Pulmonary Embolism

Summary

Pulmonary embolism is a potentially life-threatening condition that occurs when blood clots obstruct pulmonary arteries. It represents the third leading cause of cardiovascular death after myocardial infarction and stroke, with annual mortality rates ranging from 3.7% in stable patients to over 20% in those with hemodynamic instability. The disease spectrum ranges from asymptomatic, incidentally discovered PEs to catastrophic events causing immediate cardiovascular collapse. Treatment approach is based on careful risk stratification, with options ranging from anticoagulation alone to advanced therapies including catheter-directed interventions, surgical embolectomy, and mechanical circulatory support.

Definitions

PE severity is classified into low, intermediate, and high-risk PE based on hemodynamic status, RV dysfunction, and biomarker elevation.

Low-Risk (PESI I-II)

Hemodynamically stable without evidence of RV strain.

• SBP >90 mmHg
• No RV dysfunction
• No elevated cardiac biomarkers

Low-Intermediate Risk (PESI III)

Hemodynamically stable with evidence of RV strain OR elevated cardiac biomarkers, but not both.

• NT-pro-BNP >500
• Elevated troponin
• Echocardiographic e/o dysfunction or overload

High-Intermediate Risk (PESI III)

Hemodynamically stable with evidence of RV strain AND elevated cardiac biomarkers. These patients have a higher risk fo deterioration and may benefit from more aggressive treatments if they show signs of clinical worsening.

High-Risk (PESI IV+)

PE causing hemodynamic instability due to RV failure. Previously known as “massive” PE.

• SBP <90 not due to hypovolemia for >15 minutes or requiring vasopressors
• Severe RV dysfunction of imaging
• Lactic acidosis, hypoxia, or cardiogenic shock

Etiology

The vast majority of pulmonary emboli originate from deep venous thrombosis (DVT) in the lower extremities. Proximal DVT (ilac, femoral, popliteal) increase the risk for PE whereas distal (below the knee) are of less concern.

Key risk factors include:

• OR >10 - hip or leg fracture or replacement, major surgery or trauma, spinal cord injury
• OR 2-9 - OCP, paresis, hospitalized/SNF, previous VTE, active cancer, CVC, sepsis, HF
• OR < 2 - bed rest > 3 days, long travel, increased age, obesity, smoking, cirrhosis, CKD

Major Risk Factors:

• Recent surgery or trauma (especially orthopedic)
• Active malignancy
• Prolonged immobilization
• Previous VTE history
• Known thrombophilia

Moderate Risk Factors:

• Pregnancy and postpartum state
• Hormone therapy (including oral contraceptives)
• Obesity (BMI > 30)
• COVID-19 infection

Pathophysiology

PE affects the cardiopulmonary system through multiple mechanisms:

• Mechanical Obstruction: Clots physically block pulmonary arteries, increasing pulmonary vascular resistance
• Humoral Effects: Release of vasoactive substances (serotonin, thromboxane) causes:
  • Pulmonary vasoconstriction
  • Bronchial constriction
  • Ventilation-perfusion mismatch
• Right Ventricular Response:
  • Acute increase in RV afterload
  • RV dilation and dysfunction
  • Reduced LV preload from septal bowing
  • Potential progression to cardiogenic shock

Signs and Symptoms

• Common Presentations:
  • Dyspnea (most common, >75% of cases)
  • Pleuritic chest pain (~20%)
  • Cough
  • Hemoptysis (less common)
  • Syncope/near-syncope (indicates severe disease)
• Physical Exam Findings:
  • Tachypnea (up to 50%)
  • Tachycardia (up to 50%)
  • Hypoxemia
  • Signs of DVT (unilateral leg swelling) in 30-50% of cases
  • Signs of right heart failure in severe cases (JVD, peripheral edema

Diagnostic Workup

Initial Assessment:

There are many ways to rule out the need for further testing for PE. In general, start by calculating Wells. If high, go straight to imaging. If low, see if the patient has any PERC crteria. If not, stop. If yes, get a D-Dimer.

• Vital signs with pulse oximetry
• Wells' Criteria - note there are two different scores for DVT and for PE
  • If Low pre-test probability for PE (or Mod for DVT), get D-Dimer
  • If Mod or High pre-test probability for PE (or High for DVT), go straight to imaging

Calculating Well’s Score

Interprerting Well’s Score (Two Ways)

• PERC Score
  • Calculated after a patient is alredy determined to have a low pre-test probability for PE.
  • Essentially rules out PE if ALL criteria are negative and the clinician has “implicit sense” there is less than 15% probability of PE.
  • When using the PERC score only 0.3% of PEs would have been missed, and 22% of D-dimer testing would have been safely avoided.

