> Table of Contents > Pulmonary Embolism
Pulmonary Embolism
Karla A. Oliveros, MD
Alfonso Tafur, MD, MS, RPVI
image BASICS
DESCRIPTION
  • Pulmonary embolism (PE) is the most serious presentation of venous thromboembolism (VTE).
  • Mortality exceeds 15% during the first 3 months. In 25% of patients, first manifestation is sudden death.
EPIDEMIOLOGY
Case fatality rate 1-60%. For patients with intermediate risk, mortality rate is 3-15% if right ventricular (RV) dilation or dysfunction. If hemodynamically unstable, mortality is >15% due to worsening RV failure and cardiogenic shock.
Incidence
  • Approximately 60 to 70 per 100,000, with >100,000 cases annually in the United States.
  • Incidence increases with age, most occurring at 60 to 70 years of age.
  • 250,000 hospitalizations per year in the United States, 10-60% in hospitalized patients.
    • Highest risk for orthopedic patients
    • 1:1,000 pregnancies (including postpartum)
ETIOLOGY AND PATHOPHYSIOLOGY
  • Venous stasis, endothelial damage, and changes in coagulation properties trigger formation of thrombus (1).
  • Causes increased pulmonary vascular resistance, impaired gas exchange, and decreased pulmonary compliance. RV failure due to pressure overload is usually the primary cause of death (1).
  • DVT in the proximal veins is the most common source of PE, up to 85% of the cases.
Genetics
  • Factor V Leiden: Most common thrombophilia. +5.5% in Caucasian, 2.2% in Hispanics, 1.2% in African American, 0.5% in Asian. Associated with 20% of all VTE
  • Prothrombin G20210A: 3% of Caucasians, rare in African American, Asian, and Native American; 6% in patients with VTE
  • Deficiencies in protein C, S, and antithrombin
RISK FACTORS
  • Acquired: age, immobilization, surgery, major trauma, lower limb fractures, joint replacement, spinal cord injury, cancer, hormonal replacement therapy, pregnancy/puerperium, previous thrombosis, paroxysmal nocturnal hemoglobinuria, antiphospholipid syndrome, prolonged travel
  • Oral contraceptives is the most frequent medication (1).
  • Inherited: Antithrombin deficiency, protein C or S deficiency, factor V Leiden, prothrombin gene mutation G20210A (1)
GENERAL PREVENTION
  • Mechanical thromboprophylaxis: early ambulation after surgery, compression stockings, and intermittent pneumatic compression
  • Intermediate risk: general, gynecologic, or urologic surgery; prophylaxis is recommended with low-molecular-weight heparin (LMWH), unfractionated heparin (UFH), or fondaparinux.
  • High risk: 10 or more days prophylaxis in hip or knee arthroplasty, with LMWH, fondaparinux, apixaban, dabigatran, rivaroxaban, or low-dose UFH. 28 to 35 days with LMWH, fondaparinux, UFH, or vitamin K antagonists (VKA) in hip fracture surgery. LMWH or UFH in major trauma, spinal cord injury
  • Long-distance travel (>8 hours): hydration, walking, avoidance of constrictive clothing and frequent calf exercises; if additional risk factors, then compression stockings below knee
  • Patients with factor V Leiden, prothrombin G20210A with no previous thrombosis do not need long-term daily prophylaxis.
image DIAGNOSIS
  • Establish a pretest probability based on clinical criteria (2).
    • Wells score
      • Clinical signs and symptoms of DVT +3
      • Alternative diagnosis is less likely than PE +3
      • Heart rate >100 +1.5
      • Immobilization previous 4 weeks +1.5
      • Previous DVT/PE +1.5
      • Hemoptysis +1
      • Malignancy +1
      • <2 points, low clinical probability; 2 to 6 points, moderate; >7 points, high
  • Recently, Wells and revised Geneva score were simplified (2).
    • Wells score: Each predictor is +1. PE unlikely if 0 to 1, PE likely if >2.
