Failure of the Ottawa Score to Predict the Risk of Recurrent Venous Thromboembolism in Cancer Patients: The Prospective PREDICARE Cohort Study.

INTRODUCTION: Recurrent venous thromboembolism (VTE) despite curative anticoagulation is frequent in patients with cancer. Identifying patients with a high risk of recurrence could have therapeutic implications. A prospective study was designed to validate the Ottawa risk score of recurrent VTE in cancer patients. METHODS: In a prospective multicenter observational cohort, adult cancer patients with a recent diagnosis of symptomatic or incidental lower limb deep vein thrombosis or pulmonary embolism (PE) were treated with tinzaparin for 6 months. The primary endpoint was the recurrence of symptomatic or asymptomatic VTE within the first 6 months of treatment. All clinical events were centrally reviewed and adjudicated. Time-to-event outcomes were estimated by the Kalbfleisch and Prentice method to take into account the competing risk of death. A C-statistic value of > 0.70 was needed to validate the Ottawa score. RESULTS: A total of 409 patients were included and analyzed on an intention-to-treat basis. Median age was 68 years, 60.4% of patients had PE, and VTE was symptomatic in 271 patients (66.3%). The main primary sites were lung (31.3%), lower digestive tract (14.4%), and breast (13.9%) cancers. The Ottawa score was high (≥ 1) in 58% of patients. The 6-month cumulative incidence of recurrent VTE was 7.3% (95% confidence interval [CI]: 4.9-11.1) overall, and 5.0% (95% CI: 2.3-10.8) versus 9.1% (95%CI: 6.1-13.6) in the Ottawa low versus high risk groups, respectively. The C-statistic value was 0.60 (95% CI: 0.55-0.65). CONCLUSION: In this prospective cohort of patients with cancer receiving tinzaparin for VTE, the Ottawa score failed to accurately predict recurrent VTE.

Tinzaparin inhibits VL30 retrotransposition induced by oxidative stress and/or VEGF in HC11 mouse progenitor mammary cells: Association between inhibition of cancer stem cell proliferation and mammosphere disaggregation.

Tinzaparin is an anticoagulant and antiangiogenic drug with inhibitory properties against tumor growth. VEGF stimulates angiogenesis, while an association between reactive oxygen species (ROS) and angiogenesis is involved in tumor progression. The present study aimed to investigate the effect of tinzaparin on VL30 retrotransposition­positive mouse HC11 mammary stem­like epithelial cells, previously reported to be associated with induced mammosphere/cancer stem cell (CSC) generation and tumorigenesis. Under 24 h serum starvation, 15.2% nominal retrotransposition frequency was increased to 29%. Additionally, while treatment with 3­12 ng/ml VEGF further induced retrotransposition frequency in a dose­dependent manner (up to 40.3%), pre­incubation with tinzaparin (2 IU/ml) for 0.5­4 h reduced this frequency to 18.3% in a time­dependent manner, confirmed by analogous results in NIH3T3 fibroblasts. Treatment with 10­40 pg/ml glucose oxidase (GO) for 24 h induced HC11 cell retrotransposition in a dose­dependent manner (up to 82.5%), while a 3 h pre­incubation with tinzaparin (1 or 2 IU/ml) elicited a 13.5 or 25.5% reduction in retrotransposition, respectively. Regarding tumorigenic VL30 retrotransposition­positive HC11 cells, treatment with 2 IU/ml tinzaparin for 5 days reduced proliferation rate in a time­dependent manner (up to ~55%), and after 3 weeks, disaggregated soft agar­formed foci, as well as low­adherent mammospheres, producing single mesenchymal­like cells with a ~50% reduced retrotransposition. With respect to the VL30 retrotransposition mechanism: While 12 ng/ml VEGF increased the level of VL30 and endogenous reverse transcriptase (enRT) transcripts ~1.41­ and ~1.16­fold, respectively, subsequent tinzaparin treatment reduced both endogenous/ROS­ and VEGF­induced levels 1.15­ and 0.40­fold (VL30) and 0.60­ and 0.52­fold (enRT), respectively. To the best of our knowledge, these data demonstrate for the first time, the novel inhibition activity of tinzaparin against ROS­ and VEGF­induced VL30 retrotransposition, and the proliferation and/or aggregation of mouse HC11 mammosphere/tumor­initiating CSCs, thus contributing to the inhibition of VL30 retrotransposition­induced primary tumor growth.

Combinatorial Treatment of Tinzaparin and Chemotherapy Can Induce a Significant Antitumor Effect in Pancreatic Cancer.

Pancreatic Cancer (PC) is recognized as a highly thrombogenic tumor; thus, low-molecular-weight heparin (LMWH) such as tinzaparin is routinely used for PC patients. On the basis of combinatorial therapy approaches to treat highly malignant and refractory cancers such as PC, we hypothesized that tinzaparin can augment the effectiveness of traditional chemotherapeutic drugs and induce efficient antitumor activity. PANC-1 and MIAPaCa-2 were incubated alone or in combination with tinzaparin, nab-paclitaxel and gemcitabine. In vivo evaluation of these compounds was performed in a NOD/SCID mouse using a model injected with PANC-1. Tinzaparin enhances the anti-tumor effects of nab-paclitaxel and gemcitabine in mtKRAS PC cell lines via apoptosis in in vitro experiments. The triple combination power acts through the induction of apoptosis, reduction of the proliferative potential and angiogenesis; hence, contributing to a decrease in tumor volume observed in vivo. The triple regimen provided an extra 24.3% tumor reduction compared to the double combination (gemcitabine plus nab-paclitaxel). Combinatorial strategies can create novel therapeutic approaches for the treatment of patients with PC, achieving a better clinical outcome and prolonged survival. Further prospective randomized research is needed and the investigation of various concentrations of tinzaparin above 150 UI/Kg, would potentially provide a valuable synergistic effect to the conventional therapeutic compounds.

