11 (01) 21
    CrossrefPubMedGoogle Scholar
  • 40 Ortel TL, Neumann I, Ageno W. et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv 2020; 4 (19) 4693-4738
    CrossrefPubMedGoogle Scholar
  • 41 Kearon C, Akl EA, Ornelas J. et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016; 149 (02) 315-352
    CrossrefPubMedGoogle Scholar
  • 42 National Institute for Health and Care Excellence. Venous Thromboembolic Diseases: Diagnosis, Management and Thrombophilia Testing (NG158). 2019
    PubMedGoogle Scholar
  • 43 Lee AY, Levine MN, Baker RI. et al; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349 (02) 146-153
    CrossrefPubMedGoogle Scholar
  • 44 Young AM, Marshall A, Thirlwall J. et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a Randomized Trial (SELECT-D). J Clin Oncol 2018; 36 (20) 2017-2023
    CrossrefPubMedGoogle Scholar
  • 45 Raskob GE, van Es N, Verhamme P. et al; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018; 378 (07) 615-624
    CrossrefPubMedGoogle Scholar
  • 46 McBane II RD, Wysokinski WE, Le-Rademacher JG. et al. Apixaban and dalteparin in active malignancy-associated venous thromboembolism: the ADAM VTE trial. J Thromb Haemost 2020; 18 (02) 411-421
    CrossrefPubMedGoogle Scholar
  • 47 Agnelli G, Becattini C, Meyer G. et al; Caravaggio Investigators. Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med 2020; 382 (17) 1599-1607
    CrossrefPubMedGoogle Scholar
  • 48 Key NS, Khorana AA, Kuderer NM. et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO Clinical Practice Guideline Update. J Clin Oncol 2020; 38 (05) 496-520
    CrossrefPubMedGoogle Scholar
  • 49 Khorana AA, Noble S, Lee AYY. et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost 2018; 16 (09) 1891-1894
    CrossrefPubMedGoogle Scholar
  • 50 Houghton DE, Casanegra AI, Peterson LG. et al. Treatment of upper extremity deep vein thrombosis with apixaban and rivaroxaban. Am J Hematol 2020; 95 (07) 817-823
    CrossrefPubMedGoogle Scholar
  • 51 Ferro JM, Coutinho JM, Dentali F. et al; RE-SPECT CVT Study Group. Safety and efficacy of dabigatran etexilate vs dose-adjusted warfarin in patients with cerebral venous thrombosis: a randomized clinical trial. JAMA Neurol 2019; 76 (12) 1457-1465
    CrossrefPubMedGoogle Scholar
  • 52 Hanafy AS, Abd-Elsalam S, Dawoud MM. Randomized controlled trial of rivaroxaban versus warfarin in the management of acute non-neoplastic portal vein thrombosis. Vascul Pharmacol 2019; 113: 86-91
    CrossrefPubMedGoogle Scholar
  • 53 Di Nisio M, Valeriani E, Riva N, Schulman S, Beyer-Westendorf J, Ageno W. Anticoagulant therapy for splanchnic vein thrombosis: ISTH SSC Subcommittee Control of Anticoagulation. J Thromb Haemost 2020; 18 (07) 1562-1568
    CrossrefPubMedGoogle Scholar
  • 54 Moran J, Bauer KA. Managing thromboembolic risk in patients with hereditary and acquired thrombophilias. Blood 2020; 135 (05) 344-350
    CrossrefPubMedGoogle Scholar
  • 55 Elsebaie MAT, van Es N, Langston A, Büller HR, Gaddh M. Direct oral anticoagulants in patients with venous thromboembolism and thrombophilia: a systematic review and meta-analysis. J Thromb Haemost 2019; 17 (04) 645-656
    CrossrefPubMedGoogle Scholar
  • 56 Pengo V, Denas G, Zoppellaro G. et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood 2018; 132 (13) 1365-1371
    CrossrefPubMedGoogle Scholar
  • 57 Ordi-Ros J, Sáez-Comet L, Pérez-Conesa M. et al. Rivaroxaban versus vitamin k antagonist in antiphospholipid syndrome: a randomized noninferiority trial. Ann Intern Med 2019; 171 (10) 685-694
    CrossrefPubMedGoogle Scholar
  • 58 Cohen H, Arachchillage DR, Middeldorp S, Beyer-Westendorf J, Abdul-Kadir R. Management of direct oral anticoagulants in women of childbearing potential: guidance from the SSC of the ISTH. J Thromb Haemost 2016; 14 (08) 1673-1676
