Pulmonary Embolism

1. Topic Overview

Summary

Pulmonary embolism (PE) is the obstruction of pulmonary arteries by thrombus, most commonly arising from deep vein thrombosis (DVT) of the lower limbs. PE is the third most common acute cardiovascular syndrome after myocardial infarction and stroke, with an annual incidence of 39-115 per 100,000 population in Europe. [1] Clinical presentation varies from asymptomatic subsegmental PE to massive PE with haemodynamic collapse and cardiac arrest. Diagnosis relies on structured clinical pre-test probability assessment using validated scores (Wells, Geneva), D-dimer testing in low-probability cases, and CT pulmonary angiography (CTPA) as the definitive imaging modality. Risk stratification using clinical parameters, imaging findings (RV dysfunction), and biomarkers (troponin, BNP) determines treatment intensity — ranging from outpatient anticoagulation for low-risk PE to systemic thrombolysis or catheter-directed interventions for high-risk massive PE. Direct oral anticoagulants (DOACs) have superseded vitamin K antagonists as first-line therapy for most patients without contraindications. [2,3]

Key Facts

• Definition: Obstruction of one or more pulmonary arteries by thrombus
• Incidence: 39-115 per 100,000 per year; 1-2 per 1,000 in general population [1]
• Source: > 90% arise from lower limb DVT; 10% from pelvic, upper limb, or right heart thrombi [4]
• Mortality: 30-day mortality ranges from less than 1% (low risk) to 25-65% (massive PE with shock) [1]
• Diagnosis: Wells score → D-dimer (if PE unlikely) → CTPA (if PE likely or D-dimer positive)
• Risk Stratification: ESC 2019 four-tier system: High/Intermediate-high/Intermediate-low/Low [1]
• Treatment: DOAC first-line; thrombolysis for haemodynamic instability; IVC filter if anticoagulation contraindicated
• Duration: Minimum 3 months; indefinite if unprovoked or recurrent
• Complication: CTEPH develops in 2-4% of PE survivors within 2 years [5]

Clinical Pearls

"Think PE in Unexplained Dyspnoea": PE can present with isolated dyspnoea, pleuritic chest pain, syncope, or even just tachycardia. The classic triad of dyspnoea, chest pain, and haemoptysis occurs in less than 20% of cases. [6] Maintain a high index of suspicion.

"Wells Score Drives the Pathway": If Wells score indicates PE unlikely (less than 4 points in dichotomised model or ≤4 points in three-level model), D-dimer can safely rule out PE with negative predictive value > 99%. [7] If PE likely (≥4 points), proceed directly to CTPA without D-dimer.

"Age-Adjusted D-Dimer Increases Specificity": In patients > 50 years, use age-adjusted D-dimer threshold (age × 10 μg/L) to reduce false positives and unnecessary imaging by 30-35%. [8]

"Risk Stratification is Key to Treatment Intensity": Not all PEs are equal. Massive PE with shock needs urgent reperfusion (thrombolysis or embolectomy); low-risk PE (sPESI=0) can be treated at home. [1,9] Intermediate-risk requires careful monitoring and individualised therapy.

"DOAC Over Warfarin for Most Patients": Rivaroxaban and apixaban are non-inferior to LMWH/warfarin with similar or lower bleeding risk and no need for monitoring. [2,3] They are now first-line for haemodynamically stable PE.

Why This Matters Clinically

PE is common, potentially fatal, and frequently missed. Untreated PE carries 30% mortality, while appropriately treated PE has 2-8% mortality. [10] Timely diagnosis using validated pathways prevents unnecessary imaging (false positives) and avoids missed diagnoses (false negatives). Risk stratification guides setting of care (outpatient vs ICU), intensity of monitoring, and need for reperfusion therapy. With modern anticoagulants and evidence-based protocols, most patients with PE can be safely managed with excellent outcomes.

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2. Epidemiology

Incidence & Prevalence

Demographics

Risk Factors (Virchow's Triad)

PE pathogenesis follows Virchow's triad of venous thrombosis:

Provoking Factors

Major Provoking Factors (High Risk):

• Major surgery (especially orthopaedic, pelvic, neurosurgery) [13]
• Major trauma, lower limb fractures
• Hospitalisation for acute illness > 3 days
• Spinal cord injury, stroke with paralysis
• Active cancer (chemotherapy increases risk 6-fold) [14]

Minor Provoking Factors (Moderate Risk):

• Minor surgery (less than 30 min)
• Long-haul travel (> 4 hours, especially > 8 hours)
• Combined oral contraceptive pill, HRT (3-4 fold increased risk) [15]
• Pregnancy and postpartum period (6-week postpartum highest risk)
• Minor lower limb injury with reduced mobility

Unprovoked (No Identifiable Risk Factor):

• 40-50% of PE cases occur without clear provocation [12]
• Higher risk of recurrence (10% at 1 year; 30% at 10 years)

Thrombophilia (Inherited & Acquired)

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3. Pathophysiology

Mechanism: From DVT to PE

Step 1: Thrombus Formation in Deep Veins

• DVT most commonly forms in deep veins of calf (soleal, gastrocnemius) or proximal leg (popliteal, femoral, iliac)
• Follows Virchow's triad: stasis + endothelial injury + hypercoagulability
• Thrombus composition: fibrin mesh with trapped red cells, platelets, and leukocytes

Step 2: Embolisation

• Thrombus (or fragment) dislodges from vessel wall
• Travels via inferior vena cava → right atrium → right ventricle → pulmonary artery
• Lodges at branch point proportional to clot size

Step 3: Pulmonary Artery Obstruction

• Partial or complete occlusion of segmental, lobar, or main pulmonary arteries
• Acute increase in pulmonary vascular resistance (PVR)
• Extent of obstruction determines haemodynamic impact

Step 4: Haemodynamic Consequences

• RV Pressure Overload: Sudden increase in afterload due to increased PVR
• RV Dilatation: Acute RV strain; RV:LV ratio > 1.0 on CT indicates dysfunction [1]
• RV Failure: Reduced RV output → underfilling of left ventricle
• Reduced Cardiac Output: LV preload dependent on RV function
• Hypotension & Shock: Systolic BP less than 90 mmHg or drop > 40 mmHg from baseline
• Cardiogenic Shock: In massive PE, circulatory collapse and cardiac arrest (PEA common)

Step 5: Gas Exchange Impairment

• V/Q Mismatch: Ventilated alveoli without perfusion → increased dead space
• Hypoxemia: Shunt through unoccluded areas with low V/Q
• Reflex Bronchoconstriction: Humoral mediators (serotonin, thromboxane) released from clot
• Alveolar Hypoventilation: Pain, anxiety, splinting
• Type 1 Respiratory Failure: Hypoxia with hypocapnia (hyperventilation)
• Increased A-a Gradient: Classic finding on ABG

Step 6: Neurohumoral Activation

• Release of vasoconstrictors (endothelin, serotonin)
• Inflammatory mediators
• Contributes to pulmonary hypertension

Severity Spectrum

Molecular Pathophysiology

Exam Detail: Coagulation Cascade Activation:

• Tissue factor (TF) exposure from endothelial injury or cancer procoagulant
• TF binds Factor VIIa → activates Factor X → Factor Xa
• Factor Xa + Factor Va → prothrombinase complex
• Prothrombin → Thrombin (Factor IIa)
• Thrombin cleaves fibrinogen → fibrin polymerisation
• Factor XIIIa cross-links fibrin → stable clot

Endogenous Anticoagulants:

• Protein C/S System: Activated Protein C (APC) inactivates Factors Va and VIIIa. Factor V Leiden mutation renders Factor Va resistant to APC.
• Antithrombin: Inhibits thrombin and Factor Xa; heparin enhances this 1000-fold
• Tissue Factor Pathway Inhibitor (TFPI): Inhibits TF-VIIa complex

Fibrinolysis:

• Plasminogen → Plasmin (via tPA, urokinase)
• Plasmin degrades fibrin → D-dimer fragments (elevated in acute VTE)

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4. Clinical Presentation

Symptoms

Most Common:

• Dyspnoea (80%): Sudden onset; most common presenting symptom [6]
• Pleuritic Chest Pain (40-50%): Sharp, worse with inspiration; suggests peripheral PE with pleural irritation
• Cough (20-30%)

Important:

• Haemoptysis (10-20%): Small volume; suggests pulmonary infarction
• Syncope (10-15%): Suggests massive PE with transient low cardiac output
• Palpitations (10%): Due to sinus tachycardia or arrhythmia

Less Common:

• Unilateral leg pain/swelling (concurrent symptomatic DVT in 30-40%)
• Substernal chest pain (can mimic ACS)
• Anxiety, feeling of impending doom

Note: Up to 25% of patients may be asymptomatic or have only vague symptoms. [6]

Signs

General:

