A patient who was admitted with deep vein thrombophlebitis is complaining

Table of Contents

1. Abstract
2. Case Presentations
3. Introduction
4. Critical Appraisal of the Literature
5. Epidemiology
6. Pathophysiology
   1. Causes of Unprovoked Deep Vein Thrombosis
      1. Genetics
         • Non-O Blood Group
         • Factor V Leiden
         • Prothrombin Gene Mutation
         • Protein C and Protein S Deficiency
   2. Causes of Provoked Deep Vein Thrombosis
      1. Cancer
      2. Oral Contraceptives and Pregnancy
      3. Long-Distance Travel
      4. Surgery
      5. Trauma
7. Anatomy
8. Differential Diagnosis
9. Prehospital Care
10. Emergency Department Evaluation
    1. History and Physical Examination
    2. Risk Stratification
11. Diagnostic Testing
    1. D-Dimer
    2. Ultrasound
       1. Ultrasound for Upper Extremity Deep Vein Thrombosis
    3. Computed Tomographic Venography
    4. Magnetic Resonance Venography
12. Treatment
    1. Initial Anticoagulation
       1. Heparin and Low-Molecular-Weight Heparin
       2. Warfarin
       3. Direct Oral Anticoagulants
       4. Concerns With Direct Oral Anticoagulants
    2. Extended Anticoagulation
    3. Aspirin
    4. Other Treatment Modalities
       1. Compression Stockings
       2. Inferior Vena Cava Filters
       3. Thrombolysis
13. Special Populations
    1. Upper Extremity Deep Vein Thrombosis
    2. Recurrent Deep Vein Thrombosis
    3. Patients With Active Malignancy
    4. Pregnant Patients
    5. Elderly Patients
    6. Phlegmasia Alba Dolens and Phlegmasia Cerulea Dolens
14. Controversies and Cutting Edge
    1. Distal Calf Vein Deep Vein Thrombosis
15. Disposition
16. Time- and Cost-Effective Strategies
17. Summary
18. Risk Management Pitfalls for Deep Vein Thrombosis in the Emergency Department
19. Case Conclusions
20. Clinical Pathways
    1. Clinical Pathway for Risk Stratification for Deep Vein Thrombosis in the Emergency Department
    2. Clinical Pathway for Treatment of Deep Vein Thrombosis in the Emergency Department
21. Tables and Figures
22. References

Deep vein thrombosis (DVT) can present with a variety of nonspecific signs and symptoms, and can involve the upper or lower extremities. Management of patients with DVT has changed markedly over the last 10 years, moving from hospital admission for initiation of anticoagulation to outpatient management. Diagnosis requires a risk stratification process involving clinical decision rules, D-dimer testing, and ultrasonography. Once the diagnosis is confirmed, the patient should be engaged in shared decision-making regarding treatment options. Recurrent DVT, as well as managing DVT in pregnant women, the elderly population, and patients with malignancies are also discussed.

Case Presentations

A 20-year-old woman presents with a 3-day history of left lower extremity pain and swelling. On examination, her left lower leg is visibly larger than the right. She is concerned that she has a “blood clot,” because her mother had one several years ago. She says that she does not have health insurance and will be self-paying for her visit. She asks you to keep the cost of the visit as low as possible. You wonder whether there is clinical decision rule that could be used to aid in choosing a cost-effective diagnostic strategy…

Your next patient is a 56-year-old man who is also complaining of left lower extremity pain and swelling. A venous duplex ultrasound confirms a deep vein thrombosis (DVT) in the popliteal vein. He notes that he is the primary breadwinner for his family and cannot stay in the hospital for treatment. He asks if there is any way he could be discharged to home with treatment. You recall that patients with an isolated DVT can be discharged home, but you cannot remember the protocol to initiate the discharge process…

Your last patient of the shift is a 76-year-old woman with right lower extremity pain and swelling. On examination, her right lower leg is swollen, but she has no discoloration or loss of pedal pulse. A venous duplex ultrasound confirms an extensive proximal DVT in the extremity. You anticoagulate the patient and call the internist for admission. The internist would like you to discuss the case with a vascular surgeon for possible thrombolysis. You wonder what the evidence is supporting thrombolysis in these patients . . . ….

