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Introduction: International clinical practice guidelines (ITAC, ASCO, NCCN and ASH) have progressively endorsed direct factor Xa inhibitors (edoxaban, rivaroxaban and apixaban) as an alternative to monotherapy with low-molecular-weight heparin (LMWH) for the treatment of venous thromboembolism (VTE) in cancer patients. The results from new randomized controlled trials (RCT) which assessed the efficacy and the safety of direct oral anticoagulants (DOAC) compared to LMWH for the treatment of cancer-associated thrombosis (CAT) were released during the past months. We therefore performed an updated meta-analysis of all publicly available data from RCT comparing DOAC with LMWH for the treatment of CAT. Methods: Embase, MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL) and conference proceedings from all languages were searched up to August 2, 2021. Search strategy, study selection, data extraction and statistical analysis were performed in accordance with the Preferred Reporting Items for Meta-Analyses (PRISMA) guidelines. The primary efficacy outcome was recurrent VTE, and the primary safety outcome was major bleeding. Secondary outcomes included clinically relevant nonmajor bleeding (CRNMB), and all-cause mortality. Risk of bias was assessed by using the Cochrane risk-of-bias tool in randomized controlled trials version 2.0. Pooled relative risk (RR) and 95% confidence intervals (CIs) were estimated using the Mantel-Haenszel method of Der Simonian and Laird within a random-effect model. Heterogeneity of effect size across studies was assessed using the I 2 statistic. Publication bias was assessed by visual inspection of funnel plots. All the statistical analyses were performed with the RevMan 5.3 software. Results: Six RCT comparing the efficacy and safety of DOAC versus LMWH, which enrolled a total of 3,690 cancer patients with acute VTE (1850 randomized to the DOAC arms and 1840 randomized to the LMWH arms), were included in the pooled analysis. Main study characteristics are summarized in Table 1. During a follow-up of 3 to 6 months under anticoagulant treatment, recurrent VTE occurred in 99 of 1,850 (5.3%) patients receiving DOACs versus 152 of 1,840 (8.3%) patients receiving LMWH. The risk of recurrent VTE was significantly lower with DOAC than with LMWH (RR 0.67, 95% CI 0.52-0.85, p = 0.001, I 2 = 0%, Figure 1A). Major bleeding occurred in 78 (4.2%) patients with CAT treated with DOAC versus 65 (3.5%) patients treated with LMWH. The risk of major bleeding was non significantly higher with DOAC (RR 1.20, 95% CI 0.85-1.70, p = 0.31, I 2= 7%, Figure 1B). CRNMB was more frequent in cancer patients receiving DOAC compared to those receiving LMWH (10.3% versus 6.3%, RR 1.63, 95% CI 1.25-2.11, p = 0.0003, I²= 6%, Figure 1C). The rates of all-cause mortality did not differ between the two groups (23.6% in the DOAC arms versus 23.3% in the LMWH arms, RR 1.02, 95% CI 0.89-1.16, p = 0.80, I² = 13%, Figure 1D). Conclusions: In this August 2021 meta-analysis of 3,690 patients treated for CAT, DOAC significantly reduced the risk of recurrent VTE compared with LMWH, without increasing the risk of major bleeding. However, as previously highlighted, the use of DOAC was associated with an increased risk of CRNMB. Our results provide additional evidence for the use of DOAC as a safe and effective first-line option for the treatment of CAT in patients who are not at high risk of bleeding. These findings may increase the level of certainty for the evidence used in the national or international clinical practice guidelines supporting the use of DOAC in cancer patients with CAT. Figure 1 Figure 1. Disclosures Connors: CSL Behring: Research Funding; Pfizer: Honoraria; Alnylam: Consultancy; takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Abbott: Consultancy.