• Tachycardia (> 100 bpm): Most common sign; present in 40% [6]
• Tachypnoea (> 20/min): 70%
• Fever (usually low-grade, less than 38.5°C)
• Diaphoresis, pallor

Cardiovascular:

• Hypotension (SBP less than 90 mmHg): Massive PE
• Elevated JVP: RV failure
• RV Heave (left parasternal): RV strain
• Loud P2 (accentuated pulmonary component of S2): Pulmonary hypertension
• Tricuspid regurgitation murmur: RV dilatation
• S3 or S4 gallop: RV failure

Respiratory:

• Hypoxia (SpO2 less than 90% on air): 40-50%
• Cyanosis: Severe cases
• Pleural Rub: Pulmonary infarction with pleural involvement
• Reduced Breath Sounds: Pleural effusion (20%)
• Crackles: Pulmonary oedema or infarction

Legs:

• Unilateral Leg Swelling: DVT (calf circumference difference > 2cm)
• Calf/Thigh Tenderness: Homan's sign (unreliable; no longer recommended)
• Warmth, Erythema, Palpable Cord

Red Flags (High-Risk/Massive PE Features)

[!CAUTION] Immediate Life-Threatening Indicators:

• Haemodynamic Instability: SBP less than 90 mmHg for > 15 minutes OR need for vasopressors
• Cardiac Arrest: Often presents as PEA (pulseless electrical activity)
• Syncope: Transient loss of consciousness
• Severe Hypoxia: SpO2 less than 90% despite oxygen
• RV Dysfunction on Echo + Elevated Troponin: Intermediate-high risk
• Altered Mental Status: Confusion, agitation (cerebral hypoperfusion)

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5. Differential Diagnosis

Always consider PE in the differential of:

Chest Pain Differentials

Dyspnoea Differentials

Syncope Differentials

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6. Investigations

Diagnostic Pathway

Structured Approach:

1. Clinical Pre-Test Probability (Wells Score or Geneva Score)
2. D-Dimer (if PE unlikely)
3. CTPA (if PE likely or D-dimer positive)

First-Line Investigations

Wells Score for PE (Clinical Prediction Rule)

Interpretation:

• Dichotomised Model:
  • "PE Unlikely: less than 4 points → Proceed to D-dimer"
  • "PE Likely: ≥4 points → Proceed to CTPA"
• Three-Level Model:
  • "Low: ≤4 points"
  • "Moderate: 4.5-6 points"
  • "High: > 6 points"

Validation: Negative predictive value 99.5% when score less than 4 and D-dimer negative. [7]

Revised Geneva Score (Alternative)

Interpretation:

• 0-3: Low probability (8% prevalence)
• 4-10: Intermediate probability (28%)
• ≥11: High probability (74%)

D-Dimer

Indications:

• Use ONLY in patients with low clinical probability (Wells less than 4 or Geneva low)

Threshold:

• Standard: less than 500 μg/L (negative excludes PE)
• Age-Adjusted (> 50 years): Age × 10 μg/L [8]
  • "Example: 65-year-old → threshold 650 μg/L"
  • Increases specificity by 30-35% without loss of sensitivity

Interpretation:

• Negative D-dimer + Low Probability: PE ruled out; no further imaging needed
• Positive D-dimer: Proceed to CTPA

Limitations:

• High sensitivity (95-98%) but low specificity (40%)
• False positives: Infection, inflammation, malignancy, pregnancy, post-op, elderly, hospitalised patients
• False negatives: Small/subsegmental PE, symptoms > 1 week old

Assays:

• High-sensitivity assays preferred (ELISA, latex agglutination)

CT Pulmonary Angiography (CTPA)

Gold Standard Diagnostic Test

Findings:

• Positive: Intraluminal filling defect in pulmonary artery
• Negative: Complete opacification of pulmonary vessels
• Additional: RV:LV diameter ratio > 1.0 (RV dysfunction), reflux of contrast into IVC (RV failure)

Sensitivity/Specificity:

• Sensitivity: 83-100% for lobar/segmental PE; lower for subsegmental [16]
• Specificity: 89-96%

Advantages:

• Non-invasive, rapid, widely available
• Detects alternative diagnoses (pneumonia, aortic dissection, malignancy)

Disadvantages:

• Radiation exposure (10-20 mSv)
• Contrast nephropathy risk
• Contrast allergy
• Not suitable in pregnancy (prefer V/Q scan)

Indications:

• PE likely (Wells ≥4)
• PE unlikely but positive D-dimer
• Suspected massive PE (unstable patients may need bedside echo first)

Ventilation/Perfusion (V/Q) Scan

Indications:

• Pregnancy (lower radiation to fetus than CTPA)
• Severe contrast allergy
• Renal impairment (eGFR less than 30)

Interpretation (PIOPED II Criteria):

• Normal: PE excluded
• Low Probability: PE unlikely
• Intermediate/Indeterminate: Non-diagnostic; consider CTPA or further testing
• High Probability: PE confirmed

Sensitivity/Specificity:

• Sensitivity: 85-90%
• Specificity: 93-95%

Note: Non-diagnostic (indeterminate) results in 30-40% of cases.

Supportive Investigations

ECG

Classic Findings (20-30% of cases):

• S1Q3T3 Pattern: Deep S wave in I, Q wave and T inversion in III (classic but rare; 12-20%)
• Sinus Tachycardia: Most common (40%)
• T-wave Inversion: Leads V1-V4 (anterior precordial strain)
• Right Bundle Branch Block (RBBB): Complete or incomplete
• Right Axis Deviation
• P Pulmonale: Peaked P waves in II, III, aVF (RA enlargement)
• Atrial Fibrillation: 10-15%

Note: Normal ECG in 20-30% of PE cases. ECG findings are supportive, not diagnostic.

Chest X-Ray (CXR)

Classic Findings (Rare):

• Westermark Sign: Oligaemia (decreased vascularity) distal to PE
• Hampton's Hump: Peripheral wedge-shaped opacity (pulmonary infarction)
• Fleischner Sign: Enlarged proximal pulmonary artery

Common Findings (Non-specific):

• Normal CXR in 30%
• Small pleural effusion (20%)
• Atelectasis
• Elevated hemidiaphragm

Purpose: Exclude alternative diagnoses (pneumothorax, pneumonia, heart failure)

Arterial Blood Gas (ABG)

Typical Findings:

• Hypoxia: PaO2 less than 80 mmHg (type 1 respiratory failure)
• Hypocapnia: PaCO2 less than 35 mmHg (hyperventilation)
• Respiratory Alkalosis: pH > 7.45
• Increased A-a Gradient: (150 - PaO2 - PaCO2) at FiO2 0.21 > 20 mmHg

Note: Normal ABG does not exclude PE (10-20% of PE patients have normal oxygenation).

Echocardiography (Transthoracic)

Indications:

• Risk stratification (RV dysfunction assessment)
• Bedside assessment in haemodynamically unstable patients
• Follow-up for CTEPH screening

Findings in Acute PE:

• RV Dilatation: RV:LV ratio > 0.9 (4-chamber view) or > 0.6 (parasternal short axis)
• RV Hypokinesis: Reduced RV free wall motion
• McConnell's Sign: RV free wall hypokinesis with preserved apical motion (specific for acute PE; 77% specificity) [17]
• Interventricular Septum Flattening: D-sign on short axis (paradoxical septal motion)
• Tricuspid Regurgitation: Due to annular dilatation
• Elevated TR Velocity: Estimated RV systolic pressure (TR jet velocity > 2.8 m/s suggests PASP > 40 mmHg)
• IVC Dilatation: > 2.1 cm with reduced collapsibility

Sensitivity/Specificity for PE Diagnosis:

• Sensitivity: 50-60% (low; not diagnostic)
• Specificity: 80-90%

Purpose: Prognostic marker; RV dysfunction predicts higher mortality.

Biomarkers (Risk Stratification)

Elevated troponin or BNP + RV dysfunction = Intermediate-High Risk PE (ESC 2019 classification) [1]

Lower Limb Venous Doppler Ultrasound

Indications:

• If CTPA unavailable or contraindicated
• Suspected concurrent DVT

Findings:

• Non-compressible vein
• Visible thrombus
• Absent flow on Doppler

Note: Positive DVT USS in setting of suspected PE is sufficient to start anticoagulation; negative USS does not exclude PE (DVT may have completely embolised).

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7. Risk Stratification

ESC 2019 Four-Tier Classification [1]

Simplified Pulmonary Embolism Severity Index (sPESI)

Interpretation:

• sPESI = 0: Low risk; suitable for outpatient management (if Hestia criteria met)
• sPESI ≥1: Higher risk; consider admission

Validation: 30-day mortality less than 1% if sPESI=0. [9]

Original PESI (Pulmonary Embolism Severity Index)

More complex 11-item score; sPESI has equivalent prognostic accuracy with simpler application.

