Pulmonary embolism

Definition:

Pulmonary embolism (PE) is a blockage of one or more arteries in the lungs that occurs when a blood clot or material such as fat, air, or amniotic fluid travels from another part of the body, usually the legs, through the bloodstream and lodges in the lungs. PE can lead to serious complications, including low oxygen levels in the blood and damage to the lungs, and can be life-threatening if not treated promptly.

Non-thrombotic pulmonary emboli sources include ³⁰: 

• gas embolism, e.g. air embolism, carbon dioxide embolism, nitrogen, helium

• fat embolism

• tumour embolism: comprised of tumour thrombus

• infectious agents

  • parasitic embolism

  • hydatid embolism

  • septic embolism

• amniotic fluid embolism

• catheter embolism

• brachytherapy seeds

• particulate material embolism, e.g.

  • talc embolism

  • cement embolism: comprised of polymethyl methacrylate (PMMA)

  • iodinated oil embolism

  • metallic pulmonary embolism

    • barium embolism

    • mercury embolism

Terminology

PE is sometimes referred to as a thromboembolic event, and the term thromboembolism is used to describe both PE and deep vein thrombosis (DVT).

Classification of a pulmonary embolism may be based upon: 

• the presence or absence of haemodynamic compromise

• temporal pattern of occurrence

• the presence or absence of symptoms

• the vessel which is occluded

Epidemiology:

PE is a common medical emergency, with a reported incidence of between 60 and 300 cases per 100,000 population per year. The incidence of PE increases with age and is higher in males compared to females. Other risk factors for PE include immobility, obesity, cancer, hormonal therapy, and surgery.

Clinical presentation

Symptoms of PE include chest pain, shortness of breath, cough, rapid heartbeat, and sudden collapse. The clinical presentation can vary greatly, and some patients may present with only mild symptoms or no symptoms at all.

The patient may report a history of recent immobilisation or surgery, active malignancy, hormone usage, or a previous episode of thromboembolism. The physical exam may reveal suggestive features such as:

• clinical signs of deep venous thrombosis (DVT)

  • asymmetric pitting lower extremity oedema

  • prominent superficial collateral vessels

  • tenderness to palpation along the deep venous system

• tachycardia

• dyspnoea

• pleuritic chest pain

• haemoptysis

Clinical decision rules, in conjunction with physician gestalt and estimated pretest probability of disease, may serve as a supplement in risk stratification:

• Wells score

• Geneva score

• PERC rule

ECG

• sinus tachycardia: the most common abnormality

• right heart strain pattern

  • incomplete or complete right bundle branch block

  • prominent R wave in lead V1

  • right axis deviation

  • T-wave inversion in the right precordial leads +/- the inferior leads is seen in up to 34% of patients and is associated with high pulmonary artery pressures ²⁵

    • simultaneous T-wave inversion in lead III and V₁ has been repeatedly shown to have strong sensitivity (90%), specificity (97%), positive predictive value (92%), negative predictive value (96%) and overall predictive accuracy of 95% ^25,26

• S_IQ_IIIT_III pattern: this refers to a deep S wave in lead I, Q wave and T wave inversion in lead III; this sign is seen as classical of PE but is, in fact, poor in terms of both sensitivity and specificity as a sign of PE

Pathology

Pathophysiology:

The triad of Virchow, which consists of endothelial injury, stasis and hypercoagulability, is considered to be the underlying pathophysiology of PE. Endothelial injury refers to damage to the inner lining of blood vessels that increases the risk of blood clots forming. Stasis, or reduced blood flow, can occur in certain parts of the body, such as the legs, when a person is bedridden or has a long-standing medical condition. Hypercoagulability is a tendency to form clots more easily. The majority of PE cases result from deep vein thrombosis (DVT), with less than 10% originating from the pulmonary veins themselves.

PE leads to increased pressure in the pulmonary artery, which can cause lung damage and lead to a condition called pulmonary hypertension (PHT). Blockage and vasospasm of the pulmonary artery also leads to a condition called cor pulmonale, which results from the heart having to work harder to pump blood through the lungs. Neurogenic release of thrombotic substances such as A2 and serotonin can occur, leading to further clot formation and worsening of PE.

