fibrin and Diabetes-Mellitus

Fibrinogen is a unique protein that is converted into an insoluble fibrin in a single enzymatic event, which is a characteristic feature of fibrinogen due to its susceptibility to fibrinolytic degradation and dissolution. Although thrombosis is a result of activated blood coagulation, no explanation is being offered for the persistent presence of fibrin deposits in the affected organs. A classic example is stroke, in which the thrombolytic therapy is effective only during the first 3-4 h after the onset of thrombosis. This phenomenon can now be explained in terms of the modification of fibrinogen structure induced by hydroxyl radicals generated during the period of ischemia caused, in turn, by the blocking of the blood flow within the obstructed vessels. Fibrinogen modification involves intra-to intermolecular disulfide rearrangement induced by the reductive power of hydroxyl radicals that result in the exposition of buried hydrophobic epitopes. Such epitopes react readily with each other forming linkages stronger than the peptide covalent bonds, thus rendering them resistant to the proteolytic degradation. Also, limited reduction of human serum albumin (HSA) generates hydrophobic polymers that form huge insoluble complexes with fibrinogen. Consequently, such insoluble copolymers can be deposited within the circulation of various organs leading to their dysfunction. In conclusion, the study of protein hydrophobic interactions induced by a variety of nutritional and/or environmental factors can provide a rational explanation for a number of pathologic conditions including cardiovascular, neurologic, and other degenerative diseases including cancer.

Topics: Animals; Arthritis; Cardiovascular Diseases; Diabetes Mellitus; Fibrin; Fibrinogen; Fibrinolysis; Humans; Hydrophobic and Hydrophilic Interactions; Kidney Diseases; Lung Diseases; Models, Biological; Neoplasms; Nervous System Diseases; Polymerization; Protein Interaction Domains and Motifs; Serum Albumin, Human; Solubility; Thrombosis

Despite advances in therapy, individuals with diabetes remain at high risk of cardiovascular disease and their clinical prognosis following vascular ischemia is worse than that of individuals with normal glucose metabolism. Current evidence suggests that the enhanced thrombotic environment in diabetes represents a key abnormality contributing to the adverse clinical outcome following vascular occlusion in this population. Thrombus formation occurs following a complex process that encompasses both the cellular (represented by platelets) and fluid phase of coagulation, involving a large number of plasma proteins. In the current review, we discuss some of the abnormalities encountered in coagulation factor levels or activity in diabetes. In particular, we focus on the pathological processes that lead to the formation of compact fibrin networks with increased resistance to lysis. We describe current knowledge on the mechanistic pathways responsible for the increased fibrin‑related thrombosis risk in diabetes and explore alternative therapeutic targets. We also briefly cover various management strategies that may help control the enhanced thrombotic milieu in this population of patients at high cardiovascular risk.

Topics: Diabetes Mellitus; Fibrin; Humans; Risk Factors; Thrombosis

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. The formation of a fibrin clot is one of the key events in atherothrombotic vascular disease. This review discusses how genetic and environmental factors alter fibrin structure and function and the implications this has for the clinical presentation of vascular disease.

Topics: Afibrinogenemia; Arteriosclerosis; Blood Coagulation; Diabetes Mellitus; Factor XIII; Fibrin; Fibrinogen; Fibrinolysis; Glycosylation; Humans; Hyperhomocysteinemia; Life Style; Lipoproteins; Polymorphism, Genetic; Protein Conformation; RNA Splicing; Structure-Activity Relationship; 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

Fibrinogen is a protein synthesised by the liver. It is converted by thrombin to an insoluble fibrin network to induce, together with platelet aggregates, haemostasis in response to rupture of endothelium. This change includes several steps and implied factor XIII. Molecular properties of fibrin are responsible for its important role in hemostasis which goes beyond the one of a simple final inert product of coagulation. In fact, fibrin regulates thrombin and factor XIII activities and its own destruction also called fibrinolysis. The multiple domains of fibrinogen and fibrin confer a role not only in haemostasis but also in wound healing, cellular migration and proliferation, due to interactions with endothelial cells, leukocytes and components of the extracellular matrix. Fibrin must be removed once its haemostatic role has been reached. The fibrinolytic process takes place in the vessel lumen. It is strongly regulated by the plasma concentration of an inhibitor called plasminogen activator inhibitor-1 (PAI-1) which synthesis strongly increases in obese insulin resistant and diabetic patients. Data from animal models show that increased PAI-1 production represents a prothrombotic state. Fibrinolysis plays also a role in tissue remodeling (vascular wall, placenta, adipose tissue....) by degrading the extracellular matrix, by activating growth factors or modifying cellular adhesion and migration properties. It has been proposed that PAI-1 in excess could be directly responsible for the development of atherothrombosis in insulin resistant subjects. Moreover recent results from transgenic mice indicate that PAI-1 in excess interferes also with weight gain. These data point out the importance of the haemostatic system in the extra vascular phenomenon of tissue remodeling.