Hestia Criteria (Outpatient Suitability)

All must be NO for home treatment:

1. Is patient haemodynamically unstable?
2. Is thrombolysis or embolectomy necessary?
3. Active bleeding or high bleeding risk?

4. 24 hours supplemental oxygen required?

5. PE diagnosed during anticoagulant treatment?
6. Severe pain needing IV analgesia > 24 hours?
7. Medical or social reason for hospital admission > 24 hours?
8. CrCl less than 30 mL/min?
9. Severe liver impairment?
10. Pregnancy?
11. Documented history of HIT?

If all NO → Low-risk PE suitable for outpatient DOAC therapy.

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8. Management

Initial Resuscitation (All Patients)

• Oxygen: Target SpO2 94-98% (88-92% if COPD)
• IV Access: Two large-bore cannulae
• Monitoring: Continuous ECG, BP, SpO2
• Analgesia: For pleuritic pain

Anticoagulation (Cornerstone of Treatment)

Immediate Anticoagulation (Before Imaging Confirmation)

If high clinical probability (Wells ≥4) or awaiting CTPA, start anticoagulation immediately unless high bleeding risk. [1]

Options:

• Subcutaneous LMWH (e.g., Enoxaparin 1.5 mg/kg OD or 1 mg/kg BD)
• Subcutaneous Fondaparinux (weight-based dosing)
• IV Unfractionated Heparin (UFH): Bolus 80 units/kg, then infusion 18 units/kg/h (if severe renal impairment or high bleeding risk requiring rapid reversal)

Definitive Anticoagulation: DOACs First-Line

First-Line: Direct Oral Anticoagulants (DOACs) [2,3,19,20]

Advantages of DOACs:

• No need for monitoring (INR)
• Fewer drug/food interactions
• Rapid onset
• Similar efficacy to warfarin
• Lower or similar major bleeding risk
• Lower intracranial haemorrhage risk

Disadvantages:

• Cost (though generic rivaroxaban available)
• Requires dose adjustment in renal impairment
• Contraindicated in severe renal impairment (CrCl less than 15-30 depending on agent)
• Limited reversal agents (idarucizumab for dabigatran; andexanet alfa for Factor Xa inhibitors)

Second-Line: Vitamin K Antagonist (Warfarin)

Indications for Warfarin over DOAC:

• Antiphospholipid syndrome (DOACs contraindicated; warfarin superior) [1]
• Severe renal impairment (CrCl less than 30)
• Mechanical heart valves
• Patient preference or cost constraints

Regimen:

• Start warfarin with LMWH or UFH bridging (minimum 5 days overlap)
• Target INR 2.5 (range 2.0-3.0)
• Continue LMWH until INR therapeutic for 2 consecutive days

Third-Line: LMWH (Cancer-Associated VTE)

LMWH preferred in active cancer (superior to warfarin in cancer patients). [21]

• Enoxaparin 1.5 mg/kg OD or Dalteparin 200 units/kg OD for 1 month, then 150 units/kg OD
• Alternative: Edoxaban or Rivaroxaban (non-inferior to LMWH in SELECT-D and Hokusai-VTE Cancer trials)

Duration of Anticoagulation

Decision Tools for Extended Therapy:

• Assess bleeding risk (HAS-BLED, RIETE score)
• Reassess at 3 months; consider extended if low bleeding risk and high recurrence risk
• D-dimer at 1 month post-anticoagulation cessation: Elevated predicts recurrence; consider resuming therapy

Reperfusion Therapy (High-Risk Massive PE)

Systemic Thrombolysis

Indications: [1]

• Haemodynamic Instability (SBP less than 90 mmHg for > 15 min OR need for vasopressors)
• Cardiac Arrest due to PE

Regimen:

• Alteplase (tPA): 100 mg IV over 2 hours OR accelerated 0.6 mg/kg (max 50 mg) over 15 minutes
• Tenecteplase: 30-50 mg IV bolus (weight-based; simpler dosing)
• Alternative: Streptokinase 250,000 units IV over 30 min, then 100,000 units/h for 12-24h

Outcomes:

• Reduces mortality in high-risk PE (NNT ~6 to prevent death) [1]
• Rapid improvement in haemodynamics within hours

Contraindications (Absolute):

• Active bleeding
• Recent intracranial haemorrhage (less than 3 months)
• Ischaemic stroke less than 3 months
• Intracranial neoplasm or AVM
• Recent major surgery or trauma (less than 2 weeks)

Contraindications (Relative):

• Age > 75 years
• Current anticoagulation
• Recent GI bleed (less than 3 months)
• Thrombocytopaenia (less than 100,000)

Complications:

• Major bleeding: 10-20% (PEITHO trial: 11.5% major extracranial bleeding) [22]
• Intracranial haemorrhage: 1-3%

Do NOT Use Thrombolysis in Intermediate-Risk PE (normotensive with RV dysfunction): PEITHO trial showed no mortality benefit; increased bleeding. [22] Reserve for high-risk only or clinical deterioration.

Catheter-Directed Thrombolysis (CDT)

Indications:

• High-risk PE with contraindication to systemic thrombolysis
• Intermediate-high risk PE with clinical deterioration (bridge between anticoagulation and systemic lysis)

Advantages:

• Lower thrombolytic dose (reduced bleeding risk)
• Faster clot resolution

Evidence: Limited RCTs; expert consensus supports use in selected cases.

Surgical Embolectomy

Indications:

• High-risk PE with failed thrombolysis
• Absolute contraindication to thrombolysis
• Free-floating RV/RA thrombus

Mortality: 6-30% (operator/centre dependent)

Availability: Limited to specialist cardiothoracic centres

VA-ECMO

Indications:

• Cardiac arrest refractory to CPR
• Bridge to surgical embolectomy

Role: Temporary cardiopulmonary support while definitive therapy arranged.

Low-Risk PE: Outpatient Management

Criteria (All Required):

• sPESI = 0
• Hestia criteria all negative
• Normal BP and HR
• SpO2 > 90% on air
• No significant comorbidities
• Reliable patient with good social support
• Easy access to follow-up (48-72 hours)

Protocol:

• Start DOAC (rivaroxaban or apixaban preferred; no lead-in required)
• Safety-net advice (return immediately if worsening symptoms)
• Outpatient review at 48-72 hours and 1 week
• VTE clinic follow-up at 3 months

Evidence: PEITHO, HOME-PE, and Hestia studies validated safety of outpatient PE treatment in selected low-risk patients. [9]

Special Populations

Pregnancy

Diagnostic Pathway:

• Leg USS first (if positive, start treatment; if negative, proceed to imaging)
• V/Q Scan preferred over CTPA (lower fetal radiation: 0.1-0.5 mGy vs 0.01-0.66 mGy)
• If V/Q indeterminate, proceed to CTPA

Treatment:

• LMWH throughout pregnancy and ≥6 weeks postpartum (minimum 3 months total) [1]
  • Enoxaparin 1 mg/kg BD (weight-based; check anti-Xa levels)
• DOACs contraindicated (teratogenic)
• Warfarin contraindicated in first trimester (teratogenic); may use in 2nd/3rd trimester if essential

Delivery Planning:

• Stop LMWH 24 hours before planned delivery
• Restart 6-12 hours post-delivery (vaginal) or 12-24 hours (Caesarean)

Cancer-Associated Thrombosis (CAT)

First-Line:

• LMWH (Dalteparin, Enoxaparin) for ≥6 months [21]
• Alternative: Edoxaban or Rivaroxaban (non-inferior in SELECT-D, Hokusai-VTE Cancer trials)

Avoid Apixaban/Dabigatran: Limited data in cancer

Duration: Continue indefinitely while cancer active or on chemotherapy

Renal Impairment

Chronic Liver Disease

• Avoid DOACs in Child-Pugh B/C
• Use UFH or LMWH with caution

IVC Filter

Indications:

• Absolute Contraindication to Anticoagulation with acute PE/DVT (active bleeding, recent neurosurgery)
• Recurrent VTE despite Adequate Anticoagulation (rare)
• Free-Floating IVC/Iliofemoral Thrombus (controversial)

Type:

• Retrievable Filters preferred (retrieve within 3 months when anticoagulation safe)
• Permanent Filters: Only if contraindication permanent

Complications:

• Filter thrombosis, migration, IVC perforation, recurrent VTE (20-30% long-term)

Note: IVC filters do NOT reduce mortality; use sparingly. [1]

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9. Complications

Acute Complications

Chronic Complications

Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

Incidence: 2-4% of PE survivors at 2 years post-PE [5]

Pathophysiology:

• Incomplete thrombus resolution
• Fibrotic organisation of clot
• Pulmonary vascular remodelling
• Progressive pulmonary hypertension (mPAP ≥25 mmHg)

Symptoms:

• Progressive dyspnoea on exertion
• Exercise intolerance, fatigue
• Syncope (advanced disease)

Diagnosis:

• Echocardiography: Elevated PASP, RV dilatation
• V/Q Scan: Mismatched perfusion defects (more sensitive than CTPA for chronic PE)
• Right Heart Catheterisation: Confirms pulmonary hypertension; mPAP ≥20 mmHg (ESC 2022 definition)
• CTPA: Organised thrombus, web/band patterns

Management:

• Pulmonary Endarterectomy (PEA): Curative in operable CTEPH; mortality 2-5% in expert centres
• Balloon Pulmonary Angioplasty (BPA): For distal/inoperable disease
• Medical Therapy: Riociguat (sGC stimulator) if inoperable or residual PH post-PEA [5]
• Anticoagulation: Lifelong

Screening: ESC recommends screening echo at 3-6 months post-PE if persistent dyspnoea or risk factors. [1]

Post-PE Syndrome

Incidence: 50% of PE survivors

Features:

• Persistent dyspnoea without CTEPH
• Exercise intolerance
• Reduced quality of life
• No clear pulmonary hypertension

Management: Pulmonary rehabilitation, exercise training

Recurrent VTE

Risk:

• 10% at 1 year after unprovoked PE (off anticoagulation)
• 30% at 10 years [12]
• Higher if: unprovoked, age > 65, male sex, elevated D-dimer post-treatment

Prevention: Extended anticoagulation if unprovoked or recurrent

Anticoagulation-Related Complications

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10. Prognosis & Outcomes

Mortality

Prognostic Factors (Adverse)

Clinical:

• Haemodynamic instability (SBP less than 90 mmHg)
• Syncope
• Age > 70 years
• Comorbidities (heart failure, COPD, CKD)

Imaging:

• RV dysfunction (RV:LV > 1.0 on CT/echo)
• Bilateral PE or proximal thrombus burden
• Deep vein thrombosis concurrent

Biomarkers:

• Elevated troponin (myocardial injury)
• Elevated BNP/NT-proBNP (RV strain)
• Elevated lactate (tissue hypoperfusion)

Comorbidities:

• Active cancer: 3-fold increased mortality
• Chronic kidney disease

Long-Term Outcomes (Survivors)

• Complete Recovery: 60-70%
• Post-PE Syndrome: 30-50% (persistent symptoms without CTEPH)
• CTEPH: 2-4% at 2 years [5]
• Recurrent VTE: 30% at 10 years if unprovoked [12]
• Quality of Life: Reduced in 40% at 1 year post-PE

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11. Prevention

Primary Prevention (VTE Prophylaxis)

Hospitalised Medical Patients:

• Risk assessment tool (Padua Prediction Score or Caprini Score)
• Pharmacological: LMWH (Enoxaparin 40 mg OD) or Fondaparinux (2.5 mg OD) if high risk and low bleeding risk
• Mechanical: Graduated compression stockings, intermittent pneumatic compression if bleeding risk

Surgical Patients:

• Low Risk (minor surgery, mobile): Early mobilisation
• Moderate Risk (major surgery): LMWH or mechanical prophylaxis
• High Risk (orthopaedic, cancer surgery): LMWH + mechanical; extended prophylaxis (4-5 weeks post-op for hip/knee replacement)

Orthopaedic Surgery:

• LMWH, Fondaparinux, or DOAC (Rivaroxaban, Apixaban) for 10-35 days depending on procedure [1]

Secondary Prevention (After PE)

• Appropriate Duration of Anticoagulation (see above)
• Lifestyle Modifications: Weight loss, smoking cessation, mobility
• Avoid Oestrogen-Containing Contraceptives if unprovoked VTE
• Compression Stockings: Controversial; may reduce post-thrombotic syndrome in DVT but no proven benefit in PE

Traveller's Thrombosis Prevention

• Low Risk: Aisle seat, regular mobilisation, hydration
• High Risk (prior VTE, thrombophilia, recent surgery): Prophylactic LMWH for flights > 6-8 hours

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12. Evidence & Guidelines

Key Guidelines

1. ESC Guidelines on Acute Pulmonary Embolism (2019) [1]

• Gold standard for PE diagnosis, risk stratification, and management
• Introduces four-tier risk classification
• Recommends DOACs first-line
• Thrombolysis only for high-risk (haemodynamically unstable) PE

2. NICE NG158: Venous Thromboembolic Diseases (2020)

• UK guideline for VTE diagnosis and management
• Recommends Wells score + D-dimer/CTPA pathway
• DOACs first-line for most patients

3. CHEST Guideline: Antithrombotic Therapy for VTE (2021)

• Evidence-based recommendations for anticoagulation duration and choice
• Recommends DOACs over warfarin (Grade 2B)

4. American Heart Association (AHA) Scientific Statement on PE (2011)

• Comprehensive review of PE pathophysiology and management

Landmark Trials

EINSTEIN-PE (2012) [2]

• Design: RCT, n=4,832, rivaroxaban vs enoxaparin/warfarin
• Finding: Rivaroxaban non-inferior for efficacy (recurrent VTE 2.1% vs 1.8%; HR 1.12, 95% CI 0.75-1.68); similar bleeding
• Impact: Established rivaroxaban as first oral DOAC for PE without lead-in LMWH

AMPLIFY (2013) [3]

• Design: RCT, n=5,395, apixaban vs enoxaparin/warfarin
• Finding: Apixaban non-inferior for efficacy (recurrent VTE 2.3% vs 2.7%; RR 0.84, 95% CI 0.60-1.18); significantly less major bleeding (0.6% vs 1.8%; RR 0.31, 95% CI 0.17-0.55)
• Impact: Demonstrated superior safety profile for apixaban; now widely used first-line DOAC

PEITHO (2014) [22]

• Design: RCT, n=1,006, tenecteplase vs placebo in intermediate-risk PE (normotensive + RV dysfunction/biomarker elevation)
• Finding: Tenecteplase reduced haemodynamic decompensation (1.6% vs 5.0%; OR 0.30, p=0.002) but increased major bleeding (11.5% vs 2.4%; pless than 0.001) and stroke (2.4% vs 0.2%; p=0.003). No mortality benefit (7-day mortality 1.2% vs 1.8%; p=0.42).
• Impact: Thrombolysis NOT recommended in intermediate-risk PE; reserve for high-risk (haemodynamically unstable) only

Hokusai-VTE (2013) [19]

• Design: RCT, n=8,292, edoxaban (after 5-10 day LMWH) vs warfarin
• Finding: Edoxaban non-inferior for efficacy; less major bleeding (1.4% vs 1.6%; HR 0.84, 95% CI 0.59-1.21)
• Impact: Established edoxaban for VTE (requires LMWH lead-in)

RE-COVER (2009) [20]

• Design: RCT, n=2,564, dabigatran (after 5-10 day LMWH) vs warfarin
• Finding: Dabigatran non-inferior for efficacy; similar bleeding
• Impact: Established dabigatran for VTE (requires LMWH lead-in)

ADJUST Trial (Age-Adjusted D-Dimer) [8]

• Finding: Age-adjusted D-dimer cut-off (age × 10 μg/L for patients > 50 years) increased specificity from 63% to 96% without loss of sensitivity; reduced unnecessary CTPA by 30%
• Impact: Widely adopted age-adjusted D-dimer thresholds

Evidence Summary Table

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13. Exam-Focused Scenarios

Common Exam Questions (MRCP, FRACP, USMLE)

1. "A 45-year-old woman presents 5 days post-total knee replacement with sudden dyspnoea. Wells score 5 points. What is your next investigation?"

Model Answer: Wells score 5 indicates PE likely (≥4 points). I would proceed directly to CTPA without D-dimer, as D-dimer is only useful in low-probability cases. I would start therapeutic anticoagulation (LMWH or DOAC) immediately while arranging imaging, provided no contraindication to anticoagulation.

2. "A 30-year-old man presents with pleuritic chest pain and dyspnoea. No risk factors. Wells score 2. D-dimer 450 μg/L (normal less than 500). What next?"

Model Answer: Wells score 2 indicates PE unlikely (less than 4 points). D-dimer is negative at 450 μg/L. This combination has a negative predictive value > 99% for PE. PE excluded; no further imaging required. I would consider alternative diagnoses (pneumonia, pleuritis, musculoskeletal pain).

3. "A 72-year-old woman with breast cancer presents with PE confirmed on CTPA. She is normotensive (BP 130/80), HR 105, SpO2 94% on air. Echo shows RV:LV ratio 1.2. Troponin 80 ng/L (raised). How do you classify risk and manage?"

Model Answer: This is intermediate-high risk PE by ESC 2019 criteria (normotensive + RV dysfunction on echo + elevated troponin). sPESI likely ≥1 (age > 80=1, HR ≥110=0, cancer=1). Management:

• Admit for monitoring (not suitable for outpatient)
• Anticoagulation: LMWH preferred (cancer-associated VTE) for ≥6 months; alternative DOAC (edoxaban/rivaroxaban)
• Close monitoring for haemodynamic deterioration (consider ICU or HDU)
• NO thrombolysis (not haemodynamically unstable; PEITHO showed no benefit and increased bleeding in intermediate-risk)
• If deteriorates (hypotension, shock) → thrombolysis

4. "A 55-year-old with unprovoked PE has completed 3 months of rivaroxaban. What determines anticoagulation duration?"

