16.1 Pulmonary Embolism & Deep Vein Thrombosis

Pathophysiology of Venous Thromboembolism & Virchow's Triad

Venous thromboembolism (VTE), which encompasses deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third most common cardiovascular emergency globally, trailing only acute myocardial infarction and stroke. Venous thrombi arise through the convergent pathophysiologic mechanisms historically identified as Virchow's Triad:

1. Hemodynamic Stasis: Impaired venous return and blood pooling—promoted by prolonged immobility (bed rest $\ge 3$ consecutive days, long-haul travel $>4$ hours), lower extremity orthopedic plaster casting, obesity, stroke with hemiplegia, or extrinsic venous compression (e.g., pelvic masses, pregnant uterus, or May-Thurner syndrome [compression of the left common iliac vein by the right common iliac artery]). Stasis permits accumulation of activated coagulation factors while preventing their clearance by hepatic circulation and endogenous inhibitors.
2. Endothelial / Vascular Wall Injury: Disruption of the vascular endothelium exposes subendothelial collagen, tissue factor, and von Willebrand factor, triggering platelet adhesion and the extrinsic coagulation cascade. Precipitating factors include major orthopedic trauma, pelvic and lower extremity fractures, hip or knee arthroplasty, indwelling central venous catheters, and prior intravenous drug use or phlebitis.
3. Hypercoagulability (Thrombophilia): Systemic derangement of the procoagulant-anticoagulant balance. Hypercoagulable states are divided into:
   • Acquired: Active malignancy (adenocarcinomas of the pancreas, lung, gastrointestinal tract, and ovary secrete tissue factor-like procoagulants and mucins), pregnancy and the early puerperium (elevated fibrinogen, factors VII, VIII, X; decreased protein S), exogenous estrogens (combined hormonal contraceptives, hormone replacement therapy, selective estrogen receptor modulators like tamoxifen and raloxifene), antiphospholipid syndrome (lupus anticoagulant, anticardiolipin, anti-beta-2-glycoprotein I), nephrotic syndrome (urinary loss of antithrombin III), and heparin-induced thrombocytopenia (HIT).
   • Inherited: Factor V Leiden mutation (resistance to activated protein C; most common inherited thrombophilia in Caucasian populations), Prothrombin G20210A gene mutation, Antithrombin III deficiency (carries highest relative risk of thrombosis), Protein C deficiency, and Protein S deficiency.

Cardiopulmonary Hemodynamics of Pulmonary Embolism

When a thrombus dislodges from the deep venous system of the lower extremities (most commonly the iliofemoral or popliteal veins; calf vein DVTs embolize in $<10%$ unless propagating proximally) or pelvic veins, it traverses the inferior vena cava, right atrium, and right ventricle, lodging within the pulmonary arterial circulation:

• Mechanical Obstruction & Vasoconstriction: The physical occlusion of pulmonary arterial branches, compounded by the localized release of vasoconstrictive neurohumoral mediators (thromboxane A2 and serotonin from activated platelets), abruptly elevates pulmonary vascular resistance (PVR).
• Right Ventricular Failure & The Spiral of Shock: The thin-walled right ventricle (RV) is physiologically unadapted to acute afterload spikes. When $>30%$ to $50%$ of the pulmonary arterial bed is occluded, the RV dilates and wall tension surges. This produces severe tricuspid regurgitation and shifts the interventricular septum leftward (the echocardiographic "D-sign"). Leftward septal shifting impedes left ventricular (LV) diastolic filling, precipitating a dramatic reduction in LV stroke volume, systemic cardiac output, and mean arterial pressure.
• Myocardial Ischemia: Elevated RV intracavitary pressure combined with systemic hypotension precipitously reduces right coronary artery perfusion pressure, inducing acute RV subendocardial ischemia, cardiogenic shock, and pulseless electrical activity (PEA) cardiac arrest.
• Gas Exchange Derangements: V/Q mismatching results from alveolar dead space ventilation (ventilated alveoli lacking pulmonary perfusion). Concurrently, blood shunts toward non-embolized, hyperperfused lung zones, producing hypoxemia and reflex tachypnea mediated by vagal pulmonary J-receptors, leading to hypocapnia and respiratory alkalosis.

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Clinical Prediction Rules & Triage Algorithms

Unstratified ordering of diagnostic imaging for suspected DVT and PE leads to contrast-induced nephropathy, radiation exposure, false-positive overdiagnosis, and prolonged emergency department lengths of stay. Validated clinical decision algorithms are mandatory.

