Glycosylation of human fibrinogen in vivo

Lütjens, A.; Velde, Anje A. te; Veen, E. A. Van De; Meer, Jehangir

doi:10.1007/bf00279921

Cited by 49 publications

(23 citation statements)

References 11 publications

(12 reference statements)

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“…This may be caused by concomitant glycosylation of the proteins involved in fibrin clot formation. 92 It is of interest that 4 to 6 months of insulin treatment with continuous subcutaneous insulin infusion in patients with longstanding type 1 diabetes led to an increase in fibrin gel porosity independent of improved glycemic control or insulin levels, but this appeared to be related to total cholesterol and plasma fibrinogen levels. 93 Other drugs used to treat diabetes have effects on fibrin structure and function.…”

Section: Glucose and Treatmentmentioning

confidence: 99%

Genetic and Environmental Determinants of Fibrin Structure and Function

Scott

Ariëns

Grant

2004

ATVB

138

131

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Abstract-The formation of a fibrin clot is one of the key events in atherothrombotic vascular disease. The structure of the fibrin clot and the genetic and environmental factors that modify it have effects on its biological function. Alterations in fibrin structure and function have implications for the clinical presentation of vascular disease. This review briefly describes the key features involved in the formation of a fibrin clot, its typical structure, and function. This is followed by a review of the current literature on genetic and environmental influences on fibrin structure/function and the relationship to clinical disease. Key Words: fibrin Ⅲ hemostatis Ⅲ genetic Ⅲ environment Ⅲ atherothrombosis D iseases associated with the development of thrombosis are a major cause of morbidity and mortality in the developed world. Atherothrombotic vascular disorders develop over many decades and involve the interaction of classic atherogenic risk factors such as diabetes, hyperlipidemia, and hypertension with abnormalities of the inflammatory and hemostatic systems. Arterial disease develops in a high-pressure, high-flow system, with lipid deposition and smooth muscle hyperplasia occurring to form an atherosclerotic plaque. 1 Subsequently, the plaque becomes unstable and ruptures exposing a prothrombotic lipid core activating the clotting cascade and leading to the development of a platelet-rich fibrin blood clot and arterial thrombotic occlusion. The extent of this process determines clinical outcome, ranging from no clinically noticeable event to acute coronary artery syndromes including myocardial infarction (MI), cerebrovascular and peripheral vascular disease, or sudden death. The Formation of a Fibrin ClotFibrin is the major protein constituent of the blood clot and is formed from fibrinogen, a glycoprotein that circulates largely inactively, in the blood stream. Fibrinogen consists of 6 polypeptide chains (A␣, B␤, ␥) 2 held together by disulphide bonds in a molecule with bilateral symmetry (Figure 1). The molecule consists of 3 main structural regions, 2,3 including a central region (E), which contains fibrinopeptides A and B and the amino acid termini of all 6 polypeptide chains, 2 distal regions (D) connected to the E region by 2 ␣-helical coiled segments and the D regions containing the carboxyl termini of the B␤ and ␥ chains, and those of the A␣ chain, which extend to form relatively flexible ␣C-domains, each ending in a globular domain. 2,3 In situations of tissue injury and inflammation, thrombin is generated after cleavage of prothrombin by the Xase complex. Thrombin subsequently binds to fibrinogen and cleaves the amino termini of the fibrinogen A␣ and B␤ chains at region E. This results in the release of fibrinopeptides A and B from fibrinogen, producing fibrin and initiating fibrin clot formation. Release of fibrinopeptide A by thrombin is fast and exposes a polymerization site on the E region of fibrin. 4,5 This combines with a complementary binding site on the ␥ chain in the D region of an adjac...