Introduction

Venous thromboembolism (VTE) is a spectrum of diseases that includes superficial thrombophlebitis, deep vein thrombosis (DVT), and pulmonary embolism. The annual cost of treatment in the United States for these conditions is between $7 and $10 billion, and they represent a major healthcare concern.1 DVT can present a diagnostic dilemma for the emergency clinician due to the overlapping of symptoms with other diseases.

Over the last decade, new treatment paradigms have revolutionized the care of patients with DVT, moving from the inpatient setting to outpatient management; however, despite these advances, a large proportion of patients will develop complications from the disease process. This issue of Emergency Medicine Practice reviews the evidence regarding the pathophysiology, diagnosis, and management of DVT in the emergency department (ED).

Critical Appraisal of the Literature

A literature search was conducted utilizing multiple available databases. A MEDLINE® search with the MeSH heading of deep vein thrombosis restricted to studies involving humans published from January 2014 through June 2020 yielded over 21,000 results, with 1002 being clinical trials, 642 being randomized. Additional databases and search strategies were queried, including Google Scholar and the Cochrane Database of Systematic Reviews. Reference lists from the identified articles and abstracts, as well as major textbooks in internal medicine, emergency medicine, hematology, and critical care were reviewed. Clinical practice guidelines and position statements from major relevant professional organizations were also reviewed.

Boolean operators and MeSH headings were applied to structure the literature search and included: deep vein thrombosis and emergency medicine, deep vein thrombosis and risk stratification, deep vein thrombosis and treatment. Two authors screened these results independently for articles considered to be landmark publications, highly impactful, or from high-quality journals. A total of 97 articles were included in this review.

Epidemiology

Although the true incidence of VTE is unknown, the overall incidence in the general population has been postulated to be 100 cases per 100,000 persons per year, with an annual incidence rate of 0.1% in the United States.2 The overall incidence of VTE increases exponentially with age. Once a patient reaches age 80 years, the incidence of VTE rises to 450 cases per 100,000 per year.3 The incidence of DVT in the general population has been estimated to range from 45 to 117 cases per 100,000 persons per year.4 Much like VTE, the risk for DVT increases with age, and approximately 1% of the population aged > 60 years will develop a DVT.4 Black persons have the highest incidence of DVT (29.3 cases per 100,000), followed by White persons (23 cases per 100,000), Latinos (13.9 cases per 100,000), and Asian-Pacific Islanders (0.6 cases per 100,000).5 Although the incidence of DVT is relatively equal among the sexes, men present more often with a proximal DVT and women present more often with a distal DVT.6,7 There also appears to be a seasonal variation with DVT, with the winter months having a higher number of cases.8 Recurrence rates depend upon the original cause of the thrombus, but have been reported to be 8.6% at 6 months and up to 30.3% at 8 years.4 Post thrombotic syndrome, a complication of DVT, has been reported to be as high as 50%, despite anticoagulation.9 The mortality for those diagnosed with a DVT is 3.8% at 7 days, 5.5% at 30 days, and 14.6% at 1 year.10

Risk Management Pitfalls for Deep Vein Thrombosis in the Emergency Department

1. “The patient’s leg was red and only slightly swollen, but he didn’t have calf pain. I started him on antibiotics for cellulitis and sent him home.”

Although the majority of patients who present with leg pain will be diagnosed with a nonthrombotic condition, the physical examination can be misleading. Patients should be risk stratified using the Wells score to determine a diagnostic strategy.

3. “I use an age-adjusted D-dimer in elderly patients to help rule out DVT.”

The age adjusted D-dimer has been proven to be accurate in patients with pulmonary embolism, but it has not been studied extensively in patients with possible DVT.

5. “The patient had a negative ultrasound and D-dimer, so I sent him home to follow up with his primary care provider in the coming weeks.”

Diagnostic strategies should be based upon the sensitivity of the tests being obtained. If a whole-leg ultrasound was obtained, then further testing is not required. If another form of extremity ultrasound was obtained, then a repeat ultrasound is warranted.

Tables and Figures

References

Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.

To help the reader judge the strength of each reference, pertinent information about the study, such as the type of study and the number of patients in the study is included in bold type following the references, where available. The most informative references cited in this paper, as determined by the authors, are noted by an asterisk (*) next to the number of the reference.

