血小板改变在卵巢癌转移中的作用

Pretreatment Plasma D-Dimer,Fibrinogen,and Platelet Levels Significantly Impact Prognosis in Patients With Epithelial Ovarian Cancer Independently ofVenous ThromboembolismYa-Nan Man,MM,*ÞYa-Nan Wang,MM,*Jian Hao,MB,*Xiaohui Liu,MM,*Chang Liu,MB,*Cuihong Zhu,MB,*and Xiong-Zhi Wu,PhD*Objective:The study aimed to evaluate the prognostic value of pretreatment plasmadimerized plasmin fragment D(D-dimer),fibrinogen,and platelet levels in epithelialovarian cancer(EOC)after adjusting for venous thromboembolism(VTE)and to screen outthe patients with the greatest risk for poor prognosis.Methods:The study comprised190patients with EOC.The plasma D-dimer,fibrinogen,and platelet levels were examined before treatment and analyzed with patient clinico-pathological parameters,progression-free survival(PFS),and overall survival(OS).Thesurvival analysis was performed using the Kaplan-Meier method,and prognostic factorswere assessed using the Cox proportional hazards regression model.Results:The incidences of elevated plasma D-dimer levels,hyperfibrinogenemia,andthrombocytosis were40%,42.11%,and45.26%,respectively.Elevated plasma D-dimerlevel,hyperfibrinogenemia,and thrombocytosis were associated with advanced tumorstage(P G0.001,P=0.013,P G0.001).In addition,the elevated plasma D-dimer levels wereassociated with macroscopic postoperative residual disease(P=0.002)and VTE events(P=0.006).In multivariate Cox regression model,plasma D-dimer,fibrinogen,and plateletlevels were identified as independent prognostic factors for OS(P=0.039,P=0.002,andP=0.049).However,plasma fibrinogen and platelet levels,but not D-dimer levels,hadindependent prognostic value for PFS(P=0.012and P=0.022).Patients with at least any2abnormalities of plasma D-dimer,fibrinogen,and platelet levels showed shorter PFS and OSthan did patients with at most1abnormality of3parameters(P G0.001).Conclusions:Pretreatment plasma D-dimer,fibrinogen,and platelet levels,which impactprognosis independently of VTE,were demonstrated to be potential markers to predictdisease progression and surgery outcome in patients with EOC.The combined use of plasmaD-dimer,fibrinogen,and platelet levels may help to identify the high-risk populations fortreatment decisions.Key Words:Thrombocytosis,D-dimer,Fibrinogen,Venous thromboembolism,Epithelial ovarian cancer,PrognosisReceived March26,2014,and in revised form September10,2014.Accepted for publication September11,2014.(Int J Gynecol Cancer2014;00:00Y00)O RIGINAL S TUDY*Zhong-Shan-Men In-patient Department,Tianjin Medical Uni-versity Cancer Institute and Hospital,National Clinical Center for Cancer,Key Laboratory of Cancer Prevention and Therapy and †Department of Radiation Oncology,The Second Hospital of Tianjin Medical University,Tianjin,China.Address correspondence and reprint requests to Xiongzhi Wu,PhD, Zhong-Shan-Men In-patient Department,Tianjin MedicalUniversity Cancer Institute and Hospital,Key Laboratory ofCancer Prevention and Therapy,Huan-Hu-Xi Rd,He-Xi District, Tianjin,300060,China.E-mail:ilwxz@.Supported by grants from the National Science Foundation of China (No.81173376)and New Century Excellent Talent(NCET-11-1068). The authors declare no conflicts of interest.Authors Y a-Nan Man and Y a-Nan Wang contributed equally to this article.Copyright*2014by IGCS and ESGO ISSN:1048-891XDOI:10.1097/IGC.0000000000000303E pithelial ovarian cancer(EOC)encompasses90%of allovarian malignant tumors and is the second most frequent gynecologic malignancy.1,2The annual incidence of EOC exceeded204,000cases worldwide and was responsible for approximately125,000cancer-related deaths.3Although the currently established therapy for ovarian cancer includes radical surgical tumor debulking and subsequent platinum-based che-motherapy,EOC is still associated with the highest case-fatality ratio of all gynecologic cancers partly because of the propensity for early peritoneal dissemination and advanced-stage disease at clinical diagnosis.2,4The majority of advanced-stage patients relapses after initial response and ultimately dies of