Pulmonary Embolism

Pulmonary embolism (PE) is the obstruction of pulmonary arterial blood flow by a thrombus, most commonly originating from the deep veins of the lower extremities, that lodges in the pulmonary circulation and impairs gas exchange and hemodynamics. PE represents one of the most common and preventable causes of hospital mortality, with an annual incidence of approximately 1-2 per 1,000 persons in developed countries, affecting all age groups but with increasing incidence with age and in hospitalized patients. The spectrum of disease ranges from subclinical small peripheral PE to massive PE causing acute right ventricular failure and sudden cardiopulmonary collapse, making early recognition and risk stratification essential for optimal outcomes. PE remains a leading cause of preventable in-hospital deaths and accounts for significant morbidity through post-thrombotic syndrome, chronic thromboembolic pulmonary hypertension, and increased healthcare expenditures. Understanding PE pathophysiology, risk stratification, and treatment algorithms is critical for board examinations and daily clinical practice, as missed or delayed diagnosis carries mortality rates exceeding 25-30% without treatment. The interplay between clinical suspicion, validated risk assessment tools, appropriate diagnostic testing, and evidence-based anticoagulation strategies forms the foundation of modern PE management.

The development of venous thromboembolism (VTE), of which PE is the most serious manifestation, occurs through the classical framework of Virchow's triad: blood stasis, endothelial injury, and alterations in blood composition (hypercoagulability). Endothelial damage exposes tissue factor and von Willebrand factor, activating the extrinsic coagulation cascade and promoting platelet adhesion through glycoprotein Ib and IIb/IIIa receptors. Stasis in the deep venous system, particularly the soleal and gastrocnemius sinuses of the calf and the popliteal and femoral veins, allows platelet aggregation and fibrin deposition to proceed unopposed by flowing blood's naturally anticoagulant properties. Hypercoagulable states arise through multiple mechanisms including acquired factors (cancer-associated hypercoagulability via tissue factor expression, estrogen-induced increases in prothrombin and factors VII and X, postoperative inflammation and cytokine release) and inherited thrombophilias affecting the protein C pathway, protein S, antithrombin, or resulting in factor V Leiden or prothrombin G20210A mutations. The prothrombinase complex assembles on exposed phosphatidylserine on activated platelets and microparticles, converting factor X to Xa and prothrombin to thrombin, generating fibrin strands that stabilize the platelet plug through factor XIII cross-linking.

Once formed, venous thrombi may remain attached to the vessel wall or embolize when hemodynamic forces or inflammatory changes destabilize the thrombus. Approximately 90-95% of pulmonary emboli originate from deep leg veins, with the remainder arising from upper extremity veins, right heart chambers, or paradoxically from left-sided thrombi crossing through a patent foramen ovale (PFO) or other intracardiac shunts. Upon embolization, the thrombus traverses the right heart chambers and lodges in progressively smaller pulmonary arterial branches based on its size: large emboli may lodge in the main or lobar pulmonary arteries causing massive PE, while smaller emboli fragment and lodge in segmental and subsegmental vessels causing distal microinfarction. The mechanical obstruction of the pulmonary vascular bed increases pulmonary vascular resistance (PVR) acutely, creating a mismatch between right ventricular afterload and contractile function, as the normal right ventricle cannot rapidly adapt to acute resistance increases. Perfusion-ventilation (V/Q) mismatch develops as ventilation continues to perfused lung units while perfusion ceases in obstructed segments, reducing arterial oxygen saturation and increasing alveolar dead space.

