Increased activity of procoagulant factors in patients with small cell lung cancer

Abstract

Small cell lung cancer (SCLC) patients have augmented risk of developing venous thromboembolism, but the mechanisms triggering this burden on the coagulation system remain to be understood. Recently, cell-derived microparticles carrying procoagulant phospholipids (PPL) and tissue factor (TF) in their membrane have attracted attention as possible contributors to the thrombogenic processes in cancers. The aims of this study were to assess the coagulation activity of platelet-poor plasma from 38 SCLC patients and to provide a detailed procoagulant profiling of small and large extracellular vesicles (EVs) isolated from these patients at the time of diagnosis, during and after treatment compared to 20 healthy controls. Hypercoagulability testing was performed by thrombin generation (TG), procoagulant phospholipid (PPL), TF activity, Protein C, FVIII activity and cell-free deoxyribonucleic acid (cfDNA), a surrogate measure for neutrophil extracellular traps (NETs). Our results revealed a coagulation activity that is significantly increased in the plasma of SCLC patients when compared to age-related healthy controls, but no substantial changes in coagulation activity during treatment and at follow-up. Although EVs in the patients revealed an increased PPL and TF activity compared with the controls, the TG profiles of EVs added to a standard plasma were similar for patients and controls. Finally, we found no differences in the coagulation profile of patients who developed VTE to those who did not, i.e. the tests could not predict VTE. In conclusion, we found that SCLC patients display an overall increased coagulation activity at time of diagnosis and during the disease, which may contribute to their higher risk of VTE.

Circulating microvesicles and exosomes in small cell lung cancer by quantitative proteomics

“…Plasma proteins of circulating MVs and exosomes were characterized and confirmed as previously described [ 26 ] and in accordance with the Minimal Information for Studies of Extracellular Vesicles (MISEV) criteria [ 27 ]. Due to analytical troubleshooting, only 23 of the 24 SCLC samples could be used to investigate exosomes.…”

Preliminary investigation of elevated collagen and blood‐clotting markers as potential noninvasive biomarkers for small cell lung cancer

“…Patients with SCLC are more susceptible to thrombogenic events, and coagulation factors have previously been associated with SCLC 23,48 . High levels of pretreatment D‐dimer or fibrinogen have been linked to inferior survival outcomes 49–51 and poorer response to chemotherapy 51,52 .…”

“…Patients with SCLC are more susceptible to thrombogenic events, and coagulation factors have previously been associated with SCLC. 23 , 48 High levels of pretreatment D‐dimer or fibrinogen have been linked to inferior survival outcomes 49 , 50 , 51 and poorer response to chemotherapy. 51 , 52 In the current study, we included two blood coagulation markers: the PRO‐FIB marker, which reflects the thrombin‐mediated degradation of fibrinogen to fibrin, and vWF‐N, which reflects the formation of vWF.…”

Plasma tissue factor activity in lung cancer patients predicts venous thromboembolism and poor overall survival

“…The predictive value of tumor TF expression or its plasma level on VTE occurrence and prognosis in LC patients is controversial [ [28] , [29] , [30] , [31] , [32] , [33] , [34] ], possibly because of the method used to detect TF. Some studies evaluated the presence of TF (protein or RNA levels) in tumor tissues [ 28 , 29 ], and others assessed the presence of TF-exposing EVs in blood by flow cytometry or immunocapture, but the specificity of the antibody against TF was sometimes questionable [ 35 ].…”

“…Furthermore, antigenic determination of TF is not predictive of its activity, and it has been shown that LC chemotherapy could increase its procoagulant activity via protein disulfide isomerase-dependent TF decryption [ 36 ]. Lastly, there are few prospective studies evaluating TF in LC [ [28] , [29] , [31] , [32] , [33] , 37 ].…”