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Venous thromboembolism (VTE) is a frequent complication of malignancy. The aim of this study was to investigate whether multi-state modelling may be a useful quantitative approach to dissect the complex epidemiological relationship between hypercoagulability, VTE, and death in cancer patients. We implemented a three-state/three-transition unidirectional illness-death model of cancer-associated VTE in data of 1,685 cancer patients included in a prospective cohort study, the Vienna Cancer and Thrombosis Study (CATS). During the two-year follow-up period, 145 (8.6 %) patients developed VTE, 79 (54.5 %) died after developing VTE, and 647 (38.4 %) died without developing VTE, respectively. VTE events during follow-up were associated with a three-fold increase in the risk of death (Transition Hazard ratio (HR)=2.98, 95 % confidence interval [CI]: 2.36-3.77, p< 0.001). This observation was independent of cancer stage. VTE events that occurred later during follow-up exerted a stronger impact on the risk of death than VTE events that occurred at earlier time points (HR for VTE occurrence one year after baseline vs at baseline=2.30, 95 % CI: 1.28-4.15, p=0.005). Elevated baseline D-dimer levels emerged as a VTE-independent risk factor for mortality (HR=1.07, 95 % CI: 1.05-1.08, p< 0.001), and also predicted mortality risk in patients who developed VTE. A higher Khorana Score predicted both the risk for VTE and death, but did not predict mortality after cancer-associated VTE. In conclusion, multi-state modeling represents a very potent approach to time-to-VTE cohort data in the cancer population, and should be used for both observational and interventional studies on cancer-associated VTE.

Background: In cancer patients, reduced serum albumin has been described as a marker for global declining health and poor prognosis. Our aim was to investigate the association of albumin concentrations with the occurrence of venous thromboembolism (VTE) and mortality in patients with cancer., Methods: This investigation was performed in the framework of the Vienna Cancer and Thrombosis Study (CATS), a prospective observational cohort study. We included 1,070 patients with active cancer and assayed serum albumin from venous blood taken at study inclusion. Risk for occurrence of VTE was calculated in a proportional subdistribution hazard regression model with respect to competing risk of death and adjusted for cancer site, leukocyte count, estimated glomerular filtration rate, and cholinesterase., Results: Patients (630 males [58.9%] and 440 females [41.1%]) were observed for a median of 723 days. During follow-up, 90 VTE events (8.4%) and 396 deaths (37.0%) occurred. The median albumin was 41.3 g/L (25th-75th percentile, 37.6-44.2). Patients with albumin levels below the 75th percentile had a 2.2-fold increased risk of VTE (95% confidence interval [CI] 1.09-4.32), as well as a 2.3-fold increased risk of death (95% CI 1.68-3.20) compared with patients with albumin above the 75th percentile., Conclusion: Decreased serum albumin levels in cancer patients were significantly associated with increased risk of VTE and mortality. Serum albumin, a marker of a cancer patient's overall prognosis, could be considered for risk assessment of important clinical outcomes such as VTE and mortality., Implications for Practice: Cancer patients are at increased risk of venous thromboembolism (VTE). In this prospective cohort study of 1,070 cancer patients, decreased serum albumin was a marker for risk of VTE and mortality, independent of kidney or liver function and inflammation markers. The study identified a group of patients with high risk of cancer-associated VTE and a reduced prognosis who may benefit from supportive therapy such as primary VTE prophylaxis., (©AlphaMed Press.)

Unlabelled: ESSENTIALS: Hemostasis biomarkers impact thrombosis occurrence and survival in cancer patients. We performed a longitudinal analysis of hemostatic parameters in 112 cancer patients. Hemostatic parameters are associated with disease state, patients' prognosis, and the risk of VTE. The procoagulant state exists not only at diagnosis, but also during the course of disease., Background: Hemostasis biomarkers are known to have an impact on venous thromboembolism (VTE) occurrence and survival in cancer patients., Objectives: As there are almost no data on longitudinal changes, we aimed to evaluate those in the present prospective observational study during chemotherapy and the course of disease., Patients/methods: Patients with cancer of the brain (n = 39), lung (n = 41), colon (n = 15) or pancreas (n = 17) were included before initiation of antitumor therapy. Blood samples for determination of factor VIII, thrombin peak height, D-dimer, F1 + 2 , fibrinogen and soluble P-selectin (sP-selectin) were drawn on a monthly basis. The study endpoints were death, VTE occurrence, or completion of the study period., Results: Overall, 546 blood samples of 112 patients were analyzed. D-dimer and sP-selectin levels were significantly higher in patients with distant metastasis than in those without. Patients with complete remission had significantly lower levels of F1 + 2 , D-dimer and fibrinogen. Peak height thrombin levels showed a decrease over time in all tumor types. Levels of biomarkers behaved differently in the various tumor types. Patients who developed VTE (n = 14) showed increasing levels of FVIII, sP-selectin, and D-dimer. At the last blood sampling time-point before VTE occurrence, in 13 patients the D-dimer level was above the median, and in seven of these patients it was even above the 75th percentile; however, the individual course was highly variable. Regarding survival, steadily increased FVIII, sP-selectin and D-dimer levels were associated with higher mortality., Conclusions: Hemostatic parameters show an association with disease state, prognosis, and the risk of VTE, not only at diagnosis, but also during the course of antineoplastic treatment., (© 2015 International Society on Thrombosis and Haemostasis.)