In addition to the increased pressure in the pulmonary artery, PE also leads to ischaemia of the downstream lung parenchyma, resulting in reduced oxygen supply to the affected areas. The consequences of PE can range from mild to severe and can be life-threatening, making prompt diagnosis and treatment essential.

Gross anatomical pathology:

Gross anatomical pathology in pulmonary emboli (PE) is characterised by a sudden blockage of the pulmonary arterial circulation, resulting in a lack of oxygen to the affected lung parenchyma. This obstruction causes ischaemia, which can lead to infarction of the affected lung tissue. The consequences of this increased elevated pulmonary arterial pressure include cor pulmonale and pulmonary hypertension (PHT), both of which can result from blockage and vasospasm. This obstruction can also lead to neurogenic release of thrombotic, A2, and serotonin, which can contribute to further thrombus formation. Virchow's triad (endothelial injury, stasis, and hypercoagulable states) plays a crucial role in the development of PE, with a large number of DVTs causing PE, with only 10% or less originating in the pulmonary veins themselves. The ischaemia of the downstream parenchyma, as a result of the PE, can also cause a wide range of clinical manifestations and lead to significant morbidity and mortality.

Risk factors

The following are the risk factors for PE:

1. Primary hypercoagulable states: including protein C deficiency, protein S deficiency, antithrombin III deficiency, lupus anticoagulant, factor V Leiden.

2. Recent surgery and prolonged bed rest/immobility: both increase the risk of DVT, which can progress to PE.

3. Malignancy: including multiple myeloma and HIV, which increase the risk of blood clots.

4. Medications: such as oral contraceptives and thalidomide, lenalidomide.

5. Pregnancy

6. Previous history of DVT

7. Presence of certain venous aneurysms, such as popliteal venous aneurysm.

Links to the risk factures are as follows:

• primary hypercoagulable states

  • protein C deficiency

  • protein S deficiency

  • antithrombin III deficiency

  • lupus anticoagulant

  • factor V Leiden

• recent surgery

• prolonged bed rest/immobility

• malignancy: including multiple myeloma²³

• HIV²²:

  • 2-10 x increased risk, cf. non-HIV matched controls

• COVID-19²⁷

• medication

  • oral contraceptives

  • thalidomide, lenalidomide ³¹

• pregnancy

• known or previous DVT

• presence of certain venous aneurysms

  • e.g. popliteal venous aneurysm¹⁵

Markers 

D-dimer (ELISA) is commonly used as a screening test in patients with a low and moderate probability clinical assessment, in these patients:

• normal D-dimer has almost 100% negative predictive value (virtually excludes PE): no further testing is required

• raised D-dimer is seen with PE but has many other causes and is, therefore, non-specific: it indicates the need for further testing if pulmonary embolism is suspected ⁴

In patients with a high probability clinical assessment, a D-dimer test is not helpful because a negative D-dimer result does not exclude pulmonary embolism in more than 15%. Patients are treated with anticoagulants while awaiting the outcome of diagnostic tests ⁴. 

Classification

PE can be classified based on its haemodynamic impact, temporal pattern, and location in the lung vessels. Haemodynamic classification categorises PE into three types: massive PE, submassive PE, and low-risk PE. Temporal pattern classification categorises PE into acute, subacute, and chronic PE. Vessel classification categorises PE into saddle, lobar, segmental, and subsegmental PE.

• haemodynamic

  • massive PE

  • submassive PE

  • low-risk

• temporal pattern

  • acute

  • subacute

  • chronic

• vessel

  • saddle

  • lobar

  • segmental

  • subsegmental

Radiographic features

The diagnosis of PE can be challenging, and a variety of imaging modalities are used to diagnose and evaluate the extent of the disease and on whether it is acute or chronic.

Overall, there is a predilection for the lower lobes.

