Hamostaseologie 2024; 44(02): 097-110
DOI: 10.1055/a-2178-6574
Review Article

Management of Deep Vein Thrombosis: An Update Based on the Revised AWMF S2k Guideline

Birgit Linnemann
1   Cardiology III – Angiology, Department of Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
,
Jan Beyer-Westendorf
2   Thrombosis Research Unit, Division of Haematology, Department of Medicine I, Carl Gustav Carus University Hospital, University Hospital Carl-Gustav Carus, Dresden, Germany
,
Christine Espinola-Klein
1   Cardiology III – Angiology, Department of Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
,
Katja S. Mühlberg
3   Department of Angiology, University Hospital Leipzig, Leipzig, Germany
,
Oliver J. Müller
4   Department of Internal Medicine III, University Hospital Schleswig - Holstein, Campus Kiel, Kiel, Germany
,
Robert Klamroth
5   Department of Internal Medicine, Angiology and Haemostaseology, Vivantes Klinikum im Friedrichshain, Berlin, Germany
› Author Affiliations

Abstract

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are the most common manifestations of venous thromboembolism (VTE). Most DVTs affect the lower-extremity veins. Since the symptoms of DVT are non-specific, a prompt and standardised diagnostic work-up is essential to minimise the risk of PE in the acute phase and to prevent thrombosis progression, post-thrombotic syndrome and VTE recurrence in the long-term. Only recently, the AWMF S2k guidelines on Diagnostics and Therapy of Venous Thrombosis and Pulmonary Embolism have been revised. In the present article, we summarize current evidence and guideline recommendations focusing on lower-extremity DVT (LEDVT). Depending on whether the diagnostic work-up is performed by a specialist in vascular medicine or by a primary care physician, different diagnostic algorithms are presented that combine clinical probability, D-dimer testing and diagnostic imaging. The diagnosis of ipsilateral recurrent DVT poses a particular challenge and is presented in a separate algorithm. Anticoagulant therapy is an essential part of therapy, with current guidelines clearly favouring regimens based on direct oral anticoagulants over the traditional sequential therapy of parenteral anticoagulants and vitamin K antagonists. For most DVTs, a duration of therapeutic-dose anticoagulation of at least 3 to 6 months is considered sufficient, and this raises the question of the risk of VTE recurrence after discontinuation of anticoagulation and the need for secondary prophylaxis in the long-term. Depending on the circumstances and trigger factors that have contributed to the occurrence of DVT, management strategies are presented that allow decision-making taking into account the individual bleeding risk and patient's preferences.



Publication History

Received: 20 August 2023

Accepted: 19 September 2023

Article published online:
30 April 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 White RH. The epidemiology of venous thromboembolism. Circulation 2003; 107 (23, Suppl 1): I4-I8
  • 2 Wendelboe AM, Raskob GE. Global burden of thrombosis: epidemiologic aspects. Circ Res 2016; 118 (09) 1340-1347
  • 3 Strijkers RHW, Cate-Hoek AJ, Bukkems SFFW, Wittens CH. Management of deep vein thrombosis and prevention of post-thrombotic syndrome. BMJ 2011; 343: d5916
  • 4 Hach-Wunderle V, Bauersachs R, Gerlach HE. et al. Post-thrombotic syndrome 3 years after deep venous thrombosis in the Thrombosis and Pulmonary Embolism in Out-Patients (TULIPA) PLUS Registry. J Vasc Surg Venous Lymphat Disord 2013; 1 (01) 5-12
  • 5 Rabinovich A, Kahn SR. How I treat the postthrombotic syndrome. Blood 2018; 131 (20) 2215-2222
