Pulmonary Embolism and Infarction Pathology

Thromboembolism and Obstruction

• Venous thrombi, primarily from the deep veins of the leg (popliteal, femoral, and iliac veins), dislodge and travel through the right heart chambers into the pulmonary circulation
• The embolus lodges at branch points where vessel diameter decreases; larger emboli occlude the main pulmonary artery or saddle the bifurcation, while smaller emboli lodge in segmental or subsegmental vessels
• Mechanical obstruction increases pulmonary vascular resistance, precipitating acute right ventricular strain and elevation of pulmonary arterial pressure

Hemodynamic Consequences

• Acute elevation in afterload on an unprepared right ventricle leads to acute cor pulmonale (right heart failure); the right ventricle dilates acutely and may fail, resulting in decreased left ventricular preload and shock
• Loss of perfusion to ventilated lung units creates ventilation-perfusion (V/Q) mismatch, causing hypoxemia; regional atelectasis may develop
• Activation of tissue factor and release of serotonin and thromboxane A2 from platelets in the embolus promote further thrombosis and vasoconstriction, amplifying hemodynamic compromise
• Reflex bronchoconstriction and pulmonary edema may develop, exacerbating gas exchange impairment

Pulmonary Infarction (Hemorrhagic Consolidation)

• Infarction occurs only when the bronchial circulation is also compromised or when the patient has elevated pulmonary venous pressure (left heart failure, mitral stenosis), eliminating the protective dual blood supply
• Embolic occlusion combined with these conditions causes ischemic necrosis of alveolar epithelium and endothelium
• The infarcted lung tissue becomes hemorrhagic and edematous as microthrombi form in the capillary network and red blood cells extravasate; fibrin deposition and platelet aggregation occur within the necrotic zone
• Within 24–72 hours, neutrophilic infiltration begins at the margins, followed by macrophage infiltration and eventual fibroblast proliferation with organization and scarring over weeks to months
• The classic infarct lesion is pyramidal (wedge-shaped) with its apex at the hilum and base at the pleural surface, reflecting the segmental bronchopulmonary anatomy

Sources of Pulmonary Emboli

• Deep vein thrombosis (DVT) of the lower extremities — accounts for >95% of clinically significant PE; originates primarily from the popliteal, femoral, and iliac veins
• Right heart chamber thrombi — occur in patients with acute myocardial infarction, dilated cardiomyopathy, atrial fibrillation, or acute right ventricular infarction
• Paradoxical embolism — venous thrombi bypass the lungs through a patent foramen ovale (PFO) or other right-to-left shunt, lodging in systemic circulation (less common)
• Fat embolism — from long bone fractures or orthopedic surgery; lipid droplets occlude small pulmonary vessels
• Air embolism, septic emboli, tumor fragments, and amniotic fluid — less common sources in specific clinical contexts

Virchow's Triad: Risk Factors for Venous Thromboembolism

• Immobilization (prolonged bed rest, long flights, long car rides)
• Atrial fibrillation (impaired atrial contraction and irregular ventricular rate)
• Cardiac insufficiency and venous obstruction
• Pregnancy and the postpartum period (up to 6 weeks post-delivery)

• Trauma and surgery, particularly orthopedic procedures (hip/knee replacement, femur fracture)
• Indwelling central venous catheters
• Intravenous drug use
• Prior DVT or PE

• Inherited thrombophilias: Factor V Leiden (most common, ~5% population prevalence), prothrombin gene mutation (G20210A), antithrombin III deficiency, protein C/S deficiency
• Acquired hypercoagulable states: Malignancy (especially adenocarcinomas; hypercoagulability results from cancer cell procoagulant activity and tissue factor expression), antiphospholipid syndrome, estrogen-containing oral contraceptives and hormone replacement therapy, nephrotic syndrome (loss of protein C and S in urine)
• Acute infection, especially pneumonia and sepsis
• Disseminated intravascular coagulation (DIC)
• Polycythemia vera and other myeloproliferative disorders

Major Clinical Risk Groups

• Orthopedic and major surgical patients (especially hip/knee replacement, abdominal/pelvic cancer surgery)
• Acute medical illness (myocardial infarction, stroke, heart failure, pneumonia)
• Malignancy (adenocarcinoma of lung, pancreas, colon; ovarian and breast cancers; lymphoma)
• Immobilized patients (bed rest, paralysis)
• Pregnancy and puerperium

