thromboplastin and Iron-Overload

Iron overload-induced cardiovascular toxicity is one of the most common causes of morbidity and mortality in beta-thalassemia major patients. We have previously shown that iron overload-induced systemic arterial changes characterized by endothelial dysfunction are associated with increased endothelial microparticle (EMP) release. In this study, we further demonstrate how EMP release is associated with iron-induced mitochondrial injury and apoptosis of endothelial cells. Iron increased the production of reactive oxygen species (ROS) and calcium influx into mitochondria [Ca

Topics: Adenosine Triphosphate; Apoptosis; Cell-Derived Microparticles; Cells, Cultured; Deferiprone; Endothelial Cells; Humans; Iron Overload; Mitochondria; Oxidative Stress; Pyridones; Reactive Oxygen Species; Thromboplastin

Iron overload has been implicated in the pathogenesis of ischemic cardiovascular events. However, the effects of iron excess on vascular function and the thrombotic response to vascular injury are not well understood.. We examined the effects of chronic iron dextran administration (15 mg over 6 weeks) on thrombosis, systemic and vascular oxidative stress, and endothelium-dependent vascular reactivity in mice. Thrombus generation after photochemical carotid artery injury was accelerated in iron-loaded mice (mean time to occlusive thrombosis, 20.4+/-8.5 minutes; n=10) compared with control mice (54.5+/-35.5 minutes, n=10, P=0.009). Iron loading had no effect on plasma clotting, vessel wall tissue factor activity, or ADP-induced platelet aggregation. Acute administration of dl-cysteine, a reactive oxygen species scavenger, completely abrogated the effects of iron loading on thrombus formation, suggesting that iron accelerated thrombosis through a pro-oxidant mechanism. Iron loading enhanced both systemic and vascular reactive oxygen species production. Endothelium-dependent vasorelaxation was impaired in iron-loaded mice, indicating reduced NO bioavailability.. Moderate iron loading markedly accelerates thrombus formation after arterial injury, increases vascular oxidative stress, and impairs vasoreactivity. Iron-induced vascular dysfunction may contribute to the increased incidence of ischemic cardiovascular events that have been associated with chronic iron overload.

Topics: Adenosine Diphosphate; Animals; Blood Coagulation; Carotid Arteries; Carotid Artery Thrombosis; Cysteine; Disease Models, Animal; Disease Progression; Endothelium, Vascular; Free Radical Scavengers; Iron; Iron Overload; Iron-Dextran Complex; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Oxidative Stress; Platelet Aggregation; Reactive Oxygen Species; Thromboplastin; Time; Vascular Patency; Vasodilation; Vasodilator Agents