Decoding Pulmonary Embolism: Pathophysiology, Diagnosis, and Treatment
Abstract
:1. Pulmonary Embolism (PE)
2. Diagnosis and Severity
2.1. Scoring Systems Diagnosis
2.2. Risk Stratification of PE
- Low Probability of PE: to safely exclude PE in this subset of patients, the physician can use the Pulmonary Embolism Rule Out Criteria (PERC) or D-dimer testing. Patients with a low probability of PE but a non-negative PERC rule should be tested with D-dimer to safely exclude PE.
- Intermediate Probability of PE: The initial diagnostic step involves the measurement of D-dimer levels. Negative D-dimer results, indicating levels below 500 ng/mL, allow for the confident exclusion of PE. However, a positive D-dimer test, defined as D-dimer levels above 500 ng/mL, indicates that CTPA should be applied next. If the CTPA results are inconclusive or contraindicative, a V/Q scan should be considered (Figure 1) [13].
- High Probability of PE: CTPA should be performed promptly. In situations where the CTPA yields inconclusive results, a V/Q scan is recommended. The V/Q scan findings may either be normal, effectively ruling out PE, or they may indicate a “high probability of PE”, which is considered diagnostic for PE. When the V/Q scan results fall into the intermediate probability range, further assessment with lower extremity compression ultrasonography (CUS) is warranted (Figure 1) [13].
3. Treatment
3.1. Conventional Anticoagulation Therapy
- Heparin, a glycosaminoglycan, acts as an indirect anticoagulant by enhancing antithrombin III activity. When activated by heparin, antithrombin III effectively inhibits key coagulation factors, including thrombin (factor IIa) and factor Xa (Figure 2). Thrombin is pivotal in clot formation by converting fibrinogen to fibrin. By inactivating thrombin and factor Xa, heparin reduces clot formation, indirectly supporting endothelial function and preventing vascular obstruction [35]. There are three main types of heparins: standard heparin, low-molecular weight heparin (LMWH), and Fondaparinux. LMWH’s functions are similar to standard heparin by binding to and boosting the activity of antithrombin III (AT), but it mainly targets factor Xa and has a longer-lasting effect. In addition, LMWH has a reduced ability to bind and inhibit thrombin compared to standard heparin. LMWH has a smaller size which results in less binding to plasma proteins and endothelial cells, resulting in a significant amount of unbound LMWH. This leads to a high bioavailability rate of 85–99%, enhancing its anticoagulant effect, prolonging its action, and reducing patients’ variability. Fondaparinux binds to antithrombin III with high specificity, minimizing non-specific interactions with other plasma proteins. It significantly increases AT’s activity, especially in inhibiting factor Xa. Fondaparinux does not directly impact thrombin and exhibits high bioavailability when administered subcutaneously [4].
- Warfarin is an oral anticoagulant that hinders the synthesis of vitamin K-dependent clotting factors (II, VII, IX, and X) by inhibiting the enzyme vitamin K epoxide reductase, which recycles vitamin K (Figure 2). This disruption in clotting factor production reduces the blood’s clotting ability, indirectly supporting endothelial function by preventing new clot formation and the extension of existing clots [36].
3.2. Direct-Acting Oral Anticoagulants
- Anti-Xa agents are highly specific direct inhibitors of factor Xa, a central enzyme in the blood coagulation cascade. It achieves its specificity by directly binding to factor Xa’s active site, thereby preventing the enzyme from carrying out its crucial function (Figure 2). By directly inhibiting factor Xa, it effectively interrupts the production of thrombin, which, in turn, prevents the formation of fibrin, a key component for the stability of blood clots [39,41,43,44].
- Antithrombin agents interact with antithrombin, a crucial endogenous anticoagulant protein (Figure 2). Their primary molecular role is to potentiate antithrombin’s inhibitory capacity against key coagulation factors, with particular emphasis on thrombin (factor IIa) and factor Xa. This interaction induces significant conformational changes in antithrombin, effectively boosting its ability to neutralize thrombin and factor Xa. As a result, the coagulation cascade is disrupted, and the formation of blood clots is impeded [38].
3.3. Anti-XI Agents
3.4. Thrombolytic Therapy
3.5. Thrombectomy Procedure
3.5.1. Mechanical Thrombectomy (MT)
3.5.2. Catheter-Directed Thrombolysis (CDT)
3.6. Supportive Care
3.7. Multidisciplinary Pulmonary Embolism Response Teams
4. Potential Biomarkers in PE
4.1. Vascular Biomarkers of PE
4.2. Cardiac Biomarkers of PE
4.3. Inflammatory Biomarkers of PE
4.4. RNA Biomarkers of PE
- MicroRNAs (miRNAs) are non-coding small RNA molecules with specific tissue expression patterns. Their expression changes significantly in some diseases, especially thrombosis and tumor diseases [87]. Certain miRNAs such as miR-210, miR-221, miR-222, miR-126-3p, miR-92a, and miR-132, which are known as angiomiRs (Table 3), have an essential function in regulating angiogenesis. Hembron et al. have reported more novel biomarkers, such as miR-223, miR-145, miR-582, miR-195, miR-150, miR-21, and miR-424, which are related to the changes in vascular diseases [88]. In addition, other studies have identified miR-134 [89], miR-28-3p [90], and miR-1233 [91] as potential biomarkers for PE diagnosis.