Calculating PERC Score

• D-Dimer
  • A fibrin degredation product formed when clots (composed of fibrin) are broken down by plasmin that is a marker of active clot formation and subsequent breakdown
  • Highly sensitive (95-99%), but low specificity since many conditions can cause an elevated D-Dimer
  • Most valuable to rule out PE only if there is a low/intermediate pretest probability of PE; a patient with high enough pre-test probability can have a PE despite a normal D-Dimer

Causes of Elevated D-Dimer

Imaging:

• CT pulmonary angiogram is the gold standard
  • Highly sensitive (85-95%) for segmental and larger PE, but may miss small subsegmental emboli
  • Highly specific (95-98%) with few false positives (”filling defects”)
• V/Q scan if CTPA contraindicated (i.e pregnancy)
• EKG
  • Normal (20-25%)
  • Tachycardia (28-38%)
  • T-wave Inversions V1-V4 (7-38%)
  • S1Q3T3 / McGinn-White Sign (~4-8%)
  • New RBBB (9-10%)
  • ST-elevations in aVR
  • Right-Axis Deviation (4.2%)

Risk Stratification

• Troponin, NT-proBNP, lactate
• Echocardiogram
  • Enlarged RV with RV/LV diameter > 0.9
  • Moderate/Severe tricuspid regurgitation (TR) suggests elevated RV systolic pressure
  • McConnell’s Sign - RV apex is contracting but the mid and basal RV free wall is not
  • Interventricular septum bulging into the LV
• PESI Score
  • Used to predict 30-day mortality in patients diagnosed with PE which helps to guide disposition and treatment decisions

Calculating PESI Score

Interpreting PESI Score

Treatment

Treatment strategy depends on risk stratification:

1. High-Risk/Massive PE

• Immediate anticoagulation (IV UFH preferred)
• Consider reperfusion therapy:
  • Catheter-directed intervention if available
  • Systemic thrombolysis if severe instability
  • Surgical embolectomy in select cases where thrombolysis is contraindicated
• VA-ECMO for refractory shock

2. Intermediate-Risk PE:

• Anticoagulation (see below)
• Close monitoring
• Consider catheter-directed therapy if high-risk features
• Rescue thrombolysis if clinical deterioration

3. Low-Risk PE:

• Anticoagulation (DOACs preferred):
  • Apixaban 10mg BID x 7 days then 5mg BID
  • Rivaroxaban 15mg BID x 21 days then 20mg daily
  • Alternative: LMWH with transition to warfarin

Duration of Treatment

Determined by careful assessment of individual’s risk for recurrent VTE weighted agaisnt risk of rebleeding and patient preference.

PE are considered “provoked” if associated with a transient risk factor such as surgery, trauma, immobility, pregnancy/peripartum period, or in the setting of overt cancer. It is considered unprovoked in the absence of a transient risk factor. Note that the presence of thrombophilia does not alter the classification of provoked vs unprovoked, but is still can impact decisions for the length of AC treatment based on risk of recurrence.

• Provoked PE - 3 months, provided risk factor no longer present
• Unprovoked PE - at least 3 months; can be extended if bleeding risk is low, there is a high risk of recurrence due to persistent risk factors or previous unprovoked PEs
• Recurrent VTE - long-term, indefinite AC generally recommended
• Active Cancer - at least 6 months, as long as the cancer is active or patient is receiving treatment; historically LMWH was preferred, however apixaban is now accepted as a first-line treatment

Contraindications to Thrombolysis

Absolute Contraindications:

• Active internal bleeding
• Recent intracranial hemorrhage (ICH) (some guidelines specify within 3 months, others 6 months or any history of ICH)
• Ischemic stroke within the past 3 months (some exceptions may be made for very recent strokes within 4.5 hours in carefully selected cases)
• Intracranial neoplasm (primary or metastatic)
• Recent intracranial or spinal surgery or head trauma (within the past 3 months)
• Severe uncontrolled hypertension (e.g., systolic blood pressure > 200 mmHg or diastolic blood pressure > 110 mmHg despite treatment)
• Known bleeding diathesis or severe coagulopathy
• Suspected aortic dissection

Relative Contraindications:

• Recent major surgery (within the past 14 days)
• Recent trauma (within the past 14 days)
• Cardiopulmonary resuscitation (CPR) for more than 10 minutes
• Recent internal bleeding (within 2-4 weeks)
• Non-compressible vascular punctures
• Pregnancy
• Active peptic ulcer disease
• Mild to moderate hypertension, well-controlled
• Anticoagulant use (depends on the specific agent and level of anticoagulation)
• Dementia

Special Populations

• Pregnancy - preference for LMWH
• Renal Impairment - UFH or apixaban favored for those with CKD
• APLS - warfarin is preferred treatment

Pearls

Epidemiology and General Information:

• Venous thromboembolism (VTE) is an umbrella term including both PE and DVT
• 50-60% percent of VTE events are provoked by surgery/hospitalization, 20% are associated with cancer, and 20%-30% are “unprovoked”
• Patients with cancer have a 7-fold increased risk of developing VTE with a 5% to 20% risk of developing VTE within one year of diagnosis
• Half of DVTs embolize to the lungs
• 10% of DVTs are in the upper extremities, a majority of which are associated with either central venous catheters or a malignancy
• PE accounts for ~40,000-100,000 deaths annually in the US
• PE is the leading cause of cardiovascular death after MI and stroke
• Diagnosis rates have increased with CT availability
• Only 5% present as high-risk PE but in such cases, mortality exceeds 30%
• The term “massive PE” has fallen out of favor; the size of the clot (while likely correlated with risk) is not directly taken into account, but is still important to keep in mind
• A “Saddle PE” is a large thrombus that straddles the bifurcation of the main pulmonary artery, extending into both the right and left pulmonary arteries; it often leads to high-risk classification, but not always
• VTE is considered recurrent if it happens after receiving 2 weeks of AC

Pathophysiology:

• Virchow's Triad - venous stasis, vascular injury, hypercoagulability
• The signs/symptoms of PE come from a combination of infarction and inflammation of lung tissue (hemoptysis, chest pain, fever, cough), V/Q mismatch from decreased perfusion (dyspnea), and sometimes cardiac compromise due to elevated pulmonary artery pressure (tachycardia, shock, syncope)
• Smaller PEs can be clinically significant if cardiopulmonary reserve is limited
• RV failure is the primary cause of death
• High-Risk PE is a common cause of PEA arrest
• High-Risk PE leads to increased RV afterload, reducing CO, leading to obstructive shock - SVR will increase in response to the reduced CO and shock; PCWP will be lower; RV pressure will push septum against the LV leading to less LV diastolic filling, further dropping CO
• In PE, postitive-pressure ventilation (PPV) decreases venous return, decreases RV output, and increases RV failure - if you can avoid intubating these patients and and instead keep them on HFNC, you might save their life. Patients with high-risk PE who get intubated can have hemodynamic collapse and code. If you have to, consider pulmonary vasodilators, have epinephrine ready at bedside, try to use sedatives that will not lead to hypotension (ketamine).

Clinical Presentation and Diagnosis:

• Normal oxygen saturation doesn't rule out PE
• PE Prevalence in Syncope - 1 in 6 among patient’s hospitalized for the first episode of syncope (NEJM, 2016) ; However, among patients who just present to the ED, it’s more like 1% (J Am Coll Cardiol, 2019) (note these patients were not the first episode of syncope); and for those who ended up getting admitted it was more like 2-3%
• In PE, fever can be present without infection
• EKG changes are often non-specific
• Vignettes will often include hemoptysis, JVD, and Kussmaul sign, but all are rare in real life
• Troponin and lactate are good markers for risk of death even if not specific to PE
• Troponin is elevated if there is a sudden rise in RV pressure which can damage myocardial tissue; BNP elevated due to the myocardial stretch
• NT-proBNP is not specific to PE since it also measures LV stretch and can be high in those with ADHF and CKD/ESRD
• D-Dimer has high sensitivity and NPV, but poor specificity
• D-Dimer <500 and moderate pre-test probability OR D-Dimer <1000 and low PTP essentially rules out DVT/PE (NEJM, 2019)
• Age-adjusted D-Dimer cutoff is “Age x 10” since older patients can have higher levels  (JAMA, 2014)
• The DDx for elevated D-Dimer includes arterial clot (MI, stroke, acute limb ischemia), DIC, cancer, infection, cirrhosis, renal disease, increased age, trauma, surgery
• Duplex ultrasonography refers to the dual nature of the imaging (anatomical and functional) via taking images and measuring blood flow via Doppler (named for the Doppler shift it is measuring); Compression ultrasonography involves attempting to manually compress the veins with the probe to assess for the presence of clot
• A negative US study does not rule out PE, as clots can migrate
• Hampton Hump - a wedge-shaped opacity on CXR that suggests infarction; not specific for PE
• “Wedge-shaped infarction” on CT is essentially pathognomonic for PE, but is rarely seen
• A hypercoagulability workup should not be done at the time of the acute VTE or while a patient is on AC - one exception is if there is high concern for APLS (young woman, previous lost pregnancies, arterial clotting)