  • 6 Linnemann B, Blank W, Doenst T. et al. Diagnostics and Therapy of Venous Thrombosis and Pulmonary Embolism. The revised AWMF S2k Guideline. Vasa. 2023 Oct; 52(S111): 1–146. PMID: 37904504. DOI: 10.1024/0301-1526/a001089
  • 7 Schellong SM. Complete compression ultrasound for the diagnosis of venous thromboembolism. Curr Opin Pulm Med 2004; 10 (05) 350-355
  • 8 Johnson SA, Stevens SM, Woller SC. et al. Risk of deep vein thrombosis following a single negative whole-leg compression ultrasound: a systematic review and meta-analysis. JAMA 2010; 303 (05) 438-445
  • 9 Kraaijpoel N, Carrier M, Le Gal G. et al. Diagnostic accuracy of three ultrasonography strategies for deep vein thrombosis of the lower extremity: a systematic review and meta-analysis. PLoS One 2020; 15 (02) e0228788
  • 10 Riley RS, Gilbert AR, Dalton JB, Pai S, McPherson RA. Widely used types and clinical applications of D-dimer assay. Lab Med 2016; 47 (02) 90-102
  • 11 Stricker H, Marchetti O, Haeberli A, Mombelli G. Hemostatic activation under anticoagulant treatment: a comparison of unfractionated heparin vs. nadroparin in the treatment of proximal deep vein thrombosis. Thromb Haemost 1999; 82 (04) 1227-1231
  • 12 Nybo M, Hvas A-M. Age-adjusted D-dimer cut-off in the diagnostic strategy for deep vein thrombosis: a systematic review. Scand J Clin Lab Invest 2017; 77 (08) 568-573
  • 13 van der Hulle T, Tan M, den Exter PL. et al. Selective D-dimer testing for the diagnosis of acute deep vein thrombosis: a validation study. J Thromb Haemost 2013; 11 (12) 2184-2186
  • 14 Parpia S, Takach Lapner S, Schutgens R, Elf J, Geersing GJ, Kearon C. Clinical pre-test probability adjusted versus age-adjusted D-dimer interpretation strategy for DVT diagnosis: a diagnostic individual patient data meta-analysis. J Thromb Haemost 2020; 18 (03) 669-675
  • 15 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
  • 16 van Dam LF, Gautam G, Dronkers CEA. et al. Safety of using the combination of the Wells rule and D-dimer test for excluding acute recurrent ipsilateral deep vein thrombosis. J Thromb Haemost 2020; 18 (09) 2341-2348
  • 17 Carrier M, Rodger MA, Wells PS, Righini M, LE Gal G. Residual vein obstruction to predict the risk of recurrent venous thromboembolism in patients with deep vein thrombosis: a systematic review and meta-analysis. J Thromb Haemost 2011; 9 (06) 1119-1125
  • 18 Linkins L-A, Stretton R, Probyn L, Kearon C. Interobserver agreement on ultrasound measurements of residual vein diameter, thrombus echogenicity and Doppler venous flow in patients with previous venous thrombosis. Thromb Res 2006; 117 (03) 241-247
  • 19 Ageno W, Squizzato A, Wells PS, Büller HR, Johnson G. The diagnosis of symptomatic recurrent pulmonary embolism and deep vein thrombosis: guidance from the SSC of the ISTH. J Thromb Haemost 2013; 11 (08) 1597-1602
  • 20 Maufus M, Elias A, Barrellier M-T, Pernod G. French Society for Vascular Medicine. Diagnosis of deep vein thrombosis recurrence: ultrasound criteria. Thromb Res 2018; 161: 78-83
  • 21 Aguilar C, del Villar V. Combined D-dimer and clinical probability are useful for exclusion of recurrent deep venous thrombosis. Am J Hematol 2007; 82 (01) 41-44
  • 22 Prandoni P, Tormene D, Dalla Valle F, Concolato A, Pesavento R. D-dimer as an adjunct to compression ultrasonography in patients with suspected recurrent deep vein thrombosis. J Thromb Haemost 2007; 5 (05) 1076-1077
  • 23 van Dam LF, Dronkers CEA, Gautam G. et al; Theia Study Group. Magnetic resonance imaging for diagnosis of recurrent ipsilateral deep vein thrombosis. Blood 2020; 135 (16) 1377-1385