Plain radiograph

Chest X-rays can provide information about the presence of pleural effusions and the overall lung architecture. However, chest X-rays have limited sensitivity and specificity in diagnosing PE, with the most commonly described signs including the Fleischner sign, Hampton hump, Westermark sign, knuckle sign, Palla sign, Chang sign, and elevated diaphragm. The sensitivity and specificity of these signs vary, with the Westermark sign having the highest positive predictive value (38%) and the Fleischner sign being present in 20% of cases.

Described chest radiographic signs include:

• Fleischner sign: enlarged pulmonary artery (20%)

• Hampton hump: peripheral wedge of airspace opacity and implies lung infarction (20%)

• Westermark sign: regional oligaemia and highest positive predictive value (10%)

• pleural effusion (35%) - pleural effusions in pulmonary embolism

• knuckle sign¹¹

• Palla sign¹⁷: enlarged right descending pulmonary artery

• Chang sign¹⁸: dilated right descending pulmonary artery with sudden cut-off

Sensitivity and specificity of chest x-ray signs ¹:

• Westermark sign

  • sensitivity: ~14% 

  • specificity: ~92% 

  • positive predictive value: ~38%

  • negative predictive value: ~76%

• vascular redistribution

  • sensitivity: ~10% 

  • specificity: ~87% 

  • positive predictive value: ~21%

  • negative predictive value: ~74%

• Hampton hump

  • sensitivity: ~22% 

  • specificity: ~82%

  • positive predictive value: ~29%

  • negative predictive value: ~76%

• pleural effusion

  • sensitivity: ~36% 

  • specificity: ~70%

  • positive predictive value: ~28%

  • negative predictive value: ~76%

• elevated diaphragm

  • sensitivity: ~20% 

  • specificity: ~85%

  • positive predictive value: ~30%

  • negative predictive value: ~76%

Ultrasound:

Doppler ultrasound of the legs may be used to identify DVT, but is not typically used for diagnosis of PE.

CT

Acute pulmonary emboli

CT pulmonary angiography (CTPA) will show filling defects within the pulmonary vasculature with acute pulmonary emboli. When the artery is viewed in its axial plane the central filling defect from the thrombus is surrounded by a thin rim of contrast, which has been called the Polo Mint sign.

Emboli may be occlusive or non-occlusive, the latter is seen with a thin stream of contrast adjacent to the embolus. Typically the embolus makes an acute angle with the vessel, in contrast to chronic emboli. The affected vessel may also enlarge ⁹.

Acute pulmonary thromboemboli can rarely be detected on non-contrast chest CT as intraluminal hyperdensities ¹².

Dual-energy CT holds much promise for the diagnosis and prognosis of PE. Z effective and iodine maps provide lung perfusion assessment. The use of low monoenergetic reconstructions (low monoE) allows 'iodine boosting' of the pulmonary arteries which are useful during suboptimal contrast opacification thereby preventing the need to repeat undiagnostic scans ^ref.

Chronic pulmonary emboli

In contrast to acute pulmonary embolism, chronic thromboemboli are often complete occlusions or non-occlusive filling defects in the periphery of the affected vessel which form obtuse angles with the vessel wall ⁹. The thrombus may be calcified.

Features noted with chronic pulmonary emboli include:

• webs or bands, intimal irregularities ³

• abrupt narrowing or complete obstruction of the pulmonary arteries ³

• “pouching defects” which are defined as chronic thromboembolism organised in a concave shape that “points” toward the vessel lumen ³

Indirect signs include ⁷:

• mosaic perfusion

• vascular calcification

• bronchial or systemic collateralisation

Ultrasound/Echocardiography

Acute pulmonary emboli

Point-of-care ultrasonography is currently not recommended for a haemodynamically stable patient with suspected pulmonary embolism. In the presence of haemodynamic compromise, echocardiography may be of value to assess for the presence of severe right ventricular dysfunction;

• if absent, another cardiopulmonary derangement is likely responsible

• if unequivocally present, it can establish the need for emergent treatment

Echocardiographic features which may be suggestive include:

• thrombus-in-transit

• right ventricular dysfunction

  • commonly dilated and hypocontractile

• flattening or dyskinesis of the interventricular septum

• 60/60 sign

• McConnell sign

Of note, transoesophageal echocardiography has a reported sensitivity of 80.5% and a specificity of 97.2% for ruling in acute pulmonary embolism after the detection of right ventricular overload on transthoracic echocardiography²⁴. 

