fibrin and Obesity

Obesity and exercise constitute important factors for cardiovascular disease risk, but the long-term effects of different exercise modalities on haemostatic biomarkers are not well elucidated. We investigated the effects of 6 months of active commuting or leisure-time exercise on measures of fibrin turnover in individuals who are overweight and obese. Ninety younger (20-40 years), sedentary, healthy women and men who are overweight and obese (BMI: 25-35 kg/m

Topics: Adult; Blood Coagulation; Exercise; Female; Fibrin; Fibrinolysis; Humans; Lipids; Male; Obesity; Overweight; Oxygen Consumption; Transportation

While there is indisputable evidence supporting the beneficial role of aerobic exercise in reducing cardiovascular risk factors, there are few dose-response studies of this relationship. Increasingly, it is thought that the cardiovascular benefits of exercise are significantly influenced by adaptations within skeletal muscle and its vasculature. However, little is known about the molecular mechanisms underlying these adaptations. To address this need, we initiated a study utilizing longitudinal, microarray-based gene expression profiling of serial skeletal muscle biopsies obtained from the study of targeted risk reduction intervention through defined exercise (STRRIDE). STRRIDE participants were overweight and exhibited symptoms characteristic of the metabolic syndrome that typically precedes type II diabetes such as insulin resistance, abnormal lipids and glucose intolerance. Expression data were statistically filtered and sorted into exercise training-responsive clusters based on gene product knowledge. One such cluster included genes that promote the degradation of fibrin clots such as tissue plasminogen activator (t-PA), connective tissue activation peptide III (CTAP III) and tetranectin. The fibrinolytic activity and protein levels of tetranectin, and t-PA and its endogenous inhibitor PAI-1, were subsequently shown to change significantly in both skeletal muscle and serum in response to exercise training. Our data show that the rigors of exercise directly induce fibrinolytic genes and protein cascades, both within muscle, and in the systemic circulation. This finding is particularly significant given that the metabolic syndrome is an independent risk factor for peripheral vascular disease and thrombotic events within the heart and brain. We conclude that aerobic exercise training induces both local and systemic changes in fibrinolysis and vascular homeostasis that are probably protective against cardiovascular disease.

Topics: Adaptation, Physiological; Blotting, Western; Enzyme-Linked Immunosorbent Assay; Exercise; Fibrin; Fibrinolysis; Fluorescent Antibody Technique; Gene Expression; Homeostasis; Humans; Lectins, C-Type; Male; Metabolic Syndrome; Middle Aged; Multigene Family; Muscle Proteins; Muscle, Skeletal; Obesity; Physical Fitness; Plasminogen Activator Inhibitor 1; Plasminogen Activators; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; RNA, Messenger

Repeated weight loss cycles are associated with increased cardiovascular morbidity. Meal-induced thrombin formation, measured as prothrombin fragment 1+2 (F1+2), is observed in individuals with overweight after weight loss, and postprandial effects can be one of the mechanisms underlying harmful effects during intentional weight loss. We hypothesize that consumption of high-fat meals during intentional weight loss triggers a prothrombotic state by increasing postprandial F1+2 or decreasing fibrin clot lysis in individuals with obesity, and that the response associates with the gut bacteria composition. A cross-over meal study was conducted in patients admitted to bariatric surgery during dietary weight loss (N = 20) and surgical weight loss (N = 16) (weight loss groups). High-fat (67 E%) and low-fat (16 E%) meals were served at 08:15 and 10:00 on 2 study days. Blood samples collected at 08:00 (fasting), 12:00, and 14:00 were analyzed for triglycerides, activated factor VII (FVIIa), F1+2, D-dimer, fibrinogen, tissue factor , and fibrin clot lysis. The proportion of Gram-negative bacteria and bacterial diversity were analyzed in fecal samples obtained less than 24 hours before the meal test. Triglyceride and FVIIa increased after high-fat meals in both weight loss groups, whereas D-dimer (dietary group) and F1+2 decreased and tissue factor and fibrin clot lysis did not change. There was a negative association between the proportion of Gram-negative bacteria and changes in FVIIa in the surgery group. Postprandial FVII activation after high-fat meals is not accompanied by increased F1+2, irrespective of the weight loss intervention, but might be associated with the proportion of Gram-negative gut bacteria.