For a long time, blood coagulation and innate immunity have been viewed as interrelated responses. Recently, the presence of leukocytes at the sites of vessel injury has been described. Here we analyzed interaction of neutrophils, monocytes, and platelets in thrombus formation after a laser-induced injury in vivo. Neutrophils immediately adhered to injured vessels, preceding platelets, by binding to the activated endothelium via leukocyte function antigen-1–ICAM-1 interactions. Monocytes rolled on a thrombus 3 to 5 minutes postinjury. The kinetics of thrombus formation and fibrin generation were drastically reduced in low tissue factor (TF) mice whereas the absence of factor XII had no effect. In vitro, TF was detected in neutrophils. In vivo, the inhibition of neutrophil binding to the vessel wall reduced the presence of TF and diminished the generation of fibrin and platelet accumulation. Injection of wild-type neutrophils into low TF mice partially restored the activation of the blood coagulation cascade and accumulation of platelets. Our results show that the interaction of neutrophils with endothelial cells is a critical step preceding platelet accumulation for initiating arterial thrombosis in injured vessels. Targeting neutrophils interacting with endothelial cells may constitute an efficient strategy to reduce thrombosis.

Background: Symptomatic Catheter Related Thrombosis (CRT) occurs in 3-5% of cancer patients with Central Venous Catheters (CVC) and, overall, the incidence of CRT could reach 30% when including asymptomatic cases (1). In women with Breast Cancer (BC), the most frequent cancer in females world-wide, the high risk of Venous Thromboembolism (VTE) during chemotherapy may be related in part to CRT (2). We therefore designed the CAVECCAS (Cathéter VEineux Central et CAncer du Sein) study to analyze CRT incidence and CRT risk factors in BC patients with CVC receiving (neo)adjuvant chemotherapy (NAC). Methods: CAVECCAS is a prospective, multicenter cohort study of patients with non metastatic invasive BC undergoing insertion of a single lumen CVC for at least 3 months of NAC. All included patients with signed informed consent between September 2008 and December 2011 underwent repeated double-blind Doppler US evaluation before (D0) and at 7, 30 and 90 days (D) after CVC insertion. In case of VTE symptoms, diagnosis was confirmed by venography, ultrasonography and/or computed tomography. Venous blood samples were systematically drawn before and 2 days after CVC insertion to determine D-Dimers levels (VIDAS® D-Dimer Exclusion™), Platelet-derived MPs (Pd-MPs) and Pd-MPs expressing phosphatidyl serin (Pd-MP/PS+) levels (3), thrombin generation (Calibrated Automated Thrombogram assay®, Stago) and endogenous thrombin potential (ETP). After completing recruitment and follow-up (D90), a nested case-control study analyzed additional individual thrombophilic risk factors (Antithrombin, Protein C and Protein S levels, presence of Factor V and Factor II Leiden mutations, presence of antiphospholipid, anticardiolipin and antiβ2GP1 antibodies) using two controls without CRT from the CAVECCAS cohort matched for TNM status with each symptomatic or asymptomatic CRT patient. Statistical analysis used Fisher or Wilcoxon tests for univariate analysis; step down selection procedure with p-values < 0.10 for multivariate models; conditional logistic model to study the occurrence of CRT based on thrombophilia testing (open-source software R Version 2.15.2 (2012-10-26). Results(expressed as median and inter-quartile range [IQR] for quantitative data and numbers and percentages for categorical data). 524 patients with non metastatic BC (85% ductal carcinoma, 12.2% Lobular carcinoma, 2.8% other) with respective T0/T1/T2/T3/T4 staging (0.5%/47.6%/43.3%/8.0%/0.7%), SBR 1/2/3 grading (11.2%/53%/35.8%), 49.2 % having node involvement and 79.5% steroid hormone receptors, were analyzed. During follow-up, the overall CRT incidence rate was 2.18 cases/100 patient-months, with 14 symptomatic and 46 asymptomatic patients, 27, 10 and 9 of the asymptomatic CRT being respectively diagnosed on D8, 30 and day 90 US. In univariate analysis, increased age (>50 years) (OR, 1.80; 95% CI, 1.01-3.22; p=0.048), BMI> 30 kg/m² (OR, 2.64; 95% CI, 1.46-4.76; p=0.001) and comorbidities (OR, 2.05; 95% CI, 1.18-3.56; p=0.011) were associated with CRT. CRT was less frequent in ductal (OR, 0.55; 95% CI, 0.28-1.07; p=0.078) versus lobular carcinoma (OR, 2.53; 95% CI, 1.32-4.85; p= 0.005). In multivariate analysis, BMI>30 kg/m² (OR, 2.66: 99%CI, 1.46-4.84, p=0.001) and lobular carcinoma histology (OR, 2.56; 95%CI, .32-4.96, p=0.005) remained CRT risk factors. Pd-MPs (981.5 [518-2147] vs 758.5 [416.5-373] /mL; p Conclusion: In this large sample size study with serial measurements of clinical parameters and biomarkers for thrombosis, only obesity and lobular carcinoma histology appeared strong risk factors for CRT in non metastatic BC treated with NAC. Further studies will elucidate how individual stratification of BC patients may identify those who may benefit from CRT prophylaxis. 1) Debourdeau P and Farge D et al. J Thromb Haemost 2013; 11:71-80 2) Walker AJ et al. Blood 2016;127(7):849-57 3) Robert S et al J Thromb Haemost 2009;7:190-7 Disclosures No relevant conflicts of interest to declare.

