| Background Hypercoagulable state(HCS),an abnormal coagulation state that predisposes to thrombosis,is one of the most common complications of malignant tumours.Patients with advanced malignancies,treated with surgery,radiotherapy and chemotherapy,are often combined with HCS;HCS can further develop into venous thromboembolism(VTE),which increases the morbidity and mortality of patients with malignancies and seriously affects their quality of life,as well as making the treatment of malignancies more diffcult.Early detection and timely intervention to prevent and reduce thrombosis is expected to significantly improve the prognosis of patients with malignancy.It is currently thought that HCS may be associated with severe metabolic disorders and inflammatory responses,but there is a lack of evidence-based basis for this and the mechanisms are still unclear.In this study,we propose to conduct a clinical study on the intervention of HCS with Yiqi Huoxue formula on the basis of the previous study,to explore new markers of hypercoagulable state in patients with advanced malignancies,and to further explore the possible mechanisms associated with the intervention of HCS in malignancies with empirically effective formula.Objective This research is divided into three parts.The first part is a literature review to sort out the epidemiology,pathogenesis,risk factors,risk assessment,diagnostic criteria,prevention and treatment tools for the development of HCS in patients with malignant tumours,as well as the current state of knowledge and research on HCS complicating the development of malignant tumours in Chinese medicine.The second part is a clinical study:1.A retrospective study,VTE is the most common as well as the most easily identifiable pathophysiological outcome in the development of hypercoagulable state,therefore by retrospectively analysing patients admitted to our oncology and critical care departments during the five years from 1 January 2015 to 31 December 2019 who were diagnosed with VTE caused by malignant tumours combined with HCS,to understand the epidemiology,clinical characteristics and TCM syndrome type distribution of patients with malignant tumor complicated with venous thromboembolism.2.Randomized and controlled clinical study,study supervisor’s empirical formula:Yiqi Huoxue formula,on the treatment of patients with advanced malignant tumours combined with HCS,and to evaluate the effects on coagulation function,evaluation of the efficacy of the Chinese medical evidence,incidence of VTE,cytokines,immune function and quality of life,and to understand their safety.The third part is a metabolomics-based mechanism exploration.Blood specimens from patients in the clinical study were selected,and additional blood specimens from patients with advanced malignancies not combined with HCS were collected for metabolomic analysis to understand patients with advanced malignancies,the presence of HCS and the metabolic pathways that may be affected by using Yiqi Huoxue Formula to intervent HCS.Methods 1.Literature review:The latest literature at home and abroad was reviewed and sorted to understand the epidemiological characteristics,risk factors,evaluation methods,as well as diagnostic criteria and prevention and treatment means for the occurrence of HCS in patients with malignant tumours;and to understand the latest research progress in Chinese medicine on the understanding of patients with malignant tumours combined with HCS,as well as the etiology,pathogenesis and diagnosis and treatment.2.Retrospective study:Case data of malignant tumor patients admitted to the oncology and critical care departments of our hospital during the 5-year period from January 2015 to December 2019 were collected and sorted,and statistical analysis was carried out to understand the incidence rate of malignant tumor complicated with VTE,the general situation of patients,tumor distribution characteristics,risk factors and the rule of TCM syndrome classification.3.Clinical study:Based on the retrospective study on the distribution of TCM syndrome types,a total of 72 patients with advanced malignant tumor were included by the principle of randomization and control,divided into experimental group and control group,36 cases in each.The control group received conventional treatment,and the experimental group was orally supplemented with Yiqi Huoxue formula,one dose a day,twice in the morning and evening,for a total of 4 weeks.At the end of treatment,the coagulation status of the two groups,the incidence of VTE,and changes in the evaluation of the efficacy of the Chinese medical evidence,cytokine assay,immune function,quality of life score,and bleeding and metastasis were observed.4.Non-targeted metabolomics study:with informed consent,patients were selected for the clinical study:22 patients in the Yiqi Huoxue Formula group and 23 patients in the control group,and additional 46 blood specimens were collected from patients with advanced malignancies without hypercoagulable state.A LC-MS based non-targeted metabolomics study was conducted to reveal the differences in metabolites and pathways between the hypercoagulable and non-hypercoagulable states in patients with advanced malignancies,as well as between patients in the Yiqi Huoxue Formula group and the control group and patients with non-hypercoagulable states.using multivariate statistical analysis including principal component analysis(PCA)and orthogonal partial least squares analysis(OPLS-DA),and functional analysis such as metabolic pathways to discover The relevant biological significance was found.Results 1.A total of 6,305 patients were included in the retrospective analysis,and after screening out the same patients with repeated hospitalizations,a total of 1342 entered the analysis,including 148 with combined VTE,with a prevalence of 11.02%.The 148 patients ranged in age from 30 to 92 years old,with an average age of 70.21 and 12.91 years old.There were 25 cases of PTE alone(16.89%of patients with VTE),5 cases of PTE combined with DVT(3.38%of patients with VTE oncology);118 