Table of Contents

 

The management of patients presenting to the ED with deep vein thrombosis (DVT) has changed in several ways over the last decade, and emergency clinicians have more tools to manage a safe and cost-effective disposition.

What are the possible causes of unprovoked versus provoked DVT, and how do they factor into diagnosis and treatment?

How much of a risk factor for DVT does oral contraceptive use and pregnancy present?

When a patient reports a feeling of heaviness and cramping in the leg, what are the historical and physical examination findings that can risk stratify for DVT?

What is the historical finding most likely to point to DVT? What is the least likely finding?

Under what circumstances can a negative D-dimer rule out DVT?

What does the lack of specificity of a positive D-dimer mean for ordering further testing? How does age affect its specificity?

What are the types of ultrasound tests that can be used to rule in or rule out DVT, and which tests need to be repeated?

Which patients should receive warfarin? Heparin? Direct oral anticoagulants? When should a patient be admitted for anticoagulation and when can they be sent home?

What does the evidence show regarding aspirin, compression stockings, IVC filters, and thrombolysis in the treatment of DVT?

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
    1. Table 1. Differential Diagnosis For Bleeding Disorders By Abnormality In Prothrombin Time & Partial Thromoboplatin Time Studies
    2. Table 2. Likelihood Ratios of Clinical Features Ruling Out Deep Vein Thrombosis
    3. Table 3. Three-Tiered Wells Scoring for Predicting Pretest Probability for Deep Vein Thrombosis
    4. Table 4. Recommendations/Evidence Grading Definitions
    5. Figure 1. Veins of the Leg
    6. Figure 2. Veins of the Arm
    7. Figure 3. Deep Vein Thrombosis of Lower Extremity
    8. Figure 4. Deep Vein Thrombosis of Upper Extremity
    9. Figure 5. Negative Venous Duplex Image of the Left Lower Extremity
    10. Figure 6. Positive Venous Duplex With Inability to Compress the Right Common Femoral Vein
    11. Figure 7. Phlegmasia Cerulea Dolens
22. References

Abstract

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.

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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

Points and Pearls Excerpt

• Pathophysiology for deep vein thrombosis (DVT) is related to the Virchow triad: venous stasis, endothelial vascular injury, and hypercoagulability.
• Unprovoked DVT can be due to genetic causes, such as having a non-O blood group, factor V Leiden mutation, prothrombin gene mutation, or protein C and protein S deficiency.
• Provoked DVT can result as a complication of cancer, oral contraceptive use, pregnancy, long-distance travel, surgery, or trauma.
• Classic signs and symptoms of DVT include pain, swelling, discoloration, heaviness, and cramping sensation.
• The Wells criteria, validated and endorsed by the American College of Emergency Physicians (ACEP), stratifies patients as low, moderate, or high pre-test probability of having a DVT.

Most Important References

• White RH. The epidemiology of venous thromboembolism. Circulation. 2003;107(23 Suppl 1):I4-8. (Review) DOI: 10.1161/01.CIR.0000078468.11849.66
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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