Topics: Animals; Arteriosclerosis; Carboxypeptidase B2; Cell Movement; Diabetes Mellitus; Disease Models, Animal; Endothelial Cells; Factor XIII; Fibrin; Fibrinogen; Fibrinolysis; Hemostasis; Humans; Insulin Resistance; Metalloproteases; Mice; Mice, Transgenic; Plasminogen Activator Inhibitor 1; Risk Factors; Thrombin; Thrombosis; Wound Healing

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

Topics: Arachidonic Acids; Arteriosclerosis; Aspirin; Blood Platelets; Calcium; Coronary Disease; Cyclic AMP; Diabetes Mellitus; Dietary Fats; Female; Fibrin; Humans; Myeloproliferative Disorders; Nephrotic Syndrome; Oxygenases; Platelet Adhesiveness; Platelet Aggregation; Pre-Eclampsia; Pregnancy; Prostaglandins; Thrombosis

Topics: Animals; Antibodies; Basement Membrane; Blood Glucose; Collagen; Diabetes Mellitus; Fibrin; Glycoproteins; Humans; Hydroxylysine; Kidney Glomerulus; Permeability

The replicative capacity of cultured human fibroblasts is discussed in relation to three areas, diabetes mellitus, expression of HL-A antigens, and interactions with polymerizing fibrin. The replicative capacity of cells is dimished in diabetes mellitus and certain related disorders such as progeria and Werner's syndrome, all of which feature accelerated aging. Expression of HL-A antigens is reduced in progeria fibroblasts compared to normal cultures at corresponding stages of passage. Normal cells show more subtle alteration during aging in vitro probably related to clonal heterogeneity and/or selection within mass cultures. Early-passage fibroblasts interact rapidly with polymerizing fibrin to form a mature clot which is then retracted by a process dependent on cellular integrity and active metabolism. Late-passage cultures are less active in both parameters as are fibroblasts from a subject with progeria. These observations, in total, may relate to altered self-recognition and certain autoimmune concomitants of aging in vivo. They may also help to explain impaired wound healing and increased predisposition to atherothrombosis in aging and diabetic individuals. This system of cultured human fibroblasts should serve as an excellent model to investigate the cellular and molecular basis of diabetes mellitus, aging and related pathology.

Topics: Adolescent; Adult; Aged; Aging; Carbohydrate Metabolism, Inborn Errors; Cell Division; Cell Survival; Cells, Cultured; Child; Clone Cells; Diabetes Mellitus; Fibrin; Fibroblasts; Glucose; HLA Antigens; Humans; Models, Biological; Progeria; Werner Syndrome

The activation of blood coagulation leads to the formation of thrombin that, in turn, converts soluble plasma fibrinogen into insoluble fibrin clot. In healthy individuals, fibrin is effectively degraded; however, in prothrombotic states, proteolysis of fibrin clots are often delayed or even inhibited, and is associated with altered fibrin structure. We have previously shown that in inflammatory conditions like stroke and diabetes, this fibrin forms dense matted deposits. Although there are several factors that modify fibrin structure and delay fibrinolysis in these conditions, no mechanism is yet known to be responsible for a persistent presence of thrombi in the coronary and/or cerebral circulations. It seems, therefore, desirable to better understand this phenomenon in order to improve the effectiveness of thrombolytic therapies. Here, we show that ferric ions can activate non-enzymatic blood coagulation resulting in the formation of fibrin-like dense matted deposits (DMD) demonstrable by electron scanning microscopy (SEM). These DMDs are similar to those found in stroke and diabetes. On the basis of these findings we can conclude that the spontaneous formation of fibrin-like dense deposits in patients' blood may be a consequence of what is known as iron overload. Therefore, it is possible that inactivation of unbound iron in blood by small molecular weight chelating agents may prevent thrombotic consequences of the excessive accumulation of iron in the circulation.

Topics: Blood Coagulation; Diabetes Mellitus; Female; Ferric Compounds; Fibrin; Humans; Iron Chelating Agents; Iron Overload; Male; Stroke; Thrombin; Thrombosis

