fibrin and Coronary-Artery-Disease

Despite improved diagnosis and treatment options, coronary artery disease (CAD) is still the leading cause of mortality and morbidity worldwide. Established risk factors such as smoking, hypercholesterolemia, and hypertension only partly explain the pathophysiology of CAD. Besides the well-known role of platelets in atherosclerosis and arterial thrombus formation, reduced endogenous fibrinolytic activity may play a key role in CAD formation and progression. Thus, biomarkers of fibrinolysis may be future CAD risk markers. In this review, we provide an overview of regulators of fibrinolysis and the main factors of importance to fibrin clot formation including coagulation factor XIII, thrombin, and fibrinogen. We summarize markers of altered fibrinolysis and current laboratory methods applied in clinical practice and research. We present today’s evidence on fibrin clot properties in patients with stable CAD or acute coronary syndrome compared with healthy individuals and the significance of altered fibrinolysis as a risk for coronary thrombotic disease. In conclusion, we found evidence that altered fibrin clot properties and impaired fibrinolysis appear to contribute significantly to the thromboembolic risk in CAD patients. Therefore, more research is crucial in order to clarify whether modulation of the fibrinolytic system may pave the way for improved treatment of CAD.

Topics: Biomarkers; Coronary Artery Disease; Fibrin; Fibrinolysis; Humans; Prognosis; Thrombosis

Although mortality rates from coronary heart disease in the western countries have declined in the last few decades, morbidity caused by this disease is increasing and a substantial number of patients still suffer acute coronary syndrome (ACS) and sudden cardiac death. Acute coronary syndrome occurs as a result of myocardial ischaemia and its manifestations include acute myocardial infarction and unstable angina. Culprit plaque morphology in these patients varies from thrombosis with or without coronary occlusion to sudden narrowing of the lumen from intraplaque haemorrhage. The coronary artery plaque morphologies primarily responsible for thrombosis are plaque rupture, and plaque erosion, with plaque rupture being the most common cause of acute myocardial infarction, especially in men. Autopsy data demonstrate that women <50 years of age more frequently have erosion, whereas in older women, the frequency of rupture increases with each decade. Ruptured plaques are associated with positive (expansive) remodelling and characterized by a large necrotic core and a thin fibrous cap that is disrupted and infiltrated by foamy macrophages. Plaque erosion lesions are often negatively remodelled with the plaque itself being rich in smooth muscle cells and proteoglycans with minimal to absence of inflammation. Plaque haemorrhage may expand the plaque rapidly, leading to the development of unstable angina. Plaque haemorrhage may occur from plaque rupture (fissure) or from neovascularization (angiogenesis). Atherosclerosis is now recognized as an inflammatory disease with macrophages and T-lymphocytes playing a dominant role. Recently at least two subtypes of macrophages have been identified. M1 is a pro-inflammatory macrophage while M2 seems to play a role in dampening inflammation and promoting tissue repair. A third type of macrophage, termed by us as haemoglobin associated macrophage or M(Hb) which is observed at site of haemorrhage also can be demonstrated in human atherosclerosis. In order to further our understanding of the specific biological events which trigger plaque instability and as well as to monitor the effects of novel anti-atherosclerotic therapies newer imaging modalities in vivo are needed.

Topics: Acute Coronary Syndrome; Cardiac Imaging Techniques; Chronic Disease; Coronary Artery Disease; Coronary Thrombosis; Female; Fibrin; Hemorrhage; Humans; Macrophages; Male; Necrosis; Plaque, Atherosclerotic; Platelet Aggregation; Risk Factors; Rupture, Spontaneous; Vascular Calcification

Coronary stents have been used for the treatment of patients with coronary artery disease (CAD), and significantly improved procedural safety and are associated with a lower rate of restenosis compared with balloon angioplasty alone. Drug-eluting stents (DES) have been dominant for the treatment of CAD with efficacy in significantly reducing both restenosis and target lesion revascularization. However, late and very late stent thrombosis have become a major concern in DES-implanted arteries compared with those treated with bare-metal stents (BMS). This review focuses on the feature of DES thrombosis and pathological examination and dual antiplatelet therapy for prevention of stent thrombosis. Currently, the incidence of stent thrombosis associated with first-generation and second-generation DES remains unclear in data from real-world cohort registry studies. Further studies of larger multicenter trials would give us insight into the specific mechanisms of stent thrombosis among different generations of DES.

Topics: Cohort Studies; Coronary Artery Disease; Coronary Restenosis; Coronary Vessels; Drug-Eluting Stents; Fibrin; Humans; Incidence; Meta-Analysis as Topic; Multicenter Studies as Topic; Platelet Aggregation Inhibitors; Regeneration; Registries; Risk Factors; Thrombosis

The fibrinolytic system includes a broad spectrum of proteolytic enzymes with physiological and pathophysiological functions in several processes, such as haemostatic balance, tissue remodeling, tumor invasion, angiogenesis and reproduction. The main enzyme of the plasminogen activator system is plasmin, which is responsible for the degradation of fibrin into soluble degradation products. The activation of plasminogen into plasmin is mediated by two types of activators, urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA). The activity of both is regulated by specific plasminogen activator inhibitors (PAIs). There are 3 types of PAIs described so far but the most important fibrinolytic inhibitor in vivo is PAI type 1 (PAI-1). Among others, the presence of metabolic syndrome and the -675 4G/5G promoter polymorphism are known to be modulators of PAI-1 levels. Besides their fibrinolytic profile, plasmin and plasminogen activators are implicated in tissue proliferation and cellular adhesion, as they can proteolytically degrade the extracellular matrix and regulate the activation of both growth factors and matrix metalloproteinases. By all these means, the fibrinolytic system is also involved in physiological processes, and in pathological situations such as thrombosis, arteriosclerosis, endometriosis and cancer. PAI 1 has been studied in different settings with thrombotic pathophysiology, such as coronary artery disease and ischaemic stroke. Controversial results have been published and concerns about study designs or presence of confounders have been claimed to be responsible of them. Recently, its involvement in adverse thrombotic events related to the modern drug-eluting coronary stents has renewed the interest of its study. PAI-1 also plays an important role in signal transduction, cell adherence, and migration. Indeed, studies of several types of cancers, including breast cancer, have shown that increased uPA and PAI-1 levels are associated with aggressive tumor behavior and poor prognosis. Endometriosis is defined by the presence of endometrial glands and stroma outside the uterus with marked ability to attach and invade the peritoneum. It is one of the most frequent benign gynecological diseases that affect women with pelvic pain or infertility during their reproductive age. Immune system disorders, genetic predisposition, altered peritoneal environment and endometrial alterations are believed to increase the susceptib

Topics: Coronary Artery Disease; Endometriosis; Female; Fibrin; Fibrinolysin; Fibrinolysis; Humans; Matrix Metalloproteinases; Neoplasms; Plasminogen; Plasminogen Activators; Plasminogen Inactivators; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator

Topics: Blood Coagulation; Blood Viscosity; Coronary Artery Disease; Elasticity; Fibrin; Fibrinolysis; Gels; Humans

Intravascular fibrin deposition is believed to play an important role in the development of intimal hyperplasia, which is a hallmark of several human vascular disorders, including atherosclerosis and restenosis after balloon angioplasty. Plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor or tissue- and urinary-type plasminogen activator, plays a key role in fibrin homeostasis by controlling plasmin formation. PAI-1 may also modulate vascular pathology via alternative pathways, such as inhibiting activated protein C and altering interactions between vascular smooth muscle cells and the extracellular matrix. The diverse functional profile of PAI-1 likely accounts for the variation observed in its impact on intimal hyperplasia in different disease models. This review examines recent studies addressing the vascular function of PAI-1, and those assessing the role of fibrin as a downstream mediator of PAI-1's effects.