tumor re-currence.Given the high mortality and recurrence rate,it is very important to identify prognostic factors for EOC that can help clinical decision.Activation of coagulation and fibrinolytic pathways is often observed in cancer.5Y7Tumor cells can release tissue factor,procoagulant molecules,and proinflammatory cyto-kines that can activate the coagulation system leading to hemostatic abnormalities.6Like other malignancies,ovarian cancer is associated with a state of hypercoagulation and enhanced fibrinolysis with further enhanced thrombin gen-eration.8Dimerized plasmin fragment D(D-dimer),a final degradation product of crossed-link fibrin,is a marker of activation of coagulation and fibrinolysis.9,10Levels of D-dimer have been found to be markedly elevated in plasma from patients with different malignancies including EOC. Elevated levels of D-dimer have been predictive of survival in several malignancies including lung cancer,11Y14breast can-cer,15,16colorectal cancer,17Y20prostate cancer,21,22and cer-vical cancer.23However,the prognostic value of D-dimer in EOC is still uncertain because elevated pretreatment D-dimer levels have been associated with poor survival in some se-ries24,25but not in others.26In addition,high D-dimer levels were found to predict the occurrence of venous thrombo-embolism(VTE)in patients with cancer.Furthermore,cancer that is discovered simultaneously with or after VTE tends to have poor prognosis.27Y29However,no studies have addressed whether plasma D-dimer levels can impact prognosis inde-pendently of VTE in patients with EOC.Fibrinogen always enhanced in response to inflammatory disorders.Because a malignant tumor usually links with in-flammatory response,thus,high fibrinogen level with malig-nant tumor is probably an event for inflammatory response caused by tumor progression.30A growing body of evidence has shown that fibrinogen plays a role in tumor biology.Similar to elevated levels of D-dimer,hyperfibrinogenemia was useful for predicting several malignancies,such as stomach cancer,31 lung cancer,and colorectal cancer.32Thrombocytosis is often associated with malignancies, and the rate of pretreatment thrombocytosis in primary EOC has been reported to range from31%to42%.33,34Recently, thrombocytosis has been identified as an important prognostic factor for EOC in some retrospective studies.33,35However,to our knowledge,an investigation evaluating prognostic values of plasma D-dimer,fibrinogen,and platelet levels synchronously in ovarian cancer has not been reported and the combined ef-fects of them on prognosis are still unknown.In the present study,we assessed the relationship between clinicopathological factors and pretreatment plasma D-dimer/fibrinogen/platelet levels in patients with EOC.Then,we investigated the ability of plasma D-dimer,fibrinogen,and platelet levels to predict PFS and OS independently of VTE.Further,we evaluated the combined effects of the3parameters on prognosis and then screen out the patients with the greatest risk for poor prognosis for the first time.MATERIALS AND METHODS PatientsThe study was approved by the ethics committee of Tianjin Medical University Cancer Institute and Hospital.The inclusion criteria for this study were as follows:(1)pathologically diag-nosed EOC,(2)treatment with cytoreductive surgery between December2000and May2010in our hospital,and(3)adequate clinical information in the medical record.Patients were excluded from the study for the following criteria:(1)histology consistent with borderline ovarian tumors;(2)serious disabling diseases that would contraindicate cytoreductive surgery or platinum-based chemotherapy;(3)overt bacterial or viral infection;and(4) known congenital thrombophilia,ongoing anticoagulant treat-ment,pregnancy,or stroke or neurosurgery within6months. Finally,190consecutive patients diagnosed with EOC were in-cluded in the present retrospective study.Tumor staging was based on the International Federation of Gynecologists and Obstetrics(FIGO)guidelines.The patients were treated with primary debulking