Safety and Efficacy of Tinzaparin Anticoagulation during Nocturnal Hemodialysis.

BACKGROUND: The safety and efficacy of low-molecular-weight heparin in the prevention of extracorporeal dialysis circuit clotting among in-center extended duration nocturnal hemodialysis (INHD) patients are unknown. The aim of this study was to determine the safety and efficacy of 2 doses of tinzaparin, among INHD patients receiving 6-8 h hemodialysis, 3 times per week. METHODS: We conducted a retrospective cohort study to examine antifactor Xa levels at time 0, 2 h, 4 h mid-hemodialysis (mid-HD), 6 h, and at end of each INHD session for 4 weeks and to determine extracorporeal dialysis circuit clotting and bleeding events after switching from unfractionated heparin to tinzaparin, using a standard protocol of tinzaparin delivery at the initiation and midpoint of HD. RESULTS: All 16 patients in The Ottawa Hospital INHD program were converted to tinzaparin and followed for 177 INHD sessions. Mean antifactor Xa level at 2 h of HD was 0.41 ± 0.21 (SD) IU/mL, at 4 h (mid-HD) 0.19 ± 0.17 IU/mL, at 6 h 0.44 ± 0.21 IU/mL, and at dialysis end 0.26 ± 0.14 IU/mL. Antifactor Xa levels were undetectable at the start of INHD, suggesting no tinzaparin accumulation. Five patients required an increase in tinzaparin due to extracorporeal dialysis circuit clotting. There were no bleeding events. One patient required a switch to fondaparinux due to an adverse reaction. CONCLUSION: Tinzaparin was safe and efficacious for most INHD patients without accumulation or bleeding. The conversion from unfractionated heparin to tinzaparin required an increased tinzaparin dose for 31% of INHD patients.

The Low Molecular Weight Heparin Tinzaparin Attenuates Platelet Activation in Terms of Metastatic Niche Formation by Coagulation-Dependent and Independent Pathways.

An intimate interplay with platelets is an initial key issue for tumor cells in terms of hematogenous metastasis. Tumor cells activate platelets by different pathways and receive, upon forming a platelet cloak, protection from immune surveillance and support in metastatic niche creation. Therapeutic intervention with this early interaction is promising to antagonize the whole metastatic cascade. Here we aimed to investigate the capability of low molecular weight heparin (LMWH), unfractionated heparin (UFH), and a non-anticoagulant heparin derivative or FXa inhibitor fondaparinux to interfere with platelet activation by tumor cells. Coagulation-dependent and independent pathways of platelet activation by three tumor cell lines, and interference therewith were analyzed by fluorigenic thrombin formation assay, platelet aggregometry, ATP and VEGF release and endothelial tube formation assay. LMWH and UFH were found to repress various routes of platelet activation, reflected by attenuated endothelial tube formation. This confirms the duality of anti-coagulative and anti-adhesive properties of heparin. While non-anticoagulative heparin (RO-heparin) depressed platelets' ATP and VEGF release by contact inhibition sufficiently, fondaparinux just attenuated tissue factor mediated thrombin generation. Concluding, these data suggest that LMWH as a guideline-based drug for anticoagulative strategies in oncology is promising to provide additional benefit for interference with metastatic activities.

Tinzaparin for the treatment of foetal growth retardation: An open-labelled randomized clinical trial.

OBJECTIVE: Foetal growth retardation (FGR) is a leading cause of perinatal death and long-term harms at survivors. Placental infarction plays a role in FGR, yet, no trials have evaluated whether low molecular weight heparins increase birth weight in ongoing FGR pregnancies. METHODS: An open-labelled randomized trial in Denmark during 2011-2016, including singleton pregnant women with FGR (estimated foetal weight < 2.3 percentile) diagnosed before gestational weeks 32. Participants were randomly assigned using sealed, blinded envelopes 1:1 to tinzaparin (4500 IU daily until 37 gestational weeks) or no tinzaparin. The primary outcomes were the observed birthweight relative to the expected for gestational age and gender, and foetal growth rates in the two trial groups evaluated by an intention to treat analysis. RESULTS: We enrolled 53 women. The mean gestational age was 261 days in the tinzaparin group and 246 days in the no treatment group. The mean birth weight was 2229 g in the tinzaparin group compared to 1968 g in the no treatment group. However, the birth weight relative to the expected from gestational age and gender was only 2.5 percentage points higher in the tinzaparin group [-5.1 to 10.0] (p = 0.51). The foetal growth rate during follow-up was 124 g/week in the tinzaparin group and 119 g/week in the no treatment group, a difference of 5 g/week [-19 to 29] (p = 0.67). Two perinatal deaths both occurred in the no treatment group. CONCLUSION: We found no evidence of a tinzaparin effect on the foetal growth rate or the birth weight after adjustment for gestational age.