Topics: Dietary Fats; Factor VIIa; Fibrin; Humans; Meals; Obesity; Postprandial Period; Thrombin; Weight Loss

Obesity is associated with increased serum fibrinogen level. Myostatin (MSTN), a strong inhibitor of skeletal muscle growth, is recognized as a potential target for obesity. However, the effect of MSTN inhibition on fibrinogen is not largely known. The objective of the present study was to explore fibrinogen levels after MSTN inhibition. Fibrinogen levels and the fibrin clot structure of MSTN homozygous knockout (KO) and wild-type (WT) pigs (n = 4 in each group) were investigated. The protein expression of fibrinogen in the serum and liver of KO pigs decreased greatly (1.6-fold loss for serum and 2.5-fold loss for liver). KO pigs showed significantly decreased gene expression of fibrinogen chains: FGA (fibrinogen-α; 11-fold), FGB (fibrinogen-β; 8-fold) and FGG (fibrinogen-γ; 7.4-fold). The basal transcriptional regulators of fibrinogen, HNF1 (hepatocyte nuclear factor 1) and CEBP-α (CCAAT/Enhancing-binding protein-alpha) were remarkably down-regulated after interruption of MSTN expression by siRNA (small interfering RNA) in cultured hepatocytes (about 2- and 4-fold, respectively). Compared with WT pigs, KO pigs displayed altered fibrin clot structure with thinner fibers, decreased turbidity and increased permeability. The findings indicate that the inhibition of MSTN could affect fibrinogen levels and the fibrin clot structure.

Topics: Animals; Fibrin; Fibrinogen; Homozygote; Muscle, Skeletal; Myostatin; Obesity; Swine; Swine Diseases

Obesity predisposes individuals to metabolic syndrome, which increases the risk of cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD), and type 2 diabetes. A pathological manifestation of obesity is the activation of the coagulation system. In turn, extravascular fibrin(ogen) deposits accumulate in adipose tissues and liver. These deposits promote adiposity and downstream sequelae by driving pro-inflammatory macrophage function through binding the leukocyte integrin receptor α. An unresolved question is whether conversion of soluble fibrinogen to a crosslinked fibrin matrix is required to exacerbate obesity-driven diseases.. Here, fibrinogen-deficient/depleted mice (Fib- or treated with siRNA against fibrinogen [siFga]), mice expressing fibrinogen that cannot polymerize to fibrin (Fib. Consistent with prior studies, Fib

Topics: Afibrinogenemia; Animals; Diabetes Mellitus, Type 2; Diet; Factor XIII; Fibrin; Fibrinogen; Hemostatics; Mice; Non-alcoholic Fatty Liver Disease; Obesity; Polymers

Pre-existing comorbidities such as obesity or metabolic diseases can adversely affect the clinical outcome of COVID-19. Chronic metabolic disorders are globally on the rise and often a consequence of an unhealthy diet, referred to as a Western Diet. For the first time in the Syrian hamster model, we demonstrate the detrimental impact of a continuous high-fat high-sugar diet on COVID-19 outcome. We observed increased weight loss and lung pathology, such as exudate, vasculitis, hemorrhage, fibrin, and edema, delayed viral clearance and functional lung recovery, and prolonged viral shedding. This was accompanied by an altered, but not significantly different, systemic IL-10 and IL-6 profile, as well as a dysregulated serum lipid response dominated by polyunsaturated fatty acid-containing phosphatidylethanolamine, partially recapitulating cytokine and lipid responses associated with severe human COVID-19. Our data support the hamster model for testing restrictive or targeted diets and immunomodulatory therapies to mediate the adverse effects of metabolic disease on COVID-19.