Topics: Animals; Coronary Artery Disease; Disease Models, Animal; Fibrin; Humans; Mice; Plasminogen Activator Inhibitor 1; Reperfusion Injury

Fibrin clot structure/function contributes to cardiovascular disease. We examined sulfur-containing metabolites as determinants of fibrin clot lysis time (CLT) and maximum absorbance (Absmax) in relation to outcomes in coronary artery disease (CAD) patients. Effects of B-vitamin/folate therapy on CLT and Absmax were studied. Plasma samples were collected from 1,952 CAD patients randomized in a 2 x 2 factorial design to (i) folic acid, vitamins B12, B6; (ii) folic acid, vitamin B12; (iii) vitamin B6; (iv) placebo for 3.8 years in the Western Norway B-Vitamin Intervention Trial. Clot lysis time (CLT) and maximum absorbance (Absmax) were determined using a validated turbidimetric assay. Acute myocardial infarction (AMI) and mortality were assessed during a 7-year follow-up. Data were analyzed using bivariate and multiple regression. Survival free of events was studied using Kaplan Mayer plots. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. Baseline urinary homocysteine (uHcy)-thiolactone and plasma cysteine (Cys) were significantly associated with CLT while plasma total Hcy was significantly associated with Absmax, independently of fibrinogen, triglycerides, vitamin E, glomerular filtration rate, body mass index, age, sex plasma creatinine, CRP, HDL-C, ApoA1, and previous diseases. B-vitamins/folate did not affect CLT and Absmax. Kaplan-Meier analysis showed associations of increased baseline CLT and Absmax with worse outcomes. In Cox regression analysis, baseline CLT and Absmax (>cutoff) predicted AMI (CLT: HR 1.58, 95% CI 1.10-2.28; P = 0.013. Absmax: HR 3.22, CI 1.19-8.69; P = 0.021) and mortality (CLT: HR 2.54, 95% CI 1.40-4.63; P = 0.002. Absmax: 2.39, 95% CI 1.17-4.92; P = 0.017). After adjustments for other prognostic biomarkers these associations remained significant. Cys and uHcy-thiolactone, but not tHcy, were significant predictors of AMI in Cox regression models that included CLT. Conclusions uHcy-thiolactone and plasma Cys are novel determinants of CLT, an important predictor of adverse CAD outcomes. CLT and Absmax were not affected by B-vitamin/folate therapy, which could account for the lack of efficacy of such therapy in CAD. Trial registration: URL: http://clinicaltrials.gov. Identifier: NCT00354081.

Topics: Coronary Artery Disease; Fibrin; Folic Acid; Homocysteine; Humans; Myocardial Infarction; Prognosis; Risk Factors; Thrombosis; Vitamin B 12; Vitamin B Complex

Co-existence of vulnerable plaque and pro-thrombotic state may provoke acute coronary events. It was hypothesized that elevated serum levels of fibrin and fibrinogen degradation products (FDP) are associated with larger total plaque and necrotic core (NC) areas.. Seventy-five patients presenting with stable anginal symptoms (69%) or stabilized acute coronary syndrome (ACS; 31%), and found to have non-obstructive coronary artery disease (CAD) with a fractional flow reserve >0.8, were studied. Invasive virtual histology intravascular ultrasound (VH-IVUS) was performed in 68 LAD arteries, 6 circumflex arteries, and 1 right coronary artery. Serum FDP levels were measured using ELISA technique. Plaque volumetrics and composition were assessed in each VH-IVUS frame and averaged. The median age of patients was 56 (47-63) years; 52% were men and 23% had diabetes. The average length of coronary artery studied was 62 mm. After adjustment for systemic risk factors, medications, CRP levels and ACS, male gender (P<0.001) and serum FDP levels (P=0.02) were independent predictors of a larger NC area. Older age (P<0.001), male gender (P<0.0001) and increased serum FDP level (P=0.03) were associated with a larger plaque area.. In patients with CAD, a higher serum level of FDP is independently associated with larger plaques and greater plaque NC.

Topics: Angina, Stable; Coronary Artery Disease; Female; Fibrin; Fibrinogen; Humans; Male; Middle Aged; Necrosis; Plaque, Atherosclerotic; Ultrasonography, Interventional

The goal of this study was to investigate whether omega-3 polyunsaturated fatty acids (n-3 PUFA) are able to alter plasma fibrin clot properties and reduce thrombin formation in stable coronary artery disease patients undergoing percutaneous coronary intervention (PCI).. In an investigator-initiated, prospective, double-blind, placebo-controlled, randomized study, patients undergoing PCI who received standard pharmacotherapy were assigned to the treatment with 1 g/day n-3 PUFA (n = 30) or placebo (n = 24) for 1 month. Plasma fibrin clot permeability (K(s)); lysis time (t(50%)); prothrombin fragment 1.2; and peak thrombin generation from automated thrombogram, 8-isoprostaglandin F(2α) (8-iso-PGF(2α), an oxidative stress marker), and C-reactive protein were determined at baseline, 3 to 5 days after randomization, and 30 days after randomization. At baseline, both treatment groups did not differ significantly. A 1-month treatment with n-3 PUFA compared with placebo was associated with 15.3% higher K(s), indicating larger pores in the fibrin network (P = 0.0005); 14.3% shorter t(50%), indicating increased susceptibility to fibrinolysis (P<0.0001); 33.8% lower prothrombin fragment 1.2 (P = 0.0013); 13.4% lower peak thrombin generation (P = 0.04); and 13.1% lower 8-iso-PGF(2α) (P = 0.009). Treatment with n-3 PUFA had no effect on fibrinogen and C-reactive protein. After 1 month of treatment, fibrinogen (r = -0.53, P<0.0001), treatment assignment (r = 0.29, P = 0.006) and 8-iso-PGF(2α) (r = -0.27, P = 0.015) were independently associated with clot permeability (P<0.0001, R(2) = 0.66).. Adding n-3 PUFA to standard therapy in stable patients undergoing PCI significantly decreases thrombin formation and oxidative stress and favorably alters fibrin clot properties. These findings indicate novel antithrombotic effects induced by n-3 PUFA in humans.

Topics: Aged; Analysis of Variance; Angioplasty, Balloon, Coronary; Aspirin; Biomarkers; Blood Coagulation; C-Reactive Protein; Chi-Square Distribution; Clopidogrel; Coronary Artery Disease; Dinoprost; Double-Blind Method; Down-Regulation; Drug Therapy, Combination; Fatty Acids, Omega-3; Female; Fibrin; Humans; Linear Models; Male; Middle Aged; Oxidative Stress; Peptide Fragments; Platelet Aggregation; Platelet Aggregation Inhibitors; Poland; Prospective Studies; Prothrombin; Thrombin; Thrombosis; Ticlopidine; Time Factors; Treatment Outcome

Heparinization requires monitoring, but optimal methods for measuring the anticoagulant effects of heparin remain to be determined. We compared prothrombinase-induced clotting time (PiCT) and two chromogenic anti-factor Xa activity (anti-Xa) assays in monitoring high-dose heparinization during cardiopulmonary by-pass (CPB). Heparin effects were serially measured with PiCT and two anti-Xa assays in 100 patients. Antithrombin and protein C activities were measured preoperatively, and antithrombin activity was measured during CPB. Activation of coagulation was assessed with measurements of prothrombin fragment F1+2, soluble fibrin complexes, and D-dimer before, during, and after CPB. During CPB mean ranges of PiCT and of anti-Xa heparin levels measured with (anti-Xa A) and without (anti-Xa B) dextran sulfate and antithrombin supplementation were 5.0-5.2, 4.7-5.0, and 4.5-4.9 IU/ml, respectively. There was poor agreement between PiCT and anti-Xa and between the two anti-Xa assays (r = 0.32-0.65 and broad limits of agreement). Patients with low preoperative antithrombin or protein C levels had lower PiCT (p = 0.028 and p = 0.01) and anti-Xa A (both p<0.001) levels during CPB than others. Patients with the lowest heparin activities during CPB (lowest deciles of PiCT and anti-Xa A) had higher subsequent F1+2 after CPB (p = 0.002 and p = 0.02), and patients with high heparin levels required fewer transfusions of packed red blood cells than others. In conclusion, in the challenging setting of CPB there is poor agreement between anti-Xa assays and PiCT. However, coagulation-based PiCT could provide an alternative to the chromogenic anti-Xa assays. Higher heparin levels during CPB were confirmed to associate with reduced transfusion requirements.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Blood Coagulation; Blood Coagulation Tests; Blood Loss, Surgical; Cardiopulmonary Bypass; Chromogenic Compounds; Coronary Artery Bypass; Coronary Artery Disease; Drug Monitoring; Erythrocyte Transfusion; Factor Xa; Factor Xa Inhibitors; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Heparin; Humans; Male; Middle Aged; Monitoring, Intraoperative; Peptide Fragments; Prospective Studies; Protein C; Prothrombin; Thromboplastin

