What is deep venous thrombosis, including its definition, risk factors, clinical presentation, diagnostic approach, and recommended treatment and duration?

Deep Venous Thrombosis: Comprehensive Overview

Definition

Deep venous thrombosis (DVT) is the formation of blood clots within the deep venous system, most commonly affecting the lower extremity veins including the calf, femoral, popliteal, iliac, and pelvic veins, as well as the inferior and superior vena cava. 1 The deep venous system specifically includes the femoral, popliteal, iliac, and calf veins—distinguishing true DVT from superficial or perforating vein thrombosis. 2

DVT is classified into five anatomic categories based on location and associated morbidity: upper extremity/superior vena cava, lower extremity (including IVC, pelvis, iliac, femoral, popliteal), distal lower extremity (calf), splanchnic vasculature, and central venous access device-related DVT. 1

Epidemiology and Mortality Impact

DVT affects approximately 0.1% of persons per year (1 per 1,000 people), with incidence increasing substantially after age 60 years. 3, 4 The occurrence of VTE increases the likelihood of death in cancer patients by 2- to 6-fold, and VTE is the most common cause of death at 30-day follow-up among cancer patients undergoing surgery. 1 Untreated DVT carries a 50-60% risk of pulmonary embolism with subsequent mortality of 25-30%. 1

Risk Factors and Pathophysiology

The pathophysiology follows Virchow's Triad—venous stasis, vascular injury, and hypercoagulability. 3

Key risk factors include: 1, 4

• Active malignancy (particularly with tissue factor expression by cancer cells)
• Indwelling venous devices (central lines, PICCs, pacemakers)—the highest risk factor for upper extremity DVT 5
• Recent surgery (especially abdominal/pelvic cancer surgery)
• Prolonged immobilization
• Chemotherapy regimens
• Acquired or congenital thrombophilia (antiphospholipid syndrome, factor V Leiden)
• Advanced age (>60 years)
• Previous VTE history

In cancer patients specifically, VTE incidence ranges from 2.7-12.1% during first hospitalization depending on malignancy type, compared to 1.4% in age-matched controls without cancer. 1

Clinical Presentation

Approximately one-third of patients with DVT are completely asymptomatic, making clinical diagnosis challenging and objective testing mandatory. 6

When present, symptoms include: 6, 7

• Unilateral pain and swelling of the affected extremity (most common)
• Deep tension, heaviness, or "dead weight" sensation
• Erythema and warmth over the affected area
• Dilated superficial collateral veins
• Tenderness along the deep venous system
• Symptoms worsening with prolonged standing/walking, improving with rest or elevation

Advanced presentations: 6

• Venous claudication (bursting leg pain during exercise) with iliofemoral or popliteal involvement
• Post-thrombotic syndrome: chronic edema, hyperpigmentation, lipodermatosclerosis, venous ulceration

Critical anatomic considerations: Proximal (above-knee) DVT is strongly associated with increased pulmonary embolism risk, while distal calf DVT may have milder symptoms but extends proximally in approximately one-sixth of cases. 6

Diagnostic Approach

The diagnostic strategy must combine pretest probability assessment, D-dimer testing, and objective imaging—clinical evaluation alone is unreliable with only 20% of suspected cases actually having DVT. 1

Step 1: Pretest Probability Assessment

Use the Wells criteria to stratify patients into low (5% prevalence), moderate (17% prevalence), or high (53% prevalence) probability categories based on: 1

• Active cancer
• Paralysis/recent immobilization
• Recent surgery or bedridden >3 days
• Localized tenderness along deep veins
• Entire leg swelling
• Calf swelling >3 cm compared to asymptomatic leg
• Pitting edema
• Collateral superficial veins
• Alternative diagnosis more likely

Step 2: D-Dimer Testing (for Low/Moderate Probability)

For low or moderate pretest probability, obtain quantitative D-dimer using highly sensitive ELISA or enzyme-linked assays. 1 A negative D-dimer combined with low/moderate pretest probability excludes DVT without further imaging. 1 If D-dimer is elevated, proceed to compression ultrasound. 7

For high pretest probability, proceed directly to compression ultrasound without D-dimer testing. 1

Important caveat: In cancer patients, proceed directly to compression ultrasonography without using clinical prediction rules or D-dimer testing. 6

Step 3: Compression Ultrasound (CUS)

Compression ultrasound with Doppler is the first-line imaging modality for suspected lower extremity DVT. 1, 7 CUS is non-invasive, widely available, and highly accurate for proximal DVT.

