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International audience; Severe 2019 novel coronavirus infectious disease (COVID-19) with pneumonia is associated with high rates of admission to the intensive care unit (ICU). Bacterial coinfection has been reported to be rare. We aimed at describing the rate of bacterial coinfection in critically ill adult patients with severe COVID-19 pneumonia. All the patients with laboratory-confirmed severe COVID-19 pneumonia admitted to the ICU of Tenon University-teaching hospital, from February 22 to May 7th, 2020 were included. Respiratory tract specimens were obtained within the first 48 h of ICU admission. During the study period, 101 patients were referred to the ICU for COVID-19 with severe pneumonia. Most patients (n = 83; 82.2%) were intubated and mechanically ventilated on ICU admission. Overall, 20 (19.8%) respiratory tract specimens obtained within the first 48 h. Staphylococcus aureus was the main pathogen identified, accounting for almost half of the early-onset bacterial etiologies. We found a high prevalence of early-onset bacterial coinfection during severe COVID-19 pneumonia, with a high proportion of S. aureus. Our data support the current WHO guidelines for the management of severe COVID-19 patients, in whom antibiotic therapy directed to respiratory pathogens is recommended. Keywords Coronavirus disease 2019 • Bacterial coinfection • Staphylococcus aureus • Intensive care unit • Pneumonia Abbreviations COVID 19 Coronavirus infectious disease ICU Intensive care unit SAPSII Simplified acute physiology score SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 SOFA Sequential Organ Failure Assessment

A B S T R A C T Important progress has been made in the development of risk assessment models (RAM) for the identification of outpatients on anticancer treatment at risk of venous thromboembolism (VTE). Since the breakthrough publication of the original Khorana risk score (KRS) more than 10 years ago, a new generation of KRS-based scores have been developed, including the Vienna Cancer and Thrombosis Study, PROTECHT, CONKO, ONCOTEV, TicOnco and the CATS/MICA score. Among these the CATS/MICA score showed that a simplified score composed of only two calibrated predictors, the type of cancer and the D-dimer levels, offers a user-friendly tool for the evaluation of cancer-associated thrombosis (CAT) risk. The COMPASS-CAT score is the first that introduced a more synthetic approach of risk evaluation by combining cancer-related predictors with patient comorbidity in a score which is designed for the types of cancer frequently seen in the community (i.e. breast, lung colon or ovarian cancers) and has been externally validated in independent studies. The Throly score is registered as part of the same group as it has a similar structure to the COMPASS-CAT score and is applicable in patients with lymphoma. The incorporation of specific biomarkers of hypercoagulability to the RAM for CAT offers the possibility to perform a precision medicine approach in the prevention of CAT. The improvement of RAM for CAT with artificial intelligence methodologies and deep learning techniques is the challenge in the near future.

International audience; COVID-19 is a systemic infection with a significant impact on the hematopoietic system and hemostasis. Lymphopenia may be considered as a cardinal laboratory finding, with prognostic potential. Neutrophil/lymphocyte ratio and peak platelet/lymphocyte ratio may also have prognostic value in determining severe cases. During the disease course, longitudinal evaluation of lymphocyte count dynamics and inflammatory indices, including LDH, CRP and IL-6 may help to identify cases with dismal prognosis and prompt intervention in order to improve outcomes. Biomarkers, such high serum procalcitonin and ferritin have also emerged as poor prognostic factors. Furthermore, blood hypercoagulability is common among hospitalized COVID-19 patients. Elevated D-Dimer levels are consistently reported, whereas their gradual increase during disease course is particularly associated with disease worsening. Other coagulation abnormalities such as PT and aPTT prolongation, fibrin degradation products increase, with severe thrombocytopenia lead to life-threatening disseminated intravascular coagulation (DIC), which necessitates continuous vigilance and prompt intervention. So, COVID-19 infected patients, whether hospitalized or ambulatory, are at high risk for venous thromboembolism, and an early and prolonged pharmacological thromboprophylaxis with low molecular weight heparin is highly recommended. Last but not least, the need for assuring blood donations during the pandemic is also highlighted.

Background One year after the declaration of the coronavirus disease 2019 (COVID-19) pandemic by the World Health Organization (WHO) and despite the implementation of mandatory physical barriers and social distancing, humanity remains challenged by a long-lasting and devastating public health crisis. Management Non-pharmacological interventions (NPIs) are efficient mitigation strategies. The success of these NPIs is dependent on the approval and commitment of the population. The launch of a mass vaccination program in many countries in late December 2020 with mRNA vaccines, adenovirus-based vaccines, and inactivated virus vaccines has generated hope for the end of the pandemic. Current Issues The continuous appearance of new pathogenic viral strains and the ability of vaccines to prevent infection and transmission raise important concerns as we try to achieve community immunity against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and its variants. The need of a second and even third generation of vaccines has already been acknowledged by the WHO and governments. Perspectives There is a critical and urgent need for a balanced and integrated strategy for the management of the COVID-19 outbreaks organized on three axes: (1) Prevention of the SARS-CoV-2 infection, (2) Detection and early diagnosis of patients at risk of disease worsening, and (3) Anticipation of medical care (PDA). Conclusion The “PDA strategy” integrated into state policy for the support and expansion of health systems and introduction of digital organizations (i.e., telemedicine, e-Health, artificial intelligence, and machine-learning technology) is of major importance for the preservation of citizens' health and life world-wide.

Introduction Hypercoagulability is a common blood alteration in newly diagnosed chemotherapy naïve patients with multiple myeloma. The identification of the procoagulant potential of cancer cells, which is principally related to tissue factor (TF) expression, attracts particular interest. The mechanisms by which myeloma plasma cells (MPCs) activate blood coagulation have been poorly investigated. Aim To identify the principal actors related with MPCs that boost thrombin generation (TG). Methods TF and annexin V expression by MPCs and MPC-derived microparticles (MPC-dMPs) was analyzed by flow cytometry. TF activity (TFa) and TF gene expression were also determined. TG in the presence of MPCs or MPC-dMPs was assessed with the calibrated automated thrombogram assay (CAT) in normal human PPP and in plasma depleted of factor VII or XII. TG was also assessed in plasma spiked with MPCs and MPC-dMPs. Results MPC-dMPs expressed approximately twofold higher levels of TF as compared with MPCs. The TFa expressed by MPC-dMPs was significantly higher compared with that expressed by MPCs. MPCs and MPC-dMPs enhanced TG of human plasma. TG was significantly higher with MPC-dMPs compared with MPCs. Conclusion MPCs indirectly induce blood-borne hypercoagulability through the release of MPC-dMPs rich in TF. Since MPCs, expressing low TFa, represent a weak procoagulant stimulus, the hypercoagulability at the microenvironment could be the resultant of MPC-dMPs rich in TF.