Topics: Animals; COVID-19; Cricetinae; Cytokines; Diet, High-Fat; Dietary Carbohydrates; Disease Models, Animal; Edema; Fibrin; Hemorrhage; Humans; Interleukin-10; Interleukin-6; Lipid Metabolism; Lipidomics; Lipids; Liver; Lung; Male; Mesocricetus; Obesity; SARS-CoV-2; Severity of Illness Index; Sugars; Vasculitis; Virus Shedding

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

Topics: Animals; Anticoagulants; Blood Coagulation; Fibrin; Humans; Liver; Non-alcoholic Fatty Liver Disease; Obesity; Prognosis; Risk Factors; Signal Transduction; Thrombosis

Obesity promotes a chronic inflammatory and hypercoagulable state that drives cardiovascular disease, type 2 diabetes, fatty liver disease, and several cancers. Elevated thrombin activity underlies obesity-linked thromboembolic events, but the mechanistic links between the thrombin/fibrin(ogen) axis and obesity-associated pathologies are incompletely understood. In this work, immunohistochemical studies identified extravascular fibrin deposits within white adipose tissue and liver as distinct features of mice fed a high-fat diet (HFD) as well as obese patients. Fibγ390-396A mice carrying a mutant form of fibrinogen incapable of binding leukocyte αMβ2-integrin were protected from HFD-induced weight gain and elevated adiposity. Fibγ390-396A mice had markedly diminished systemic, adipose, and hepatic inflammation with reduced macrophage counts within white adipose tissue, as well as near-complete protection from development of fatty liver disease and glucose dysmetabolism. Homozygous thrombomodulin-mutant ThbdPro mice, which have elevated thrombin procoagulant function, gained more weight and developed exacerbated fatty liver disease when fed a HFD compared with WT mice. In contrast, treatment with dabigatran, a direct thrombin inhibitor, limited HFD-induced obesity development and suppressed progression of sequelae in mice with established obesity. Collectively, these data provide proof of concept that targeting thrombin or fibrin(ogen) may limit pathologies in obese patients.

Topics: Adipose Tissue; Adiposity; Amino Acid Motifs; Animals; Blood Glucose; Body Composition; Body Weight; Coagulants; Dabigatran; Diet, High-Fat; Fatty Liver; Female; Fibrin; Genotype; Homozygote; Inflammation; Liver; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity; Thrombin; Weight Gain

Topics: Adipose Tissue; Blood Platelets; Cohort Studies; Elasticity; Female; Fibrin; Humans; Male; Mean Platelet Volume; Middle Aged; Obesity; Platelet Aggregation; Prognosis; Thrombelastography; Thrombophilia

Obesity predisposes to a prothrombotic state in humans, but whether a similar state occurs in obese animals is unknown. The objective of the current study was to examine the effect of body fat percentage (BF) on haemostatic parameters including thromboelastography with tissue factor as activator (TF-TEG) in client owned indoor-confined physically inactive cats. Seventy-two cats were included following an initial thorough health examination, and a complete blood count, biochemistry panel, conventional coagulation panel and a TF-TEG analysis were performed with tissue factor (1:50,000) as activator. The cats were anaesthetized, and BF was measured using Dual-energy X-ray absorptiometry. Significant difference between lean (BF < 35%, n = 26), overweight (35% < BF < 45%, n = 28) and obese (BF > 45%, n = 18) cats was identified using ANOVA. The correlation between BF, serum leptin and total adiponectin, respectively, with individual TEG and conventional coagulation parameters was evaluated. Obese cats showed a faster rate of fibrin formation (TF-TEG(R), p < 0.05), and TF-TEG(R) was positively correlated with plasma leptin levels. Increasing BF did not affect other conventional coagulation or TF-TEG parameters. In conclusion, this study indicates a connection between body fat content and altered haemostasis, also in cats. Whether feline obesity causes a hypercoagulable state of clinical relevance should be further investigated.

