9.1 Venous Thromboembolism & Pulmonary Embolism

Venous thromboembolism (VTE), encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE), is a major cause of acute morbidity and mortality in hospitalized and ambulatory patients. In the MRCP(UK) Part 1 examination, questions frequently test clinical pre-test probability scoring, rational imaging selection, interpretation of subtle markers of right heart strain, and evidence-based anticoagulation algorithms based on NICE and European Society of Cardiology (ESC) guidelines.

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1. Pathophysiology & Virchow's Triad

Pulmonary embolism arises when an organized thrombus from the deep venous system—predominantly the proximal veins of the lower extremities (iliofemoral and popliteal veins in >90% of cases) or pelvic venous plexuses—dislodges, migrates through the inferior vena cava, traverses the right heart, and lodges within the pulmonary arterial tree.

Virchow's triad delineates the fundamental predisposing pathophysiology:

1. Endothelial Injury: Prior vascular trauma, indwelling central venous catheters, recent orthopedic surgery, or local vasculitis.
2. Venous Stasis: Prolonged immobility (bed rest >=3 days, flights >4 hours), lower limb paralysis, general anaesthesia, congestive cardiac failure, or chronic venous insufficiency.
3. Hypercoagulability: Active malignant disease, inherited thrombophilias (Factor V Leiden mutation, prothrombin G20210A mutation, antithrombin III deficiency, protein C or protein S deficiency), acquired antiphospholipid syndrome (lupus anticoagulant, anticardiolipin antibodies, anti-beta-2-glycoprotein I), pregnancy, and exogenous estrogen therapy (combined oral contraceptive pill or hormone replacement therapy).

Cardiorespiratory Hemodynamics

Embolic mechanical obstruction of the pulmonary vascular bed triggers immediate neurohumoral reflex vasoconstriction mediated by thromboxane A2 and serotonin release. This precipitates:

• Dead Space Ventilation & Hypoxaemia: Non-perfused but ventilated alveoli produce a high ventilation-perfusion ratio (V/Q = infinity), increasing alveolar dead space. Subsequent reflex hyperventilation causes hypocapnia and respiratory alkalosis. Hypoxaemia arises predominantly from intrapulmonary shunting, atelectasis secondary to local surfactant depletion, and ventilation-perfusion mismatch.
• Acute Cor Pulmonale & Cardiogenic Shock: The pulmonary circulation is a low-resistance, high-capacitance system. Abrupt mechanical occlusion exceeding 30–50% of the total pulmonary arterial cross-sectional area abruptly elevates pulmonary vascular resistance (PVR). The thin-walled right ventricle (RV) cannot generate systolic pressures exceeding 50–60 mmHg acutely, resulting in acute RV dilatation, elevated wall tension, subendocardial ischaemia, and progressive tricuspid regurgitation. Interventricular septal bowing into the left ventricle (septal flattening) impairs left ventricular filling, precipitating a precipitous drop in stroke volume, systemic hypotension, and cardiogenic shock.

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2. Clinical Assessment & Probability Scoring

Clinical signs and symptoms of PE—such as sudden-onset pleuritic chest pain, dyspnoea, tachypnoea, tachycardia, hemoptysis, and syncope—are notoriously non-specific. Objective risk stratification using validated clinical prediction rules is mandatory before diagnostic testing.

The Wells Score for Pulmonary Embolism

Two-Level Wells Stratification (Preferred by NICE & ESC)

• PE Likely (>4 points): Pre-test probability is high. D-dimer testing should not be performed as a negative result does not safely exclude PE. Arrange immediate CT Pulmonary Angiography (CTPA). If CTPA cannot be obtained immediately, initiate interim therapeutic anticoagulation (e.g., apixaban or rivaroxaban) unless absolute contraindications exist.
• PE Unlikely (<=4 points): Pre-test probability is low. Perform a high-sensitivity D-dimer assay.