Direct oral anticoagulants (DOACs) represent an attractive alternative to low-molecular-weight heparins (LMWHs) for the long-term treatment of cancer-associated thrombosis (CT) since they avoid the burden of daily injections. Analyses in subgroups of cancer patients from large randomized trials suggested that DOACs were at least as effective as vitamin K antagonists, while indirect comparisons suggested that DOACs' efficacy and safety profile were comparable to those of LMWHs. In the randomized controlled HOKUSAI-VTE Cancer study, currently the only completed phase III trial on DOACs in CT patients, edoxaban was shown noninferior to dalteparin on the composite primary endpoint of time to first recurrent venous thromboembolism or major bleeding during the 12 months after randomization. Study results suggest that both agents had comparable benefit/risk ratio in patients with CT. Even though this conclusion was valid from a strict statistical viewpoint, it was potentially misleading when interpreting benefit/risk ratios. Besides the obvious heterogeneity of the study population (e.g., 23% of patients no longer had cancer) and significantly different treatment durations between arms, secondary outcomes for efficacy were in favor of edoxaban for recurrent deep-vein thrombosis but not for recurrent pulmonary embolism, and major bleeding episodes were significantly more frequent in the edoxaban group, with an excess of gastrointestinal (GI) bleeding episodes observed mainly but not only in patients with GI cancers. More research is needed regarding specific patients' profiles, cancer types, and treatment period to better clarify the respective roles of DOACs and LMWHs in CT patients.

International audience; Today the coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has become a global health problem. After more than a year with the pandemic, although our knowledge has progressed on COVID-19, there are still many unknowns in virological, pathophysiological and immunological aspects. It is obvious that the most efficient solution to end this pandemic are safe and efficient vaccines. This manuscript summarizes the pathophysiological and thrombotic features of COVID-19 and the safety and efficacy of currently approved COVID-19 vaccines with an aim to clarify the recent concerns of thromboembolic events after COVID-19 vaccination. The influx of newer information is rapid, requiring periodic updates and objective assessment of the data on the pathogenesis of COVID-19 variants and the safety and efficacy of currently available vaccines.

Attention has to be payed to patients with vascular disease (VD) cardiovascular risk factors (VD-CVR) and COVID-19. In fact, COVID-19 is also manifested with hypercoagulability, pulmonary intravascular coagulation, microangiopathy, and venous thromboembolism (VTE) or arterial thrombosis and VP are a frail population. Predisposing risk factors to severe COVID-19 are male sex, underlying cardiovascular disease, or cardiovascular risk factors including non-controlled diabetes mellitus or arterial hypertension, obesity, and advanced age. The VAS-European Independent Foundation in Angiology/Vascular Medicine has recently published an integral strategy for the management of patients with VD or cardiovascular risk factors (VD-CVR) and COVID-19. This paper represents a short summary.

Background The ROADMAP-EOP study aimed to identify clinically relevant biomarkers of hypercoagulability for the identification of pregnant women at risk of early onset preeclampsia worsening. Methods The ROADMAP-EOP observational single center retrospective case–control study was conducted in Greece (Centre for Human Reproduction, Genesis Athens Clinic, Athens, Greece) from July 2020 to July and enrolled pregnant women diagnosed with EOP stratified in mild EOP group (n = 34) and severe EOP group (n = 15) as well as women with uncomplicated pregnancy (control group; n = 35). All women were assessed with thromboelastometry (ROTEM®), Calibrated Automated Thrombogram®, tissue factor activity (TFa), procoagulant phospholipid dependentclotting time (Procoag-PPL®), Proteins S (PS), TFPI, D-dimer, antithrombin (AT), thrombomodulin (TM), fibrinogen, prothrombin time (PT) and activated partial thromboplastin time (aPTT). The primary study end-point was severe earlyonset preeclampsia. Principal component analysis (PCA) was performed. Results The PCA analysis showed that a score composed of the lag-time, ttPeak and Procoag-PPL accurately predicted severe EOP (sensitivity 71.4%, specificity 61.8%, and AUC of the ROC analysis 0.953). Conclusion The pilot ROADMAP-EOP shows that activation of endothelial cells and blood hypercoagulability are driven events in the worsening of EOP. Among a large panel of biomarkers and coagulation assays, thrombingeneration test and procoagulant phospholipid dependent clotting time emerged as clinically relevant for the evaluation of the risk of severe EOP. This methodology for the development of a new clinic-biological risk assessment model for prompt identification of pregnant women at risk of severe EOP must be validated in a large multi-centerprospective study.

Thrombotic and hemorrhagic complications are related to a significant rate of morbidity and mortality in patients with myeloproliferative neoplasms (MPNs), they are therefore called “thrombohemorrhagic” syndromes. Several clinical factors, such as age and presence of cardiovascular comorbidities are responsible for thrombotic complications. High blood counts, platelet alterations, presence of JAK2 mutation and possibly of other CHIP mutations such as TET2, DNMT3A, and ASXL1, procoagulant microparticles, NETs formation, endothelial activation and neo-angiogenesis are some of the parameters accounting for hypercoagulability in patients with myeloproliferative neoplasms. Bleeding complications emerge as a result of platelet exhaustion. They can be also linked to a functional deficiency of von Willebrand factor, when platelet counts rise above 1000G/L. The mainstay of management consists on preventing hemostatic complications, by antiplatelet and/or anticoagulant treatment and myelosuppressive agents in high-risk patients.Circumstances related to a high thrombohemorrhagic risk, such as pregnancy and the perioperative period, prompt for specific management with regards to anticoagulation and myelosuppression treatment type. In order to apply a patient-specific treatment strategy, there is a need for a risk score assessment tool encompassing clinical parameters and hemostasis biomarkers.

Venous thromboembolism (VTE) is a common complication in newly diagnosed symptomatic multiple myeloma (NDMM) patients. We explored cellular and plasma hypercoagulability in NDMM patients to identify relevant biomarkers that can be used in combination with clinical factors in the development of a risk assessment model (RAM) for VTE. Untreated patients (n = 144) with NDMM were prospectively enrolled, baseline biomarkers prior to anti-myeloma treatment and thromboprophylaxis initiation were obtained. These were compared against values in a group of healthy individuals with similar age and sex distribution. The primary study end point was symptomatic VTE occurrence. At 12-month follow-up cumulative VTE rate was 10.4%. NDMM patients showed biological signs of cellular and plasma hypercoagulability and endothelial cell activation. Procoagulant phospholipid clotting time (Procoagulant-PPL) was shorter, P-selectin levels lower and thrombin generation attenuated overall compared to healthy subjects. Longer Procoag-PPL®, lower endogenous thrombin potential (ETP), and higher levels of tissue factor pathway inhibitor (TFPI) were associated with VTE occurrence. Multivariate analysis showed that Procoag-PPL® and ETP were independent risk factors for VTE. We conclude that Procoag-PPL® and ETP can be prospectively incorporated into a RAM for VTE in MM in combination with clinical and disease risk factors.

Background Venous thromboembolism (VTE) is associated with significant morbidity and mortality. Objectives We investigated the impact of direct and AT-dependent FXa or thrombin inhibitors on thrombus formation. Methods Whole blood thromboelastometry and thrombin generation were assessed after triggering the TF pathway. Clinically relevant concentrations of rivaroxaban, fondaparinux, dabigatran or tinzaparin and an association of rivaroxaban and dabigatran were examined. Results All agents delayed thrombus formation in a concentration-dependent manner, as documented by the prolongation of the clotting time (CT) and clot formation time (CFT). Rivaroxaban did not significantly alter the α-angle or maximum clot firmness (MCF). In contrast, dabigatran and fondaparinux altered the process of clot structure by decreasing the α-angle, but did not modify clot firmness. The later property was significantly affected only by tinzaparin that also reduced the MCF. The association of rivaroxaban and dabigatran did not affect the MCF, although it amplified the effect on CFT and α-angle. Conclusions All agents delayed thrombus formation. However, the compounds differed substantially with respect to fibrin polymerization rate and clot firmness. Comparison of the data obtained by thrombin generation assessment with those obtained by the thromboelastometric study shows that the delay in clot formation is principally associated with prolongation of the initiation phase of thrombin formation as well as a reduction of the propagation phase. Tinzaparin was much more potent than the other agents both with regard to suppression of thrombin generation and by delay in clot formation.