    • Geneva score: Each predictor is +1 except for heart rate >95 which is +2. PE unlikely if 0 to 2 and PE likely if >3.
PHYSICAL EXAM
  • Dyspnea, syncope, hemoptysis, tachycardia, tachypnea, accentuated S2. Pleuritic chest pain, pleural friction rub, rales (1)
  • Signs of DVT, leg swelling, tenderness, visible collateral veins (1)
  • Signs of RV failure: jugular vein distention, third or fourth sound, systolic murmur at left sternal edge, hepatomegaly (1)
DIFFERENTIAL DIAGNOSIS
  • Pulmonary: pneumonia, bronchitis, pneumothorax, pneumonitis, chronic obstructive pulmonary disease (COPD) exacerbation, pulmonary edema, pneumothorax
  • Cardiac/vascular: myocardial infarction, pericarditis, congestive heart failure (CHF), aortic dissection
  • Musculoskeletal: rib fracture(s), musculoskeletal chest wall pain
DIAGNOSTIC TESTS & INTERPRETATION
  • D-dimer ELISA: In patients with low pretest probability, it can rule out PE if it is negative (high negative predictive value [NPV]) (1)[A]. It is not diagnostic if positive (low positive predictive value [PPV]) and it is not helpful if pretest probability is intermediate or high (1)[B].
  • CBC, creatinine, aPTT and PT, ABG: In young patients with idiopathic, recurrent, or significant family history of VTE, consider testing for hypercoagulable tests.
    • Do not test for protein C, S, factor VIII, or antithrombin in the acute setting or while on treatment, as may be falsely abnormal.
    • Patients with intermediate or high pretest probability and low probability with elevated D-dimer need further diagnostic testing.
  • Chest x-ray (CXR): Westermark sign (lack of vessels in an area distal to the embolus), Hampton hump (wedge-shaped opacity with base in pleura), Fleischner sign (enlarged pulmonary arteries), atelectasis, pleural effusion, pulmonary infarct, hemidiaphragm elevation (1)
  • ECG: right heart strain, nonspecific rhythm abnormalities, S1Q3T3
  • CT pulmonary angiography: sensitivity 96-100%, specificity 86-89%; NPV 99.8%. If normal, it safely excludes PE if low or intermediate clinical probability (1)[A].
  • Ventilation/perfusion scintigraphy (V/Q scan): safe with few allergic reactions. Use if CT angiography is not available or contraindicated. A high-probability V/Q scan makes the diagnosis of PE; normal V/Q scan excludes PE (1)[B].
  • Pulmonary angiography: gold standard but invasive and technically difficult: 2% morbidity and <0.01 mortality risk (1)[C]
  • Echocardiogram: Assess RV function, found in 25% of patients with PE.
  • Magnetic resonance angiography: lower sensitivity and specificity than CT angiography
  • Compression venous ultrasound (CUS): noninvasive. Sensitivity >90%, specificity approximately 95%. It confirms the diagnosis of PE in patients with clinical suspicion (1)[B].
  • CT venography: can be done at the same time as CT angiography; increases diagnostic yield (1)
Follow-Up Tests & Special Considerations
Elevated troponin I or T and elevated BNP are markers for higher risk patients.
image TREATMENT
MEDICATION
  • If clinical suspicion is high and no contraindications, start treatment immediately.
  • Start LMWH, fondaparinux, UFH, as initial therapy for first 5 to 10 days. VKA can be started the 1st day and must overlap with parenteral treatment for minimum of 5 days, until international normalized ratio (INR) is 2 to 3 for 24 hours.
  • Following 5 to 10 days of parenteral therapy, dabigatran or edoxaban are also approved (1).
  • P.885

  • An oral option for initial and long-term treatment is rivaroxaban or apixaban (1).
