Keywords
pulmonary embolism - pulmonary angiography - pulmonary hypertension - hypoxia - Virchow's
triad - thromboembolic disease - deep venous thrombosis
Venous thromboembolic (VTE) disease presents as a major burden to health care and
affects approximately 10 million cases per year.[1]
[2]
[3]
[4] In clinical practice, it is encountered as either deep vein thrombosis (DVT) and/or
pulmonary embolism (PE) and is thought to affect as many as 900,000 individuals in
the United States each year and associated with substantial morbidity and mortality.
It is estimated that there are approximately 10 million new cases of VTE in the world
on an annual basis. In the United States, it is estimated that the incidence of diagnosed
VTE is 117 per 100,000, but this number may be an underestimation as most cases are
frequently not diagnosed or only discovered on autopsy.[1]
PE is thought to develop in approximately 10% of patients with acute DVT and it can
lead to approximately 10% of hospital deaths. It is also a known fact that most patients
(up to 75%) with PE are asymptomatic. It is further thought that about one-third of
the hospitalized patients in the United States are at high risk of developing VTE
and about 100,000 deaths are related to this disease per year.[2]
[3]
[4]
The annual incidence of venous thrombosis, including DVT and PE, is estimated to occur
in 1 out of 1,000 adults. Rates increase significantly after age 45 years and are
higher in males than in females.[3]
In this article, we discuss the pathophysiology of PE and management of this condition.
Pathophysiology
The pathogenesis of PE is dictated by the Virchow's triad like other intravascular
thrombi and is a combination of venous stasis, endothelial injury, and a hypercoagulable
state ([Table 1]). The etiology/risk factors leading to culmination of the triad can be inherited
or acquired ([Table 2]).
Table 1
Virchow's triad
|
Venous stasis
|
|
Endothelial injury
|
|
Hypercoagulable state
|
Table 2
Risk factors for pulmonary emboli
|
Acquired
|
|
Immobilization
|
|
Major trauma or surgery within 4 weeks
|
|
Active cancer (treatment within 6 months or palliative therapy)
|
|
Prior history of thromboembolism
|
|
Reduced cardiac output/Heart Failure
|
|
Obesity
|
|
Pregnancy, early puerperium
|
|
Estrogen/ oral contraceptives
|
|
Indwelling catheters
|
|
Antiphospholipid antibodies
|
|
Thrombocytosis
|
|
Postsplenectomy
|
|
Heparin induced thrombocytopenia
|
|
Primary hypercoagulable states/ Thrombophilia
|
|
Deficiency of antithrombin III, protein C or S
|
|
Resistance to activated protein C (factor V Leiden)
|
|
Elevated plasminogen activator inhibitor
|
|
Hyperhomocysteinemia
|
|
High plasma concentration of factor VIII
|
|
Prothrombin gene mutation (G20210A polymorphism)
|
Most PEs originate from the deep veins of lower extremity. The common sites of thrombus
formation are in the calf veins followed by femoropopliteal veins and finally the
iliac veins. A blood clot dislodges from the vessel wall and travels into the pulmonary
system, eventually lodging in the pulmonary arteries. When large pulmonary vessels
are involved, it could cause severe hemodynamic instability including right ventricular
(RV) pressure overload, RV failure, and eventually death ([Fig. 1]).
Fig. 1 Pathophysiology of right ventricular failure. LV, left ventricle; RV, right ventricle.