  • 24 Limone BL, Hernandez AV, Michalak D, Bookhart BK, Coleman CI. Timing of recurrent venous thromboembolism early after the index event: a meta-analysis of randomized controlled trials. Thromb Res 2013; 132 (04) 420-426
  • 25 Appelen D, van Loo E, Prins MH, Neumann MH, Kolbach DN. Compression therapy for prevention of post-thrombotic syndrome. Cochrane Database Syst Rev 2017; 9 (09) CD004174
  • 26 Amin EE, Bistervels IM, Meijer K. et al. Reduced incidence of vein occlusion and postthrombotic syndrome after immediate compression for deep vein thrombosis. Blood 2018; 132 (21) 2298-2304
  • 27 Kahn SR, Comerota AJ, Cushman M. et al; American Heart Association Council on Peripheral Vascular Disease, Council on Clinical Cardiology, and Council on Cardiovascular and Stroke Nursing. The postthrombotic syndrome: evidence-based prevention, diagnosis, and treatment strategies: a scientific statement from the American Heart Association. Circulation 2014; 130 (18) 1636-1661
  • 28 Schulman S, Kearon C, Kakkar AK. et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361 (24) 2342-2352
  • 29 Schulman S, Kakkar AK, Goldhaber SZ. et al; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014; 129 (07) 764-772
  • 30 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
  • 31 Büller HR, Décousus H, Grosso MA. et al; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369 (15) 1406-1415
  • 32 Büller HR, Prins MH, Lensin AWA. et al; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366 (14) 1287-1297
  • 33 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
  • 34 van der Hulle T, den Exter PL, Kooiman J, van der Hoeven JJM, Huisman MV, Klok FA. Meta-analysis of the efficacy and safety of new oral anticoagulants in patients with cancer-associated acute venous thromboembolism. J Thromb Haemost 2014; 12 (07) 1116-1120
  • 35 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
  • 36 Brandjes DPM, Büller HR, Heijboer H. et al. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet 1997; 349 (9054) 759-762
  • 37 Prandoni P, Lensing AWA, Prins MH. et al. Below-knee elastic compression stockings to prevent the post-thrombotic syndrome: a randomized, controlled trial. Ann Intern Med 2004; 141 (04) 249-256
  • 38 Jayaraj A, Meissner M. Impact of graduated compression stockings on the prevention of post-thrombotic syndrome - results of a randomized controlled trial. Phlebology 2015; 30 (08) 541-548
  • 39 Arpaia G, Cimminiello C, Mastrogiacomo O, de Gaudenzi E. Efficacy of elastic compression stockings used early or after resolution of the edema on recanalization after deep venous thrombosis: the COM.PRE Trial. Blood Coagul Fibrinolysis 2007; 18 (02) 131-137
  • 40 Prandoni P, Noventa F, Quintavalla R. et al; Canano Investigators. Thigh-length versus below-knee compression elastic stockings for prevention of the postthrombotic syndrome in patients with proximal-venous thrombosis: a randomized trial. Blood 2012; 119 (06) 1561-1565
  • 41 Ten Cate-Hoek AJ, Amin EE, Bouman AC. et al; IDEAL DVT Investigators. Individualised versus standard duration of elastic compression therapy for prevention of post-thrombotic syndrome (IDEAL DVT): a multicentre, randomised, single-blind, allocation-concealed, non-inferiority trial. Lancet Haematol 2018; 5 (01) e25-e33
  • 42 Kakkos SK, Gohel M, Baekgaard N. et al; ESVS Guidelines Committee. Editor's Choice - European Society for Vascular Surgery (ESVS) 2021 Clinical Practice Guidelines on the Management of Venous Thrombosis. Eur J Vasc Endovasc Surg 2021; 61 (01) 9-82
  • 43 Broderick C, Watson L, Armon MP. Thrombolytic strategies versus standard anticoagulation for acute deep vein thrombosis of the lower limb. Cochrane Database Syst Rev 2021; 1 (01) CD002783