  • Patients with massive PE with low bleeding risk: Consider systemic thrombolytics if no contraindications. Also in patients <75 years old with submassive PE. Greater benefit if initiated within 48 hours of symptoms onset (1)
First Line
  • UFH (3)[A]:
    • IV bolus of 80 U/kg or 5,000 U followed by continuous infusion (initially 18 U/kg/hr or 1,300 U/hr) with dose adjustments to maintain aPTT that corresponds to anti-Xa levels of 0.3 to 0.7
    • SC injection: 2 options:
      • Monitored: 17,500 U or 250 U/kg BID with dose adjustments to maintain an aPTT that corresponds to anti-Xa levels of 0.3 to 0.7 measured 6 hours after a dose
      • Fixed dose: 333 U/kg initial dose, followed by 250 U/kg BID
  • LMWH: preferred due to lower risk of major bleeding and heparin-induced thrombocytopenia (HIT) (1),(3)[A]
    • Enoxaparin (Lovenox) 1 mg/kg/dose SC q12h
    • Dalteparin (Fragmin 200 U/kg SC q24h
    • Fondaparinux (Arixtra): 5 mg (body weight <50 kg), 7.5 mg (body weight 50 to 100 kg), or 10 mg (body weight >100) SC q24h
  • Maintenance therapy: Warfarin on day 1, if possible; 5 mg/day for 3 days in hospitalized or older patients, and at a dose of 10 mg in <60 years of aged patients; adjust dose to maintain an INR of 2 to 3. Needs to overlap with UFH, LMWH, or fondaparinux: 5 to 7 days, until 2 consecutive days of therapeutic INR (1).
  • Rivaroxaban: 15 mg BID for 3 and then 20 mg once daily to complete treatment. Compared to warfarin, it has less major bleeding side effects while having same efficacy (1)[B].
  • Edoxaban: 60 mg once daily (reduced to 30 mg once daily if CrCl 30 to 50 mL/min or body weight <60 kg). Patients require initial treatment with LMWH at least 5 days before starting edoxaban. Less bleeding risk compared to warfarin (1)[B]
  • Apixaban: 10 mg BID for 7 days, followed by 5 mg once daily was compared to conventional therapy. Compared to warfarin, noninferior against recurrent symptomatic VTE or death related to VTE, with less frequently major bleeding episodes (1)[B]
  • Dabigatran: Require initial treatment with LMWH. Compared to warfarin, 150 mg BID had noninferior efficacy and no differences in major bleeding and fewer episodes of any bleeding (1)[B].
  • Active bleeding.
  • Heparin: HIT
  • LMWH: HIT, renal failure
  • Warfarin: pregnancy
  • Rivaroxaban and Fondaparinux: renal failure (1)[A]
  • Edoxaban: severe kidney or liver failure (1)[A]
  • Apixaban: renal impairment and nonvalvular atrial fibrillation (1)[A]
  • Dabigatran: severe kidney problems. Use of dronedarone or ketoconazole increase risk.
Pregnancy Considerations
  • Warfarin is teratogenic and should not be used in pregnant patients (especially in 1st trimester); safe while breastfeeding
  • LMWH: Dalteparin, enoxaparin, and fondaparinux are Category B; heparin is Category C, use if the benefit overweight risks.
  • UFH: Require aPTT monitoring. Can cause osteoporosis if used for prolonged period
  • Rivaroxaban is Category C.
  • Edoxaban and Apixaban: Category B; increases risk of hemorrhage
  • Dabigatran: Category C; use it only if benefit overweight side effects.
Second Line
Massive PE: Consider thrombolytics if the patient has hemodynamic compromise and low bleeding risk, intracranial hemorrhage risk: 0.7 to 6.4%: (1),(3)[B]
  • Tissue plasminogen activator (tPA) 100 mg infused over 2 hours. Absolute contraindications:
    • Intracranial hemorrhage, known intracranial cerebrovascular or malignant disease, ischemic stroke within 3 months, suspected aortic dissection, bleeding diathesis, active bleeding, recent neurosurgery, or major trauma
SURGERY/OTHER PROCEDURES
  • Inferior vena cava (IVC) filter placement if absolute contraindication for anticoagulation or recurrent PE despite adequate anticoagulation treatment (3)[B].