Treatment:

• Anticoagulation does not break up clots, but rather prevents further further clot for forming while the body breaks down clots on its own via thrombolytic pathways
• Recommendations suggest that neither age nor fall risk are reasons to withhold anticoagulation
• Unfractionated heparin (UFH) works by binding to antithrombin III, potentiating its action, resulting in the inactivation of thrombin (factor IIa) and factor Xa.
• In general, UFH is dosed based on weight with an initial 80 U/kg bolus followed by 18 U/kg/hr infusion which is then adjusted based on aPTT
• aPTT is used to monitor heparin therapy. aPTT may be unreliable in patients with lupus anticoagulant (prolongs aPTT), heparin resistance, or elevated factor VIII. In these cases, anti-factor Xa can be used instead.
• LWMH has faster therapeutic onset and longer duration compared to UFH, and you don’t need to check PTT
• Low molecular weight heparin (LMWH) has a smaller fragment size which can still inactivate factor Xa but does not exert its effect as much on thrombin - this is the reason aPTT is not useful for trending
• LWMH is renally cleared - need to reduce the dose or avoid entirely if GFR <30
• Protamine sulfate is used to reverse heparin - each 1mg neutralizes ~100U of heparin or 1mg of enoxaparin and it is expected to work within 5 minutes; assume the half-life of heparin is between 30-60 minutes; the max dose should be 50mg; protamine can lead to anaphylaxis-like reactions (derived from fish sperm)
• Warfarin inhibits vitamin K epoxide reductase, which leads to less carboxylation of coagulation factors II, VII, IX, and X along with proteins C and S; Warfarin lowers protein C levels first, so initiating treatment can cause a temporary prothrombotic state
• Warfarin should be considered in those with kidney disease, morbid obesity, a mechanical heart valve, or high-risk APLS - these are patients who were not included in the initial DOAC trials
• Warfarin is titrated to INR 2-3 - the most common causes for having non-therapeutic INR are changes in vitamin K intake, medications, and nonadherence.
• If the INR is greater than 10 in patients without bleeding, oral vitamin K should be given.
• DOACs are first-line for most patients, however you should check pricing with a patient’s insurance before aligning on the final regimen
• DOACs are generally avoided if CrCl <15 mL/min, but apixban is likely safe even in ESRD
• You don’t have to give AC for subsegmental PE with low risk of recurrence
• If there is an upper extremity DVT, you can leave in the associated PICC/CVC if it's functional and there is no concern for an infection, just initiate and continue AC for 3 months or as long as the line remains in place
• IVC filters should be rarely considered and should be removed within 25-54 days when possible

Complications:

• The is a high recurrence risk without anticoagulation (~10% first year)
• Chronic PE can lead to CTEPH
• Post-PE syndrome is persistent dyspnea anf functional limitations after acute PE
• Pulmonary infarction (~10% of cases); more common in peripheral, small PEs
• Atelectasis (~20% of cases)
• If the PE is unprovoked, on discharge ensure the patient has age-appropriate cancer screening; a hypercoagulability workup should not be done at the time of the acute VTE or on AC. One exception is if there is high concern for APLS (young woman, previous lost pregnancies, arterial clotting).

Trials and Helpful Literature

Review Articles:

• “Pulmonary Embolism” (NEJM, 2022)
• “Acute Pulmonary Embolism: A Review” (JAMA, 2022)
• "Contemporary management and outcomes of patients with high-risk pulmonary embolism" (JACC, 2024)
• "A Rational Approach to the Treatment of Acute Pulmonary Embolism" (Annu Rev Med, 2025)

Clinical Trials:

Thrombolysis

• PEITHO - tPA in intermediate-risk PE showed no long-term benefit or change in mortality but led to increased major bleeding and hemorrhagic CVA - solidified the general idea is that we give tPA in massive PE to prevent immediate death, not to help with long-term outcomes (NEJM 2014)
• Meta-Analysis - Thrombolysis for those with RV strain does improve mortality, but also increased severe bleeding episodes (JAMA 2014)

