Chronic Venous Thromboembolism

Persistent or recurrent venous thromboembolism that does not resolve with initial treatment. It includes chronic thromboembolic pulmonary disease with or without pulmonary hypertension, recurrent deep vein thrombosis and pulmonary embolism despite anticoagulation, and persistent obstruction of deep veins.

• Chronic thromboembolic pulmonary hypertension develops in about 2 to 4% of patients after acute pulmonary embolism (range 0.5 to 4%), usually within 2 years. Definition: mean pulmonary artery pressure greater than 20 mmHg, pulmonary artery wedge pressure 15 mmHg or less and pulmonary vascular resistance greater than 2 Wood units, with perfusion defects after at least 3 months of effective anticoagulation. Without pulmonary hypertension, patients with chronic perfusion defects and exercise limitation have chronic thromboembolic pulmonary disease.
• Mechanism: incomplete clot resolution with organised fibrous obstruction of pulmonary arteries, followed by secondary small vessel arteriopathy in non-obstructed areas that raises resistance further.
• Risk factors: large initial clot burden, unprovoked or recurrent embolism, previous splenectomy, ventriculo atrial shunts and infected pacemaker leads, antiphospholipid syndrome, high factor VIII, inflammatory bowel disease, chronic osteomyelitis, myeloproliferative neoplasm, thyroid replacement and cancer.
• Untreated chronic thromboembolic pulmonary hypertension has poor survival (about 30 to 70% at 3 years depending on pressure), whereas pulmonary endarterectomy gives about 90% survival at 5 years.
• Recurrent venous thromboembolism occurs in about 10% in the first year and about 30% at 8 years after a first unprovoked event once anticoagulation stops.

• Progressive exertional dyspnoea, fatigue, reduced exercise tolerance, exertional chest pain or presyncope, haemoptysis, and later right heart failure with oedema and ascites. A history of previous pulmonary embolism is present in most, though about a quarter have no recognised acute event.
• Signs: raised jugular venous pressure, loud pulmonary second sound, right ventricular heave, tricuspid regurgitation murmur, pulmonary flow murmurs or bruits over the lung fields, cyanosis and clubbing (rare).
• Differential diagnosis: pulmonary arterial hypertension, left heart disease, COPD, interstitial lung disease, pulmonary vasculitis, pulmonary artery sarcoma, fibrosing mediastinitis, congenital pulmonary artery stenosis, sleep apnoea, and deconditioning after pulmonary embolism.
• Complications: right heart failure, arrhythmia, haemoptysis, sudden death, in situ thrombosis, and reperfusion injury after intervention.

• Screen at 3 to 6 months in all patients with persistent dyspnoea or exercise limitation after pulmonary embolism, and any patient with unexplained pulmonary hypertension.
• Echocardiography: raised tricuspid regurgitant velocity (greater than 2.8 m/s), right ventricular dilatation and hypertrophy, septal flattening, pericardial effusion.
• Ventilation and perfusion scanning is the screening test of choice: normal scan excludes the disease; one or more mismatched segmental defects suggest it (CT cannot replace it).
• Confirm with right heart catheterisation (pulmonary pressure and vascular resistance) and pulmonary angiography (digital subtraction, CT or MR) to show webs, bands, tapering and occlusions and decide operability.
• Also: natriuretic peptide, six minute walk test, cardiopulmonary exercise test, thrombophilia workup (lupus anticoagulant, anticardiolipin and beta-2 glycoprotein I antibodies, factor VIII, JAK2 V617F), thyroid function, HIV test, and cancer screening.
• Duplex ultrasonography or venography of the legs and pelvis for residual deep vein obstruction.

