Deep Vein Thrombosis

Deep vein thrombosis is thrombus formation in the deep veins, most often of the legs. Together with pulmonary embolism it forms venous thromboembolism, with an incidence of 1 to 2 per 1000 adults per year rising steeply after age 60.

Pathogenesis follows Virchow triad of venous stasis, endothelial injury and hypercoagulability. Most thrombi start in the valve pockets of the calf veins. Proximal DVT involves the popliteal, femoral or iliac veins and carries the highest embolic risk.

Risk factors

• Major transient (provoked): surgery under general anaesthesia lasting over 30 minutes, hospital admission with bed rest for 3 days or more, caesarean section, lower limb fracture, trauma, and leg immobilisation.
• Minor transient: oestrogen-containing contraception or hormone therapy, pregnancy and the puerperium, long-haul travel, obesity, and acute infection.
• Persistent: active cancer, antiphospholipid syndrome, inflammatory bowel disease, nephrotic syndrome, myeloproliferative neoplasms, paroxysmal nocturnal haemoglobinuria, heart failure.
• Inherited: factor V Leiden, prothrombin G20210A, and deficiency of antithrombin, protein C or protein S.
• Anatomical: May-Thurner syndrome (left common iliac vein compressed by the right common iliac artery), which explains the left-sided predominance of iliofemoral DVT.

Complications

• Pulmonary embolism: about half of proximal DVTs have silent embolism at diagnosis. Untreated proximal DVT has a PE risk of around 30 to 50%.
• Post-thrombotic syndrome: chronic pain, swelling, hyperpigmentation and ulceration in 20 to 50% within 2 years.
• Recurrence: about 10% in the first year and 30% at 5 years after stopping treatment for an unprovoked event, higher in men.
• Phlegmasia cerulea dolens: massive iliofemoral thrombosis with arterial compromise and venous gangrene.

Distal (calf) DVT carries lower risk of embolism and propagation, but about 15% extend proximally if untreated.

Typical presentation is unilateral

• Leg swelling, with pitting oedema, calf or thigh pain, warmth and erythema.
• Tenderness along the deep venous system, and engorged superficial collaterals.
• Calf circumference more than 3 cm greater than the other side, measured 10 cm below the tibial tuberosity.
• Low grade fever and a dull ache aggravated by standing. Homans sign is unreliable.

Severity patterns

• Iliofemoral DVT: whole-leg swelling, groin and flank pain.
• Phlegmasia alba dolens: white, painful swollen leg from arteriolar spasm.
• Phlegmasia cerulea dolens: blue, tense, severely painful leg with diminished pulses, venous gangrene and compartment syndrome.

Upper extremity DVT presents with arm swelling and pain. Causes include central venous catheters and cancer, and effort thrombosis (Paget-Schroetter syndrome) in athletes with thoracic outlet compression.

Differential diagnosis

• Cellulitis, ruptured Baker cyst, muscle tear or haematoma, lymphoedema.
• Chronic venous insufficiency, superficial thrombophlebitis, compartment syndrome.
• Bilateral oedema from heart failure, nephrotic syndrome, cirrhosis or drugs such as amlodipine.

Red flags: sudden dyspnoea, pleuritic chest pain, haemoptysis, syncope or tachycardia (pulmonary embolism), massive swelling with cyanosis, and an unprovoked event at a young age or with unusual sites such as mesenteric, cerebral or portal veins.

Clinical probability is estimated with the two-level Wells score. One point is given for each of:

• Active cancer.
• Paralysis, paresis or recent plaster immobilisation of the leg.
• Bedridden for 3 days or more, or major surgery within 12 weeks.
• Localised tenderness along the deep veins.
• Entire leg swollen.
• Calf swelling more than 3 cm greater than the other leg.
• Pitting oedema confined to the symptomatic leg.
• Collateral superficial veins.
• Previous documented DVT.

Subtract 2 points if an alternative diagnosis is at least as likely. A score of 2 or more is DVT likely, and 1 or less is DVT unlikely.

Diagnostic pathway

• DVT unlikely: D-dimer. A result below 500 ng/mL (or below the age-adjusted cut-off of age multiplied by 10 ng/mL in patients over 50) excludes DVT. A positive D-dimer leads to ultrasound.
• DVT likely: proximal compression ultrasound. If positive, treat. If negative with a high D-dimer, repeat the scan at 5 to 7 days or perform a whole-leg scan.
• Compression duplex ultrasound has about 95% sensitivity for proximal DVT and 60 to 70% for isolated calf thrombus. The diagnostic criterion is a non-compressible vein.
• CT or MR venography is used for suspected iliac or inferior vena cava thrombosis, and when ultrasound is non-diagnostic.

D-dimer is unreliable in cancer, pregnancy, recent surgery, infection and advanced age.

Baseline tests before anticoagulation

• CBC with platelets, creatinine and creatinine clearance, liver enzymes, PT and aPTT, and weight.
• Pregnancy test in women of reproductive age.

Further evaluation

• Age-appropriate cancer screening with history, examination and routine tests. Extensive screening does not improve outcomes.
• Thrombophilia testing is not routine. It is considered in unprovoked thrombosis under 50, strong family history, unusual sites, or recurrent events. Antiphospholipid antibodies (lupus anticoagulant, anticardiolipin and anti beta-2 glycoprotein I) are the most clinically useful, because they change the choice of anticoagulant. Antithrombin, protein C and protein S assays are unreliable during acute thrombosis or on anticoagulation.
• Consider JAK2 and PNH testing in unexplained cases.