surgery and adjuvant chemotherapy(n=147) or neoadjuvant chemotherapy followed by interval debulking surgery(n=43).Postoperative residual disease was classified as ‘‘microscopic’’if all visible tumor lesions were removed during surgery,implying that a patient had only microscopic residual tumor cells.Conversely,residual disease was defined as‘‘mac-roscopic’’if all visible tumor lesions cannot be completely resected during surgery and the patient was left with tumor le-sions of any size or number.All patients were followed up4times annually,including a pelvic examination,abdominal ultrasound examination,and serum tumor marker evaluation.D-Dimer,Fibrinogen,and Platelet MeasurementThe pretreatment plasma D-dimer,fibrinogen,and platelet concentrations were measured from early morning samples and were collected24hours to1week before treatment after over-night fasting.To measure the plasma levels of D-dimer,pe-ripheral blood was obtained from the cubital vein.The level of D-dimer was measured using a nephelometry immunoassay (Axis-Shield PoC AS,Norway)at our hospital,and all the blood samples were processed according to the instructions of man-ufacturer.The standard cutoff level of0.3mg/L was used to distinguish high and normal results.Blood samples for evalu-ation of plasma fibrinogen levels were obtained by peripheral venous puncture as a part of the clinical routine.Plasma fi-brinogen levels of2to4g/L were defined as normal;plasma fibrinogen level above4g/L was defined as hyperfibri-nogenemia in this study.To measure the platelet concentrations, a blood sample was obtained as fibrinogen.A complete blood count was regularly taken,and thrombocytosis was defined as platelet count greater than300Â109/L.36Man et al International Journal of Gynecological Cancer&Volume00,Number00,Month2014Diagnosis of VTEThere was no routine screening for VTE.Objective imaging methods and D-dimer measurement were performed to confirm or exclude the diagnosis only when a patient de-veloped the symptoms of VTE.Ultrasonography,computed tomography,and magnetic resonance imaging were used to diagnose deep vein thrombosis,pulmonary embolism,and cerebral infarction,respectively.Death certificates were reviewed to establish a diagnosis of fatal pulmonary embolism in patients who died during the follow-up.Statistical AnalysisAll the categorical variables were analyzed using W2test. Survival probabilities were calculated by the product limit method of Kaplan and Meier.The end points of the analyses were progression-free survival(PFS)and overall survival(OS). Progression-free survival was defined as the time from diag-nosis to the time when progressive disease or relapse was reported,whichever occurred first.Overall survival was de-fined as the time from diagnosis to the time of last follow-up or death.Survival times of patients who were progression-free or still alive or dead as a result of other causes were censored with the last follow-up date.Variables that were identified as sta-tistically significant by univariate analysis were considered in multivariate analysis using the Cox proportional hazards model to assess the independence of different prognostic factors.All statistical analyses were performed using SPSS17.0statistical software(SPSS Inc,Chicago,IL).P values less than0.05were considered statistically significant.RESULTSRelationship Between Clinicopathological Parameters and PlasmaD-Dimer/Fibrinogen/Platelet Levels in EOC The median age of the190patients was55years(range, 25Y83years).The common histopathology was serous car-cinoma(n=99),and106patients(55.79%)had high-grade tumors.Slightly more than half(53.16%)of the patients had late-stage diseases(stages III Y IV).Postoperative residual disease defined as microscopic was achieved in approxi-mately62.11%.A standard chemotherapeutic scheme,plat-inum combined with paclitaxel,was performed in most patients(81.05%).The mean follow-up period was48months(range, 2Y150months).Plasma D-dimer and fibrinogen levels were above the normal value in76(40.00%)and80(42.11%) patients,respectively.The incidence