This study investigated the effect of L-PRF on promoting full-thickness skin grafting for the treatment of diabetic foot ulcer wounds and attempted to characterize the mechanism. In a retrospective study, we centrifugated 10-20 ml of venous blood at 1006.2 g for 20 min. The fibrin clot between the top oligocellular plasma layer and the bottom erythrocyte layer was extracted and directly used, without compression, to cover the wound after debridement. Patients who received L-PRF before skin grafting underwent surgery earlier than patients in the control group. Skin necrosis occurred in 7 patients (28%) in the L-PRF group and 16 (64%) in the control group. The difference was statistically significant, P < .05. The postoperative infection rate in the control group (56%) was significantly higher than that in the L-PRF group (24%), P < .05. During a mean follow-up of 1 year, ulcer recurrence occurred in 9 patients (36%) in the control group compared with 4 patients (16%) in the L-PRF group, P < .05. The final amputation rate was also higher in the control group (48%) than in the L-PRF group (20%). The difference is statistically significant, P < .05. The Maryland scale score and SF-36 score of the two groups of patients after treatment were significantly better than those before treatment, and the difference was statistically significant (P < .05). The L-PRF group (94.80 ± 4.14) had better foot scores at the last follow-up after treatment than the control group (88.84 ± 5.22) (P < .05). The results showed that L-PRF played a positive role in the treatment of Wagner grade 4 ulcer gangrene with free full-thickness skin grafts.. What is the context?● Diabetic foot is a serious complication in the later stage of the disease course of diabetic patients. The incidence rate is increasing year by year. In severe cases, it can lead to amputation or even death.● For diabetic ulcer wounds, dressings such as L-PRF or autologous fat are often used in the initial stage to speed up wound healing. For advanced wounds, especially patients with local tissue gangrene, simple wound dressings cannot meet the needs of wounds. People often use skin flaps or different types of skin grafts to treat advanced wounds.● Flap or skin grafting has been shown to be effective, but because of the patient’s own neurovascular injury and infection, the rate of graft necrosis and ulcer recurrence is extremely high. What is new?● This study discusses the treatment of advanced wounds in diabetes. After thorough debridement and before skin grafting, we first covered the wound with L-PRF and observed the wound condition. Studies have shown that the use of L-PRF can allow the original poor wound to be reconstructed: the content of growth factors and growth-related cells is increased, blood circulation is improved and granulation tissue growth, bone and tendon exposure is improved, and infection is controlled. What is the impact?● This study provides evidence that using L-PRF to reconstruct wounds can greatly shorten the preparation time for elective surgery. Reconstructed wounds can better accept free skin grafts, and the incidence of postoperative complications and amputation (particularly, toe amputation) is also lower.

Topics: Diabetes Mellitus; Diabetic Foot; Fibrin; Gangrene; Humans; Leukocytes; Retrospective Studies; Skin Transplantation; Toes; Wound Healing

A non-healing wound is a common problem associated with diabetes mellitus. Chronic inflammation, challenging re-epithelization, unusual growth factors, and impaired angiogenesis are the multifactorial events that contribute to impaired wounds. Hence, in the present work, an innovative GA-CSNPs nanocomposite scaffold has been fabricated by integrating Gallic acid (GA) loaded chitosan nanoparticles (GA-CSNPs) into a genipin crosslinked collagen-fibrin (Col-fibrin) scaffold as wound dressing material. The in vitro RT-PCR study carried out using NIH/3T3 mouse fibroblast cells showed that treatment with GA-CSNPs nanocomposite scaffold aids in an upsurge in the expression of Col-I, III, and VEGF, which further supports the synthesis of extracellular matrix, increases neovascularization and development of the established vascular system. In vivo wound contraction study results revealed that diabetic wounds treated with GA-CSNPs nanocomposite scaffold show a faster rate of wound closure (p < .001), histopathology results showed accelerated fibroblast cell migration, reduction of the inflammatory cells, enhanced collagen along with hexosamine synthesis. In addition, immunohistochemistry results showed increased vascularization, a significant decrease in macrophage recruitment, and reduced expression of MMP-9 compared to the Col-fibrin scaffold and Control groups. Overall data suggest that the fabricated GA-CSNPs nanocomposite porous 3-D scaffold can be a hopeful therapeutic choice for diabetic wound management.

Topics: Animals; Collagen; Diabetes Mellitus; Fibrin; Gallic Acid; Mice; Nanocomposites; Wound Healing

Topics: Cataract; Cataract Extraction; Diabetes Mellitus; Fibrin; Humans; Pupil Disorders