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Section: Glucose and Treatmentmentioning

confidence: 99%

Genetic and Environmental Determinants of Fibrin Structure and Function

Scott

Ariëns

Grant

2004

ATVB

138

131

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“…The changes found were inversely correlated to glycaemic control (HbA 1 c) [17], leading the authors to suggest that this effect may result from glycation of the fibrinogen molecule. Indeed, fibrinogen has been shown to be glycated in vivo [20], and in vitro glycation of fibrinogen has been shown to influence its interaction with other coagulation/fibrinolytic proteins [21][22][23].…”

Section: Introductionmentioning

confidence: 99%

The influence of type 2 diabetes on fibrin structure and function

2005

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Aims/hypothesis: The precise mechanisms underlying the increased risk of cardiovascular disease (CVD) in type 2 diabetes are unclear. Fibrin clot structure has been related to CVD risk in the general population. We therefore assessed this in type 2 diabetic patients as a potential mechanism whereby diabetes influences CVD risk. Methods: Fibrin clots were formed from fibrinogen purified from 150 subjects with type 2 diabetes and varying degrees of glycaemic control (assessed by HbA 1 c), and from 50 matched control subjects. Clot structure was assessed by turbidity, permeation and confocal microscopy. The specific effect of glucose itself was assessed by analysing the structure of clots formed from purified fibrinogen in the presence of increasing concentrations of the sugar. Results: Clots formed by fibrinogen purified from type 2 diabetic subjects had a denser, less porous structure than those from control subjects. The structural changes found were related to the individual's glycaemic control; HbA 1 c correlated negatively with permeation coefficient (K s ) values (indicates clot pore size) (r=−0.57, p<0.0001) and positively with maximum absorbance (indicator of fibre size) (r=0.33, p<0.0001), branch point number (r=0.78, p<0.0001) and fibre density (r=0.63, p<0.0001). The ambient glucose level influenced clot structure; hypo-(<5 mmol) and hyperglycaemia (≥10 mmol/l) were both associated with a reduction in K s values and maximum absorbance, and with increased fibre density and branch point number within clots. Conclusions/ interpretation: The structural differences found to occur in type 2 diabetes and in association with hypo-and hyperglycaemia may confer increased resistance to fibrinolysis, and in consequence contribute to the increase in CVD risk in diabetic patients.

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“…. Glycation of fibrin(ogen) was estimated by a modification of the hydroxymethylfurfural method as described previously [10]. …”

Section: Me~o~mentioning

confidence: 99%

“…Non-enzymatical glycation of proteins results from sustained hyperglycaemia [8]. Fibrinogen turned out to be no exception [9,10]. Glycation takes place at lysine molecules, which play an important role in the fibrinogen metabolism [11].…”

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confidence: 99%

Polymerisation and crosslinking of fibrin monomers in diabetes mellitus

et al. 1988

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Summary. Polymerisation and crosslinking of fibrin monomers was studied in 35 healthy volunteers and in 42 poorly controlled diabetic patients. Polymerisation did not show any difference between control subjects (n = 10) and diabetic patients (n = 11) (p > 0.1), although fibrinogen was 35% more glycated in the diabetic patients (/)<0.001). Alpha chain crosslinking in the diabetic patients, however, was impaired as is shown from an increase in intermediate alpha polymers with a concomitant decrease in alpha monomer disappearance. A significant positive correlation was found between the degree of glycation of fibrinogen and the defective alpha chain polymerisation (r = 0.86, p < 0.005). These results were consistent with the results of thrombin and reptilase experiments. The reaction rate with reptilase did not show any difference between the two groups (p > 0.1), whereas the reaction rate with thrombin was significantly slower in the diabetic group compared to the control subjects (p < 0.001). Purified fibrin clots obtained from the diabetic patients were more susceptible to plasmin than clots obtained from control subjects. It is concluded that in poorly controlled diabetic patients polymerisation of fibrin monomers is normal, but crosslinking of the alpha chains is impaired, leading to a higher susceptibility of the clots to plasmin degradation.

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Glycosylation of human fibrinogen in vivo

Cited by 49 publications

References 11 publications

Genetic and Environmental Determinants of Fibrin Structure and Function

Genetic and Environmental Determinants of Fibrin Structure and Function

The influence of type 2 diabetes on fibrin structure and function

Polymerisation and crosslinking of fibrin monomers in diabetes mellitus

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