fibrin and Diabetic-Angiopathies

Accelerated atherosclerosis is the main underlying factor contributing to the high risk of atherothrombotic events in patients with diabetes mellitus and atherothrombotic complications are the main cause of mortality. Like with many bodily systems, pathology is observed when the normal processes are exaggerated or uncontrolled. This applies to the processes of coagulation and thrombosis as well. In diabetes, in fact, the balance between prothrombotic and fibrinolytic factors is impaired and thus the scale is tipped towards a prothrombotic and hypofibrinolytic milieu, which in association with the vascular changes accompanying plaque formation and ruptures, increases the prevalence of ischaemic events such as angina and myocardial infarction. Apart from traditional, modifiable risk factors for cardiovascular disease like hypertension, smoking, elevated cholesterol; rheological properties, endogenous fibrinolysis and impaired platelet activity are rapidly gaining significance in the pathogenesis of atherosclerosis especially in diabetic subjects. Blood clot formation represents the last step in the athero-thrombotic process, and the structure of the fibrin network has a role in determining predisposition to cardiovascular disease. It is no surprise that just like platelets and fibrin networks, erythrocytes have been shown to play a role in coagulation as well. This is in striking contrast to their traditional physiological role of oxygen transport. In fact, emerging evidence suggests that erythrocytes enhance functional coagulation properties and platelet aggregation. Among the spectrum of haematological abnormalities in diabetes, erythrocyte aggregation and decreased deformability of erythrocytes predominate. More importantly, they are implicated in the pathogenesis of microvascular complications of diabetes. The morphology of platelets, fibrin networks and erythrocytes are thus essential role players in unravelling the pathogenesis of cardiovascular complications in diabetic subjects.

Topics: Animals; Atherosclerosis; Blood Coagulation; Blood Platelets; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Erythrocytes; Fibrin; Fibrinolysis; Humans; Plaque, Atherosclerotic; Risk Assessment; Risk Factors; Thrombosis

Diabetes is associated with an increased risk of developing cardiovascular disease, which is not fully accounted for by the accumulation of classic cardiovascular risk factors in patients. Recent evidence has demonstrated fibrinogen to be a powerful independent risk marker for cardiovascular disease in the general population, and it is also likely to contribute toward the increased atherosclerotic risk in diabetes. The etiology of hyperfibrinogenemia in diabetes is likely to be multifactorial, and at present the mechanisms involved have not been clarified. However, insulin, insulin resistance and inflammation are likely to be involved, especially in type 2 diabetes. The influence of diabetes in determining an individual's atherothrombotic risk is likely to extend beyond that of elevated fibrinogen levels, and may also act via changes in the structure and function of the fibrin clot that forms. Further research is needed to determine the mechanisms underlying these changes, which may lead to development of future interventions to reduce the excessive vascular risk associated with this disease.

Topics: Animals; Blood Coagulation; Diabetes Mellitus; Diabetic Angiopathies; Fibrin; Fibrinogen; Humans; Models, Immunological; Signal Transduction

Topics: Arteriosclerosis; Cardiovascular Diseases; Diabetes Mellitus; Diabetic Angiopathies; Fibrin; Fibrinogen; Fibrinolysis; Humans; Plasminogen Activator Inhibitor 1; Risk Factors

This article reviews the evidence supporting a relationship between an enhanced tissue injury, increased fibrin formation, defective fibrinolysis, and the evolution of the complications of late diabetic disease. Particular attention is drawn to the role of a defective endothelial cell mediated fibrinolysis with respect to increased fibrin formation and a delayed tissue repair in diabetic patients. Reviewed are studies that indicate that it is possible in patients with diabetes by means of sulfonylurea compounds to increase endothelial cell-produced t-PA without affecting PAI-1. It is advocated that potent compounds should be searched for, with the capability to modify the hemostatic process of the diabetic endothelial cell in order to express more fibrinolytic activity independent of the patient's metabolic state in an attempt to delay the complications of late diabetes.

