Etiology

The coagulation system in blood is complex and highly regulated. Slight perturbations in the systems that regulate coagulation can lead to bleeding or thrombosis.[16] Most cases of pulmonary embolism are caused by three factors acting individually or together (Virchow triad):

  • Vessel injury

  • Venous stasis

  • Activation of the clotting system.

Thus, patients who develop venous thromboembolism (VTE) have typically experience a trigger that leads to blood coagulation (e.g., surgery or trauma that activates the coagulation system), prolonged immobility that leads to stasis, or medications or illnesses (e.g., cancers, antiphospholipid syndrome) that can stimulate clotting.[17] Susceptibility to thrombosis is genetically mediated. Several genetic variants in the coagulation system itself (e.g., the factor V Leiden mutation), as well as outside the coagulation system (e.g., non-O blood type), increase the risk of thrombosis. All of these factors may interact, further increasing the risk of PE.

There is a clear association between PE and the following:

  • Active malignancy

  • Recent major surgery (especially major orthopedic procedures)

  • Recent hospitalization

  • Recent trauma

  • Medical illness (especially diseases associated with inflammation, such as acute infection)

  • Hormone replacement and oral contraceptive estrogen therapy.

Coronavirus disease 2019 (COVID-19), an infection caused by the SARS-CoV-2 virus, has been associated with risk for PE.[18]

The presence or absence and timing of these risk factors relative to the diagnosis of PE has a major impact on determining the duration of anticoagulant therapy.[19] The International Society on Thrombosis and Haemostasis has published a four-category classification system (presented in order of increasing risk of recurrent venous thromboembolism after an initial episode) that is consistent with UK National Institute of Clinical Excellence and American College of Chest Physicians guidance:[20][21][22]

  • Major transient risk factor provocation (e.g., surgery lasting >60 minutes), occurring within 3 months prior to thrombosis

  • Minor transient risk factor provocation (e.g., oral contraceptives, medical hospitalization), occurring within 2 months prior to thrombosis

  • Unprovoked (no identifiable risk provoking factor)

  • Persistent risk factor provocation (e.g., active cancer).

Other US and European guidelines employ a similar framework, though with slight differences in terminology.[4]​​[23]

Pathophysiology

PE occurs when a thrombus originating in the veins of the lower extremities (or other location) dislodges and travels via venous blood flow to become trapped in the pulmonary arteries. This obstruction increases pulmonary vascular resistance (PVR), increasing the work of the right ventricle. The right ventricle compensates by increasing heart rate using the Frank-Starling preload reserve via dilation. In severe cases of PE, increases in PVR may overwhelm the right ventricular (RV) compensatory mechanisms, leading to over-distention of the right ventricle, increased RV end-diastolic pressure, and decreased RV cardiac output. Decreased RV output leads to decreased left ventricular (LV) preload. As left ventricle filling and cardiac output decrease, lowered mean arterial pressure progresses to hypotension and shock. In previously healthy individuals, this can occur when as little as 50% of the pulmonary vasculature is occluded. There is, however, inter-individual variation in the ability to tolerate PE, and the anatomic degree of obstruction does not always correlate well with the physiologic severity of PE.[24]

Thrombi rarely develop de novo in the pulmonary vasculature, but may occur, for example, in the setting of some subtypes of pulmonary arterial hypertension and in the setting of COVID-19. Deep vein thrombosis (DVT) in the upper extremities is associated with a lower incidence of PE, as are thrombi in unusual sites, such as the cerebral veins.[25]​[26] A small portion of PE cases may arise from thrombus formation in the right atrium in the setting of atrial arrhythmias.​[27]

Endothelial damage appears to be less important in DVT than in arterial thrombosis.[28] Unlike platelet-rich arterial thrombi, DVT is composed mainly of fibrin and entrapped erythrocytes (red clots). Although platelet aggregation is seen, it is not evident at the site of thrombus attachment, suggesting that activation of the coagulation cascade precedes platelet activation.[28][29]

Classification

Anatomic classification

PE may be described by location and extent of thrombi in the pulmonary arterial tree.

  • Most proximal vessel type: main, lobar, segmental, subsegmental (PE isolated to only subsegmental vessels [ISSPE] may have different management options).

  • Number of vessels or percentage of vasculature affected. Formal quantitative systems are available.[3]

Physiologic classification

PE may be classified according to its physiologic impact on the cardiovascular system. This classification has better correlation with clinical prognosis and typically informs treatment strategies in major guidelines.

  • Massive versus submassive

    • Massive PE describes PE resulting in shock or hypotension

    • Submassive PE results in abnormal right ventricular (RV) size or function but with normotension.

  • European Society of Cardiology Classification[4]​​

    • High-risk PE: PE resulting in hypotension or shock

    • Intermediate-high risk PE: PE resulting in both abnormal RV parameters on imaging and abnormal cardiac biomarkers, but with normotension

    • Intermediate-low risk PE: PE resulting in either abnormal RV parameters on imaging or abnormal cardiac biomarkers (but not both), and with normotension

    • Low-risk PE: meets none of the criteria for high or intermediate risk.

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