The acute elevation in RV afterload from pulmonary vascular obstruction triggers several pathophysiological cascades with profound consequences for systemic hemodynamics. The RV responds to afterload stress through increased contractility via the Frank-Starling mechanism and sympathetic activation, but when the obstruction exceeds a critical threshold (typically requiring obstruction of >50% of the pulmonary circulation), RV contractility becomes insufficient, causing RV dilatation. RV dilatation bulges the interventricular septum leftward into the LV cavity, impairing LV filling and reducing LV stroke volume (septal reversal), thereby reducing systemic cardiac output and promoting hypotension, shock, and syncope in massive PE. Simultaneously, tricuspid regurgitation develops secondary to RV dilatation and annular dilatation, with regurgitant flow raising right atrial pressures and promoting hepatic engorgement and peripheral edema; tricuspid regurgitation waveforms characteristically show the prominent systolic reversal wave. The increased RV wall tension from dilatation and afterload elevation increases myocardial oxygen demand while simultaneously reducing RV perfusion pressure (diastolic pressure gradient across the RV wall), creating a mismatch between oxygen supply and demand that may cause RV infarction, particularly when RV-dependent coronary perfusion is compromised.

Hypoxemia in PE results from multiple mechanisms beyond simple anatomical shunting. Ventilation-perfusion (V/Q) mismatch predominates, where obstructed lung segments continue to be ventilated without perfusion (dead space), while non-obstructed perfused segments receive ventilation from adjacent areas. Increased physiological dead space (rising from the normal 150 mL to 300-400 mL or greater) necessitates increased minute ventilation to maintain CO2 elimination, placing stress on the respiratory system and contributing to tachypnea. Intracardiac right-to-left shunting may occur when increased RA pressures open or enlarge a patent foramen ovale, permitting deoxygenated venous blood to bypass the lungs entirely. Low mixed venous oxygen saturation (SvO2) develops when cardiac output falls, as tissues extract a greater fraction of oxygen from available blood; in shock states, SvO2 may fall from the normal 75% to critically low levels, worsening hypoxemia despite adequate lung function. Hypoxemia triggers reflexive hyperventilation through chemoreceptor stimulation, creating characteristic respiratory alkalosis with low PaCO2; if respiratory fatigue develops or if RV failure progresses to cardiogenic shock with hepatic congestion and lactic acidosis, mixed or metabolic acidosis may supervene, indicating decompensation.

The presence of thrombus and endothelial injury initiates a robust inflammatory response through activation of the coagulation cascade's inflammatory properties. Thrombin directly activates protease-activated receptors (PARs) on endothelial cells, macrophages, and mast cells, triggering release of interleukin-1β, interleukin-6, and tumor necrosis factor-α that amplify the inflammatory cascade. Tissue factor on circulating microparticles (released from activated endothelial cells, platelets, and leukocytes) perpetuates thrombosis through the extrinsic pathway while simultaneously triggering inflammatory gene expression. Complement activation occurs through both tissue factor and thrombin-mediated pathways, generating C3a and C5a anaphylatoxins that increase vascular permeability, promote leukocyte recruitment, and contribute to systemic inflammatory response features including fever, elevated cytokine levels, and sometimes acute respiratory distress syndrome in severe PE. This inflammatory milieu explains clinical findings such as elevated D-dimer levels (from plasmin-mediated fibrin degradation), elevated C-reactive protein and procalcitonin, and elevated troponin and B-type natriuretic peptide from myocardial stress, all of which have prognostic implications in PE severity assessment.

In approximately 10% of PE cases, particularly those with underlying cardiopulmonary disease or prolonged hemodynamic compromise, pulmonary infarction develops when distal PE occludes subsegmental vessels that lack adequate collateral circulation from the bronchial arteries. Pulmonary infarction results in hemorrhagic necrosis of the peripheral lung tissue and presents clinically with pleuritic chest pain, hemoptysis, and pleural friction rub (the Hampton's hump on imaging represents wedge-shaped peripheral consolidation). The ischemic lung tissue activates local inflammatory cascades and releases tissue factor-bearing microparticles, perpetuating the thrombotic state and explaining why pulmonary infarction-associated PE often exhibits more dramatic D-dimer elevation. Infarction is more common with pre-existing heart or lung disease that limits alternative perfusion, a factor explaining why elderly patients with chronic lung disease have higher rates of infarction-type PE presentations.