Standard biomarkers have been widely used for COVID-19 diagnosis and prognosis. We hypothesize that thrombogenicity metrics measured by thromboelastography will provide better diagnostic and prognostic utility versus standard biomarkers in COVID-19 positive patients. In this observational prospective study, we included 119 hospitalized COVID-19 positive patients and 15 COVID-19 negative patients. On admission, we measured standard biomarkers and thrombogenicity using a novel thromboelastography assay (TEG-6s). In-hospital all-cause death and thrombotic occurrences (thromboembolism, myocardial infarction and stroke) were recorded. Most COVID-19 patients were African--Americans (68%). COVID-19 patients versus COVID-19 negative patients had higher platelet-fibrin clot strength (P-FCS), fibrin clot strength (FCS) and functional fibrinogen level (FLEV) (P ≤ 0.003 for all). The presence of high TEG-6 s metrics better discriminated COVID-19 positive from negative patients. COVID-19 positive patients with sequential organ failure assessment (SOFA) score at least 3 had higher P-FCS, FCS and FLEV than patients with scores less than 3 (P ≤ 0.001 for all comparisons). By multivariate analysis, the in-hospital composite endpoint occurrence of death and thrombotic events was independently associated with SOFA score more than 3 [odds ratio (OR) = 2.9, P = 0.03], diabetes (OR = 3.3, P = 0.02) and FCS > 40 mm (OR = 3.4, P = 0.02). This largest observational study suggested the early diagnostic and prognostic utility of thromboelastography to identify COVID-19 and should be considered hypothesis generating. Our results also support the recent FDA guidance regarding the importance of measurement of whole blood viscoelastic properties in COVID-19 patients. Our findings are consistent with the observation of higher hospitalization rates and poorer outcomes for African--Americans with COVID-19.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Black or African American; Cardiovascular Diseases; Comorbidity; COVID-19; COVID-19 Testing; Diabetes Mellitus; Early Diagnosis; Female; Fibrin; Fibrin Clot Lysis Time; Fibrinogen; Hospitalization; Humans; Hyperlipidemias; L-Lactate Dehydrogenase; Male; Middle Aged; Obesity; Organ Dysfunction Scores; Prognosis; Prospective Studies; SARS-CoV-2; Thrombelastography; Thrombophilia; Treatment Outcome; White People

Subjects with diabetes mellitus (DM) have an increased risk of arterial thrombosis, to which changes in clot structure and mechanics may contribute. Another contributing factor might be an increased formation of neutrophil extracellular traps (NETs) in DM. NETs are mainly formed during the acute phase of disease and form a network within the fibrin matrix, thereby influencing clot properties. Previous research has shown separate effects of NETs and DM on clot properties, therefore our aim was to study how DM affects clot properties in a model resembling an acute phase of disease with NETs formation. Clots were prepared from citrated plasma from subjects with and without DM with the addition of NETs, induced in neutrophils by

Topics: Adult; Biomechanical Phenomena; Blood Coagulation; Diabetes Complications; Diabetes Mellitus; Elastic Modulus; Extracellular Traps; Female; Fibrin; Fibrinolysis; Humans; Male; Middle Aged; Thrombosis

Leukocyte- and platelet-rich fibrin (L-PRF) represents a natural, low-cost product which may promote tissue healing by mechanisms not fully elucidated. Diabetes mellitus (DM) disrupts bone healing by inducing inflammation and oxidative stress (OS), mechanisms regulated by microRNAs (miRs). The aim of the present study was to investigate the microRNA-21 (miR-21) involvement in diabetic bone regeneration using L-PRF alone or in combination with a standard grafting material.. After the induction of diabetes (alloxan 100 mg/kg), four cranial osteotomies were made in diabetic (n = 12) and non-diabetic (n = 12) rabbits: one was left empty and the remaining three were grafted with L-PRF, bovine hydroxyapatite (Bio-Oss. Diabetic rabbits showed decreased miR-21 and matrix metalloproteinase-9 (MMP-9) protein expression while increased malondialdehyde (MDA) levels two weeks postoperatively; however, there were no significant differences in miR-21 and MMP-9 levels between diabetic and non-diabetic rabbits in samples taken eight weeks postoperatively. Application of L-PRF and L-PRF + Bio-Oss. L-PRF alone or in combination with bovine hydroxyapatite as bone graft could be beneficial in DM since it seems to improve inflammation-modulatory miR-21 expression and decreases oxidative stress.

Topics: Animals; Blood Platelets; Cattle; Diabetes Mellitus; Fibrin; MicroRNAs; Oxidative Stress; Platelet-Rich Fibrin; Rabbits

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

This study aimed to investigate the effect of platelet-rich fibrin on bone regeneration in critical size defects in the calvaria of diabetic rabbits.. In total, 40 male New Zealand rabbits, were divided into two groups a non-diabetic control group (Group A) and a diabetic experimental group (Group B). Two bicortical circular defects 15 mm in diameter were created in the parietal bone of each animal. Each group was further divided into four groups: subgroup E, the defect was left empty; subgroup PRF, the defects were filled only with PRF; subgroup AB, the defects were filled with autogenous bone; subgroup AB + PRF, the defects were filled with autogenous bone combined with PRF. The animals sacrificed at 4 weeks and 8 weeks. Bone formation was assessed by micro-computed tomography (micro-CT) scanning, histological and histomorphometric analysis.. The total percent of new bone was the lowest in group A-E (6.77 ± 0.21 at 4 weeks, 11.01 ± 0.37 at 8 weeks) and highest in group A-AB + PRF (21.66 ± 0.91 at 4 weeks, 37.46 ± 1.25 at 8 weeks; p < 0.05). The mean percent of new bone was greatest in group B-AB + PRF at 4 and 8 weeks (16.87 ± 0.92, 29.59 ± 1.09, respectively) and lowest in group B-E (5.83 ± 0.09 at 4 weeks, 7.36 ± 1.02 at 8 weeks).. This study, despite its limitations, showed that PRF can be used safely and that PRF induced bone healing in diabetic rabbits.