Catheter-Directed Therapy and Thrombectomy

• Catheter-directed tPA appears to be superior to peripherally administered tPA at the same dose in terms of reducing mortality and intracranial hemorrhage in patients with pulmonary embolism; however there is currently no quality clinical trial data to support this
• ULTIMA - In patients with intermediate-risk pulmonary embolism, ultrasound-assisted catheter-directed thrombolysis led to improved right ventricular function at 24 hours compared to anticoagulation alone, without increased major bleeding complications. (Circulation, 2014)
• SEATTLE II - In patients with acute massive or submassive PE, ultrasound-facilitated, catheter-directed, low-dose fibrinolysis decreased RV dilation, reduced pulmonary hypertension, and decreased anatomic thrombus burden without causing intracranial hemorrhage when compared to baseline measurements. (JACC, 2015)
• FLARE Trial - thrombectomy (FlowTriever) to remove clot had good data in a single-arm study in patients with submassive PE - reduced RV/LV ratio and need for thrombolytic (JACC Cardiovasc Interv, 2019)
• HI-PEITHO (ongoing): Ultrasound-assisted thrombolysis vs anticoagulation (Am Heart J, 2022)
• PEERLESS II (ongoing): Large-bore thrombectomy vs anticoagulation in intermediate-risk PE (J Soc Cardiovasc Angiogr Interv, 2024)

Anticoagulation

• The CLOT Trial - LMWH is better than Warfarin at preventing recurrent DVT in Patients with Malignancy (NEJM, 2003)
• RE-COVER - DOAC (Dabigatran/Pradaxa) non-inferior to warfarin for treatment of VTE at 7 days and 6 months follow up (NEJM, 2009)
• EINSTEIN-PE - Rivaroxaban to treat PE - Oral factor Xa inhibitor non-inferior in preventing recurrent VTE after PERate of major bleeding is significantly lower with rivaroxaban (NEJM, 2012)
• AMPLIFY - Apixaban in VTE - Apixaban non-inferior to lovenox followed by warfarin in the treatment of VTE with significantly less major bleeding with apixaban vs. conventional therapy (NEJM, 2013)
• PREPIC-2 - IVC filters + AC vs just AC in patients with submassive IVC had a trend towards harm (JAMA, 2015)
• SELECT-D - Rivaroxaban low VTE recurrence but high clinically relevant bleeds v.s. dalteparin (JCO, 2018)
• HOKUSAI-VTE - edoxaban (DOAC) was noninferior to dalteparin for VTE recurrence but with higher rate of major bleeding (NEJM, 2018)
• CARAVAGGIO - apixaban was non-inferior to deltaparin for recurrent PE (5.6% vs 7.9%) with similar rates of major bleeding (NEJM, 2020)

Other

• Vena Cava Filters in PE ppx - Prevents the short-term occurrence of PE, but increased risk of recurrent DVT; After IVC filter placement can use either LMWH or UFH (NEJM, 1998)
• iNOPE Trial - inhaled NO vs placebo in submassive PE - increased likelihood of having normal-sized RV, and is well tolerated (Am Heart J, 2017)
• The SOME Trial Screening for Occult Malignancy in Unprovoked VTE - First unprovoked VTE - normal age-appropriate cancer screening vs. the addition of CTAP to look foro cancer; No sig differences in the number of occult malignancies diagnosed with CTAP; the most commonly missed cancers were lymphomas, gynecologic, colorectal (NEJM, 2015) ; A Meta-Analysis on the topic - occult cancer detected in 1 of 20 patients within 1 year of receiving a diagnosis of unprovoked VTE; extra screening does not clearly improve outcomes

Other Resources

Blogs and Summaries

• Internet Book of Critical Care - Submassive and Massive PE
• PE Risk stratification algorithm from IBCC/EMCrit - link
• Example of thoughtful lytic dosing based on risk-stratification from IBCC/EMCrit - link

Podcasts

• Curbsiders Podcast - DVT/PE Triple Distilled, PE for the Internist, DVT/PE Masterclass
• Core EM - CORE EM PE

Clinical Calculators

• MD Calc - PESI Score - risk of 30-day mortality and complications in patients diagnosed with PE; may not be terribly useful in the immediate setting when trying to risk stratify and make decisions on admission
• MD Calc - PERC Score - rules out PE if all criteria are negative and patient low-risk
• MD Calc - Well’s DVT - outpatient and ED - if low risk and neg D-Dimer, no need for US
• MD Calc - Well’s PE - inpatient and ED - likely vs unlikely for D-dimer vs. CTPE

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