1. Grosse SD, Nelson RE, Nyarko KA, et al. The economic burden of incident venous thromboembolism in the United States: a review of estimated attributable healthcare costs. Thromb Res. 2016;137:3-10. (Literature review; 3 studies)
2. White RH. The epidemiology of venous thromboembolism. Circulation. 2003;107(23 Suppl 1):I4-8. (Review) DOI: 10.1161/01.CIR.0000078468.11849.66
3. Silverstein MD, Heit JA, Mohr DN, et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med. 1998;158(6):585-593. (Retrospective study; 2218 patients)
4. Prandoni P, Lensing AW, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996;125(1):1-7. (Prospective study; 355 patients)
5. White RH, Zhou H, Romano PS. Incidence of idiopathic deep venous thrombosis and secondary thromboembolism among ethnic groups in California. Ann Intern Med. 1998;128(9):737-740. (Retrospective study; 17,991 patients)
6. Bauersachs RM, Riess H, Hach-Wunderle V, et al. Impact of gender on the clinical presentation and diagnosis of deep-vein thrombosis. Thromb Haemost. 2010;103(4):710-717. (Prospective study; 4976 patients)
7. Trinchero A, Scheres LJJ, Prochaska JH, et al. Sex-specific differences in the distal versus proximal presenting location of acute deep vein thrombosis. Thromb Res. 2018;172:74-79. (Meta-analysis; 7 manuscripts)
8. Boulay F, Berthier F, Schoukroun G, et al. Seasonal variations in hospital admission for deep vein thrombosis and pulmonary embolism: analysis of discharge data. BMJ. 2001;323(7313):601-602. (Retrospective study; 127,381 patients)
9. Kahn SR. The post-thrombotic syndrome. Hematology Am Soc Hematol Educ Program. 2016;2016(1):413-418. (Review)
10. Heit JA, Silverstein MD, Mohr DN, et al. Predictors of survival after deep vein thrombosis and pulmonary embolism: a population-based, cohort study. Arch Intern Med. 1999;159(5):445-453. (Retrospective study; 2218 patients)
11. Gill JC, Endres-Brooks J, Bauer PJ, et al. The effect of ABO blood group on the diagnosis of von Willebrand disease. Blood. 1987;69(6):1691-1695. (Prospective study; 1117 patients)
12. Wu O, Bayoumi N, Vickers MA, et al. ABO(H) blood groups and vascular disease: a systematic review and meta-analysis. J Thromb Haemost. 2008;6(1):62-69. (Meta-analysis; 21 studies)
13. Spiezia L, Campello E, Bon M, et al. ABO blood groups and the risk of venous thrombosis in patients with inherited thrombophilia. Blood Transfus. 2013;11(2):250-253. (Prospective study; 1424 patients)
14. Ornstein DL, Cushman M. Cardiology patient page. Factor V Leiden. Circulation. 2003;107(15):e94-97. (Review)
15. Simone B, De Stefano V, Leoncini E, et al. Risk of venous thromboembolism associated with single and combined effects of Factor V Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls. Eur J Epidemiol. 2013;28(8):621-647. (Meta-analysis; 31 studies)
16. Rosendaal FR, Doggen CJ, Zivelin A, et al. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost. 1998;79(4):706-708. (Retrospective study; 5527 patients)
17. Wypasek E, Undas A. Protein C and protein S deficiency - practical diagnostic issues. Adv Clin Exp Med. 2013;22(4):459-467. (Review)
18. Manzoli L, De Vito C, Marzuillo C, et al. Oral contraceptives and venous thromboembolism: a systematic review and meta-analysis. Drug Saf. 2012;35(3):191-205. (Meta-analysis; 55 studies)
19. Stegeman BH, de Bastos M, Rosendaal FR, et al. Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis. BMJ. 2013;347:f5298. (Systematic review and network meta-analysis; 26 studies )
20. James AH, Tapson VF, Goldhaber SZ. Thrombosis during pregnancy and the postpartum period. Am J Obstet Gynecol. 2005;193(1):216-219. (Retrospective study; 34 patients)
21. Heit JA, Kobbervig CE, James AH, et al. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med. 2005;143(10):697-706. (Retrospective study; 50,800 patients)
22. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 196: thromboembolism in pregnancy. Obstet Gynecol. 2018;132(1):e1-e17. (Practice bulletin; updated guidance)
23. James AH, Jamison MG, Brancazio LR, et al. Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am J Obstet Gynecol. 2006;194(5):1311-1315. (Retrospective study; 17,730 patients)
24. Jacobsen AF, Skjeldestad FE, Sandset PM. Incidence and risk patterns of venous thromboembolism in pregnancy and puerperium--a register-based case-control study. Am J Obstet Gynecol. 2008;198(2):233.e231-237. (Register-based case-control study; 613,232 pregnancies)
25. Chandra D, Parisini E, Mozaffarian D. Meta-analysis: travel and risk for venous thromboembolism. Ann Intern Med. 2009;151(3):180-190. (Meta-analysis; 14 studies)
26. Lapostolle F, Le Toumelin P, Chassery C, et al. Gender as a risk factor for pulmonary embolism after air travel. Thromb Haemost. 2009;102(6):1165-1168. (Retrospective study; 116 patients)
27. Cannegieter SC, Doggen CJ, van Houwelingen HC, et al. Travel-related venous thrombosis: results from a large population-based case control study (MEGA study). PLoS Med. 2006;3(8):e307. (Retrospective study; 1906 patients)
28. White RH, Zhou H, Romano PS. Incidence of symptomatic venous thromboembolism after different elective or urgent surgical procedures. Thromb Haemost. 2003;90(3):446-455. (Retrospective study; 1,653,275 patients)
29. Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e227S-e277S. (Guideline)
30. Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 ;141(2 Suppl):e278S-e325S. (Guideline)
31. van Stralen KJ, Rosendaal FR, Doggen CJ. Minor injuries as a risk factor for venous thrombosis. Arch Intern Med. 2008;168(1):21-26. (Retrospective study; 6005 patients)
32. Geerts WH, Code KI, Jay RM, et al. A prospective study of venous thromboembolism after major trauma. N Engl J Med. 1994;331(24):1601-1606. (Prospective study; 716 patients)
33. Chang SL, Huang YL, Lee MC, et al. Association of varicose veins with incident venous thromboembolism and peripheral artery disease. JAMA. 2018;319(8):807-817. (Retrospective study; 425,968 patients)
34. Lindblad B, Tengborn L, Bergqvist D. Deep vein thrombosis of the axillary-subclavian veins: epidemiologic data, effects of different types of treatment and late sequelae. Eur J Vasc Surg. 1988;2(3):161-165. (Retrospective study; 296 patients)
35. DiFelice GS, Paletta GA Jr, Phillips BB, et al. Effort thrombosis in the elite throwing athlete. Am J Sports Med. 2002;30(5):708-712. (Retrospective review; 4 cases)
36. Kaltenmeier CT, Erben Y, Indes J, et al. Systematic review of May-Thurner syndrome with emphasis on gender differences. J Vasc Surg Venous Lymphat Disord. 2018;6(3):399-407 e394. (Meta-analysis; 174 studies)
37. ten Cate-Hoek AJ, van der Velde EF, Toll DB, et al. Common alternative diagnoses in general practice when deep venous thrombosis is excluded. Neth J Med. 2012;70(3):130-135. (Prospective study; 1028 patients)
38. Adhikari S, Zeger W. Non-thrombotic abnormalities on lower extremity venous duplex ultrasound examinations. West J Emerg Med. 2015;16(2):250-254. (Retrospective study; 2390 patients)
39. Prandoni P, Kahn SR. Post-thrombotic syndrome: prevalence, prognostication and need for progress. Br J Haematol. 2009;145(3):286-295. (Review)
40. Goodacre S, Sutton AJ, Sampson FC. Meta-analysis: the value of clinical assessment in the diagnosis of deep venous thrombosis. Ann Intern Med. 2005;143(2):129-139. (Meta-analysis; 51 studies) DOI: 10.7326/0003-4819-143-2-200507190-00012
41. Joffe HV, Kucher N, Tapson VF, et al. Upper-extremity deep vein thrombosis: a prospective registry of 592 patients. Circulation. 2004;110(12):1605-1611. (Prospective study; 592 patients)