Anticoagulation (cornerstone)

Direct oral anticoagulants are preferred for most patients without cancer, renal failure, pregnancy or antiphospholipid syndrome:

• Apixaban 10 mg twice daily for 7 days, then 5 mg twice daily.
• Rivaroxaban 15 mg twice daily with food for 21 days, then 20 mg daily with food.
• Dabigatran 150 mg twice daily after at least 5 days of parenteral anticoagulation.
• Edoxaban 60 mg daily after at least 5 days of parenteral anticoagulation, reduced to 30 mg for weight 60 kg or below, creatinine clearance 15 to 50 mL/min, or interacting P-glycoprotein inhibitors.

Parenteral and vitamin K antagonist options

• Enoxaparin 1 mg/kg SC every 12 hours, or 1.5 mg/kg once daily. Dalteparin 200 units/kg daily, or tinzaparin 175 units/kg daily.
• Fondaparinux 5 mg (under 50 kg), 7.5 mg (50 to 100 kg) or 10 mg (over 100 kg) SC daily.
• Unfractionated heparin 80 units/kg IV bolus then 18 units/kg/h, titrated to an aPTT 1.5 to 2.5 times control. Preferred for severe renal impairment (creatinine clearance below 30 mL/min), high bleeding risk or planned thrombolysis.
• Warfarin 5 mg daily (lower in older patients), overlapped with parenteral therapy for at least 5 days and until the INR is 2 or more for 24 hours. Target INR is 2.0 to 3.0.

Special populations

• Cancer: apixaban, edoxaban or rivaroxaban, or dalteparin 200 units/kg daily for 1 month then 150 units/kg daily. Caution with edoxaban and rivaroxaban in gastrointestinal and genitourinary tumours because of bleeding.
• Pregnancy and postpartum: enoxaparin 1 mg/kg twice daily throughout pregnancy and for at least 6 weeks postpartum, with a minimum total treatment of 3 months. Warfarin and DOACs are avoided. All are compatible with breastfeeding except dabigatran, for which data are limited.
• Triple-positive antiphospholipid syndrome: warfarin rather than a DOAC.
• Renal failure: UFH or reduced-dose LMWH with anti-Xa monitoring, or warfarin.
• Heparin-induced thrombocytopenia: stop all heparin, then give argatroban 2 micrograms/kg/min (0.5 micrograms/kg/min in hepatic impairment) or fondaparinux or a DOAC once platelets recover. Avoid warfarin until platelets exceed 150 x 10^9/L.

Duration

• Provoked by a major transient factor: 3 months.
• Unprovoked or persistent risk factor: at least 3 to 6 months, then extended therapy if bleeding risk is acceptable, with a reduced dose after 6 months (apixaban 2.5 mg twice daily or rivaroxaban 10 mg daily).
• Cancer-associated: at least 6 months, and continued while cancer is active.
• Isolated distal DVT with severe symptoms or risk factors for extension: 3 months. For mild symptoms, serial ultrasound at 1 and 2 weeks is an alternative.
• Recurrent unprovoked DVT, antiphospholipid syndrome and strong thrombophilia: indefinite anticoagulation.

Advanced and interventional therapy

• Catheter-directed or pharmacomechanical thrombolysis is considered for iliofemoral DVT with symptoms for under 14 days, good functional status and low bleeding risk. Alteplase is infused at about 0.5 to 1 mg/h through a multi-sidehole catheter. Stenting of underlying iliac vein stenosis, as in May-Thurner syndrome, follows.
• Phlegmasia cerulea dolens: heparin, limb elevation, urgent catheter-directed thrombolysis or thrombectomy, and fasciotomy for compartment syndrome.
• Systemic thrombolysis is not used for DVT alone.
• Inferior vena cava filter (retrievable) only for acute proximal DVT or PE with an absolute contraindication to anticoagulation, or recurrence despite therapeutic anticoagulation. Remove it once anticoagulation can start.

Supportive care

• Early ambulation as pain permits. Bed rest does not reduce embolism.
• Analgesia with paracetamol. Avoid NSAIDs while on anticoagulants.
• Graduated compression stockings (30 to 40 mmHg) for symptom relief, not for routine prevention of post-thrombotic syndrome.
• Review at 3 months for symptoms, bleeding, adherence and decision on extended treatment. Persistent dyspnoea warrants evaluation for chronic thromboembolic pulmonary hypertension.

Post-thrombotic syndrome

• Compression stockings, exercise, weight loss and leg elevation. Venous ulcers need compression bandaging. Iliac vein stenting for severe obstruction.

Prophylaxis

• Medical inpatients at risk: enoxaparin 40 mg SC daily, or unfractionated heparin 5000 units SC every 8 to 12 hours, or fondaparinux 2.5 mg daily.
• Hip and knee arthroplasty: enoxaparin 40 mg daily, rivaroxaban 10 mg daily, apixaban 2.5 mg twice daily, or aspirin 100 mg daily in selected patients, for 10 to 35 days.
• Mechanical prophylaxis with intermittent pneumatic compression where anticoagulants are contraindicated.
• Early mobilisation, hydration, and review of oestrogen use in high-risk patients.