Austrian Science Fund, Austrian National Bank Memorial Fund, and participating hospitals.

Venous thromboembolism (VTE) is common in patients with brain tumors, and underlying mechanisms are unclear. We hypothesized that podoplanin, a sialomucin-like glycoprotein, increases the risk of VTE in primary brain tumors via its ability to induce platelet aggregation. Immunohistochemical staining against podoplanin and intratumoral platelet aggregates was performed in brain tumor specimens of 213 patients (mostly high-grade gliomas [89%]) included in the Vienna Cancer and Thrombosis Study, a prospective observational cohort study of patients with newly diagnosed cancer or progressive disease aimed at identifying patients at risk of VTE. Platelet aggregation in response to primary human glioblastoma cells was investigated in vitro. During 2-year follow-up, 29 (13.6%) patients developed VTE. One-hundred fifty-one tumor specimens stained positive for podoplanin (33 high expression, 47 medium expression, 71 low expression). Patients with podoplanin-positive tumors had lower peripheral blood platelet counts ( < .001) and higher D-dimer levels ( < .001). Podoplanin staining intensity was associated with increasing levels of intravascular platelet aggregates in tumor specimens ( < .001). High podoplanin expression was associated with an increased risk of VTE (hazard ratio for high vs no podoplanin expression: 5.71; 95% confidence interval, 1.52-21.26; 010), independent of age, sex, and tumor type. Podoplanin-positive primary glioblastoma cells induced aggregation of human platelets in vitro, which could be abrogated by an antipodoplanin antibody. In conclusion, high podoplanin expression in primary brain tumors induces platelet aggregation, correlates with hypercoagulability, and is associated with increased risk of VTE. Our data indicate novel insights into the pathogenesis of VTE in primary brain tumors.

Platelets are the smallest circulating blood cells and their major function is the maintenance of haemostasis. They do not have a nucleus, but instead a multitude of granules that contain molecules important for several physiological processes. These granules can be released after platelet activation and thereby platelets take part in haemostasis, wound repair or immunological processes. Furthermore, platelets are also involved in the pathophysiology of several diseases, including cancer. Platelets can support various steps of cancer development and progression by promoting tumour growth, angiogenesis and metastasis. Moreover, platelets contribute to the hypercoagulable state frequently observed in cancer patients, leading to an increased risk of venous thromboembolism (VTE). In previous studies a high platelet count was repeatedly found to be associated with an elevated risk of VTE and a worse prognosis in patients with cancer. The aim of this review is to give an overview of the most important alterations of platelet physiology in cancer patients and how these alterations may influence cancer disease and contribute to 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.

Platelets are suggested to play a crucial role in cancer progression and the prothrombotic state of cancer patients. Here, we aimed to examine the activation status of platelets in cancer patients and investigate their association with risk of death and occurrence of venous thromboembolism (VTE) in a prospective observational cohort study. We measured platelet surface P-selectin, activated glycoprotein (GP) IIb/IIIa and monocyte-platelet aggregate (MPA) formation in vivo and platelet response to ex vivo stimulation with agonists of protease-activated receptor (PAR) -1, -4, and GPVI, by whole blood flow cytometry, before beginning of chemotherapy and repeatedly during the first six months thereafter (total number of samples analysed: 230). Endpoints of the study were occurrence of death or VTE during a two-year follow-up, respectively. Of 62 patients (median age [interquartile range, IQR]: 63 [54-70] years, 48 % female), 32 (51.6 %) died and nine (14.5 %) developed VTE. Association with a higher risk of death was found for lower platelet surface expression of P-selectin and activated GPIIb/IIIa in vivo and in response to PAR-1, -4 and GPVI activation, but not for MPA formation. Furthermore, reduced platelet responsiveness to PAR-1 and GPVI agonists was associated with higher risk of VTE (hazard ratio per decile increase of percentage P-selectin positive platelets: 0.73 [0.56-0.92, p=0.007] and 0.77 [0.59-0.98, p=0.034], respectively). In conclusion, cancer patients with a poor prognosis showed decreased platelet reactivity, presumably as a consequence of continuous activation. Our data suggest that decreased platelet reactivity is associated with increased mortality and VTE in cancer.

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.

BackgroundCancer 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.MethodsRBC 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.ResultsDuring 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).ConclusionsRDW 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.

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.