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.[12] Most cases of pulmonary embolism are caused by embolization of deep vein thrombosis (DVT), which arise from three factors acting individually or together (Virchow triad)​:[13]

  • Vessel injury: endothelial cell damage promotes thrombus formation, usually at the venous valves, which can result in DVT, which subsequently embolizes to form pulmonary embolism (PE). Damage to the vessel wall can occur after a number of insults including trauma, previous DVT, surgery, venous harvest, and central venous catheterization.[14]​ Occasionally, PE can arise from thrombus which forms in the right heart, which can occur in atrial fibrillation.[15] De novo thrombosis may also occur in the pulmonary arteries, such as in infection with COVID-19.

  • Venous stasis: poor blood flow and stasis promote the formation of thrombi. Venous stasis and congestion result in valvular damage, further promoting thrombus formation. Increased venous stasis is associated with age >40 years, immobility, obesity, general anesthesia, paralysis, spinal cord injury, myocardial infarction, prior stroke, varicose veins, advanced congestive heart failure, and advanced COPD.

  • Activation of the clotting system: a number of other conditions (both inherited and acquired) increase the risk of PE. These include cancer, high-estrogen states (oral contraceptives, hormone replacement, obesity, pregnancy), inflammatory bowel disease, nephrotic syndrome, sepsis, blood transfusion, and inherited thrombophilia (factor V Leiden mutation, prothrombin gene mutation, protein C and S deficiency, antithrombin deficiency, and antiphospholipid antibody syndrome).

Thus, patients who develop venous thromboembolism (VTE) have typically experienced a trigger that leads to blood coagulation (e.g., surgery or trauma that activates the coagulation system), prolonged immobility that leads to stasis, or drugs or illnesses (e.g., cancers, antiphospholipid syndrome) that can stimulate clotting. 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:[16]

  • 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

  • Pregnancy and the postpartum

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.[17] The International Society on Thrombosis and Haemostasis has published a four-category classification system (presented in order of increasing risk of recurrent VTE after an initial episode) that is consistent with UK National Institute of Clinical Excellence and American College of Chest Physicians guidance:[18][19][20]

  • 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)

The American Society of Hematology and the European Society of Cardiology guidelines employ a similar framework, with some differences in terminology.[3][21][22]​​​​​​

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.[23]

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.[24][25] A small portion of PE cases may arise from thrombus formation in the right atrium in the setting of atrial arrhythmias.​[26]

Endothelial damage appears to be less important in venous thromboembolism (VTE) than in arterial thrombosis.[27] Unlike platelet-rich arterial thrombi, VTE 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.[27][28]

Acute thrombus begins to be dissolved by the body's fibrinolytic system as soon as a clot begins to form. Thus, elevated levels of breakdown products of cross-linked fibrin, particularly the fragment called D-dimer, appear in the blood soon after a clot begins to form. Therefore, testing for D-dimer is an important component of the evidence-based approach to diagnosing suspected PE.[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.[2]

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[3]​​

    • High-risk PE: PE resulting in hypotension or shock. Pulmonary Embolism Severity Index (PESI) Class III-V or Simplified PESI (sPESI) ≥1.

    • Intermediate-high risk PE: PE resulting in both abnormal RV parameters on imaging and abnormal cardiac biomarkers, but with normotension. PESI Class III-V or sPESI ≥1.

    • Intermediate-low risk PE: PE resulting in either abnormal RV parameters on imaging or abnormal cardiac biomarkers (but not both), and with normotension. PESI Class III-V or sPESI ≥1.

    • Low-risk PE: meets none of the criteria for high or intermediate risk. PESI Class I-II or sPESI <1.

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