Venous thromboembolism (VTE) is a typical complication in patients with lung cancer. Khorana score is an established tool for thromboembolic risk stratification of ambulatory patients with cancer undergoing outpatient chemotherapy. The aim of this study was to evaluate the predictive value of the Khorana score for VTE and death in patients with lung adenocarcinoma during first-line or adjuvant chemotherapy. Medical records of 130 patients with lung adenocarcinoma receiving first-line or adjuvant chemotherapy were retrospectively studied during the time period June 2013 to May 2015. Venous thromboembolism occurred in 13 (10.0%) patients. Thromboembolic events were significantly correlated with reduced survival during treatment period (hazard ratio [HR]: 3.24; 95% confidence interval [CI]: 1.11-9.49; P = .032). The VTE rates did not present statistically significant difference between different Khorana score groups ( P = .96). In univariate analysis, the risk of death during treatment period (median: 16 weeks) was 3.75 times higher in high-risk versus intermediate-risk patients (HR: 3.75, 95% CI: 1.36-10.36; P = .001) and had 2.25 times higher per point increase in the Khorana score (HR: 2.25, 95% CI: 1.36-3.73; P = .002); the above results were also reproduced in multivariate analysis. Khorana score represents a valuable tool for identifying patients with cancer in low thromboembolic risk but does not preserve its predictive value for higher risk individuals. Khorana score is an independent risk factor for death in patients with lung adenocarcinoma receiving first-line or adjuvant chemotherapy.

Venous thromboembolism (VTE) occurring in hospitalized medical patients is associated with increased length of hospitalization, high rate of acute care hospital transfer, longer inpatient rehabilitation and multiplication of health-care costs. Identification of acutely ill hospitalized medical patients eligible for thromboprophylaxis is a sophisticated process. Global VTE risk stems from the combination of predictors related with the acute medical illness, comorbidities, associated treatments and patients' intrinsic risk factors. Emerging clinical risk factors related to underlying pathologies should be considered when VTE risk is assessed. The Padua Prediction Score (PPS), the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE-RAM) and the Geneva Risk Score are three robust risk assessment models (RAM) which underwent extensive external validation in cohorts of acutely ill hospitalized medical patients. The development of the IMPROVE bleeding risk assessment model and the identification of D-Dimer increase as a biomarker-predictor of VTE are some steps forward for personalized thromboprophylaxis. The beneficial impact of the RAMs in VTE prevention is already seen by the decrease of in-hospital VTE rates when RAMs are incorporated in electronic alert systems.

Few geriatric patients were included in studies on direct oral anticoagulants and data on dabigatran concentration and safety are needed in this population. Our objectives were to evaluate peak and trough dabigatran plasma concentrations over time in a geriatric population and to identify factors associated with dabigatran plasma concentrations and to assess the relationship with bleeding events. Peak and trough dabigatran plasma concentration were performed 4,8,15,30,45 days after inception of dabigatran treatment in 68 consecutive patients≥75 years old hospitalized in a geriatric hospital with atrial fibrillation. Bleeding events were monitored for 1 year. Mean age was 85.8(5.1) years old and 76.5% were women. Overall, 541 dabigatran plasma measurements (270 peak, 271 trough) were performed. Mean dabigatran concentrations of the 5 sequential measurements ranged 106-146ng/mL for peak and 66-84ng/mL for trough. Renal failure was associated with high peak and trough dabigatran concentration. Inter- and intra-individual coefficients of variation were 59.5% and 44.7% for peak and 74.5% and 44.6% for trough. Participants in the lower two tertiles of dabigatran concentration at day 8 (D8) remained below the 90th percentile (243.9ng/ml) on the next measurements. Bleeding events were associated with high trough dabigatran concentrations. Trough dabigatran concentration at D8>243.9ng/mL significantly predicted bleeding. In this geriatric population, renal function and low albumin were associated with dabigatran concentrations. Despite large variability, participants in the lower two tertiles of dabigatran concentration at D8 remained below the 90th percentile on the following measurements. D8 dabigatran trough concentration≥243.9ng/mL identified patients at risk of bleeding.

Background: COVID-19 has been associated with hypercoagulability, endothelial cell injury and frequent thrombotic complications resulting both from direct effects of the virus on the endothelium and from the 'cytokine storm' resulting from the host's immune response. Since the COVID-19 vaccines have been shown to effectively prevent symptomatic infection including hospital admissions and severe disease, the risk of COVID-19-related thrombosis should be expected to (almost) disappear in vaccinated individuals. However, some rare cases of venous thrombosis have been reported in individuals vaccinated with mRNA vaccines. Thus, there is a sharp contrast between the clinical or experimental data reported in the literature on COVID-19 and on the rare thrombotic events observed after the vaccination with these vaccines. This phenomenon raised some scepticism of even some fear about the safety of these vaccines which could compromise the adhesion of the citizens in the vaccination program. Aims: We conducted a prospective observational study, to explore the impact of vaccination with the BNT162b2 (Pfizer/BioNTech) on blood hypercoagulability and endothelial cell activation and to investigate if this is modified by the presence of active cancer. Methods: In total 229 subjects were prospectively included in the study from April to June 2021. Subjects were stratified in three predefined groups: 127 vaccinated patients with active cancer (VOnco group), 72 vaccinated health care workers (VHcw group) and 30 non vaccinated health individuals (Control group). Blood samples were obtained 2 days after the administration of the first dose of BNT162b2 vaccine and collected in Vacutainer® tubes (0.109 mol/L trisodium citrate). Platelet poor plasma (PPP) was prepared by double centrifugation at 2000 g for 20 minutes at room temperature and plasma aliquots were stored at -80°C until assayed. Samples of PPP were assessed for thrombin generation (TG) with PPP-Reagent® (Thrombogram-Thrombinoscope assay with PPP-Reagent®TF 5pM), E-selectin, D-dimers, (D-Di), Tissue Factor (TFa), procoagulant phospholipid-dependent clotting time (Procag-PPL) and von Willebrand factor (vWF), thrombomodulin (TM), tissue factor pathway inhibitor (TFPI), and platelet factor 4 (PF4). All assays were from Diagnostica Stago (France). The upper and lower normal limits (UNL and LNL) for each biomarker were calculated by the mean±2SD for the control group. Results: All vaccinated subjects showed significantly increased levels of PF4 (71% >UNL, pUNL, pUNL, pUNL, pUNL, pUNL, pUNL, p Conclusion: The ROADMAP-COVID-19-Vaccine study shows that administration of the first dose of the BNT162b2 vaccine induced significant platelet activation documented by shorter Procoag-PPL associated with increased levels of PF4. Plasma hypercoagulability was less frequent in vaccinated individuals whereas there was no evidence of significant endothelial cells activation after vaccination. Interestingly, the presence of active cancer was not associated with an enhancement of platelet activation, hypercoagulability, or endothelial cell activation after the vaccination. Probably, the generated antibodies against the spike protein or lead to platelet activation in a FcyRIIa dependent manner that results in PF4 release. The implication of the mild inflammatory reaction triggered by the vaccination could be another possible pathway leading to platelet activation. Nevertheless, vaccination does not provoke endothelial activation even in patients with cancer. The findings of the ROADMAP-COVID-19-Vaccine study support the concept administration of mRNA based vaccines does not directly cause a systematic hypercoagulability. Disclosures Gligorov: Roche-Genentech: Research Funding; Novartis: Research Funding; Onxeo: Research Funding; Daichi: Research Funding; MSD: Research Funding; Eisai: Research Funding; Genomic Heatlh: Research Funding; Ipsen: Research Funding; Macrogenics: Research Funding; Pfizer: Research Funding. Terpos: Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding. Dimopoulos: Amgen: Honoraria; BMS: Honoraria; Janssen: Honoraria; Beigene: Honoraria; Takeda: Honoraria.

