The clinical manifestations of acute pulmonary embolism (PE) are complex, and early diagnosis, correct judgment and reasonable treatment have a significant impact on the prognosis. Selective pulmonary angiography has become the clinical “gold standard” for the diagnosis of PE because of its low false-positive rate and the difficulty of missing the diagnosis, but this test is invasive, expensive and sometimes difficult to perform. Therefore, in addition to non-invasive comprehensive ultrasound imaging, enhanced CT or radionuclide imaging, some laboratory tests [such as D-dimer, brain natriuretic peptide (BNP) and cardiac troponin] are also useful for the diagnosis and prognosis of PE, taking into account the patient’s symptoms, signs and past medical history.
Laboratory tests for pulmonary embolism
D-dimer
D-dimer is a degradation product of cross-linked fibrin. Activation of the coagulation and fibrinolytic system by acute clot formation can increase the level of D-dimer. Therefore, D-dimer is rarely at normal levels in the setting of acute PE and deep vein thrombosis (DVT), but may be elevated in the setting of tumor, inflammation, infection, necrosis, aortic tear, hospitalization, or pregnancy.
When acute PE or DVT occurs, the detection of D-dimer by quantitative enzyme-linked immunoassay (ELISA) or ELISA-derived (ELISA-derived) methods has high sensitivity (>95%) and low specificity (about 40%), whereas the sensitivity of D-dimer measurement by whole blood agglutination and quantitative latex agglutination is 85% to 90%. Studies have shown that D-dimer negativity is extremely unlikely to establish a diagnosis of PE in patients with a low or moderate likelihood of PE (<11 on the Wells scale or <7 on the modified Geneva scale), but D-dimer negativity may exclude PE in those with a Wells scale score ≤4.
Based on the high negative predictive value and low positive predictive value of D-dimer for PE, a normal D-dimer level cannot exclude the diagnosis of PE, but it is well established as a primary screening indicator for acute PE. Therefore, all patients with suspected PE should be tested for D-dimer as an indicator to exclude the diagnosis.
Arterial blood gas analysis
Arterial blood gas analysis is the preferred test for suspected PE and is used to assess arterial oxygenation and acid-base metabolism. patients with PE may present with hypoxemia, but normal blood gas results do not exclude PE, and hypoxemia combined with hypocapnia may increase the suspicion of PE.
In a study by SteinPD et al, 14% of patients with normal arterial partial pressure of oxygen (PaO2), arterial partial pressure of carbon dioxide (PaCO2), and differential alveolar arterial partial pressure of oxygen [P(A-a)O2] (PaO2 > 80 mmHg, PaCO2 > 35 mmHg, P(A-a)O2 < 20 mmHg) and cardiovascular risk factors were diagnosed with PE. PE was diagnosed in 14% of patients with cardiovascular risk factors and in 38% of patients without cardiovascular risk factors, but a normal PaO2 and a negative D-dimer completely ruled out PE, and patients did not need to undergo lung CT.
The prognostic value of each blood gas analysis index varies between young and old patients. Young patients with P(A-a)O2 > 50 mmHg and alveolar arterial partial pressure of oxygen ratio < 0.5 suggest a poor prognosis; in old patients, the short-term poor prognosis is only related to low oxygen saturation and not to P(A-a)O2.
Brain natriuretic peptide (BNP)
There is increasing evidence that acute PE leading to right ventricular insufficiency can increase myocardial load and contribute to BNP release into the blood. Therefore, elevated levels of BNP or N-terminal natriuretic peptide precursor (NT-proBNP) may reflect the severity of right heart insufficiency with hemodynamic changes.
Recent studies have shown that BNP provides more information related to prognosis than echocardiography. Although elevated levels of BNP or NT-proBNP are associated with poor prognosis, their positive value for predicting poor prognosis is low (12%-26%), while low levels of BNP (<50 pg/ml) or NT-proBNP (<500 pg/ml) have a higher value for predicting a benign prognosis (negative predictive value of 95%-97%).