Cardinal Symptoms

• Sudden onset dyspnea — the most common symptom (>85% of patients); results from V/Q mismatch, hypoxemia, and reflex bronchoconstriction; severity correlates with size of embolus and cardiopulmonary reserve
• Pleuritic chest pain — sharp, lateralized pain exacerbated by breathing and coughing; occurs in ~50% of cases, particularly when peripheral/pleural infarction is present (pain results from pleural inflammation)
• Syncope or presyncope — indicates massive PE with acute hemodynamic collapse and cardiogenic shock; results from acute right heart failure and decreased left ventricular preload
• Hemoptysis — uncommon (occurs in only ~7% of PE); specifically suggests pulmonary infarction with erosion into a bronchus; bloody sputum is a late finding
• Nonspecific symptoms: Diaphoresis, anxiety, palpitations (from tachycardia and arrhythmias), sensation of impending doom

Physical Examination Findings

• Tachycardia (heart rate >100 bpm) — present in ~90% of hemodynamically significant PE; reflects sympathetic activation and attempt to maintain cardiac output
• Tachypnea (respiratory rate >20 breaths/min) — compensatory response to hypoxemia and hypocapnia
• Hypoxemia (SpO2 <90% on room air) — due to V/Q mismatch; normal A-a gradient does not exclude PE
• Hypotension — indicates massive PE with right heart failure; finding of shock (systolic BP <90 mmHg with signs of hypoperfusion) portends very high mortality
• Signs of right heart strain: Elevated jugular venous pressure (JVP), right ventricular heave (parasternal lift), loud P2 (pulmonary component of S2), right-sided S3 gallop, tricuspid regurgitation murmur (holosystolic at left lower sternal border, increases with inspiration—Carvallo sign)
• Unilateral leg swelling, erythema, warmth — suggests concurrent DVT (present in ~25% of PE patients)
• Pleural friction rub — scratching sound heard on auscultation; specific for pleural inflammation from pulmonary infarction
• Cyanosis — may be present in massive PE with severe hypoxemia and right-to-left shunting

Laboratory and Imaging Correlates

• Troponin elevation (cardiac troponin I or T) — indicates right myocardial injury from acute strain; prognostic indicator of more severe PE
• Elevated B-type natriuretic peptide (BNP) — reflects right ventricular stretch
• D-dimer elevation — highly sensitive but nonspecific marker of thrombin generation and fibrin degradation; normal D-dimer effectively excludes PE in low-risk patients (negative predictive value >99%)
• Arterial blood gas abnormalities: Hypoxemia (PaO2 <80 mmHg on room air), hypocapnia (PaCO2 <35 mmHg) from hyperventilation, respiratory alkalosis
• Elevated lactate — indicates tissue hypoxia and poor perfusion
• Chest radiograph findings: Often normal or nonspecific; may show Westermark sign (focal oligemia/hypoperfusion distal to massive PE), Hampton hump (wedge-shaped opacity representing pulmonary infarction, classically with pleural base), atelectasis, small pleural effusion, or elevated hemidiaphragm
• Electrocardiogram (ECG): Classically shows sinus tachycardia; massive PE may show S1Q3T3 pattern (though rare and nonspecific); right ventricular strain pattern with T-wave inversion in leads V1–V4; atrial fibrillation may develop
• Echocardiography: Demonstrates acute right ventricular dilation (RV/LV ratio >0.9) and right ventricular dysfunction (decreased RV ejection fraction, reduced tricuspid annular plane systolic excursion); may show McConnell's sign (RV free wall hypokinesis with apical RV sparing), elevated right atrial pressure; helps stratify severity
• CT pulmonary angiography (CTPA): Gold standard imaging; shows intraluminal filling defect in pulmonary arteries; allows assessment of clot burden and right heart strain
• Ventilation-perfusion (V/Q) imaging: Shows segmental or subsegmental perfusion defects without corresponding ventilation defects (ventilation-perfusion mismatch)
• Pulmonary angiography: Invasive gold standard; demonstrates intraluminal thrombus and vessel occlusion; rarely performed given availability of CTPA