Venous thromboembolism (VTE) is a frequent complication in cancer patients. Platelet activation is thought to be involved in cancer-associated VTE. Here, we determined the association between evolving markers of platelet activation (soluble P-selectin [sP-selectin], soluble CD40 ligand [sCD40L], thrombospondin-1 [TSP-1] and platelet factor-4 [PF-4]) and the development of cancer-associated VTE. A nested matched case-control study was applied within a cohort of 1779 patients with different types of cancer that had been included in the Vienna Cancer and Thrombosis Study (CATS), a prospective, observational study on patients with newly diagnosed or progressive cancer after remission. Primary endpoint is symptomatic VTE during a maximum follow-up of 2 years. Cases (patients who developed VTE during follow-up) were matched in a 1:2 ratio to controls without VTE during follow-up with respect to tumor type, stage and time of observation in the study. In total, 131 VTE cases were compared to 262 controls. In logistic regression analysis, only sP-selectin was associated with risk of VTE. The odds ratios (OR) per double increase of sP-selectin, sCD40L, TSP-1 and PF-4 were 1.66 (95% confidence interval: 1.17-2.35, p = 0.005), 1.04 (0.89-1.21, p = 0.635), 1.09 (0.90-1.32, p = 0.360) and 1.03 (0.87-1.21, p = 0.737), respectively. In conclusion, sP-selectin, but not sCD40L, TSP-1 or PF-4 were associated with risk of VTE in cancer patients in this nested case-control study.

Purpose: Cancer patients are at an increased risk of venous thromboembolism (VTE). VEGF promotes the growth of highly thrombogenic tumor vessels. Here, we explored the utility of soluble plasma VEGF-A (sVEGF) as a biomarker for the prediction of VTE in patients with cancer., Experimental Design: Eight hundred four patients with newly diagnosed cancer or progression after remission were prospectively followed for 2 years until the occurrence of VTE or death [tumor sites: brain (n = 87), breast (n = 137), lung (n = 120), gastrointestinal (n = 143), pancreas (n = 53), prostate (n = 95), kidney (n = 22), myeloma and lymphoma (n = 99), and others (n = 48)]. Primary endpoint was symptomatic or fatal VTE. sVEGF was measured by immunoassay in baseline plasma., Results: Fifty-five patients developed VTE (6.8%) and 364 patients (45.3%) died. Five-hundred and forty-two (68.3%) participants had sVEGF levels above the detection limit of 0.5 pg/mL. The median sVEGF level (25th-75th percentile) was 8.1 pg/mL (0-17.7). The cumulative 2-year incidence of VTE was 10.2% [95% confidence interval (CI), 6.4-14.9] in patients with sVEGF greater than the 75th percentile of the sVEGF distribution (Q3, cutoff: 17.7 pg/mL), and 5.9% (95% CI, 4.2-7.9) in patients with lower levels (P = 0.03). The corresponding 2-year risk of death was 52.8% (95% CI, 46.0-60.0) and 43.9% (95% CI, 40.0-48.0), respectively (P = 0.02). In univariable time-to-VTE regression, elevated sVEGF was associated with VTE [subhazard ratio (SHR) per 10 pg/mL increase, 1.04; 95% CI,1.00-1.09; P = 0.04)]. The association between sVEGF and risk of VTE prevailed after multivariable adjustment for high-risk tumor sites, age, gender, factor VIII, thrombin generation potential, and soluble P-Selectin (adjusted SHR, 1.04; 95% CI, 1.00-1.09, P = 0.05)., Conclusions: Elevated sVEGF is associated with an increased risk of VTE in patients with cancer., (©2015 American Association for Cancer Research.)

Introduction: Low-molecular-weight heparin (LMWH) and vitamin K antagonists (VKA) are current treatment options for cancer patients suffering from acute venous thromboembolism (VTE). The role of direct-acting oral anticoagulants (DOACs) for the treatment of VTE in cancer patients, particular in comparison with the current standard of care which is LMWH, remains unclear. In this network meta-analysis, we compared the relative efficacy and safety of LMWH, VKA, and DOAC for the treatment of cancer-associated VTE., Methods: A pre-specified search protocol identified 10 randomized controlled trials including 3242 cancer patients. Relative risks (RR) of recurrent VTE (efficacy) and major bleeding (safety) were analyzed using a random-effects meta-regression model., Results: LMWH emerged as significantly superior to VKA with respect to risk reduction of recurrent VTE (RR=0.60, 95%CI:0.45-0.79, p<0.001), and its safety was comparable to VKA (RR=1.08, 95%CI:0.70-1.66, p=0.74). For the DOAC vs. VKA efficacy and safety comparison, the relative risk estimates were in favor of DOAC, but had confidence intervals that still included equivalence (RR for recurrent VTE=0.65, 95%CI:0.38-1.09, p=0.10; RR for major bleeding=0.72, 95%CI:0.39-1.37, p=0.32). In the indirect network comparison between DOAC and LMWH, the results indicated comparable efficacy (RR=1.08, 95%CI:0.59-1.95, p=0.81), and a non-significant relative risk towards improved safety with DOAC (RR=0.67, 95%CI:0.31-1.46, p=0.31). The results prevailed after adjusting for different risk of recurrent VTE and major bleeding between LMWH vs. VKA and DOAC vs. VKA studies., Conclusion: The efficacy and safety of LMWH and DOACs for the treatment of VTE in cancer patients may be comparable., Funding: Austrian Science Fund (FWF-SFB-54)., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: In studies on cancer-associated venous thromboembolism (VTE), patients not only are at risk for VTE but also may die from their underlying malignancy., Objectives: In this competing-risk (CR) scenario, we systematically compared the performance of standard (Kaplan-Meier estimator [1-KM]), log-rank test, and Cox model) and specific CR methods for time-to-VTE analysis., Patients and Methods: Cancer patients (1542) were prospectively followed for a median of 24 months. VTE occurred in 112 (7.3%) patients, and 572 (37.1%) patients died., Results: In comparison with the CR method, 1-KM slightly overestimated the cumulative incidence of VTE (cumulative VTE incidence at 12 and 24 months [1-KM vs. CR]: 7.22% vs. 6.74%, and 8.40% vs. 7.54%, respectively). Greater bias was revealed in tumor entities with high early mortality (e.g., pancreatic cancer, n = 99, 24-month cumulative VTE incidence: 28.37% vs. 19.30%). Comparing the (subdistribution) hazard of VTE between patients with low and high baseline D-dimer, the Cox model yielded a higher estimate than the corresponding CR model (hazard vs. subdistribution hazard ratio [95% CI] 2.85 [1.92-4.21] vs. 2.47 [1.67-3.65]). For this comparison, the log-rank test yielded a higher test statistic and smaller P-value than Gray's test (χ(2) on 1 degree of freedom: 29.88 vs. 21.34)., Conclusion: In patients with cancer who are at risk for VTE and death, standard and CR methods for time-to-VTE analysis can generate differing results. For 1-KM, the magnitude of bias is a direct function of competing mortality. Consequently, bias tends to be negligible in cancer patient populations with low mortality but can be considerable in populations at high risk of death., (© 2014 International Society on Thrombosis and Haemostasis.)