Wells Criteria for Deep Vein Thrombosis

• Two-Tier Clinical Model:
  • Score $<2.0$ (DVT Unlikely): Obtain high-sensitivity D-dimer assay. If D-dimer is negative ($<500$ µg/L), DVT is ruled out. If positive, proceed to venous duplex ultrasonography.
  • Score $\ge 2.0$ (DVT Likely): Proceed directly to compression venous duplex ultrasonography without relying on D-dimer.

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Wells Criteria for Pulmonary Embolism

• Two-Tier Scoring (Standard Guideline Model):
  • Score $\le 4.0$ (PE Unlikely): Prevalence ~12%. Evaluate with the Pulmonary Embolism Rule-out Criteria (PERC) or quantitative D-dimer assay.
  • Score $>4.0$ (PE Likely): Prevalence ~37%. Skip D-dimer; proceed immediately to Computed Tomographic Pulmonary Angiography (CTPA).
• Three-Tier Scoring:
  • Low Risk (0–1 points): ~10% prevalence. Proceed to PERC or D-dimer.
  • Moderate Risk (2–6 points): ~30% prevalence. Proceed directly to quantitative D-dimer.
  • High Risk ($\ge 7$ points): ~65% prevalence. Proceed directly to CTPA.

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The Pulmonary Embolism Rule-out Criteria (PERC Rule)

The PERC rule was developed to eliminate unnecessary D-dimer testing and imaging in patients presenting with clinical suspicion of PE who have a LOW pretest probability (Wells score $\le 4.0$ or Low Risk). If a low-risk patient fulfills ALL 8 OF THE FOLLOWING CRITERIA, the probability of PE is $<1%$, and diagnostic workup halts without any blood testing or imaging:

1. Age $<50$ years
2. Heart rate $<100$ beats/min
3. Oxygen saturation ($\text{SaO}_2$) $\ge 95%$ on room air
4. No prior history of venous thromboembolism (DVT or PE)
5. No recent trauma or surgery requiring hospitalization within the preceding 4 weeks
6. No hemoptysis
7. No exogenous estrogen use (oral contraceptives, hormone therapy, or SERMs)
8. No unilateral lower extremity swelling

Critical Rule: PERC is applied only when the pretest probability is low. If even a single criterion is positive (e.g., patient is 52 years old, or taking combined oral contraceptives), the PERC rule is "failed," and the clinician must obtain a quantitative D-dimer assay.

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Diagnostic Testing Cascade & Modalities

Age-Adjusted D-Dimer Cutoffs

Quantitative D-dimer is a degradation product of cross-linked fibrin produced during endogenous fibrinolysis. High-sensitivity ELISA or immunoturbidimetric assays possess an exceptional negative predictive value ($>99%$), making a normal value ideal for ruling out VTE. However, circulating D-dimer physiologically increases with advancing age, pregnancy, malignancy, active inflammation, sepsis, and recent surgery, rendering the conventional fixed cutoff ($500$ µg/L or 0.50 µg/mL FEU) non-specific in older adults.

• The Formula (for patients $>50$ years of age): $\text{Age-Adjusted D-dimer Cutoff} = \text{Age (years)} \times 10\ \mu\text{g/L FEU (or ng/mL FEU)}$ (or $\text{Age} \times 0.01\text{ mg/L FEU}$).
• Clinical Validation (ADJUST-PE Trial): In a 78-year-old patient with low or intermediate pretest probability, a D-dimer result of $680$ µg/L is elevated compared to the conventional $500$ µg/L threshold, but falls below the age-adjusted cutoff of $780$ µg/L ($78 \times 10$). PE is safely excluded without obtaining a CTPA, avoiding intravenous contrast, radiation, and unnecessary cost.

Diagnostic Imaging Modalities

1. Computed Tomographic Pulmonary Angiography (CTPA):

   • Definitive Gold Standard: First-line diagnostic imaging modality for PE. Rapidly identifies filling defects within the main, lobar, segmental, and subsegmental pulmonary arteries.
   • Assessment of RV Strain: Provides immediate morphological evaluation of RV dilation (transverse RV/LV diameter ratio $>0.9$ on axial reformatted images) and reflux of IV contrast into the inferior vena cava, which independently predicts in-hospital mortality.
   • Contraindications / Cautions: Severe iodinated contrast allergy and severe acute or chronic renal failure (estimated GFR $<30$ mL/min/1.73m²). In unstable patients, moving to the CT scanner is hazardous.

