Perioperative Treatment with Rivaroxaban and Dabigatran on Changes of Coagulation and Platelet Activation Biomarkers following Left Atrial Appendage Closure.

Insufficient data exist regarding the investigation of the impact of novel oral anticoagulants (NOACs) on coagulation activation biomarkers in the context of left atrial appendage closure (LAAC) and device-related thrombosis (DRT). The study was designed to investigate the changes and presence of coagulation activation biomarkers between different antithrombotic strategies following LAAC. A total of 120 nonvalvular atrial fibrillation patients intolerant of long-term anticoagulants, who underwent successful WATCHMAN closure implantation, were enrolled (rivaroxaban, n = 82; dabigatran, n = 38). Blood samples were obtained from left atrium (LA) and left atrial appendage (LAA) during the operation and fasting blood samples on the same day of LAAC and 45 days after discharge. The biochemical indicators, thrombin-antithrombin complex (TAT), soluble P-selectin (sP-selectin), von Willebrand factor (vWF), and CD40 ligand (CD40L), were measured by enzyme-linked immunosorbent assay. The primary endpoints of this study were the efficacy and safety characteristics of different antithrombotic strategies, including DRT incidence, stroke or transient ischemic attack, systemic embolism, and clinical major and nonmajor bleeding complications during the follow-up of 180 days. The results revealed that TAT, vWF, sP-selectin, and CD40L levels in vein were significantly reduced by 2.4% (p = 0.043), 5.0% (p < 0.001), 8.7% (p < 0.001), and 2.5% (p = 0.043) from their baseline levels after rivaroxaban treatment. Conversely, no significant changes were detected in the dabigatran group. Furthermore, the plasma levels of platelet activation biomarkers (CD40L and sP-selectin) in both LA and LAA groups were significantly lower after anticoagulation with rivaroxaban, as compared to dabigatran treatment (CD40L: 554.62 ± 155.54 vs. 445.02 ± 130.04 for LA p = 0.0013, 578.51 ± 156.28 vs. 480.13 ± 164.37 for LAA p = 0.0052; sP-selectin: 2849.07 ± 846.69 vs. 2225.54 ± 799.96 for LA p = 0.0105, 2915.52 ± 1402.40 vs. 2203.41 ± 1061.67 for LAA p = 0.0022). Notably, the present study suggests that rivaroxaban may be more effective in the prevention of DRT for patients undergoing LAAC.

Immunomodulatory Therapy of Inflammatory Liver Disease Using Selectin-Binding Glycopolymers.

Immunotherapies have the potential to significantly advance treatment of inflammatory disease and cancer, which are in large part driven by immune cells. Selectins control the first step in immune cell adhesion and extravasation, thereby guiding leukocyte trafficking to tissue lesions. We analyzed four different highly specific selectin-binding glycopolymers, based on linear poly(2-hydroxypropyl)-methacrylamide (PHPMA) polymers. These glycopolymers contain either the tetrasaccharide sialyl-LewisX (SLeX) or the individual carbohydrates fucose, galactose, and sialic acids mimicking the complex SLeX binding motive. The glycopolymers strongly bind to primary human macrophages, without activating them, and also to primary human blood leukocytes, but poorly to fibroblasts and endothelial cells in vitro. After intravenous injection in mice, all glycopolymers accumulated in the liver without causing hepatotoxicity. The glycosylated binder most potently targeted resident hepatic macrophages (Kupffer cells) and protected mice from acute toxic liver injury in the two different experimental models, carbon tetrachloride (CCl4) or Concanavalin A (ConA)-based hepatitis. Its sulfated counterpart, on the other hand, induced a decrease in infiltrating and resident macrophages, increased T helper cells, and aggravated immune-mediated liver injury. We demonstrate that, in the context of selectin-binding glycopolymers, minor modifications strongly impact leukocyte influx and macrophage activation, thereby ameliorating or aggravating liver inflammation depending on the underlying immunopathology. The nonsulfated random glycopolymer is a promising candidate for the treatment of inflammatory disease. The modulation of hepatic immune cells by selectin-binding glycopolymers might breach the immunosuppressive hepatic microenvironment and could improve efficacy of immunotherapies for inflammatory disease and cancer.

Selectins-an emerging target for drug delivery.

Selectins are multifunctional adhesion molecules that mediate the initial interactions between circulating leukocytes and cells of the endothelium. First identified over a decade ago, selectins have provided insight into areas as diverse as normal lymphocyte homing, leukocyte recruitment during inflammatory responses, carbohydrate ligand biosynthesis and adhesion-mediated signalling. Of late, selectins were introduced as targets for drug delivery in the development of new anti-inflammatory therapeutics and in anti-cancer therapy. This review will examine the selectins and their ligands with a focus on recent findings on their role in physiology and pathophysiology as well as the emerging role of selectins as targets in controlled drug delivery.

[Human lectins and their correspondent glycans in cell biology and clinical medicine]. / Endogene Lectine des Menschen und ihre Zuckerliganden. Zellbiologische und klinische Bedeutung.

Lectins are phylogenetically ancient proteins that have specific recognition and binding functions for complex carbohydrates of glycoconjugates, i. e., of glycoproteins, proteoglycans/glycosaminoglycans and glycolipids. This class of proteins mediates important processes of adhesion and communication both inside and outside cells. A large variety of lectins are expressed in the human organism. This article reviews the current knowledge of human lectins with a focus on biochemistry and pathobiochemistry (principles of protein glycosylation and defects of glycosylation as a basis of disease) and cell biology (protein sorting, exocytosis and endocytosis, apoptosis, cell adhesion, cell differentiation, and malignant transformation). The clinical significance of lectin-glycoconjugate interactions is described by example of inflammatory diseases, defects of immune defense, autoimmunity, infectious diseases, and tumor invasion/metastasis. Moreover, therapeutic perspectives of novel drugs that interfere with lectin-carbohydrate interactions are discussed.

Adhesion molecules and gene transfer.

Cell adhesion molecules are a large group of molecules involved in a variety of cell-to-cell and cell-to-extra-cellular matrix (ECM) interactions. Apart from their cellular function these molecules are exploited by a number of pathogenic micro-organisms as receptors for cell entry. Discovery of the use of adhesion molecules for binding and internalisation by naturally occurring pathogens has fuelled much research, in recent years, into the utilisation of these molecules for the targeting and uptake of both gene and drug delivery systems. This review describes the development of such systems and their potential advantages over other receptor-targeted delivery systems.