Resident Editor: Kenneth Pettersen, M.D.

Faculty Editor: Sarah Summerville M.D.

Background

• Venous thromboembolism (VTE) is a relatively common condition (1/1000 people per year in the US). 2/3 of those present with deep venous thrombosis (DVT) but up to 1/3 present with PE.
• Risk factors for VTE:
  • Recent surgery
  • Nonsurgical transient risk factor: trauma, travel (greater than 4-6 hour trip), pregnancy, OCPs or HRT (weak risk factor), severe acute illness (usually requiring hospitalization).
  • Permanent or non-transient risk factor: malignancy, genetic and acquired thrombophilias, prior VTE, permanent immobility (ie hemiplegia), heart failure, IBD, nephrotic syndrome.
  • COPD exacerbations: In a meta-analysis of 5 studies of patients with COPD exacerbations, the prevalence of pulmonary embolism was 20%. It is not clear from this study if the PE is an inciting factor, consequence, or bystander, but evaluation for PE should be considered for certain patients with COPD exacerbations.

Signs and Symptoms

• DVT: Lower limb pain, swelling, or “Charlie horse” in a person with risk factors should raise suspicion for DVT. Features such as warmth, erythema, and Homan sign have limited diagnostic utility. 
• PE: Sudden shortness of breath, chest pain, hemoptysis; the presence of tachypnea (70% of pts with PE), tachycardia (43%), hypoxemia (18%), or hypotension (10%).

Evaluation

• The Wells Score can be used to predict the likelihood of proximal DVT. For high pre-test probability, ultrasonography should be pursued. In a setting of low or moderate pretest probability, a normal D-Dimer rules out DVT. 

Pretest probability of DVT: the Wells Score
Clinical Characteristic	Score
Active cancer	1
Recent immobilization of lower extremities	1
Bedridden >3 days or major surgery in last 12 weeks	1
Localized tenderness in the deep venous system	1
Entire leg swollen	1
Unilateral calf swelling (>3 cm larger than the asymptomatic side)	1
Pitting edema in the symptomatic leg only	1
Collateral superficial veins	1
Alternative diagnosis at least as likely as DVT	-2
Low probability	0
Moderate probability	1-2
High probability	≥ 3

• The Pulmonary Embolism Rule-out Criteria (PERC) has been well-validated in the emergency department setting as a cost-effective strategy to rule out pulmonary embolism in low pretest probability patients (as defined by the Wells Score) without a D-dimer or imaging. Of patients without any criteria, < 1.8% will have PE, which is the risk/benefit threshold for further testing and treatment (ie contrast allergy, radiation, bleeding, etc). These criteria likely apply to populations in the ambulatory setting, though no formal studies to date have been conducted outside of the emergency department.

Pulmonary Embolism Rule-out Criteria (PERC)

Age ≥ 50

HR ≥ 100

SpO2 < 95% on RA

Hemoptysis

Unilateral leg swelling

Recent surgery or trauma within 4 weeks requiring general anesthesia

Hormone use

Previous VTE

 

Pretest probability of PE: the Wells Score
Clinical Characteristic	Score
Previous PE or DVT	1.5
Heart rate > 100 beats per minute	1.5
Recent surgery or immobilization	1.5
Clinical signs of DVT	3
Alternative diagnosis less likely than PE	3
Hemoptysis	1
Cancer	1
Low probability		0-1
Moderate probability		2-6
High probability		≥7

 

• Age-adjusted D-dimer: validated age-adjusted D-dimer cutoffs should be used for patients over the age of 50 (defined as age in years x 10 ng/mL). For example, the threshold for a 75-year-old patient is 750 ng/mL, instead of the usual threshold of 500 ng/mL.

Testing for DVT

• Doppler ultrasonography: non-invasive, low-cost, high sensitivity (89-100%), high specificity (86-100%).
• If whole-leg ultrasonography is negative, no further testing is required
• If proximal ultrasonography is negative without evaluation of distal veins but suspicion remains high, distal vein ultrasonography can be pursued immediately or proximal vein ultrasonography can be repeated in 1 week to determine if a distal DVT has extended proximally (see therapy of distal vs proximal DVT).

Testing for PE:

• Chest CT PE protocol: Sensitivity (> 90%), specificity (95%).
• V/Q scan: 
  • Useful in cases of renal insufficiency or other scenarios when IV contrast (or radiation) is contraindicated.
  • Usually requires otherwise normal lung parenchyma at baseline (ie normal CXR).
  • Often difficult to interpret since test characteristics have a greater dependency on pre-test probability and results are imprecise (ranging from normal to “high-probability PE”).
• Pregnant women: Wells Score is not validated in pregnancy. The presence of DVT symptoms warrants lower extremity ultrasound and treatment if positive. If there are no DVT symptoms, consider a V/Q scan if CXR is normal or proceed to CT if CXR is abnormal.