Topics: Diabetes Mellitus; Diabetic Angiopathies; Fibrin; Fibrinolysis; Humans

Patients with diabetes mellitus (DM) exhibit increased risk of recurrent myocardial infarction. Maximal clot strength measured by thrombelastography (TEG) is a risk factor for recurrent ischemic events. We hypothesized that diabetic subjects exhibit increased fibrin clot strength in platelet-poor plasma and that glycemic control correlates with maximal fibrin clot strength.. We collected plasma samples from subjects with known or suspected coronary artery disease undergoing cardiac catheterization (. Plasma fibrin MA was increased among subjects with DM (. Subjects with diabetes mellitus exhibit increased maximal fibrin clot strength measured by TEG in platelet-poor plasma.

Topics: Adult; Aged; Blood Coagulation; Case-Control Studies; Diabetes Mellitus; Diabetic Angiopathies; Female; Fibrin; Humans; Male; Middle Aged; Thrombelastography; Thrombosis

Type 2 diabetes mellitus (T2DM) increases the risk of coronary thrombosis and both conditions are associated with altered fibrin clot properties. However, the influence of T2DM on fibrin clot properties in patients with coronary artery disease (CAD) remains unclear. We aimed to investigate the influence of T2DM on fibrin clot properties in patients with CAD. Fibrin clot structure and fibrinolysis were investigated in 581 CAD patients (148 with T2DM) using turbidimetric assays, confocal and scanning electron microscopy. Clots made from plasma and plasma-purified fibrinogen were studied, and plasma levels of inflammatory markers were analysed. T2DM patients had increased clot maximum absorbance compared with non-diabetic patients (0.36 ± 0.1 vs 0.33 ± 0.1 au; p=0.01), displayed longer lysis time (804 [618;1002] vs 750 [624;906] seconds; p=0.03) and showed more compact fibrin structure assessed by confocal and electron microscopy. Fibrinogen levels were elevated in T2DM (p< 0.001), but clots made from purified fibrinogen showed no differences in fibrin properties in the two populations. Adjusting for fibrinogen levels, T2DM was associated with C-reactive protein and complement C3 plasma levels, with the former correlating with clot maximum absorbance (r=0.24, p< 0.0001) and the latter with lysis time (r=0.30, p< 0.0001). Independent of fibrinogen levels, females had more compact clots with prolonged lysis time compared with males (all p-values< 0.001). In conclusion, T2DM is associated with prothrombotic changes in fibrin clot properties in patients with CAD. This is related to quantitative rather than qualitative changes in fibrinogen with a possible role for inflammatory proteins.

Topics: Aged; Aspirin; Blood Coagulation Tests; C-Reactive Protein; Case-Control Studies; Complement C3; Coronary Artery Disease; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Fibrin; Fibrinogen; Fibrinolysis; Humans; Inflammation Mediators; Male; Microscopy, Confocal; Microscopy, Electron, Scanning; Middle Aged; Nephelometry and Turbidimetry; Platelet Aggregation Inhibitors; Registries; Risk Factors; Sex Factors; Time Factors

The development and progression of diabetic retinopathy (DR) in type 2 diabetes mellitus (T2DM) have been associated with poor glycaemic control, long disease duration and other clinical features. However, the pathogenesis of the complication is still poorly understood. As the formation of dense fibrin clots resistant to lysis has been described in diabetes patients, this study tested the hypothesis that altered clot structure and function are associated with DR in T2DM patients.. The study included 101 T2DM subjects without DR (NDR) and 60 with DR. Plasma fibrin-clot permeation was assessed using a pressure-driven system, and expressed as the permeation coefficient (K(s)), indicating pore size, and as the time required for a 50% decrease in clot turbidity (t(50%)) as a marker of susceptibility to fibrinolysis. All patients underwent ophthalmological examination. Clinical and biochemical co-variables were also measured. Determinants of DR were identified using stepwise, multivariable, logistic-regression analyses.. Patients with DR had lower clot permeability (K(s): 6.15 ± 1.18 vs. 7.53 ± 1.24 10(-9) cm(2); P < 0.0001) and slower fibrin-clot lysis (t(50%): 10.12 ± 1.24 vs. 9.12 ± 1.4 min; P < 0.0001) than NDR subjects. Logistic analysis revealed associations between DR and K(s), t(50%), fasting glucose and diabetes duration, as well as insulin treatment and statin non-use (P < 0.05). After adjusting for these variables as well as for age and gender, associations between K(s) and t(50%) with DR proved to be significant.. Formation of compact fibrin clots and impaired clot lysis are both associated with DR in T2DM patients. However, it is unclear whether these abnormalities lead to the development of DR or merely constitute a marker of its presence.