42. Chastre J, Cornud F, Bouchama A, et al. Thrombosis as a complication of pulmonary-artery catheterization via the internal jugular vein: prospective evaluation by phlebography. N Engl J Med. 1982;306(5):278-281.
43. American College of Emergency Physicians ACEP Clinical Policies Committee, ACEP Clinical Policies Subcommittee on Suspected Lower-Extremity Deep Venous Thrombosis. Clinical policy: critical issues in the evaluation and management of adult patients presenting with suspected lower-extremity deep venous thrombosis. Ann Emerg Med. 2003;42(1):124-135. (Clinical policy) DOI: 10.1067/mem.2003.181
44. Lim W, Le Gal G, Bates SM, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: diagnosis of venous thromboembolism. Blood Adv. 2018;2(22):3226-3256. (Guideline)
45. Bates SM, Jaeschke R, Stevens SM, et al. Diagnosis of DVT: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e351S-e418S. (Guideline) DOI: 10.1378/chest.11-2299
46. Wells PS, Hirsh J, Anderson DR, et al. Accuracy of clinical assessment of deep-vein thrombosis. Lancet. 1995;345(8961):1326-1330. (Prospective study; 529 patients)
47. Wells PS, Anderson DR, Bormanis J, et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet. 1997;350(9094):1795-1798. (Prospective study; 593 patients) DOI: 10.1016/S0140-6736(9 7)08140-3
48. Wells PS, Anderson DR, Rodger M, et al. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. New Engl J Med. 2003;349:1227-1235. (Prospective study; 1096 patients)
49. Wells PS, Owen C, Doucette S, et al. Does this patient have deep vein thrombosis? JAMA. 2006;295(2):199-207. (Meta-analysis; 14 studies, 8000 patients) DOI: 10.1001/jama.295.2.199
50. Needleman L, Cronan JJ, Lilly MP, et al. Ultrasound for lower extremity deep venous thrombosis: multidisciplinary recommendations from the Society of Radiologists in Ultrasound consensus conference. Circulation. 2018;137(14):1505-1515. (Guideline)
51. Wolf SJ, Hahn SA, Nentwich LM, et al. Clinical Policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with suspected acute venous thromboembolic disease. Ann Emerg Med. 2018;71(5):e59-e109. (Clinical Policy) DOI: 10.1016/j.annemergmed.2018.03.006
52. Kearon C, Akl EA, Omelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. CHEST. 2016;149(2):315-352. (Guideline) DOI: 10.1016/j.chest.2015.11.026
53. Singer AJ, Zheng H, Francis S, et al. D-dimer levels in VTE patients with distal and proximal clots. Am J Emerg Med. 2019;37(1):33-37. (Prospective study; 1752 patients). )
54. Righini M, Goehring C, Bounameaux H, et al. Effects of age on the performance of common diagnostic tests for pulmonary embolism. Am J Med. 2000;109(5):357-361. (Retrospective study; 1029 patients)
55. Nybo M, Hvas AM. Age-adjusted D-dimer cut-off in the diagnostic strategy for deep vein thrombosis: a systematic review. Scand J Clin Lab Invest. 2017;77(8):568-573. (Systematic review; 8 studies)
56. Hanley M, Steigner ML, Ahmed O, et al. ACR Appropriateness Criteria®: suspected lower extremity deep vein thrombosis. J Am Coll Radiol. 2018;15(11):S413-S417. (Guideline) DOI: 10.1016/j.jacr.2018.09.028
57. Goodacre S, Sampson F, Stevenson M, et al. Measurement of the clinical and cost-effectiveness of non-invasive diagnostic testing strategies for deep vein thrombosis. Health Technol Assess. 2006;10(15):1-168, iii-iv. (Meta-analysis)
58. 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(5):438-445. (Meta-analysis; 7 studies, 4731 patients)
59. Zitek T, Baydoun J, Yepez S, et al. Mistakes and pitfalls associated with two-point compression ultrasound for deep vein thrombosis. West J Emerg Med. 2016;17(2):201-208. (Prospective study; 288 patients)
60. Crisp JG, Lovato LM, Jang TB. Compression ultrasonography of the lower extremity with portable vascular ultrasonography can accurately detect deep venous thrombosis in the emergency department. Ann Emerg Med. 2010;56(6):601-610. (Prospective study; 199 patients)