Topics: Animals; Blood Coagulation; Cat Diseases; Cats; Female; Fibrin; Male; Obesity; Thrombelastography

Leonotis leonurus L. (Lamiaceae) is used as a traditional medicine for a variety of ailments in South Africa. The diterpene marrubiin is the major product constituent in specimens of this plant occurring in South Africa.. Marrubiin isolated from South African specimens of L. leonurus in addition to an organic extract of L. leonurus were tested in vivo, ex vivo and in vitro for their anticoagulant, antiplatelet and anti-inflammatory activities.. Marrubiin and the organic extract suppressed coagulation, platelet aggregation and inflammatory markers. For the coagulation markers it was found that the organic extract and marrubiin significantly prolonged activated partial thromboplastin time (APTT). Fibrin and D-dimer formation were drastically decreased. These findings were observed in an ex vivo model and an obese rat model. Chemokines enhance leukocyte recruitment to inflammatory sites. TNF-α and RANTES secretion were significantly reduced by the extract and marrubiin when determined in the obese rat model relative to the controls. Calcium mobilization and TXB(2) synthesis were suppressed by the extract and marrubiin. An in vitro model was used to elucidate the antiplatelet mechanism and it was found that the extract and marrubiin inhibited platelet aggregation by inhibiting the binding of fibrinogen to glycoprotein (GP) IIb/IIIa receptor in a concentration dependent manner.. The findings reflect that marrubiin largely contributes to the extract's anticoagulant, antiplatelet and anti-inflammatory effects observed.

Topics: Animals; Anti-Inflammatory Agents; Anticoagulants; Blood Coagulation; Calcium; Chemokine CCL5; Diterpenes; Dose-Response Relationship, Drug; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolytic Agents; Glycoproteins; Inflammation; Lamiaceae; Male; Obesity; Partial Thromboplastin Time; Phytotherapy; Plant Extracts; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Rats, Wistar; Thromboxanes; Tumor Necrosis Factor-alpha

We investigated whether targeted cleavage of PAI-1 mRNA might prevent post-angioplasty neointima formation in diabetic JCR:LA-cp/cp rats with naturally elevated PAI-1 levels. Catalytic DNA enzymes targeting rat PAI-1 mRNA (PAI-1 DNA enzyme, n = 12) or a random sequence as control (scrambled DNA enzyme, n = 12) were infused at the site of arterial damage. Control animals demonstrated prominent PAI-1 protein expression in the arterial endothelium at 48 hours, and robust neointimal proliferation by two weeks, with 60 +/- 10% mean occlusion of the artery lumen. The neointimal lesion consisted of dense fibrin deposition and numerous proliferating smooth muscle cells, as determined by dual alpha-smooth muscle actin/Ki67 expression. Treatment with PAI-1 DNA enzyme resulted in marked early (48 hour) reduction of endothelial PAI-1 protein expression, which persisted for the next two weeks as well as a two fold reduction of expression of PAI-1 mRNA by RT-PCR at the same time point, (P < 0.05). By two weeks, PAI-1 DNA enzyme treated animals demonstrated significantly reduced levels of fibrin deposition and 5-fold lower levels of proliferating smooth muscle cells at the site of arterial injury compared to controls (P < 0.01), and a 2-fold lower neointima/media ratio (0.67 +/- 0.11 vs 1.39 +/- 0.12) (P < 0.05). Treatment with a catalytic PAI-1 DNA enzyme successfully prevents neointimal proliferation after balloon injury in diabetic animals.