Topics: Biomarkers; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Retinopathy; Female; Fibrin; Humans; Male; Middle Aged; Risk Factors

Diabetes is associated with increased risk of cardiovascular disease. Advanced glycation end-products (AGEs) are considered to be a major pathogenic factor for diabetic vascular complications. The levels of AGEs are increased in diabetic patients. We have studied the presence of the major AGE methylglyoxal (MGO)-derived hydroimidazolone in human aorta and carotid arteries, using immunohistochemistry (IHC), western blotting and mass spectrometry. By IHC, MGO-derived modifications were detected mainly associated with cells in intimal thickenings and cells in microvessels in adventitia. In type V lesions MGO-derived AGE was also present, extracellular in the necrotic core and in cells at the border of the core. The highest degree of modification was probably associated with cell nuclei. By western blotting and mass spectrometry fibrin(ogen), the cytoskeleton-associated protein moesin and the nuclear proteins lamin A and C were identified as putative main targets for MGO-derived modification. LC-MS/MS studies of fibrin(ogen) modified in vitro with low concentrations of MGO identified the sites that were most prone to modification. These results indicate that AGE modifications occur preferentially on specific proteins. The modification of these proteins may play a role in vascular dysfunction and development of atherosclerosis in diabetes.

Topics: Aged; Aged, 80 and over; Amino Acid Sequence; Aorta; Blotting, Western; Carotid Artery, Common; Case-Control Studies; Chromatography, Liquid; Diabetic Angiopathies; Elasticity; Female; Fibrin; Fibrinogen; Glycation End Products, Advanced; Humans; Imidazoles; Immunohistochemistry; Male; Middle Aged; Molecular Sequence Data; Necrosis; Norway; Protein Processing, Post-Translational; Proteomics; Pyruvaldehyde; Tandem Mass Spectrometry

Acute hyperglycemia on admission for acute coronary syndrome worsens the prognosis in patients with and without known diabetes. Postulated mechanisms of this observation include prothrombotic effects. The aim of this study was to evaluate the effect of elevated glucose levels on blood clotting in acute coronary syndrome patients.. We studied 60 acute coronary syndrome patients within the first 12 h after pain onset, including 20 subjects with type 2 diabetes, 20 subjects with no diagnosed diabetes but with glucose levels >7.0 mmol/l, and 20 subjects with glucose levels <7.0 mmol/l. We determined generation of thrombin-antithrombin complexes (TATs) and soluble CD40 ligand (sCD40L), a platelet activation marker, at the site of microvascular injury, together with ex vivo plasma fibrin clot permeability and lysis time.. The acute coronary syndrome patients with no prior diabetes but elevated glucose levels had increased maximum rates of formation and total production of TATs (by 42.9%, P < 0.0001, and by 25%, P < 0.0001, respectively) as well as sCD40L release (by 16.2%, P = 0.0011, and by 16.3%, P < 0.0001, respectively) compared with those with normoglycemia, whereas diabetic patients had the highest values of TATs and sCD40L variables (P < 0.0001 for all comparisons). Patients with hyperglycemia, with no previously diagnosed diabetes, had longer clot lysis time (by approximately 18%, P < 0.0001) similar to that in diabetic subjects, but not lower clot permeability compared with that in normoglycemic subjects.. Hyperglycemia in acute coronary syndrome is associated with enhanced local thrombin generation and platelet activation, as well as unfavorably altered clot features in patients with and without a previous history of diabetes.

