What are the pathophysiology, risk factors, diagnostic work‑up, and evidence‑based management recommendations for deep‑vein thrombosis (DVT)?

Deep Vein Thrombosis: Pathophysiology and Management

Pathophysiology

DVT results from an imbalance between pro- and anti-coagulant factors, classically described by Virchow's Triad: venous stasis, vascular injury, and hypercoagulability. 1

• Venous stasis occurs with prolonged immobilization, hospitalization, or reduced mobility, allowing clotting factors to accumulate rather than being cleared by normal blood flow 1, 2
• Vascular injury can result from trauma, surgery, central venous catheters, or inflammatory processes that damage endothelial integrity 1, 3
• Hypercoagulability arises from inherited thrombophilias (Factor V Leiden, prothrombin G20210A mutation, protein C/S deficiency), acquired conditions (malignancy, antiphospholipid syndrome), or hormonal states (pregnancy, oral contraceptives) 4, 5

The thrombus typically forms in valve pockets of deep leg veins (calf, popliteal, femoral) or pelvic veins, where stasis is greatest 2. Once formed, the clot can propagate proximally, embolize to the lungs causing pulmonary embolism (PE), or organize and damage venous valves leading to post-thrombotic syndrome 4.

Risk Factors

Major Risk Factors (Consistently Associated)

• Hospitalization for acute medical illness accounts for 22% of all community VTE events 4
• Active malignancy confers a 4-7 times higher VTE risk through direct coagulation pathway activation and tumor-induced platelet aggregation 4
• Recent surgery or trauma (within 1 month) 4
• Central venous catheters cause 50-80% of pediatric DVT and are a major acquired risk factor 4
• Previous VTE history 4
• Pregnancy and puerperium increase risk through hypercoagulability, with most pregnancy-related CVT occurring in third trimester or postpartum 4
• Oral contraceptives increase risk 4-fold alone, but 30-fold when combined with Factor V Leiden mutation 5, 6

Inherited Thrombophilias

• Factor V Leiden (most common): present in 15-20% of VTE patients; heterozygotes have ~10% lifetime VTE risk, homozygotes >80% 4, 5, 7
• Prothrombin G20210A mutation (second most common): present in 6% of VTE patients, increases risk 2-4 fold 4, 7
• Protein C, protein S, or antithrombin III deficiency: rare but high-risk, with OR of 11.1 for protein C deficiency 4
• Antiphospholipid antibodies: detected in 22.6% of CVT patients versus 3.2% of controls 4

Additional Risk Factors

• Age >70 years 4
• Obesity 4
• Reduced mobility (Padua score assigns 3 points) 4
• Heart and/or respiratory failure 4
• Acute myocardial infarction or ischemic stroke 4

The Padua VTE Risk Assessment Model identifies high-risk hospitalized patients (score ≥4) who benefit from prophylaxis. 4

Diagnostic Work-Up

Diagnosis requires an algorithmic approach combining clinical probability assessment, D-dimer testing, and compression ultrasonography—never rely on clinical features alone. 8, 9

Step 1: Clinical Probability Assessment

Use a validated clinical decision rule to stratify patients into "unlikely" (low) or "likely" (intermediate/high) probability 8, 9:

• Look for: unilateral leg pain, swelling, erythema, dilated superficial veins, calf tenderness, pitting edema 8
• High-risk features: active cancer, paralysis/recent immobilization, bedridden >3 days, localized tenderness along deep veins, entire leg swelling, calf swelling >3 cm compared to asymptomatic leg 9

Step 2: D-Dimer Testing (If DVT "Unlikely")

• If D-dimer is normal: DVT is excluded, no further testing needed 8, 9
• If D-dimer is elevated: proceed to compression ultrasound 8

Step 3: Compression Ultrasonography

• If clinical probability is "likely": proceed directly to ultrasound without D-dimer 8
• Positive ultrasound + intermediate/high probability: DVT confirmed 9
• Negative ultrasound + low probability: DVT excluded 9
• Discordant results (low probability + positive ultrasound, or high probability + negative ultrasound): perform serial ultrasound or venography 9

Important Diagnostic Caveats

• Disease prevalence affects failure rates: the diagnostic threshold has lowered over time, with DVT prevalence now <10% in examined patients, requiring adjustment of post-test probability expectations 4
• Proximal versus distal DVT: femoral/iliac vein thrombosis carries higher PTS risk than popliteal thrombosis (RR 1.3) 4
• Asymptomatic DVT detected on systematic imaging may or may not progress to symptomatic disease 4

Genetic Testing Recommendations

Routine genetic thrombophilia testing is NOT recommended for adults with a first unprovoked DVT, as it does not change management or improve outcomes. 7

When to Consider Testing

Testing may be considered in specific scenarios 5, 7:

• Age <50 years with any venous thrombosis 5, 7
• Unusual thrombosis sites (cerebral, mesenteric, portal veins) 7
• Recurrent thrombosis 7
• Strong family history of VTE in first-degree relatives 7
• Thrombosis during pregnancy 7

Tests to Order (If Indicated)

• Factor V Leiden (R506Q) mutation 7
• Prothrombin G20210A mutation 7
• Plasma homocysteine level (>15 μmol/L confers increased risk) 7

Critical caveat: The annual major bleeding risk on anticoagulation (3%, with 0.6% fatality) exceeds the absolute VTE risk in asymptomatic mutation carriers, making prophylactic anticoagulation based solely on genetic testing inappropriate. 7

Management

Acute Treatment

Direct oral anticoagulants (DOACs) are the preferred first-line treatment for DVT because they are at least as effective, safer, and more convenient than warfarin. 8, 2

DOAC Regimens

• Apixaban or rivaroxaban: can be started immediately without parenteral bridging 8
• Dabigatran or edoxaban: require 5 days of initial parenteral anticoagulation (LMWH or UFH) before transition 8

