Study On The Risk Factors Of Tumor-associated Thrombosis And The Influence And Mechanism Of Antiangiogenic Drugs On Tumor-associated Thrombosis

Tumor patients have a higher incidence of venous thromboembolism than normal people,and the death rate caused by it accounts for the second highest mortality rate among cancer patients.Accurately evaluating the risk of VTE in patients can better prevent the occurrence of VTE and reduce the occurrence of deaths.However,at present,the risk assessment system for VTE in hospitalized tumor patients is very limited at home and abroad.Antiangiogenic drugs have a good effect in the treatment of tumor,but they have been found to promote the occurrence of thrombosis complications in clinical application,and the relevant verification studies and mechanism exploration studies are still few.ObjectivesEstablish a VTE risk scoring model in line with hospitalized tumor patients,and explore the effects of anti-angiogenic drugs on tumor-related thrombosis and related mechanisms.MethodsClinical study: Patients were included in accordance with clinical requirements,and clinical information was collected;In univariate analysis and multivariate analysis of all included variables,a VTE risk assessment form suitable for cancer patients was established.Use H-L to test the fit of the model,and the ROC curve was used to test the discriminative validity of the model.Basic Research:(1)Divide nude mice into 5 groups: blank group,control group,bevacizumab group,PAI-039 group,bevacizumab+PAI-039 group;(2)Except for the blank group,the other groups used A549 cells to construct a subcutaneous tumor model and record the tumor growth curve;(3)Nude mice with tumors up to 500mm3 were administered according to the grouping situation.After the administration,all mice were subjected to IVC model construction;(4)Analyze the size of thrombus in the blank group,bevacizumab group,control group 8 hours after operation and 24 hours after operation in all groups.And use HE staining to analyze thrombolysis rate;(5)C31 immunohistochemical analysis was performed on the tumor tissue;(6)ELISA was used to analyze the concentration of PAI-1 and t-PAIC in the serum of nude mice;(7)Western Blot technique and RT-PCR technique were used to detect the expression levels of PAI-1 and VEGF in each group of tumor tissues and tumor cells.ResultsClinical study: A total of 944 eligible tumor patients were included in this study,including 472 in the thrombosis group and 472 in the control group.According to the random number table,the enrolled patients were randomly assigned to the modeling database and the model verification database.After analyzing the modeling database,it was finally found that chemotherapy,hypertension,a history of VTE,a history of surgery within one month,PICC catheterization,D dimer≥1.805(μg/m L),PT<12.85 s,hemoglobin ≤ 114.5(g/L)and CRP ≥ 7.575(mg/L)are risk factors for thrombosis in tumor patients.Using the above risk factors,a new risk assessment model for tumor-related thrombosis is constructed.The model has a good degree of fit and good discrimination ability.The model was verified by an external population using the model test database,and the results showed that the model can better identify the risk of thrombosis in hospitalized tumor patients.Basic Research:(1)This study successfully constructed a nude mouse subcutaneous tumor model;(2)According to the tumor growth curve and the immunohistochemical results of the tumor tissue,the number of neovascularization in the tumor tissue of the bevacizumab treatment group was significantly reduced,which affected the growth process of the tumor.(3)Through the analysis of the rapid volume and weight of thrombus,it can be known that the tumor microenvironment will promote the formation of thrombus,and the use of bevacizumab will aggravate the formation of thrombus in the tumor microenvironment,and PAI-1 has a potential role in it;(4)HE staining results show that the use of bevacizumab can inhibit the natural dissolution process of thrombus.(5)ELISA results show that bevacizumab can increase the concentration of tumor-derived PAI-1 in the blood and the activity of PAI-1 to inhibit fibrinolysis;(6)Western Blot and RT-PCR technology results show that bevacizumab In the tumor tissues and tumor cells in the monoclonal antibody treatment group,the expression level of VEGF protein was suppressed,while the expression of PAI-1 protein and PAI-1 m RNA was promoted.ConclusionClinical research: Starting from the actual situation of the Chinese population,we developed a new scoring system based on nine risk factors: high blood pressure,PICC catheterization is performed,D dimer≥1.805(μg/m L),PT<12.85 s,hemoglobin≤114.5(g/L)and,history of major surgery(within one month),CRP≥7.575(mg/L),a history of VTE to assess the risk of VTE in cancer patients.Basic research: The tumor microenvironment promotes thrombosis;the use of the anti-angiogenic drug bevacizumab inhibits the expression of tumor VEGF protein,interrupts the inhibition of VEGF on the expression of PAI-1 in tumor cells,thereby increasing the expression of PAI-1.Thereby promoting the formation of thrombus.