Markers of myocardial injury
Elevated cardiac troponin T (cTnT) and troponin I (cTnI) have been found to be associated with a poorer prognosis in patients with PE. Giannitsis et al. showed that cTnT was elevated in 50% of patients with massive PE (>0.1 ng/ml) and in 35% of patients with submassive and non-massive PE. A large prospective study by Jimènez D et al. showed that in hemodynamically stable patients, elevated cTnI (>0.1 ng/ml) suggested the possibility of fatal PE, while those with negative cTnI had a better prognosis (negative predictive value of 93%).
Some studies have found a mortality rate of 44% in patients with PE with elevated cTnT, compared with only 3% in those with negative cTnT. Other studies have shown that patients with elevated cTnI (>0.5 ng/ml) have a higher risk of death within 3 months, which is 3.5 times higher than in cTnI-negative patients.
Heart-type fatty acid binding protein (H-FABP)
It has been shown that cardiac-type fatty acid binding protein (H-FABP) can reflect myocardial injury at an early stage and better predict the prognosis of PE patients compared with BNP, troponin and myoglobin.
With a cut-off value of 6 ng/ml for H-FABP, its positive predictive value for short-term mortality in PE patients ranged from 23% to 37%, and its negative predictive value ranged from 96% to 100%. Therefore, the determination of H-FABP can further clarify the risk stratification of patients and help to develop treatment strategies.
Risk stratification of patients with pulmonary embolism
The European Society of Cardiology (ESC) Guidelines for the Diagnosis and Treatment of Acute Pulmonary Embolism, published in 2000, first classified PE as “large” or “non-large” based on hemodynamic status. “In 2008, the ESC guidelines for pulmonary embolism pointed out that the terms “large area”, “sub-large area” and “non-large area” are easy to use in clinical practice. The 2008 ESC Pulmonary Embolism Guidelines point out that the terms “large area”, “sub-large area”, and “non-large area” are clinically confusing in relation to the shape, distribution, and anatomical load of the thrombus. The terms “large area”, “sub-large area” and “non-large area” should be replaced by “high, medium and low risk”. The new terminology of risk stratification reflects the latest advances in PE and has practical implications for the adoption of targeted treatment strategies and prognosis improvement.
Risk indicators associated with early death (hospitalization or 30-day mortality) in PE include clinical indicators (shock or hypotension), indicators of right heart insufficiency (right ventricular enlargement, hypokinesis or pressure overload on echocardiography, right ventricular enlargement on spiral CT, elevated BNP or NT-proBNP, elevated right heart pressure on right heart catheterization), and markers of myocardial injury (cTnT or cTnT or cTnI positive). Risk stratification of PE based on the above indicators enables rapid identification of high-risk versus non-high-risk patients at the bedside (Table 1), and this risk stratification is also applicable to patients with suspected PE. High-risk PE is a life-threatening emergency (short-term mortality rate >15%) that requires rapid and accurate diagnosis and treatment. Non-high-risk PE can be further classified as intermediate-risk or low-risk (short-term PE-related mortality <1%) based on the presence or absence of right ventricular insufficiency and myocardial injury.
The new guidelines also mention that the Geneva Prognostic Scale applies an 8-point scoring system of 6 risk factors [cancer, hypotension (<100 mmHg), 2 points each of the above; heart failure, history of deep vein thrombosis (DVT), hypoxemia (PaO2 <8 kPa), and ultrasound-confirmed DVT, 1 point each of the above] to risk-stratify patients to determine suitability for outpatient treatment (2.2% for low-risk patients with a score of ≤2 and 26.1% for high-risk patients with a score of ≥3). In addition, 11 clinical manifestations associated with prognosis, including male, rapid heart rate, hypothermia, altered mental status, and decreased oxygen saturation, comprised another scoring system that was also applicable to risk stratification of patients with acute PE to predict mortality within 30 days.
In conclusion, timely risk stratification of PE patients will help to select the best diagnostic measures and treatment options, as well as to scientifically determine the prognosis.