Model Answer: Unprovoked PE has 10% recurrence at 1 year and 30% at 10 years if anticoagulation stopped. I would:

• Assess bleeding risk (HAS-BLED score)
• Reassess at 3 months: If low bleeding risk, I would recommend indefinite anticoagulation (ESC Class IIa recommendation)
• If patient declines or high bleeding risk, consider stopping and monitoring with D-dimer at 1 month post-cessation (elevated D-dimer predicts recurrence; may restart therapy)
• Provoked PE (major surgery/trauma) → stop at 3 months

5. "A pregnant woman at 20 weeks presents with confirmed PE. What is your management?"

Model Answer:

• Diagnostic pathway: Leg USS first; if negative, V/Q scan preferred over CTPA (lower fetal radiation)
• Treatment: LMWH (enoxaparin 1 mg/kg BD; therapeutic weight-based dosing) throughout pregnancy and ≥6 weeks postpartum (minimum 3 months total)
• DOACs contraindicated (teratogenic)
• Stop LMWH 24 hours before planned delivery; restart 6-12 hours post-delivery
• Multidisciplinary care (obstetrician, haematology, anaesthetics)

Viva Points

Viva Point: Opening Statement: "Pulmonary embolism is the obstruction of pulmonary arteries by thrombus, most commonly originating from lower limb deep vein thrombosis. It is the third most common acute cardiovascular syndrome with an annual incidence of approximately 60-100 per 100,000. Mortality ranges from less than 1% in low-risk cases to 30-65% in massive PE with haemodynamic compromise."

Key Facts to Mention:

• Diagnosis: Wells score-driven pathway: if PE unlikely (less than 4 points), use D-dimer to rule out; if PE likely (≥4 points) or D-dimer positive, proceed to CTPA
• Risk Stratification: ESC 2019 four-tier classification guides management intensity
• Treatment: DOACs (rivaroxaban, apixaban) first-line for most patients; non-inferior to warfarin with similar or lower bleeding risk (EINSTEIN-PE, AMPLIFY trials)
• Thrombolysis: Reserved for high-risk (haemodynamically unstable) PE only; PEITHO trial showed no benefit in intermediate-risk PE with increased bleeding
• Duration: Minimum 3 months; indefinite if unprovoked or recurrent
• Complication: CTEPH develops in 2-4% at 2 years; screen with echo at 3-6 months if persistent symptoms

Evidence Base:

• EINSTEIN-PE (2012): Rivaroxaban non-inferior to enoxaparin/warfarin [PMID: 22449293]
• AMPLIFY (2013): Apixaban non-inferior with less bleeding [PMID: 23808982]
• PEITHO (2014): Thrombolysis in intermediate-risk PE increased bleeding without mortality benefit [PMID: 24716681]
• ESC Guidelines 2019: Current gold standard [PMID: 31504429]

Common Mistakes

❌ Using D-dimer in high-probability PE: D-dimer is only useful for ruling out PE in low-probability cases. If Wells ≥4 (PE likely), proceed directly to CTPA.

❌ Thrombolysing intermediate-risk PE: Thrombolysis is ONLY for haemodynamically unstable (high-risk) PE. PEITHO showed no mortality benefit and increased bleeding in intermediate-risk.

❌ Stopping anticoagulation at 3 months in unprovoked PE: Unprovoked PE has 30% recurrence at 10 years. Consider indefinite anticoagulation if low bleeding risk.

❌ Using DOACs in antiphospholipid syndrome: Warfarin is superior; DOACs contraindicated.

❌ Forgetting age-adjusted D-dimer in elderly: Standard cut-off (less than 500 μg/L) has poor specificity in elderly. Use age × 10 for patients > 50 years.

❌ Missing CTEPH screening: 2-4% develop CTEPH. Screen with echo at 3-6 months if persistent dyspnoea.

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14. Imaging Interpretation Pearls

CTPA Interpretation

Direct Signs of PE

Intraluminal Filling Defect:

• Central/Acute: Sharply marginated, hypodense filling defect surrounded by contrast
• Partial Occlusion: Tramline sign — contrast on either side of thrombus
• Complete Occlusion: Abrupt cut-off of vessel; no contrast beyond occlusion
• Saddle Embolus: Straddles bifurcation of main or lobar pulmonary arteries

Location Classification:

• Central: Main pulmonary artery or lobar arteries
• Segmental: Segmental artery level
• Subsegmental: Distal segmental/subsegmental (clinical significance debated)

Clot Characteristics:

• Acute Thrombus: Lower attenuation than contrast; well-defined margins
• Chronic/Organised Thrombus: Higher attenuation; eccentric; vessel stenosis; calcification; webs/bands

Indirect Signs of PE (RV Dysfunction/Strain)

Qanadli Score (Clot Burden):

• Assigns points based on location and degree of obstruction
• Maximum score: 40 (complete occlusion of all vessels)
• Score > 50% associated with RV dysfunction and higher mortality

Ancillary Findings

• Pulmonary Infarction: Wedge-shaped peripheral opacity (Hampton's hump)
• Pleural Effusion: Usually small; unilateral or bilateral
• Mosaic Attenuation: Heterogeneous lung parenchyma (areas of oligaemia)
• Dilated Bronchial Arteries: Chronic PE/CTEPH

V/Q Scan Interpretation (PIOPED II Criteria)

Normal:

• Uniform perfusion matching ventilation
• Conclusion: PE excluded

Low Probability (less than 20% chance of PE):

• Small perfusion defects
• Matched V/Q defects (suggests alternative pathology)

Intermediate Probability (20-79%):

• Single moderate mismatched defect
• Multiple small mismatched defects
• Conclusion: Non-diagnostic; further testing required (CTPA or pulmonary angiography)

High Probability (≥80%):

• ≥2 large (> 75% of segment) mismatched perfusion defects
• Conclusion: PE confirmed

Limitations:

• 30-40% of V/Q scans are intermediate/indeterminate
• Requires normal CXR for accurate interpretation
• Less useful in COPD, heart failure, prior lung disease

Echocardiography Findings

Acute PE

Differential: Chronic PH vs Acute PE

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15. DOAC Pharmacology & Practical Considerations

Mechanism of Action

Dosing Regimens for PE

Rivaroxaban

• Initial (Days 1-21): 15 mg BD with food
• Maintenance (Day 22 onwards): 20 mg OD with food
• Renal Adjustment:
  • "CrCl 30-50: 15 mg OD (after initial phase)"
  • "CrCl 15-29: Avoid (consider apixaban)"
  • "CrCl less than 15: Contraindicated"

Apixaban

• Initial (Days 1-7): 10 mg BD
• Maintenance (Day 8 onwards): 5 mg BD
• Dose Reduction to 2.5 mg BD if ≥2 of:
  • Age ≥80 years
  • Weight ≤60 kg
  • Serum creatinine ≥133 μmol/L (1.5 mg/dL)
• Renal Adjustment:
  • "CrCl 15-29: 2.5 mg BD (off-label; limited data)"
  • "CrCl less than 15: Contraindicated"

Edoxaban

• Requires 5-10 days LMWH lead-in
• Dose: 60 mg OD
• Dose Reduction to 30 mg OD if any:
  • CrCl 15-50 mL/min
  • Weight ≤60 kg
  • P-glycoprotein inhibitors (ciclosporin, dronedarone, erythromycin, ketoconazole)
• Contraindicated if CrCl > 95 mL/min (reduced efficacy due to rapid excretion)

Dabigatran

• Requires 5-10 days LMWH lead-in
• Dose: 150 mg BD
• Dose Reduction to 110 mg BD if:
  • Age ≥80 years
  • Concurrent verapamil
  • High bleeding risk
• Renal Adjustment:
  • "CrCl 30-50: Use with caution; consider 110 mg BD"
  • "CrCl less than 30: Contraindicated"

Drug Interactions

P-Glycoprotein (P-gp) Inhibitors (↑ DOAC levels):

• Strong Inhibitors (avoid combination): Ketoconazole, itraconazole, ciclosporin, tacrolimus, dronedarone
• Moderate Inhibitors (reduce dose or avoid): Verapamil, amiodarone, quinidine, clarithromycin, erythromycin

P-gp Inducers (↓ DOAC levels; avoid combination):

• Rifampicin, carbamazepine, phenytoin, St John's Wort

Antiplatelet Agents:

• Concurrent aspirin/clopidogrel increases bleeding risk
• Avoid triple therapy (DOAC + DAPT) unless compelling indication (e.g., recent PCI)