Suggested algorithm for workup of PE in the outpatient and emergency department settings

 Workup Following VTE Diagnosis

• This remains a controversial topic; approximately 10% of pts with unprovoked VTE are diagnosed with cancer within 2 years.
  • Order: CBC with smear, LFTs, ESR, calcium, UA, and age-appropriate cancer screening.
  • Consider more extensive testing for occult malignancy based on symptoms.
• Thrombophilia: about 50% of patients with unprovokedVTE have lab evidence of inherited thrombophilic disorder. However, the completion of thrombophilia workup is not associated with improved outcomes.
  • Work-up during acute thrombosis leads to false positivity (↓protein C, ↓protein S, ↓antithrombin, ↑anticardiolipin Abs, ↑lupus anticoagulants, ↑Factor VIII).
  • Work-up during heparin and warfarin treatment leads to false results (↓protein C, ↓protein S, ↓antithrombin, ↔lupus anticoagulants).
  • Therefore, given the recommendations for treatment duration (see below) and rates of false values, testing is not likely to change management and should be deferred in most cases (and never done acutely)! Benefits of testing primarily include family counseling and informing aggressiveness of anticoagulation when bleeding risk is elevated.
  • Consider selective thrombophilia work-up in the following scenarios:
    • Recurrent, unprovoked VTE
    • 1^st-degree relatives with VTE before the age of 45
    • Clot at a young age (<40) with a plan for pregnancy or OCPs
    • > 3 miscarriages (particularly in the late 2^nd and 3^rd trimester)
    • A young patient with high suspicion for APLS:
      • Wait 30 days from clot: send Lupus Anticoagulant and Anticardiolipin Antibody IgG and IgM 
      • If one is +, resend in 90 days to confirm, while continuing anticoagulation
      • In cases of clots at multiple or unusual sites (ie mesenteric vein)

Treatment

At-Home vs In-Hospital treatment

• DVT: At-home treatment recommended over in-hospital treatment for patients with “adequate home circumstances” (well-maintained living conditions, strong support from family or friends, phone access, ability to quickly return to the hospital if deterioration). 
• Other risk factors favoring in-hospital treatment: cancer, bilateral DVT, renal insufficiency (LMWH contraindicated), CHF, weight less than 70kg, immobility.
• PE: Outpatient treatment can be considered on a case-by-case basis for patients with PE severity index (PESI) class I or II, normal vital signs, no recent history of bleeding, no serous comorbidities such as renal disease, CHF, or thrombocytopenia, and adequate home support, although additional data is needed for definitive clinical recommendations.
• PE Severity Index (PESI): The PESI score is a validated tool to risk-stratify outcomes in PE. Class I and II have 30-day mortality of < 2%. A prospective RCT demonstrated that these patients can be safely treated in the outpatient setting.

Proximal vs Distal DVT

• Proximal DVT always requires treatment given the risk for embolic events and post-thrombotic syndrome.
• Distal DVT has a lower risk of embolic events, thus treatment is ultimately influenced by symptoms and risk of proximal extension.
  • Surveillance ultrasound: recommended in cases of isolated distal DVT without risk factors for proximal extension (see below) or in cases of high bleeding risk. Typically performed after 7 days; anticoagulation is recommended if the distal DVT has demonstrated extension to the proximal veins.
  • Anticoagulation: consider if severe symptoms, elevated D-dimer without alternative explanation, active cancer, lack of reversible risk factors, history of VTE, inpatients, or concerning clot characteristics ( > 7mm in diameter, > 5cm in length, close to proximal veins, or involvement of multiple veins or the true deep veins [ie peroneal or tibial]).

Regimen for outpatient treatment 

• Initial anticoagulation: outpatient options include LMWH versus Direct Oral AntiCoagulants (DOACs; ie factor Xa or thrombin inhibitors); see anticoagulation appendix for specific options and dosing.
• Long-term anticoagulation (see appendix for dosing):
  • Non-cancer VTE: new guidelines favor factor Xa or thrombin inhibitors over warfarin or LMWH; in patients who cannot undergo treatment with factor Xa or thrombin inhibitors, warfarin is favored over LMWH
  • Cancer VTE: LMWH
  • Pregnancy: LMWH (does not cross the placenta)
  • Coagulopathy or liver disease: LMWH (DOACs contraindicated and INR monitoring with warfarin is not possible)
  • Renal impairment (CrCl < 30): Warfarin (LMWH and DOACs are renally secreted)
• Compression stockings are recommended at the time of DVT diagnosis and for at least 2 years for acute DVT management to reduce post-thrombotic syndrome by up to 50%.
• After 3 months, re-evaluate for the possibility of “extended” treatment duration(see guidelines below):
  • If patient declines extended anticoagulation therapy:
    • Aspirin>placebo in patients with unprovoked VTE – 1/2 the risk of recurrent VTE in RCT (WARFASA study, NEJM)
    • Prophylactic LMWH prior to travel such as flights, road trip >4-6 hrs (no data available)