  • 44 Stevens SM, Woller SC, Kreuziger LB. et al. Antithrombotic therapy for VTE disease: second update of the CHEST Guideline and Expert Panel Report. Chest 2021; 160 (06) e545-e608
  • 45 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
  • 46 Donadini MP, Ageno W, Antonucci E. et al. Prognostic significance of residual venous obstruction in patients with treated unprovoked deep vein thrombosis: a patient-level meta-analysis. Thromb Haemost 2014; 111 (01) 172-179
  • 47 White RH. Identifying risk factors for venous thromboembolism. Circulation 2012; 125 (17) 2051-2053
  • 48 Coppens M, Reijnders JH, Middeldorp S, Doggen CJ, Rosendaal FR. Testing for inherited thrombophilia does not reduce the recurrence of venous thrombosis. J Thromb Haemost 2008; 6 (09) 1474-1477
  • 49 Stevens SM, Woller SC, Bauer KA. et al. Guidance for the evaluation and treatment of hereditary and acquired thrombophilia. J Thromb Thrombolysis 2016; 41 (01) 154-164
  • 50 Garcia-Horton A, Kovacs MJ, Abdulrehman J, Taylor JE, Sharma S, Lazo-Langner A. Impact of thrombophilia screening on venous thromboembolism management practices. Thromb Res 2017; 149: 76-80
  • 51 Carrier M, Le Gal G, Wells PS, Fergusson D, Ramsay T, Rodger MA. Systematic review: the Trousseau syndrome revisited: should we screen extensively for cancer in patients with venous thromboembolism?. Ann Intern Med 2008; 149 (05) 323-333
  • 52 van Es N, Le Gal G, Otten H-M. et al. Screening for occult cancer in patients with unprovoked venous thromboembolism: a systematic review and meta-analysis of individual patient data. Ann Intern Med 2017; 167 (06) 410-417
  • 53 Marks MA, Engels EA. Venous thromboembolism and cancer risk among elderly adults in the United States. Cancer Epidemiol Biomarkers Prev 2014; 23 (05) 774-783
  • 54 Rosell A, Lundström S, Mackman N, Wallén H, Thålin C. A clinical practice-based evaluation of the RIETE score in predicting occult cancer in patients with venous thromboembolism. J Thromb Thrombolysis 2019; 48 (01) 111-118
  • 55 Khan F, Tritschler T, Kimpton M. et al; MAJESTIC Collaborators. Long-term risk for major bleeding during extended oral anticoagulant therapy for first unprovoked venous thromboembolism: a systematic review and meta-analysis. Ann Intern Med 2021; 174 (10) 1420-1429
  • 56 Klok FA, Huisman MV. How I assess and manage the risk of bleeding in patients treated for venous thromboembolism. Blood 2020; 135 (10) 724-734
  • 57 Badescu MC, Ciocoiu M, Badulescu OV. et al. Prediction of bleeding events using the VTE-BLEED risk score in patients with venous thromboembolism receiving anticoagulant therapy. (Review) Exp Ther Med 2021; 22 (05) 1344
  • 58 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
  • 59 Prandoni P, Lensing AWA, Prins MH. et al. Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism. Ann Intern Med 2002; 137 (12) 955-960
  • 60 Siragusa S, Malato A, Anastasio R. et al. Residual vein thrombosis to establish duration of anticoagulation after a first episode of deep vein thrombosis: the Duration of Anticoagulation based on Compression UltraSonography (DACUS) study. Blood 2008; 112 (03) 511-515
  • 61 Tan M, Mos ICM, Klok FA, Huisman MV. Residual venous thrombosis as predictive factor for recurrent venous thromboembolism in patients with proximal deep vein thrombosis: a systematic review. Br J Haematol 2011; 153 (02) 168-178
  • 62 Prandoni P, Prins MH, Lensing AWA. et al; AESOPUS Investigators. Residual thrombosis on ultrasonography to guide the duration of anticoagulation in patients with deep venous thrombosis: a randomized trial. Ann Intern Med 2009; 150 (09) 577-585