of thrombocytosis was 45.26%(86/190;cutoff value,300Â109/L).Moreover,there were15patients with VTE,which were confirmed by imageological diagnosis or death certificates.Age at diag-nosis(P=0.001),FIGO stage(P G0.001),postoperative residual disease(P=0.002),and VTE(P=0.006)were as-sociated with plasma D-dimer levels.In addition,a significant relationship between plasma D-dimer levels and surgery(P G 0.001),but not histological type,histological grade,and platinum combined with paclitaxel chemotherapy,was ob-served(Table1).According to Table1,plasma fibrinogen levels were closely correlated with age(P=0.017),stage(P=0.013), and surgery(P=0.006),but not other clinicopathological pa-rameters.The relationship between pretreatment plasma platelet levels and clinicopathological parameters were also analyzed. Elevated platelet levels were significantly associated with ad-vanced tumor stage(P G0.001)and surgery(P G0.001)but not with age,histological type,histological grade,platinum com-bined with paclitaxel chemotherapy,and VTE(P90.05).In addition,the percentage of thrombocytosis in patients with macroscopic postoperative residual disease was higher than that in patients with microscopic postoperative residual disease (54.17%vs39.83%;P=0.054),although this was not statisti-cally significant(Table1).Prognostic Relevance of Clinicopathological Parameters,Plasma D-Dimer,Fibrinogen, and Platelet Levels in Univariate Analysis We assessed the prognostic values of the pretreatment plasma D-dimer,fibrinogen,and platelet levels in the patients with cancer included in our study,as shown in Table2.Patients with normal plasma D-dimer levels(e0.3mg/L)had a signif-icantly improved3-year PFS rate of66%as opposed to33%in patients with elevated plasma D-dimer levels(90.3mg/L)(P G 0.001;Fig.1A).Compared with hyperfibrinogenemia,normal plasma fibrinogen levels(2-4g/L)owned a better3-year PFS (41%vs61%,P=0.001;Fig.1B).Normal plasma platelet level groups showed a better3-year PFS rate than the higher groups did(66%vs36%,P G0.001;Fig.1C).In addition,FIGO stage (P G0.001),histological grade(P=0.047),postoperative re-sidual disease(P G0.001),surgery(P G0.001),platinum combined with paclitaxel chemotherapy(P=0.025),and VTE event(P G0.001)were significantly associated with PFS in the univariate analysis.The normal plasma D-dimer level groups had a better3-year OS rate than the higher groups did(80%vs 55%,P G0.001;Fig.1D),and the normal plasma fibrinogen level groups showed obvious improved3-year OS rate than the elevated groups did(78%vs59%,P G0.001;Fig.1E).Patients with thrombocytosis(plasma platelet level,9300Â109/L) clearly had a worse3-year OS rate than the group with normal levels did(56%vs82%;P G0.001;Fig.1F).The other fac-tors affecting EOC overall survival included age at diagnosis (P=0.017),FIGO stage(P G0.001),histological grade(P=0.035), postoperative residual disease(P G0.001),surgery(P G 0.001),platinum combined with paclitaxel chemotherapy (P=0.008),and VTE event(P G0.001).Prognostic Relevance of Clinicopathological Parameters,Plasma D-Dimer,Fibrinogen, and Platelet Levels in Multivariate Analysis We performed multivariate analysis on the factors that were statistically significant in the univariate analysis,and these results are shown in Table3.Multivariate evaluation of plasma D-dimer,fibrinogen,and platelet levels considered age, FIGO stage,grade,surgery,postoperative residual disease,International Journal of Gynecological Cancer&Volume00,Number00,Month2014D-Dimer,Fibrinogen,and Platelet LevelsT A B L E 1.R e l a t i o n s h i p b e t w e e n c l i n i c o p a t h o l o g i c a l p a r a m e t e r s ,p l a s m a D -d i m e r c o n c e n t r a t i o n (e 0.3m g /L v s 90.3m g /L ),f i b r i n o g e n l e v e l (2Y 4g /L v s 94g /L ),a n d p l a t e l e t c o u n t (e 300Â109/L v s 9300Â109/L )i n t h e 190p a t i e n t s w i t h E O CV a r i a b l enP l a s m a D -D i m e r ,m g /L P P l a s m a F i b r i n o g e n ,g /L )PP l a t e l e t ,Â109/LPe 0.390.32-494e 3009300A g e ,y 0.0010.0170.124e 5510071296634604095590434744464446S