  • PREPIC2 trial showed that retrievable IVC filters at 3 months plus anticoagulation compared to anticoagulation alone among patients with severe PE had no benefit reducing the risk of symptomatic recurrent PE (3%, 95% CI, 1.1-6.5% vs. 1.5%, 95% CI, 0.3-4.3%) (3)[C].
  • Emergency embolectomy can be considered in patients with massive PE with contraindications for thrombolysis (3)[C].
  • Consider catheter-based interventions if massive PE and thrombolytic contraindications (3)[C].
  • Consider ultrasound-assisted catheter-directed thrombolysis (USAT) in patients with intermediate risk of death or submassive PE, superior than heparin alone in reversing RV dilation at 24 hours without increase in bleeding complications.
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
ICU-level care if hemodynamically unstable
image ONGOING CARE
Duration of anticoagulation
  • Provoked PE (trigger no longer present): 3 months (1)[B]
  • Unprovoked PE: Minimum of 3 months, consider long-term or prolonged secondary prophylaxis if bleeding risk is low (1)[B].
  • Cancer-related PE: LMWH first 3 to 6 months. Consider secondary prophylaxis as long as the patient has active cancer (1)[B].
  • Recurrent PE: long-term anticoagulation
FOLLOW-UP RECOMMENDATIONS
  • If concomitant DVT, knee-height compression stockings, 30 to 40 mm Hg knee height
  • If an IVC filter was placed, follow-up for retrieval.
Patient Monitoring
  • INR should be checked regularly; target is 2 to 3 (1).
  • aPTT needs to be monitored in SC UFH (1).
  • Anti-Xa can be checked in special circumstances if treated with LMWH, including pregnancy, younger patients, renal disease.
DIET
Warfarin use; recommend a vitamin K diet.
PROGNOSIS
  • Massive PE 50% versus nonmassive PE 8-14%
  • Simplified Pulmonary Embolism Severity Index score predicts acute mortality (any one of the following defines high-risk: age >80 years, history of cancer, chronic cardiopulmonary disease, heart rate 110/min, systolic blood pressure <100 mm Hg, O2 saturation <90%) (1)[B].
  • High early mortality risk: shock or hypotension, +SPESI index >1 + RV dysfunction signs by imaging and cardiac laboratory biomarkers (1)
  • Intermediate high early mortality risk: no shock or hypotension + SPESI >1 + RV dysfunction signs by imaging and cardiac laboratory biomarkers (1)
  • Intermediate low early mortality risk: no shock or hypotension + SPESI >1 + either RV dysfunction by imaging or cardiac laboratory biomarkers (1)
  • Low early mortality risk: no shock or hypotension, no SPESI; imaging is optional (if assessed is negative) (1).
REFERENCES
1. Konstantinides SV, Torbicki A, Agnelli G, et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014;35(43):3033-3069, 3069a-3069k.
2. El Wahsh R, Agha M. Clinical probability of pulmonary embolism: comparison of different scoring systems. Egypt J Chest Dis Tuberc. 2012;61(4):419-424.
3. Jaff MR, McMurtry MS, Archer SL, et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation. 2011;123(16):1788-1830.
Codes
&NA;
ICD10
  • I26.99 Other pulmonary embolism without acute cor pulmonale
  • I27.82 Chronic pulmonary embolism
Clinical Pearls
&NA;
  • PE can be excluded in patients who have low pretest probability and negative D-dimer testing.
  • Perform cancer-oriented review of systems and age/gender-appropriate cancer screening in patients >40, recurrent VTE, upper extremity DVT (not related to catheter or lines), bilateral lower extremity DVT, intra-abdominal DVT, resistance to treatment.
  • In patients with prolonged baseline aPTT, adjust heparin dose with anti-Xa levels (therapeutic range 0.3 to 0.7).