title: The effects of hyperglycaemia on thrombin-activatable fibrinolysis inhibitor.
abstract: Epidemiological studies have shown a strong association between type 2 diabetes mellitus and cardiovascular diseases, and hypofibrinolysis may contribute to this phenomenon. The aim of this study was to determine the effect of hyperglycaemia on thrombin-activatable fibrinolysis inhibitor (TAFI). Hyperglycaemia was mimicked in vitro by incubation of TAFI with glyceraldehyde and in vivo by hyperglycaemic clamping of healthy volunteers. The effects of long-term hyperglycaemia in vivo on TAFI were investigated by comparing TAFI from poorly regulated and tightly regulated patients with type 2 diabetes. In vitro glycated TAFI showed an altered migration pattern on SDS-PAGE due to aggregation. Glycated TAFI showed decreased activity after activation by thrombin-thrombomodulin in a glyceraldehyde-dose-dependent manner and a reduced anti-fibrinolytic potential. In vivo, no differences in TAFI parameters were found after hyperglycaemic clamping of healthy volunteers and between tightly and poorly regulated patients with type 2 diabetes. Moreover, TAFI purified from poorly regulated and tightly regulated patients with type 2 diabetes migrated similarly on SDS-PAGE, indicating little or no glycation of the protein. Despite the deleterious effects of glycation of TAFI in vitro on its function, TAFI was neither affected by hyperglycaemic clamping, nor by long-term hyperglycaemia in patients with type 2 diabetes. This is in contrast to fibrinolytic factors as plasminogen-activator inhibitor I and tissue-type plasminogen activator, which are affected. We therefore hypothesise that a normally functioning TAFI under hyperglycaemic conditions may tip the haemostatic balance towards hypofibrinolysis, which may contribute to the development of cardiovascular diseases in type 2 diabetic patients.
authors.affiliation: Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, 1100 DD Amsterdam, The Netherlands.
authors.forename: Chantal J N
authors.initials: CJ
authors.lastname: Verkleij
authors.forename: Max
authors.initials: M
authors.lastname: Nieuwdorp
authors.forename: Victor E A
authors.initials: VE
authors.lastname: Gerdes
authors.forename: Matthias
authors.initials: M
authors.lastname: Mörgelin
authors.forename: Joost C M
authors.initials: JC
authors.lastname: Meijers
authors.forename: Pauline F
authors.initials: PF
authors.lastname: Marx
mesh_terms: D025901:Carboxypeptidase B2 / Q000737:chemistry*; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000209:etiology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005342:Fibrinolysis / Q000187:drug effects; D015309:Glucose Clamp Technique; D005985:Glyceraldehyde / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D008297:Male; D013917:Thrombin / Q000737:chemistry; D018180:Thrombomodulin / Q000737:chemistry; D013997:Time Factors
chemical_list: D018180:Thrombomodulin; D005985:Glyceraldehyde; D025901:Carboxypeptidase B2; D013917:Thrombin