Download PDF
Thromb Haemost 2008; 99(04): 691-700
DOI: 10.1160/TH07-11-0699
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Glycaemic control improves fibrin network characteristics in type 2 diabetes – A purified fibrinogen model

Marlien Pieters
1   Department of Nutrition, North-West University, Potchefstroom, South Africa
,
Namukolo Covic
1   Department of Nutrition, North-West University, Potchefstroom, South Africa
,
Francois H. van der Westhuizen
2   School of Biochemistry, North-West University, Potchefstroom, South Africa
,
Chandrasekaran Nagaswami
3   Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
,
Yelena Baras
3   Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
,
Du Toit Loots
1   Department of Nutrition, North-West University, Potchefstroom, South Africa
,
Johann C. Jerling
1   Department of Nutrition, North-West University, Potchefstroom, South Africa
,
Dale Elgar
4   School of Pharmacy, North-West University, Potchefstroom, South Africa
,
Kathryn S. Edmondson
3   Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
,
Danie G. van Zyl
5   Department of Internal Medicine, University of Pretoria, Pretoria, South Africa
,
Paul Rheeder
6   Division of Clinical Epidemiology, University of Pretoria, Pretoria, South Africa
,
John W. Weisel
3   Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
› Author AffiliationsFinancial support: The study was funded by research funds from the North-West University, the University of Pretoria, Sugar Association (Project 209) and NIH grant HL30954. Insulin was provided by Sanofi-Aventis and Novo-Nordisk and glucometers by Roche Diagnostics.
Further Information

Publication History

Received: 23 November 2007

Accepted after major revision: 26 February 2008

Publication Date:
25 November 2017 (online)

Also available at
    Permissions and Reprints

Summary

Diabetic subjects have been shown to have altered fibrin network structures. One proposed mechanism for this is non-enzymatic glycation of fibrinogen due to high blood glucose. We investigated whether glycaemic control would result in altered fibrin network structures due to decreased fibrinogen glycation. Twenty uncontrolled type 2 diabetic subjects were treated with insulin in order to achieve glycaemic control. Twenty age- and body mass index (BMI)-matched non-diabetic subjects were included as a reference group. Purified fibrinogen, isolated from plasma samples was used for analysis. There was a significant decrease in fibrinogen glycation (6.81 to 5.02 mol glucose/mol fibrinogen) with a corresponding decrease in rate of lateral aggregation (5.86 to 4.62) and increased permeability (2.45 to 2.85 × 10−8 cm2) and lysis rate (3.08 to 3.27 μm/min) in the diabetic subjects after glycaemic control. These variables correlated with markers of glycaemic control. Fibrin clots of non-diabetic subjects had a significantly higher ratio of inelastic to elastic deformation than the diabetic subjects (0.10 vs. 0.09). Although there was no difference in median fiber diameter between diabetic and non-diabetic subjects, there was a small increase in the proportion of thicker fibers in the diabetic samples after glycaemic control. Results from SDS-PAGE indicated no detectable difference in factor XIIIa-crosslinking of fibrin clots between uncontrolled and controlled diabetic samples. Diabetic subjects may have altered fibrin network formation kinetics which contributes to decreased pore size and lysis rate of fibrin clots. Achievement of glycaemic control and decreased fibrinogen glycation level improves permeability and lysis rates in a purified fibrinogen model

Keywords

Diabetes - fibrin network - fibrinogen glycation - glycaemic control - hyperglycaemia
 