Background: The efficacy and safety of direct oral anticoagulants (DOACs) in patients with thromboembolic disease is closely related to patient's adherence to therapy. Objective documentation of drug intake is a useful tool for patients' education and improvement of adherence to treatment but may be improved by accurate point-of-care (POCT) testing. Results of DOAC Dipstick may be one of these methods but may depend on interpretation variability. Aim: We aim to analyze the inter-observer agreement of DOAC Dipstick near-patient device in outpatients on stable anticoagulation with rivaroxaban (R), apixaban (A) and dabigatran (D). Methods: A prospective observational cohort study was performed including patients on active treatment with R, A, and D for secondary VTE prevention. All participants were routinely assessed for DOACs' plasma concentration using STA ® Liquid anti-Xa and STA ® Liquid anti-IIa chromogenic assays , and creatinine clearance (Cockroft -Gault equation). DOAC Dipstick test was performed in patients' urine samples were performed by trained staff according the instructions for use. The assessment was based on pads'colors which are specific for indicating the presence and absence of factor -Xa (FXA) and thrombin inhibitors (THI). In order to assess inter-observer agreement, the study nurse performing the test and the medication-prescribing physician were in charge of evaluating independently each test strip. THI pad and FXA pad served as negative control for patients treated with R and A, and D, respectively. Inter-observer agreement was calculated by Cohen's kappa coefficient (kappa index). Results: A new interim analysis shortly before study termination was performed after enrolment of 79 patients (female/ male 44/35, age 56 ± 18 years, mean and standard deviation). Of those, 20% (n=17) were treated for deep vein thrombosis, 13% (n=10) for pulmonary embolism (PE), 40% (n=32) for recurrent thromboembolic disease, 18.3% (n=13), for cancer-associated thrombosis, 6 for antiphospholipid syndrome (n= 5), 2 % (n=2) for AF. 60 % (n=48 ) were treated with R, 37% (n=29) with A and 3% (n=2) with D. All patients had normal renal function. Anti-factor Xa levels were determined with a median value of 156.6±129.2 ng/ml and anti-factor IIa levels with 191.66±110.34 ng/mL. The inter- observer agreement of colors of FXA and THI pads of urine samples was 0.99 for positivity for R, A, and D. Pads that served as negative controls were assessed correctly as negative by both observers in all cases (kappa index 1.0). Conclusion: Given the encouraging results, the ongoing study should allow the device's validation as an accurate, easy-to-use assessment tool for determination of the presence or absence of DOACs in patients' urine samples also based on a very low inter-observer variability. The aforementioned data confirm the results of the first interim analysis presented in the ISTH 2021 congress. Disclosures Harenberg: DOACSENCE: Other: Founder and managing director.

Currently there are no available methods for prediction of thrombotic complications in Coronary Artery disease. Additionally, blood coagulation tests are mainly performed in a steady system while coagulation in vivo occurs under flow conditions. In this work, a phenomenological model for coagulation up-to thrombin generation is proposed; the model is mainly based on the results of thrombin generation assays and therefore it can account for the variation of the coagulability that is observed in different individuals. The model is applied on 3 cases of left anterior descending arteries (LAD) with 50% maximum stenosis placed at a different location and have been statistically assessed as of different complication risk. The simulations showed that parameters of thrombin generation assays obtain different values when they refer to thrombin generation under realistic coronary flow conditions. The flow conditions prevailing locally because of the geometric differences among the arterial trees can lead to different initiation times and thrombin production rates and it also alters the spatial distribution of the coagulation products. Similarly, small changes of the coagulation characteristics of blood under identical flow conditions can allow or prevent the initiation of coagulation. The results indicate that combined consideration of geometry and coagulation characteristics of blood can lead to entirely different conclusions compared to independent assessment of each factor.

Hypercoagulablity is a common alteration of blood coagulation in cancer patients. However, the procoagulant activity of cancer cells is not sufficient to induce hypercoagulability. The present study was aimed to identify the mechanism with which hypercoagulabilty is produced in the presence of cancer cells. We focused on the analysis of the procoagulant elements carried by cancer cell-derived microparticles (CaCe-dMP) and we evaluated the impact of microparticles associated with the cancer cells from which they stem on thrombin generation. CaCe-dMP from the cancer cells were isolated from the conditioned medium and analyzed for tissue factor (TF) and procoagulant phospholipid expression. Thrombin generation of normal plasma was assessed by the Thrombinoscope (CAT®) in the presence or absence of pancreas adeno-carcinoma cells (BXPC3) or breast cancer MCF7 cells supplemented with the respective CaCe-dMP. Both BXPC3 and MCF7 cells express abundant amounts of active TF. Phosphatidylserine was identified on the surface of CaCe-dMP, unlike the cancer cells themselves. The expression of TFa by the microparticles was significantly higher to that observed on the cancer cells. Culture of the cancer cells with their microparticles resulted in thrombin generation significantly higher as compared to the upper normal limit. In conclusion, cancer cells 'enrich' the microenvironment with procoagulant elements, especially procoagulant micro-particles which express TF and procoagulant phospholipids. The association of cancer cells with procoagulant microparticles is necessary for a state of hypercoagulability, at the level of the tumoral microenvironment. The intensity of the hypercoagulability depends on the histological type of the cancer cells.

The beneficial effect of autologous peripheral blood stem cell transplantation (APBSCT) may be compromised by acute vascular complications related to hypercoagulability. We studied the impact of graft product on thrombin generation of normal plasma and the expression of tissue factor (TF) and procoagulant platelet-derived procoagulant microparticles (Pd-MPs) in samples of graft products. Graft products from 10 patients eligible for APBSCT were mixed with platelet-poor plasma (PPP) or platelet-rich plasma (PRP) from healthy volunteers and assessed for in vitro thrombin generation. In control experiments, thrombin generation was assessed in (1) PPP and PRP without any exogenous TF and/or procoagulant phospholipids, (2) PPP with the addition of TF (5 pM) and procoagulant phospholipids (4 μM), (3) in PRP with the addition of TF (5 pM). Graft products were assessed with Western blot assay for TF expression, with a specific clotting assay for TF activity and with flow cytometry assay for Pd-MPs. The graft product enhanced thrombin generation and its procoagulant activity was related to the presence of Pd-MPs and TF. The concentration of Pd-MPs in the graft product was characterized by a significant interindividual variability. The present study reveals the need for a thorough quality control of the graft products regarding their procoagulant potential.