Recent clinical studies are testing strategies for short (1-3 months) dual antiplatelet therapy following newer-generation drug-eluting stent (DES) placement. However, detailed biological responses to newer-generation DES remain unknown in humans.. We sought to evaluate early pathologic responses to abluminal biodegradable polymer-coated (BP-) DES compared with circumferential durable polymer-coated (DP-) DES in human autopsy cases.. The study included 38 coronary lesions with newer-generation DES implanted for <90 days (DP-DES=24, BP-DES=14) in 26 autopsy cases. The degree of strut coverage was defined as follows: grade 0 (bare), grade 1 (with fibrin or tissues/cells without endothelium), grade 2 (with single-layered endothelium), and grade 3 (with endothelium and underlying smooth muscle cell layers)..  The duration following implantation was similar in DP- and BP-DES (median=20 vs 17 days). A total of 2,022 struts (DP-DES=1,297, BP-DES=725) were pathologically analysed. Focal grade 2 coverage was observed as early as 5 days after the implantation in both stents. The multilevel mixed-effects ordered logistic regression model demonstrated that BP-DES exhibited greater strut coverage compared with DP-DES (odds ratio [OR]: 3.64, 95% confidence interval [CI]: 1.37-9.67; p=0.009), which remained significant after adjustment for the duration following implantation and underlying tissue characteristics (OR: 2.74, 95% CI: 1.10-6.80; p=0.030). The predictive probability of grade 2 and 3 coverage was comparably limited at 30 days (DP-DES=17.1%, BP-DES=28.7%) and increased at 90 days (DP-DES=76.5%, BP-DES=86.6%). Both stents showed low inflammation and a similar degree of fibrin deposition.. Single-layered endothelial coverage begins in the days after newer-generation DES placement, and BP-DES potentially exhibit faster strut coverage with smooth muscle cell infiltration than DP-DES in humans. Nevertheless, vessel healing remains suboptimal in both stents at 30 days.

Topics: Absorbable Implants; Coronary Artery Disease; Drug-Eluting Stents; Fibrin; Humans; Percutaneous Coronary Intervention; Polymers; Prosthesis Design; Treatment Outcome

Multiple pleiotropic effects of statins include antithrombotic properties with formation of looser fibrin networks more susceptible to lysis. Recently, rosuvastatin 20 mg/d has been reported to decrease coagulation factors (F) VII, FVIII and FXI in venous thrombosis patients.. We investigated how high-dose statin therapy recommended in coronary artery disease (CAD) alters plasma levels of coagulation factors and if such changes might affect fibrin clot properties.. We studied 130 advanced CAD patients, who initially did not achieve the target low-density lipoprotein cholesterol (LDL-C). Before high-dose statin therapy (rosuvastatin 40 mg/d or atorvastatin 80 mg/d) and 6-12 months after its initiation, FII, FV, FVII, FVIII, FIX, FX, FXI and fibrinogen were assessed. We evaluated the impact of statin-induced alterations to the factors on plasma fibrin clot permeability (Ks) reflecting a fibrin pore size, and clot lysis time (CLT) reflecting fibrinolytic potential.. At baseline LDL-C (median 3.2, interquartile range 2.7-3.7 mmol/L) was independently associated solely with FXI (β = 0.58, P < 0.001). Median LDL-C reduction by 25% (P < 0.001) on high-dose statin treatment was accompanied by lowering of FVII, FVIII, and FXI (for all P < 0.001). On high-dose statin treatment, Ks (R = 0.65, P < 0.001) inversely associated with CRP (β = -0.41, P < 0.001), LDL-C (β = -0.26, P = 0.001), and FXI (β = -0.18, P = 0.016). In turn, CLT (R = 0.45, P < 0.001) was positively associated with LDL-C (β = 0.19, P = 0.043) and FXI (β = 0.17, P = 0.049).. High-dose statin therapy in CAD patients decreases FVII, FVIII, and FXI. The statin-induced reduction in FXI may contribute to less prothrombotic fibrin clot phenotype, indicating additional antithrombotic effect of high-dose statins.

Topics: Blood Coagulation Factors; Cholesterol, LDL; Coronary Artery Disease; Factor XI; Fibrin; Fibrinolytic Agents; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Rosuvastatin Calcium; Thrombin; Thrombosis

Patients with coronary artery disease (CAD) display a prothrombotic fibrin clot phenotype, involving low permeability and resistance to lysis. The determinants of this phenotype remain elusive. Circulating tissue factor (TF) and activated factor XI (FXIa) are linked to arterial thromboembolism. We investigated whether detectable active TF and FXIa influence fibrin clot properties in CAD.. In 118 CAD patients (median age 65 years, 78% men), we assessed Ks, an indicator of clot permeability, and clot lysis time (CLT) in plasma-based assays, along with the presence of active TF and FXIa. We also analysed proteins involved in clotting and thrombolysis, including fibrinogen, plasminogen activator inhibitor-1 (PAI-1) and thrombin activatable thrombolysis inhibitor (TAFI). During a median 106 month (interquartile range 95-119) follow-up, myocardial infarction (MI), stroke, systemic thromboembolism (SE) and cardiovascular (CV) death were recorded.. Circulating TF and FXIa, detected in 20.3% and 39.8% of patients, respectively, were associated with low Ks and prolonged CLT. Solely FXIa remained an independent predictor of low Ks and high CLT on multivariable analysis. Additionally, fibrinogen and PAI-1 were associated with low Ks, while PAI-1 and TAFI-with prolonged CLT. During follow-up low Ks and prolonged CLT increased the risk of MI and the latter also a composite endpoint of MI, stroke/SE or CV death.. To our knowledge, this study is the first to show that circulating FXIa is associated with prothrombotic fibrin clot properties in CAD, suggesting additional mechanisms through which FXIa inhibitors could act as novel antithrombotic agents in CAD.

Topics: Coronary Artery Disease; Factor XIa; Fibrin; Fibrin Clot Lysis Time; Fibrinogen; Fibrinolysis; Humans; Plasminogen Activator Inhibitor 1; Stroke; Thromboembolism; Thrombosis

Mortality after coronary artery bypass grafting (CABG) is primarily thromboembolic by nature. We investigated whether impaired fibrinolysis observed in cardiovascular diseases is associated with long-term mortality following CABG.. The study population comprised 292 consecutive patients (aged 64.6 ± 8.1 years) who underwent scheduled CABG. We measured plasma clot lysis time (CLT) preoperatively as a measure of fibrinolysis capacity. Cardiovascular and all-cause deaths were recorded during a median follow-up of 13.8 years.. CLT positively correlated with age (r = .56, p < .001), fibrinogen (r = .25, p = .002) and EuroSCORE I (r = .32, p < .001). The cardiovascular and overall mortality rates were 3.0 and 4.9 per 100 patient-years (32.4% vs 52.8%) respectively. In patients who died from cardiovascular and all causes, CLT was prolonged compared with survivors (both p < .050). Multivariable Cox regression analysis adjusted for potential confounders showed that long-term cardiovascular and all-cause deaths were associated with CLT (HR per 10 min 1.206; 95% CI 1.037-1.402, p = .015 and HR 1.164; 96% CI 1.032-1.309, p = .012), low-density lipoprotein cholesterol (HR per 1 mmol/L 1.556; 95% CI 1.205-2.010, p < .001 and HR 1.388; 96% CI 1.125-1.703, p = .002), C-reactive protein (HR per 10 mg/L 1.171; 95% CI 1.046-1.312, p = .006 and HR 1.127; 95% CI 1.005-1.237, p = .022) and EuroSCORE I (HR 1.173; 95% CI 1.016-1.355, p = .030 and HR 1.183; 95% CI 1.059-1.317, p = .003 respectively). Type 2 diabetes was solely associated with overall mortality (HR 1.594; 96% CI 1.088-2.334, p = .017).. In this study, we showed that reduced fibrin clot susceptibility to fibrinolysis is weekly associated with long-term mortality in advanced CAD.

