Pulmonary embolism

01Definition and overview

Pulmonary embolism is obstruction of the pulmonary arterial bed by material from elsewhere, in nearly all cases a thrombus from the deep veins of the legs and pelvis. Venous thromboembolism (VTE), the term for deep vein thrombosis (DVT) and PE together, is one disease with two presentations: about 70 per cent of people with symptomatic PE have a DVT too, though it is symptomatic in about a quarter of them, and at least a third of those with DVT have clinically silent emboli.

PE is classified by the size of the clot and the haemodynamic effect, which determine the risk of early death:

A patient with a low PESI who has right ventricular dysfunction on imaging or a raised troponin is classed as intermediate risk. Other labels are by timing (acute, or chronic thromboembolic disease), by position (central, lobar, segmental or subsegmental) and by cause (provoked or unprovoked).

02Etiology and pathophysiology

Why thrombi form

Virchow's triad describes the three factors behind venous thrombosis: stasis of blood flow, hypercoagulability, and vessel wall (endothelial) injury or dysfunction. In veins, stasis and hypercoagulability dominate. A thrombus begins in the pocket behind a valve cusp of a deep leg vein, where flow is slow or disturbed and the endothelium becomes hypoxic. If it stays in the calf (a distal DVT) it rarely embolises, but if it extends to the popliteal vein or above (a proximal DVT) it is much more likely to break off.

Risk factors:

No cause is found in up to half of cases. Cancer is found in 10 to 20 per cent of those with VTE, and up to 5 per cent of patients with an apparently unprovoked VTE are diagnosed with cancer within a year.

What the embolus does

1. 1

   Vascular obstruction

   The clot travels through the right heart and wedges in the pulmonary arteries. The pulmonary vascular resistance rises, from the blockage itself and from vasoconstriction triggered by mediators released from platelets in the clot (thromboxane, serotonin) and by hypoxia.
2. 2

   Right ventricular strain

   The thin-walled right ventricle faces a sudden rise in afterload. It dilates, the septum bows into the left ventricle, and the output from both sides falls. Large emboli cause hypotension, syncope or shock, and death usually comes from right ventricular failure.
3. 3

   Dead space and mismatch

   Ventilated areas of lung lose their blood flow (dead space), and the blood is diverted to the rest of the lung, so ventilation–perfusion mismatch causes hypoxaemia. Alveolar hyperventilation by the stimulated breathing lowers the PaCO2.
4. 4

   Infarction

   If the embolus is peripheral, the area of lung can bleed and infarct (a pulmonary infarct), with pleural inflammation. This gives pleuritic pain, haemoptysis and a small pleural effusion.

The thrombus is normally dissolved by fibrinolysis over weeks to months. In some patients it organises into scar, causing chronic thromboembolic pulmonary hypertension.

03Clinical features

The features are non-specific, and most patients with suspected PE (more than 80 per cent) do not have it. PE presents in three ways:

• about 65 per cent with pleuritic chest pain and breathlessness, sometimes with haemoptysis; tachypnoea and tachycardia are typical, and crackles or a rub may be heard over an infarct;
• about 25 per cent with isolated breathlessness, sometimes only on exertion; and
• about 10 per cent with the severe form: syncope, systolic hypotension or shock, and central chest pain from right ventricular ischaemia. The patient is tachypnoeic and tachycardic, with a raised JVP, a right ventricular heave, a gallop rhythm and a widely split second heart sound.

A low-grade fever may be present. Look for the signs of a DVT: a swollen, tender, warm leg. A good history also asks about the risk factors above.

Initial tests are not diagnostic:

• ECG: sinus tachycardia is commonest. Right ventricular strain shows as T-wave inversion in V1 to V4 and in the inferior leads, a right bundle branch block, and, in a minority, the classic S1Q3T3. A normal ECG does not exclude PE.
• Chest X-ray: often normal, or atelectasis, a raised hemidiaphragm, a small effusion, a wedge-shaped peripheral opacity (Hampton's hump) or an area of oligaemia (Westermark's sign). It is done mainly to exclude other causes.
• Arterial blood gas: hypoxaemia with hypocapnia (a respiratory alkalosis), though neither is always present.
• BNP and troponin may be raised from right ventricular strain, which marks a worse prognosis, but are not diagnostic.

The differential diagnosis includes pneumonia, pneumothorax, heart failure, acute coronary syndrome, pericarditis, aortic dissection, a COPD or asthma exacerbation, costochondritis, anxiety and hyperventilation.

04Diagnosis and management

Diagnosis

Diagnosis follows the clinical probability, so that the right patients get imaged, and the others are spared radiation and anticoagulation.

1. 1

   Is the patient unstable?