The COMPASS‐CAT study was undertaken in outpatients with breast, colon, lung, or ovarian cancer. The aim of the study was to identify the most relevat risk factors for symptomatic thromboembolism and to develop a risk assessment model applicable to patients after the initiation of anticancer treatment., Background. The stratification of outpatients on chemotherapy for breast, colorectal, lung, and ovarian cancers at risk of venous thromboembolism (VTE) remains an unmet clinical need. The derivation of a risk assessment model (RAM) for VTE in these patients was the aim of the study “Prospective Comparison of Methods for thromboembolic risk assessment with clinical Perceptions and AwareneSS in real life patients–Cancer Associated Thrombosis” (COMPASS–CAT). Patients and Methods. The derivation cohort consisted of 1,023 outpatients. Patients on low molecular weight heparin (LMWH) thromboprophylaxis were excluded. Documented symptomatic VTE was the endpoint of the study. Results. Patients had breast (61%), colorectal (17%), lung (13%), or ovarian cancer (8.6%) at localized (30%) or advanced stage (70%). In 64% of patients, cancer was diagnosed within the last 6 months prior to inclusion. Most of them were on chemotherapy when assessed. Symptomatic VTE occurred in 8.5% of patients. The COMPASS–CAT RAM includes the following variables: (a) anthracycline or anti‐hormonal therapy, (b) time since cancer diagnosis, (c) central venous catheter, (d) stage of cancer, (e) presence of cardiovascular risk factors, (f) recent hospitalization for acute medical illness, (g) personal history of VTE, and (h) platelet count. At 6 months, patients stratified at low/intermediate and high‐risk groups had VTE rates of 1.7% and 13.3%, respectively. The area under the curve of receiver operating characteristics analysis was 0.85. The sensitivity and specificity of the RAM were 88% and 52%, respectively. The negative and positive predictive values of the RAM were 98% and 13%, respectively. Conclusion. The COMPASS–CAT RAM includes reliable and easily collected VTE risk predictors and, in contrast to the Khorana score, it is applicable after the initiation of anticancer treatment in patients with common solid tumors. Its robustness for stratification of patients at high and low/intermediate VTE risk needs to be externally validated. Implications for Practice. The Prospective Comparison of Methods for thromboembolic risk assessment with clinical Perceptions and AwareneSS in real life patients–Cancer Associated Thrombosis (COMPASS–CAT) study provides a new risk assessment model (RAM) for venous thromboembolism (VTE) applicable in outpatients with breast, colorectal, lung or ovarian cancer. The COMPASS–CAT RAM is robust, applicable during chemotherapy and determines the need for VTE prévention by including reliable and easily collected VTE predictors associated with cancer status, its treatment as well as with patients' characteristics and comorbidities. An independent external validation of the RAM is indicated before its use in clinical practice.

Cancer is a leading cause of venous thromboembolism (VTE) and vice versa. Pulmonary embolism is the second cause of death in cancer patients. Tumor progression is associated with coagulation activation. The pathogenesis of thrombosis during cancer is particularly complex stemming from multiple connections of this disease with both systems of inflammation and hemostasis. The risk of VTE depends on cancer type and the stage of the disease, the anticancer treatments and the time since cancer diagnosis as well as on the presence of patient-related risk factors (i.e. age, obesity, previous history of VTE, underlying diseases…). The presence of other precipitating factors and the duration of the exposure to them are also key elements in the assessment of such a thrombotic risk. It is therefore important to identify all the VTE risk factors to identify patients at high vascular risk and to determine the period during which this risk is significantly increased. The integration of biomarkers of hypercoagulability in proposed risk assessment models for VTE will improve their capacity to identify patients eligible for pharmacological thromboprophylaxis. In this review, we report the current status of knowledge on the connection between cancer and hypercoagulability, the numerous risk factors for VTE must be identified in cancer patients and the best methodology to build a more accurate assessment of this vascular risk in such a complex medical context.

Introduction: Multiple myeloma (MM) is an hematological disease linked to a high thrombotic risk, estimated at around 10%/year, irrespective to disease onset. An important proportion of MM patients presents at least one of the well-defined vascular risk factors, such as diabetes, cardiac disease, hypertension or hyperlipidemia, which contribute to thrombotic risk. Thrombin Generation Test (TGT) could be an useful biomarker reflecting the prothrombotic profile of MM patients. Aim: To evaluate the potential correlation between vascular risk factors and TGT in MM patients. Materials and methods: This is a monocentric, prospective, non-interventional study on a cohort of 82 MM patients referred to the Hemostasis Center at Tenon University Hospital. Patients receiving already anticoagulant treatment of any kind were excluded. Thrombin generation was performed at their first visit using the Calibrated Thrombogram Assay (CAT®,Stago, Genevilliers, France), according to manufacturer's instructions. We collected all TGT parameters: lag time (LT), Endogenous Thrombin Potential (ETP) and Mean Rate Index (MRI).We also measured factor VIII activity (FVIII). Results were statistically analyzed using a two-sample t-test. Results: Among 82 patients with a male/female ratio of 44/35 and a median age at 65.2 years, 39 patients (48%) presented at least one cardiovascular risk factor (group A) and 42 had no vascular risk factors (group B) The LT value was reduced but not reaching a statistical difference between groups A and B (3 vs 3.95 sec, p= 0.8). MRI representing velocity was statistically shorter in group A (100 vs 118 nmol/min , p< 0.001). Surprisingly, ETP was significantly reduced in group A (1392 vs 1717 nmol/l x min, p < 0.001). FVIII levels were increased in group A (216% vs 192 %, p Conclusion: MM hypercoagulability can be easily identified with MRI, a chronometric TGT parameter. Increased FVIII levels observed in vascular patients are also facilitating an accelerated thrombin generation and are correlated with an endothelial activation. ETP decrease, reflecting the link between both content and container, must be seen as an adaptative response. Thus, endothelial activation could lead to TFPI release and this particular TGT profile in high vascular risk MM patients with a hypercoagulable state. Disclosures No relevant conflicts of interest to declare.

