ALBERT

Description: Introduction Previous research from the Europe and Canada has identified several areas of unmet clinical and support need for cancer patients diagnosed with venous thromboembolism (VTE). It is not known whether such experiences are restricted to those particular countries healthcare systems and/ or cultures. We sought to evaluate patients' experience of cancer-associated thrombosis (CAT) within France. Methods Purposive sampling of twenty three patients with CAT were recruited from a thrombosis service in a general hospital in Colombes, France, Semi structured interviews were audio recorded and transcribed. Transcripts were coded using Invivo software. Analysis was undertaken using an applied framework matrix with an inductive approach to identify any new themes. This was in order to explicate potential cultural and operational differences that were not apparent in the previous datasets. Results Twenty three patients (11 male, 13 female) aged 51-83 (mean 69) participated. The main commonality observed between French patients and those interviewed in the United Kingdom, Spain and Canada was the lack of information regarding the risks of CAT or signs and symptoms, which would necessitate medical attention. In addition patients reported a similar lack of verbal and written information regarding treatment choices and how to administer low molecular weight heparin (LMWH). However, French patients were not concerned by this since they perceived the doctor knew best and did not see information giving as a necessary aspect of their healthcare. They adopted a passive unquestioning role whereby the doctor was always right. This lack of desire to understand about their condition and in particular CAT, resulted in two major themes which are , thus far, have only been observed in this cohort of patients. 1. Lack of understanding and desire to know about CAT meant that patients knew less about their condition than other patients. Whereas patients from other countries were significantly distressed by knowing the potentially fatal nature of CAT, French patients were not distressed by their diagnosis, its implications on their cancer journey or the future. 2. Patients did not appreciate the utility of shared decision making and relied on the doctor to decide on the drug of choice. They did not wish to understand the rationale for this and thereby did not view the LMWH as a necessary inconvenience. Consequently they were very resistant to LMWH. Conclusion The dynamics of the doctor patient relationship in French patients differed from other countries, with patients adopting a passive role with respect to information requirements and their role in shared decision making. This dynamic appears to be a "two edged sword" whereby distress around CAT was minimal, in contrast to all other countries interviewed, yet a lack of knowledge impacted on acceptability of LMWH patient groups. This data has implications for the choice of anticoagulant in the treatment of CAT, particularly now that several DOACS have been evaluated for this indication. Disclosures Mahe: Leo Pharma: Research Funding, Speakers Bureau; BMS: Research Funding, Speakers Bureau; Bayer: Speakers Bureau; Pfizer: Speakers Bureau. Noble:Leo Pharma: Research Funding; Daiichi Sankyo: Speakers Bureau; Bayer: Speakers Bureau; Pfizer: Speakers Bureau.

Description: Abstract 3124 Poster Board III-61 Aim of the study Tissue factor is normally absent from monocytes in circulating blood. It can be induced by inflammatory mediators leading to the formation of monocyte-associated prothrombinase activity, which participates to thrombin generation. This activity appears to be important in both thrombosis (venous and arterial) and in chronic inflammation by inducing the release of inflammatory cytokines. This could be attributed to the activation of PAR-1 and PAR-2 (protease-activated receptors) by factor Xa or by thrombin. In this study, we compared the action of Rivaroxaban and Fondaparinux, two specific factor Xa inhibitors, on the activation of coagulation and on the secretion of inflammatory cytokines in both activated monocytes and activated human monocyte/macrophage cell line THP1. Methods 1-Monocytes were isolated from healthy volunteers and THP-1 cells were used as macrophages. 2- Activation of cells was performed by adding 1 μg/ml LPS for 2 hours at 37°C, in the presence of defibrinated human plasma which provides plasma coagulation factors, in the absence (control) or presence of Fondaparinux (500, 1000 and 1500 ng/ml) or Rivaroxaban (150, 250, 350 ng/ml, final concentrations). After incubation, the cells were isolated and their supernatants collected. 3- The procoagulant activity of cells was tested by measuring their effect on the clotting time of normal plasma in presence of calcium. 4- The release of cytokines was tested by antibody-cytokines array in the supernatants (RayBio®). 5-To test the neutralization of factor Xa bound to monocytes, activated monocytes were incubated with human purified factor Xa (100 ng/ml) for 10 min at room temperature. After isolation of the cells, 250 ng/ml Rivaroxaban or the appropriate solvent was added for 1, 10 and 30 min. The Xa activity associated to monocytes was measured by its amidolytic activity. Results 1- The procoagulant activity of monocytes and macrophages was reduced by Rivaroxaban and not by Fondaparinux. Results of prothrombinase activity in the presence of Rivaroxaban at 150, 250, 350 ng/ml, expressed as percentage of the control value was: 30 ± 3, 16 ± 4 and 12 ± 2 % for monocytes and: 43 ± 2, 24 ±3, 15 ± 1 % for THP-1 cells. In contrast, Fondaparinux did not modify the prothrombinase activity of monocytes (105 ± 12%). It was also shown that in the conditions used, Rivaroxaban (250 ng/ml) inhibited completely the amidolytic activity of factor Xa bound to activated monocytes. 