Topics: Acute Coronary Syndrome; Acute Disease; Aged; Blood Coagulation; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Fibrin; Fibrinolysis; Humans; Hyperglycemia; Hypoglycemic Agents; Male; Middle Aged; Myocardial Infarction; Platelet Activation; Prognosis; Thrombin

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.. Fibrin clots were formed from fibrinogen purified from 150 subjects with type 2 diabetes and varying degrees of glycaemic control (assessed by HbA1c), 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.. 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; HbA1c correlated negatively with permeation coefficient (Ks) 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 (> or = 10 mmol/l) were both associated with a reduction in Ks values and maximum absorbance, and with increased fibre density and branch point number within clots.. 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.

Topics: Blood Coagulation; Body Mass Index; Body Size; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Factor XIII; Female; Fibrin; Fibrinogen; Humans; Hypoglycemic Agents; Lipids; Male; Middle Aged; Reference Values; Risk Factors

The antihyperglycemic drug dimethylbiguanide (DMB, also known as metformin) reduces the risk of cardiovascular complications in type 2 diabetes, although the mechanism(s) involved are unclear. DMB reduces glycosylation-related protein cross-linking, a process similar to fibrin cross-linking catalyzed by activated factor XIII (FXIII). To investigate whether the cardioprotective effect of DMB could be related to effects on clot stabilization, we studied the effects of DMB on FXIII, thrombin activity, and cleavage of fibrin(ogen). Activity of purified and plasma FXIII was inhibited by DMB. Analysis by mass spectrometry and FXIII-coupled magnetic particles excluded binding of DMB to FXIII. Thrombin-induced cleavage of the activation peptide from FXIII was inhibited in a dose-dependent manner, as was fibrinopeptide cleavage from fibrinogen. Ancrod-induced cleavage of fibrinopeptide A was not affected. DMB prolonged clotting time of normal plasma. Fiber thickness and pore size of fibrin clots, measured by permeation experiments and visualized by scanning electron microscopy, decreased significantly with DMB. No interactions between DMB and the active site of thrombin were found. Turbidity experiments demonstrated that DMB changed polymerization and lateral aggregation of protofibrils. These results suggest that DMB interferes with FXIII activation and fibrin polymerization, but not only by binding to thrombin on a different location than the active site. In patients on DMB therapy, FXIII antigen and activity levels in vivo were reduced over a 12-week period. These findings indicate that part of the cardioprotective effect of DMB in patients with type 2 diabetes may be attributed to alterations in fibrin structure/function.

Topics: Blood Coagulation; Cardiotonic Agents; Diabetic Angiopathies; Enzyme Activation; Factor XIII; Fibrin; Fibrinogen; Humans; Hypoglycemic Agents; Kinetics; Metformin; Thrombin

Estimations of soluble fibrin monomer complexes (SFMC) in plasma are a convenient index of thrombin activation. Renal venous-arterial differences in plasma SFMC concentrations were determined in 16 randomly chosen diabetic patients by sampling directly and simultaneously from the renal artery and vein according to the method of Seldinger. In all subjects, SFMC concentrations were higher in the renal vein than in the renal artery, indicating that the kidney is an important source of SFMC. Venous-arterial differences were markedly elevated in patients with severe renal and retinal microangiopathy coupled with hypertension. The hypothesis is advanced that elevated plasma SFMC levels lead to abnormal fibrin deposits in lesioned glomeruli and retinal vessels. It is postulated that plasma SFMC may be a useful parameter for the assessment of diabetic vascular complications.

