What might be the cause of unilateral leg swelling in a 32-year-old female after prolonged walking, without signs of Deep Vein Thrombosis (DVT) or Pulmonary Embolism (PE), and in the absence of diabetes and hypertension?

Unilateral Leg Swelling After Prolonged Walking in a Young Female

Despite the absence of obvious DVT or PE signs, this patient still requires objective testing to definitively exclude venous thromboembolism, as clinical assessment alone is unreliable. Even in young, healthy individuals without traditional risk factors, prolonged walking can trigger DVT, and clinical examination has poor sensitivity and specificity for detecting thrombosis 1.

Immediate Diagnostic Approach

Perform proximal compression ultrasound (CUS) or whole-leg ultrasound as the initial test, rather than relying on clinical assessment alone 1. The American College of Chest Physicians guidelines emphasize that objective testing is essential even when clinical suspicion seems low 1.

Key Testing Strategy:

• If ultrasound is negative but clinical concern persists, obtain a highly sensitive D-dimer test 1
• If D-dimer is positive with negative initial ultrasound, repeat proximal CUS in 1 week 1
• In patients with extensive unexplained leg swelling and negative proximal/whole-leg US, image the iliac veins to exclude isolated iliac DVT 1

This last point is particularly important—isolated iliac vein thrombosis can present with unilateral leg swelling and may be missed on standard lower extremity ultrasound 1.

Alternative Diagnoses to Consider

Musculoskeletal Causes

Prolonged walking can cause muscle strain, compartment syndrome (if severe), or soft tissue injury that presents as unilateral swelling 2. These are benign but require differentiation from thrombotic causes.

Venous Insufficiency

Chronic venous insufficiency is the most common cause of leg edema in adults, though it typically develops gradually rather than acutely after a single walking episode 2. However, prolonged walking can exacerbate underlying venous insufficiency, causing acute-on-chronic swelling 1.

• Symptoms worsen with prolonged standing or walking and improve with rest or elevation 1
• May present with heaviness, aching, or fatigue in the affected limb 1

Superficial Vein Thrombosis

Superficial vein thrombosis (SVT) can occur after prolonged walking and presents with unilateral leg swelling 3. Importantly, approximately 15% of SVT cases have concomitant DVT and 5% have pulmonary embolism 3. Therefore, ultrasound evaluation is still warranted to exclude deep system involvement 3.

Lymphatic Obstruction

Unilateral lymphedema can develop from various causes including occult malignancy, though this is less likely in a young patient without other risk factors 2.

Critical Pitfalls to Avoid

Do not rely on the absence of traditional risk factors (diabetes, hypertension) to exclude DVT 1, 4. Young, otherwise healthy individuals can develop DVT, particularly with provocation such as prolonged immobility during extended walking or travel 1.

Do not assume bilateral examination is unnecessary 5. Studies show that patients with unilateral symptoms have bilateral DVT in approximately 7% of cases and unsuspected contralateral DVT in 1% of cases 5. Bilateral ultrasound examination is recommended 5.

Do not dismiss the possibility of occult DVT based on negative clinical signs alone 1. Most DVTs originate in the calf and may not produce obvious clinical findings initially 4. Approximately 70% of patients with proven PE have proximal thrombus, often clinically undetectable 1.

When DVT is Excluded

If serial ultrasounds and D-dimer testing definitively exclude DVT, consider:

• Conservative management with leg elevation, compression stockings, and NSAIDs for presumed musculoskeletal etiology 2
• Evaluation for underlying venous insufficiency if symptoms persist or recur 2
• Reassessment if symptoms worsen or new concerning features develop (dyspnea, chest pain, worsening swelling) 1