Background: Patients with cancer are at an increased risk for venous thromboembolism (VTE). The risk varies markedly in different patient populations. Factor V (FV) Leiden is the most common genetic risk factor for VTE, and the impact of FV Leiden on cancer-associated thrombosis is not yet fully elucidated., Objective: To study the impact of FV Leiden on the risk of thrombosis in cancer patients., Methods: In the prospective observational Vienna Cancer And Thrombosis Study (CATS), 982 patients were included and were followed until occurrence of VTE or death, for a maximum period of 2 years. FV Leiden was determined by genotyping at inclusion. Main outcome measures were symptomatic or lethal objectively confirmed VTE., Results: Of the 982 patients, FV Leiden was diagnosed in 72 (7.3%, 70 were heterozygous and 2 were homozygous). Ten of 72 (13.9%) patients with FV Leiden developed VTE, whereas this was the case in 69 of 910 (7.6%) patients without FV Leiden. In multivariate analysis that included age, sex, different tumor types, tumor stage, newly diagnosed vs. recurrence of disease, and the treatment modalities, the hazard ratio was 2.0 (95% confidence interval 1.0-4.0). In Kaplan-Meier analysis, the probability for development of VTE was 13% in those with and 5.7% in those without FV Leiden after 6 months; after 1 year, the corresponding risks were 15% and 7.3%., Conclusions: FV Leiden is a genetically determined and thus disease-independent parameter, which is associated with VTE in cancer patients and could therefore be used for individual risk assignment., (© 2014 International Society on Thrombosis and Haemostasis.)