Hypoxia is common in the setting of PE, and the degree of respiratory compromise is
multifactorial and influenced by underlying cardiac function, clot location, and ability
to compensate with respiratory mechanics.[5]
[6] Embolus size does not correlate with severity of hypoxia.[7] There are multiple mechanisms that eventually lead to hypoxia, including (1) ventilation
perfusion mismatch causing redistribution of perfusion to nonoccluded areas, leading
to regional lower perfusion and hence skewing the V/Q ratio; (2) regional bronchoconstriction
leading to reduced ventilation atelectasis, which further causes intrapulmonary shunting
leading to hypoxia; (3) reduced cardiac output leading to reduced central venous oxygen
pressures and hence hypoxia; (4) increase in right atrial pressure that can open the
patent foramen ovale, thereby leading to intracardiac right-to-left shunting and hence
hypoxia.[5]
[8]
[9]
[10]
[11]
[12]
RV dysfunction/failure is the more profound cardiovascular impact of acute PE and
occurs due to sudden increase in afterload. This is also the primary cause of death
in PE. At baseline, the RV is a thin-walled chamber that pumps against a low-pressure
and low-resistance pulmonary vasculature. Increase in afterload is due to mechanical
obstruction of the pulmonary vasculature that impedes blood flow and release of vasoconstrictors
like TXA2. (Thromboxane) due to hypoxia.[6]
[13]
[14]
[15] TXA2 is a hormone of the prostacyclin type released from blood platelets. It induces
platelet aggregation and produces local vasoconstriction. This increase in afterload
and pulmonary vascular resistance stretches the RV, increases wall tension, and causes
compensatory increase in chronotropy and inotropy to maintain the Frank-Starling mechanism
and adequate cardiac function at the expense of pulmonary hypertension.[16]
[17]
[18] The compensation reaches a tipping point, beyond which the increase in PA pressures
cannot generate further RV dilation, causing RV failure. Increased myocardial wall
tension and transmural pressure cause ischemia by impeding coronary flow. This, in
the presence of hypoxia and increased afterload, precipitates a vicious cycle of worsening
myocardial ischemia, reduced RV contractility, reduced cardiac output, and eventual
RV failure. Progressive RV dilation will also exacerbate previously nascent tricuspid
regurgitation that can then trigger arrhythmias and hence worse cardiac performance.[19]
[20] There is also an inflammatory component, as evidenced by the influx of granulocytes
and monocytes that suggests myocarditis.[21]
[22]
Diagnostic Evaluation
Thorough history and identification of risk factors and physical exam are essential
in guiding the appropriate diagnostic evaluations. Preliminary evaluation would include
12-lead electrocardiogram, on which the most common findings are sinus tachycardia
(44%), RV strain pattern/T-wave inversions (34%), right axis deviation (16%), and
right bundle branch block (18%).[23]
Chest X-ray features of acute PE include enlarged pulmonary artery (Fleischner sign),
regional oligemia (Westermark sign), and Hampton hump (wedge-shaped distal infarct)
that have high specificity, but very low sensitivity.
Multiple risk scores have been developed to quantify the pre-test probability of PE
and help guide the diagnostic process and triage them accordingly. The Wells score
and modified Wells score use seven clinical indicators to stratify in to “PE likely”
and “PE unlikely” groups ([Table 3]). The Geneva score relies only on objective data to stratify in to low-, intermediate-,
and high-risk categories ([Table 4]). The pulmonary embolism rule out criteria rule can be used in low-risk patients to avoid unnecessary
diagnostics ([Table 5]).
Table 3
Wells criteria and modified Wells criteria: clinical assessment for pulmonary embolism
|
Clinical symptoms of DVT (leg swelling, pain with palpation)
|
3.0
|
|
Other diagnosis less likely than PE
|
3.0
|
|
Heart rate >100
|
1.5
|
|
Immobilization (≥3 days) or surgery in the previous 4 weeks
|
1.5
|
|
Previous DVT/PE
|
1.5
|
|
Hemoptysis
|
1.0
|
|
Malignancy
|
1.0
|
|
Probability
|
Score
|
|
Traditional clinical probability assessment (Wells criteria)
|
|
High
|
>6.0
|
|
Moderate
|
2.0–6.0
|
|
Low
|
<2.0
|
|
Simplified clinical probability assessment (modified Wells criteria)
|
|
PE likely
|
>4.0
|
|
PE unlikely
|
≤4.0
|
Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism.
Source: Data from van Belle A, Buller 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; 295:172.