    CrossrefPubMedGoogle Scholar
  • 59 Bapat P, Kedar R, Lubetsky A. et al. Transfer of dabigatran and dabigatran etexilate mesylate across the dually perfused human placenta. Obstet Gynecol 2014; 123 (06) 1256-1261
    CrossrefPubMedGoogle Scholar
  • 60 Wang L, He K, Maxwell B. et al. Tissue distribution and elimination of [14C]apixaban in rats. Drug Metab Dispos 2011; 39 (02) 256-264
    CrossrefPubMedGoogle Scholar
  • 61 Eikelboom JW, Connolly SJ, Brueckmann M. et al; RE-ALIGN Investigators. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med 2013; 369 (13) 1206-1214
    CrossrefPubMedGoogle Scholar
  • 62 Aujesky D, Obrosky DS, Stone RA. et al. Derivation and validation of a prognostic model for pulmonary embolism. Am J Respir Crit Care Med 2005; 172 (08) 1041-1046
    CrossrefPubMedGoogle Scholar
  • 63 Donzé J, Le Gal G, Fine MJ. et al. Prospective validation of the Pulmonary Embolism Severity Index. A clinical prognostic model for pulmonary embolism. Thromb Haemost 2008; 100 (05) 943-948
    Article in Thieme ConnectPubMedGoogle Scholar
  • 64 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
    CrossrefPubMedGoogle Scholar
  • 65 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
    CrossrefPubMedGoogle Scholar
  • 66 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
    CrossrefPubMedGoogle Scholar
  • 67 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
    CrossrefPubMedGoogle Scholar
  • 68 Vanassche T, Verhamme P. Rivaroxaban for the treatment of pulmonary embolism. Adv Ther 2013; 30 (06) 589-606
    CrossrefPubMedGoogle Scholar
  • 69 Meyer G, Vicaut E, Danays T. et al; PEITHO Investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 2014; 370 (15) 1402-1411
    CrossrefPubMedGoogle Scholar
  • 70 Konstantinides S. Thrombolysis in submassive pulmonary embolism? Yes. J Thromb Haemost 2003; 1 (06) 1127-1129
    CrossrefPubMedGoogle Scholar
  • 71 Wan S, Quinlan DJ, Agnelli G, Eikelboom JW. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation 2004; 110 (06) 744-749
    CrossrefPubMedGoogle Scholar
  • 72 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
    CrossrefPubMedGoogle Scholar
  • 73 Todoran TM, Petkovich B. Aggressive therapy for acute pulmonary embolism: Systemic thrombolysis and catheter-directed approaches, Semin Crit Care Med. 2021 42. (02)
    PubMedGoogle Scholar
  • 74 Murray JL, Zapata D, Keeling WB. High-risk pulmonary embolism: embolectomy and extracorporeal membrane oxygenation, Semin Crit Care Med. 2021 42. (02)
    PubMedGoogle Scholar
  • 75 Xu K, Chan NC. The conundrum of resuming anticoagulant therapy after intracerebral bleeding: In whom, when, and how?. Vasc Med 2020; 25 (01) 60-62
    CrossrefPubMedGoogle Scholar
  • 76 Witt DM, Nieuwlaat R, Clark NP. et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv 2018; 2 (22) 3257-3291
    CrossrefPubMedGoogle Scholar
  • 77 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
    CrossrefPubMedGoogle Scholar
  • 78 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
    CrossrefPubMedGoogle Scholar
  • 79 Agnelli G, Prandoni P, Santamaria MG. et al; Warfarin Optimal Duration Italian Trial Investigators. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. N Engl J Med 2001; 345 (03) 165-169
    CrossrefPubMedGoogle Scholar
  • 80 Kearon C, Ageno W, Cannegieter SC, Cosmi B, Geersing GJ, Kyrle PA. Subcommittees on Control of Anticoagulation, and Predictive and Diagnostic Variables in Thrombotic Disease. Categorization of patients as having provoked or unprovoked venous thromboembolism: guidance from the SSC of ISTH. J Thromb Haemost 2016; 14 (07) 1480-1483
    CrossrefPubMedGoogle Scholar