Topics: Animals; Blood Platelets; Bone Regeneration; Diabetes Mellitus; Fibrin; Male; Platelet-Rich Fibrin; Rabbits; X-Ray Microtomography

Preclinical evaluation of the vascular response of drug-eluting stents is limited especially in the setting of diabetes mellitus preventing the evaluation of changes in drug-eluting stent design and eluted drugs after clinical use.. Cultured human aortic endothelial cells were used to assess the differences between sirolimus and its analog, everolimus, in the setting of hyperglycemia on various cellular functions necessary for endothelial recovery. A diabetic rabbit model of iliac artery stenting was used to compare histological and morphometric characteristics of the vascular response to everolimus-eluting, sirolimus-eluting, and bare metal stent placement. Under hyperglycemic conditions, sirolimus impaired human aortic endothelial cell barrier function, migration, and proliferation to a greater degree compared with everolimus. In our in vivo model of diabetes mellitus, endothelialization at 28 days was significantly lower and endothelial integrity was impaired in sirolimus-eluting stent compared with both everolimus-eluting and bare metal stents. Neointimal area, uncovered struts, and fibrin deposition were significantly higher in sirolimus-eluting compared with everolimus-eluting and bare metal stents.. Use of everolimus-eluting stent results in improved vascular response in our preclinical models of diabetes mellitus.

Topics: Animals; Aorta; Cell Movement; Cells, Cultured; Diabetes Mellitus; Disease Models, Animal; Drug-Eluting Stents; Endothelial Cells; Everolimus; Fibrin; Humans; Hyperglycemia; Iliac Artery; Male; Neointima; Rabbits; Sirolimus

Topics: Cell Shape; Chlorides; Diabetes Mellitus; Erythrocytes; Ferric Compounds; Ferritins; Fibrin; Humans; Iron; Microscopy, Electron, Scanning; Transferrin

Fibrinogen (FBG) is a high-molecular-weight protein and precursor to the enzymatically formed fibrin. It has been recently discovered that FBG can be converted into an insoluble, fibrin-like polymer by a nonenzymatic action of hydroxyl radicals (HRs). These free radicals are generated due to the reaction between hydroxyl groups of water and trivalent ferric ions without the participation of any redox agent. The interaction between HRs and FBG occurs in a purified system, as well as in human plasma and in whole blood. Scanning electron microscopy (SEM) of thrombin-induced fibers and those generated with ferric chloride has shown substantial differences in their morphology and susceptibility to enzymatic degradation. Fibrin strands caused by thrombin are thick and easily digested with chymotrypsin. By contrast, the dense matted deposits formed from FBG in the presence of ferric ions are remarkably resistant to proteolytic and chemical degradations due to the presence of intermolecular hydrophobic bonds. Thus, we postulate that this iron-catalyzed reaction represents a novel blood coagulation pathway operating in degenerative diseases. By means of SEM, we showed the presence of dense fibrin-like deposits in the blood of diabetic patients. Therefore, the prothrombotic state and cardiovascular complications observed in diabetes can be explained in terms of the persistent in vivo action of free iron. This phenomenon may explain hemorheologic disturbances in patients with metabolic syndrome and other diseases caused by iron overload. Of note, HRs can be effectively scavenged by phenolic substances; therefore, certain natural polyphenolic substances, which also scavenge HRs, may be considered to have a potential antidiabetic effect. Moreover, natural or synthetic iron-binding substances may also be considered as a new class of antidiabetic drugs.

Topics: Blood Coagulation; Diabetes Complications; Diabetes Mellitus; Fibrin; Fibrinogen; Humans; Iron; Iron Overload

Maximum engraftment of transplanted islets is essential for the clinical application of a subcutaneous site. Significant barriers to the current approaches are associated with their low effectiveness, complexity and unproven biosafety. Here, we evaluated and optimized a fibrin-islet composite for effective glycemic control in a subcutaneous site whose environment is highly hypoxic due to low vascularization potential. In the setting of xenogeneic porcine islet transplantation into the subcutaneous space of a diabetic mouse, the in vivo islet functions were greatly affected by the concentrations of fibrinogen and thrombin. The optimized hydrogel-type fibrin remarkably reduced the marginal islet mass to approximately one tenth that of islets without fibrin. This marginal islet mass was comparable to that in the setting of the subcapsular space of the kidney, which is a highly vascularized organ. Highly vascularized structures were generated inside and on the outer surface of the grafts. A hydrogel-type fibrin-islet composite established early diabetic control within an average of 3.4days after the transplantation. In the mechanistic studies, fibrin promoted local angiogenesis, enhanced islet viability and prevented fragmentation of islets into single cells. In conclusion, in situ application of hydrogel-type fibrin-islet composite may be a promising modality in the clinical success of subcutaneous islet transplantation.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Fibrin; Hydrogels; Islets of Langerhans Transplantation; Mice; Mice, Inbred NOD; Mice, SCID; Swine; Transplantation, Heterologous