61. Lee JH, Lee SH, Yun SJ. Comparison of 2-point and 3-point point-of-care ultrasound techniques for deep vein thrombosis at the emergency department: a meta-analysis. Medicine (Baltimore). 2019;98(22):e15791. (Meta-analysis; 17 studies, 2372 patients)
62. Burnside PR, Brown MD, Kline JA. Systematic review of emergency physician-performed ultrasonography for lower-extremity deep vein thrombosis. Acad Emerg Med. 2008;15(6):493-498. (Meta-analysis; 6 studies, 936 patients)
63. Pomero F, Dentali F, Borretta V, et al. Accuracy of emergency physician-performed ultrasonography in the diagnosis of deep-vein thrombosis: a systematic review and meta-analysis. Thromb Haemost. 2013;109(1):137-145. (Meta-analysis and systematic review; 16 studies, 2379 patients)
64. Di Nisio M, Van Sluis GL, Bossuyt PM, et al. Accuracy of diagnostic tests for clinically suspected upper extremity deep vein thrombosis: a systematic review. J Thromb Haemost. 2010;8(4):684-692. (Meta-analysis and systematic review; 17 papers, 793 patients)
65. Thomas SM, Goodacre SW, Sampson FC, et al. Diagnostic value of CT for deep vein thrombosis: results of a systematic review and meta-analysis. Clin Radiol. 2008;63(3):299-304. (Meta-analysis; 13 studies)
66. Sampson FC, Goodacre SW, Thomas SM, et al. The accuracy of MRI in diagnosis of suspected deep vein thrombosis: systematic review and meta-analysis. Eur Radiol. 2007;17(1):175-181. (Systematic review and meta-analysis; 14 studies)
67. Robertson L, Strachan J. Subcutaneous unfractionated heparin for the initial treatment of venous thromboembolism. Cochrane Database Syst Rev. 2017;2:CD006771. (Systematic review; 16 studies, 3593 patients)
68. Erkens PM, Prins MH. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database Syst Rev. 2010(9):CD001100. (Meta-analysis; 23 studies, 9587 patients)
69. Robertson L, Kesteven P, McCaslin JE. Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of deep vein thrombosis. Cochrane Database Syst Rev. 2015(6):CD010956. (Meta-analysis; 11 studies, 2795 patients)
70. Kabrhel C, Rosovsky R, Baugh C, et al. Multicenter implementation of a novel management protocol increases the outpatient treatment of pulmonary embolism and deep vein thrombosis. Acad Emerg Med. 2019;26(6):657-669. (Observational study; 2212 patients)
71. Kahler ZP, Beam DM, Kline JA. Cost of treating venous thromboembolism with heparin and warfarin versus home treatment with rivaroxaban. Acad Emerg Med. 2015;22(7):796-802. (Case control study; 97 patients)
72. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342-2352. (Prospective study; 2539 patients)
73. Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-2510. (Prospective study; 3449 patients)
74. Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013;368(8):699-708. (Prospective study; 6528 patients)
75. Kakkos SK, Kirkilesis GI, Tsolakis IA. Editor’s choice - efficacy and safety of the new oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban in the treatment and secondary prevention of venous thromboembolism: a systematic review and meta- analysis of phase III trials. Eur J Vasc Endovasc Surg. 2014;48(5):565-575. (Meta-analysis; 10 studies, 38,000 patients)
76. Gomez-Outes A, Lecumberri R, Suarez-Gea ML, et al. Case fatality rates of recurrent thromboembolism and bleeding in patients receiving direct oral anticoagulants for the initial and extended treatment of venous thromboembolism: a systematic review. J Cardi ovasc Pharmacol Ther. 2015;20(5):490-500. (Systematic review; 10 trials, 35,029 patients)
77. Pollack CV, Reilly PA, van Ryn J, et al. Idarucizumab for dabigatran reversal — full cohort analysis. N Engl J Med. 2017;377(5):431-441. (Prospective study; 503 patients)