Table 4
Modified Geneva score
|
Variables
|
Points
|
|
Risk factors
|
Age >65 years
|
1
|
|
Previous deep venous thrombosis or pulmonary embolism
|
3
|
|
Surgery under general anesthesia or fracture of the lower limbs within 1 month
|
2
|
|
Active malignancy (solid or hematologic; currently active or cured within the last
year)
|
2
|
|
Symptoms
|
Unilateral lower-limb pain
|
3
|
|
Hemoptysis
|
2
|
|
Signs
|
Heart rate 75 to 94 beats per minute
|
3
|
|
≥95 beats per minute
|
5
|
|
Pain on lower limb deep venous palpation and unilateral edema
|
4
|
|
Total points
|
|
Pre-test probability assessment
|
Low
|
0 to 3
|
|
Intermediate
|
4 to 10
|
|
High
|
≥ 11
|
Source: From Annals of Internal Medicine, Le Gal G, Righini M, Roy PM, et al. Prediction
of pulmonary embolism in the emergency department: the revised Geneva score. Ann Intern
Med 2006; 144(3);165-71. Copyright © 2006 American College of Physicians. All rights
reserved. Reprinted with the permission of American College of Physicians, Inc.
Table 5
Pulmonary embolism rule out criteria (PERC rule)[a]
|
Age <50 years
|
|
Heart rate <100 bpm
|
|
Oxyhemoglobin saturation ≥95%
|
|
No hemoptysis
|
|
No estrogen use
|
|
No prior DVT or PE
|
|
No unilateral leg swelling
|
|
No surgery/trauma requiring hospitalization within the prior 4 weeks
|
Abbreviations: DVT, deep venous thrombosis; PE, pulmonary embolus; bpm: beats per
minute.
a This rule is only valid in patients with a low clinical probability of PE (gestalt
estimate <15%). In patients with a low probability of PE who fulfill all eight criteria,
the likelihood of PE is low and no further testing is required. All other patients
should be considered for further testing with sensitive D-dimer or imaging.
Source: Kline JA, Courtney DM, Kabrhel C, et al. Prospective multicenter evaluation of the
pulmonary embolism rule-out criteria. J Thromb Haemost 2008;6:772.
In clinically stable patients obtaining a D-dimer, a soluble fibrin degradation product,
is typically the next diagnostic step. Due to the high diagnostic sensitivity (>95%)
and negative predictive value, it is primarily used to help exclude PE when the levels
are normal. D-dimer, however, has poor diagnostic specificity (41%), and when elevated,
it can be due to other various conditions such as sepsis, trauma, cancer, surgery,
other thrombosis, or disseminated intravascular coagulation, among others.[24]
In patients with high clinical probability or abnormal D-dimer, computed tomography
(CT) angiography of the pulmonary vasculature is the next diagnostic step ([Fig. 2]) Advancements in imaging have reduced acquisition times to a few seconds, making
it possible to get high-resolution images even in the presence of dyspnea. CT also
provides assessment for other conditions in the differential diagnosis of dyspnea
and tachycardia like pneumonia, coronavirus disease 2019, and effusions.[25] If computed tomography angiography (CTA) is contraindicated (renal failure, allergy,
pregnancy), ventilation perfusion scans can be utilized, which have a sensitivity
and specificity of 85 and 93%, respectively.[26]
Fig. 2 Pre- and post-computed tomography angiography (CTA) images following thrombolysis
showing significant improvement in pulmonary.
Echocardiography can be helpful in assessing RV function and subsequent risk stratification
since it is typically associated with worse outcomes. PE can also cause RV failure
and cardiogenic shock due to obstruction and increased pulmonary vasoconstriction.[27]
Treatment
PE can range from acute massive PE causing pulmonary infarction or could be secondary
to small emboli that do not cause hemodynamic instability. Patients with PE can present
with minor nonspecific symptoms like dyspnea, to symptoms of shock with systolic blood
pressures less than 90 mm Hg or a decrease in systolic arterial pressure of at least
40 mm Hg for 15 minutes or more.
Treatment is dependent on clinical presentation and initially involves providing adequate
oxygenation and stabilizing hemodynamics. Treatment of the PE per se is guided by
presence or absence of shock.
