Increased plasma fibrin gel porosity in patients with Type I diabetes during continuous subcutaneous insulin infusion

Jörneskog, Gun; Lo, Hansson; Nh, Wallén; Yngen, Marianne; Blombäck, Margareta

doi:10.1046/j.1538-7836.2003.00301.x

Cited by 38 publications

(32 citation statements)

References 45 publications

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“…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. Gliclazide increases fibrin fiber thickness but reduces permeability, overall rendering the clot more susceptible to fibrinolysis.…”

Section: Glucose and Treatmentmentioning

confidence: 99%

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Genetic and Environmental Determinants of Fibrin Structure and Function

Scott

Ariëns

Grant

2004

ATVB

139

129

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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%

“…It has been shown that total cholesterol may determine fibrin clot structure, 93 and fibrin gel porosity has been associated with lipoproteins in young patients sustaining MI. 13 It is of interest that statins appear to reduce thrombin formation and inhibit FXIII activation, reducing the formation of a stable clot.…”

Section: Lipids and Treatmentmentioning

confidence: 99%

Genetic and Environmental Determinants of Fibrin Structure and Function

Scott

Ariëns

Grant

2004

ATVB

139

129

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“…Previous work has shown more compact fibrin clots in type 1 diabetic patients compared with healthy controls [7], and limited evidence suggests a thrombotic and hypofibrinolytic state in individuals with type 1 diabetes by mechanisms that are not entirely understood [8]. Manipulating glycaemia in type 1 diabetes is associated with fewer thrombotic fibrin clots but the effect on fibrinolysis has not been studied [9,10].…”

Section: Introductionmentioning

confidence: 99%

A novel mechanism for hypofibrinolysis in diabetes: the role of complement C3

et al. 2011

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Aims/hypothesis Impaired fibrin clot lysis is a key abnormality in diabetes and complement C3 is one protein identified in blood clots. This work investigates the mechanistic pathways linking C3 and hypofibrinolysis in diabetes using ex vivo/in vitro studies. Methods Fibrinolysis and C3 plasma levels were determined in type 1 diabetic patients and healthy controls, and the effects of glycaemia investigated. C3 incorporation into fibrin clots and modulation of fibrinolysis were analysed by ELISA, immunoblotting, turbidimetric assays and electron and confocal microscopy. Results Clot lysis time was longer in diabetic children than in controls (599±18 and 516±12 s respectively; p<0.01), C3 levels were higher in diabetic children (0.55±0.02 and 0.43± 0.02 g/l respectively; p<0.01) and both were affected by improving glycaemia. An interaction between C3 and fibrin was confirmed by the presence of lower protein levels in sera compared with corresponding plasma and C3 detection in plasma clots by immunoblot. In a purified system, C3 was associated with thinner fibrin fibres and more prolongation of lysis time of clots made from fibrinogen from diabetic participants compared with controls (244±64 and 92±23 s respectively; p<0.05). Confocal microscopy showed higher C3 incorporation into diabetic clots compared with controls, and fully formed clot lysis was prolonged by 764±76 and 428±105 s respectively (p<0.05). Differences in lysis, comparing diabetes and controls, were not related to altered plasmin generation or C3-fibrinogen binding assessed by plasmon resonance. Conclusions/interpretation C3 incorporation into clots from diabetic fibrinogen is enhanced and adversely affects fibrinolysis. This may be one novel mechanism for compromised clot lysis in diabetes, potentially offering a new therapeutic target.

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“…53 The above findings may explain improved clot porosity after continuous subcutaneous insulin infusion, despite no improvement in HbA 1c , as this treatment is typically associated with less hypoglycemic episodes. 32 Therefore, clinical studies investigating the effects of glycemia on cardiovascular event and thrombosis risk should not only rely on HbA 1c but should take into account glucose variability and hypoglycemia, 54 which will only be possible using continuous glucose monitoring. With the development of new continuous glucose devices, a more sophisticated approach to monitoring glycemia is now a real possibility that should be explored in future cardiovascular studies in diabetes.…”

Section: Modulation Of Fibrin-related Thrombosis Risk In Diabetesmentioning

confidence: 99%

“…Initial attempts at optimizing glucose control with continuous subcutaneous insulin infusion were associated with increased plasma fibrin gel porosity, but, unexpectedly, this was not related to an improvement in glycemic control as the fall in HbA 1c was minor and nonsignificant. 32 Subsequent work from our laboratory has shown that a mean drop in HbA 1c by 13 mmol/mol is associated with a decrease in plasma clot final turbidity, indicating the formation of less compact clots. 21 Others have demonstrated that improving glycemic control in 20 subjects with type 2 diabetes has no effect on fibrinogen levels, plasma clot porosity, or turbidity curves but it results in a small reduction in clot compaction.…”

mentioning

confidence: 94%