  • 81 Prins MH, Lensing AWA, Prandoni P. et al. Risk of recurrent venous thromboembolism according to baseline risk factor profiles. Blood Adv 2018; 2 (07) 788-796
    CrossrefPubMedGoogle Scholar
  • 82 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
    CrossrefPubMedGoogle Scholar
  • 83 Tran HA, Gibbs H, Merriman E. et al. New guidelines from the Thrombosis and Haemostasis Society of Australia and New Zealand for the diagnosis and management of venous thromboembolism. Med J Aust 2019; 210 (05) 227-235
    CrossrefPubMedGoogle Scholar
  • 84 Tosetto A, Iorio A, Marcucci M. et al. Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH). J Thromb Haemost 2012; 10 (06) 1019-1025
    CrossrefPubMedGoogle Scholar
  • 85 Tosetto A, Testa S, Martinelli I. et al. External validation of the DASH prediction rule: a retrospective cohort study. J Thromb Haemost 2017; 15 (10) 1963-1970
    CrossrefPubMedGoogle Scholar
  • 86 Eichinger S, Heinze G, Jandeck LM, Kyrle PA. Risk assessment of recurrence in patients with unprovoked deep vein thrombosis or pulmonary embolism: the Vienna prediction model. Circulation 2010; 121 (14) 1630-1636
    CrossrefPubMedGoogle Scholar
  • 87 Eichinger S, Heinze G, Kyrle PA. D-dimer levels over time and the risk of recurrent venous thromboembolism: an update of the Vienna prediction model. J Am Heart Assoc 2014; 3 (01) e000467
    CrossrefPubMedGoogle Scholar
  • 88 Rodger MA, Kahn SR, Wells PS. et al. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ 2008; 179 (05) 417-426
    CrossrefPubMedGoogle Scholar
  • 89 Rodger MA, Le Gal G, Anderson DR. et al; REVERSE II Study Investigators. Validating the HERDOO2 rule to guide treatment duration for women with unprovoked venous thrombosis: multinational prospective cohort management study. BMJ 2017; 356: j1065
    CrossrefPubMedGoogle Scholar
  • 90 Timp JF, Braekkan SK, Lijfering WM. et al. Prediction of recurrent venous thrombosis in all patients with a first venous thrombotic event: The Leiden Thrombosis Recurrence Risk Prediction model (L-TRRiP). PLoS Med 2019; 16 (10) e1002883
    CrossrefPubMedGoogle Scholar
  • 91 Albertsen IE, Søgaard M, Goldhaber SZ. et al. Development of sex-stratified prediction models for recurrent venous thromboembolism: a Danish Nationwide Cohort Study. Thromb Haemost 2020; 120 (05) 805-814
    Article in Thieme ConnectPubMedGoogle Scholar
  • 92 Xu K, Chan NC. Refining risk prediction for recurrent venous thromboembolism: can we do better?. Thromb Haemost 2020; 120 (05) 725-727
    Article in Thieme ConnectPubMedGoogle Scholar
  • 93 Pabinger I, Ay C. Biomarkers and venous thromboembolism. Arterioscler Thromb Vasc Biol 2009; 29 (03) 332-336
    CrossrefPubMedGoogle Scholar
  • 94 Stevens H, Peter K, Tran H, McFadyen J. Predicting the risk of recurrent venous thromboembolism: current challenges and future opportunities. J Clin Med 2020; 9 (05) 9
    CrossrefPubMedGoogle Scholar
  • 95 Kearon C, Gent M, Hirsh J. et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999; 340 (12) 901-907
    CrossrefPubMedGoogle Scholar
  • 96 Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med 2003; 139 (11) 893-900
    CrossrefPubMedGoogle Scholar
  • 97 Agnelli G, Buller HR, Cohen A. et al; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013; 368 (08) 699-708
    CrossrefPubMedGoogle Scholar
  • 98 Schulman S, Kearon C, Kakkar AK. et al; RE-MEDY Trial Investigators, RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013; 368 (08) 709-718
    CrossrefPubMedGoogle Scholar
  • 99 Bauersachs R, Berkowitz SD, Brenner B. et al; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363 (26) 2499-2510
    CrossrefPubMedGoogle Scholar
  • 100 Raskob G, Ageno W, Cohen AT. et al. Extended duration of anticoagulation with edoxaban in patients with venous thromboembolism: a post-hoc analysis of the Hokusai-VTE study. Lancet Haematol 2016; 3 (05) e228-e236