2- Both Rivaroxaban and Fondaparinux modify the profile of chemokines secretion by activated monocytes and THP-1. In monocytes and THP-1 cells, LPS induced an important increase in Il-8 and angiogenin and a moderate increase in MIP-1d (Macrophage Inflammatory Protein-1) and RANTES, a member of the Il-8 superfamily. Both Rivaroxaban and Fondaparinux decreased the secretion of these chemokines to the basal level of secretion by non activated monocytes or THP-1. The secretion of leptin was only induced by LPS- treated THP-1 and was strongly decreased by both FXa inhibitors. In contrast, secretion of EGF (epithelial growth factor) was only induced by activated monocytes and strongly decreased by Rivaroxaban and moderately by Fondaparinux. Discussion and conclusion The results show that 1- Rivaroxaban induced a concentration-dependent inhibition of the procoagulant activity of activated monocytes and macrophages, whereas fondaparinux was devoid of this effect. This difference is attributed to a better access of Rivaroxaban to FXa bound to monocytes, as compared to the Fondaparinux-antithrombin complex. This inhibitory effect of Rivaroxaban could contribute to its antithrombotic activity. 2- Rivaroxaban inhibited the secretion of inflammatory chemokines by activated monocytes and THP-1. This decreased secretion was also observed with Fondaparinux, suggesting that it could be due to the decrease in thrombin generation in plasma, affecting the PAR-1 cell signaling system. As it was reported that that elevated IL-8 is associated with recurrent venous thrombosis and that these inflammatory cytokines are involved in plaque progression and rupture by recruitment of subpopulations of leukocytes and by potent angiogenic activity, this decrease in cytokines could also contribute to the antithrombotic efficacy of Rivaroxaban. This study received a support from Bayer Schering Pharma, France. Equal contribution of Marc Laurent and Rémi Varin Disclosures No relevant conflicts of interest to declare.

Description: Abstract 1064 Poster Board I-86 Introduction: Decreased fibrinolysis has been reported in venous thrombosis. Thrombus degradation depends on its structure: thicker fibrin fibers are permeable to blood flow and highly susceptible to fibrinolytic enzymes, while thinner fibers are poorly permeable to flow and are resistant to fibrinolysis. Thrombin concentration present at the time of gelation profoundly influences fibrin clot structure: decrease in thrombin generation leads to the formation of thick fibrin fibers and to a decrease in activation of thrombin-activated fibrinolysis inhibitor (TAFI). Rivaroxaban, an oral direct factor Xa inhibitor, is in late stage clinical development for the prevention and treatment of venous and arterial thrombosis. The objective of this study was to evaluate the effect of Rivaroxaban on whole blood (WB) clot structure and degradability by t-PA. Compared to plasma clots, WB clots might better represent the in vivo formed thrombi. Methods: 1- Clots were formed by adding to WB or to corresponding plasma, low concentration of tissue factor and calcium in the presence or absence of Rivaroxaban at therapeutic concentrations (0.15 and 0.25 μg/ml). 2- Clot permeability was calculated by measuring the flow rate of liquid through the clot. It was expressed as Darcy constant. 3- Clot degradability was evaluated by D dimers generation during clot perfusion with plasminogen and tissue-type plasminogen activator (t-PA). Results: 1- In the absence of Rivaroxaban, WB clots had a lower porosity than that of corresponding plasma clots: Darcy constant of WB clots was 3.1 –fold lower than that of plasma clots. This decreased porosity of WB clots leads to thrombolysis resistance by preventing access of fibrinolytic enzymes to fibrin network: D dimers generation in t-PA-perfused clots for 60 min was 38 -fold lower in WB clots compared to plasma clots. 2- Rivaroxaban increased the permeation rate of WB clots and thrombolysis by t-PA: the addition of Rivaroxaban at 0.15 μg/ml in WB (corresponding in fact to plasma concentration of 0.25 μg/ml), increased the Darcy constant by 5.5 –fold and the clot degradability in 60 min by 108 -fold. These effects of Rivaroxaban were higher in WB clots than in corresponding plasma clots, as Rivaroxaban at 0.25 μg/ml in plasma clots increased the Darcy constant by 2.5-fold and clot degradation by 9.6-fold. In the presence of Rivaroxaban, the Darcy constant and the degradability of WB clots and of plasma clots were nearly identical. 