Monitoring

Routine Monitoring: NOT required (major advantage over warfarin)

When to Check Levels (specialist use only):

• Suspected overdose or accumulation
• Bleeding event
• Before urgent surgery
• Renal function decline

Assays:

• Rivaroxaban/Apixaban/Edoxaban: Anti-Xa assay (drug-specific calibration required)
• Dabigatran: Dilute Thrombin Time (dTT) or Ecarin Clotting Time (ECT); aPTT insensitive at therapeutic levels

Reversal Agents

Indications for Reversal:

• Life-threatening bleeding (intracranial, GI with haemodynamic instability)
• Urgent surgery/procedure that cannot be delayed
• Trauma with high bleeding risk

Minor Bleeding:

• Stop DOAC
• Local haemostatic measures
• Supportive care (fluids, transfusion if needed)
• Resume DOAC once bleeding controlled

Switching Anticoagulants

LMWH → DOAC

• Start DOAC at next scheduled LMWH dose (rivaroxaban, apixaban) OR after 5-10 days LMWH (edoxaban, dabigatran)

Warfarin → DOAC

• Stop warfarin; start DOAC when INR ≤2.0 (rivaroxaban, apixaban) or ≤2.5 (edoxaban, dabigatran)

DOAC → Warfarin

• Start warfarin + continue DOAC until INR ≥2.0 for 2 consecutive days
• Check INR just before next DOAC dose (to avoid falsely elevated INR from DOAC effect on aPTT/INR)

DOAC → LMWH (e.g., for surgery)

• Start LMWH at time of next missed DOAC dose

Perioperative Management

Elective Surgery:

Low Bleeding Risk Procedures (dental extraction, cataract surgery, minor dermatology):

• Dabigatran/Edoxaban: Omit morning dose on day of procedure; resume evening dose post-procedure
• Rivaroxaban/Apixaban: Continue; or omit 1 dose before procedure

High Bleeding Risk Procedures (major surgery, neuraxial anaesthesia):

• CrCl > 50: Stop DOAC 48 hours before
• CrCl 30-50: Stop DOAC 72-96 hours before
• No bridging required (DOACs have rapid offset)
• Resume DOAC 24-48 hours post-op if haemostasis achieved

Emergency Surgery:

• Delay surgery 12-24 hours if possible (allows DOAC clearance)
• If cannot delay: Reversal agent (idarucizumab for dabigatran; andexanet alfa for Xa inhibitors) or 4F-PCC

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16. Follow-Up & Long-Term Management

Immediate Post-Discharge (First Month)

Week 1-2:

• Early review (in-person or telephone) to assess:
  • Treatment adherence
  • Bleeding complications
  • Symptom resolution
  • Adverse effects of anticoagulation

Week 4:

• Clinical review
• Renal function (eGFR) — assess for DOAC accumulation
• Full blood count (check haemoglobin for occult bleeding)
• Symptom assessment (dyspnoea scale, functional capacity)

3-Month Review (End of Initial Anticoagulation)

Assessment:

1. Symptom Review: Persistent dyspnoea? Exercise intolerance? → Consider CTEPH screening
2. Identify PE Type:
   • Provoked (major surgery, trauma) → Stop anticoagulation
   • Provoked (minor risk factor: OCP, travel) → Consider 3-6 months
   • Unprovoked → Assess for extended therapy
3. Bleeding Risk Assessment: HAS-BLED score, prior bleeds, fall risk
4. Patient Preference: Discuss risks/benefits of extended therapy

Decision Tool: Extended Anticoagulation

Extended Therapy Options:

• Full-Dose DOAC: Continue rivaroxaban 20 mg OD, apixaban 5 mg BD, edoxaban 60 mg OD, dabigatran 150 mg BD
• Reduced-Dose DOAC (off-label, emerging evidence): Rivaroxaban 10 mg OD or apixaban 2.5 mg BD after initial 6-12 months
• Aspirin: Inferior to anticoagulation (ASPIRE, WARFASA trials); not recommended if anticoagulation tolerated

6-Month Review

CTEPH Screening (if indicated):

Indications for Screening:

• Persistent dyspnoea (NYHA class II-IV)
• Reduced exercise capacity
• Massive/submassive PE at presentation
• Recurrent PE
• Chronic thromboembolic disease on CTPA

Screening Protocol:

1. Transthoracic Echocardiography:
   • Assess PASP (TR jet velocity > 2.8 m/s suggests PASP > 40 mmHg)
   • RV size and function
   • If elevated PASP or RV dysfunction → proceed to further testing
2. V/Q Scan: More sensitive than CTPA for chronic organised thrombus
3. CTPA: Look for chronic changes (webs, bands, eccentric thrombus, vessel stenosis)
4. Right Heart Catheterisation: Gold standard for confirming pulmonary hypertension (mPAP ≥20 mmHg)

If CTEPH Confirmed:

• Refer to specialist pulmonary hypertension centre
• Lifelong anticoagulation
• Assess operability for pulmonary endarterectomy (PEA)

Annual Review (Indefinite Anticoagulation)

Reassess Annually:

• Bleeding Events: Major or clinically relevant non-major bleeds → consider stopping or dose reduction
• Falls: Assess fall risk (≥2 falls/year → consider stopping)
• Renal Function: Decline in eGFR → adjust DOAC dose or switch to warfarin
• Comorbidities: New diagnoses affecting bleeding risk (e.g., severe liver disease, thrombocytopenia)
• Patient Adherence: Non-adherence → consider switch to LMWH (if cancer) or supervised therapy
• Quality of Life: Impact of long-term anticoagulation

Patient Education & Self-Monitoring

Key Messages:

1. Medication Adherence: Take DOAC at same time daily; do NOT miss doses (short half-life)
2. Bleeding Precautions: Use soft toothbrush, electric razor; avoid contact sports
3. Red Flag Symptoms (seek immediate help):
   • Unexplained bruising, prolonged bleeding from cuts
   • Blood in urine (haematuria) or stool (melaena, haematochezia)
   • Severe headache, confusion, focal neurology (ICH)
   • Severe abdominal pain (retroperitoneal bleed)
   • Shortness of breath, chest pain (recurrent PE or bleeding)
4. Inform Healthcare Providers: Always mention anticoagulation before procedures, dental work, new medications
5. Avoid NSAIDs: Increase bleeding risk; use paracetamol for pain relief
6. Alcohol Moderation: Excessive alcohol increases bleeding risk and affects drug metabolism

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17. Clinical Case Scenarios (Exam Practice)

Case 1: Low-Risk PE Suitable for Outpatient Management

Presentation: A 42-year-old woman presents to ED with 2-day history of right-sided pleuritic chest pain and mild dyspnoea. She returned from a 10-hour flight from Australia 5 days ago. No past medical history. Wells score: 3.5 points (recent travel). D-dimer: 1200 μg/L. CTPA confirms segmental PE right lower lobe.

Examination:

• BP 128/82, HR 88, RR 16, SpO2 97% on air
• Cardiovascular and respiratory examination unremarkable

Investigations:

• Troponin: Normal
• Echo: Normal RV size and function
• sPESI: 0

Question: Is she suitable for outpatient management? What is your plan?

Model Answer: This is a low-risk PE (sPESI=0, normotensive, normal oxygenation, no RV dysfunction, normal biomarkers). She meets criteria for outpatient management if Hestia criteria all negative:

• NOT haemodynamically unstable ✓
• NO need for thrombolysis ✓
• NO active bleeding/high bleeding risk ✓
• NO oxygen requirement > 24h ✓
• NOT on pre-existing anticoagulation ✓
• NO severe pain needing IV analgesia ✓
• NO medical/social reason for admission ✓
• CrCl likely > 30 (young, no comorbidities) ✓
• NO severe liver disease ✓
• NOT pregnant ✓
• NO prior HIT ✓

Management Plan:

1. Start apixaban 10 mg BD (or rivaroxaban 15 mg BD) in ED
2. Provide safety-net advice (return immediately if worsening symptoms, bleeding)
3. Arrange 48-72 hour follow-up (GP or VTE clinic)
4. Continue apixaban: 10 mg BD for 7 days, then 5 mg BD
5. Duration: 3 months (provoked by travel)
6. Patient education leaflet on anticoagulation, bleeding precautions
7. VTE clinic review at 1 month and 3 months

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Case 2: Intermediate-High Risk PE Requiring Admission

Presentation: A 68-year-old man presents with sudden dyspnoea and syncope. Background: prostate cancer on active surveillance, hypertension. Wells score: 7.5 points (cancer, clinical signs of DVT, HR 115). CTPA: Bilateral lobar PE.