  • 63 Palareti G, Legnani C, Cosmi B. et al. Predictive value of D-dimer test for recurrent venous thromboembolism after anticoagulation withdrawal in subjects with a previous idiopathic event and in carriers of congenital thrombophilia. Circulation 2003; 108 (03) 313-318
  • 64 Cosmi B, Legnani C, Tosetto A. et al; PROLONG Investigators (on behalf of Italian Federation of Anticoagulation Clinics). Usefulness of repeated D-dimer testing after stopping anticoagulation for a first episode of unprovoked venous thromboembolism: the PROLONG II prospective study. Blood 2010; 115 (03) 481-488
  • 65 Verhovsek M, Douketis JD, Yi Q. et al. Systematic review: D-dimer to predict recurrent disease after stopping anticoagulant therapy for unprovoked venous thromboembolism. Ann Intern Med 2008; 149 (07) 481-490 , W94
  • 66 Douketis J, Tosetto A, Marcucci M. et al. Patient-level meta-analysis: effect of measurement timing, threshold, and patient age on ability of D-dimer testing to assess recurrence risk after unprovoked venous thromboembolism. Ann Intern Med 2010; 153 (08) 523-531
  • 67 Palareti G, Cosmi B, Legnani C. et al; PROLONG Investigators. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med 2006; 355 (17) 1780-1789
  • 68 Palareti G, Cosmi B, Legnani C. et al; DULCIS (D-dimer and ULtrasonography in Combination Italian Study) Investigators. D-dimer to guide the duration of anticoagulation in patients with venous thromboembolism: a management study. Blood 2014; 124 (02) 196-203
  • 69 Palareti G, Poli D, Ageno W. et al. D-dimer and reduced-dose apixaban for extended treatment after unprovoked venous thromboembolism: the Apidulcis study. Blood Adv 2022; 6 (23) 6005-6015
  • 70 Kearon C, Kahn SR. Long-term treatment of venous thromboembolism. Blood 2020; 135 (05) 317-325
  • 71 Prandoni P, Vedovetto V, Ciammaichella M. et al; Morgagni Investigators. Residual vein thrombosis and serial D-dimer for the long-term management of patients with deep venous thrombosis. Thromb Res 2017; 154: 35-41
  • 72 Mearns ES, Coleman CI, Patel D. et al. Index clinical manifestation of venous thromboembolism predicts early recurrence type and frequency: a meta-analysis of randomized controlled trials. J Thromb Haemost 2015; 13 (06) 1043-1052
  • 73 Palareti G, Legnani C, Antonucci E. et al. Management and outcomes of isolated distal deep vein thromboses: a questionable trend toward long-lasting anticoagulation treatment. results from the START-Register. TH Open 2021; 5 (03) e239-e250
  • 74 Schellong S, Ageno W, Casella IB. et al. Profile of patients with isolated distal deep vein thrombosis versus proximal deep vein thrombosis or pulmonary embolism: RE-COVERY DVT/PE Study. Semin Thromb Hemost 2022; 48 (04) 446-458
  • 75 Kirkilesis G, Kakkos SK, Bicknell C, Salim S, Kakavia K. Treatment of distal deep vein thrombosis. Cochrane Database Syst Rev 2020; 4 (04) CD013422
  • 76 Dentali F, Pegoraro S, Barco S. et al. Clinical course of isolated distal deep vein thrombosis in patients with active cancer: a multicenter cohort study. J Thromb Haemost 2017; 15 (09) 1757-1763
  • 77 Dentali F, Barco S, Pegoraro S. et al. Residual vein obstruction in patients diagnosed with acute isolated distal deep vein thrombosis associated with active cancer. J Thromb Thrombolysis 2018; 46 (03) 404-408
  • 78 Galanaud J-P, Sevestre M-A, Pernod G. et al. Long-term outcomes of cancer-related isolated distal deep vein thrombosis: the OPTIMEV study. J Thromb Haemost 2017; 15 (05) 907-916
  • 79 Kuczmik W, Wysokinski WE, Hesley GK. et al. Calf vein thrombosis comparison of outcomes for axial and muscular venous thrombosis. Thromb Haemost 2021; 121 (02) 216-223
  • 80 Henry JC, Satiani B. Calf muscle venous thrombosis: a review of the clinical implications and therapy. Vasc Endovascular Surg 2014; 48 (5-6): 396-401