fondaparinux and Ischemia

To evaluate the safety and effectiveness of fondaparinux in addition to dual antiplatelet therapy (DAPT) in patients with critical limb-threatening ischaemia (CLTI).. Fondaparinux (2.5 mg/d) was administered for 1-4 weeks after endovascular procedures together with DAPT (. Adding fondaparinux to DAPT does not seem to result in excess of clinically relevant bleeding. Our preliminary data suggest that prospective studies are now warranted in larger patient cohorts.. DRKS00015856.

Topics: Anticoagulants; Endovascular Procedures; Female; Femoral Artery; Fondaparinux; Humans; Ischemia; Limb Salvage; Peripheral Arterial Disease; Pilot Projects; Platelet Aggregation Inhibitors; Popliteal Artery; Prospective Studies; Retrospective Studies; Stents; Treatment Outcome; Vascular Patency

Antithrombin (AT) is a plasma serpin inhibitor that regulates the proteolytic activity of procoagulant proteases of the clotting cascade. In addition to its anticoagulant activity, AT also possesses potent anti-inflammatory properties.. The objective of this study was to investigate the anti-inflammatory activity of wild-type AT (AT-WT) and a reactive centre loop mutant of AT (AT-RCL) which is not capable of inhibiting thrombin.. The cardioprotective activities of AT-WT and AT-RCL were monitored in a mouse model of ischemia/reperfusion (I/R) injury in which the left anterior descending coronary artery was occluded and then released.. We demonstrate that AT markedly reduces myocardial infarct size by a mechanism that is independent of its anticoagulant activity. Thus, AT-RCL attenuated myocardial infarct size to the same extent as AT-WT in this acute injury model. Further studies revealed that AT binds to vascular heparan sulfate proteoglycans via its heparin-binding domain to exert its protective activity as evidenced by the therapeutic AT-binding pentasaccharide (fondaparinux) abrogating the cardioprotective activity of AT and a heparin-site mutant of AT exhibiting no cardioprotective property. We further demonstrate that AT up-regulates the production of prostacyclin in myocardial tissues and inhibits expression of pro-inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6 in vivo by attenuating ischemia/reperfusion-induced JNK and NF-κB signaling pathways.. The present results suggest that both AT and the non-anticoagulant AT-RCL, through their anti-inflammatory signaling effects, elicit potent cardioprotective responses. Thus, AT may have therapeutic potential for treating cardiac I/R injury.

Topics: Animals; Anti-Inflammatory Agents; Antithrombins; Cardiotonic Agents; Fondaparinux; Heparin; Inflammation; Interleukin-6; Ischemia; Leukocytes; Male; MAP Kinase Kinase 4; Mice; Mice, Inbred C57BL; Mutation; Myocardial Ischemia; NF-kappa B; Polysaccharides; Reperfusion Injury; Signal Transduction; Thrombin; Troponin I; Tumor Necrosis Factor-alpha

Thrombin is involved in mediating neuronal death in cerebral ischemia. We investigated its so far unknown mode of activation in ischemic neural tissue. We used an in vitro approach to distinguish the role of circulating coagulation factors from endogenous cerebral mechanisms. We modeled ischemic stroke by subjecting rat organotypic hippocampal slice cultures to 30-min oxygen (5%) and glucose (1 mmol/L) deprivation (OGD). Perinuclear activated factor X (FXa) immunoreactivity was observed in CA1 neurons after OGD. Selective FXa inhibition by fondaparinux during and after OGD significantly reduced neuronal death in the CA1 after 48 h. Thrombin enzyme activity was increased in the medium 24 h after OGD and this increase was prevented by fondaparinux suggesting that FXa catalyzes the conversion of prothrombin to thrombin in neural tissue after ischemia in vitro. Treatment with SCH79797, a selective antagonist of the thrombin receptor protease-activated receptor-1 (PAR-1), significantly decreased neuronal cell death indicating that thrombin signals ischemic damage via PAR-1. The c-Jun N-terminal kinase (JNK) pathway plays an important role in excitotoxicity and cerebral ischemia and we observed activation of the JNK substrate, c-Jun in our model. Both the FXa inhibitor, fondaparinux and the PAR-1 antagonist SCH79797, decreased the level of phospho-c-Jun Ser73. These results indicate that FXa activates thrombin in cerebral ischemia, which leads via PAR-1 to the activation of the JNK pathway resulting in neuronal death.

Topics: Animals; Animals, Newborn; Anticoagulants; Cell Death; Factor Xa; Fondaparinux; Gene Expression Regulation; Glucose; Hippocampus; Hypoxia; Ischemia; JNK Mitogen-Activated Protein Kinases; Organ Culture Techniques; Polysaccharides; Pyrroles; Quinazolines; Rats; Receptor, PAR-1; Serine; Signal Transduction; Thrombin

In recent years it has become increasingly clear that a cross-talk between the inflammatory response and blood coagulation exists, although many of the underlying mechanisms remain unclear. In the present study we investigated the potential anti-inflammatory properties of two different anticoagulant compounds, i.e. active-site inactivated FVIIa (FVIIai) and fondaparinux sodium, a selective FXa inhibitor, administered as pretreatment in a model of intestinal I/R in rats.. Endothelial barrier permeability was assessed using the vascular leakage of radiolabelled human serum albumin, tissue neutrophil sequestration was quantitated by myeloperoxidase (MPO) activity, and plasma levels of macrophage inflammatory protein (MIP)-2 were examined using an enzyme-linked-immuno-sorbent assay after 40 min of intestinal ischaemia and 6 h of reperfusion in the rat (n = 34). Pretreatment with FVIIai or fondaparinux sodium was administered 90 min before initiation of ischaemia.. Endothelial-barrier permeability in all examined organs, myeloperoxidase activity in the lungs, and ileum and MIP-2 levels in plasma increased after intestinal I/R. Pretreatment with FVIIai decreased the endothelial barrier permeability and MPO activity in the ileum, and a tendency towards decreased permeability was also observed in the lungs. Fondaparinux did not affect the endothelial barrier permeability or MPO activity. Both FVIIai and fondaparinux decreased the MIP-2 levels in plasma after intestinal I/R.. Inhibition of the TF-FVIIa complex by FVIIai can attenuate inflammatory responses in connection with intestinal I/R-injury and could represent a potentially important therapeutic strategy for the prevention of organ dysfunction. Potential anti-inflammatory properties of fondaparinux and other inhibitors of FXa are not excluded and need further investigation.

Topics: Animals; Anticoagulants; Blood Cell Count; Cell Membrane Permeability; Chemokine CXCL2; Chemokines, CXC; Endothelium; Factor VIIa; Factor Xa Inhibitors; Fondaparinux; Hemostasis; Intercellular Signaling Peptides and Proteins; Interleukin-8; Intestines; Ischemia; Male; Neutrophil Infiltration; Peroxidase; Polysaccharides; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Reperfusion Injury