2. Ventilation-Perfusion (V/Q) Scintigraphy:

   • Visualizes pulmonary capillary perfusion (via IV technetium-99m labeled macroaggregated albumin [Tc-99m MAA]) alongside alveolar ventilation (via inhaled xenon-133 or Tc-99m DTPA aerosol).
   • Strict Indications:
     1. Severe renal insufficiency (eGFR $<30$ mL/min/1.73m² or acute oliguric kidney injury);
     2. Documented severe, life-threatening anaphylactic hypersensitivity to iodinated contrast media;
     3. Pregnancy with a normal baseline chest radiograph: V/Q scanning delivers a substantially lower radiation dose to maternal breast tissue than CTPA (reducing lifetime breast cancer risk) while maintaining high diagnostic accuracy when the baseline chest X-ray is clear.
   • Interpretation: A High-Probability scan ($\ge 2$ large mismatched segmental perfusion defects without matching ventilation defects) diagnostic of PE ($>85%$ PPV); a Normal scan definitively excludes PE; Intermediate / Low Probability scans are indeterminate and mandate further testing (e.g., lower extremity venous ultrasound).

3. Venous Duplex Compression Ultrasonography:

   • First-line diagnostic study for suspected DVT. Complete compressibility of the venous lumen under direct transducer probe pressure is the single most sensitive and specific criterion for ruling out DVT. Non-compressibility, intraluminal echogenicity, and absence of Doppler flow augmentation confirm deep venous thrombosis.
   • If lower extremity ultrasound demonstrates a proximal DVT in a patient with suspected PE, anticoagulation is indicated immediately, often obviating the need for CTPA if renal function or contrast allergy is a concern.

4. Electrocardiography & Echocardiography Findings:

   • ECG: Sinus tachycardia is the most common rhythm abnormality ($>40%$). Classic signs of acute cor pulmonale include the S1Q3T3 pattern (deep S wave in lead I, prominent Q wave in lead III, and T-wave inversion in lead III; present in $<20%$ of PE cases), new complete or incomplete right bundle branch block (RBBB), and T-wave inversions across anterior precordial leads (V1–V4).
   • Transthoracic Echocardiography (TTE): Demonstrates RV enlargement, tricuspid regurgitant jet velocity $>2.8$ m/s, flattened interventricular septum, and McConnell's sign (severe hypokinesis of the mid-free RV wall with normal or hyperdynamic apical contraction; highly specific for acute PE).

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Hemodynamic Risk Stratification & Clinical Staging

Once PE is diagnosed, management is dictated entirely by hemodynamic stability, right ventricular strain, and myocardial biomarker release:

• Subclassification of Intermediate-Risk (Submassive) PE:
  • Intermediate-High Risk: BOTH right ventricular strain (echo or CTPA) AND elevated biomarkers (troponin or BNP) are present. These patients carry a substantial risk of secondary hemodynamic collapse; ICU or step-down admission is required, and rescue reperfusion teams should be alerted.
  • Intermediate-Low Risk: Either RV dysfunction OR an elevated biomarker is present, but NOT both. Managed with standard therapeutic anticoagulation on an inpatient telemetry ward.
• Prognostic Clinical Scores (PESI and sPESI): The Pulmonary Embolism Severity Index (PESI) and simplified PESI (sPESI) stratify 30-day all-cause mortality. An sPESI of 0 points (age $<80$, no history of cancer, no chronic cardiopulmonary disease, heart rate $<100$, SBP $\ge 100$, SaO2 $\ge 90%$) designates Low Risk and qualifies patients for consideration of early outpatient therapy.

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Acute Therapeutic Management & Anticoagulation Protocols

1. Direct Oral Anticoagulants (DOACs) — Preferred First-Line for Stable VTE

DOACs are now recommended over vitamin K antagonists (warfarin) and low-molecular-weight heparin for the acute and long-term treatment of VTE in patients without active cancer, severe renal dysfunction, or antiphospholipid syndrome:

• Apixaban (Eliquis): 10 mg orally twice daily for 7 days, followed by a maintenance dose of 5 mg orally twice daily. Key Exam Pearl: Apixaban does NOT require parenteral heparin lead-in.
• Rivaroxaban (Xarelto): 15 mg orally twice daily taken WITH FOOD for 21 days, followed by 20 mg orally once daily taken with food. Key Exam Pearl: Rivaroxaban does NOT require parenteral heparin lead-in.
• Dabigatran (Pradaxa) (direct thrombin inhibitor) and Edoxaban (Savaysa) (factor Xa inhibitor): Require 5 to 10 days of initial parenteral anticoagulation (LMWH or UFH) prior to initiating oral therapy. Dabigatran dose: 150 mg BID; Edoxaban dose: 60 mg daily.
• Advantages: Immediate onset of action, fixed dosing, no routine coagulation monitoring, and a $>50%$ reduction in major life-threatening intracranial hemorrhage compared to warfarin.