INTRODUCTION: Thromboembolism (TE) in lymphoma patients is gathering substantial attention due to its impact on morbidity and mortality of those patients. The association between lymphoma and increased risk for TE development, especially venous thromboembolism (VTE), has lately been well established through numerous publications. Thrombosis Lymphoma (ThroLy) score has been initially developed as a simple risk assessment model for the risk of TE development in lymphoma patients. It has been both internally and externally validated in several studies, which dominantly included patients with non-Hodgkin lymphoma (NHL). Therefore, aim of our study is to analyse and validate ThroLy score in an extensive cohort of Hodgkin lymphoma (HL) patients. METHODS: A total of 5509 newly diagnosed HL patients, from the German Hodgkin Study Group (GHSG) HD13-15 trials, were included in this study. Data has been obtained for all venous and arterial TE events in HL patients from time of diagnosis to 3 months after the last cycle of therapy. TE was diagnosed objectively based on radiographic studies (duplex venous ultrasound, contrast-enhanced thoracic computed tomography scan, magnetic resonance imaging (MRI) - for central nervous system (CNS) thrombosis, or angiograms (for arterial thrombosis), clinical examination and laboratory evaluation. Based on ThroLy score, patients were divided in three risk categories: low (score 0-1), intermediate (score 2-3) and high risk (score >3). Patients with intermediate and high-risk score were classified at risk. The validation was conducted through Chi-square test, ROC analysis and logistic regression. RESULTS: The mean patients' age was 35.9 years (range, 18-75 years); 55.7% were males. The majority of patients had limited or intermediate stage of disease: Ann Arbor stage I 10.6%, and stage II 57.5%. 190 (3.4%) patients developed thromboembolic events, 173 patients with VTE (3.14%), and 17 with arterial TE (0.31%), respectively. Chi-square test showed statistically significant association between TE and ThroLy score, both in three risk groups (chi-square = 18.236, p≤0.001) and two risk groups: low and at risk (chi-square = 18.029, p≤0.001). The sensitivity, specificity, negative and positive predictive value were 49%, 65%, 95%, and 97%, respectively. Binary logistic regression of ThroLy score showed statistically significant performance in prediction of TE events in HL patients, with satisfactory validity indicators (Ombinus Test chi-square = 11.668, p=0.001; AIC=44.956, BIC = 97.869). Diagnostic accuracy of ThroLy score was calculated via ROC curve (area under curve (AUC)=0.57). CONCLUSION: ThroLy score demonstrated its capability of risk prediction for TE events in HL patients. The limited statistical performance of the ThroLy score requires further research towards possible score enhancement. Disclosures Engert: AstraZeneca: Honoraria; MSD Sharp & Dohme: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Affimed Therapeutics: Research Funding; Sandoz: Honoraria; Takeda: Honoraria, Research Funding.

The prevalence of thrombosis in lymphoma patients is reportedly high and ranges from 3-10%. Vascular malfunction and inflammatory processes further contribute to the thrombotic activation process in these patients. Andexanet alfa (AA) is an antidote for factor Xa inhibitors and its usage has been reported with thrombotic complications. This study was designed to compare the effect of AA on the thrombin generation (TG) potential. Blood samples from 78 patients with confirmed diagnosis of non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL) and Chronic lymphocytic leukemia (CLL) were collected from the University of Belgrade Clinic, Serbia. Normal human plasma (NHP) was used for referencing purposes. Individual samples were supplemented with AA at 100 ug/ml. TG studies were carried out using a commercially available fluorogenic substrate method. TG parameters such as peak thrombin (PT), lag time (LT) and area under the curve (AUC) were compiled. Cumulatively, lymphoma patients showed an increase in LT compared to NHP which decreases with AA. The PT and AUC levels were decreased compared to NHP and increases with AA. Upon sub-grouping of lymphoma patients, PT levels for all sub-groups were increased with AA. The AUC values increased for HL and NHL and decreased for CLL with AA. Variations in lag time were noted in all 3 sub-groups. Lymphoma represents a heterogenous group of patients where both the hypercoagulable state and inflammatory responses simultaneously occur. Increased thrombin generation in post AA supplemented samples suggest that the use of this agent may potentially be associated with thrombotic complications.

It is widely recognized that a strong correlation exists between cancer and aberrant hemostasis. Patients with various types of cancers often develop thrombosis, a phenomenon commonly referred to as Trousseau syndrome. Tissue factor (TF) is expressed by tumor cells and contributes to a variety of pathologic processes, such as thrombosis, tumor growth, tumor angiogenesis, and metastasis. Tissue factor is expressed in two naturally occurring protein isoforms: membrane-bound full-length TF (flTF) and soluble alternatively spliced TF (asTF). Tissue factor is the primary initiator of blood coagulation, and it triggers intracellular signaling through protease-activated receptors (PARs). PARs are activated either by TF/FVIIa complexes or by thrombin generated following coagulation activation. Furthermore, the noncoagulant asTF retains an integrin-binding site and stimulates angiogenesis by ligating endothelial integrins αvβ3 and α6β1. Lastly, the increased TF expression in tumors is associated with the release in blood of TF-positive procoagulant microparticles that favor thromboembolic complications. Therefore, the interruption of asTF and flTF signaling represents a potential antiangiogenic strategy. In this review, we summarize the current knowledge on the role of TF in cancer, and we explore therapeutic perspectives based on TF targeting.

Background The aim of this prospective study was to identify the most clinically relevant hypercoagulability biomarkers in lung adenocarcinoma patients for elaboration of an improved risk assessment model (RAM) for venous thromboembolism (VTE). Subjects, Materials, and Methods One hundred fifty ambulatory patients with lung adenocarcinoma were prospectively enrolled. Thrombin generation, procoagulant phospholipid-dependent clotting time (Procoag-PPL), tissue factor activity (TFa), factor VIIa (FVIIa), factor V (FV), antithrombin, D-Dimers, P-selectin, and heparanase levels were assessed in platelet-poor plasma at inclusion (baseline) and at the end of the third chemotherapy cycle (third chemotherapy). Cox regression analysis was used to identify independent VTE predictors. Results At baseline, patients had significantly attenuated thrombin generation, shorter Procoag-PPL, higher levels of TFa, D-Dimers, and heparanase, and lower levels of FVIIa and P-selectin, compared with controls. A significant increase in Procoag-PPL, FV, and FVIIa and a decrease of P-selectin levels were observed between baseline and third chemotherapy. Hospitalization within the last 3 months prior to assessment, time since cancer diagnosis less than 6 months, mean rate index (MRI) of thrombin generation, and Procoag-PPL were independently associated with symptomatic VTE. Accordingly, a prediction model including Procoag-PPL and MRI showed significant discriminating capacity (area under the curve: 0.84). Conclusion Ambulatory patients with lung adenocarcinoma may display pronounced blood hypercoagulability due to decreased Procoag-PPL, increased endothelial cell activation, and increased degradation of fibrin. Incorporation of Procoag-PPL and MRI of thrombin generation may improve the accuracy of a VTE-RAM in the above setting. Implications for Practice The prospective ROADMAP-CAT study identified two biomarkers of hypercoagulability, the procoagulant phospholipid-dependent clotting time (Procoag-PPL) and the mean rate index (MRI) of the propagation phase of thrombin generation assessed with the Calibrated Automated Thrombinoscope, as being clinically relevant for the classification of ambulatory patients with lung adenocarcinoma receiving a maximum of one cycle of chemotherapy into high and intermediate/low risk for venous thromboembolism. Measurement of Procoag-PPL and MRI within 1 month after the administration of the first chemotherapy cycle provides significant accuracy of the assessment. Association of the Procoag-PPL and MRI with the clinical risk assessment model for cancer-associated thrombosis in ambulatory patients with solid tumors (COMPASS-CAT RAM) further improved its accuracy.

International audience; Disseminated intravascular coagulation (DIC) is an acquired clinicobiological syndrome characterized by widespread activation of coagulation leading to fibrin deposition in the vasculature, organ dysfunction, consumption of clotting factors and platelets, and life-threatening hemorrhage. Disseminated intravascular coagulation is provoked by several underlying disorders (sepsis, cancer, trauma, and pregnancy complicated with eclampsia or other calamities). Treatment of the underlying disease and elimination of the trigger mechanism are the cornerstone therapeutic approaches. Therapeutic strategies specific for DIC aim to control activation of blood coagulation and bleeding risk. The clinical trials using DIC as entry criterion are limited. Large randomized, phase III clinical trials have investigated the efficacy of antithrombin (AT), activated protein C (APC), tissue factor pathway inhibitor (TFPI), and thrombomodulin (TM) in patients with sepsis, but the diagnosis of DIC was not part of the inclusion criteria. Treatment with APC reduced 28-day mortality of patients with severe sepsis, including patients retrospectively assigned to a subgroup with sepsis-associated DIC. Treatment with APC did not have any positive effects in other patient groups. The APC treatment increased the bleeding risk in patients with sepsis, which led to the withdrawal of this drug from the market. Treatment with AT failed to reduce 28-day mortality in patients with severe sepsis, but a retrospective subgroup analysis suggested possible efficacy in patients with DIC. Clinical studies with recombinant TFPI or TM have been carried out showing promising results. The efficacy and safety of other anticoagulants (ie, unfractionated heparin, low-molecular-weight heparin) or transfusion of platelet concentrates or clotting factor concentrates have not been objectively assessed.