Prolonged immobilization from hospitalization, surgery, long-distance travel, paralysis, or chronic bedridden states represents one of the most significant risk factors for VTE, with the risk increasing substantially after 3-4 days of immobilization. Surgical procedures, particularly orthopedic surgery (hip fracture repair, total hip arthroplasty, total knee arthroplasty), carry extremely high baseline VTE risk (40-60% without thromboprophylaxis) due to the combined effects of surgical trauma, immobility, endothelial injury, and inflammatory activation. General surgery, abdominal surgery, and neurosurgery also carry elevated risk (15-30% without prophylaxis), while minimally invasive laparoscopic procedures carry lower risk. Long-distance travel (flights >4 hours, prolonged car or train travel) creates VTE risk through sustained leg immobility, with absolute risk of symptomatic VTE estimated at 0.5-1% in healthy travelers but substantially higher in those with underlying thrombophilia or cancer.

Cancer represents one of the highest-risk conditions for VTE, with cancer patients experiencing 4-7 fold increased VTE risk compared to matched controls and accounting for 10-20% of all VTE events. Multiple mechanisms contribute to cancer-associated thrombosis: direct tissue factor expression by malignant cells, release of cancer cell-derived microparticles bearing tissue factor, production of procoagulant cytokines (IL-1, TNF-α, IL-6), and direct vessel wall invasion and endothelial injury. Certain malignancies carry disproportionately high VTE risk including adenocarcinoma (particularly lung, gastric, pancreatic, and ovarian), lymphomas, and brain tumors; conversely, squamous cell carcinomas and melanomas carry lower baseline risk. Chemotherapy administration, particularly with chemotherapy regimens containing bevacizumab, thalidomide/lenalidomide, or newer targeted agents, dramatically increases VTE risk above the baseline cancer risk. Cancer-associated VTE often presents atypically, may involve unusual sites (upper extremity, hepatic, splenic, mesenteric veins), and carries worse prognosis with higher recurrence rates even with anticoagulation, necessitating indefinite anticoagulation and often combined pharmacological and mechanical prophylaxis during treatment.

Factor V Leiden (the most common inherited thrombophilia in Caucasians, present in 3-7% of the population) results from a point mutation (1691G→A) creating a cleavage-resistant form of factor Va that remains active despite protein C activation, resulting in approximately 3-8 fold increased VTE risk in heterozygotes and >80-fold risk in homozygotes. Prothrombin G20210A mutation (present in 1-3% of Caucasians) increases prothrombin levels and VTE risk approximately 2-4 fold in heterozygotes. Protein C deficiency (inherited in ~0.2-0.5% of population; both Type 1 with reduced protein C activity and antigen, and Type 2 with normal antigen but reduced activity), protein S deficiency, and antithrombin deficiency are less common but confer higher VTE risk (5-10 fold), with antithrombin deficiency carrying the highest individual risk. These inherited thrombophilias explain familial clustering of VTE and younger age of presentation in affected families. Acquired thrombophilias include the antiphospholipid syndrome, characterized by persistent antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, anti-β2 glycoprotein I antibodies) and associated with both arterial and venous thrombosis, catastrophic thrombotic complications, and pregnancy loss; this diagnosis requires confirmation on repeat testing 12 weeks apart due to transient antibody elevation with acute infection or illness.

Oral contraceptive pills increase VTE risk approximately 3-4 fold in users, with risk higher in first-year users and in those using third- and fourth-generation progestins compared to second-generation formulations; older estrogen doses (≥50 μg) conferred higher risk, while current lower-dose formulations (<35 μg) demonstrate reduced but persistent risk. Hormone replacement therapy (HRT) in postmenopausal women increases VTE risk approximately 2-3 fold, with higher risk in transdermal preparations and in those with underlying thrombophilia. The mechanism involves estrogen-induced increases in prothrombin, factors VII, VIII, IX, and X, reduced protein S levels, and enhanced inflammation. Pregnancy and the postpartum period represent a particularly high-risk situation, with pregnancy increasing VTE risk 5-10 fold over baseline and the immediate postpartum period (first 6 weeks) carrying risk approximately equivalent to pregnancy itself, explaining why pregnant women represent a growing proportion of PE cases. Cesarean delivery further elevates risk compared to vaginal delivery, and the combination of pregnancy with underlying thrombophilia (inherited or acquired) dramatically escalates risk to 20-40 fold baseline.