   If there is shock or persistent hypotension, the next test is an immediate CT pulmonary angiogram if available, or a bedside echocardiogram showing right ventricular overload. If PE is the likely cause, treat without waiting.
2. 2

   Estimate the clinical probability

   Use the two-level Wells score for PE. Points are given for clinical signs of DVT (3), an alternative diagnosis less likely than PE (3), a pulse above 100 (1.5), immobilisation of more than 3 days or surgery in the last 4 weeks (1.5), previous DVT or PE (1.5), haemoptysis (1), and cancer (1). A score above 4 means PE is likely, and 4 or less unlikely.
3. 3

   PE unlikely: D-dimer

   D-dimer is a fibrin degradation product, raised in thrombosis but also with age, infection, inflammation, surgery, cancer and pregnancy. A normal result with a low probability excludes PE (the failure rate is under 2 per cent in 3 months). An abnormal result needs imaging. (The YEARS algorithm and an age-adjusted cut-off reduce the number of scans.)
4. 4

   PE likely, or D-dimer raised: imaging

   CT pulmonary angiography (CTPA) is the usual test: it shows filling defects in the pulmonary arteries, and can find alternative diagnoses. A ventilation–perfusion (V/Q) scan is the alternative, with a lower radiation dose, preferred in renal impairment, contrast allergy and pregnancy. A mismatch (a perfusion defect with normal ventilation) indicates PE, a normal scan excludes it, and many results are non-diagnostic when other lung disease is present.

A CTPA is done immediately where possible, and testing is finished within 24 hours. Give interim therapeutic anticoagulation if imaging cannot be done at once (some textbooks say if it will take more than an hour), or, when PE is unlikely, if the D-dimer result will take more than 4 hours. When suspicion is low, the PERC rule can avoid D-dimer and imaging in some patients. The Wells and D-dimer pathway suits outpatients and emergency presentations: inpatients and pregnant women are often treated as high-risk, to be imaged, and D-dimer is not useful in pregnancy. Further tests assess the risk: echocardiography or CT for right ventricular dilatation, and troponin; the Pulmonary Embolism Severity Index (PESI) and its simplified version (sPESI) estimate the 30-day mortality, from age, sex, cancer, heart failure, chronic lung disease, pulse, blood pressure, respiratory rate, temperature, mental state and saturation. Compression ultrasound of the leg veins can confirm a DVT when imaging of the chest is not possible. Look for cancer if the history, examination and basic tests suggest it. Testing for thrombophilia is not routine.

Treatment

Anticoagulation is the treatment, in three phases: an acute phase of the first 5 to 10 days; a maintenance phase of at least 3 months; and an optional extended phase.

• Heparin works immediately: low-molecular-weight heparin (LMWH, subcutaneous) or unfractionated heparin (by infusion, for unstable patients, severe renal impairment or planned thrombolysis). Patients at intermediate-high risk start on LMWH and are monitored for the first 2 to 3 days before an oral drug.
• Direct oral anticoagulants (DOACs) are now preferred to warfarin for most patients. The factor Xa inhibitors apixaban (10 mg twice a day for 7 days, then 5 mg twice a day) and rivaroxaban (15 mg twice a day for 21 days, then 20 mg once a day) can be used alone from the start, and are usually offered first. Edoxaban and dabigatran are started after at least 5 days of parenteral anticoagulation, and dabigatran is not used if the creatinine clearance is below 30 mL/min. Kidney function and interacting drugs (such as rifampicin and some antiepileptics) are checked.
• Warfarin (target INR 2.0 to 3.0) is started with parenteral cover for at least 5 days and until the INR is 2.0 or more on two consecutive readings. It remains the choice in antiphospholipid syndrome (DOACs are not an alternative, especially in triple-positive disease, which starts on LMWH with warfarin). With a creatinine clearance of 15 to 50 mL/min apixaban or rivaroxaban can still be used; below 15, heparin is given, with or without warfarin.
• Cancer-associated PE: LMWH was the standard, and a DOAC (edoxaban, rivaroxaban or apixaban) is now an option. They are as effective, but edoxaban and rivaroxaban increase bleeding, especially in gastrointestinal and genitourinary cancers; apixaban did not raise major bleeding in a trial against LMWH.
• Pregnancy: LMWH. Warfarin and DOACs cross the placenta; warfarin is an embryotoxin in weeks 6 to 12. LMWH and warfarin are safe in breast-feeding; the DOACs are avoided.

Oxygen for hypoxaemia, fluids with caution (the dilated right ventricle can be harmed by overloading), and vasopressors for shock.