Background: High-grade gliomas (HGGs) are among the most prothrombotic of malignancies., Methods: We performed a prospective study to investigate 11 potential biomarkers for prediction of venous thromboembolism (VTE) in newly diagnosed HGG patients who had undergone a neurosurgical intervention. In addition, we tested 2 VTE risk assessment models (RAMs). The strongest predictors of VTE, which were identified by statistical forward selection, were used for the first RAM. The parameters used for the second RAM were both predictive of VTE and available in routine clinical practice., Results: One hundred forty-one HGG patients were included in this study, and 24 (17%) of them developed VTE during follow-up. An association with the risk of future VTE was found for the following parameters: leukocyte count, platelet count, sP-selectin, prothrombin-fragment 1 + 2, FVIII activity, and D-dimer. The first RAM included low platelet count (<25th percentile of the study population) and elevated sP-selectin (≥75th percentile). The cumulative VTE probability after 12 months was 9.7% for score 0 (n = 76), 18.9% for score 1 (n = 59), and 83.3% for score 2 (n = 6). The second RAM included low platelet count (<25th percentile), elevated leukocyte count, and elevated D-dimer (≥75th percentile). The probability of VTE was 3.3% for score 0 (n = 63), 23.0% for score 1 (n = 53), and 37.7% for score 2 (n = 22) or score 3 (n = 3)., Conclusions: We identified biomarkers suitable for assessing the VTE risk in newly diagnosed HGG patients. The application of 2 RAMs allowed identification of patients at high risk of developing VTE. We could also define patients at low risk of VTE, who would most probably not benefit from extended primary thromboprophylaxis., (© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Patients with cancer are at risk of venous thromboembolism (VTE). Statin-use has been shown to be associated with low risk of VTE in patients without cancer, but data in cancer patients is scarce. The objective of this study was to evaluate the association of statins with risk of VTE in cancer patients in a prospective observational cohort study., Materials and Methods: Patients with newly diagnosed cancer or progression of disease after remission were included and prospectively followed for a maximum of 2 years. Study endpoint was occurrence of symptomatic VTE., Results: Patients (n=1434) were followed over a median observation period of 729 days. VTE occurred in 107 (7.5%) patients. At study inclusion, 170 (11.9%) patients took statins. Simvastatin (n=96) and atorvastatin (n=48) were the most frequently prescribed statins. VTE occurred in 6 (3.5%) patients with statins. Patients with statins had a lower risk of VTE than patients without (subhazard ratio 0.43, 95% confidence interval 0.19 to 0.98; p=0.04). In competing risk analysis, the cumulative probability of VTE in patients with statins was 2.94% after 12 months and 3.54% after 24 months, compared to 7.13% and 8.13% in the group without statins (Gray's test: p=0.04)., Conclusion: This study provides observational evidence for an association between statin use and low risk of VTE in patients with cancer. The role of statins for prevention of cancer-associated VTE needs to be confirmed in randomized, controlled trials., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Cancer patients are at high risk of developing venous thromboembolism (VTE). Red cell distribution width (RDW) has been reported to be associated with arterial and venous thrombosis and mortality in several diseases. Here, we analyzed the association between RDW and other red blood cell (RBC) parameters with risk of VTE and mortality in patients with cancer., Methods: RBC parameters were measured in 1840 patients with cancers of the brain, breast, lung, stomach, colon, pancreas, prostate, kidney; lymphoma, multiple myeloma and other tumor sites, that were included in the Vienna Cancer and Thrombosis Study (CATS), which is an ongoing prospective, observational cohort study of patients with newly diagnosed or progressive cancer after remission. Primary study outcome is occurrence of symptomatic VTE and secondary outcome is death during a maximum follow-up of 2 years., Results: During a median follow-up of 706 days, 131 (7.1%) patients developed VTE and 702 (38.2%) died. High RDW (>16%) was not associated with a higher risk of VTE in the total study cohort; in competing risk analysis accounting for death as competing variable the univariable subhazard ratio (SHR) was 1.34 (95% confidence interval [CI]: 0.80-2.23, p = 0.269). There was also no significant association between other RBC parameters and risk of VTE. High RDW was associated with an increased risk of mortality in the total study population (hazard ratio [HR, 95% CI]: 1.72 [1.39-2.12], p<0.001), and this association prevailed after adjustment for age, sex, hemoglobin, leukocyte and platelet count (HR [95% CI]: 1.34 [1.06-1.70], p = 0.016)., Conclusions: RDW and other RBC parameters were not independently associated with risk of VTE in patients with cancer and might therefore not be of added value for estimating risk of VTE in patients with cancer. We could confirm that high RDW is an independent predictor of poor overall survival in cancer.

Cytokines have been found to be elevated in cancer patients and have been associated with worse prognosis in single tumour entities. We investigated the association of eight different cytokines with venous thromboembolism (VTE) and prognosis in cancer patients. The Vienna Cancer and Thrombosis Study (CATS), a prospective study, includes patients with newly diagnosed tumour or disease progression. Patients with an overt infection are excluded. Study end-points are VTE, death, loss to follow-up or study completion. Interleukin (IL) serum levels were measured using the xMAP technology developed by Luminex. Among 726 included patients, no associations between IL levels and VTE were found, with the exception of a trend for IL-1β and IL-6 in pancreatic cancer. Elevated levels of IL-6 [as continuous variable per double increase hazard ratio (HR) = 1·07, 95% confidence interval (CI) = 1·027-1·114, P = 0·001, IL-8 (HR = 1·12, 95% CI = 1·062-1·170, P < 0·001) and IL-11 (HR = 1·37, 95% CI = 1·103-1·709, P = 0·005] were associated with worse survival. In subgroup analyses based on tumour type, colon carcinoma patients, who had higher IL-6 levels, showed a shorter survival (HR = 2·405, 95% CI = 1·252-4·618, P = 0·008). A significant association of elevated IL-10 levels with a decrease in survival (HR = 1·824, 95% CI = 1·098-3·031, P = 0·020) was seen among patients with lung cancer. No correlation between VTE and IL levels was found, but higher IL-6, IL-8 and IL-11 levels were associated with worse survival in cancer patients. Further, elevated IL-6 levels might be a prognostic marker in colorectal cancer and elevated IL-10 levels in lung cancer patients., (© 2014 British Society for Immunology.)

Venous thromboembolism (VTE) is a frequent complication in cancer patients. Mean platelet volume (MPV) has been associated with arterial and venous thrombosis in patients without cancer. We analysed MPV in cancer patients and investigated the association of MPV with risk of VTE and mortality. MPV was routinely determined in the Vienna Cancer and Thrombosis Study, a prospective, observational cohort study of patients with newly diagnosed or progressive cancer after remission. Study endpoints were occurrence of symptomatic VTE or death during a maximum follow-up of two years. Out of 1,544 included patients, 114 (7.4%) developed VTE and 573 (37.1%) died during a median observation time of 576 days. High MPV ≥75th percentile of the study population; ≥10.8 fL) was associated with decreased risk of VTE compared to MPV below the 75th percentile (HR [95% CI]: 0.59 [0.37-0.95], p=0.031). In multivariable analysis, including age, sex, cancer groups, newly diagnosed vs recurrent disease, platelet count and soluble P-selectin, this association remained statistically significant (0.65 [0.37-0.98], p=0.041). Mortality of patients with MPV (≥75th percentile was significantly decreased compared to those with lower MPV (0.72 [0.59-0.88], p=0.001). Two-year probability of VTE and overall survival was 5.5% and 64.7% in patients with high MPV compared to 9% and 55.7% in those with lower MPV. In conclusion, high MPV is associated with decreased VTE risk and improved survival in cancer patients. This finding is contrary to results observed in patients without cancer. Further studies are needed to confirm our results and elucidate underlying mechanisms.