Introduction Cancer cells may alter the efficiency of the antithrombotic agents. To explore this possibility, the present study compared the capacity of the LMWH enoxaparin and the specific inhibitors of Xa (apixaban and fondaparinux) to inhibit thrombin generation triggered by pancreas adenocarcinoma cells (BXPC3) and human breast carcinoma cells (MCF7). Materials and methods Samples of platelet poor (PPP) or platelet rich plasma (PRP) spiked with apixaban, fondaparinux or enoxaparin were added in micro wells carrying cancer cells and assessed for thrombin generation. In the control experiment thrombin generation was triggered with tissue factor reagent. Results The three antithrombotics inhibited thrombin generation in a concentration dependent manner. The BXPC3 and MCF7 cells reversed in a different intensity the effect of the studied agents. According to the histological type of the cancer the antithrombotic efficiency of apixaban was preserved or partially reversed. Fondaparinux, was more vulnerable to the presence of cancer cells as compared to apixaban. The effect of BXCP3 or MCF7 cells on the antithrombotic potency of enoxaparin was of similar magnitude as that on apixaban. Conclusions The type of cancer cells is determinant for the antithrombotic efficiency of the specific factor Xa inhibitors. In contrast it does not significantly influence the potency of enoxaparin. The present study shows that the impact of the type of cancer cells on the antithrombotic activity of the specific Xa inhibitors should not be neglected. This has to be taken into consideration for the design of dose-finding studies of the direct orally active FXa inhibitors in patients with different histological types of cancer.

Background: The patent protection of low-molecular-weight heparins (LMWHs) expired, so the definition of criteria for the biological similarity between LMWH copies and the original product is a real need. Aim: The present in vitro study compared copies and branded enoxaparin using the specific anti-Xa activity and the calibrated automated thrombogram assay. Methods: Samples of platelet-poor plasma (PPP) and platelet-rich plasma (PRP) from 15 healthy volunteers were spiked with branded enoxaparin (Lovenox) or its copies (Cutenox, Dilutol, Enoxa, Fibrinox, Loparin, Lupenox, Novex, Noxprin, and Versa). The specific anti-Xa activity was measured in PPP, and thrombin generation was assessed in PPP and PRP in the presence of tissue factor or pancreatic cancer cells BXPC3. Results: The anti-Xa activity of enoxaparin copies ranged from 0.072 to 0.088 IU/μg, being lower as compared to the branded enoxaparin (0.095 anti-Xa IU/μg). The potency of each copy to inhibit thrombin generation varied in the 3 experimental systems. The presence of platelets or pancreatic cancer cells BXPC3 in human plasma induced significant modifications in the inhibitory efficiency of enoxaparin copies on thrombin generation, which distinguished them from the branded product. Conclusion: Enoxaparin copies showed significant variability regarding their inhibitory potency on thrombin generation. Platelets and cancer cells significantly increased the variability of the antithrombotic efficiency of the copies as compared to the branded enoxaparin. The present study underlines the need for the elaboration of additional functional criteria to evaluate the global antithrombotic capacity of enoxaparin copies in order to evaluate their potential sameness with the branded drug.

Most cancer cells trigger thrombin generation (TG) to various extent. In the present study, we dissected the mechanisms responsible for the procoagulant activity of pancreatic adenocarcinoma cells (BXPC3), a highly thrombogenic cancer type, and breast cancer cells (MCF7), a less thombogenic tumor type. TG of normal plasma was assessed by the Thrombinoscope (CAT®) in the presence or absence of cancer cells. TG was also assessed in plasma depleted of clotting factors, in plasma spiked with tissue factor (TF) and/or procoagulant phospholipids, in plasma spiked with an anti-TF monoclonal antibody or with corn trypsin inhibitor (CTI). The presence of alternatively spliced TF (asTF), TF activity (TFa) and cancer procoagulant (CP) levels were determined. TFa and asTF were highly expressed by BXPC3 cells, compared to MCF7 cells, while CP levels were higher in MCF7 cells. BXPC3 cells had a stronger effect on TG than MCF7 cells. Accordingly, anti-TF had more inhibitory activity on TG triggered by BXPC3 cells while CTI had more pronounced inhibitory effect on TG triggered by MCF7 cells. TG enhancement by both BXPC3 and MCF7 cells was mediated by FVII and intrinsic tenase while FXII and FXI were also important for MCF7 cells. The induction of TG by BXPC3 cells was mainly driven by the TF pathway while TG generation triggered by MCF7 cells was also driven by FXII activation. Therefore, hypercoagulability results from a combination of the inherent procoagulant properties of cancer cell-associated TF as well as of procoagulant phospholipids in the plasma microenvironment.

Low molecular weight heparins (LMWHs) and fondaparinux are widely used for prophylaxis and treatment of venous thromboembolic disease in cancer patients. However, the optimization of the antithrombotic treatment especially in patients with adenocarcinoma of the pancreas is a challenging issue. The understanding of the mechanism of action of the LMWHs and fondaparinux in cancer-induced hypercoagulability might help to optimize antithrombotic treatment. To this aim, we investigated the influence of BXPC3 pancreas adenocarcinoma cells on the antithrombotic activity of LMWHs and fondaparinux. Thrombin generation (TG) in normal platelet poor (PPP) and platelet rich plasma (PRP) spiked with clinically relevant concentrations of dalteparin, enoxaparin, nadroparin tinzaparin and fondaparinux was assessed with the Calibrated Automated Thrombogram assay. BXPC3 (5 cells/μl) were added to plasma. The mean rate index (MRI) of the propagation phase of TG and the endogenous thrombin potential (ETP) were analyzed. The IC50 of the studied compounds were determined and compared on the basis of anti-Xa and anti-IIa equivalent units. We demonstrate that the specific antithrombin (AT)-dependent anti-Xa activity of LMWHs and fondaparinux almost selectively inhibits the propagation phase of TG. The synergy between the anti-Xa and anti-IIa activities of LMWHs rather than the selective inhibition of FXa warrants abrogation of TG. The mean molecular weight and anti-Xa/anti-IIa ratio of the AT-dependent agents cannot predict the alteration of their capacity to inhibit TG. Tinzaparin was the most potent inhibitor of TG than the other LMWHs. Enoxaparin was more potent than nadroparin and dalteparin.

