Hemostatic Biomarkers and Venous Thromboembolism Are Associated With Mortality and Response to Chemotherapy in Patients With Pancreatic Cancer

Author(s):  
Florian Moik ◽  
Gerald Prager ◽  
Johannes Thaler ◽  
Florian Posch ◽  
Sarah Wiedemann ◽  
...  

Objective: Pancreatic cancer activates coagulation and increases risk of venous thromboembolism (VTE). We aimed at characterizing the association of hemostatic biomarkers and VTE with mortality and chemotherapy response. Approach and Results: Pancreatic cancer patients (n=145) were included in a prospective, observational cohort study (CATS [Vienna Cancer and Thrombosis Study]). Hemostatic biomarkers (D-dimer, extracellular vesicle–tissue factor activity, prothrombin fragment 1+2, fibrinogen, factor VIII, PAI-1 [plasminogen activator inhibitor 1], sP-selectin [soluble P-selectin], thrombin generation assay) were measured at inclusion. The impact of VTE on overall survival/progression-free survival (OS/PFS) was evaluated by multistate modeling. The association of biomarkers with OS was analyzed by Cox-regression and with PFS and disease control rate in patients initiating palliative chemotherapy (n=95) by Cox-regression and logistic regression. Multivariable analysis included stage, grade, sex, age, performance status, VTE (time-dependent), vascular infiltration/compression, and tumor marker levels (carbohydrate-antigen 19-9, carcinoembryonic antigen). VTE occurrence was associated with shorter OS (transition hazard ratio, 3.40 [95% CI, 2.05–5.64]) and shorter PFS (transition hazard ratio, 2.10 [1.16–3.79]). Median post-VTE OS/PFS in months was 5.5 [2.2–6.5] and 3.0 [1.5–3.9], compared with 13.4 [9.7–16.6] and 7.5 [5.9–9.8] in patients without VTE (both P <0.001). D-dimer, extracellular vesicle–tissue factor activity, PAI-1, and sP-selectin were associated with increased mortality (hazard ratio per doubling, 1.27 [1.00–1.61]; 1.63 [1.14–2.36]; 1.25 [1.06–1.47]; 1.52 [1.05–2.20]). In patients initiating palliative chemotherapy, higher D-dimer predicted shorter PFS (hazard ratio per doubling, 1.27 [1.01–1.60]) and lower disease control rate (odds ratio per doubling, 0.59 [0.36–0.98]). Conclusions: VTE diagnosis is associated with shorter OS and PFS. Higher baseline levels of D-dimer, extracellular vesicle–tissue factor activity, PAI-1, and sP-selectin were independently prognostic for increased mortality, and D-dimer predicted response to palliative chemotherapy.

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 7-8
Author(s):  
Florian Moik ◽  
Gerald Prager ◽  
Sarah Wiedemann ◽  
Florian Posch ◽  
Ingrid Pabinger ◽  
...  

Background: Patients with pancreatic cancer have a high risk for venous thromboembolism (VTE). Activation of haemostasis has been suggested to contribute to the progression of cancer and its metastatic spread. However, clinical data to support the contribution of activation of haemostasis to disease progression are scarce. Our aim was to evaluate the association biomarkers indicating activation of haemostasis and/or hypercoagulability and of VTE occurrence with survival and therapy response in patients with pancreatic cancer. Methods: Within a prospective, observational cohort study (Vienna Cancer and Thrombosis Study, CATS), we evaluated the subgroup of patients with pancreatic cancer (n=145). Levels of a comprehensive panel of haemostatic biomarkers (D-dimer, prothrombin fragment 1+2, fibrinogen, factor VIII, plasminogen activator inhibitor 1 (PAI-1), soluble (s)P-selectin, peak thrombin generation, endogenous thrombin potential) were measured at baseline. Differences in levels of haemostatic biomarkers between disease stages were tested for statistical significance by Kruskal-Wallis-test. The association of biomarker levels with overall survival (OS) and therapy response (progression-free survival (PFS) and radiological disease control rate; sub-cohort of patient initiating palliative chemotherapy, n=95) was analysed by multivariable Cox regression, adjusting for disease stage, grade, sex, age, ECOG, VTE (as time-dependent covariable) and vascular infiltration or compression by the primary tumour. Cumulative incidence of VTE was estimated in competing risk analysis, considering death as competing outcome event. The impact of VTE on OS and PFS was evaluated by multi-state modelling, adjusting for stage, grade, sex, age, ECOG and vascular involvement. Results: We observed higher baseline levels of biomarkers according to increasing stage of disease for D-dimer (stage I/II: median 1.25 µg/ml [interquartile range (IQR): 0.65-2.10]; stage III: 1.41 µg/ml [IQR: 0.65-2.24]; stage IV: 1.68 µg/ml [IQR: 0.98-3.82], p=0.035), and sP-selectin (stage I/II: median 34.2 ng/ml [IQR: 26.8-43.1]; stage III: 37.6 ng/ml [IQR: 31.4-49.1]; stage IV: 38.8 ng/ml [IQR:32.9-51.5], p=0.033). Higher levels of D-dimer, PAI-1 and sP-selectin were associated with shorter OS in multivariable analysis (hazard ratio (HR) for death per doubling: 1.33 [95% confidence interval (CI): 1.08-1.66], 1.25 [95% CI: 1.08-1.45, and 1.42 [95% CI: 1.00-2.01] (Figure 1). In the subgroup of patients initiating palliative chemotherapy, pre-therapeutic levels of D-dimer predicted for shorter PFS (HR for disease progression per double: 1.29 [95% CI: 1.03-1.61]) and a decreased probability for radiological therapy response (odds ratio to achieve radiological disease control per double: 0.61 [95% CI: 0.38-0.99]). Cumulative incidence estimates of VTE in competing risk analysis at 3, 6, 12, and 24 months were 9.0% [95% CI: 5.0-14.3], 13.1% [95% CI: 8.2-19.1], 16.6% [95% CI: 11.1-23.1], and 19.5% [95% CI: 13.4-26.2], respectively. The occurrence of VTE was associated with an immediate increase in risk of death (transition hazard ratio, (THR): 2.37 [95% CI: 1.47-3.84]) and early disease progression (THR: 2.34 [95% CI: 1.50-3.66]), which prevailed upon multivariable adjustment. In landmark analyses, median OS and PFS after VTE were 5.5 months [95% CI: 2.2-6.5] and 3.0 months [95% CI: 1.5-3.9] compared to 13.4 months [95% CI: 9.7-16.6] and 7.5 months [95% CI: 5.9-9.8] in those without VTE (Mantel-Byar: both p&lt;0.001). Figure 2 displays landmark analyses of OS and PFS according to occurrence of VTE within the first 3 months of observation. Conclusion: Occurrence of VTE, activation of haemostasis and hypercoagulability, as indicated by elevated levels of D-dimer, PAI-1 and sP-selectin are associated with poor prognosis and D-dimer predicts for unfavourable response to palliative chemotherapy in patients with pancreatic cancer. Disclosures No relevant conflicts of interest to declare.


