Analysis of Prognosis and Factors of Abnormal Coagulation in Patients with Non-small Cell Lung Cancer
|School||Hebei Medical University|
|Keywords||Non-small cell lung cancer Blood coagulation Thrombophilia Venous thromboembolism Survival analysis Prognosis|
Objective: Activation of coagulation and fibrinolysis is frequentlyencountered among cancer patients. Such tumors are supposed to beassociated with higher risk of invasion, metastases and eventually worseoutcome. It is now well established that clotting activation is frequentlyencountered in cancer, typically manifesting as venous thromboembolism or alow-grade disseminated intravascular coagulation either due to cancer itself oragents used for treatment. Lung cancer is one of the most common tumorsassociated with thrombosis. Blood hypercoagulability is an important causeof thromboembolic disease in patients with lung cancer, such asdeep venous thrombosis,(DVT)and pulmonary thromboembolism(PTE), which is common in adenocarcinoma. VTE can occur in different stages ofdisease, and has become the second leading cause of death of cancer patients.Patients with tumors of lung, pancreas and gastrointestinal tract are supposedto be more prone to hypercoagulable state. Thus, clinical consequences ofthrombosis can be serious with a negative impact on the course of disease,increasing morbidity and mortality. Importantly, rather than being merely atrigger of increased thromboembolic events, cancer induced hemostaticactivity has been shown to promote tumor growth and cancer celldissemination. High levels of circulating biomarkers resembling activatedcoagulation and fibrinolytic system such as fibrinogen, fibrin (ogen) splitproducts and D-dimer have been associated with decreased survival forseveral tumor types in previous studies. Research activities among lung cancerpatients investigating the relationship between activated hemostatic systemand prognosis have revealed similar results. At present, thrombophilia andVTE for tumor patients has become one of the hot research. Non-small celllung cancer (NSCLC) accounts for about80%-85%of all lung malignancies. The aim of this study is analysis retrospectively the relationship betweenblood coagulation tests and pathophysiological characteristics in patients withnon-small cell lung cancer and investigate the prognostic value of bloodcoagulation tests and the risk factors of VTE for non-small cell lung cancerpatients, which is to provide a reference for patients with NSCLC aboutprevention and treatment of thrombophilia.Methods: In this study, the data were collected from604cases (including15patients with VTE) of hospitalized patients with histologically orcytologically confirmed NSCLC in January2009to December2012in theFourth Hospital of Hebei Medical University. The data included the relatedindexes of coagulation function in patients before treatment (includingPT, PTA, INR, APTT, Fib), D-dimer, platelet count),sex, age, pathologicaltype, TNM stage, lymph node status, whether the underlyingdiseases (including infections, kidney disease, cardiovascular disease anddiabetes), whether for central venous catheterization, VTE diagnosis etc.50controls without cancer were included in the analysis. The main mode offollow-up included the phone, out-patient and in-patient. All patients werefollowed up until December31,2013. Establishing a database of all the dataand Statistical analysis was carried out using SPSS13.0software.Measurement data were described as median, count data using Mann-WhitneyU test. Count data using χ2test, and to multivariate analysis by Logisticregression. KaplaneMeier method was used forestimation of survivaldistribution; differences in survival were assessed by the log-rank statistic.Multivariate survival analysis was performed using the Cox’s proportionalhazards regression model. P<0.05was considered statistically significant.Results:1The plasma level of all coagulation tests including D-dimer,fibrinogen (F), prothrombin time (PT), activated partial thromboplastin time(aPTT), international normalized ratio (INR) and platelet counts revealedstatistically significant difference between patient and control group (P <0.001for all variables but for F and platelet counts; P=0.0015, P=0.0045,respectively). PT, INR, Fib,,D-dimer, Plt increased significantly and APTT shortened for patients group with NSCLC than the control group.2The correlations of coagulation tests with clinical and pathological features:Compared with female patients, PT, aPTT and INR extended (P=0.007, P <0.001and P=0.0135), PTA decreased (P=0.0025), Fib significantly increasedin male patients with NSCLC (P <0.001).There was statistically no significantrelationship between age distributions and coagulation tests. Adenocarcinomasubtype exhibited higher plasma Fib, PT, INR levels(P<0.001, P=0.0065, P=0.0085, respectively) and lower PTA levels (P=0.0025) when compared withsquamous cell lung cancer patients. Fib, Plt levels was elevated (P<0.001, P=0.014), aPTT was shortened (P <0.001)in patients withⅢ, Ⅳ stages thaninpatients withⅠ~Ⅱ stages. Compared with N1-3patients andN0patients, aPTT was shortened significantly (P <0.001), and Fib, D-dimerlevels were increased (P <0.001; P=0.048); while the PT,INR extension wasno statistical significance (P=0.124; P=0.295).3Comparative study on survival rate display that evaluation of clottingfactors revealed that prolongation of PT and INR, higher plasma Fib levels,and lower PTA levels had statistically significant adverse effect on survival (P=0.032, P=0.001, P <0.001, and P=0.005, respectively). Although patientswith higher levels of aPTT and D-Dimer had prominently worse outcomewhen compared with those below the median range, the difference in survivalwas not statistically significant(P=0.2, P=0.105, respectively).4Multivariate analyses were performed with Cox’s proportional hazardsregression analyses. Consequently, only elevated INR was independentlyassociated with worse survival in addition to TNM stage (HR:1.666, P=0.017).5The incidence rates of VTE in patients with adenocarcinoma andnon-adenocarcinoma were3.51％(13/370)and0.85％(2/234),respectively,andthe difference was statistically significant(P=0.041)．The incidence rate ofVTE in stageⅠ-Ⅲ A lung cancer patients was significantly lower than that instage ⅢB-IV lung cancer patients(0.8％(2/250)vs3.67％(13/354)：P=0.025).Significant difference of incidence rate of VTE was also found between the patients with and without co-morbidity(4.31％(10/232)v s1.34％(5/372)： P=0.023). The incidence rates of VTE in patients with normal levels of plateletcount, D-dimer, were1.5％and1.10％，respectively：whereas，the incidencerates in patients with increased levels of these measurements were4.43％and6.67％，respectively：the differences between two groups were allsignificant(P <0.05).6Logistic multivariant regression analysis revealed that the clinical factorsof adenocarcinoma, Co-morbidy and high levels of D-dimer in blood wereassociated with increased risk of VTE(P <0.05).7In NSCLC patients complicated with VTE, the median survival time was12months (95%C I:9.52-14.48months); while the patients without VTE, themedian survival time was20months (95%C I:16.81-23.19months). Thesurvival time in patients with VTE is significantly lower than that in patientswithout VTE（P=0.003).Conclusion:1NSCLC patients often have activation of coagulationand fibrinolysis system, resulting in subclinical changes of coagulation andfibrinolysis, which suggests thrombophilia.2The patients with lung adenocarcinoma, and the NSCLC patients withadvanced stage,lymph node metastasis are moreprone to thrombophilia, whichis beneficial for the formation of thrombus.3Prolongations of PT and INR have been associated with poor prognosis,and elevated INR was independently associated with worse survival. we mayadvocate the use of PT and INR test in lung carcinoma patient to provide aforesight about the outcome. PT, INR may become a prognostic marker inNSCLC in the future.4The risk factors of VTE include adenocarcinoma, co-morbidity and highlevels of D-dimer in NSCLC patients. The survival time of these patients issignificantly lower than that in patients without VTE.