Background: Cancer patients are at increased risk of venous thromboembolism (VTE)., Objective: We investigated the association of a history of VTE, superficial thrombophlebitis, or the presence of varicose veins with the occurrence of VTE during the course of cancer., Methods: Cancer patients were recruited in a prospective cohort study, the Vienna Cancer and Thrombosis Study. Patients who had VTE within 3 months before study inclusion were excluded. At study inclusion, history of VTE, history of superficial thrombophlebitis, and presence of varicose veins were recorded. Primary end point was the occurrence of symptomatic VTE. Hazard ratios were obtained using the competing risk analysis according to Fine and Gray., Results: The cohort consisted of 1270 patients followed over a median of 590 days. A history of VTE was found in 66 patients (5.2%), superficial thrombophlebitis in 79 patients (6.2%), and varicose veins in 160 patients (12.6%). Ninety-eight patients (7.7%) developed VTE during follow-up. The hazard ratios for the risk of VTE in patients with a history of VTE or superficial thrombophlebitis were 1.44 (95% confidence interval: 0.67-3.07) and 1.94 (1.04-3.61), respectively, and 2.01 (1.26-3.21) in those with varicose veins. In multivariable analysis including history of VTE, history of superficial thrombophlebitis, presence of varicose veins, and other patient-related factors, the presence of varicose veins (2.10 [1.29-3.41]) remained significantly associated with an increased risk of VTE., Conclusion: The presence of varicose veins is associated with an elevated risk of VTE in cancer patients. This clinical parameter could be useful for individual risk assessment of VTE in these patients., (© 2013 International Society on Thrombosis and Haemostasis.)

Advanced cancer is a risk factor for venous thromboembolism. However, lymph node metastases are usually not considered an established risk factor. In the framework of the prospective, observational Vienna Cancer and Thrombosis Study we investigated the association between local (N0), regional (N1-3), and distant (M1) cancer stages and the occurrence of venous thromboembolism. Furthermore, we were specifically interested in the relationship between stage and biomarkers that have been reported to be associated with venous thromboembolism. We followed 832 patients with solid tumors for a median of 527 days. The study end-point was symptomatic venous thromboembolism. At study inclusion, 241 patients had local, 138 regional, and 453 distant stage cancer. The cumulative probability of venous thromboembolism after 6 months in patients with local, regional and distant stage cancer was 2.1%, 6.5% and 6.0%, respectively (P=0.002). Compared to patients with local stage disease, patients with regional and distant stage disease had a significantly higher risk of venous thromboembolism in multivariable Cox-regression analysis including age, newly diagnosed cancer (versus progression of disease), surgery, radiotherapy, and chemotherapy (regional: HR=3.7, 95% CI: 1.5-9.6; distant: HR=5.4, 95% CI: 2.3-12.9). Furthermore, patients with regional or distant stage disease had significantly higher levels of D-dimer, factor VIII, and platelets, and lower hemoglobin levels than those with local stage disease. These results demonstrate an increased risk of venous thromboembolism in patients with regional disease. Elevated levels of predictive biomarkers in patients with regional disease underpin the results and are in line with the activation of the hemostatic system in the early phase of metastatic dissemination.

Background: Brain tumor patients have an increased risk of venous thromboembolism (VTE). An important role in cancer-related VTE has been suggested for tissue factor (TF), the main initiator of the coagulation cascade. We conducted a prospective cohort study to determine whether expression levels of TF in brain tumors are associated with future VTE., Patients and Methods: We immunohistochemically determined TF-expression in brain tumor specimens of 96 adult patients (8 low-grade and 82 high-grade gliomas, 6 embryonal tumors) that were included in the Vienna Cancer and Thrombosis Study (CATS). Each patient was prospectively followed until the occurrence of VTE and/or death within a period of two years or loss of follow-up., Results: Fifteen brain tumor patients (15.6%) developed VTE during follow-up. Seventy-seven brain tumors (80.2%) stained positive for TF. Staining was strong in 13 (13.5%), moderate in 64 (66.7%) and negative in 19 (19.8%) tumors. No statistically significant association between TF-expression (negative, focal, widespread) and the occurrence of VTE was found. The hazard ratio (HR) for VTE was 1.30 (95% confidence interval [CI]: 054 - 3.14, p=0.567) when patients with negative-, focal- and widespread TF expression were compared and not statistically significant. Also when tumors were categorized into two groups (focal/widespread versus negative TF-expression), the HR for future VTE was not statistically significant (HR: 1.45, 95% CI: 0.44 - 7.37; p=0.578). An association can still not be definitely excluded, as this study was underpowered., Conclusions: Our data indicate that TF-expression levels in brain tumors are not strongly associated with future VTE., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose: Patients with cancer are at risk of venous thromboembolism (VTE). Tumor-related factors could help estimate patients' individual risk for VTE. Currently, only scarce information on the association between tumor grade and VTE is available. We thus evaluated the role of tumor grade and its association with VTE., Patients and Methods: The Vienna Cancer and Thrombosis Study is a prospective, observational cohort study including patients with newly diagnosed cancer or progression of disease after remission. Study end point is the occurrence of symptomatic VTE., Results: Seven hundred forty-seven patients with solid tumors received follow-up for a median of 526 days. VTE occurred in 52 patients (7.0%). At study inclusion, 468 patients had low-grade tumors (G1 and G2) and 279 had high-grade tumors (G3 and G4). In multivariable Cox regression analysis including tumor grade, tumor histology, tumor sites, stage, sex, and age, patients with high-grade tumors had a significantly higher risk of VTE compared with those with low-grade tumors (hazard ratio, 2.0; 95% CI, 1.1 to 3.5; P = .015). The cumulative probability of developing VTE after 6 months was higher in patients with high-grade tumors than in those with low-grade tumors (8.2% v 4.0%; log-rank test P = .037). Patients with high-grade tumors had higher D-dimer levels (P = .008) and leukocyte counts (P < .001), and lower hemoglobin levels (P = .008)., Conclusion: The tumor grade may help identify patients with cancer who are at high risk of VTE. The association of tumor grade with recently identified biomarkers indicates a link between tumor differentiation and pathogenesis of cancer-associated VTE.