2020 ◽  
Vol 195 ◽  
pp. 215-218
Author(s):  
Eva-Maria Reitter ◽  
Alexandra Kaider ◽  
Gerald Prager ◽  
Cihan Ay ◽  
Ingrid Pabinger ◽  
...  

2009 ◽  
Vol 101 (04) ◽  
pp. 734-740 ◽  
Author(s):  
Nadine Ajzenberg ◽  
Laurent Feldman ◽  
Marie-Claude Guillin ◽  
Philippe Gabriel Steg ◽  
Marie-Geneviève Huisse

SummaryFibrinolysis for acute ST-segment elevation MI achieves early recanalisation of the infarct artery in approximately 60% of cases. The aim of the study was to determine whether failure to achieve recanalisation was associated with differences in haemostasis biomarkers compared to patients with successful fibrinolysis. Fourty-three patients were prospectively enrolled in a case-control study. All patients had received tenecteplase (TNKtPA) together with aspirin (500 mg) and heparin (5,000 IU). Emergency angiography within 90 minutes of bolus TNK-tPA identified 13 TIMI 0–2 patients (cases) and 30 TIMI 3 patients (controls). Blood samples were collected before angiography to determine tissue factor activity associated with microparticles (TF-MP); soluble platelet glycoprotein V (sGPV) and thrombinantithrombin complexes (TAT) as markers of thrombin generation; tissue plasminogen activator (endogenous tPA+ TNKtPA), plasminogen activator inhibitor (PAI-1) and plasmin-anti-plasmin complexes (PAP) as markers of plasmin generation. The baseline characteristics of the two patients’ groups were similar with respect to sex, age, and risks factors. Cases differed from controls by higher TF-MP levels (1.9 [1–13] vs. 1 [0.6–1.3] pM), sGPV (67 [51–126] vs. (48 [39–72] ng/ml), p=0.039 and TAT (10 [4–37.5] vs. 4 [2.9–7.2] ng/ml), p=0.035. TAT correlated with TF-MP (r=0.51, p=0.0064) and sGPV (r=0.51, p=0.0018). No significant difference was observed in tPA or PAI-1 levels. PAP were lower in cases (18.83 [14.83–40.43] μg/ml) than in controls (35.83 [27.9–43.94] μg/ml), p=0.045. In conclusion, fibrinolysis failure in AMI is characterised by a higher procoagulant state associated with TF-MP and a lower plasmin generation.


PLoS ONE ◽  
2019 ◽  
Vol 14 (1) ◽  
pp. e0210835 ◽  
Author(s):  
Thøger Nielsen ◽  
Søren Risom Kristensen ◽  
Henrik Gregersen ◽  
Elena Manuela Teodorescu ◽  
Gunna Christiansen ◽  
...  

Author(s):  
Axel Rosell ◽  
Sebastian Havervall ◽  
Fien von Meijenfeldt ◽  
Yohei Hisada ◽  
Katherina Aguilera ◽  
...  

Objective: Patients with coronavirus disease 2019 (COVID-19) have a high rate of thrombosis. We hypothesized that severe acute respiratory syndrome coronavirus 2 leads to induction of TF (tissue factor) expression and increased levels of circulating TF-positive extracellular vesicles (EV) that may drive thrombosis. Approach and Results: We measured levels of plasma EV TF activity in 100 patients with COVID-19 with moderate and severe disease and 28 healthy controls. Levels of EV TF activity were significantly higher in patients with COVID-19 compared with controls. In addition, levels of EV TF activity were associated with disease severity and mortality. Finally, levels of EV TF activity correlated with several plasma markers, including D-dimer, which has been shown to be associated with thrombosis in patients with COVID-19. Conclusions: Our results indicate that severe acute respiratory syndrome coronavirus 2 infection induces the release of TF-positive EVs into the circulation that are likely to contribute to thrombosis in patients with COVID-19. EV TF activity was also associated with severity and mortality.


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