Rivaroxaban and apixaban are less effective than enoxaparin for the prevention of catheter-induced clotting in vitro.

BACKGROUND: Central venous catheters are prone to clotting, particularly in patients with cancer. Although low-molecular-weight heparin and direct oral anticoagulants, such as apixaban and rivaroxaban, have been evaluated for the prevention of catheter thrombosis, their efficacy remains uncertain. OBJECTIVES: Compare apixaban and rivaroxaban with enoxaparin for the prevention of catheter-induced clotting in vitro. METHODS: To address this uncertainty, we used a well-established microplate-based assay to compare the effects of enoxaparin, apixaban, and rivaroxaban on catheter-induced thrombosis and thrombin generation in human plasma. RESULTS: Consistent with our previous findings, catheter segments shortened the clotting time and promoted thrombin generation. When compared at concentrations with similar anti-factor Xa activity as enoxaparin, apixaban and rivaroxaban were >20-fold less potent than enoxaparin for the prevention of catheter-induced clotting and thrombin generation. CONCLUSION: The prevention of catheter thrombosis in patients with cancer is challenging. Clinical trials are needed to compare the efficacy of low-molecular-weight heparin with that of direct oral anticoagulants both for the prevention and treatment of catheter thrombosis.

Human La binds mRNAs through contacts to the poly(A) tail.

In addition to a role in the processing of nascent RNA polymerase III transcripts, La proteins are also associated with promoting cap-independent translation from the internal ribosome entry sites of numerous cellular and viral coding RNAs. La binding to RNA polymerase III transcripts via their common UUU-3'OH motif is well characterized, but the mechanism of La binding to coding RNAs is poorly understood. Using electromobility shift assays and cross-linking immunoprecipitation, we show that in addition to a sequence specific UUU-3'OH binding mode, human La exhibits a sequence specific and length dependent poly(A) binding mode. We demonstrate that this poly(A) binding mode uses the canonical nucleic acid interaction winged helix face of the eponymous La motif, previously shown to be vacant during uridylate binding. We also show that cytoplasmic, but not nuclear La, engages poly(A) RNA in human cells, that La entry into polysomes utilizes the poly(A) binding mode, and that La promotion of translation from the cyclin D1 internal ribosome entry site occurs in competition with cytoplasmic poly(A) binding protein (PABP). Our data are consistent with human La functioning in translation through contacts to the poly(A) tail.

Conservation of RNA chaperone activity of the human La-related proteins 4, 6 and 7.

The La module is a conserved tandem arrangement of a La motif and RNA recognition motif whose function has been best characterized in genuine La proteins. The best-characterized substrates of La proteins are pre-tRNAs, and previous work using tRNA mediated suppression in Schizosaccharomyces pombe has demonstrated that yeast and human La enhance the maturation of these using two distinguishable activities: UUU-3'OH-dependent trailer binding/protection and a UUU-3'OH independent activity related to RNA chaperone function. The La module has also been identified in several conserved families of La-related proteins (LARPs) that engage other RNAs, but their mode of RNA binding and function(s) are not well understood. We demonstrate that the La modules of the human LARPs 4, 6 and 7 are also active in tRNA-mediated suppression, even in the absence of stable UUU-3'OH trailer protection. Rather, the capacity of these to enhance pre-tRNA maturation is associated with RNA chaperone function, which we demonstrate to be a conserved activity for each hLARP in vitro. Our work reveals insight into the mechanisms by which La module containing proteins discriminate RNA targets and demonstrates that RNA chaperone activity is a conserved function across representative members of the La motif-containing superfamily.