  • References

  • 1 Rett K. The relation between insulin resistance and cardiovascular complications of the insulin resistance syndrome. Diabetes Obes Metab 1999; 1 (Suppl. 01) S8-16.
    CrossrefPubMedGoogle Scholar
  • 2 Fatah K, Silveira A, Tornvall P. et al. Proneness to formation of tight and rigid fibrin gel structures in men with myocardial infarction at a young age. Thromb Haemost 1996; 76: 535-540.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Collet JP, Allali Y, Lesty C. et al. Altered fibrin architecture is associated with hypofibrinolysis and premature coronary atherothrombosis. Arterioscler Thromb Vasc Biol 2006; 26: 2567-2573.
    CrossrefPubMedGoogle Scholar
  • 4 Collet JP, Park D, Lesty C. et al. Influence of fibrin network conformation and fibrin fiber diameter on fibrinolysis speed: dynamic and structural approaches by confocal microscopy. Arterioscler Thromb Vasc Biol 2000; 20: 1354-1361.
    CrossrefPubMedGoogle Scholar
  • 5 Bobbink IW, Tekelenburg WL, Sixma JJ. et al. Glycated proteins modulate tissue-plasminogen activatorcatalyzed plasminogen activation. Biochem Biophys Res Commun 1997; 240: 595-601.
    CrossrefPubMedGoogle Scholar
  • 6 Krantz S, Lober M, Thiele M. et al. Properties of in vitro nonenzymatically glycated plasma fibrinogens. Exp Clin Endocrinol 1987; 90: 37-45.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Ney KA, Pasqua JJ, Colley KJ. et al. In vitro preparation of nonenzymatically glucosylated human transferrin, alpha 2-macroglobulin, and fibrinogen with preservation of function. Diabetes 1985; 34: 462-470.
    CrossrefPubMedGoogle Scholar
  • 8 Mirshahi M, Soria J, Soria C. et al. Glycosylation of human fibrinogen and fibrin in vitro. Its consequences on the properties of fibrin(ogen). Thromb Res 1987; 48: 279-289.
    CrossrefPubMedGoogle Scholar
  • 9 Brownlee M, Vlassara H, Cerami A. Nonenzymatic glycosylation reduces the susceptibility of fibrin to degradation by plasmin. Diabetes 1983; 32: 680-684.
    CrossrefPubMedGoogle Scholar
  • 10 Dunn EJ, Ariens RA, Grant PJ. The influence of type 2 diabetes on fibrin structure and function. Diabetologia 2005; 48: 1198-1206.
    CrossrefPubMedGoogle Scholar
  • 11 Nair CH, Azhar A, Wilson JD. et al. Studies on fibrin network structure in human plasma. Part II–Clinical application: diabetes and antidiabetic drugs. Thromb Res 1991; 64: 477-485.
    CrossrefPubMedGoogle Scholar
  • 12 Lutjens A, Jonkhoff-Slok TW, Sandkuijl C. et al. Polymerisation and crosslinking of fibrin monomers in diabetes mellitus. Diabetologia 1988; 31: 825-830.
    CrossrefPubMedGoogle Scholar
  • 13 Jorneskog G, Egberg N, Fagrell B. et al. Altered properties of the fibrin gel structure in patients with IDDM. Diabetologia 1996; 39: 1519-1523.
    CrossrefPubMedGoogle Scholar
  • 14 Pieters M, Covic N, Loots dT. et al. The effect of glycaemic control on fibrin network structure of type 2 diabetic subjects. Thromb Haemost 2006; 96: 623-629.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Dunn EJ, Philippou H, Ariens RA. et al. Molecular mechanisms involved in the resistance of fibrin to clot lysis by plasmin in subjects with type 2 diabetes mellitus. Diabetologia 2006; 49: 1071-1080.
    CrossrefPubMedGoogle Scholar
  • 16 Jorneskog G, Hansson LO, Wallen NH. et al. Increased plasma fibrin gel porosity in patients with Type I diabetes during continuous subcutaneous insulin infusion. J Thromb Haemost 2003; 1: 1195-1201.
    CrossrefPubMedGoogle Scholar
  • 17 Dunn EJ, Ariens RA. Fibrinogen and fibrin clot structure in diabetes. Herz 2004; 29: 470-479.
    PubMedGoogle Scholar