Treatment duration

• Despite evidence-based guidelines, treatment duration is typically influenced by patient-specific values.
•  “Extended” therapy refers to indefinite treatment; re-evaluation should be done periodically regarding the risk/benefit ratio of bleeding versus clot.
• The main determinant of therapy: was VTE provoked or unprovoked? (Refer to transient risk factors above; note weaker associations of OCPs/HRT and shorter travel.)
• Recommended duration of therapy for 1^st and 2^nd unprovoked DVT are essentially identical.
• Estimation of individual risk: Prediction of recurrence remains a challenge, but several criteria can be considered in discussion with patients about “extended” therapy.
  • Location: Risk of recurrence is greatest in symptomatic PE>proximal DVT (iliofemoral vein highest risk)>distal DVT. 
  • D-dimer: elevated D-dimer at any time before discontinuation and 3 months off anticoagulation indicates a high risk of recurrent VTE.
  • Low-risk women: A large prospective cohort study identified high-risk features for recurrence: (1) Hyperpigmentation, edema, or redness of either leg (2) D-dimer >250mcg/L while taking warfarin (3) BMI >30 (4) Age>65 years. Women with 0-1 of these risk factors remained at low risk of recurrence (1.6%). The study was unable to identify criteria for low-risk men, who remained at higher risk of recurrence than women.

Provoked VTE (recent surgery or non-surgical transient risk factor): treat with anticoagulation for 3 months	Unprovoked VTE with low/moderate bleeding risk: treat with “extended” anti-coagulation
	Unprovoked VTE with high bleeding risk: treat with anticoagulation for 3 months
	Unprovoked VTE and active cancer: treat with “extended” anti-coagulation regardless of bleeding risk

Post-thrombotic syndrome

• Presents with recurrent pain and swelling with signs of stasis skin changes and ulceration.  Must consider recurrent DVT as well.
• Advise leg elevation and prescribe compression stockings (20, 30, or 40 mmHg depending on severity of edema). Stockings should be replaced every 6 months or when elastic wears out.

When to Refer

• VTE despite anticoagulation for consideration of increased INR goal versus alternative agent/dosing.
• Women with a history of unprovoked VTE who are on long-term anticoagulation and considering pregnancy.

References

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; 172:1041.

Aujesky D, et al. Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomized, non-inferiority trial. Lancet 2011. Jul 2;378(9785):41-8.

Baglin T, Douketis J, Tosetto A, et al. Does the clinical presentation and extent of venous thrombosis predict the likelihood and type of recurrence? A patient-level meta-analysis. J Thromb Haemost. 2010; 8(11):2436.

Becattini C, et al. Aspirin for preventing the recurrence of venous thromboembolism.  N Engl J Med. 2012; 366:1959-67. (WARFASA study).

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Engelberger RP, et al. Comparison of the diagnostic performance of the original and modified Wells score in inpatients and outpatients with suspected deep vein thrombosis. Thrombosis Research. 2011 Jun;127(6):535-9.

Freund Y, et al. Effect of the Pulmonary Embolism Rule-Out Criteria on Subsequent Thromboembolic Events Among Low-Risk Emergency Department PatientsThe PROPER Randomized Clinical Trial. JAMA. 2018;319(6):559-566.

Guyatt GH, et al. Antithrombotic therapy and prevention of thrombosis,9^th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012; 141(2)(Suppl):7S-47S.  

Kearon C, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. CHEST 2016; 149(2):315-352.

Leung AN, et al. An Official American Thoracic Society/Society of Thoracic Radiology Clinical Practice Guideline: Evaluation of Suspected Pulmonary Embolism In Pregnancy. Am J Respir Crit Care Med 2011; 184:1200.

Minichiello, T and Fogarty, PF. Diagnosis and management of venous thromboembolism. Med Clin N Am. 2008. 92; 443-465. 

Rizkallah J, Man SF, Sin DD. Prevalence of pulmonary embolism in acute exacerbations of COPD: a systematic review and metaanalysis. Chest. 2009;135(3):786.  

Schouten HJ, 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.

Vickars L, Ramsay T, Betancourt MT, et al. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ. 2008; 179(5):417.

Verhovsek M, Douketis JD, Yi Q, Shrivastava S, et al. Systematic review: D-dimer to predict recurrent disease after stopping anticoagulant therapy for unprovoked venous thromboembolism. Ann Intern Med. 2008; 149(7):481