Topics: Coronary Artery Bypass; Coronary Artery Disease; Diabetes Mellitus, Type 2; Fibrin; Fibrin Clot Lysis Time; Follow-Up Studies; Humans; Treatment Outcome

Pathological changes after third-generation drug-eluting stent implantation remain unclear. We compared the tissue responses of coronary arteries after the implantation of third-generation abluminal biodegradable-polymer everolimus-eluting stent (3rd EES) and second-generation durable-polymer EES (2nd EES) using autopsy specimens and an atherosclerotic porcine model. We compared the histology of stented coronary arteries obtained by autopsy performed 1-10 months after 3rd EES (n (number of cases) = 4, stent-implanted period of 3-7 months) and 2nd EES (n (number of cases) = 9, stent-implanted period of 1-10 months) implantations. The ratio of covered stent struts was higher with 3rd EESs than with 2nd EESs (3rd; 0.824 ± 0.032 vs. 2nd; 0.736 ± 0.022, p = 0.035). Low-density lipoprotein receptor knockout minipigs were stented with 3rd or 2nd EES in the coronary arteries and the stented regions were investigated. The fibrin deposition around the 2nd EES was more prominent. Additionally, higher density of smooth muscle cells was confirmed after the 3rd EES implantation. Pathological examination after the 3rd EES demonstrated a combination of less fibrin deposition and more rapid acquisition of well-developed neointima as compared to the 2nd EES at autopsy and the atherosclerotic porcine model.

Topics: Absorbable Implants; Aged; Aged, 80 and over; Animals; Animals, Genetically Modified; Autopsy; Coronary Artery Disease; Coronary Vessels; Disease Models, Animal; Drug-Eluting Stents; Everolimus; Female; Fibrin; Gene Knockout Techniques; Humans; Male; Middle Aged; Neointima; Percutaneous Coronary Intervention; Plaque, Atherosclerotic; Prosthesis Design; Receptors, LDL; Swine; Swine, Miniature; Treatment Outcome

 Despite long-term antiplatelet therapy with aspirin, recurrent cardiovascular events remain common in patients with coronary artery disease (CAD)..  We aimed to determine whether fibrin network characteristics are predictive of vascular events in patients with stable CAD treated with aspirin monotherapy..  We included 786 patients with angiographically documented CAD and either prior myocardial infarction, type 2 diabetes mellitus, or both. Median follow-up time was 3 years. At inclusion, fibrin clot properties were evaluated using a turbidimetric assay and the following clot parameters were studied: (1) maximum absorbance, a measure of clot density and fiber thickness; (2) lysis time, assessing fibrinolysis potential; and (3) area under the curve (AUC), a measure of clot formation and lysis. The primary endpoint was the composite of nonfatal myocardial infarction, ischemic stroke, and cardiovascular death. Hazard ratios (HRs) were estimated using multivariable Cox proportional hazards regression..  We demonstrate that increased clot AUC predicts future cardiovascular events in stable CAD patients receiving aspirin monotherapy.

Topics: Aged; Aspirin; Blood Coagulation; Coronary Artery Disease; Fibrin; Fibrinolysis; Follow-Up Studies; Humans; Male; Middle Aged; Myocardial Infarction; Nephelometry and Turbidimetry; Prognosis; Survival Analysis; Thrombosis

Fibrin formation and histidine-rich glycoprotein (HRG) are involved in primary hemostasis and wound healing. Little is known regarding the relationship of clot characteristics, bleeding time, and wound healing.. We studied 154 patients with coronary artery disease (CAD) and 154 subjects free of CAD matched for age, obesity, and current smoking. We evaluated bleeding time (BT) using standardized skin incisions on a forearm, along with plasma clot permeability (. The study shows that plasma fibrin clot density and HRG may influence BT and that appropriate skin wound healing is associated with medium BT.

Topics: Aged; Bleeding Time; Case-Control Studies; Coronary Artery Disease; Female; Fibrin; Fibrin Clot Lysis Time; Humans; Male; Middle Aged; Proteins; Wound Healing

Topics: Ankle Brachial Index; Blood Platelets; Coronary Artery Disease; Female; Fibrin; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Peripheral Arterial Disease; Postoperative Complications; Prevalence; Republic of Korea; Risk Assessment; Severity of Illness Index; Thrombelastography; Thrombosis

 The.  We included 773 stable CAD patients. Patients were genotyped for 45 genome-wide CAD risk variants, including rs495828 at the.  The rs495828 risk allele was present in 13.2% of patients and associated with higher clot maximum absorbance (adjusted effect size per risk allele: 1.05 [1.01 - 1.09],

Topics: ABO Blood-Group System; Aged; Blood Coagulation; Coronary Artery Disease; Female; Fibrin; Galactosyltransferases; Genetic Loci; Genetic Predisposition to Disease; Genetic Variation; Humans; Male; Middle Aged; Myocardial Infarction

Fibrin clot lysability is associated with development of cardiovascular disease (CVD). We evaluated sex-differences in fibrin clot lysability and the association with coronary plaque composition determined by computed tomography angiography (CTA).. Middle-aged citizens without known CVD were randomly selected from a national registry. A coronary CTA assessed volumes of calcified-, non-calcified-, low-density non-calcified-, and total- plaque using a validated plaque quantification software. A non-enhanced cardiac CT scan assessed the Agatston score. Fibrin structure properties were determined using turbidimetric methods. Plasma concentrations of C-reactive protein and fibrinogen were assessed.. 138 individuals (71 women) participated. Men more frequently had coronary plaques compared to women, P < 0.05. Coronary plaque features were comparable between men and women, P > 0.05. Women with total plaque volume > 0 mm. Asymptomatic women with coronary plaques assessed by coronary CTA have reduced fibrin clot lysability compared to both women without coronary plaques and men, suggesting a sex-dependent link between coronary atherosclerosis and fibrin clot lysability.

Topics: Aged; Cardiovascular Diseases; Cohort Studies; Coronary Artery Disease; Cross-Sectional Studies; Female; Fibrin; Humans; Male; Middle Aged; Plaque, Atherosclerotic; Risk Factors; Sex Characteristics

Current drug-eluting stents have abluminal polymer coating; however, thrombus formation in these compared with that in uniformly coated stents remains controversial. We evaluated thrombus formation and early endothelialization after using abluminal biodegradable polymer-coated sirolimus- (BP-SES), and everolimus-eluting stents (BP-EES) versus a durable polymer-coated everolimus-eluting stent (DP-EES) in an in vivo setting. BP-SES, BP-EES, and DP-EES (n = 6 each) were implanted in coronary arteries of 12 mini-pigs that were then sacrificed after 7 and 10 days. Stents were stained with hematoxylin and eosin, and a combined Verhoeff and Masson trichrome stain. Areas of fibrin deposition were digitally detected and measured with off-line morphometric software. Stents were investigated for re-endothelialization by transmission electron microscopy. At 7 days, histological analysis revealed the lowest area of fibrin deposition in BP-SES (BP-SES vs. BP-EES vs. DP-EES; 0.10 ± 0.06 mm2 vs. 0.15 ± 0.07 mm2 vs. 0.19 ± 0.06 mm2, p = 0.0004). At 10 days, the area of fibrin deposition was significantly greater in DP-EES (0.13 ± 0.04 mm2 vs. 0.14 ± 0.05 mm2 vs. 0.19 ± 0.08 mm2, p = 0.007). Endothelial cells in BP-SES demonstrated a significantly greater number of tight junctions than those in DP-EES according to by transmission electron microscopy for both days (p<0.05). Various parameters, including an inflammatory reaction and neointimal formation, were comparable among the groups at 7 and 10 days. An abluminal biodegradable polymer-coated SES showed the least fibrin deposition and greatest endothelial cell recovery at an early stage following implantation in the coronary arteries of mini-pigs.