Chronic pulmonary emboli

Again not recommended as part of first-line work up. 

Cumulative damage from repeated embolic insults is a common cause of chronic thromboembolic pulmonary hypertension, which demonstrates a variable degree of the aforementioned signs, but with significantly higher right ventricular pressures, right ventricular hypertrophy and diastolic dysfunction, and a higher degree of tricuspid regurgitation. 

MRI

It is difficult to obtain technically adequate images for pulmonary embolism patients using MRI. Magnetic resonance pulmonary angiography (MRPA) should be considered only at centres that routinely perform it well and only for patients for whom standard tests are contraindicated. Technically-adequate magnetic resonance angiography has a sensitivity of 78% and a specificity of 99% ¹³.

Nuclear medicine

A ventilation/perfusion (V/Q) scan will show ventilation-perfusion mismatches. A high probability scan is defined as showing two or more unmatched segmental perfusion defects according to the PIOPED criteria.

Treatment and prognosis

Providing cardiopulmonary support is the initial treatment. Anticoagulation is provided in patients without risk of active bleeding. If the emboli are large or there is a large clot burden, thrombolysis is an option. In some cases, embolectomy or placement of vena cava filters is required.

The right ventricular failure due to pressure overload is considered the primary cause of death in severe PE ¹⁴.

Complications

• acute emboli

  • pulseless electrical activity (PEA) in the context of a large obstructing saddle embolus (see mnemonic for causes of PEA)

• acute or chronic emboli

  • right ventricular dysfunction

    • CT features suggestive of right ventricular dysfunction include ⁸:

      • abnormal position of the interventricular septum

      • inferior vena cava contrast reflux

      • RVD (right ventricular diameter): LVD (left ventricular diameter) ratio >1 on reconstructed four-chamber views

        • RVD:LVD ratio >1 on standard axial views is not considered to be a good predictor of right ventricular dysfunction ⁸

    • termed submassive PE when right ventricular dysfunction demonstrated on imaging (CT or echo) but without clinical haemodynamic compromise ¹⁹

• subacute-to-chronic emboli

  • pulmonary infarction

  • pulmonary hypertension

  • pulmonary arterial sclerosis

• chronic emboli

  • cor pulmonale

Resolution over time

Several studies report around 80% emboli resolving at around 30 days ^20,21. According to one study, residual pulmonary obstruction at 6 months after the first episode of pulmonary embolism was shown to be an independent predictor of recurrent venous thromboembolism and/or chronic thromboembolic pulmonary hypertension²⁸.

Differential diagnosis

Consider:

• pulmonary artery sarcoma

• pulmonary artery vasculitis e.g. Takayasu arteritis

• misidentification of pulmonary veins for arteries

• arterial bifurcations (or branch points) can mimic PE but usually easily distinguished on multiplanar assessment

• artifact may cause pseudo-filling defects and can be caused by:

  • breathing motion

  • beam hardening

    • hyperconcentrated contrast in the superior vena cava

    • medical devices e.g. catheters, orthopaedic prostheses

    • patient's arms in a down position

  • patient movement

  • transient contrast bolus interruption¹⁶, due to Valsalva or a patent foramen ovale, causing non-opacified blood to enter the right ventricle and pulmonary arteries (scanning in end-expiration can reduce or eliminate this artifact)

• chronic emboli may be mistaken for acute emboli 

  • or vice-versa

• thromboembolic emboli may be mistaken for other embolised material

  • or vice-versa

See also

• pulmonary embolism rule-out criteria (PERC)

• Wells criteria for pulmonary embolism

• Geneva score

• YEARS criteria for pulmonary embolism