Alternative: Traditional Approach

• LMWH or UFH bridged to warfarin (target INR 2.0-3.0) 5, 1, 2
• This remains appropriate when DOACs are contraindicated 1

Duration of Anticoagulation

Minimum 3 months of anticoagulation is required for all DVT patients to prevent extension, PE, recurrence, and post-thrombotic syndrome. 9

Provoked DVT (Reversible Risk Factor)

• 3 months of anticoagulation is sufficient if the provoking factor has resolved 6, 9

Unprovoked DVT or High-Risk Thrombophilia

• Consider indefinite anticoagulation for unprovoked DVT, recurrent VTE, or severe thrombophilias (antithrombin/protein C/protein S deficiency) 5, 9
• Weigh bleeding risk versus recurrence risk: decision influenced by patient preference, bleeding history, and fall risk 9

Cancer-Associated DVT

• Long-term anticoagulation (>6 months) is recommended over short-term treatment (3-6 months) 4
• Continue indefinitely while cancer remains active 4
• LMWH or DOACs are both acceptable for long-term treatment, though gastrointestinal cancer patients have higher bleeding risk with DOACs 4, 8

Special Populations

Hospitalized Medical Patients (Prophylaxis)

LMWH is strongly recommended over DOACs for VTE prophylaxis in acutely ill hospitalized medical patients. 4

• Inpatient-only prophylaxis is preferred over extended-duration outpatient prophylaxis 4
• Pneumatic compression devices or graduated compression stockings are suggested for patients receiving mechanical prophylaxis 4
• Chronically ill or nursing home patients: prophylaxis is NOT routinely recommended unless status changes to acute illness 4

Pregnancy

• DOACs are contraindicated in pregnancy 8
• LMWH is the anticoagulant of choice 8
• Requires multidisciplinary management with hematology and maternal-fetal medicine 5

Renal Dysfunction

• DOACs may require dose reduction or avoidance depending on creatinine clearance 8
• LMWH requires dose adjustment or monitoring of anti-Xa levels 8

Recurrent VTE Despite Anticoagulation

• Increase LMWH to supratherapeutic dose or continue therapeutic dose 4
• IVC filter is NOT recommended for recurrent VTE on anticoagulation 4

Prevention of Post-Thrombotic Syndrome

Post-thrombotic syndrome occurs in 22.8% at 2 years, 28% at 5 years, and 29.1% at 8 years after DVT, with leg pain, swelling, and skin changes. 4

Primary Prevention

• Thromboprophylaxis in high-risk patients prevents DVT and therefore PTS 4

Secondary Prevention

• Adequate anticoagulation (therapeutic intensity and appropriate duration) reduces recurrent ipsilateral DVT and consequent PTS 4
• Elastic compression stockings reduce PTS risk by 50% after first DVT episode 4
• Subtherapeutic anticoagulation increases PTS risk up to 2-fold 4

Risk Factors for PTS

• Extensive thrombosis (common femoral or iliac vein) predicts higher PTS severity 4
• Age >33 years at time of pregnancy-associated DVT (OR 3.9) 4
• Daily smoking (OR 2.9) 4
• Recurrent ipsilateral DVT significantly increases PTS risk 4

Hormonal Therapy Considerations

Combined Oral Contraceptives

• Absolute contraindication in women with prior VTE, regardless of Factor V Leiden status 5, 6
• Absolute contraindication in known Factor V Leiden carriers due to 30-fold thrombotic risk increase 5, 6

Vaginal Estradiol (Low-Dose Local Therapy)

Vaginal estradiol may be considered in select Factor V Leiden heterozygotes with prior provoked DVT, but only after meeting strict criteria. 6

Prerequisites that MUST be met 6:

• Completed ≥3 months of anticoagulation after DVT
• Provoked DVT with resolved trigger
• Heterozygous Factor V Leiden only (not homozygous)
• No additional thrombophilias (negative workup for antiphospholipid syndrome, protein C/S deficiency, prothrombin G20210A)
• No active cancer (not metastatic, not on therapy, >6 months from remission)

Mechanism of safety: Vaginal estradiol delivers minimal systemic absorption, avoiding hepatic first-pass metabolism that triggers prothrombotic changes with oral estrogen. 6

Prescribing approach: Use lowest effective dose (10 μg tablets or 0.5 g cream 1-2 times weekly for maintenance), with situational prophylaxis during high-risk periods (surgery, immobilization, travel >6 hours). 6

Long-Distance Travel Prophylaxis

For travelers with genetic thrombophilia 5:

• Frequent ambulation during travel
• Calf muscle exercises while seated
• Aisle seating to facilitate movement
• Below-knee graduated compression stockings (15-30 mmHg at ankle)

Common Pitfalls to Avoid

• Do not skip clinical probability assessment: proceeding directly to D-dimer or ultrasound without risk stratification increases false positives and unnecessary testing 8, 9
• Do not order genetic testing routinely: it does not change management for most patients and leads to unnecessary anxiety and cost 7
• Do not use DOACs in pregnancy: they are teratogenic; LMWH is the only safe option 8
• Do not stop anticoagulation at 3 months automatically: reassess bleeding versus recurrence risk, especially for unprovoked DVT or high-risk thrombophilia 5, 9
• Do not prescribe combined oral contraceptives to women with prior VTE or known Factor V Leiden—this is an absolute contraindication 5, 6
• Do not use extended-duration outpatient prophylaxis in hospitalized medical patients—inpatient-only prophylaxis is preferred 4
• Do not assume vaginal estradiol is safe without confirming heterozygous Factor V Leiden status, completed anticoagulation, provoked DVT with resolved trigger, and absence of other thrombophilias 6