Topics: Absorbable Implants; Animals; Cardiovascular Agents; Coated Materials, Biocompatible; Coronary Angiography; Coronary Artery Disease; Coronary Vessels; Drug-Eluting Stents; Endothelial Cells; Everolimus; Fibrin; Models, Animal; Percutaneous Coronary Intervention; Polymers; Prosthesis Design; Sirolimus; Swine; Swine, Miniature; Thrombosis; Treatment Outcome

Incidence and prevalence of cardiovascular disease (CVD) differ between sexes, and women experience CVD later than men. Changes in fibrin clot lysability are associated with CVD, and the present study addresses sex differences in fibrin clot lysability in asymptomatic middle-aged individuals and the relation to coronary artery calcification (CAC).. Participants free of morbidities and medication, N = 163, were randomly chosen from a national registry among citizens, 50 or 60 years of age, and were followed for 5 years. CAC was determined by the Agatston (Ag) score both at baseline and at follow-up. Based on the changes in Ag, the population was divided into two groups: ΔAg = 0 U or ΔAg > 0 U. Fibrin clot analyses were based on turbidimetric methods.. At baseline, 116 women and 97 men were included; 84 women and 79 men completed the 5-year follow-up (77%). Independently of covariates, women with ΔAg > 0 had reduced mean (SD) fibrin lysability at follow-up, 40.2% (15.9), both in comparison to baseline, 47.8% (20.4), p = 0.001, to women with ΔAg = 0 U, 51.2% (24.5), p = 0.028, and to men with ΔAg > 0 U, 54.4% (21.0), p = 0.002.. Fibrin clot lysability changes over time with considerable sex differences. Women with progression of CAC have reduced fibrin clot lysability compared to men, indicating a sex-specific association between morphological vessel wall changes and fibrin clot lysability.

Topics: Coronary Artery Disease; Coronary Vessels; Female; Fibrin; Fibrinolysis; Humans; Male; Middle Aged; Sex Characteristics; Vascular Calcification

Topics: Blood Coagulation Tests; Calibration; Case-Control Studies; Coronary Artery Disease; Feasibility Studies; Fibrin; Fibrinolysis; Humans; Myocardial Infarction; Nephelometry and Turbidimetry; Observer Variation; Pilot Projects; Predictive Value of Tests; Reference Standards; Reproducibility of Results; Spectrophotometry; Time Factors

Topics: Aged; Blood Coagulation; Coronary Angiography; Coronary Artery Disease; Coronary Thrombosis; Female; Fibrin; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Predictive Value of Tests; Proportional Hazards Models; Risk Factors; Stents; Tensile Strength; Thrombelastography; Time Factors; Treatment Outcome

Atherosclerosis, a chronic vascular disease, leads to molecular events bound with interplaying processes of inflammation and coagulation. In the present study, fibronectin (FN), FN containing extra domain A (EDA-FN), frequency of occurrence, and relative amounts of soluble plasma FN-fibrin complexes were analyzed in 80 plasma samples of patients suspected of coronary artery disease based on clinical evaluation and changes in arteries found by computed tomographic coronary angiography. The study showed that in the plasma of the patients' group with high risk of coronary artery disease EDA-FN concentration was significantly higher (3.5 ± 2.5 mg/L; P < 0.025) and the molecular FN-fibrin complexes of 1000 kDa and higher occurred more often than in the groups of patients with mild risk of coronary artery disease and the normal age-matched. The increased level of EDA-FN and occurrence of FN-fibrin complexes could have a potential diagnostic value in the diagnosis and management of patients with coronary artery disease.

Topics: Atherosclerosis; Cohort Studies; Coronary Artery Disease; Fibrin; Fibronectins; Humans; Risk

We investigated whether and to what extent the ratio between circulating fibrinogen (Fg) and its degradation products (FDP) reflects the severity of coronary artery disease (CAD) in type 2 diabetic patients.. Plasma levels of Fg and FDP were determined, and Fg/FDP ratio was calculated in 344 consecutive patients with type 2 diabetes and chest pain on exertion undergoing coronary angiography. The severity of CAD was evaluated by the number of significant CAD (>50% luminal diameter narrowing) and Gensini score.. Plasma Fg was higher, but Fg/FDP ratio was lower in patients with significant CAD (n = 255) compared with those without (n = 89), due to a disproportionate increase in FDP. Fg and FDP correlated positively, while Fg/FDP ratio negatively, with the number of diseased coronary arteries and the tertile of Gensini score (all P values for trend < 0.01). After adjusting for age, sex, risk factors for CAD, lipid profiles, glycosylated hemoglobin A1c, creatinine, leukocyte count, and high-sensitivity C-reactive protein, Fg/FDP ratio remained an independent determinant for multivessel coronary disease (MVD) (odds ratio [OR], 0.869; 95% confidence interval [CI], 0.788-0.958, P = 0.005) and high tertile of Gensini score (OR, 0.797, 95% CI, 0.682-0.930, P = 0.004). The area under the curve of Fg/FDP ratio was larger than that of Fg for predicting the presence of MVD (0.647 vs. 0.563, P = 0.048) and Gensini score ≥ 30 (0.656 vs. 0.538, P = 0.026).. Elevated plasma Fg and FDP level and reduced Fg/FDP ratio are associated with presence of CAD, and Fg/FDP ratio is superior to Fg in reflecting severe coronary atherosclerosis for patients with type 2 diabetes.

Topics: Aged; Coronary Angiography; Coronary Artery Disease; Diabetes Mellitus, Type 2; Female; Fibrin; Fibrinogen; Humans; Male; Middle Aged

Factor XIII (FXIII) is necessary for cross linking of fibrin strands and generation of stable fibrin clot. FXIII Val34Leu is a common genetic single nucleotide polymorphism that has been associated with accelerated fibrin stabilization and reduced rate of fibrinolysis. The contribution of Val34Leu to long term risk of recurrent myocardial infarction (MI) in patients with coronary stenting has not been conclusively established. The objective of the study was to examine the effects of Val34Leu on fibrin generation, platelet aggregation, and long term clinical outcomes in patients with coronary artery disease treated with dual antiplatelet therapy. Patients with angiographically documented coronary artery disease who were treated with aspirin and clopidogrel were enrolled (n = 211). Light transmittance aggregometry and plasma fibrin clot formation using thrombelastography (TEG) were determined. Genotyping of Val34Leu was performed using Taqman assay. Clinical events during follow up were recorded. Homozygous carriers of 34 Leu variant had significantly shorter fibrin clot formation time as compared to wild type individuals (TEG K: 1.27 ± 0.3 vs. 1.68 ± 1.1 min, p = 0.011). The Val34Leu variant was associated with gene dose dependent increased risk of MI (log rank, p = 0.002) or occurrence of composite of MI and CV death (log rank, p = 0.005) with highest event rates observed in homozygous carriers of 34 Leu. In summary, FXIII Val34Leu polymorphism was associated with increased rate of fibrin stabilization in homozygous carriers of the variant and may increase risk of recurrent MI and death in patients with angiographically established coronary artery disease treated with dual antiplatelet therapy.

Topics: Adult; Aged; Amino Acid Substitution; Aspirin; Clopidogrel; Coronary Artery Disease; Factor XIII; Female; Fibrin; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation; Platelet Aggregation Inhibitors; Polymorphism, Genetic; Thrombelastography; Ticlopidine

Topics: Aged; Blood Platelets; Coronary Artery Disease; Female; Fibrin; Humans; Male; Middle Aged; Platelet Count

Peri-strut low-intensity area (PLI) is a common imaging finding during the evaluation of in-stent neointima using optical coherence tomography (OCT). We aimed to determine the biological significance of PLI by comparing in-vivo OCT images with the corresponding histological sections obtained from the familial hypercholesterolemic swine model of coronary stenosis.. A total of 26 coronary vessels of nine familial hypercholesterolemic swine were injured with 30% balloon overstretch and then immediately followed by everolimus eluting or bare metal stent placement at 20% overstretch. At 30 days, all stented vessels were subjected to in-vivo OCT analysis and were harvested for histological evaluation. For OCT analysis, stent cross-sections (three per stent) were categorized into presence (PLI+) or absence (PLI-) of PLI. In histology, inflammation and fibrin deposition were scored semiquantitatively from 0 (none) to 3 (severe).. PLI was found in 64.9% of stent sections. Peri-strut inflammation was more frequently observed in OCT sections PLI (+) compared with PLI (-) (56.0 vs. 7.4%, P=0.01). In contrast, peri-strut fibrin deposits was similar in both groups (PLI+=58.0% vs. PLI-=59.3%, P=0.94). Histological neointimal thickness was significantly higher in PLI (+) sections (mean±SE: 0.68±0.06 vs. 0.34±0.02 mm; P<0.01), yielding a higher percent area stenosis compared with PLI (-) (mean±SE: 59.0±4.4 vs. 34.1±2.2%, P<0.01). The PLI diagnostic sensitivity and specificity for inflammation were 80 and 76.1%, respectively (>56% PLI, area under the curve=0.86, P<0.01), whereas for fibrin deposition, the sensitivity and specificity were 42.2 and 76.1%, respectively (area under the curve=0.56, P=NS). Area under the receiver operating characteristic curve was significantly higher for identifying inflammation than fibrin (0.86 vs. 0.56, P<0.01). The severity of PLI correlated with the neointimal thickness when assessed by OCT (R=0.79, P<0.001).. The presence of PLI in OCT correlates with neointimal thickness and appears to have a diagnostic value in the recognition of peri-strut inflammation, therefore possibly serving as a surrogate for in-vivo assessment of stent efficacy.