Diabetes is a condition defined by hyperglycaemia and these patients have a high risk of thrombosis. Previous research showed that ultrastructural changes in clot formation occur in patients in whom there are changes in the coagulation system due to, for example, an inflammatory condition. In the current study, the ultrastructures of platelets and fibrin networks were investigated in 25 diabetic patients. Plasma smears, with and without the addition of thrombin, were prepared. Results indicated that the fibrin network in all diabetic patients had thickened masses of thin, minor fibres over the major fibres, a profile typical of an inflammatory condition. A changed platelet membrane ultrastructure could also be observed in the diabetic patients that revealed typical apoptotic morphology, in whom membrane blebbing could be seen. It can, therefore, be concluded that in diabetic patients, the ultrastructure of fibrin networks show a typical systemic inflammatory profile, although platelets seem to be apoptotic.

Topics: Adolescent; Adult; Aged; Blood Coagulation; Blood Coagulation Tests; Blood Platelets; Case-Control Studies; Diabetes Complications; Diabetes Mellitus; Female; Fibrin; Humans; Male; Microscopy, Electron, Scanning; Middle Aged; Platelet Count; South Africa; Thrombin; Thrombosis

To investigate the latest development of tissue engineered regenerative medicine in industrialization, with the intention to direct work in practical area.. A complete insight of regenerative medicine in industrialization was obtained through referring to update publications, visiting related websites, as well as learning from practical experience.. The aerial view of the future of regenerative medicine was got based on knowledge of four different tissue engineering projects.. All present efforts should be devoted to regenerative medicine area meeting the industrialized trends.

Topics: Animals; Biocompatible Materials; Cell Differentiation; Cell Proliferation; Chitosan; Diabetes Mellitus; Fibrin; Fibroblast Growth Factors; Heart Diseases; Humans; Hyaluronic Acid; Mice; Regenerative Medicine; Spinal Injuries; Stem Cell Transplantation; Stem Cells; Tissue Engineering

Homocysteine (Hcy) is a risk factor for thrombosis. We investigated a hypothesis that the clot permeability and its resistance to fibrinolysis is associated with plasma total Hcy (tHcy) in human subjects.. We studied healthy men not taking any medication (n=76), male patients with advanced coronary artery disease (CAD) taking low-dose aspirin (n=33), men with diabetes mellitus diagnosed recently (median hemoglobin A(1c) 7.65%; n=16), and patients with isolated hypercholesterolemia (>7.0 mmol/L; n=15). We assessed clot permeability and turbidimetric lysis time as the determinants of fibrin clot structure. In a regression model, including age and fibrinogen, plasma tHcy was an independent predictor of clot permeation and fibrinolysis time in healthy subjects (R2=0.88, P<0.0001 and R2=0.54, P<0.0001, respectively). In CAD patients, tHcy and fibrinogen were stronger predictors of the permeation coefficient (R2=0.84; P<0.0001) than was fibrinogen alone (R2=0.66; P<0.0001), whereas tHcy was the only predictor of lysis time (R2=0.69; P<0.0001). Elevated tHcy levels observed after methionine load were not associated with any of the fibrin clot properties. In patients with diabetes or hypercholesterolemia, the influence of Hcy on permeation and, to a lesser extent, on the lysis time was obscured by dominant effects of glucose and cholesterol. In 20 asymptomatic men with hyperhomocysteinemia treated with folic acid, reduction in tHcy levels resulted in increased clot permeability (P=0.0002) and shorter lysis time (P<0.0001).. Our results indicate that plasma tHcy predicts clot permeation and susceptibility to fibrinolysis in healthy men and CAD patients. Our data are consistent with a mechanism of thrombosis in hyperhomocysteinemia, which involves modification of fibrinogen by Hcy-thiolactone.

Topics: Acute Disease; Adult; Aged; Blood Coagulation; Case-Control Studies; Coronary Artery Disease; Diabetes Mellitus; Drug Resistance; Fibrin; Fibrinolytic Agents; Folic Acid; Hematinics; Homocysteine; Humans; Hypercholesterolemia; Hyperhomocysteinemia; Male; Middle Aged; Permeability; Recombinant Proteins; Tissue Plasminogen Activator

Fibrinogen circulating in human blood is comprised of high molecular weight (HMW) and lower molecular weight (LMW) fractions. As previously documented by means of SDS-polyacrylamide gel electrophoresis (PAGE), LMW fraction was significantly increased in patients with cardiovascular disease and with diabetes mellitus (DM). We have recently observed that the values of fibrinogen measured by thrombin clotting time (the method of Clauss) were consistently lower in EDTA plasma than those obtained with citrated plasma. However, supplementation of EDTA plasma with magnesium (Mg) ions gave comparable results. In this study we documented by SDS-PAGE that fibrin formed with thrombin alone in EDTA plasma originated from HMW fibrinogen, whereas that formed after addition of Mg was derived from LMW fibrinogen. Thus, measurement of thrombin clotting time in EDTA plasma with and without Mg may serve as a quick method for the determination of HMW and LMW fibrinogens in human blood. Preliminary result obtained with this new method revealed that LMW fibrinogen was significantly increased in DM patients. We have therefore concluded that measurement of this fraction of fibrinogen may prove to be of clinical diagnostic significance.