• Lifelong anticoagulation for all patients with chronic thromboembolic pulmonary hypertension:
  • Warfarin to INR 2.0 to 3.0 is preferred. Direct oral anticoagulants (apixaban 5 mg twice daily or rivaroxaban 20 mg once daily) are used when warfarin is not possible, though evidence is limited and recurrence may be higher; avoid them in antiphospholipid syndrome.
  • Antiphospholipid syndrome: warfarin to INR 2.0 to 3.0 (3.0 to 4.0 with recurrent events on treatment).
• Refer to a specialist centre; treatment is multimodal:
  • Pulmonary endarterectomy (surgical removal of organised thromboembolic material under deep hypothermic circulatory arrest) is the treatment of choice for accessible proximal and segmental disease: perioperative mortality about 2 to 5%, and about 90% improve haemodynamically, with 5-year survival about 90%. About 10 to 30% have residual pulmonary hypertension needing drugs. Complications: reperfusion pulmonary oedema, residual hypertension, airway haemorrhage.
  • Balloon pulmonary angioplasty for inoperable or residual distal disease: multiple sessions (usually 4 to 6, 2 to 4 weeks apart) dilating a few segments at each session; complications include reperfusion pulmonary oedema, vessel injury with haemoptysis, and rarely death (about 1 to 3%).
  • Riociguat 1 mg three times daily (0.5 mg three times daily if at risk of hypotension), increased by 0.5 mg every 2 weeks to a maximum of 2.5 mg three times daily while systolic pressure is 95 mmHg or more. Contraindicated with nitrates and phosphodiesterase-5 inhibitors, and in pregnancy (teratogenic); check blood pressure at each titration.
  • Macitentan 10 mg once daily (teratogenic; check haemoglobin and liver enzymes); subcutaneous treprostinil (start 1.25 nanograms/kg/min, increase weekly) for severe disease; sildenafil 20 mg three times daily has limited evidence.
  • Use drugs for inoperable disease, persistent hypertension after surgery or angioplasty, or as a bridge to intervention.
• Supportive therapy:
  • Furosemide 20 to 80 mg daily with spironolactone 25 to 50 mg for right heart failure; oxygen for SpO2 less than 90% at rest or on exertion; vaccination (influenza, pneumococcus); supervised exercise training; avoid pregnancy and high altitude.
  • Iron replacement for deficiency (ferrous sulfate 200 mg once or twice daily).
• Recurrent venous thromboembolism despite anticoagulation:
  • Confirm the event, check adherence and INR, review interactions (rifampicin, antiepileptics).
  • Exclude cancer, antiphospholipid syndrome, myeloproliferative neoplasm, paroxysmal nocturnal haemoglobinuria and heparin induced thrombocytopenia.
  • Switch to enoxaparin 1 mg/kg SC twice daily (increase by 25% if the event occurred on this dose); in cancer use enoxaparin 1 mg/kg twice daily rather than a direct oral anticoagulant.
  • Retrievable inferior vena cava filter for recurrent embolism despite therapeutic anticoagulation, kept with anticoagulation unless contraindicated.
• Persistent deep vein obstruction: compression stockings 30 to 40 mmHg, and iliofemoral stenting for severe symptoms (anticoagulation for at least 3 to 6 months after stenting).
• Special groups:
  • Pregnancy: avoid riociguat, macitentan and warfarin; use enoxaparin 1 mg/kg SC twice daily; pregnancy is high risk with pulmonary hypertension, so advise against it.
  • Cancer: enoxaparin 1 mg/kg twice daily or apixaban 5 mg twice daily.
  • Renal impairment: warfarin or unfractionated heparin; adjust drugs.
  • HIV and tuberculosis: avoid direct oral anticoagulants with rifampicin and ritonavir.
• Red flags: syncope, haemoptysis, rapidly worsening dyspnoea, right heart failure, new chest pain, recurrent event on anticoagulation.
• Follow up: review every 3 to 6 months with six minute walk test, natriuretic peptide and echocardiography; repeat catheterisation 3 to 6 months after endarterectomy or angioplasty; lifelong anticoagulation with monthly INR when on warfarin.