Background: Tissue factor (TF) expression by tumors contributes to tumor growth. Release of TF-positive microparticles (MPs) may contribute to venous thromboembolism (VTE)., Objectives: To conduct a prospective cohort study to determine whether elevated MP-associated TF (MP-TF) activity is predictive of VTE and mortality in four cancer types., Patients/methods: We determined MP-TF activity in pancreatic, gastric, colorectal and brain cancer patients. We used a chromogenic endpoint assay for all patients and also a chromogenic kinetic assay for patients with pancreatic and brain cancer., Results: During follow-up, 12/60 (20%) pancreatic, 6/43 (14%) gastric, 12/126 (10%) colorectal and 19/119 (16%) brain cancer patients developed VTE; 46/60 (77%), 30/43 (70%), 47/126 (37%) and 67/119 (56%), respectively, died. MP-TF activity levels were highest in pancreatic cancer. We did not find a statistically significant association of MP-TF activity with the risk of VTE in any of the four cancer types by using two statistical methods. An association of MP-TF activity with the risk of mortality was detected in pancreatic cancer with the endpoint assay (hazard ratio [HR] 1.8 and 95% confidence interval [CI] 1.4-2.3 per doubling of activity, P < 0.001) and the kinetic assay (HR 1.2, 95% CI 1.1-1.4, P < 0.001); adjustment for type of treatment was not performed. In pancreatic cancer, MP-TF activity correlated with D-dimer level (endpoint assay, r = 0.51; chromogenic assay, r = 0.48), and a correlation between assays (r = 0.61) was found., Conclusion: MP-TF activity was not associated with future VTE in pancreatic, gastric, colorectal and brain cancer. However, we found a strong association of MP-TF activity with mortality in pancreatic cancer. MP-TF activity might be reflective of an aggressive pancreatic cancer phenotype., (© 2012 International Society on Thrombosis and Haemostasis.)

Venous thromboembolism (VTE) is a life-threatening complication in cancer patients. Identification of risk factors has been in focus in the past years. Functional single nucleotide polymorphisms (SNP) of coagulation factors known to influence the concentration or function may be considered to influence the risk of VTE in cancer patients. We evaluated the influence of fibrinogen plasma levels, the -455G>A SNP in the fibrinogen beta gene and the Val34Leu (163G>T) SNP in the factor XIII A-subunit (FXIII-A) gene on the risk of VTE. In 1,079 tumour patients recruited for the prospective Vienna Cancer and Thrombosis Study (CATS) fibrinogen levels were determined by the Clauss method. The FXIII-A Val34Leu and the fibrinogen -455G>A SNPs were tested by allele-specific PCR. The median follow-up time was 604 days, 83 thrombotic events occurred. The median fibrinogen level was 381 mg/dl (25th-75th percentile: 312 to 467). In a multivariable Cox model adjusted to chemotherapy, surgery, radiotherapy, age and sex, neither the fibrinogen concentration (hazard ratio [HR] =1.05, confidence interval [CI] 0.839-1.310 p=0.68), nor the -455G>A SNP (HR=0.77, 95%CI 0.491-1.197; p=0.24), nor the Val34Leu SNP (HR=0.99, 95%CI 0.646-1.542 p=0.99) were associated with occurrence of VTE. The fibrinogen concentration was not significantly different among the fibrinogen -455G or A genotype carriers (p = 0.33). Disseminated intravascular coagulation was observed in only five patients, none of these developed VTE. In conclusion, fibrinogen plasma levels, the fibrinogen -455G>A and the FXIII-A Val34Leu polymorphisms were not associated with VTE in our study.

Purpose: Patients with cancer are at increased risk of venous thromboembolism (VTE). Laboratory tests measuring the overall thrombophilic tendency might be useful to assess VTE risk. The aim of this study was to investigate thrombin generation, a key process in hemostasis, as predictor of cancer-associated VTE., Patients and Methods: The Vienna Cancer and Thrombosis Study (CATS) is a prospective observational cohort study of patients with newly diagnosed cancer or progression of disease after remission. The study end point is occurrence of objectively confirmed symptomatic or fatal VTE within a follow-up period of 2 years. Thrombin generation was measured with a commercially available assay., Results: One thousand thirty-three patients with malignancies of the breast (n = 151), lung (n = 148), upper (n = 44) and lower gastrointestinal tract (n = 125), pancreas (n = 67), kidney (n = 34), prostate (n = 122), and brain (n = 134) or lymphoma (n = 126), multiple myeloma (n = 26), and other tumor types (n = 56) were observed for a median observation period of 517 days. VTE occurred in 77 patients (7.5%). Patients with elevated peak thrombin (defined as values ≥ 611 nM thrombin, representing the 75th percentile of the total study population) had an increased risk of VTE with a hazard ratio of 2.1 (95% CI, 1.3 to 3.3, P = .002) in multivariable analysis including age, sex, surgery, chemotherapy, and radiotherapy. The cumulative probability of developing VTE after 6 months was significantly higher in patients with elevated peak thrombin than in those with lower peak thrombin (11% v 4%; log-rank test: P = .002)., Conclusion: Measurement of thrombin generation may help identify patients with cancer at high risk of VTE.