Thrombin, the major enzyme of the hemostatic system, is involved in biological processes associated with several human diseases. The capacity of a given individual to generate thrombin, called the thrombin generation potential (TGP), can be robustly measured in plasma and was shown to associate with thrombotic disorders. To investigate the genetic architecture underlying the interindividual TGP variability, we conducted a genome-wide association study in 2 discovery samples (N = 1967) phenotyped for 3 TGP biomarkers, the endogenous thrombin potential, the peak height, and the lag time, and replicated the main findings in 2 independent studies (N = 1254). We identified the ORM1 gene, coding for orosomucoid, as a novel locus associated with lag time variability, reflecting the initiation process of thrombin generation with a combined P value of P = 7.1 × 10(-15) for the lead single nucleotide polymorphism (SNP) (rs150611042). This SNP was also observed to associate with ORM1 expression in monocytes (P = 8.7 × 10(-10)) and macrophages (P = 3.2 × 10(-3)). In vitro functional experiments further demonstrated that supplementing normal plasma with increasing orosomucoid concentrations was associated with impaired thrombin generation. These results pave the way for novel mechanistic pathways and therapeutic perspectives in the etiology of thrombin-related disorders.

Recent studies revisiting the association between plasma thrombin-activatable fibrinolysis inhibitor (TAFI) Ag levels and polymorphisms of the CPB2 gene (coding for TAFI) suggested that TAFI Ag levels were influenced by 2 major quantitative trait nucleotides (QTNs) in European whites. However, the strong linkage disequilibrium (LD) between CPB2 polymorphisms in European whites did not allow one to distinguish which polymorphisms could be the putative QTNs. To get a better insight into the identification of QTNs, a transethnic haplotype analysis contrasting 2 populations of African and European subjects was performed using 13 CPB2 polymorphisms. Results of the haplotype analyses suggested that 3 QTNs had independent effects and explained about 15% of the TAFI variability, consistently in the 2 populations. The lower LD observed in the African population enabled us to identify the 1583T>A SNP located in 3′UTR as one of these QTNs, whereas the -2599C>G and -2345--2344insG SNPs located in the 5′ region might be the 2 other QTNs. A phylogenetic study suggested that these 3 polymorphisms occurred before the period of migration “out of Africa.” Although this transethnic comparison contributed to better map the putative CPB2 QTNs, further studies are required to clarify the role of the promoter region.

Plasma TAFI antigen (Ag) levels are almost entirely under the control of the TAFI gene.[1-3][1] Several polymorphisms found to be associated with TAFI Ag levels have been already described,[1-4][1] but a recently performed segregation-linkage analysis indicates that the TAFI-linked quantitative