The PERC Rule (Pulmonary Embolism Rule-out Criteria)

The PERC rule is applied exclusively in patients categorized as having a very low clinical pre-test probability (gestalt <15%). If all 8 criteria are fulfilled, PE can be safely ruled out without blood testing or imaging (failure rate <1%):

1. Age <50 years
2. Heart rate <100 bpm
3. Oxygen saturation (SpO2) >=95% on ambient room air
4. No unilateral leg swelling
5. No hemoptysis
6. No recent major trauma or surgery requiring hospitalization within the past 4 weeks
7. No previous history of venous thromboembolism (DVT or PE)
8. No exogenous estrogen use (oral contraceptives, hormone replacement therapy, or selective estrogen receptor modulators)

If any single criterion is positive, the PERC rule is failed, and the patient must undergo D-dimer testing.

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3. Diagnostic Pathway & Modalities

D-Dimer Assay & Age-Adjusted Cut-Offs

D-dimer is a fibrin degradation product generated during endogenous fibrinolysis of cross-linked fibrin. It exhibits high sensitivity (>95%) but low specificity, as it is elevated in pregnancy, advanced age, cancer, sepsis, trauma, and postoperative convalescence.

• Age-Adjusted D-Dimer: In patients older than 50 years with an "unlikely" pre-test probability, standard cut-offs (typically 500 µg/L or 0.5 mg/L FEU) produce excessive false-positive rates. The validated age-adjusted cut-off formula is: $\text{Age-Adjusted Cut-Off} = \text{Age (years)} \times 10\ \mu\text{g/L}$ For example, in a 74-year-old patient, a D-dimer concentration up to 740 µg/L is considered negative, safely avoiding unnecessary imaging.

CT Pulmonary Angiography (CTPA) vs V/Q Scintigraphy

• CTPA (First-Line): The definitive imaging investigation of choice for suspected PE. It demonstrates intraluminal filling defects in central, lobar, segmental, and subsegmental pulmonary arteries, while simultaneously providing alternate explanations for symptoms (e.g., consolidation, pneumothorax, aortic dissection).
• Ventilation-Perfusion (V/Q) Scintigraphy: Evaluates regional pulmonary ventilation versus perfusion. A high-probability V/Q scan (demonstrating two or more segmental perfusion defects with normal ventilation—V/Q mismatch) confirms PE. V/Q scanning is indicated in:
  1. Severe renal impairment (eGFR <30 mL/min/1.73 m²) where iodinated contrast risks contrast-induced nephropathy.
  2. Documented severe anaphylactoid allergy to iodinated contrast media.
  3. Pregnancy with a normal baseline chest radiograph (CXR): A normal CXR is an absolute prerequisite for V/Q scanning; V/Q scintigraphy in this setting delivers a significantly lower radiation dose to maternal breast tissue compared to CTPA (reducing long-term maternal breast cancer risk), while fetal radiation remains well below teratogenic thresholds in both modalities.

Electrocardiography (ECG)

The most frequent electrocardiographic finding in PE is sinus tachycardia (present in ~40% of patients). Signs reflecting acute right ventricular strain include:

• McGinn-White Sign (S1Q3T3): Prominent S wave in lead I, pathological Q wave in lead III, and inverted T wave in lead III. Present in <15–20% of cases, reflecting acute cor pulmonale rather than serving as a sensitive screening sign.
• T-Wave Inversion in Precordial Leads: T-wave inversions across leads V1–V4 and lead III (the most specific ECG sign of acute RV strain).
• Right Bundle Branch Block (RBBB): New incomplete or complete RBBB.
• Right Axis Deviation: Clockwise rotation of the heart with shift of the QRS transitional zone to V5/V6.

Transthoracic Echocardiography (TTE)

Echocardiography is not routinely required for diagnosing low-risk PE, but provides rapid, bedside risk stratification in unstable patients:

• McConnell's Sign: Distinctive regional RV free wall hypokinesia or akinesia with paradoxical sparing (hyperdynamic motion) of the RV apex. Highly specific for acute pulmonary embolism.
• Right Ventricle Dilatation: Enlarged end-diastolic RV:LV basal diameter ratio >1.0.
• Elevated Pulmonary Artery Systolic Pressure: Elevated peak tricuspid regurgitation (TR) velocity.
• The 60/60 Sign: Combination of pulmonary valve acceleration time <60 ms alongside a tricuspid regurgitant systolic gradient <=60 mmHg.