- Long non-coding RNAs (lncRNAs) are non-coding RNA molecules longer than 200 nucleotides. Some studies have shown that lncRNAs have significant level changes in chronic thromboembolic pulmonary hypertension (CTEPH) (Table 3), such as NR_036693, NR_027783, NR_033766, and NR_001284 [92,93]. Additionally, LncRNA-Ang362 has also been closely linked to PH [92,94]. Further studies are needed to determine the specific connection between lncRNAs and PE.
5. Endothelial Dysfunction in PE
6. Impact of PE in ED
6.1. Impaired Blood Flow Regulation
6.2. Pro-Thrombotic State
6.3. Inflammatory State
6.4. Increased Oxidative Stress
6.5. Altered Vascular Remodeling
7. From PE to Cardiovascular Dysfunction
7.1. Post-Thrombotic Syndrome (PTS)
7.2. Chronic Thromboembolic Pulmonary Disease
7.3. Chronic Thromboembolic Pulmonary Hypertension
7.4. Right Heart Failure
7.5. Cardiogenic Shock
8. Conclusions and Future Directions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
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Clinical Features | Predisposing Factors |
---|---|
Chest pain Dyspnea Unilateral leg swelling Syncope Hemoptysis Heart rate < 100/min Oxygen saturation < 94% | Age < 50 Familial history of PE 1 Familial history of cardiovascular diseases Recent surgery Prior venous thromboembolism event Estrogen use |
Geneva Clinical Prediction Rules | Score | Wells Criteria Rules | Score |
---|---|---|---|
Previous PE or DVT 1 HR: 75–94 beats per minute HR: ≥95 beats per minute Surgery or fracture within the past month Hemoptysis Active cancer Unilateral lower-limb pain Pain on lower-limb deep palpation and unilateral edema Age >65 years. PE—unlikely PE—likely Or Low Intermediate High | 1 1 2 1 1 1 1 1 1 0–2 ≥3 0–3 4–10 >10 | Previous PE or DVT Heart rate >100 beats per min Immobilization for ≥3 days or surgery in the previous 4 weeks Hemoptysis Malignancy Clinical symptoms of DVT Other diagnoses less likely than pulmonary embolism PE—unlikely PE—likely Or Low Intermediate High | 1.5 1.5 1.5 1 1 3 3 ≤4 >4 <2 2–6 >6 |
General Types of Biomarkers | Potential PE Biomarkers | Medical Uses |
---|---|---|
Vascular biomarkers | Leukocyte, platelet, D-dimer, fibrinogen, sP-selectin. II, IV, VII, VIII, V Leiden, X, XIII, PF1.2 protein C, protein S, TAT, PIC, TM, t-PAIC. aPTT, PT, TT, VHAs. | PE early diagnosis Risk stratification and PE progression. Monitoring anticoagulant and thrombolytic treatment. Identify DVT or cardiovascular diseases. |
Cardiac biomarkers | BNP, NT-proBNP, TnT, h-FABP, CK, myoglobin. | PE early diagnosis Risk stratification and prognostic complications. Monitoring anticoagulant and thrombolytic treatment. |
Inflammatory biomarkers | NLR, PLR, LMR, CRP, TNF-α, IL-1β, IL-4, IL-6, IL-10 and plasma copeptin levels. Anticardiolipin, IgG and IgA. | Identification of underlying inflammatory conditions. Monitoring systemic inflammation associated with PE. Prognosis and differentiation PE with higher inflammatory component vs PE with thrombotic features Monitoring thrombolytic treatment. |
RNA biomarkers | miR-210, miR-221, miR-222, miR-126-3p, miR-92a, and miR-132. miR-223, miR-145, miR-582, miR-195, miR-150, miR-21 and MiR-424, miR-134, miR-28-3p and miR-1233. | Diagnostic and prognostic of PE. Identification of underlying PE pathophysiology. Future personalized treatment strategies. |
NR_036693, NR_027783, NR_033766, NR_001284 and LncRNA-Ang362. hsa_circ_0002062, hsa_circ_0022342, hsa_circ_0016070, and hsa_circ_0046159. |
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Peracaula, M.; Sebastian, L.; Francisco, I.; Vilaplana, M.B.; Rodríguez-Chiaradía, D.A.; Tura-Ceide, O. Decoding Pulmonary Embolism: Pathophysiology, Diagnosis, and Treatment. Biomedicines 2024, 12, 1936. https://doi.org/10.3390/biomedicines12091936
Peracaula M, Sebastian L, Francisco I, Vilaplana MB, Rodríguez-Chiaradía DA, Tura-Ceide O. Decoding Pulmonary Embolism: Pathophysiology, Diagnosis, and Treatment. Biomedicines. 2024; 12(9):1936. https://doi.org/10.3390/biomedicines12091936
Chicago/Turabian StylePeracaula, Miriam, Laura Sebastian, Iria Francisco, Marc Bonnin Vilaplana, Diego A. Rodríguez-Chiaradía, and Olga Tura-Ceide. 2024. "Decoding Pulmonary Embolism: Pathophysiology, Diagnosis, and Treatment" Biomedicines 12, no. 9: 1936. https://doi.org/10.3390/biomedicines12091936