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Thromb Haemost 2009; 102(03): 460-468
DOI: 10.1160/TH09-01-0016
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

The effects of hyperglycaemia on thrombin-activatable fibrinolysis inhibitor

Chantal J. N. Verkleij
1   Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Max Nieuwdorp
2   Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Victor E. A. Gerdes
2   Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
3   Department of Internal Medicine, Slotervaart Hospital, Amsterdam, The Netherlands
,
Matthias Mörgelin
4   Department of Clinical Sciences, Section for Clinical and Experimental Infection Medicine, Lund University, Lund, Sweden
,
Joost C. M. Meijers
1   Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2   Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Pauline F. Marx
1   Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
› InstitutsangabenFinancial support: This work was supported in part by a grant from the Dutch Diabetes Research Foundation (Grant 2005.00.016 to J.C.M.M. and P.F.M.) and by a VENI grant from the Netherlands Organization for Scientific Research (Zon MW Grant 916.36.104, to P.F.M. and Zon MW Grant 016.096.044 to M.N.).
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Publikationsverlauf

Received: 09. Januar 2009

Accepted after major revision: 11. Juni 2009

Publikationsdatum:
22. November 2017 (online)

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Summary

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-dosedependent manner and a reduced anti-fibrinolytic potential. In vivo, no differences in TAFI parameters were found after hyper-glycaemic 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.

Keywords

TAFI - hyperglycaemia - diabetes mellitus - cardiovascular disease - protein glycation
 

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