t a g e G 0.0010.013G 0.001I o r I I 89672260296227I I I o r I V 101475450514259H i s t o l o g i c a l t y p e 0.4410.8410.266S e r o u s 99623758415841N o n s e r o u s 91523952394645G r a d e 0.1700.1960.141L o w 84552953315133H i g h 106594757495353P o s t o p e r a t i v e r e s i d u a l d i s e a s e 0.0020.6900.054M i c r o s c o p i c 118813767517147M a c r o s c o p i c 72333943293339S u r g e r y G 0.0010.006G 0.001I n t e r v a l 43152817261132P r i m a r y 147994893549354P l a t i n u m c o m b i n e d w i t h p a c l i t a x e l 0.8210.9530.793Y e s 154936189658569N o 36211521151917V T E e v e n t 0.0060.1440.909Y e s 154116987N o17511065104719679Man et alInternational Journal of Gynecological Cancer&Volume 00,Number 00,Month 2014platinum combined with paclitaxel chemotherapy,and VTE event.In the Cox proportional hazard model,FIGO stage(P= 0.020and P=0.045),postoperative residual disease(P G0.001 and P G0.001),and platinum combined with paclitaxel che-motherapy(P=0.039and P=0.029)were significantly as-sociated with PFS and OS.Of the2target parameters,the plasma fibrinogen and platelet level was an independent prognostic factor for both PFS and OS(P=0.012and P=0.002; P=0.022and P=0.049,respectively),but the plasma D-dimer levelwas only identified as an independent prognostic factor for OS(P=0.039).Combined Effects of Plasma D-Dimer, Fibrinogen,and Platelet Levelson PrognosisTo identify the combined effects of plasma D-dimer, fibrinogen,and platelet levels on prognosis,we further grouped the patients as follows:group1,patients with normal plasma D-dimer,fibrinogen,and platelet levels;group2,pa-tients with high plasma D-dimer level or hyperfibrinogenemia or thrombocytosis;group3,patients with any of the2param-eters that were abnormal;and group4,patients with abnormalTABLE2.Prognostic relevance of clinicopathological parameters,plasma D-dimer concentration(e0.3mg/L vs 90.3mg/L),fibrinogen level(2Y4g/L versus94g/L),and platelet count(e300Â109/L vs9300Â109/L)in the univariate analysisParameter n3-Y PFS P3-Y OS P Age,y0.0570.017 e5510061%77%9559043%62%Stage G0.001G0.001 I or II8976%90%III or IV10132%53%Histological type0.1210.071 Serous9948%66%Nonserous9158%75%Grade0.0470.035 Low8460%79%High10647%63%Postoperative residual disease G0.001G0.001 Microscopic11870%84%Macroscopic7225%47%Surgery G0.001G0.001 Interval4321%58%Primary14762%74%Platinum combined with paclitaxel0.0250.008 Y es15456%73%No3639%58%VTE event G0.001G0.001 Y es157%33%No17557%73%Plasma D-dimer,mg/L G0.001G0.001 e0.311466%80%90.37633%55%Platelet(Â109/L)G0.001G0.001 e30010466%82%93008636%56%Plasma fibrinogen,g/L0.0010.001 2Y411061%78%948041%59%International Journal of Gynecological Cancer&Volume00,Number00,Month2014D-Dimer,Fibrinogen,and Platelet Levelsplasma D-dimer,fibrinogen,and platelet levels.The result demonstrated that there were 32patients with normal plasma D-dimer,fibrinogen,and platelet levels,that 49patients had an abnormality for 1of the 3parameters,that 49patients showed an abnormality for 2of the 3parameters,and that the 60remaining patients had abnormal plasma D-dimer level,hyperfibrinogenemia,and thrombocytosis.We then assessed the combined prognostic values of plasma D-dimer,fibrinogen,and platelet levels.We found that group 1/group 2showed a markedly longer PFS and OS than group 3/group 4did (Fig.2;P G 0.001).There was no statistic difference between group 1and group 2for PFS and OS (P =0.287);there was none was between group 3and group 4(P =0.119).DISCUSSIONMuch attention has been given to the relationship be-tween D-dimer/fibrinogen/platelet levels and tumors.Ele-vated plasma D-dimer,fibrinogen,and platelet levels have been found in some malignancies,such as lung cancer,11Y 14,37colorectal cancer,17Y 20gastric cancer,38cervical cancer,23and so forth.In our present study,the incidence of high D-dimer level,hyperfibrinogenemia,and thrombocytosis was 40.00%,40.11%,and 45.26%,respectively,in the patients with EOC.We found that plasma D-dimer/fibrinogen/platelet levels were significantly associated with tumor stage,and