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4. Risk Stratification & Therapeutic Management

Patients are risk-stratified into high risk (massive), intermediate risk (submassive), and low risk.

Hemodynamically Unstable (Massive) Pulmonary Embolism

Massive PE is defined by sustained systolic blood pressure <90 mmHg or a drop in systolic BP >=40 mmHg for >=15 minutes, requiring vasopressor support, or presenting with cardiac arrest/cardiogenic shock, not attributable to sepsis, hypovolemia, or acute arrhythmia.

• Emergency Management:
  • Provide high-flow oxygen, cautious IV fluid administration (judicious bolus <=500 mL crystalloid; excessive volume overloads the dilated, failing RV), and inotropes/vasopressors (norepinephrine or epinephrine).
  • Systemic Thrombolysis: Immediate first-line therapy. Alteplase (recombinant tissue plasminogen activator, rt-PA) 100 mg administered intravenously over 2 hours (or accelerated 0.6 mg/kg over 15 minutes, maximum 50 mg, in peri-arrest resuscitation).
  • Unfractionated Heparin (UFH): Administer an initial IV bolus of UFH (80 units/kg) followed by continuous infusion titrated to an activated partial thromboplastin time (APTT) ratio of 1.5–2.5. UFH is preferred over LMWH in unstable patients due to its rapid clearance and immediate reversibility with protamine sulphate if major bleeding occurs.
  • Surgical Pulmonary Embolectomy or Catheter-Directed Thrombectomy: Indicated when systemic thrombolysis is strictly contraindicated (e.g., recent hemorrhagic stroke, active central nervous system neoplasm, recent major surgery or head trauma within 3 weeks) or when thrombolysis has failed to restore hemodynamic stability.

Hemodynamically Stable Pulmonary Embolism

• Direct Oral Anticoagulants (DOACs): First-line therapy over warfarin and LMWH in non-pregnant, stable patients without severe renal impairment (NICE guidelines):
  • Apixaban: 10 mg twice daily for 7 days, followed by 5 mg twice daily (oral monotherapy without heparin lead-in).
  • Rivaroxaban: 15 mg twice daily with food for 21 days, followed by 20 mg once daily (oral monotherapy without heparin lead-in).
  • Dabigatran (150 mg BD) or Edoxaban (60 mg OD): Both require at least 5 days of initial parenteral anticoagulation (e.g., therapeutic LMWH) before switching to the oral DOAC.
• Anticoagulation in Pregnancy: DOACs and warfarin are strictly teratogenic and contraindicated. Therapeutic Low-Molecular-Weight Heparin (LMWH) (e.g., enoxaparin 1 mg/kg twice daily or dalteparin 100 units/kg twice daily) adjusted for early pregnancy body weight is mandatory throughout pregnancy and continued for at least 6 weeks postpartum (minimum total duration 3 months).
• Cancer-Associated Thrombosis (CAT): Oral DOACs (apixaban, edoxaban, rivaroxaban) are recommended as first-line alternatives to LMWH. However, in patients with unresected gastrointestinal or genitourinary luminal malignancies, LMWH remains preferred due to increased mucosal bleeding risks observed with DOACs.

Duration of Anticoagulation

• Provoked PE: If triggered by a transient, major reversible risk factor (e.g., major abdominal/orthopedic surgery, trauma, immobilisation >=3 days): 3 months of therapeutic anticoagulation is sufficient.
• Unprovoked PE: In the absence of an identifiable reversible trigger, the recurrence risk exceeds 10% in the first year and 30% at 5 years if anticoagulation is halted. Guidelines mandate at least 3 to 6 months of therapeutic anticoagulation, followed by a structured clinical evaluation of bleeding risk (e.g., HAS-BLED or ORBIT) versus thrombotic recurrence risk to determine the appropriateness of indefinite (long-term) anticoagulation.