Accumulating evidence indicates that microparticles (MPs) are important mediators of the interaction between cancer and the hemostatic system. We conducted a large prospective cohort study to determine whether the number of circulating procoagulant MPs is elevated in cancer patients and whether the elevated MP levels are predictive of occurrence of venous thrombembolism (VTE). We analyzed plasma samples of 728 cancer patients from the ongoing prospective observational Vienna Cancer and Thrombosis Study. Study endpoint was the occurrence of symptomatic VTE. Sixty-five age- and sex-matched healthy controls were recruited for defining the cut-off point for elevated MPs (4.62 nanomolar phosphatidylserine [nM PS]), which was set at the 95th percentile of MP levels in healthy controls. The measurement of MPs was performed after capture onto immobilized annexin V, and determination of their procoagulant activity was quantified with a prothrombinase assay. During a median observation period of 710 days, 53 patients developed VTE. MP levels (nM PS) were significantly higher in cancer patients than in healthy controls (median [25th-75th percentile], 3.95 [1.74-7.96] vs. 1.19 [0.81-1.67], p<0.001). Multivariate analysis including age, sex, surgery, chemo- and radiotherapy showed no statistically significant association of the hazard ratio of elevated MPs with VTE (0.95 [95% CI, 0.55-1.64], p=0.856). In conclusion, MP levels were elevated in cancer patients compared to healthy individuals in this study. However, elevated MP levels were not predictive of VTE.

Background: The incidence of venous thromboembolism (VTE) is increased among cancer patients., Objective: We assessed serum levels of C-reactive protein (CRP) in order to study their prognostic significance for VTE and survival in the prospective observational Cancer and Thrombosis Study (CATS)., Patients and Methods: This study includes patients with recently diagnosed cancer or progression of disease after remission. Occurrence of VTE and information on the patients' anti-cancer-treatment are recorded. Observation ends with occurrence of objectively confirmed VTE, death or after 2 years. CRP levels were determined by an immunonephelometric method., Results: We included 705 consecutive patients with solid tumors. During the observation period, VTE occurred in 43 (6.1%) patients and 413 (58.6%) died. The cumulative probability of VTE was 6.6% after 1 year. In univariate analysis, CRP (as metric variable, per double increase) was associated with VTE [hazard ratio (HR) 1.2, 95% confidence interval (CI) 1.1-1.3 P = 0.048]. However, in multivariable analysis including chemotherapy, surgery and radiotherapy, metastasis, cancer-site and sP-selectin the association with VTE (HR 1.0, 95% CI 0.9-1.2 P = 0.932) was no longer observed. CRP was clearly associated with worse survival probability with a HR of 1.3 (95% CI 1.2-1.3, P < 0.0001) in multivariable analysis. The cumulative survival after 12 months was 43% in patients with CRP above the 75th percentile (1.8 mg dL(-1) ) and 82% in those below the 75th percentile., Conclusions: In cancer patients elevated CRP was not independently associated with VTE. CRP was significantly associated with worse survival., (© 2010 International Society on Thrombosis and Haemostasis.)

The risk of venous thromboembolism (VTE) is increased in cancer patients. To improve prediction of VTE in cancer patients, we performed a prospective and observational cohort study of patients with newly diagnosed cancer or progression of disease after remission. A previously developed risk scoring model for prediction of VTE that included clinical (tumor entity and body mass index) and laboratory (hemoglobin level and thrombocyte and leukocyte count) parameters was expanded by incorporating 2 biomarkers, soluble P-selectin, and D-Dimer. Of 819 patients 61 (7.4%) experienced VTE during a median follow-up of 656 days. The cumulative VTE probability in the original risk model after 6 months was 17.7% in patients with the highest risk score (≥ 3, n = 93), 9.6% in those with score 2 (n = 221), 3.8% in those with score 1 (n = 229), and 1.5% in those with score 0 (n = 276). In the expanded risk model, the cumulative VTE probability after 6 months in patients with the highest score (≥ 5, n = 30) was 35.0% and 10.3% in those with an intermediate score (score 3, n = 130) as opposed to only 1.0% in patients with score 0 (n = 200); the hazard ratio of patients with the highest compared with those with the lowest score was 25.9 (8.0-84.6). Clinical and standard laboratory parameters with addition of biomarkers enable prediction of VTE and allow identification of cancer patients at high or low risk of VTE.