it appeared that raised D-dimer,hyperfibrinogenemia,and thrombocytosiswere clinically relevant events at the advanced stage of the disease.The percentage of raised plasma D-dimer/platelet levels in patients with macroscopic postoperative residual disease was higher than that in patients with microscopic postoperative residual disease.This estimated that patients with raised plasma D-dimer/platelet level may have worse surgery outcome.There was a significant relationship be-tween plasma D-dimer level and VTE event in the cohort study,which was in accordance with previously reported data.In addition,the percentage of high plasma D-dimer/fibrinogen/platelet levels in patients treated with interval debulking sur-gery was much higher than that in those without (P G 0.01),and the significant difference was mainly caused by the fact that 35(83.3%)patients treated with interval debulking surgery were present with FIGO stages III to IV .Three parameters were then identified as independent prognostic factors for OS in the Cox proportional hazard model.However,plasma fibrinogen and platelet levels,but not D-dimer levels,have independent prog-nostic value for PFS.In addition,VTE event,platinum combined with paclitaxel chemotherapy,FIGO stage,and postoperative residual disease were also found have independent prognostic values for PFS and OS in the multivariate analysis.Dimerized plasmin fragment D,a stable final product of fibrin degradation,has been found to be markedly higher in patients with EOC than in patients with benign ovarian dis-ease.39However,the number of studies about the prognostic value of D-dimer in EOC is relatively small and no agreements have reached conclusions.Gadducci et al 26assessedwhetherFIGURE 1.Cumulative survival curves for PFS and OS according to pretreatment plasma D-dimer,fibrinogen,and platelet levels by Kaplan-Meier method in the 190patients with EOV.A to C,Progression-free survival for plasma D-dimer (P G 0.001),fibrinogen (P =0.001),and platelet levels (P G 0.001).D to F,Overall survival for plasma D-dimer (P G 0.001),fibrinogen (P =0.001),and platelet levels (P G 0.001).Man et al International Journal of Gynecological Cancer&Volume 00,Number 00,Month 2014preoperative plasma D-dimer level has a prognostic relevance for 35patients with advanced ovarian cancer.They found that survival was related to residual disease after initial surgery but not to preoperative D-dimer level.Another study,by von Tempelhoff et al,24reported the relation between plasma D-dimer level and OS in 60patients with ovarian cancer of FIGO stages I to IV ,and they reached the conclusion that plasma D-dimer level was a significant risk factor for reduced OS in univariate analysis but not in multivariate analysis.We also should notice that there are some limitations in the previously mentioned studies.First,the sample sizes were relatively small and the final conclusions may be inconvincible.Second,pa-tients with nonepithelial ovarian cancer were not excluded from the 2studies,which may be one of the confounders that affected the results.Third,the association between plasma D-dimer level and PFS for ovarian cancer was not evaluated.Finally,no studies have addressed whether the increased mortality of pa-tients with elevated D-dimer levels is independent of VTE in patients with EOC.To our knowledge,the present study is the largest to address the prognostic significance of D-dimer in patients with EOC and determine that the decreased OS with an increased D-dimer remained significant after adjusting for VTE.However,we were not able to precisely determine the mechanism underlying the prognostic value of D-dimer in EOC.We thought that D-dimer levels might represent the state of disease progression itself rather than tumor properties rep-resented by genetic changes or morphologic findings.Experimental evidence suggested that fibrinogen and platelets can actively promote cancer progression through vari-ous mechanisms.Fibrinogen,a vital protein in the coagulationTABLE 3.Prognostic relevance of plasma D-dimer concentration,fibrinogen