Examination:

• BP 108/68, HR 115, RR 24, SpO2 91% on 2L O2
• Elevated JVP, RV heave, loud P2
• Left calf swelling and tenderness

Investigations:

• Troponin I: 120 ng/L (elevated)
• NT-proBNP: 850 pg/mL (elevated)
• Echo: RV:LV ratio 1.3, RV hypokinesis, TR velocity 3.2 m/s
• sPESI: 3 (age > 80=0, cancer=1, HR ≥110=1, SpO2 less than 90%=1)

Question: How do you classify risk? What is your management?

Model Answer: This is intermediate-high risk PE by ESC 2019 criteria:

• Haemodynamically STABLE (SBP > 90 mmHg) but borderline
• RV dysfunction present (RV:LV > 1.0, RV hypokinesis)
• Elevated biomarkers (troponin and BNP)
• sPESI ≥1

Management:

1. Admit to HDU/monitored bed (close monitoring for haemodynamic deterioration)
2. Oxygen: Target SpO2 94-98%
3. Anticoagulation:
   • Start LMWH (enoxaparin 1.5 mg/kg OD) — preferred in cancer-associated VTE
   • Alternative: Edoxaban or rivaroxaban (non-inferior to LMWH in cancer; SELECT-D trial)
   • Duration: Indefinite (active cancer)
4. Close Monitoring:
   • Continuous telemetry, BP monitoring
   • Serial troponin (rising suggests deterioration)
   • If develops hypotension (SBP less than 90 mmHg) or shock → thrombolysis (alteplase 100mg IV over 2h)
5. DO NOT give thrombolysis upfront (patient is normotensive; PEITHO showed no mortality benefit and increased bleeding in intermediate-risk PE)
6. Leg USS: Confirm DVT
7. Oncology Referral: Review cancer management; optimize systemic therapy
8. VTE Clinic Follow-Up: 3 months and 6 months; CTEPH screening at 6 months

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Case 3: High-Risk Massive PE Requiring Thrombolysis

Presentation: A 55-year-old woman presents with sudden severe dyspnoea, chest pain, and collapse. Background: recent total hip replacement (2 weeks ago). Brought in by ambulance, initially BP 70/40, HR 130, SpO2 85% on 15L O2.

Examination:

• BP 82/50 (despite 500mL fluid bolus), HR 128, RR 32, SpO2 88% on 15L
• Cold peripheries, mottled skin, diaphoresis
• Elevated JVP, RV heave

Investigations:

• Bedside Echo: Severely dilated RV, RV akinesis, McConnell's sign, underfilled LV
• ECG: Sinus tachycardia, S1Q3T3, RBBB, anterior T-wave inversion
• ABG: pH 7.32, PaO2 58 mmHg, PaCO2 32 mmHg, Lactate 4.2 mmol/L

Question: How do you manage this patient?

Model Answer: This is high-risk massive PE (haemodynamic instability: SBP less than 90 mmHg + shock).

Immediate Management:

1. Resuscitation:
   • High-flow oxygen (15L non-rebreather; consider CPAP or intubation if worsening)
   • Cautious IV fluids (500mL crystalloid bolus; avoid overload as can worsen RV function)
   • Two large-bore IV cannulae
   • Continuous monitoring (ECG, BP, SpO2)
2. Anticoagulation:
   • UFH bolus 80 units/kg IV, then infusion 18 units/kg/h (prefer UFH over LMWH in unstable patients; allows rapid cessation if bleeding)
3. Confirm Diagnosis (if time permits and patient stable enough):
   • Bedside echo done (shows RV dysfunction; highly suggestive of massive PE)
   • CTPA if patient stable enough to transfer (do NOT delay thrombolysis for imaging if critically unstable)
4. SYSTEMIC THROMBOLYSIS (Class I indication):
   • Alteplase 100 mg IV over 2 hours OR Accelerated alteplase 0.6 mg/kg (max 50mg) over 15 min
   • Alternative: Tenecteplase 30-50mg IV bolus (weight-based; simpler dosing)
   • Expected response: Improvement in BP and oxygenation within 1-2 hours
5. Check Contraindications (absolute):
   • Active bleeding? NO
   • Recent intracranial haemorrhage (less than 3 months)? NO
   • Ischaemic stroke less than 3 months? NO
   • Intracranial neoplasm/AVM? NO
   • Recent major surgery (less than 2 weeks)? YES — hip replacement 2 weeks ago is a RELATIVE contraindication; however, haemodynamic instability is life-threatening → thrombolysis benefits outweigh risks
6. Escalate:
   • ICU referral (may need intubation, vasopressors)
   • If fails to respond to thrombolysis or cardiac arrest → consider:
     • Surgical embolectomy (if available; contact cardiothoracic surgery)
     • VA-ECMO (bridge to surgery or recovery)
7. Monitor for Bleeding: Major bleeding risk 10-20%; intracranial haemorrhage 1-3%

Outcome: Most patients improve within hours of thrombolysis. Continue UFH infusion (target aPTT 1.5-2.5× control), then transition to DOAC or warfarin after stabilisation.

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Case 4: PE in Pregnancy

Presentation: A 28-year-old woman at 22 weeks gestation presents with 1-day history of left-sided pleuritic chest pain and dyspnoea. Wells score: 6 points (pregnancy=minor risk factor, HR 105). No leg swelling.

Examination:

• BP 118/74, HR 105, RR 20, SpO2 96% on air
• Cardiovascular and respiratory examination normal
• No calf swelling or tenderness

Question: What is your diagnostic and management approach?

Model Answer:

Diagnostic Pathway (Pregnancy-Specific):

1. Leg Doppler USS first:
   • If positive for DVT → start treatment (no further imaging needed)
   • If negative → proceed to imaging for PE
2. Choose Imaging:
   • V/Q Scan preferred (lower fetal radiation: 0.1-0.5 mGy vs CTPA 0.01-0.66 mGy to fetus; but CTPA has lower maternal breast radiation)
   • If V/Q indeterminate → CTPA with abdominal shielding
3. D-Dimer: NOT useful in pregnancy (physiologically elevated; poor specificity)

In This Case:

• Leg USS: Negative
• V/Q Scan: High probability (mismatched perfusion defects) → PE confirmed

Management:

1. Anticoagulation:
   • LMWH (enoxaparin 1 mg/kg BD) — safe in pregnancy; does not cross placenta
   • DOACs contraindicated (teratogenic; cross placenta)
   • Weight-based dosing; check anti-Xa levels monthly (target 0.6-1.0 IU/mL at 4h post-dose for BD dosing)
2. Duration:
   • Throughout pregnancy + ≥6 weeks postpartum (minimum 3 months total)
   • If PE in early pregnancy, likely need treatment for > 6 months total
3. Delivery Planning:
   • Stop LMWH 24 hours before planned delivery/induction
   • Restart LMWH 6-12 hours post-delivery (vaginal) or 12-24 hours (Caesarean)
   • Neuraxial anaesthesia (epidural/spinal): Can use if ≥12 hours since last prophylactic LMWH dose or ≥24 hours since last therapeutic dose
4. Postpartum:
   • Continue LMWH for ≥6 weeks postpartum
   • Alternative: Switch to warfarin postpartum (safe in breastfeeding; avoid if breastfeeding and prefer to avoid)
   • DOACs contraindicated in breastfeeding (limited data; avoid)
5. Multidisciplinary Care:
   • Obstetric team (high-risk pregnancy)
   • Haematology (anticoagulation monitoring)
   • Anaesthetics (delivery planning, neuraxial anaesthesia timing)
6. Future Pregnancies: Thrombophilia screening post-pregnancy; consider prophylactic LMWH in subsequent pregnancies

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Case 5: Recurrent PE Despite Anticoagulation

Presentation: A 62-year-old man with unprovoked PE 8 months ago (on rivaroxaban 20 mg OD, good adherence confirmed) presents with new dyspnoea. CTPA confirms new segmental PE left upper lobe.

Question: What are the possible causes? How do you manage?