cases of DVT alone(79.73%of patients with VTE oncology),with no significant differences between the three groups in terms of patient age,gender,PS score and BMI.The tumour with more VTEs was gastrointestinal tumour,with 57 cases,and adenocarcinoma was the most common pathological type;TNM stage:stage Ⅳpatients were the most common,with 106 cases,and the earlier the stage,the fewer the number of cases;subgroup analysis showed that there was no significant difference in the proportion of TNM stage composition between the three groups(P>0.05).Multi-factor regression analysis revealed that smoking,TNM stage Ⅳ,lung cancer and CVC placement were independent risk factors for the occurrence of VTE;in terms of TCM evidence,Qi deficiency and blood stasis evidence was the most common evidence type among all patients.2.A total of 76 patients were enrolled in the clinical study,4 were lost to follow-up,and 72 were completed,with 36 patients in the treatment group and 36 patients in the control group.The results showed that:①there was no statistical difference between the two groups in terms of age,gender,tumour type,pathological type,comorbidity,combined bleeding and KPS score;②in terms of coagulation,platelet(PLT)was lower in the trial group than in the control group after 28 days of treatment(p=0.031);prothrombin time(PT)did not differ between the two groups before and after treatment;activated partial thromboplastin time(APTT)in the trial group was APTT)was prolonged;fibrinogen(FIB)and D-dimer were decreased and statistically significant(APTTP<0.001,FIB:P=0.042,D-D:P<0.001),suggesting an improvement in hypercoagulable state;③the incidence of VTE was not statistically different between the two groups,with 9 cases in the test group and 11 cases in the control group(P=0.078);④after 4 weeks of treatment compared with Compared with the control group after 4 weeks of treatment,the Chinese medicine symptom efficacy evaluation of the Yiqi Huoxue Formula group was superior to that of the control group(P=0.008);⑤In terms of cytokine determination,the levels of plasma VEGF,TNF-α,IL-1βand IL6 decreased significantly in the Yiqi Huoxue Formula treatment group after treatment(P<0.001);⑥Laboratory tests:lymphocyte classification:absolute number of blood lymphocytes,absolute number of helper/inducer T lymphocytes and suppressor/cy to toxic T lymphocytes and NK cells were significantly higher in the test group;quality of life assessment:KPS and fatigue scores were significantly better in the test group than in the control group after treatment;⑦there was no statistical difference in bleeding as well as metastasis between the two groups during treatment.3.The metabolomics study included a total of 91 patients with advanced malignancy,of which 45 were patients with advanced malignancy in hypercoagulable state in the clinical study,46 were patients with advanced malignancy in non-hypercoagulable state and 45 healthy physical examiners.A total of 144 differential compounds were identified in all patients with advanced malignancy compared to 45 healthy check-ups of comparable gender and age.The main differential compounds were amino acids,carnitine and sugars,and the levels of nutrients such as amino acids were significantly lower in patients with advanced malignancy than in healthy subjects.In patients with advanced malignancy,45 patients with hypercoagulable state were compared with the non-hypercoagulable state group with normal coagulation,and there were significant metabolic differences between the two groups.157 differential compounds were identified,of which 53 compounds were significantly lower in concentration in the non-hypercoagulable patients than in the hypercoagulable state group,these compounds were compounds such as C14-Carnitine and Arginine,104 compounds were significantly higher than those in the hypercoagulable state patients,including amino acid compounds such as Tryptophan,suggesting that coagulation status leads to differences in metabolic groups.There was a tendency for patients to shift to a non-hypercoagulable state in terms of metabolism after treatment with Yiqi Huoxue formula compared to the control group.148 differential compounds were also identified,with the differential compounds being fatty acids such as(±)11(12)-EET and amino acids such as Proline.metabolic pathway analysis revealed that Yiqi Huoxue formula mainly interfered with the patients’ Arginine biosynthesis.The analysis of metabolic pathways revealed that Yiqi Huoxue formula mainly interfered with Arginine biosynthesis,D-Glutamine and D-glutamate metabolism.Conclusions Through retrospective analysis,the probability of VTE caused by HCS in malignant tumor patients is 11.02%.VTE increased the risk of death and decreased the quality of life in patients with malignant tumors.Univariate and multivariate analysis showed that smoking,TNM stage Ⅳ,lung cancer and CVC placement were independent risk factors for VTE.In terms of TCM syndrome classification,Qi deficiency and blood stasis syndrome is the most frequently witnessed type in patients with tumor complicated with VTE,which also provides a theoretical basis for further clinical research on the use of Yiqi Huoxue formula.The clinical study confirmed that Yiqi Huoxue Formula could improve hypercoagulability,although it did not reduce the incidence of VTE,which may be related to the duration of intervention and the number of cases;Yiqi Huoxue Formula also reduced the levels of VEGF and TNF-α,IL-1βand IL6 inflammatory factors,and could regulate the immune status of patients with advanced malignancies without increasing the risk of bleeding and metastatic risk.Further metabolomic analysis revealed that the metabolism of patients with advanced malignancy combined with hypercoagulable states differed significantly from that of non-hypercoagulable patients and healthy subjects,mainly affecting the metabolic pathways of amino acids and carnitine,and that the mechanism of Yiqi Huoxue Formula in improving HCS may be related to amino acid metabolism. |
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