Background: In cancer patients, laboratory parameters that predict venous thromboembolism (VTE) are scarce. Increased platelet count has been found to be a risk factor for VTE in cancer patients receiving chemotherapy (CHT). We have assessed high platelet count as a risk predictor for VTE in patients with cancer undergoing discriminative anti-cancer treatments and investigated whether platelet count correlates with thrombopoietin (TPO) levels., Design and Methods: The Cancer and Thrombosis Study (CATS) is an ongoing prospective observational study of patients with newly diagnosed cancer or progression of disease, which started in October 2003. Occurrence of VTE and information on the patients' anti-cancer treatment during follow-up were recorded., Results: Between October 2003 and February 2008, 665 patients with solid tumors were included (314 female/351 male, mean age 62 years). VTE occurred in 44 patients (18 female/26 male, mean age 62 years). The cumulative probability of VTE after 1 year was 34.3% in patients with a platelet count (PC) above the 95th percentile representing 443 x 10(9)/L compared with 5.9% in those below 443 x 10(9)/L. High platelet count [hazard ratio (HR): 3.50, 95% confidence interval (CI): 1.52-8.06, P = 0.0032], soluble P-selectin [HR: 2.66, 95% CI: 1.42-4.96, P = 0.0021] and surgery [HR: 4.05, 95% CI: 1.74-9.46, P = 0.0012] were statistically significant risk factors for VTE in multivariable analysis along with leucocyte count, age, gender, radio- and CHT. We found no correlation between platelet count and TPO levels., Conclusions: High PC is a clinically important, independent risk predictor for VTE in cancer patients. PC was not found to be associated with TPO levels.

Objective: Patients with cancer are at an increased risk for venous thromboembolism (VTE). Clotting factor VIII activity (FVIII) has been established as risk factor of primary and recurrent VTE. We investigated FVIII as predictive parameter of VTE in cancer patients., Methods and Results: The prospective observational Cancer and Thrombosis Study (CATS) includes patients with newly diagnosed cancer or disease progression, study end point is symptomatic VTE. FVIII was measured on a Sysmex CA 7000 analyzer. Data on 840 patients (median age: 62 years, 25th to 75th percentile 53 to 68, 378 women) were available for analyses, of these 111 patients had hematologic malignancies and 729 solid cancer. During a median observation time of 495 days 62 events occurred. Cumulative probability of VTE after 6 months was 14% in patients with elevated FVIII-levels and 4% in those with normal levels (P=0.001). The association was strongest in younger patients: whereas in 40-year-old patients a 2-fold VTE risk per factor VIII increase of 20% was observed (HR=2.0 [95% CI: 1.5 to 2.7], P<0.0001), this association was still present but attenuated in older patients., Conclusions: FVIII is independently associated with an increased risk of VTE in cancer patients. The association between FVIII and VTE risk declines with increasing age.

Purpose: Venous thromboembolism (VTE) is a well-recognized complication of cancer. Laboratory parameters might be useful to assess the VTE risk in patients with cancer. The aim of this study was to investigate D-dimer and prothrombin fragment 1 + 2 (F 1 + 2), which reflect activation of blood coagulation and fibrinolysis, for prediction of cancer-associated VTE., Patients and Methods: In a prospective, observational, cohort study of 821 patients with newly diagnosed cancer or progression of disease who did not recently receive chemotherapy, radiotherapy, or surgery were enrolled and followed for a median of 501 days (interquartile range, 255 to 731 days). The malignancies in these patients were as follows: breast (n = 132), lung (n = 119), stomach (n = 35), lower gastrointestinal tract (n = 106), pancreas (n = 46), kidney (n = 22), and prostate (n = 101) cancers; high-grade glioma (n = 102); malignant lymphoma (n = 94); multiple myeloma (n = 17); and other tumor types (n = 47). The study end point was occurrence of objectively confirmed symptomatic or fatal VTE., Results: VTE occurred in 62 patients (7.6%). The cutoff level for elevated D-dimer and elevated F 1 + 2 was set at the 75th percentile of the total study population. In multivariable analysis that included elevated D-dimer, elevated F 1 + 2, age, sex, surgery, chemotherapy, and radiotherapy, the hazard ratios (HRs) of VTE in patients with elevated D-dimer (HR, 1.8; 95% CI, 1.0 to 3.2; P = .048) and elevated F 1 + 2 (HR, 2.0; 95% CI, 1.2 to 3.6; P = .015) were statistically significantly increased. The cumulative probability of developing VTE after 6 months was highest in patients with both elevated D-dimer and elevated F 1 + 2 (15.2%) compared with patients with nonelevated D-dimer and nonelevated F 1 + 2 (5.0%; P < .001)., Conclusion: High D-dimer and F 1 + 2 levels independently predict occurrence of VTE in patients with cancer.

Cancer patients are at high risk for venous thromboembolism (VTE). Laboratory parameters with a predictive value for VTE could help stratify patients into high- or low-risk groups. The cell adhesion molecule P-selectin was recently identified as risk factor for VTE. To investigate soluble P-selectin (sP-selectin) in cancer patients as risk predictor for VTE, we performed a prospective cohort study of 687 cancer patients and followed them for a median (IQR) of 415 (221-722) days. Main tumor entities were malignancies of the breast (n = 125), lung (n = 86), gastrointestinal tract (n = 130), pancreas (n = 42), kidney (n = 19), prostate (n = 72), and brain (n = 80); 91 had hematologic malignancies; 42 had other tumors. VTE occurred in 44 (6.4%) patients. In multivariable analysis, elevated sP-selectin (cutoff level, 53.1 ng/mL, 75th percentile of study population) was a statistically significant risk factor for VTE after adjustment for age, sex, surgery, chemotherapy, and radiotherapy (hazard ratio = 2.6, 95% confidence interval, 1.4-4.9, P = .003). The cumulative probability of VTE after 6 months was 11.9% in patients with sP-selectin above and 3.7% in those below the 75th percentile (P = .002). High sP-selectin plasma levels independently predict VTE in cancer patients. Measurement of sP-selectin at diagnosis of cancer could help identify patients at increased risk for VTE.