| dc.description.abstract | Background: Patients with lymphomas increased the risk of thrombotic complications, especially in diagnosis and during chemotherapy treatment, in the range of 2.9-4.2%.
Aims: Our hypothesis is that inflammation and provoked immunity are responsible for generation of thrombus due to disturbed balance between coagulation and fibrinolysis.
Methods: Quantification of neutrophil extracellular traps (NETs) from peripheral blood of 80 patients with Hodgkin lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (FL) measuring circulating cell-free DNA (cfDNA) and myeloperoxidase (MPO) activity. The inflammatory cytokines, coagulation factors and chemokines are measured by enzyme-linked immunosorbent assay (ELISA) and flow cytometry in peripheral blood, while fibrinolytic activity by fluorescent tissue-type plasminogen activator (tPA) and urokinase plasminogen activator (uPA) assays. Using a Boyden chamber, trans-endothelial migration of mononuclear cells (MNC) across a monolayer of human microvascular endothelial cells (HMEC-1) will be observed.
Results: The pro-inflammatory cytokines IL-1β and TNF-α were significantly increased in DLBCL and HL, but not the chemokines IL-8 and MCP-1. NETs were increased in the peripheral blood of patients with HL (p<0.05) as measured by cfDNA and MPO activity. In contrast, cfDNA was largely reduced in DLBCL with thrombosis (p<0.001). Trans-endothelial migration of MNC was decreased by IL-6, but increased by TNF-α (p<0.001) in DLBCL with thrombosis. In the absence of thrombosis, MNC of HL demonstrated increased trans-endothelial migration in the presence of pro-inflammatory IL-6 (p<0.01), while MNC of HL and DLBCL in the presence of TNF-α (p<0.05). Regarding coagulation, factor VIII was increased in HL (p<0.05), while tissue factor in non-Hodgkin lymphomas (DLBCL and FL, p<0.05). Adhesion molecule P-selectin was increased in lymphomas, mostly in non-Hodgkin lymphomas (p<0.0001), while TGF-β is only in FL (p<0.001). Fibrinogen was negatively correlated with cfDNA (p=0.021, r=-0.767) in HL, while in positive correlation with TNF-α (p=0.028, r=0.517), IL-8 (p=0.009, r=0.598) and MCP-1 (p=0.004, r=0.643) in FL and with TGF-β (p=0.007, r=0.748) in HL. In opposite to uPA, fibrinolytic activity was decreased in the plasma of patients with HL, DLBCL, and FL (p<0.05) as measured by tPA. The tPA was in negative correlation with MPO in HL (p=0.017, r=-0.783) and FL (p=0.006, r=-0.818), while positively correlated with cfDNA in DLBCL (p=0.034, r=0.402, Table 1). The uPA was in positive correlation with cfDNA (p=0.009, r=0.692) and fibrinogen (p=0.009, r=0.692) in FL. Tissue factor (CD142+) procoagulant microparticles derived from monocytes (CD14+: 7.49±0.2, p<0.001) and activated monocytes (CD14+/CD16+: 3.75±0.8%, p<0.05) were increased in DLBCL compared to healthy controls.
Summary/Conclusion: Chronic inflammation is present in the examined lymphomas where TNF-α, as an activator of the immune response, is linked with the initiation of thrombus formation. Moreover, augmented innate immunity is accompanied by procoagulants that mutually support thrombosis.
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