78. Connolly SJ, Milling TJ Jr, Eikelboom JW, et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016;375(12):1131-1141. (Prospective study; 67 patients)
79. Tritschler T, Kraaijpoel N, Le Gal G, et al. Venous thromboembolism: advances in diagnosis and treatment. JAMA. 2018;320(15):1583-1594. (Meta-analysis; 32 studies)
80. Becattini C, Agnelli G, Schenone A, et al. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012;366(21):1959-1967. (Prospective study; 402 patients)
81. Brighton TA, Eikelboom JW, Mann K, et al. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med. 2012;367(21):1979-1987. (Prospective; 822 patients)
82. Mismetti P, Laporte S, Pellerin O, et al. Effect of a retrievable inferior vena cava filter plus anticoagulation vs anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clinical trial. JAMA. 2015;313(16):1627-1635. (Prospective; 399 patients)
83. Vedantham S, Goldhaber SZ, Julian JA, et al. Pharmaco-mechanical catheter-directed thrombolysis for deep-vein thrombosis. N Engl J Med. 2017;377(23):2240-2252. (Prospective study; 692 patients)
84. Wang L, Zhang C, Mu S, et al. Safety of catheter-directed thrombolysis for the treatment of acute lower extremity deep vein thrombosis: a systematic review and meta-analysis. Medicine (Baltimore). 2017;96(35):e7922. (Systematic review and meta -analysis; 24 studies, 9157 patients)
85. Watson L, Broderick C, Armon MP. Thrombolysis for acute deep vein thrombosis. Cochrane Database Syst Rev. 2016;11:CD002783. (Cochrane review; 17 studies; 1103 patients)
86. Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2):146-153. (Prospective study; 672 patients)
87. Lee AYY, Kamphuisen PW, Meyer G, et al. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: a randomized clinical trial. JAMA. 2015;314(7):677-686. (Prospective study; 900 patients)
88. Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018;378(7):615-624. (Randomized controlled trial; 1046 patients)
89. Kline JA, Williams GW, Hernandez-Nino J. D-dimer concentrations in normal pregnancy: new diagnostic thresholds are needed. Clin Chem. 2005;51(5):825-829. (Prospective study; 50 patients)
90. Schouten HJ, Geersing GJ, Koek HL, et al. Diagnostic accuracy of conventional or age adjusted D-dimer cut-off values in older patients with suspected venous thromboembolism: systematic review and meta-analysis. BMJ. 2013;346:f2492. (Systematic review and meta-analysis; 13 studies, 12,497 patients)
91. Johnson SA, Eleazer GP, Rondina MT. Pathogenesis, diagnosis, and treatment of venous thromboembolism in older adults. J Am Geriatr Soc. 2016;64(9):1869-1878. (Review)
92. Chinsakchai K, Ten Duis K, Moll FL, et al. Trends in management of phlegmasia cerulea dolens. Vasc Endovascular Surg. 2011;45(1):5-14. (Review)
93. Fleck D, Albadawi H, Wallace A, et al. Below-knee deep vein thrombosis (DVT): diagnostic and treatment patterns. Cardiovasc Diagn Ther. 2017;7(Suppl 3):S134-s139. (Retrospective study; 102 patients)
94. Utter GH, Dhillon TS, Salcedo ES, et al. Therapeutic anticoagulation for isolated calf deep vein thrombosis. JAMA Surg. 2016;151(9):e161770. (Retrospective study; 14,056 patients)
95. De Martino RR, Wallaert JB, Rossi AP, et al. A meta-analysis of anticoagulation for calf deep venous thrombosis. J Vasc Surg. 2012;56(1):228-237. (Meta-analysis; 2 randomized controlled trials, 6 cohorts; 454 patients)
96. Righini M, Galanaud JP, Guenneguez H, et al. Anticoagulant therapy for symptomatic calf deep vein thrombosis (CACTUS): a randomised, double-blind, placebo-controlled trial. Lancet Haematol. 2016;3(12):e556-e562. (Prospective study; 259 patient s)
97. Othieno R, Okpo E, Forster R. Home versus in-patient treatment for deep vein thrombosis. Cochrane Database Syst Rev. 2018;1:CD003076. (Cochrane review; 7 randomized controlled trials, 1839 patients) DOI: 10.1002/14651858.CD003 076.pub2