    CrossrefPubMedGoogle Scholar
  • 101 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
    CrossrefPubMedGoogle Scholar
  • 102 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
    CrossrefPubMedGoogle Scholar
  • 103 Weitz JI, Lensing AWA, Prins MH. et al; EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med 2017; 376 (13) 1211-1222
    CrossrefPubMedGoogle Scholar
  • 104 Vasanthamohan L, Boonyawat K, Chai-Adisaksopha C, Crowther M. Reduced-dose direct oral anticoagulants in the extended treatment of venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost 2018; 16 (07) 1288-1295
    CrossrefPubMedGoogle Scholar
  • 105 Ratnoff OD, Colopy JE. A familial hemorrhagic trait associated with a deficiency of a clot-promoting fraction of plasma. J Clin Invest 1955; 34 (04) 602-613
    CrossrefPubMedGoogle Scholar
  • 106 Renné T, Pozgajová M, Grüner S. et al. Defective thrombus formation in mice lacking coagulation factor XII. J Exp Med 2005; 202 (02) 271-281
    CrossrefPubMedGoogle Scholar
  • 107 Renné T, Schmaier AH, Nickel KF, Blombäck M, Maas C. In vivo roles of factor XII. Blood 2012; 120 (22) 4296-4303
    CrossrefPubMedGoogle Scholar
  • 108 McFadyen JD, Peter K. Novel antithrombotic drugs on the horizon: the ultimate promise to prevent clotting while avoiding bleeding. Circ Res 2017; 121 (10) 1133-1135
    CrossrefPubMedGoogle Scholar
  • 109 Preis M, Hirsch J, Kotler A. et al. Factor XI deficiency is associated with lower risk for cardiovascular and venous thromboembolism events. Blood 2017; 129 (09) 1210-1215
    CrossrefPubMedGoogle Scholar
  • 110 Wang X, Cheng Q, Xu L. et al. Effects of factor IX or factor XI deficiency on ferric chloride-induced carotid artery occlusion in mice. J Thromb Haemost 2005; 3 (04) 695-702
    CrossrefPubMedGoogle Scholar
  • 111 Weitz JI, Chan NC. Novel antithrombotic strategies for treatment of venous thromboembolism. Blood 2020; 135 (05) 351-359
    CrossrefPubMedGoogle Scholar
  • 112 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
    CrossrefPubMedGoogle Scholar
  • 113 Weitz JI, Bauersachs R, Becker B. et al. Effect of osocimab in preventing venous thromboembolism among patients undergoing knee arthroplasty: The FOXTROT randomized clinical trial. JAMA 2020; 323 (02) 130-139
    CrossrefPubMedGoogle Scholar
  • 114 Matafonov A, Leung PY, Gailani AE. et al. Factor XII inhibition reduces thrombus formation in a primate thrombosis model. Blood 2014; 123 (11) 1739-1746
    CrossrefPubMedGoogle Scholar
  • 115 Larsson M, Rayzman V, Nolte MW. et al. A factor XIIa inhibitory antibody provides thromboprotection in extracorporeal circulation without increasing bleeding risk. Sci Transl Med 2014; 6 (222) 222ra17
    CrossrefPubMedGoogle Scholar
  • 116 Stevens H, McFadyen JD. Platelets as central actors in thrombosis-reprising an old role and defining a new character. Semin Thromb Hemost 2019; 45 (08) 802-809
    Article in Thieme ConnectPubMedGoogle Scholar
  • 117 Travers RJ, Shenoi RA, Kalathottukaren MT, Kizhakkedathu JN, Morrissey JH. Nontoxic polyphosphate inhibitors reduce thrombosis while sparing hemostasis. Blood 2014; 124 (22) 3183-3190
    CrossrefPubMedGoogle Scholar
  • 118 Smith SA, Choi SH, Collins JN, Travers RJ, Cooley BC, Morrissey JH. Inhibition of polyphosphate as a novel strategy for preventing thrombosis and inflammation. Blood 2012; 120 (26) 5103-5110
    CrossrefPubMedGoogle Scholar
  • 119 Labberton L, Kenne E, Long AT. et al. Neutralizing blood-borne polyphosphate in vivo provides safe thromboprotection. Nat Commun 2016; 7: 12616
    CrossrefPubMedGoogle Scholar