Histological Findings

• Fibrin-platelet thrombus within pulmonary arteries, appearing as an organizing thrombus with lines of Zahn (alternating layers of platelets/fibrin and red blood cells, indicating ante-mortem formation)
• Vessel wall endothelial denudation and infiltration of neutrophils around the embolus
• Pulmonary infarction (when present): Coagulative necrosis of alveolar walls with preservation of lung architecture; extensive hemorrhage within alveoli; fibrin deposition in alveolar spaces; thrombosis of capillaries within and adjacent to the infarcted zone

• Granulation tissue at the margins of infarcted zones
• Macrophage infiltration within necrotic tissue
• Fibroblast proliferation and collagen deposition (evidence of healing)
• Hemosiderin-laden macrophages (iron-laden histiocytes from red blood cell degradation)
• Recanalization of thrombus with endothelial growth and reformation of vessel patency

Gross Pathology Appearance

• Pulmonary embolus: Dark red, rubbery thrombus that may extend into branches; if massive, creates a saddle embolus straddling the main pulmonary artery bifurcation
• Pulmonary infarction (when present): Wedge-shaped or pyramidal area of dark red consolidation with apex at the hilum and base at the pleural surface; the infarcted zone is firm, dark, and often hemorrhagic ("red infarct"); margins show transition from infarcted to normal lung; overlying pleura may show fibrinous exudation
• Acute pulmonary edema: Foamy, hemorrhagic fluid in airways
• Right ventricular dilation and hypertrophy in cases of massive PE or chronic recurrent thromboembolism

Laboratory Values

• D-dimer: Elevated (>500 ng/mL or >0.5 μg/mL fibrinogen equivalent units); highest sensitivity for PE exclusion
• Troponin I or T: Often elevated in moderate-to-massive PE (indicates RV injury)
• BNP or NT-proBNP: Elevated, correlating with RV strain
• Arterial blood gas: PaO2 often <80 mmHg on room air; PaCO2 typically low (respiratory alkalosis)
• Complete blood count: May show mild leukocytosis
• Prothrombin time (PT), partial thromboplastin time (PTT): Usually normal (unless underlying coagulation disorder)
• Thrombin time and fibrinogen: May be abnormal in cases of massive PE with DIC
• Lactate: Elevated in shock states

Diagnostic Criteria and Algorithms

• Clinical Probability Assessment (Wells Score or PERC Rule): Stratifies patients into low, intermediate, or high pretest probability categories
• D-dimer testing: In low-risk patients with low Wells score or PERC-negative, a normal D-dimer effectively excludes PE; elevated D-dimer requires imaging confirmation
• CTPA: Confirms diagnosis in suspected PE; shows intraluminal filling defect
• V/Q scan: Alternative imaging in patients with contrast allergy or renal insufficiency; high-probability scan (multiple segmental perfusion defects without corresponding ventilation defects) confirms PE
• Compression ultrasound of lower extremities: Identifies DVT source; if positive in symptomatic patient, confirms VTE diagnosis without need for CTPA
• Pulmonary angiography: Gold standard but reserved for cases with indeterminate imaging or hemodynamic instability requiring intervention
• Integrated Diagnostic Approach: Low clinical probability + normal D-dimer = PE excluded; Intermediate/high clinical probability or elevated D-dimer = proceed to CTPA or V/Q imaging

First-Line Anticoagulation

• Anticoagulation prevents thrombus propagation and embolization, allowing endogenous fibrinolysis and organization to proceed
• Does NOT dissolve existing thrombus but prevents expansion and new clot formation
• Allows time for fibrinolytic mechanisms to resolve clot and restore perfusion

• Unfractionated heparin (UFH): Bolus 80 units/kg IV, then continuous infusion 18 units/kg/hr; activated partial thromboplastin time (aPTT) target 1.5–2.5× control; advantages include rapid onset (minutes), short half-life (60–90 minutes), ability to reverse with protamine, and use in renal failure and potential procedures; preferred in massive PE, hemodynamic instability, renal insufficiency (creatinine clearance <30 mL/min), or pregnancy
• Low-molecular-weight heparin (LMWH): Enoxaparin 1 mg/kg SC every 12 hours or 1.5 mg/kg SC daily; predictable pharmacokinetics allow weight-based dosing without monitoring; contraindicated in severe renal failure (CrCl <30 mL/min); comparable efficacy to UFH in hemodynamically stable PE
• Fondaparinux: Selective Factor Xa inhibitor; weight-based SC dosing once daily; alternative for heparin-induced thromb