3- To explain the greater efficacy of Rivaroxaban on WB permeation constants and thrombolysis in comparison to plasma clots a) we tested the possibility for Rivaroxaban to reduce the entrapment of red blood cells (RBC) into the network of fibrin as RBC can be responsible for fibrin pore occlusion. This possibility was excluded since Rivaroxaban had no effect on clot permeation rate in clots formed by clotting purified fibrinogen with thrombin in the presence or in the absence of RBC (condition in which there is no generation of thrombin): RBC induced a 2.5 times decrease in permeation rate due to entrapment of RBC into fibrin network, regardless of presence or absence of Rivaroxaban. b) we analyzed the effect of RBC on thrombin generation and its modification by Rivaroxaban: the addition of 0.1 ml RBC diluted ½ to 0,2 ml plasma increased the thrombin generation (540 % of control without RBC). This is probably due to exposure of phosphatidyl serine at surface of RBC during thrombin generation. The increase in thrombin generation by RBC was reduced to 140 % in presence of Rivaroxaban at 0.15 μg/ml. This is explained by Rivaroxaban's inhibition of factor Xa bound to cells. Conclusion: Thrombin generation was greater in WB than in plasma, leading to a lower porosity and degradability of WB clots as compared to plasma clots. Rivaroxaban, by decreasing thrombin generation, increased clot permeability and degradability to the same level in WB clots and plasma clots. This property of Rivaroxaban may contribute to its antithrombotic effect. This study received a support from Bayer-Schering-Pharma France. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction Few data are available about the treatment and complications beyond 6 months and up to 12 months in Cancer-associated Thrombosis (CAT) patients initially treated with low-molecular-weight (LMWH). Study objectives were to document the prescription and use of the anticoagulant treatment beyond 6 months and up to 12 months in CAT patients initially treated with tinzaparin and to measure clinical outcomes. Methods Adult CAT patients with solid tumor, previously included in 2 prospective cohort studies (AXA - NCT02898051; PREDICARE - NCT03099031) and still alive at the end of the initial 6-month treatment period with tinzaparin were eligible to participate in this retrospective non-interventional French multicenter study. Main study outcome was the description of the anticoagulant treatment in the management of CAT patients in usual medical care from the 6th month to the 12th month. Secondary objectives included the incidence of VTE recurrence, bleeding and deaths. A sample size of 250 to 300 patients was considered appropriate to allow analyses of 6-to-12-month data post-index event based on descriptive statistics. Results A total of 432 patients aged 66.5±12.7 years of whom 52.1% female alive at the end of AXA and PREDICARE 6-month treatment period were included in this retrospective study; 332 patients were followed up to 12 months while 96 patients deceased before the end of the study and 4 patients were lost-to-follow-up. Most patients (91.9%) had a single-site cancer. Cancers were mostly solid tumors and primary sites were colorectal (21.6%), lung (20.1%) or breast (16.8%); a proportion of 82.1% of patients had stage III or IV malignancy while cancer was progressing in 51.2% of patients. Beyond 6 months, the anticoagulant treatment was maintained in 290 of 421 (68.9%) patients of whom 241 (83.1% [95% CI: 78.3%; 87.2%]) patients were treated with a LMWH and 233 (80.3%) with tinzaparin, 32 (11.0%) and 13 (4.5%) patients were treated with vitamin K antagonists (VKA) and direct oral anticoagulants (DOAC), respectively. The anticoagulant treatment was discontinued in 131 of 421 (31.1%) patients of whom 63 patients had already stopped the anticoagulant before 6 months while 68 patients stopped the anticoagulant treatment at 6 months. Mean treatment duration with LMWH beyond 6 months was 121.6 ± 65.6 days representing a mean total treatment duration of 288.4 ± 85.0 days since the index event. Between 6 and 12 months, 24 (5.7%) patients experienced a VTE recurrence corresponding to a cumulative incidence of 8% [95% CI: 4.2%; 15.1%], while 11 (2.7%) patients had a major bleeding corresponding to a cumulative incidence of 2.6% [95% CI: 1.3%; 5.1%]. VTE recurrence was more frequent in patients with colorectal and lung cancer while major bleeding was more frequent in patients with colorectal cancer (Table) A total of 96 (22.3%) deaths corresponding to a cumulative incidence of 30.7% [95% CI: 22.3%; 30.7%] were reported of which 55 (12.8%) related to cancer, 1 (0.2%) to bleeding and 8 (1.9%) to another cause while the cause of death was not documented for 32 (7.5%) patients. Clinical outcomes according the type of cancer are summarized in the Table. Conclusion These results reporting the clinical course up to 12 months of a large cohort of patients still alive at the end of the initial 6-month period following the VTE index event, provide data contributing to the clinician's therapeutic decision when facing a patient completing 6 months of anticoagulant for a CAT. Site of cancer has to be taken into account when assessing the risk of subsequent VTE recurrence and bleeding. Disclosures Mahe: BMS: Research Funding, Speakers Bureau; Pfizer: Speakers Bureau; LEO Pharma: Research Funding, Speakers Bureau; Bayer: Speakers Bureau. Laporte:Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Leo-Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boston scientific: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bertoletti:Sanofi: Research Funding, Speakers Bureau; BMS-Pfizer: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Aspen: Consultancy, Speakers Bureau. Couturaud:Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Falchiero:Astra-Zeneca: Consultancy; MSD: Consultancy; Boehringer Ingelheim: Speakers Bureau; BMS: Speakers Bureau; Amgen: Consultancy; Roche: Speakers Bureau. Falvo:Medtronic: Consultancy; Toshiba: Consultancy; Leo-Pharma: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy; BMS: Consultancy; Bayer: Consultancy. Meyer:Bayer: Other: travel support; Boehringer Ingelheim: Research Funding; LEO pharma: Other: travel support, Research Funding; SANOFI: Other: travel support, Research Funding; BMS-Pfizer: Other: travel support, Research Funding.