level,and platelet count in multivariate analysis,considering age,stage,grade,surgery,postoperative residual disease,platinum and paclitaxel,and VTE eventVariablesCategoryPFSOSHR (95%CI)PHR (95%CI)PPlasma D-dimer 90.3mg/L vs e 0.3mg/L1.232(0.800Y 1.898)0.344 1.643(1.025Y2.634)0.039Platelet9300Â109/L vs e 300Â109/L 1.681(1.079Y 2.620)0.022 1.640(1.003Y 2.682)0.049Plasma fibrinogen 94vs 2-4g/L 1.713(1.124Y 2.612)0.0122.119(1.316Y3.412)0.002Age 955vs e 55V V 0.985(0.617Y 1.575)0.951Stage III,IV vs I,II 1.943(1.112Y 3.394)0.020 1.958(1.014Y 3.778)0.045Grade High vs low0.994(0.648Y 1.526)0.979 1.117(0.687Y 1.815)0.656SurgeryInterval vs primary1.294(0.777Y2.154)0.3220.871(0.495Y 1.532)0.631Postoperative residual disease Macroscopic vs microscopic 2.516(1.551Y 4.081)G 0.0013.127(1.812Y 5.397)G 0.001Platinum combined with paclitaxel Y es vs no 0.599(0.368Y 0.975)0.0390.564(0.337Y 0.945)0.029VTE eventY es vs no1.768(0.940Y 3.325)0.077 2.028(1.033Y 3.983)0.040CI,confidence interval;HR,hazardratio.FIGURE bined effect of plasma D-dimer,fibrinogen,and platelet levels on PFS and OS using the Kaplan-Meier method.Group 1,patients with normal plasma D-dimer,fibrinogen,and platelet levels;group 2,patients with any 1abnormality of plasma D-dimer,fibrinogen,and platelet levels;group 3,patients with any 2abnormalities of plasma D-dimer,fibrinogen,and platelet levels;and group 4,patients with abnormal plasma D-dimer,fibrinogen,and platelet levels.Groups 1and 2had statistic difference with groups 3and 4(P G 0.001);There was no statistic difference between groups 1and 2for PFS and OS (P =0.287)as well as between groups 3and 4(P =0.119).International Journal of Gynecological Cancer&Volume 00,Number 00,Month 2014D-Dimer,Fibrinogen,and Platelet Levelspathway,participates in several tumor biological behaviors such as proliferation,invasion,and metastasis via promoting tumor angiogenesis and supporting the sustained adhesion of tumor cells.40Platelet plays in abetting cancer progression through numerous pathways including protection of cancer cells from immune surveillance,negotiation of cancer-cell arrest in the microvasculature,increase in tumor cell proliferation,41and stimulation of angiogenesis.42Hyperfibrinogenemia and throm-bocytosis have been identified as the important prognostic fac-tors in EOC in some retrospective studies.33,38In accordance with the previously mentioned experimental studies and recent clinical research,the present study demonstrated that elevated fibrinogen and platelet levels are at substantially increased risk for advanced disease;in addition,fibrinogen and platelet levels were further identified as the independent prognostic factors for PFS and OS in patients with EOC.To identify the combined effects of plasma D-dimer, fibrinogen,and platelet levels on prognosis,we further grouped the patients according to the levels of the3param-eters.Interestingly,we found that patients with at least any2 abnormalities of plasma D-dimer,fibrinogen,and platelet levels showed a markedly worse prognosis than did patients with any1or no abnormalities of the3parameters.It means that elevated plasma D-dimer,fibrinogen,and platelets act together or that any2abnormalities contribute to the poor prognosis of EOC synergistically.Elevated D-dimer levels, hyperfibrinogenemia,and thrombocytosis are closely related to the tumor hypercoagulability.Although at least any2ab-normalities of plasma D-dimer,fibrinogen,and platelet levels can contribute to the poor prognosis synergistically in EOC, the potential association between the3parameters has not yet been confirmed,nor has which factor plays a more important role in tumor progression.The mechanisms connecting ele-vated plasma D-dimer,hyperfibrinogenemia,thrombocytosis, and cancer cells are complicated and require further study. The merits of the application of D-dimer,fibrinogen,and platelet levels for predicting oncological outcome in clinical practice were considered as being not time-and cost-efficient, a requirement of only small plasma aliquots,and a less-invasive technique.Thus,we