Emergencies (recognize immediately)

• Obstructive shock and cardiac arrest: massive clot burden raises RV afterload until the dilated RV fails, septum bows leftward, and LV preload collapses; signaled by hypotension, rising JVP with clear lungs, and arrest in pulseless electrical activity. Per the AHA/ACC and CHEST guidance on high-risk PE, systemic thrombolysis (e.g., alteplase) is indicated absent contraindication, with catheter-directed therapy or surgical embolectomy as alternatives.
• Major hemorrhage on anticoagulation or lysis: intracranial hemorrhage is the feared complication of thrombolysis; new headache, focal deficit, or altered mental status mandates stopping the drug and obtaining noncontrast head CT. Reversal is agent-specific — protamine for heparin, vitamin K plus 4-factor PCC for warfarin, idarucizumab for dabigatran, andexanet alfa for factor Xa inhibitors.
• Heparin-induced thrombocytopenia (type II): IgG against heparin–PF4 complexes activates platelets, producing a platelet drop (typically >50% from baseline) around days 5–10 with thrombosis, not bleeding. Stop all heparin and start a non-heparin anticoagulant (argatroban, bivalirudin, or fondaparinux); warfarin alone in acute HIT precipitates venous limb gangrene.

Subacute and chronic complications

• Pulmonary infarction sequelae: the hemorrhagic wedge may become secondarily infected, cavitate, or abscess (especially with septic emboli); persistent fever, purulent sputum, and an air–fluid level within the opacity are the clues. A small hemorrhagic exudative pleural effusion is common.
• Chronic thromboembolic pulmonary hypertension (CTEPH): failed thrombus resolution with fibrotic organization and vascular remodeling yields WHO Group 4 pulmonary hypertension — progressive exertional dyspnea months after PE with RV hypertrophy. The V/Q scan, not CTPA, is the screening test of choice; pulmonary thromboendarterectomy is potentially curative.
• Recurrent VTE: highest risk after unprovoked events or ongoing malignancy; CHEST guidelines favor extended anticoagulation when bleeding risk permits.
• Warfarin-induced skin necrosis: transient hypercoagulability from rapid protein C depletion in the first days; bridge with heparin.
• IVC filter complications: migration, perforation, and filter thrombosis with increased recurrent DVT; retrievable filters should be removed once anticoagulation is safe.
• Paradoxical embolism through a PFO causing stroke or limb ischemia.

• Lines of Zahn (alternating pale platelet/fibrin and red RBC layers) mean the thrombus formed antemortem in flowing blood — the classic distinguisher from the postmortem chicken-fat and currant-jelly clot found at autopsy.
• Red (hemorrhagic) infarct occurs in loose, dual–blood-supply organs: lung, small bowel, testis, and any reperfused tissue. The lung infarcts only when the bronchial supply or pulmonary venous drainage is already compromised — hence infarction complicates a minority of PEs and clusters in patients with left heart failure or mitral stenosis.
• Hampton hump = pleural-based, wedge-shaped opacity with apex toward the hilum (infarct); Westermark sign = focal oligemia distal to a large clot. Both are specific but insensitive; the chest film is most often normal.
• Single best next step depends on stability: unstable patient → bedside echocardiography looking for RV dilation and McConnell sign, then empiric anticoagulation and thrombolysis rather than a trip to CT. Stable patient → Wells/PERC risk stratification, D-dimer if low risk, CTPA if elevated or if pretest probability is high (never delay anticoagulation for imaging in high probability).
• The association examiners love: PE in a patient with adenocarcinoma (Trousseau migratory thrombophlebitis), and Factor V Leiden as the most common inherited thrombophilia — activated protein C cannot cleave factor Va.
• Common distractor 1 — the ECG: S1Q3T3 is the famous pattern but sinus tachycardia is the most common finding; do not pick S1Q3T3 as the expected tracing.
• Common distractor 2 — fat embolism: 24–72 hours after a long-bone fracture with the triad of hypoxemia, neurologic change, and a petechial rash; anticoagulation is not the answer there.
• Pregnancy: ACOG supports imaging when PE is suspected; LMWH is the anticoagulant of choice — warfarin and DOACs are avoided.