  • 18 Barazzoni R, Zanetti M, Davanzo G. et al. Increased fibrinogen production in type 2 diabetic patients without detectable vascular complications: correlation with plasma glucagon concentrations. J Clin Endocrinol Metab 2000; 85: 3121-3125.
    CrossrefPubMedGoogle Scholar
  • 19 Pieters M, Van Zyl DG, Rheeder P. et al. Glycation of fibrinogen in uncontrolled diabetic patients and the effects of glycaemic control on fibrinogen glycation. Thromb Res 2007; 120: 439-446.
    CrossrefPubMedGoogle Scholar
  • 20 Takebe M, Soe G, Kohno I. et al. Calcium ion-dependent monoclonal antibody against human fibrinogen: preparation, characterization, and application to fibrinogen purification. Thromb Haemost 1995; 73: 662-667.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Blomback B, Carlsson K, Fatah K. et al. Fibrin in human plasma: gel architectures governed by rate andnature of fibrinogen activation. Thromb Res 1994; 75: 521-538.
    CrossrefPubMedGoogle Scholar
  • 22 Fatah K, Hamsten A, Blomback B. et al. Fibrin gel network characteristics and coronary heart disease: relations to plasma fibrinogen concentration, acute phase protein, serum lipoproteins and coronary atherosclerosis. Thromb Haemost 1992; 68: 130-135.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Langer BG, Weisel JW, Dinauer PA. et al. Deglycosylation of fibrinogen accelerates polymerization and increases lateral aggregation of fibrin fibers. J Biol Chem 1988; 263: 15056-15063.
    PubMedGoogle Scholar
  • 24 Woodhead JL, Nagaswami C, Matsuda M. et al. The ultrastructure of fibrinogen Caracas II molecules, fibers, and clots. J Biol Chem 1996; 271: 4946-4953.
    CrossrefPubMedGoogle Scholar
  • 25 Sakharov DV, Nagelkerke JF, Rijken DC. Rearrangements of the fibrin network and spatial distribution of fibrinolytic components during plasma clot lysis. Study with confocal microscopy. J Biol Chem 1996; 271: 2133-2138.
    CrossrefPubMedGoogle Scholar
  • 26 Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970; 227: 680-685.
    CrossrefPubMedGoogle Scholar
  • 27 Field AP. Discovering statistics using SPSS.. 2nd London: Sage Publications; 2005
  • 28 Ryan EA, Mockros LF, Weisel JW. et al. Structural origins of fibrin clot rheology. Biophys J 1999; 77: 2813-2826.
    CrossrefPubMedGoogle Scholar
  • 29 Weisel JW, Veklich Y, Gorkun O. The sequence of cleavage of fibrinopeptides from fibrinogen is important for protofibril formation and enhancement of lateral aggregation in fibrin clots. J Mol Biol 1993; 232: 285-297.
    CrossrefPubMedGoogle Scholar
  • 30 Mihalyi E. Clotting of bovine fibrinogen. Kinetic analysis of the release of fibrinopeptides by thrombin and of the calcium uptake upon clotting at high fibrinogen concentrations. Biochemistry 1988; 27: 976-982.
    CrossrefPubMedGoogle Scholar
  • 31 Di Stasio E, Nagaswami C, Weisel JW. et al. Clregulates the structure of the fibrin clot. Biophys J 1998; 75: 1973-1979.
    CrossrefPubMedGoogle Scholar
  • 32 Veklich YI, Gorkun OV, Medved LV. et al. Carboxyl-terminal portions of the alpha chains of fibrinogen and fibrin. Localization by electron microscopy and the effects of isolated alpha C fragments on polymerization. J Biol Chem 1993; 268: 13577-13585.
    PubMedGoogle Scholar
  • 33 Weisel JW. The mechanical properties of fibrin for basic scientists and clinicians. Biophys Chem 2004; 112: 267-276.
    CrossrefPubMedGoogle Scholar
  • 34 Carr ME. Diabetes mellitus: a hypercoagulable state. J Diabetes Complications 2001; 15: 44-54.
    CrossrefPubMedGoogle Scholar
  • 35 Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 1999; 48: 1-9.
    CrossrefPubMedGoogle Scholar
  • 36 Shacter E, Williams JA, Levine RL. Oxidative modification of fibrinogen inhibits thrombin-catalyzed clot formation. Free Radic Biol Med 1995; 18: 815-821.
    CrossrefPubMedGoogle Scholar