Topics: Animals; Coronary Artery Disease; Coronary Restenosis; Coronary Vessels; Disease Models, Animal; Drug-Eluting Stents; Fibrin; Graft Occlusion, Vascular; Hyperlipoproteinemia Type II; Hyperplasia; Inflammation; Male; Neointima; Stents; Swine; Tomography, Optical Coherence

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

Inflammation is implicated in the progression of coronary artery disease and the molecular processes of inflammation and thrombosis are closely intertwined. Elevated levels of C-reactive protein (CRP) have been associated with an elevated risk of adverse ischaemic events after coronary stenting and hypercoagulability. Heightened whole blood clot strength measured by thrombelastography (TEG) has been associated with adverse ischaemic events after stenting. We intended to examine the relationship of CRP to plasma fibrin clot strength in patients after coronary stenting. Plasma fibrin clot strength was measured by TEG in 54 patients 16-24 h after undergoing elective percutaneous coronary intervention (PCI). Coagulation was induced in citrated plasma by addition of kaolin and CaCl2. Plasma levels of CRP and fibrinogen were measured by enzyme-linked immunoassay. Increasing quartiles of CRP were associated with increasing levels of maximal plasma fibrin clot strength measured by TEG (P < 0.001) and increasing BMI (P = 0.04). Patients in the highest quartile of CRP had significantly higher maximal fibrin clot strength (G) than the patients in the lowest quartile (G: 3438 ± 623 vs. 2184 ± 576 dyn/cm, P < 0.0001). Fibrinogen concentration was not significantly different across quartiles of CRP (P = 0.97). Patients with established coronary artery disease undergoing coronary stenting who have elevated CRP after PCI exhibit heightened maximal plasma fibrin clot strength as compared with those with low CRP. Thrombotic risk associated with elevated CRP may be linked to procoagulant changes and high tensile fibrin clot strength independent of fibrinogen concentration.

Topics: Aged; Angioplasty, Balloon, Coronary; Blood Coagulation; C-Reactive Protein; Calcium Chloride; Coronary Artery Disease; Female; Fibrin; Fibrinogen; Humans; Inflammation; Kaolin; Male; Middle Aged; Risk Factors; Stents; Thrombelastography; Thrombophilia; Thrombosis

Aspirin is a cornerstone in prevention of cardiovascular events and modulates both platelet aggregation and fibrin clot formation. Some patients experience cardiovascular events whilst on aspirin, often termed aspirin treatment failure (ATF). This study evaluated both platelet aggregation and fibrin clot structure in patients with ATF.. We included 177 stable coronary artery disease patients on aspirin monotherapy. Among these, 116 (66%) had ATF defined as myocardial infarction (MI) whilst on aspirin. Platelet aggregation was assessed by Multiplate® aggregometry and VerifyNow®, whereas turbidimetric assays and scanning electron microscopy were employed to study fibrin clot characteristics.. Enhanced platelet aggregation was observed in patients with ATF compared with non-MI patients following stimulation with arachidonic acid 1.0 mM (median 161 (IQR 95; 222) vs. 97 (60; 1776) AU*min, p = 0.005) and collagen 1.0 µg/mL (293 (198; 427) vs. 220 (165; 370) AU*min, p = 0.03). Similarly, clot maximum absorbance, a measure of fibrin network density, was increased in patients with ATF (0.48 (0.41; 0.52) vs. 0.42 (0.38; 0.50), p = 0.02), and this was associated with thinner fibres (mean ± SD: 119.7±27.5 vs. 127.8±31.1 nm, p = 0.003) and prolonged lysis time (552 (498; 756) vs. 519 (468; 633) seconds; p = 0.02). Patients with ATF also had increased levels of C-reactive protein (CRP) (1.34 (0.48; 2.94) and 0.88 (0.32; 1.77) mg/L, p = 0.01) compared with the non-MI group. Clot maximum absorbance correlated with platelet aggregation (r = 0.31-0.35, p-values<0.001) and CRP levels (r = 0.60, p<0.001).. Patients with aspirin treatment failure showed increased platelet aggregation and altered clot structure with impaired fibrinolysis compared with stable CAD patients without previous MI. These findings suggest that an increased risk of aspirin treatment failure may be identified by measuring both platelet function and fibrin clot structure.

Topics: Aged; Aspirin; Blood Coagulation; Blood Platelets; C-Reactive Protein; Coronary Artery Disease; Female; Fibrin; Humans; Male; Microscopy, Electron, Scanning; Middle Aged; Myocardial Infarction; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Treatment Failure

Altered fibrin clot structure has been reported both in patients with coronary artery disease (CAD) and those with type 2 diabetes mellitus (DM2). The aim of the present study was to evaluate plasma fibrin clot permeability and susceptibility to lysis in patients with DM2 and CAD. We studied 132 consecutive CAD patients, including 67 subjects with DM2, scheduled for elective coronary artery bypass grafting surgery. Ex vivo plasma fibrin clot permeability (K(s)) and lysis time (t(50%)) induced by 1 μg/mL recombinant tissue plasminogen activator (tPA), along with plasma levels of plasminogen activator inhibitor-1 (PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI), tPA, von Willebrand factor (vWF), P-selectin, soluble CD40 ligand (sCD40L), were measured. Diabetic and non-diabetic patients did not differ in regard to demographics and remaining cardiovascular risk factors. Concomitant DM2 was associated with higher glucose (+24.3%, p < 0.001), fibrinogen (+9.0%, p = 0.037), PAI-1 (+58.7%, p < 0.001), tPA (+24.0%, p < 0.001) and P-selectin (+12.2%, p < 0.001). Compared with the non-diabetic group, the CAD patients with DM2 had lower K(s) (-6.1%, p = 0.02) and prolonged t(50%) (+5.1%, p = 0.04). Multiple regression analysis of the whole study group showed that vWF, PAI-1, fibrinogen and DM2 were the independent predictors of t(50%) (R(2) = 0.58, p < 0.001), while only vWF was an independent predictor of K(s) (R(2) = 0.22, p < 0.001). This study indicates that DM2 is potent enough to unfavorably affect plasma fibrin clot characteristics despite abnormal clot phenotype typically observed in CAD. Of note, platelet and endothelial markers appear to contribute to fibrin clot properties in CAD concomitant with DM2.

Topics: Aged; Case-Control Studies; Coronary Artery Disease; Diabetes Mellitus, Type 2; Female; Fibrin; Humans; Male; Middle Aged

Type 2 diabetes is an important risk factor for the development of coronary artery disease (CAD). Focal or diffuse inflammation is often present in the vessels of patients with CAD. Mast cells are frequently present in the plaques as well as in the inflammatory infiltrates in the atherosclerotic vessel wall. In the study we wanted to examine whether there are differences in the morphology, number and distribution of mast cells and in their ability to modify the atherosclerotic process in coronary arteries (CA) in the diabetic vs. the hypertensive population of patients with CAD.. Coronary artery endarterectomy specimens were obtained from patients with diabetes or hypertension as the only risk factor for CAD. The specimens were stained with haematoxylin-eosin and Sulphated Alcian Blue for mast cells and with immunofluorescent methods for fibrinogen-fibrin and IgG deposits in the vessel wall. Both morphological and stereological assessments were conducted for mast cells and mononuclear cell infiltrates.. The histological analysis of the vessel wall of diabetic patients in comparison with hypertensive patients showed a damaged endothelial cells layer and deposits of fibrin-fibrinogen and IgG in the tunica intima and media. The stereological count revealed a diminished numerical density of mast cells and a significantly higher volume density of the mononuclear cells. Mast cells displayed cytoplasmic vacuolization, extracellular extrusion of granule and pyknotic nuclei.. This preliminary study suggests that the impaired mast cells might be the reason for more extensive inflammatory and immunologic atherosclerotic changes in the CA vessel wall of CAD patients with type 2 diabetes.