Congestive heart failure with reduced ejection fraction increases VTE risk through multiple mechanisms: blood stasis from reduced cardiac output, endothelial dysfunction, activation of neurohumoral pathways, and often accompanying immobility. Atrial fibrillation, even without heart failure, increases VTE risk through blood stasis in the left atrial appendage and is a standard indication for systemic anticoagulation. Recent myocardial infarction, particularly with anterior wall involvement and reduced LV ejection fraction, creates risk for apical thrombus formation and PE. Acute coronary syndrome represents a hypercoagulable state through platelet activation and thrombotic amplification. Dilated cardiomyopathy of any etiology increases risk through combined effects of reduced cardiac output and endocardial injury promoting mural thrombus formation. Valvular heart disease, particularly mechanical prosthetic valves, creates local endothelial injury and stasis predisposing to thrombosis. Infective endocarditis causes septic thromboembolism, while acute endocarditis-related thrombi may embolize as PE.

Trauma, particularly major trauma with associated long bone fractures or pelvic fractures, represents a profound VTE risk through multiple mechanisms: endothelial injury from direct vessel trauma, tissue factor release from damaged tissues, immobilization, surgical intervention, and systemic inflammatory activation. Spinal cord injury creates sustained VTE risk through both acute immobility and chronic changes in the paralyzed limbs affecting venous return. Burns trigger a hypercoagulable state through extensive inflammatory activation and tissue factor release. Hip fracture represents one of the highest-risk orthopedic injuries, with VTE incidence approaching 50-60% without prophylaxis and continuing high risk even with mechanical prophylaxis alone, mandating pharmacological prophylaxis whenever not contraindicated.

Inflammatory bowel disease (Crohn's disease and ulcerative colitis) increases VTE risk through chronic inflammation, hypercoagulability, and often associated immobility during disease flares or hospitalizations. Behçet's disease represents a particularly thrombotic vasculitis with high VTE risk. Sepsis creates acute thrombotic risk through endothelial activation, tissue factor expression, and platelet consumption. COVID-19 has emerged as a significant VTE risk factor, with PE occurring in 2-4% of hospitalized patients and higher rates in those requiring critical care, mediated by endothelial dysfunction, platelet aggregation, and systemic inflammation characteristic of severe viral infections. Varicose veins create local stasis and endothelial injury, modestly increasing VTE risk.

Classic stem: a patient 3–10 days after orthopedic or abdominal surgery, on day 2 of a long-haul flight, a young woman on combined oral contraceptives who smokes, a peripartum woman, or a patient with known adenocarcinoma — who develops abrupt dyspnea and becomes tachycardic and tachypneic.

Distractor to avoid: a clear lung exam and a normal chest radiograph are typical of PE, not evidence against it.

Step 2 — D-dimer, only when pretest probability is low or intermediate: highly sensitive, poorly specific (elevated in sepsis, cancer, pregnancy, postoperative states, age). A normal quantitative D-dimer excludes PE in this group. Age-adjusted threshold (age × 10 ng/mL FEU in patients >50) improves specificity without losing sensitivity.

Supporting studies: ECG most often shows sinus tachycardia; S1Q3T3 and anterior T-wave inversion are classic but insensitive. ABG shows hypoxemia with respiratory alkalosis and widened A–a gradient. Echocardiography may show RV dilation with apical sparing (McConnell's sign). Chest x-ray is usually normal; Westermark sign and Hampton's hump are rare.

Step 4 — risk stratify: PESI or sPESI plus troponin and BNP separate low-risk (outpatient-eligible) from intermediate-risk PE.

First-line therapy — anticoagulation: start empirically when clinical suspicion is high and imaging will be delayed. Per the CHEST 2021 antithrombotic guideline and ASH 2020 VTE treatment guideline:

Duration: 3 months for provoked PE; extended/indefinite therapy for unprovoked PE, recurrent VTE, or active cancer.