Patients without shock are low risk and can be treated with anticoagulation, which
is the mainstay of most PE treatments. Parenteral treatment can be started with heparin
or enoxaparin and transitioned to warfarin for a goal international normalized ratio
between 2 and 3. Direct-acting oral anticoagulants, on the other hand, have quick
onset of action and do not require bridging with parenteral anticoagulants[28] ([Table 6]). Duration of anticoagulation is 3 to 6 months but is required lifelong if there
is a recurrence of PE/DVT.[29]
Table 6
Dosing of direct oral anticoagulants
|
Anticoagulant
|
Nonvalvular AF -stroke prophylaxis
|
VTE treatment
|
VTE primary prophylaxis
|
|
Dabigatran (Pradaxa)
|
150 mg twice daily
|
Parenteral anticoagulation for 5 to 10 days; then dabigatran 150 mg twice daily
|
110 mg for the first day, then 220 mg once daily
|
|
Apixaban (Eliquis)
|
5 mg twice daily
|
10 mg twice daily for 1 week, then 5 mg twice daily
|
2.5 mg twice daily
|
|
Edoxaban (Savaysa, Lixiana)
|
60 mg once daily
|
Parenteral anticoagulation for 5 to 10 days; then edoxaban 60 mg once daily
|
|
|
Rivaroxaban (Xarelto)
|
20 mg once daily with the evening meal
|
15 mg twice daily with food for 3 weeks; then 20 mg once daily with food
|
10 mg once daily, with or without food
|
Abbreviations: AF, atrial fibrillation; VTE, venous thromboembolic.
Thrombolytic therapy is reserved for patients with cardiorespiratory compromise/shock.
It can also be used with severe right heart strain or RV failure. Thrombolytics cause
clot-lysis, hence, resuming circulation and reducing RV strain. tPA, or tissue plasminogen
activator, is the most commonly use thrombolytic and administered as a 100 mg infusion
over 2 hours. For catheter-directed thrombolysis, tPA is infused at 0.5 to 2 mg/h
for 2 to 15 hours. Contraindications for tPA are outlined in [Table 7].
Table 7
Contraindications to fibrinolytic therapy
|
Absolute contraindications
|
|
Prior intracranial hemorrhage
|
|
Known structural cerebral vascular lesion
|
|
Known malignant intracranial neoplasm
|
|
Ischemic stroke within 3 months (excluding stroke within 3 hours[a])
|
|
Suspected aortic dissection
|
|
Active bleeding or bleeding diathesis (excluding menses)
|
|
Significant closed-head trauma or facial trauma within 3 months
|
|
Relative contraindications
|
|
History of chronic, severe, poorly controlled hypertension
|
|
Severe uncontrolled hypertension on presentation (SPB >180 mm Hg or DBP > 110 mm
Hg)
|
|
History of ischemic stroke more than 3 months prior
|
|
Traumatic or prolonged (>10 minute) CPR or major surgery less than 3 weeks
|
|
Recent (within 2–4 weeks) internal bleeding
|
|
Noncompressible vascular punctures
|
|
Recent invasive procedure
|
|
For streptokinase/anistreplase—prior exposure (> 5 days ago) or prior allergic reaction
to these agents
|
|
Pregnancy
|
|
Active peptic ulcer
|
|
Pericarditis or pericardial fluid
|
|
Current use of anticoagulant (e.g., warfarin sodium) that has produced an elevated
INR >1.7 or PT >15 seconds
|
|
Age >75 years
|
|
Diabetic retinopathy
|
Abbreviations: CPR, cardiopulmonary resuscitation; DBP, diastolic blood pressure;
INR, international normalized ratio; PT, prothrombin time; SBP, systolic blood pressure.
a The American College of Cardiology suggests that select patients with stroke may
benefit from thrombolytic therapy within 4.5 hours of the onset of symptoms.
Conclusion
PE is a relatively common and serious complication of VTE disease. Its incidence appears
to be steadily increasing, possibly due to earlier recognition of symptoms and more
accurate diagnosis. The increased accuracy of CTA in detecting PE is an important
milestone in this regard. The overall mortality risk is directly related to abnormalities
of gas exchange in the pulmonary vasculature and cardiovascular complications resulting
from obstruction, which lead to increase in pulmonary vascular resistance and RV pressure
overload and RV systolic dysfunction. The underlying cardiopulmonary disease status
also contributes significantly to above-mentioned hemodynamic complications. Inherited
and acquired risk factors like blood dyscrasias, immobilization post-surgery, and
malignancy can increase the likelihood of developing VTE and PE. Anticoagulation treatment
is mandatory and needs to be initiated as soon as the diagnosis of PE is established.
Newer (novel) oral anticoagulation agents are now available in the market and show
promise in being used like warfarin, as parenteral agents, in the treatment of PE.
