title: Hyperglycemia accelerates arterial thrombus formation and attenuates the antithrombotic response to endotoxin in mice.
abstract: Recent human studies reveal that hyperglycemia induces procoagulant and antifibrinolytic effects in blood that may contribute to a greater risk of arterial thrombosis, but the direct relationship between high blood glucose levels and thrombosis has not yet been investigated. We performed a number of experiments to clarify whether hyperglycemia was causally related to arterial thrombosis and whether the combined stimulus of hyperglycemia and inflammation would enhance the thrombotic effect. In a model of ferric-chloride-induced carotid artery thrombosis, hyperglycemia did not influence the time to occlusion in mice pretreated with streptozotocin, but the rate of thrombus formation was accelerated. This effect was associated with increased thrombin generation and could not be explained by changes in vessel-wall tissue factor activity. The prothrombotic effect of hyperglycemia was assessed in a separate experiment, showing that collagen/thrombin-induced platelet procoagulant activity was increased in hyperglycemic mice. The effect of inflammation was studied by injecting a low dose of endotoxin that caused a systemic inflammatory state after 24 h (increased plasma levels of tumor necrosis factor alpha, interleukin-6 and monocyte chemotactic protein 1 in diabetic and nondiabetic mice) associated with a mild delay in thrombus formation. This reduced rate of thrombus formation was attenuated by hyperglycemia. Together, these data establish a discrete but clear contribution of hyperglycemia in experimental arterial thrombosis.
authors: Laboratory for Experimental Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Hjalmar R
authors: HR
authors: Hansen
authors: Jef L
authors: JL
authors: Wolfs
authors: Lois
authors: L
authors: Bruggemann
authors: Dirkje W
authors: DW
authors: Sommeijer
authors: Eduard
authors: E
authors: Bevers
authors: Arnaud D
authors: AD
authors: Hauer
authors: Johan
authors: J
authors: Kuiper
authors: C Arnold
authors: CA
authors: Spek
authors: Henri M H
authors: HM
authors: Spronk
authors: Pieter H
authors: PH
authors: Reitsma
authors: Hugo
authors: H
authors: ten Cate
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D002341:Carotid Artery Thrombosis / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D002712:Chlorides; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology; D004195:Disease Models, Animal; D004731:Endotoxins / Q000097:blood* / Q000494:pharmacology; D005260:Female; D005290:Ferric Compounds; D005343:Fibrinolytic Agents / Q000097:blood* / Q000494:pharmacology; D006943:Hyperglycemia / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D013311:Streptozocin; D013917:Thrombin / Q000187:drug effects; D013918:Thrombin Time / Q000379:methods; D013924:Thrombophlebitis / Q000188:drug therapy / Q000378:metabolism
chemical_list: D002712:Chlorides; D004731:Endotoxins; D005290:Ferric Compounds; D005343:Fibrinolytic Agents; D013311:Streptozocin; D013917:Thrombin; C024555:ferric chloride