2. Parenteral Anticoagulants

• Low-Molecular-Weight Heparin (LMWH, Enoxaparin):
  • Dosing: 1 mg/kg subcutaneously every 12 hours (or 1.5 mg/kg SC once daily). In severe renal impairment (CrCl $<30$ mL/min), dose is adjusted to 1 mg/kg SC once daily or switched to UFH.
  • Highly predictable bioavailability; anti-Xa monitoring is unnecessary except in extreme obesity (weight $>150$ kg), severe renal failure, or pregnancy.
  • Historical drug of choice in cancer-associated thrombosis (CAT), although DOACs (apixaban, edoxaban, rivaroxaban) are now also guideline-approved alternatives unless GI/GU luminal malignancies pose mucosal bleeding hazards.
• Unfractionated Heparin (UFH):
  • Dosing: 80 units/kg IV bolus, followed by a continuous maintenance infusion of 18 units/kg/hour, titrated to an activated partial thromboplastin time (aPTT) of 1.5 to 2.5 times control or therapeutic anti-Xa level (0.3 to 0.7 IU/mL).
  • Mandatory First-Line Choice for:
    1. Hemodynamically unstable (massive) PE: Rapid half-life (~60–90 min) and full, immediate reversibility with protamine sulfate (1 mg per 100 units heparin administered in preceding 2 hours) should urgent systemic thrombolysis or surgical embolectomy be required;
    2. Severe renal impairment (Creatinine clearance $<30$ mL/min): UFH is cleared via the reticuloendothelial system and does not rely on renal excretion.

3. Reperfusion Therapy for Massive PE

• Systemic Thrombolysis: Recommended for patients with Massive (High-Risk) PE presenting with sustained systemic hypotension (SBP $<90$ mm Hg) or cardiogenic shock, who do not have absolute bleeding contraindications.
  • Regimen: Alteplase (recombinant tPA) 100 mg IV infusion administered over 2 hours (or accelerated weight-based tenecteplase).
  • Mechanism: Cleaves plasminogen to plasmin, rapidly dissolving the obstructive pulmonary thrombus, reducing RV afterload, and reversing cardiogenic shock within hours.
  • Major Contraindications: Absolute contraindications include any prior intracranial hemorrhage, known structural cerebral vascular lesion, malignant intracranial neoplasm, ischemic stroke within 3 months, active internal bleeding (excluding menses), or recent major head/spinal trauma within 3 months.
• Catheter-Directed Therapy (CDT) & Surgical Embolectomy:
  • Catheter-Directed Thrombolysis / Mechanical Thrombectomy: Delivers ultra-low-dose tPA (e.g., 0.5–1.0 mg/hr) directly into the clot via pulmonary artery infusion catheters, with or without ultrasound agitation or aspiration. Indicated for massive PE when systemic thrombolysis is contraindicated or has failed, or in selected intermediate-high risk patients deteriorating clinically.
  • Surgical Pulmonary Embolectomy: Open sternotomy with cardiopulmonary bypass to manually extract large central saddle emboli in patients with massive PE and absolute contraindications to thrombolysis.

4. Inferior Vena Cava (IVC) Filters

An IVC filter is an expandable metallic alloy device deployed into the infrarenal inferior vena cava to intercept dislodged lower extremity thrombi.

• Strict Guideline Indications:
  1. Absolute contraindication to full therapeutic anticoagulation (e.g., active major intracranial, retroperitoneal, or gastrointestinal hemorrhage; impending emergent major neurosurgery);
  2. Active, life-threatening major bleeding occurring during therapeutic anticoagulation;
  3. Recurrent, objectively verified pulmonary embolism occurring despite documented therapeutic levels of anticoagulation.
• Filter Management & Retrieval Mandate: IVC filters do NOT reduce overall long-term mortality and increase the long-term risk of deep vein thrombosis and caval occlusion. Modern filters are retrievable and should be removed endovascularly as soon as the contraindication to anticoagulation resolves or bleeding risk diminishes (ideally within 2 to 6 months).

5. Duration of Anticoagulation Therapy

• Provoked VTE by Major Transient Risk Factor (e.g., major surgery, orthopedic trauma, hospitalization for $>3$ days): 3 months of therapeutic anticoagulation, after which therapy is discontinued.
• Unprovoked VTE or Persistent Risk Factor (e.g., active cancer, antiphospholipid syndrome, recurrent unprovoked events): Indefinite (extended) anticoagulation, with annual clinical assessments of bleeding risk versus recurrent thrombosis.