Topics: Aged; Coronary Artery Bypass; Coronary Artery Disease; Coronary Vessels; Diabetes Mellitus, Type 2; Endarterectomy; Fibrin; Fibrinogen; Fluorescent Antibody Technique; Humans; Hypertension; Immunoglobulin G; Male; Mast Cells; Middle Aged; Pilot Projects; Slovenia; Staining and Labeling

Topics: C-Reactive Protein; Coronary Artery Disease; Female; Fenofibrate; Fibrin; Fibrinolysis; Heptanoic Acids; Homocysteine; Humans; Hypersensitivity, Immediate; Laser Coagulation; Lipoprotein(a); Male; Pyrroles; Retinal Vein; Retinal Vein Occlusion; Simvastatin; Tetrahydroisoquinolines; Thrombosis; Venous Thromboembolism; Venous Thrombosis

Intraplaque haemorrhage has been shown to be important in necrotic core enlargement. Immunolocalisation of fibrin within progressive stages of plaque progression has not been extensively studied.. Histological sections (n = 74) of human coronary arteries were stained immunohistochemically for fibrin II, red blood cell antigen (glycophorin A), and CD31. Plaques were chosen to represent a range of lesions [6 adaptive intimal thickening, AIT (AHA grade I); 4 intimal xanthomas (AHA grade II), 19 pathologic intimal thickening, PIT (AHA grade III, or pre-atheroma); 34 fibroatheromas, FA (AHA grade IV and V); and 11 thin cap fibroatheromas (TCFA, AHA grade IV)].. Fibrin was generally absent in the intima of AIT and PIT, with moderate staining in cores of early FA (2.6 +/- 0.3). All late FA and TCFA demonstrated intracore fibrin, with mean scores of 2.9 +/- 0.3 and 3.0 +/- 0.3, respectively. Intimal vasa vasorum counts increased with intimal fibrin score (p < 0.0001); in 68% of cores with fibrin staining, there was minimal or no evidence of red cell breakdown.. Fibrin in necrotic cores is present proportional to intraplaque vasa vasorum and before red cells, suggesting leakage of vessels before frank intraplaque haemorrhage. Fibrin may play a role in the bridge between pre-atheroma and atheroma.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Coronary Artery Disease; Coronary Vessels; Death, Sudden, Cardiac; Disease Progression; Fibrin; Humans; Male; Middle Aged; Necrosis; Prospective Studies; Tunica Intima

Identify whether the plasma concentration of Lp(a), apo(a) size or a greater affinity for fibrin predict the likelihood of cardiac death, non-fatal myocardial infarction, unstable angina, the need for additional revascularization, and stroke (MACCE).. We analyzed the clinical prognosis of 68 patients with coronary artery disease included in a case-controlled study which evaluated Lp(a) concentration, apo(a) size, and Lp(a) fibrin-binding. Cohort was conducted over a median of 8 years. We used Kaplan-Meier survival tables to evaluate cardiovascular and cerebrovascular events in the follow-up period.. Apo(a) isoforms of small size are predictors of MACCE. We find an association between Lp(a) concentration and apo(a) fibrin-binding with major adverse cardiovascular and cerebrovascular events, although without statistically significant results.. Small-sized apo(a) isoforms are an independent risk factor for MACCE in patients with coronary artery disease in follow-up. Lp(a) plasma concentration and apo(a) fibrin-binding were associated, although not significant.

Topics: Adult; Angina, Unstable; Apolipoproteins A; Coronary Artery Disease; Electrophoresis, Polyacrylamide Gel; Female; Fibrin; Humans; Lipoprotein(a); Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Myocardial Revascularization; Phenotype; Prognosis; Protein Binding; Stroke

The objective of the study was to determine the relation of platelet reactivity, hypercoagulability and inflammation in various stages of coronary artery disease acuity (CAD). Thrombin-induced platelet-fibrin clot strength (MA), time to initial platelet-fibrin clot formation (R), C-reactive protein (CRP), prothrombotic factors, activated GPIIb/IIIa receptor expression and other biomarkers were studied in patients with asymptomatic stable CAD (AS), in patients undergoing PCI for stable (SA) and unstable angina (UA). MA and R were measured by thrombelastography, GPIIb/IIIa expression by flow cytometry and all other markers by fluorokine multianalyte profiling assays. An overall increase in all measurements from a clinically stable to an unstable disease state was observed. There was a distinct stepwise increment in MA [AS vs. SA (p = 0.02), SA vs. UA (p = 0.02) and AS vs. UA (p < 0.001)]. MA exhibited the strongest correlation with other prothrombotic markers (p < or = 0.02), with CRP (p < 0.001) at all levels of CAD acuity. A distinct pathophysiological state of heightened platelet function, hypercoagulability and inflammation marks the presence of unstable cardiovascular disease requiring intervention. Further studies are required to investigate the primary mechanisms linking the above processes associated with a prothrombotic state resulting in clinical destabilization of the disease.

Topics: Aged; Biomarkers; Blood Platelets; C-Reactive Protein; Cohort Studies; Coronary Artery Disease; Disease Progression; Female; Fibrin; Flow Cytometry; Humans; Inflammation; Male; Thrombelastography; Thrombophilia

A common G to T transition in codon 34 with the subsequent valine with leucine replacement in the factor (F) XIII A-subunit affects fibrin formation and stabilisation in vitro. Data on the effects of Leu34 allele on cardiovascular thromboembolic events in vivo are conflicting.. We investigated whether FXIII Val34Leu polymorphism is potent enough to affect fibrin clot properties in patients with advanced coronary artery disease (CAD).. We studied 113 patients, aged 62.8 +/- 6.1 years, who were scheduled for elective isolated coronary artery bypass grafting surgery (CABG). Patients were compared with 98 healthy age-matched controls. Ex vivo fibrin clot permeability and lysis time (t5oo/o) were determined in citrated plasma.. Patients scheduled for CABG had lower clot permeability (9.14 + 1.64 vs. 10.02 + 1.12 x 10(-9) cm2; p = 0.0002) and longer t50%, (8.45 +/- 1.94 vs. 7.63 +/- 1.24 min; p < 0.0001) than controls. The Leu34 carriers, i.e. 9 (8%) Leu34Leu homozygous and 23 (20%) Val34Leu heterozygous subjects, had lower permeability by 23% in the CAD group compared with 81 (72%) patients with Val34Val genotype. A similar intergroup difference was observed for t50%, which was longer in Leu34 carriers (p < 0.0001). The FXIII Leu34 allele frequency in the control group was similar as well as the impact of Leu34 allele on fibrin properties. The effect of FXIII Leu34 allele on permeability and t50%, was not affected by homocysteine, C-reactive protein and fibrinogen levels in CAD patients and controls.. Like in healthy subjects, in patients scheduled for CABG, the FXIII Leu34 allele is associated with decreased fibrin clot permeability and efficiency of lysis.

