Fig 1.
General view on APE pathogenesis. The figure presents the concept of the role of immune system and inflammation as a substrate in APE development and progression. APE, acute pulmonary embolism; CRP, C-reactive protein; IL-6, interleukin-6; NLR, neutrophil-to-lymphocyte ratio. This figure has been created with BioRender.com.
Fig 2.
Schematic of immune reactive oxygen species (ROS) response in vessel during VTE. Early in thrombogenesis, adhesion molecules initiate leukocyte accumulation, and adhesion to endothelium for subsequent platelet accumulation. Endothelium injury releases DAMP. Proinflammatory cytokines and ROS, promote inflammasome activation in innate immune cells, primarily macrophages, and neutrophils. IL-1β promotes leukocytes adhesion as well as neutrophils and PLT recruitment. IL-6 is released by infiltrating leukocytes and monocytes and induced endothelial IL-1 production and expression of adhesion molecules and prothrombotic factors, facilitating further platelet recruitment. Systemic inflammatory state can be measured by higher concentration of circulating GDF-15, IL-6, TNF-α. As a response to proinflammatory state and higher IL6 level, CRP is synthesized by the liver. IL-6 also promotes lymphocytes T activation. DAMP and PAMPs are presented to lymphocytes T, resulting in higher sCD40 in bloodstream. Activation of platelet and macrophage NLRP-3 inflammasome induces exaggerated production of IL-1 and NETosis formation. The interaction between NETs DNA and vWF, leads to further thrombus growing. Inflammasome activation results in release of TF, which leads to thrombin generation and fibrin clot formation. Neutrophil express TF resulting in extrinsic pathway activation, however, NETs lead to factor XII activation and intrinsic pathway activation, finally contributing to thrombus development and growth. CRP, C-reactive protein; DAMP, danger-associated molecular pattern; EGF, epidermal growth factor; GDF-15, growth differentiation factor-15; ICAM, intercellular adhesion molecule; IL, interleukin; miRNAs, micro-RNAs; MHC, Major histocompatibility complex; NETs, neutrophil extracellular traps; NLR, neutrophil-to-lymphocyte ratio; NLRP-3, NOD-like receptor protein 3; NT-proBNP, N-terminal pro-brain natriuretic peptide; PAMPs, pathogen-associated molecular patterns; PLT, platelets; PMN, Polymorphonuclear cells; sCD40L, soluble CD40 ligand; TCR, T-cell receptor; TF, tissue factor; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; VTE, Venous thromboembolism; vWF, von Willebrand factor. This figure has been created with BioRender.com.
Table 1.
Summary of the main studies in humans
| Marker | Author | Country | Year | Study design | Total patients | Main conclusion |
|---|---|---|---|---|---|---|
| Beckers et al. | Netherlands | 2010 | Prospective | 433 | The study demonstrated that four SNPs in inflammatory-related genes of IL-1α, IL-4, IL-6, IL-13 are related to VTE episodes. |
| IL-1 | Abuduhalike et al. | China | 2020 | Prospective | 284 | In patients with gene variant of IL-1 rs1800587 GG + GA are at higher risk of VTE than subjects with AA genotype (or 4.444, 95% CI = 1.466–13.470). |
| Zee et al. | USA | 2009 | Prospective | 22,413 | Gene polymorphism rs1143634 in the IL-1β gene was associated with a reduced risk of idiopathic VTE (hazard ratio = 0.59, 95% CI = 0.440.80, P = 0.0007, FDR = 0.02). Gene polymorphism rs1800872 in the IL-10 gene was associated with increased risk (hazard ratio = 1.42, 95% CI = 1.12–1.80, P = 0.004, FDR = 0.07). |
| NETs | Zabczyk et al. | Poland | 2020 | Prospective | 126 | Hypofibrinolysis is associated with enhanced NET formation and worst APE course. |
| IL-6 | Vormittag et al. | Austria | 2006a | Prospective | 355 | No relationship was found between IL-6 and its promoter polymorphism (–174) G > C and the risk of spontaneous VTE. |
| IL-4, IL-6, IL-8, IL-10, IL-1β, MCP-1, EGF | Bontekoe et al. | USA | 2021 | Prospective study | 157 | Cytokines IL-4, IL-6, IL-8, IL-10, IL-1β, MCP-1, and EGF demonstrated varying levels of significant increase (P < 0.05) in massive-risk PA patients compared to submassive- and low-risk PA patients. |
| CRP | Vormittag et al. | Austria | 2006b | Prospective | 355 | CRP + 1444TT genotype was significantly associated with increased CRP plasma levels in healthy individuals. CRP + 1444TT was more frequent (14%) among controls than DVT patients (9%, P = 0.26) or PE PA patients (6%, P = 0.05). |
| Stewart et al. | USA | 2017 | Prospective, double-blinded, randomized controlled trial, with 3-month follow-up | 60 | A significant reduction of IL-6, CRP, and MPO concentration was observed in the population of patients with APE after 3-month follow-up as compared to baseline (in group treated with Tenecteplase as well as placebo). | |
| Matos et al. | Brazil | 2011 | Prospective | 245 | VTE was related to higher IL-6 level and it remained significant independently of hs-CRP concentration and BMI. |
| EGF | Dirican et al. | Turkey | 2016 | Prospective | 57 | Higher SCUBE1 plasma concentration was observed in the APE than in the non-APE and controls. |
| EGF | Alqudah et al. | Jordan | 2017 | Prospective | 75 | Patients with VTE presented significantly lower EGF concentration in comparison with healthy subjects. |
| TNF-α | Mazetto et al. | Brazil | Human | Prospective | 2012 | Circulatory levels of TNF-α were significantly increased in patients with VTE compared to healthy controls. |
| TGF-β | Memon et al. | Sweden | 2014 | Prospective with 39 months follow-up | 126 | Reduced plasma concentration of TGF-β1 and TGF-β2 in patients with recurrent VTE. |
| Wang et al. | Sweden | 2019 | Prospective | 78 | 12 mRNAs: (miR-15b-5p, miR106a-5p, miR-197-3p, miR-652-3p, miR-361-5p, miR-222-3p, miR-26b-5p, miR-532-5p, miR-27b-3p, miR-21-5p, miR-103a-3p, and miR-30c-5p) were related to higher VTE reoccurrence. Eight miRNAs significantly correlated with circulating TGFβ1/2. | |
| sCD40L | Kaya et al. | Turkey | 2012 | Prospective | 84 | sCD40L concentration was significantly higher among APE patients in compare with healthy controls. |
| GDF | Lankeit et al. | Germany | 2008 | Prospective | 101 | GDF-15 is an independent predictor of a complicated 30-day outcome after APE. |
| Skowronska et al. | Poland | 2020 | Prospective | Plasma GDF‐15 concentration is a valuable biomarker in prediction of bleeding and hemodynamic destabilization in APE patients. |
[i] APE, acute pulmonary embolism; BMI, body mass index; CI, confidence interval; CRP, C-reactive protein; DVT, deep vein thrombosis; EGF, epidermal growth factor; FDR, false discovery rate; GDF-15, growth differentiation factor-15; hs-CRP, high sensitive CRP; IL, interleukin; MCP-1, monocyte chemoattractant protein-1; miRNAs, micro-RNAs; MPO, myeloperoxidase; mRNA, messenger RNA; NETs, neutrophil extracellular traps; PA, pulmonary artery; PE, pulmonary embolism; sCD40L, soluble CD40 ligand; SNP, single nucleotide polymorphisms; TGF, transforming growth factor; TGF-β, transforming growth factor-β; TNF, tumor necrosis factor; VTE, venous thromboembolism.