propose the use of the3pa-rameters in evaluation of the prognosis in patients with EOC for clinical decisions.In conclusion,pretreatment plasma D-dimer,fibrinogen, and platelet levels were demonstrated to be potential markers to predict disease progression and surgery outcome in patients with EOC.Moreover,the3parameters significantly impact prognosis independently of VTE.The combined use of plasma D-dimer,fibrinogen,and platelet levels may help us identify the high-risk populations for treatment decisions.REFERENCES1.Ng JS,Low JJ,Ilancheran A.Epithelial ovarian cancer.BestPract Res Clin Obstet Gynaecol.2012;26:337Y345.2.Jemal A,Siegel R,Xu J,et al.Cancer statistics,2010.CACancer J Clin.2010;60:277Y300.3.Sankaranarayanan R,Ferlay J.Worldwide burden ofgynaecological cancer:the size of the problem.Best Pract Res Clin Obstet Gynaecol.2006;20:207Y225.4.Cannistra SA.Cancer of the ovary.N Engl J Med.2004;351:2519Y2529.5.Beer JH,Haeberli A,V ogt A,et al.Coagulation markers predictsurvival in cancer patients.Thromb Haemost.2002;88:745Y749.6.Shorr AF,Thomas SJ,Alkins SA,et al.D-dimer correlates withproinflammatory cytokine levels and outcomes in critically ill patients.Chest.2002;121:1262Y1268.7.Shoji M,Hancock WW,Abe K,et al.Activation of coagulationand angiogenesis in cancer:immunohistochemical localization in situ of clotting proteins and vascular endothelial growth factor in human cancer.Am J Pathol.1998;152:399Y411.8.Koh SC,Tham KF,Razvi K,et al.Haemostatic and fibrinolyticstatus in patients with ovarian cancer and benign ovarian cysts: could D-dimer and antithrombin III levels be included asprognostic markers for survival outcome?Clin Appl Thromb Hemost.2001;7:141Y148.9.De Buyzere M,Philippe J,Duprez D,et al.Coagulation systemactivation and increase of D-dimer levels in peripheral arterial occlusive disease.Am J Hematol.1993;43:91Y94.10.Lippi G,Cervellin G,Franchini M,et al.Biochemical markersfor the diagnosis of venous thromboembolism:the past,present and future.J Thromb Thrombolysis.2010;30:459Y471.11.Antoniou D,Pavlakou G,Stathopoulos GP,et al.Predictivevalue of D-dimer plasma levels in response and progressivedisease in patients with lung cancer.Lung Cancer.2006;53:205Y210.12.Taguchi O,Gabazza EC,Y asui H,et al.Prognostic significanceof plasma D-dimer levels in patients with lung cancer.Thorax.1997;52:563Y565.13.Pavey SJ,Hawson GA,Marsh NA.Impact of the fibrinolyticenzyme system on prognosis and survival associated withnon-small cell lung carcinoma.Blood Coagul Fibrinolysis.2001;12:51Y58.14.Altiay G,Ciftci A,Demir M,et al.High plasma D-dimer level isassociated with decreased survival in patients with lung cancer.Clin Oncol(R Coll Radiol).2007;19:494Y498.15.Blackwell K,Haroon Z,Broadwater G,et al.Plasma D-dimerlevels in operable breast cancer patients correlate with clinical stage and axillary lymph node status.J Clin Oncol.2000;18:600Y608.16.Dirix L Y,Salgado R,Weytjens R,et al.Plasma fibrin D-dimerlevels correlate with tumour volume,progression rate andsurvival in patients with metastatic breast cancer.Br J Cancer.2002;86:389Y395.17.Kilic M,Y oldas O,Keskek M,et al.Prognostic value of plasmaD-dimer levels in patients with colorectal cancer.ColorectalDis.2008;10:238Y241.18.Xu G,Zhang YL,Huang W.Relationship between plasmaD-dimer levels and clinicopathologic parameters in respectable colorectal cancer patients.World J Gastroenterol.2004;10:922Y923.19.Oya M,Akiyama Y,Okuyama T,et al.High preoperative plasmaD-dimer level is associated with advanced tumor stage and short survival after curative resection in patients with colorectalcancer.Jpn J Clin Oncol.2001;31:388Y394.20.Blackwell K,Hurwitz H,Lieberman G,et al.CirculatingD-dimer levels are better predictors of overall survival anddisease progression than carcinoembryonic antigen level inpatients with metastatic colorectal carcinoma.Cancer.2004;101:77Y82.21.Knowlson L,Bacchu S,Paneesha S,et al.Elevated D-dimers arealso a marker of underlying malignancy and increased mortalityMan et al International Journal of Gynecological Cancer&Volume00,Number00,Month2014。