  • 120 Zwicker JI, Schlechter BL, Stopa JD. et al; CATIQ Investigators11. Targeting protein disulfide isomerase with the flavonoid isoquercetin to improve hypercoagulability in advanced cancer. JCI Insight 2019; 4 (04) 4
    CrossrefPubMedGoogle Scholar
  • 121 Hanjaya-Putra D, Haller C, Wang X. et al. Platelet-targeted dual pathway antithrombotic inhibits thrombosis with preserved hemostasis. JCI Insight 2018; 3 (15) 3
    CrossrefPubMedGoogle Scholar
  • 122 Schwarz M, Meade G, Stoll P. et al. Conformation-specific blockade of the integrin GPIIb/IIIa: a novel antiplatelet strategy that selectively targets activated platelets. Circ Res 2006; 99 (01) 25-33
    CrossrefPubMedGoogle Scholar
  • 123 Stoll P, Bassler N, Hagemeyer CE. et al. Targeting ligand-induced binding sites on GPIIb/IIIa via single-chain antibody allows effective anticoagulation without bleeding time prolongation. Arterioscler Thromb Vasc Biol 2007; 27 (05) 1206-1212
    CrossrefPubMedGoogle Scholar
  • 124 Wang Y, Gao H, Shi C. et al. Corrigendum: leukocyte integrin Mac-1 regulates thrombosis via interaction with platelet GPIbα. Nat Commun 2017; 8: 16124
    CrossrefPubMedGoogle Scholar
  • 125 Plow EF, Wang Y, Simon DI. The search for new antithrombotic mechanisms and therapies that may spare hemostasis. Blood 2018; 131 (17) 1899-1902
    CrossrefPubMedGoogle Scholar
  • 126 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
    CrossrefPubMedGoogle Scholar
  • 127 Mosnier LO, Bouma BN. Regulation of fibrinolysis by thrombin activatable fibrinolysis inhibitor, an unstable carboxypeptidase B that unites the pathways of coagulation and fibrinolysis. Arterioscler Thromb Vasc Biol 2006; 26 (11) 2445-2453
    CrossrefPubMedGoogle Scholar
  • 128 Zhou J, Miyoshi N. A first-in-human study of DS-1040, an inhibitor of the activated form of thrombin-activatable fibrinolysis inhibitor, in healthy subjects: reply. J Thromb Haemost 2017; 15 (10) 2081-2083
    CrossrefPubMedGoogle Scholar
  • 129 Singh S, Houng AK, Reed GL. Venous stasis-induced fibrinolysis prevents thrombosis in mice: role of α2-antiplasmin. Blood 2019; 134 (12) 970-978
    CrossrefPubMedGoogle Scholar
  • 130 Reed G, Kussie P, Zhao T, Postlethwaite A, Kang A. Abstract 14994: inactivation of α2-antiplasmin promotes thrombus dissolution in humans: preliminary results of the Novel α2-Antiplasmin Inactivation for Lysis of Intravascular Thrombi (NAIL-IT) Trial. Circulation 2016; 134 (Suppl. 01) A14994
    PubMedGoogle Scholar
  • 131 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
    CrossrefPubMedGoogle Scholar
  • 132 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
    CrossrefPubMedGoogle Scholar
  • 133 Jeraj L, Jezovnik MK, Poredos P. Rivaroxaban versus warfarin in the prevention of post-thrombotic syndrome. Thromb Res 2017; 157: 46-48
    CrossrefPubMedGoogle Scholar
  • 134 Utne KK, Dahm A, Wik HS, Jelsness-Jørgensen LP, Sandset PM, Ghanima W. Rivaroxaban versus warfarin for the prevention of post-thrombotic syndrome. Thromb Res 2018; 163: 6-11
    CrossrefPubMedGoogle Scholar
  • 135 Ferreira T, Huber SC, de Moraes Martinelli B. et al. Low prevalence of post-thrombotic syndrome in patients treated with rivaroxaban. Vascul Pharmacol 2020; 124: 106608
    CrossrefPubMedGoogle Scholar
  • 136 Prandoni P, Ageno W, Ciammaichella M. et al; DOAC-PTS Investigators. The risk of post-thrombotic syndrome in patients with proximal deep vein thrombosis treated with the direct oral anticoagulants. Intern Emerg Med 2020; 15 (03) 447-452
    CrossrefPubMedGoogle Scholar
  • 137 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 138 Galanaud J, Abdulrehman J, Delluc A, Schulman S, Kahn S. Tinzaparin lead-in to prevent the post-thrombotic syndrome (The TILE Pilot Study): rationale and study protocol [abstract]. Res Pract Thromb Haemost 2020 4.
    PubMedGoogle Scholar