Topics: Actins; Angioplasty, Balloon, Coronary; Animals; Diabetes Mellitus, Experimental; Disease Models, Animal; DNA, Catalytic; Fibrin; Image Interpretation, Computer-Assisted; Immunohistochemistry; Injections, Intra-Arterial; Ki-67 Antigen; Muscle, Smooth; Obesity; Plasminogen Activator Inhibitor 1; Rats; Rats, Inbred Strains; Rats, Mutant Strains; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tunica Intima

Cardiovascular/thrombotic diseases are frequently induced by a variety of stressors. Obese patients are susceptible to thrombotic diseases associated with stress, but the underlying mechanism is still unknown. We have begun to investigate the expression of a primary inhibitor of fibrinolysis, plasminogen activator inhibitor-1 (PAI-1), in association with tissue thrombosis, using restraint-stressed obese mice.. We analyzed the expression of PAI-1 after restraint (immobilization) stress in genetically obese mice in comparison with their lean counterparts. Dramatic increases in PAI-1 antigen in plasma and in tissue extracts were observed in the obese mice exposed to restraint stress. The induction of PAI-1 mRNA by stress in the tissues was also pronounced in the stressed obese mice as compared with the lean mice, especially in the hearts and adipose tissues. In situ hybridization analysis revealed that strong signals for PAI-1 mRNA were localized in the adipocytes, cardiovascular endothelial cells, and renal glomerular cells of the stressed obese mice. Histological examination revealed that renal glomerular fibrin deposition was detected only in the obese mice after 2 h of restraint stress.. Obesity enhances the stress-mediated PAI-1 induction in the blood and tissues. This phenomenon may be associated with the increased risk of stress-induced renal fibrin deposition in obese subjects.

Topics: Adipocytes; Adipose Tissue; Animals; Body Mass Index; Endothelium, Vascular; Fibrin; Fibrinolysis; Immobilization; Immunohistochemistry; In Situ Hybridization; Kidney; Kidney Glomerulus; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Myocardium; Obesity; Plasminogen Activator Inhibitor 1; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors

The morphologic features observed in the renal biopsy specimens from three patients with massive obesity complicated by the nephrotic syndrome are described. In the two patients with active disease, the majority of the glomeruli showed focal to extensive fibrin deposition both within and adjacent to capillary loops, associated with adhesions to Bowman's capsule, with a variable endocapillary proliferative response. In the patient with inactive disease, the majority of the glomeruli appeared normal. However, fibrin-like material, similar to that seen in the active phase, was infrequently found ultrastructurally in the subendothelial portion of the capillary loops. Subendothelial vacuolated material was also observed. Although intravascular coagulation was suggested in this disorder, only minor coagulation abnormalities were discovered. In two of the patients, the massive proteinuria has resolved with weight reduction.

Topics: Adult; Diagnosis, Differential; Female; Fibrin; Humans; Kidney; Kidney Glomerulus; Male; Middle Aged; Nephrotic Syndrome; Obesity

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: Complement C6; Fibrin; Humans; Immunoglobulin A; Kidney Glomerulus; Nephrotic Syndrome; Obesity; Proteinuria

In a study of 41 fasting subjects it was confirmed that fibrinolytic activity was reduced in obese persons: an increase in fibrinogen was also associated with obesity. There was no correlation between obesity and the platelet count, platelet adhesiveness to glass, the level of serum fibrin degradation products, or the whole blood clotting time in plastic tubes.

Topics: Blood Cell Count; Blood Coagulation; Blood Coagulation Tests; Body Weight; Fasting; Female; Fibrin; Fibrinogen; Fibrinolysis; Humans; Male; Obesity; Plasminogen; Platelet Adhesiveness

Topics: Adult; Appetite Depressants; Electrocardiography; Female; Fibrin; Humans; Hyperplasia; Hypertension, Pulmonary; Obesity; Pulmonary Artery; Radiography, Thoracic

Topics: Aorta; Arteriosclerosis; Blood Coagulation Tests; Colonic Neoplasms; Fibrin; Fibrinogen; Fibrinolysis; Humans; Hypertension; Hypertension, Renal; Immunoassay; Kidney; Obesity; Pyelonephritis; Renal Veins; Staphylococcus