Topics: Blood Coagulation; Calcium; Case-Control Studies; Chemistry, Clinical; Diabetes Mellitus; Edetic Acid; Electrophoresis, Polyacrylamide Gel; Fibrin; Fibrinogen; Hemostasis; Humans; Ions; Magnesium; Models, Biological; Thrombin; Time Factors

Topics: Diabetes Mellitus; Fibrin; Fibrinogen; Fibrinolytic Agents; Humans; Macromolecular Substances; Ticlopidine

Using measurements of fibrin fibre thickness (microT) derived from turbidity and permeability (tau) of clotted plasma, it has been found that glucose in vitro added to plasma decreases permeability of the network despite unaltered fibrinogen conversion. Fibrin fibre thickness (microT) in uncontrolled diabetes is found significantly reduced. In diabetic plasma the degree of conversion to fibrin is similar to that in age and sex matched plasma from non-diabetics: the effect on fibrin network and fibre thickness probably arises from glycosylation of fibrinogen. Studies with Gliclazide, Metformin, Glibenclamide and insulin have shown that while all other drugs tested have no effect, Gliclazide increases fibrin fibre thickness (microT) significantly, diminishes tensile strength and reduces permeability. In separate experiments lysability of 125I-labelled fibrin networks developed in the presence of all four hypoglycaemic agents by tissue activator was tested. Networks developed in the presence of Metformin were found to lyse more quickly, followed by insulin and Gliclazide. Alterations induced in fibrin networks in diabetes may be nullified by some oral hypoglycaemic agents such as Gliclazide and not by others. Whether nullification of such changes has long-term effects in reducing the incidence of vascular disease in diabetics remains to be established.

Topics: Adult; Blood Glucose; Diabetes Mellitus; Fibrin; Fibrinolysis; Humans; Hypoglycemic Agents; Insulin; Nephelometry and Turbidimetry; Permeability; Stimulation, Chemical

The effect of nonenzymatic glycosylation on the biologic function of human antithrombin III was evaluated using a chromogenic thrombin substrate assay in the presence of catalytic amounts of heparin. Experimental conditions that increased the rate of nonenzymatic protein glycosylation were associated with decreases in the thrombin-inhibiting activity of antithrombin III. This glycosylation-induced inhibition of heparin-catalyzed antithrombin III activity was completely reversible by preassay incubation with excess sodium heparin. These observations provide a biochemical explanation for the heparin-reversible, accelerated fibrinogen disappearance rate induced by hyperglycemia in diabetic patients. Defective inhibition of the coagulation cascade induced by excessive nonenzymatic glycosylation of antithrombin III in vivo could contribute to accumulation of fibrin in various diabetic tissues.

Topics: Antithrombin III; Catalysis; Diabetes Mellitus; Fibrin; Glucose; Heparin; Humans; Hydrolysis; Thrombin

The effect of nonenzymatic glycosylation on the susceptibility of fibrin to degradation by the specific fibrinolytic enzyme plasmin was evaluated using both a fibrin plate assay and a fluorogenic synthetic plasmin substrate assay. Data from both types of experiments demonstrate that nonenzymatic glycosylation reduces the susceptibility of fibrin to plasmin degradation. Acetylation and carbamylation have qualitatively similar effects, indicating that chemical modification of lysine amino groups is the underlying phenomenon responsible for the observed degradative defect produced by glucose. Experimental conditions that increased the rate of nonenzymatic protein glycosylation (higher monosaccharide concentration, glucose-6-phosphate) were associated with correspondingly greater degrees of resistance to degradation by plasmin. Such reduced degradation of nonenzymatically glycosylated proteins in vivo may contribute to the accumulation of fibrin and several other proteins observed in those tissues most frequently affected by the complications of diabetes.