Model Answer:

Possible Causes of Recurrent VTE on Anticoagulation:

1. Non-adherence (most common) — excluded by patient history and pharmacy records
2. Sub-therapeutic anticoagulation:
   • Drug interactions (P-gp inducers: rifampicin, carbamazepine, St John's Wort)
   • Malabsorption
3. Occult Malignancy (10-20% of unprovoked VTE have underlying cancer)
4. Antiphospholipid Syndrome (DOACs less effective than warfarin in APS)
5. Heparin-Induced Thrombocytopenia (unlikely on DOAC; relevant if on LMWH)
6. Non-compliance with lifestyle measures (prolonged immobility)
7. Progression of underlying disease (e.g., worsening cancer)

Investigations:

1. Confirm Adherence: Pharmacy records, pill count, direct questioning
2. Check for Drug Interactions: Medication review (P-gp inducers/inhibitors)
3. DOAC Level (if available): Anti-Xa assay to confirm therapeutic levels
4. Thrombophilia Screen (limited utility; rarely changes management):
   • Lupus anticoagulant, anticardiolipin antibodies, anti-β2-glycoprotein I (antiphospholipid syndrome)
   • Protein C, Protein S, Antithrombin (check when OFF anticoagulation as warfarin/DOACs affect levels)
   • Factor V Leiden, Prothrombin G20210A mutation
5. Cancer Screening (age-appropriate + symptom-directed):
   • CT chest/abdomen/pelvis
   • Colonoscopy (if > 50 years or symptoms)
   • PSA (men), mammogram (women), pelvic USS (women)
   • Consider PET-CT if CT chest/abdo/pelvis negative

Management:

1. Switch Anticoagulant:
   • If on DOAC → switch to LMWH (therapeutic dose: enoxaparin 1.5 mg/kg OD or 1 mg/kg BD)
   • If drug interactions identified → eliminate interacting drug or switch to warfarin (less affected by P-gp)
   • If Antiphospholipid Syndrome confirmed → switch to WARFARIN (target INR 2-3; DOACs inferior in APS)
2. Increase Anticoagulation Intensity:
   • LMWH at higher dose (consider 1 mg/kg BD instead of 1.5 mg/kg OD)
   • Warfarin at higher target INR (INR 2.5-3.5 in select cases; discuss with haematology)
3. IVC Filter:
   • Consider if recurrent PE despite adequate anticoagulation confirmed (check anti-Xa or INR levels to confirm therapeutic)
   • Prefer retrievable filter; remove once anticoagulation optimized
4. Treat Underlying Cause:
   • If cancer identified → optimize cancer treatment; continue LMWH indefinitely
   • If APS → lifelong warfarin
5. Specialist Referral: Haematology for complex anticoagulation management

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18. Patient/Layperson Explanation

What is a Pulmonary Embolism?

A pulmonary embolism (PE) is a blood clot that has travelled to your lungs and blocks one or more arteries that supply blood to your lungs. Most PEs start as blood clots in the deep veins of your legs (called deep vein thrombosis or DVT). Part of this clot can break off, travel through your bloodstream, and get stuck in your lungs.

What are the symptoms?

• Sudden shortness of breath (most common)
• Sharp chest pain, especially when you breathe in deeply
• Coughing, sometimes with blood-streaked mucus
• Fast or irregular heartbeat
• Feeling dizzy or fainting
• Leg pain or swelling (if you still have a clot in your leg)

Call 999 immediately if you have these symptoms, especially sudden breathlessness or chest pain.

How is it diagnosed?

1. Your doctor will ask about your symptoms and risk factors (recent surgery, long flights, cancer, etc.)
2. Blood test (D-dimer): Helps rule out PE if negative
3. CT scan (CTPA): Takes detailed pictures of your lungs to see the clot — this is the main test to confirm PE

How is it treated?

1. Blood-thinning medication (anticoagulants):

• Most people take tablets called DOACs (rivaroxaban, apixaban)
• These prevent new clots forming and allow your body to gradually dissolve the existing clot
• You'll usually take them for at least 3 months; some people need longer

2. Clot-busting drugs (thrombolysis):

• Only for severe PE where your blood pressure is dangerously low
• Given through a vein in hospital; works quickly to break up the clot

3. Oxygen and supportive care:

• Oxygen if you're short of breath
• Pain relief for chest pain
• Hospital monitoring (depending on severity)

Can I go home or do I need to stay in hospital?

It depends on how severe your PE is:

• Small PE with stable blood pressure and oxygen levels: You may be able to go home the same day with tablet treatment
• Larger PE or unstable blood pressure: You'll need to stay in hospital for monitoring and treatment

What to expect during recovery

• Most people feel better within a few days to weeks
• You'll continue blood thinners for at least 3 months
• You'll have follow-up appointments to check your progress
• Some people feel tired or short of breath for several months (this usually improves)

What happens after 3 months?

Your doctor will reassess whether you need to continue blood thinners:

• If your PE was caused by a temporary risk factor (like surgery), you may be able to stop
• If there was no clear cause ("unprovoked"), you might need to continue indefinitely to prevent another clot

Can PE happen again?

Yes, there is a risk of recurrence, especially if:

• You had no clear risk factor (unprovoked PE)
• You stop blood-thinning medication
• You have cancer or other ongoing risk factors

That's why follow-up and sometimes long-term medication are important.

How can I reduce my risk?

• Take your blood-thinning medication exactly as prescribed
• Stay active (avoid sitting for long periods)
• Keep a healthy weight
• Stop smoking
• Stay hydrated
• On long flights (> 4 hours): walk around regularly, stay hydrated, wear compression stockings if recommended

When to seek urgent help

Call 999 or go to A&E immediately if:

• You're very short of breath or can't breathe
• You have severe chest pain
• You cough up blood
• You feel faint, dizzy, or lose consciousness
• Your heart is racing and won't slow down

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15. References

Primary Guidelines

1. Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J. 2020;41(4):543-603. doi:10.1093/eurheartj/ehz405 [PMID: 31504429]

Landmark Trials

2. EINSTEIN–PE Investigators, Büller HR, Prins MH, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287-1297. doi:10.1056/NEJMoa1113572 [PMID: 22449293]

3. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799-808. doi:10.1056/NEJMoa1302507 [PMID: 23808982]

4. Kroegel C, Reissig A. Principle mechanisms underlying venous thromboembolism: epidemiology, risk factors, pathophysiology and pathogenesis. Respiration. 2003;70(1):7-30. doi:10.1159/000068427 [PMID: 12584387]

5. Pepke-Zaba J, Delcroix M, Lang I, et al. Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry. Circulation. 2011;124(18):1973-1981. doi:10.1161/CIRCULATIONAHA.110.015008 [PMID: 21969018]

6. Miniati M, Cenci C, Monti S, Poli D. Clinical presentation of acute pulmonary embolism: survey of 800 cases. PLoS One. 2012;7(2):e30891. doi:10.1371/journal.pone.0030891 [PMID: 22383976]

7. van Belle A, Büller HR, Huisman MV, et al. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA. 2006;295(2):172-179. doi:10.1001/jama.295.2.172 [PMID: 16403929]

8. Righini M, Van Es J, Den Exter PL, et al. Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study. JAMA. 2014;311(11):1117-1124. doi:10.1001/jama.2014.2135 [PMID: 24643601]

9. Zondag W, Mos IC, Creemers-Schild D, et al. Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study. J Thromb Haemost. 2011;9(8):1500-1507. doi:10.1111/j.1538-7836.2011.04388.x [PMID: 21645235]

10. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. 1999;353(9162):1386-1389. doi:10.1016/S0140-6736(98)07534-5 [PMID: 10227218]

11. Silverstein MD, Heit JA, Mohr DN, et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med. 1998;158(6):585-593. doi:10.1001/archinte.158.6.585 [PMID: 9521222]

12. Prandoni P, Noventa F, Ghirarduzzi A, et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica. 2007;92(2):199-205. doi:10.3324/haematol.10516 [PMID: 17296569]

13. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 Suppl):381S-453S. doi:10.1378/chest.08-0656 [PMID: 18574271]

14. Horsted F, West J, Grainge MJ. Risk of venous thromboembolism in patients with cancer: a systematic review and meta-analysis. PLoS Med. 2012;9(7):e1001275. doi:10.1371/journal.pmed.1001275 [PMID: 22859911]

15. Vandenbroucke JP, Rosing J, Bloemenkamp KW, et al. Oral contraceptives and the risk of venous thrombosis. N Engl J Med. 2001;344(20):1527-1535. doi:10.1056/NEJM200105173442007 [PMID: 11357156]

16. Stein PD, Fowler SE, Goodman LR, et al. Multidetector computed tomography for acute pulmonary embolism. N Engl J Med. 2006;354(22):2317-2327. doi:10.1056/NEJMoa052367 [PMID: 16738268]

17. McConnell MV, Solomon SD, Rayan ME, et al. Regional right ventricular dysfunction detected by echocardiography in acute pulmonary embolism. Am J Cardiol. 1996;78(4):469-473. doi:10.1016/s0002-9149(96)00339-6 [PMID: 8752195]

18. Becattini C, Vedovati MC, Agnelli G. Prognostic value of troponins in acute pulmonary embolism: a meta-analysis. Circulation. 2007;116(4):427-433. doi:10.1161/CIRCULATIONAHA.106.680421 [PMID: 17606934]

19. Büller HR, Décousus H, Grosso MA, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406-1415. doi:10.1056/NEJMoa1306638 [PMID: 23991658]

20. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342-2352. doi:10.1056/NEJMoa0906598 [PMID: 19966341]

21. Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2):146-153. doi:10.1056/NEJMoa025313 [PMID: 12853587]

22. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370(15):1402-1411. doi:10.1056/NEJMoa1302097 [PMID: 24716681]

Further Resources

• Thrombosis UK: thrombosisuk.org
• European Society of Cardiology: escardio.org
• National Institute for Health and Care Excellence (NICE): nice.org.uk

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Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate guidelines and specialists for patient care.