Reperfusion (dissolving or removing the clot):

• Systemic thrombolysis, for PE with persistent hypotension or shock: alteplase 100 mg over 2 hours (a weight-adjusted dose, at most 1.5 mg/kg, below 65 kg; there is also an accelerated regimen of 0.6 mg/kg over 15 minutes, up to 50 mg), with unfractionated heparin alongside or restarted afterwards. Reperfusion is the treatment of choice in high-risk PE, although no trial has shown that it lowers mortality. It carries a major bleeding risk, with about 2 per cent intracranial haemorrhage, so contraindications such as recent haemorrhage, stroke or major surgery must be sought.
• If thrombolysis is contraindicated or fails: surgical embolectomy or catheter-directed treatment.
• In intermediate-risk PE, routine thrombolysis is not recommended: in a large trial of tenecteplase, in 1005 normotensive patients with right ventricular dysfunction and a raised troponin, it halved the composite of death or haemodynamic collapse at 7 days (2.6 against 5.6 per cent), but death alone did not differ, and major extracranial bleeding (6.3 against 1.2 per cent) and stroke (2.4 against 0.2 per cent) were commoner. It is held as "rescue" if the patient deteriorates.
• An inferior vena cava filter is used when anticoagulation is contraindicated (for example, active bleeding) and is removed once it can be started.

Where to treat: low-risk patients (PESI class I–II or sPESI 0, with no right ventricular strain, and who are well supported at home) can be treated as outpatients or discharged early. Others are admitted.

Duration: at least 3 months for everyone. After that, a decision is made for each patient by weighing the risk of recurrence against the risk of bleeding:

• a major transient factor (surgery, trauma, immobility): stop at 3 months; the recurrence risk is low;
• an unprovoked event, or a persistent risk factor other than cancer or antiphospholipid syndrome: extended treatment is considered, if the bleeding risk is acceptable, and after 6 months a lower dose of apixaban (2.5 mg twice a day) or rivaroxaban (10 mg once a day) can be used;
• active cancer: 3 to 6 months of anticoagulation, often continued while the cancer is active; the lower doses were not tested in cancer;
• antiphospholipid syndrome: long-term treatment with a vitamin K antagonist, since DOACs are not an alternative;
• across all patients, if anticoagulation is stopped at 3 months the risk of recurrence in the next year is about 5 per cent, and after an unprovoked event it is about 10 per cent at 1 year and 30 per cent at 5 years; anticoagulants cut the relative risk of recurrence by 80 to 90 per cent, with a major-bleeding risk of 1 to 3 per cent a year.

Prevention: assess the VTE and bleeding risk of every patient on admission. Use early mobilisation, hydration, and mechanical measures, and give thromboprophylaxis with LMWH (or fondaparinux or a DOAC in some orthopaedic patients) to those at risk, such as after major surgery, with immobility, cancer, or acute medical illness. Advise travellers to move and drink, and consider the VTE risk before oestrogens.

05Epidemiology

VTE affects more than 5 per cent of people in their lifetime, and the risk rises with age. The annual incidence is around 1 per 1000 overall; about 1 per 10 000 young adults, 1 per 1000 in middle age and approaching 1 in 100 in the elderly. European estimates range from about 40 to 115 PE cases per 100 000 people per year. Roughly 10 per cent of hospital deaths were due to PE in historic autopsy series. The incidence is highest in people of African descent and lowest in Asians. Cancer, surgery, pregnancy and acute illness account for much of the burden.

06Prognosis

With treatment, the mortality of PE at one month is around 5 per cent, and at least half of these deaths come from comorbidity and not from the embolus; mortality at one year is 10 to 20 per cent, mostly from cancer. Short-term risk is highest in those with shock (a very high mortality without reperfusion), right ventricular dysfunction with raised troponin, and a high PESI (30-day mortality from under 2 per cent in class I to over 10 per cent in class V). Untreated, the mortality is far higher.

The long-term problems are:

• recurrence: about 5 per cent in the first year after stopping at 3 months, and about 10 per cent after an unprovoked event;
• chronic thromboembolic pulmonary hypertension (CTEPH): persistent breathlessness after PE is common, and in a few per cent (up to 5 per cent in some series) the clots fail to resolve and cause pulmonary hypertension. It is suspected from persistent symptoms, screened for with a V/Q scan and echocardiography, and managed in a pulmonary hypertension centre with lifelong anticoagulation; pulmonary endarterectomy can cure selected patients (balloon angioplasty and drugs such as riociguat are the alternatives);
• post-PE syndrome of reduced exercise capacity and quality of life; and
• the post-thrombotic syndrome after proximal DVT, in about 40 per cent, with leg pain, swelling and sometimes ulceration.

Patients should be followed up at 3 to 6 months, and referred for assessment if still breathless.