Description: Introduction The utility of D-dimer testing as a screening tool for venous thromboembolism (VTE) exclusion is uncertain in cancer patients, due to low specificity. A new fibrin assay independent of inflammation and hypercoagulability has been recently developed. Methods Non-anticoagulated patients with clinically suspected VTE from the FSET study (NCT02523937) had VTE diagnosed using the standard diagnostic algorithms, including a 3-month clinical follow-up. In all patients, the fibrin assay prototype (Diagnostica Stago) was performed at the time of admission. We divided the patients included in the FSET study in 3 groups: (i) history of cancer, (ii) active cancer (known or unequivocal evidence), and (iii) no cancer. We sought to evaluate the performances of the fibrin assay compared with the D-Dimer or age-adjusted D-Dimer test to exclude VTE in cancer patients. Results Of the 863 included patients, 83 (9.6%) had either a history of cancer (n=30) or an active cancer (known or unequivocal evidence) (n=53). The prevalence of VTE was of 3.3% and 20.7%, respectively, vs 7.6% in non-cancer patients. Patients with a history of cancer had most frequently breast cancer (40%) and genito-urinary cancer (23.3%).Of the 53 patients with active cancer (known or unequivocal evidence), 9.4% had a recurrence, and most patients had metastatic cancers (52.8%). Those patients had most frequently lung cancer (26.4 %) and breast cancer (15.1 %). Overall, 18.9% of patients with known cancer were treated with chemotherapy, 3.7% with immunotherapy and 13.2% with hormonotherapy. In the present study, 9.4% of patients with known active cancer had a high VTE probability vs 2.8% in patients without cancer. Overall, given a high VTE clinical probability score in a substantial number of cancer patients on one hand, and the DDi level most likely above the cut-off value for VTE exclusion in those with a low-to-moderate probability on the other hand, cancer patients required more often imaging to confirm or exclude VTE diagnosis, 68.7% in patients with a history of cancer or with active cancer versus 42.6% in patients without cancer, respectively. The fibrin assay specificity for VTE was highly increased compared to D-Dimer test, associated with a 100% negative predictive value [95% CI 89-100%] and [95% CI 83-100%] respectively in patients with a history of cancer or with active cancer. Fibrin assay allowed ruling out VTE in a much higher proportion of patients compared to the 500 μg/L D-Dimer cut-off / or age-adjusted D-Dimer cut-off strategy, irrespectively of clinical probability assessment: 76.7% vs 40%/60% in patients with a history of cancer, 39.6% vs 17.0%/22.6% in patients with active cancer, 76.7% vs 54.5%/60.9% in non-cancer patients. Conclusion The new fibrin assay demonstrated an increased specificity compared to DDi or age-adjusted cut-off strategy with excellent negative predictive value, resulting in safely excluding more than 25% VTE compared to DDi or more than 15% VTE compared to age-adjusted cut-off in patients with a history or an active cancer; thus reducing imaging testing in these patients, irrespectively of the clinical probability. These promising results require further confirmation in future trials. Disclosures Mahe: Leo Pharma: Research Funding, Speakers Bureau; BMS: Research Funding, Speakers Bureau; Bayer: Speakers Bureau; Pfizer: Speakers Bureau. Meyer:BMS-Pfizer: Other: travel support, Research Funding; Boehringer Ingelheim: Research Funding; LEO pharma: Other: travel support, Research Funding; SANOFI: Other: travel support, Research Funding; Bayer: Other: travel support. Contant:Diagnostica Stago: Employment. Depasse:Diagnostica Stago: Employment.