What is the differential diagnosis (DDX) for chronic worsening left lower leg swelling, mottling, and pain on exertion in a patient with a history of Venous Thromboembolism (VTE), infective endocarditis, and severe tricuspid regurgitation, with a negative D-dimer (D-dimer) test result?

Differential Diagnosis for Chronic Left Lower Leg Swelling, Mottling, and Pain on Exertion

In this 47-year-old woman with chronic worsening left lower leg symptoms and a negative D-dimer, the differential diagnosis should prioritize chronic venous insufficiency (post-thrombotic syndrome from prior VTE), right heart failure from severe tricuspid regurgitation, lymphedema, and May-Thurner syndrome, while acute DVT is effectively excluded by the negative D-dimer. 1

Primary Diagnostic Considerations

Post-Thrombotic Syndrome (Most Likely)

• Given the history of recurrent VTE, chronic post-thrombotic syndrome is the leading diagnosis, manifesting as chronic venous insufficiency with valve damage from prior thrombosis 2
• Classic features include chronic leg swelling, skin changes (mottling), pain with exertion, and progressive worsening over time 2
• The negative D-dimer effectively excludes acute or subacute DVT recurrence, making chronic venous pathology more likely 1

Right Heart Failure from Tricuspid Regurgitation

• Severe tricuspid regurgitation requiring valve replacement causes systemic venous congestion, which can manifest as unilateral or bilateral lower extremity edema 2
• The chronicity and exertional component align with cardiac-related venous hypertension
• Mottling may represent chronic venous stasis from elevated right atrial pressures

Lymphedema (Secondary)

• Chronic venous disease and prior infections (infective endocarditis) can damage lymphatic drainage, leading to secondary lymphedema 2
• The progressive nature and chronic swelling are consistent with lymphatic dysfunction
• Often coexists with chronic venous insufficiency 2

Less Common but Important Considerations

May-Thurner Syndrome (Iliac Vein Compression)

• In patients with extensive unexplained leg swelling and negative standard ultrasound, isolated iliac vein pathology must be excluded 3, 1
• The American College of Chest Physicians specifically recommends imaging iliac veins with CT or MR venography when proximal ultrasound is negative but extensive leg swelling persists 3
• This anatomic variant causes left-sided predominance and can present chronically

Popliteal Vein Entrapment

• Rare cause of chronic unilateral leg swelling that can mimic venous pathology 4
• Requires functional venography with foot positioning for diagnosis 4
• Consider if other workup is unrevealing

Medication-Related Edema

• Antipsychotics, particularly atypical agents, can cause peripheral edema through multiple mechanisms including metabolic effects and fluid retention
• Typically bilateral but can be asymmetric

Critical Diagnostic Approach

Why Acute DVT is Excluded

• The American College of Chest Physicians clearly states that a negative highly sensitive D-dimer excludes DVT and no further testing for acute thrombosis is needed 3, 1
• The negative predictive value of D-dimer is sufficiently high to rule out acute VTE 1
• However, D-dimer does not assess chronic venous pathology 1

Recommended Imaging Strategy

• Perform venous duplex ultrasound to assess for chronic venous insufficiency, valve incompetence, and residual thrombus from prior DVT 2
• If extensive swelling with negative or non-diagnostic proximal ultrasound, obtain CT venography or MR venography to evaluate iliac veins 3, 1
• Echocardiography to quantify tricuspid regurgitation severity and assess right heart function 2

Clinical Assessment Priorities

• Measure calf circumference bilaterally (>2 cm difference is significant even in chronic disease) 5
• Assess for skin changes: hyperpigmentation, lipodermatosclerosis, venous stasis dermatitis 2
• Evaluate for pitting versus non-pitting edema (venous is typically pitting, lymphedema becomes non-pitting) 2
• Assess cardiac status: jugular venous distension, hepatomegaly, ascites suggesting right heart failure 2

Common Pitfalls to Avoid

• Do not assume negative D-dimer excludes all venous pathology—it only excludes acute thrombosis, not chronic venous disease 1
• Do not overlook iliac vein pathology when standard proximal ultrasound is negative but extensive swelling persists 3, 1
• Do not attribute all symptoms to cardiac disease alone—multiple etiologies often coexist in complex patients 2
• Do not forget that antipsychotic medications can contribute to edema, though this is rarely the sole cause of unilateral symptoms

Additional Considerations for This Patient

• The combination of cardiac disease (tricuspid regurgitation), prior VTE, and chronic symptoms suggests multifactorial etiology with post-thrombotic syndrome and cardiac venous congestion as primary contributors 2
• The mottling specifically suggests chronic venous stasis changes 2
• Pain on exertion may represent venous claudication from chronic outflow obstruction 2