Topics: Binding Sites; Chemical Phenomena; Chemistry; Diabetes Mellitus; Fibrin; Fibrinogen; Fibrinolysin; Glucose; Humans; Hyperglycemia; In Vitro Techniques; Lysine; Protein Conformation; Time Factors

Topics: Adolescent; Adult; Aged; Aging; Child; Child, Preschool; Collagen; Diabetes Mellitus; Factor XIII; Fibrin; Humans; Infant; Middle Aged; Wound Healing; Wound Infection; Wounds and Injuries

The presence of soluble fibrin complexes (SFC) measured by gel filtration of plasma on 4% agarose columns, fibrinogen heterogeneity on 3.5% SDS-polyacrylamide gels and the concentrations of several plasma proteins were evaluated in 39 patients with diabetes mellitus (DM) and 19 matched control subjects. A small but significant increase of SFC was found in DM (p less than 0.01). On individual basis 51.2% of the patients had increased SFC (greater than M + 2 SD of the controls). Polyacrylamide gel electrophoresis of the SFC showed no evidence of cross-linking or proteolysis. Plasma clots formed in the presence of EDTA and trasylol were analysed in SDS-polyacrylamide gels in a normal and two lower molecular weight fibrin bands (band I, II, III). The percentage of band I fibrinogen was in diabetics (65.3 +/- 4.7%) lower than that of the controls (71.8 +/- 4.5%) (p less than 0.01). Fibrinogen levels, antithrombin III, alpha 1-antitrypsin, alpha 2-macroglobulin and plasminogen were significantly increased in DM. We suggest that in DM there is an enhancement of intravascular fibrin formation and accelerated fibrinogen degradation to lower molecular weight forms.

Topics: Adolescent; Adult; Aged; alpha 1-Antitrypsin; alpha-Macroglobulins; Antithrombin III; Blood Coagulation; Chromatography, Gel; Diabetes Mellitus; Diabetes Mellitus, Type 1; Disseminated Intravascular Coagulation; Electrophoresis, Polyacrylamide Gel; Female; Fibrin; Fibrinogen; Humans; Male; Middle Aged; Plasminogen; Solubility

Topics: Adolescent; Adult; Diabetes Mellitus; Fibrin; Fibrinogen; Fibrinolysis; Gingiva; Humans; Periodontitis

Skeletal muscle from 34 insulin-dependent diabetic patients and 20 age-matched controls was examined by immunofluorescent microscopy. Significantly increased staining of capillary and muscle basement membranes of diabetics was seen for IgG, albumin, and fibrin. The immunofluorescent pattern was identical with that observed using heterologous antibasement membrane antiserum, indicating that these proteins were present within these basement membranes. No differences were detected between males and females or between kidney-transplanted and nontransplanted diabetics. No correlation was noted between intensity of staining and duration of diabetes. The presence of certain serum proteins within vascular and nonvascular basement membranes in diabetics is not restricted to the kidney and may reflect widespread alterations in extracellular membranes that permit entrapment of these proteins.

Topics: Albumins; Basement Membrane; Diabetes Mellitus; Fibrin; Fluorescent Antibody Technique; Humans; Immunoglobulin G; Muscles

Effects of phenformin on blood sugar, serum triglyceride, thrombin time, euglobulin clot lysis time and cardiovascular complications were studied in maturity onset diabetes and in atherosclerotic patients with or without diabetes, for a period of 14-18 months. Phenformin has shown the characteristic properties of an antifibrinopathic agent in that it prolongs thrombin time and enhances fibrinolysis. The hypoglycaemic effect of phenformin was found to be directly related to its antifibrinopathic action. Plasma lipids fell in all cases. Absence of fresh cardiovascular complications and improvement in anginal symptoms were observed. The metabolic, haematological and clinical benefits of phenformin and its limitations in maturity onset diabetes and atherosclerosis may be explained by the effects of the drug upon the thrombin-fibrinogen reaction. These results lend support to the hypothesis of a primary fibrinopathic pathogenesis in maturity onset diabetes mellitus and atherosclerosis.

Topics: Adult; Aged; Arteriosclerosis; Blood Coagulation Tests; Blood Glucose; Diabetes Mellitus; Fibrin; Fibrinolysis; Fibrinolytic Agents; Humans; In Vitro Techniques; Middle Aged; Phenformin; Triglycerides

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: Diabetes Mellitus; Evaluation Studies as Topic; Female; Fibrin; Fibrinogen; Glycosuria; Humans; Immunoelectrophoresis; Latex Fixation Tests; Liver Diseases; Methods; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Urinary Tract Infections

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: Adolescent; Adult; Angina Pectoris; Chronic Disease; Diabetes Mellitus; Female; Fibrin; Fibrinogen; Hematologic Diseases; Humans; Kidney Diseases; Liver Diseases; Male; Middle Aged; Myocardial Infarction; Neoplasms

Topics: Arteries; Arteriosclerosis; Diabetes Mellitus; Fibrin; Humans; Kidney; Permeability

Topics: Arteriosclerosis; Collagen; Diabetes Mellitus; Fibrin; Geriatrics; Humans; Hyalin; Hypertension; Hypertension, Malignant; Hypertension, Pulmonary; Mitral Valve Stenosis; Pathology; Pyelonephritis

Topics: Acetates; Diabetes Mellitus; Fibrin; Humans; Insulin; Lactates; Lactic Acid; Liver