Topics: Adult; Aged; Blood Pressure; Diabetic Angiopathies; Diabetic Retinopathy; Female; Fibrin; Fibrinogen; Humans; Kidney Glomerulus; Male; Middle Aged; Renal Artery; Renal Veins; Thrombin

We studied the relationship between plasma soluble fibrin monomer complexes (SFMC) and diabetic microangiopathy. SFMC concentrations were investigated in 7 patients with advanced retinopathy (group II) and in 10 patients with both retinopathy and proteinuria (group III), and also in 12 control patients (group I). The age of the patients in each group was similar and overnight fasting blood sugar levels were below 220 mg/dl. Group II had higher levels of SFMC (21.8-3.8 mg/dl) than group I (7.3-4.8 m/dl). Group III showed the higher value of blood urea nitrogen (BUN) than other groups and showed higher levels of SFMC (31.5-12.3 mg/dl) than group II. There was no significant correlation between the levels of SFMC and blood sugar, but positive correlation between BUN concentrations and SFMC was recognized in group III. Increasing of SFMC levels were correlated to fibrinogen (Fbg) levels in all subjects. There was no correlation between the levels of SFMC and antithrombin (AT-III) except in group II. The 24-h urinary protein was significantly correlative to SFMC, and Fbg was also considered to be closely associated with microangiopathy and act to promote it.

Topics: Adult; Aged; Blood Urea Nitrogen; Creatinine; Diabetic Angiopathies; Diabetic Retinopathy; Female; Fibrin; Fibrinogen; Humans; Macromolecular Substances; Male; Middle Aged; Proteinuria; Solubility

Data from the literature concerning the frequent lack of correlation between the clinical manifestations of diabetic neuropathy on the one hand and the morphofunctional status of the appropriate nerves, disorders in carbohydrate and lipid metabolism, and the influence of antidiabetic therapy on metabolism and the clinical picture of diabetic neuropathy on the other, are presented. In this connection, abundant evidence of frequent affection of various blood vessels, particularly small and smallest, in diabetic neuropathy is considered. But even these data attest to a non-infrequent lack in diabetic neuropathy of the involvement of the appropriate vessels, particularly the lack of basal membrane thickening which is a most common indication to the diabetic involvement of capillaries. Attention is drawn to the possible role of genetic heterogeneity of people with regard to the development of various forms of diabetic neuropathy.

Topics: Adult; Aged; Basement Membrane; Blood Vessels; Chronic Disease; Diabetic Angiopathies; Diabetic Neuropathies; Diabetic Retinopathy; Endothelium; Fibrin; Gangrene; Humans; Microcirculation; Middle Aged; Nerve Fibers; Nervous System

Topics: Adult; Age Factors; Aged; Arteries; Blood Flow Velocity; Blood Pressure; Blood Vessels; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Retinopathy; Female; Fibrin; Fibrinogen; Fibrinolysis; Humans; Leg; Male; Middle Aged; Obesity; Plasminogen; Plethysmography, Impedance; Regional Blood Flow; Thrombophlebitis

Topics: Adolescent; Adult; Aged; Arteriosclerosis; Blood Coagulation Disorders; Blood Coagulation Tests; Diabetes Complications; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Fibrin; Fibrinogen; Half-Life; Humans; Iodine Radioisotopes; Middle Aged

This describes the sodium sulphate-Alcian Blue (SAB) method for staining amyloid in paraffin sections. Its value lies in the possibility of subsequent counterstaining and thus of revealing the structural relationships of amyloid. In the kidney the topical disposition of amyloid closely resembles the disposition of fibrin in the kidney of diabetics; this suggests that upset in vascular permeability plays a part in determining the site of the amyloid deposits. Furthermore, an aging process in amyloid can now be envisaged resembling the aging of extraluminal fibrin. Both materials proceed to a hyalin material that, staining like collagen, merits the name pseudo-collagen. This term we apply to a hyalin, staining like collagen, for which, we can postulate a specific precursor.

Topics: Amyloid; Amyloidosis; Collagen; Diabetes Mellitus; Diabetic Angiopathies; Fibrin; Histological Techniques; Humans; Hyalin; Kidney; Kidney Diseases; Microscopy; Staining and Labeling

Topics: Arteriosclerosis; Arteriosclerosis Obliterans; Blood Vessels; Collagen; Connective Tissue; Diabetic Angiopathies; Elastic Tissue; Embolism; Endarteritis; Fibrin; Humans; Hyalin; Ischemia; Necrosis; Vasa Vasorum