Background: Research has focused on the implications of platelet, endothelial cell and blood coagulation activation in the risk of venous thromboembolism (VTE) in patients with multiple myeloma (MM). The reciprocal interaction between cancer cells and blood coagulation renders biomarkers of hypercoagulability as potential candidates for the evaluation of resistance to treatment in patients with newly diagnosed multiple myeloma (NDMM). Aims: The aim of the current analysis of the ROADMAP-MM study was to identify among a large number of hypercoagulability biomarkers in NDMM patients the most clinically relevant for the inclusion in treatment-resistance assessment tools. Methods: The ROADMAP-MM-CAT study (NCT03405571) was an investigator initiated, prospective, non-interventional trial. Newly diagnosed, treatment naïve symptomatic patients with multiple myeloma (based on 2014 IMWG Criteria) (n=144) were enrolled prior to treatment initiation and response to treatment was assessed at 3 months. Selected biomarkers , such as STA-Procoag-PPL®, factor VIIa factor V, antithrombin, fibrin monomers, thrombomodulin, free TFPI, D-Dimers, P-selectin, heparanase and thrombin generation (Calibrated Automated Thrombogram® and PPP-Reagent®) were measured. Results: At inclusion no patient had received any anti-myeloma treatment or thromboprophylaxis. Median age was 66.0±11.6 (36-86) years and 53% of the population was male. Regarding ISS disease stage: 32% were ISS-I, 23% ISS-II and 45% ISS-III. High risk cytogenetics [defined as presence of any of t(4;14), t(14;16) or del17p by FISH] were detected in 27% of the patients. In 32% of patients the treatment was immunomodulatory drug (IMiD) (90% lenalidomide and 10% thalidomide) and in 64% proteasome inhibitor (PI) based whereas 4% of patients received other regimens. Before any treatment administration - patients showed significantly increased levels of TFa, FVIIa, D-Dimers and FM and significantly shorter Procoag-PPL® as compared to the group of healthy individuals. Levels of P-selectin and TM were significantly lower in patients as compared to healthy individuals. Overall, thrombin generation was attenuated in patients compared to healthy individuals. Lag-time and ttPeak were significantly increased and Peak, MRI and ETP were significantly lower as compared to the group of healthy individuals At 3 months from treatment initiation, 23% (n=33) of the patients showed poor response or resistance to the anti-myeloma treatment. Among them, 7.6% (n=11) had progressive disease, 9.7% (n=14) had stable disease and 5.7% (n=8) had minor response. Among responders (n=111) 42.3 % (n=61) achieved PR and 34.7% (n=50) had VGPR. Multivariate logistic regression analysis for demonstrated that Procoag-PPL®≥41.7 versus Poor response/treatment resistance was associated with longer Procoag-PPL, higher D-dimer levels and higher thrombin's Peak. The new score had 84% sensitivity and 59% specificity to identify patients who showed treatment resistance at 3 months from treatment initiation. The AUC of the ROC analysis for the model was 0.75. Conclusions: Based on the evaluation of Procoag-PPL®, D-Dimers and Peak of thrombin generation, the prospective ROADMAP-MM-CAT study led to the derivation of an original risk assessment model for the identification of NDMM patients with poor response or resistance to the anti-myeloma treatment.. The identified biomarkers of hypercoagulability need to be correlated in future studies with established clinical prognostic parameters in multiple myeloma patients and then validated clinically within the context of prospective clinical trials in order to assess their role in clinical practice and in anti-myeloma treatment optimization. Disclosures Dimopoulos: Sanofi Oncology: Research Funding. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Introduction: The prevalence of thrombosis in lymphoma patients is reportedly high and ranges from 3 - 10%, and further increased at advanced stages of the disease especially in hgNHL. Inflammation and other vascular factors contribute to the pathogenesis of these thrombotic complications. Biomarkers of hemostatic activation, vascular dysfunction and inflammation are elevated in lymphoma. We have previously reported that thrombin generation biomarkers such as D-Dimer, thrombin anti-thrombin complex (TAT) and prothrombin fragment (F1.2) along with inflammatory biomarkers are increased in cancer patients. Interestingly, despite an increase in thrombin generation markers, thrombin generation potential in these patients is decreased. This study was designed to compare the thrombin generation potential and its relevance to the generation of various biomarkers of hemostatic activation process and inflammatory responses. Methods: Citrated blood samples from 90 patients with confirmed diagnosis of non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL) and Chronic lymphocytic leukemia/Small lymphocytic lymphoma (CLL/SLL) were collected from the Clinic of Hematology Unit, University of Belgrade, Belgrade, Serbia. 50 samples of normal human plasma (NHP) was obtained from George King Biomedical (Overland park, KS). NHP was prepared for referencing purposes. Thrombin generation studies were carried out using a commercially available a kinetic fluorogenic substrate method (calibrated automated thrombogram; CAT). Thrombin generation parameters such as peak thrombin (PT), lag time (LT) and area under the curve (AUC) were compiled. Plasma levels of D-Dimer, CRP, vWF and TNF- α were measured by using commercially available Sandwich ELISA assays. Results were compiled in terms of mean ± SD. Correlation analysis carried out by using Prism, Graphpad. Results: On a cumulative basis, lymphoma patients showed an increase in lag time (2.9 1.17) in comparison to the NHP (2.7). The peak thrombin levels was decreased (119.0 46.2) in the lymphoma patients in comparison to NHP (159.7 31.1). The AUC was decreased (670.2 290.01) in the lymphoma patients in comparison to NHP (700.9 ). When the lymphoma patients were sub grouped, peak thrombin levels were similar in HL (129.9), NHL (114.7) and CLL (127.4) and were decreased compared to NHP (159.7). However the AUC was increased in the HL (769), decreased in NHL (642.4) and was comparable for CLL (715.4) compared to NHP (700.9). Variations in lag time were noted in the three groups. The lymphoma patients also exhibited elevated levels of D-Dimer (878 1205 ng/ml) in comparison to NHP (280 ng/ml), CRP (15.2 26.6 ug/ml) in comparison to NHP (0.9 ug/ml), vWF (271.8 189.7 %) in comparison to NHP (122%) and TNF-α (16.4 20.64 pg/ml) in comparison to NHP (4.2 pg/ml). Interestingly, when the lymphoma group were subdivided into various groups, the D-Dimer level was highest in HL following the order HL>NHL>CLL. CRP and vWF levels were highest in HL and comparable in both NHL and CLL. Wide scatter in TNF-α data was noted with CLL exhibiting highest levels with the ranked order CLL>NHL>HL. The composite data on thrombin generation parameters and biomarkers is shown on the table 1A. In the HL group D-Dimer and CRP correlated well with AUC and PT, in this group vWF also showed a good correlation with PT. In the NHL group, CRP correlated well with LT. In the CLL group none of the biomarkers correlated well with the thrombin generation parameters. On a cumulative basis, D-Dimer, CRP, vWF and TNF-α had no significant relevance to thrombin generation parameters. The composite regression coefficience data is shown on table 1B. Conclusion: Lymphoma patients represent a heterogenous group in which both the hypercoagulable state and inflammatory responses simultaneously occur as evident by increase in D-Dimer and inflammatory biomarkers. While the overall thrombin generation potential in the plasma of these patients is decreased, thrombin is constantly generated in some of these patient leading to the formation of fibrin. The observed decrease in thrombin generation potential in these patients may be due to the consumption of prothrombin and other coagulation factors. Wide variations among these lymphoma groups are noted. Profiling of thrombin generation and inflammatory biomarkers may be helpful in thrombotic risk stratification of lymphoma patients and their anti-thrombotic management. Disclosures No relevant conflicts of interest to declare.