Alternative imaging modalities: 1

• MR venography: when ultrasound is inconclusive or for central veins difficult to assess with ultrasound
• CT venography: when CUS cannot be performed
• Contrast venography: remains the reference standard but is rarely used due to invasiveness, contrast reactions (0-0.4% severe allergic reactions), radiation exposure, and post-venography DVT risk (0-2%) 1

Acceptable diagnostic strategies must miss ≤2% of DVT cases during initial evaluation and 3-6 month follow-up. 1 Withholding anticoagulation after technically adequate normal venography results in only 1.2% (95% CI 0.2-4.4%) subsequent symptomatic DVT or PE at 3 months. 1

Treatment and Duration

Anticoagulation is essential to control symptoms, prevent thrombus extension, reduce pulmonary embolism risk, and minimize post-thrombotic syndrome and VTE recurrence. 7, 4

Preferred Anticoagulation Regimens

Direct oral anticoagulants (DOACs) are the preferred treatment for DVT because they are at least as effective, safer, and more convenient than warfarin. 7, 8

Two DOAC strategies: 7

1. Apixaban or rivaroxaban without initial parenteral therapy (preferred for convenience)
2. Dabigatran or edoxaban following 5 days of parenteral anticoagulant (LMWH or unfractionated heparin)

Traditional therapy: Sequential parenteral anticoagulant (LMWH or unfractionated heparin) overlapped with warfarin (target INR 2-3) is now second-line. 7, 4

Duration of Anticoagulation

Standard duration is at least 3-6 months of therapeutic-dose anticoagulation for most DVTs. 7, 8

Specific scenarios: 5, 8

• Catheter-associated upper extremity DVT: Minimum 3 months OR as long as catheter remains in place
• Non-catheter-associated DVT with cancer: Continue while cancer is active or risk factors persist
• Provoked DVT (surgery, trauma): 3 months typically sufficient
• Unprovoked DVT: Consider extended anticoagulation based on bleeding risk and recurrence risk assessment

Special Populations

Cancer patients: 7

• Edoxaban (after 5 days initial LMWH) or rivaroxaban are options if patients prefer oral therapy over daily LMWH injections
• Critical caveat: Risk of gastrointestinal bleeding is higher with DOACs than LMWH in patients with gastrointestinal cancer

Renal dysfunction: DOACs may require dose reduction or should be avoided depending on creatinine clearance. 7

Pregnancy: DOACs are contraindicated; use LMWH throughout pregnancy. 7

Advanced Interventions (Select Cases Only)

Catheter-directed thrombolysis (CDT) or pharmacomechanical CDT may be considered in experienced centers for select patients with acute (≤14 days) symptomatic extensive proximal DVT who have good functional capacity, ≥1-year life expectancy, and low bleeding risk. 1 This approach aims to prevent post-thrombotic syndrome, which occurs in approximately 30% of patients at 10 years with 10% developing venous stasis ulceration. 1

Systemic anticoagulation must be provided before, during, and after any thrombolytic intervention. 1

Common Pitfalls and Caveats

Critical diagnostic pitfalls: 6, 2

• Relying solely on clinical signs leads to missed diagnoses—one-third of DVT patients are asymptomatic
• Approximately 20-40% of patients with superficial vein thrombosis have concurrent DVT requiring ultrasound evaluation
• Extensive superficial vein thrombosis in the saphenous vein can progress to the deep system at the saphenofemoral junction, causing pulmonary embolism

Anatomic considerations: 9

• Distal (calf) thrombi are more common than proximal thrombi (83% vs 53% involvement)
• Left-sided DVT is more common than right-sided (1.32:1 ratio overall, 2.4:1 for iliac DVT)
• The most common site is the peroneal vein (67% of cases)

Treatment considerations: 7, 8

• DOACs should not be used in pregnancy or severe renal dysfunction
• Gastrointestinal cancer patients on DOACs have higher bleeding risk than those on LMWH
• Post-thrombotic syndrome risk remains approximately 30% at 10 years despite anticoagulation, emphasizing the importance of early diagnosis and treatment