Topics: Aged; C-Reactive Protein; Case-Control Studies; Coronary Artery Bypass; Coronary Artery Disease; Factor XIII; Female; Fibrin; Fibrinolysis; Homocysteine; Humans; Male; Middle Aged; Permeability; Polymorphism, Genetic; Risk Assessment

Fibrinogen BbetaArg448Lys is a common polymorphism, positioned within the carboxyl terminus of the Bbeta-chain of the molecule. Studies suggest that it is associated with severity of coronary artery disease and development of stroke. The effects of the amino acid substitution on clot structure remains controversial, and the aim of this study was to investigate the effect(s) of this polymorphism on fibrin clot structure using recombinant techniques. Permeation, turbidity, and scanning electron microscopy showed that recombinant Lys448 fibrin had a significantly more compact structure, with thin fibers and small pores, compared with Arg448. Clot stiffness, measured by means of a novel method using magnetic tweezers, was significantly higher for the Lys448 compared with the Arg448 variant. Clots made from recombinant protein variants had similar lysis rates outside the plasma environment, but when added to fibrinogen-depleted plasma, the fibrinolysis rates for Lys448 were significantly slower compared with Arg448. This study demonstrates for the first time that clots made from recombinant BbetaLys448 fibrinogen are characterized by thin fibers and small pores, show increased stiffness, and appear more resistant to fibrinolysis. Fibrinogen BbetaArg448Lys is a primary example of common genetic variation with a significant phenotypic effect at the molecular level.

Topics: Amino Acid Substitution; Animals; Chlorocebus aethiops; Coronary Artery Disease; COS Cells; Fibrin; Fibrinogen; Fibrinolysis; Humans; Models, Molecular; Polymorphism, Genetic; Protein Structure, Tertiary; Recombinant Proteins; Stroke

Biocorrodible iron stents carry the potential to overcome limitations, such as chronic inflammation and premature recoil, posed by biodegradable polymer and magnesium alloy stents. This study aimed to test the safety and efficacy of biocorrodible iron stents in porcine coronary arteries.. Iron stents and cobalt chromium stents were randomly deployed in the coronary arteries of juvenile domestic pigs. Animals were sacrificed at 28 days, and the vessels were fixed and processed for histochemistry.. At 28 days, iron stents started to show signs of degradation without evidence of stent particle embolization or thrombosis without traces of excess inflammation, or fibrin deposition. At 28 days, the surface of the iron stent struts was black to brown and the vascular wall adjacent to the iron stent had a brownish tinge. There were no statistically significant differences in any of the measured parameters between segments implanted with iron and cobalt chromium stents. There were also no adverse effects in the persistent areas.. The current study demonstrates that stents made of biocorrodible iron are safe. In some of the measured parameters, such as intimal thickness, intimal area, and percentage occlusion, there was a trend in favor of the iron stents.

Topics: Animals; Biocompatible Materials; Chromium; Cobalt; Coronary Artery Disease; Coronary Restenosis; Coronary Thrombosis; Coronary Vessels; Fibrin; Inflammation; Iron Compounds; Stents; Swine

Topics: Aged; C-Reactive Protein; Case-Control Studies; Coronary Artery Disease; Female; Fibrin; Homocysteine; Humans; Lipoprotein(a); Male; Middle Aged

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

Hypofibrinolysis promotes atherosclerosis progression and recurrent ischemic events in premature coronary artery disease. We investigated the role of fibrin physical properties in this particular setting.. Biomarkers of recurrent thrombosis and premature coronary artery disease (CAD) were measured in 33 young post-myocardial infarction patients with angiographic-proven CAD and in 33 healthy volunteers matched for age and sex. Ex vivo plasma fibrin physical properties were assessed by measuring fibrin rigidity and fibrin morphological properties using a torsion pendulum and optical confocal microscopy. The fibrinolysis rate was derived from continuous monitoring of the viscoelastic properties after addition of lytic enzymes. Young CAD patients had a significant increase in plasma concentration of fibrinogen, von Willebrand factor, plasminogen activator inhibitor type 1, and lipoprotein(a) as compared with controls (P<0.05). Fibrin of young CAD patients was stiffer (P=0.002), made of numerous (P=0.002) and shorter fibers (P=0.04), and lysed at a slower rate than that of controls (P=0.03). Fibrin stiffness was an independent predictor for both premature CAD and hypofibrinolysis.. This first detailed study of clot properties in such a group of patients demonstrated that abnormal plasma fibrin architecture is an important feature of both premature CAD and fibrinolysis rate. The determinants of this particular phenotype warrant further investigation.

Topics: Adult; Coronary Artery Disease; Coronary Thrombosis; Elasticity; Female; Fibrin; Fibrinogen; Fibrinolysis; Humans; Lipoprotein(a); Male; Microscopy, Confocal; Myocardial Infarction; Plasminogen Activator Inhibitor 1; Predictive Value of Tests; Viscosity; von Willebrand Factor

To determine the proportion of platelets and fibrin in coronary thrombi.. Immunohistochemical and morphometric means to examine the coronary arteries of 31 patients who died of acute myocardial infarction.. Fresh thrombi were detected in the feeding arteries of infarction areas in 23 cases (74%) and were associated with plaque rupture in 18 (78%) and plaque erosion in 5 (22%). An immunohistochemical study showed that the thrombi consisted of a mixture of fibrin and platelets as well as some other types of blood cells. The fibrin and platelet positive areas in the thrombi associated with plaque rupture accounted for 74 (19)% and 35 (20)% (p < 0.01) and those associated with erosion accounted for 51 (6)% and 70 (21)%, respectively, of the total areas. Areas of positive immunoreactivity for tissue factor and C reactive protein were also significantly greater in ruptured than in eroded plaques.. These results indicate that the proportions of fibrin and of platelets differ in coronary thrombi on ruptured and eroded plaques. Higher proportions of tissue factor and C reactive protein contribute more significantly to thrombus formation on plaque rupture than on plaque erosion.

Topics: Aged; Aged, 80 and over; Biomarkers; Blood Platelets; C-Reactive Protein; Coronary Artery Disease; Coronary Thrombosis; Female; Fibrin; Humans; Male; Middle Aged; Risk Factors; Thromboplastin

A cross sectional and prospective analysis of 3,745 British women aged 60-79 years at baseline was undertaken. Among these women there were 570 prevalent cases of coronary heart disease (CHD) and 151 new cases among 12,641 person-years of follow up of women who were free of CHD at baseline. Both fibrinogen and CRP were associated with indicators of socioeconomic position in childhood and adulthood and there was a cumulative effect of socioeconomic position from across the life course. The age-adjusted odds ratio (95% confidence interval) of prevalent CHD for a 1 unit (1 g/L) increase in fibrinogen was 1.29 (1.12, 1.49); with full adjustment for all potential confounding factors this attenuated to 1.09 (0.93, 1.28). The hazards ratio for incident CHD among those free of disease at baseline was 1.28 (1.00, 1.64); with full adjustment for all potential confounding factors this attenuated to 1.09 (0.84, 1.44). Similar effects of adjustment for confounding factors were seen for the associations between CRP and both prevalent and incident CHD. By contrast, the strong positive association between smoking (an established causal risk factor for CHD) and CHD was not attenuated by adjustment for life course socioeconomic position or other risk factors. We conclude that fibrinogen and CRP predict CHD but may not be causally related to it.

Topics: Age Factors; Aged; Arteriosclerosis; C-Reactive Protein; Confounding Factors, Epidemiologic; Coronary Artery Disease; Coronary Disease; Female; Fibrin; Fibrinogen; Humans; Inflammation; Middle Aged; Models, Statistical; Odds Ratio; Prospective Studies; Risk Factors; Social Class

Formation of nitric oxide-derived oxidants has been linked to development of atherosclerosis and associated thrombotic complications. Although systemic levels of protein nitrotyrosine predict risk for coronary artery disease, neither specific proteins targeted for modification nor functional consequences that might contribute to disease pathogenesis have been defined. Here we report a selective increase in circulating levels of nitrated fibrinogen in patients with coronary artery disease. Exposure of fibrinogen to nitrating oxidants, including those produced by the myeloperoxidase-hydrogen peroxide-nitrite system, significantly accelerates clot formation and factor XIII cross-linking, whereas exposure of fibrinogen to non-nitrating oxidants decelerates clot formation. Clots formed with fibrinogen exposed to nitrating oxidants are composed of large bundles made from twisted thin fibrin fibers with increased permeation and a decrease in storage modulus G' value, suggesting that these clots could be easily deformed by mechanical stresses. In contrast, clots formed with fibrinogen exposed to non-nitrating oxidants showed decreased permeation with normal architecture. Fibrinogen modified by exposure to physiologic nitration systems demonstrated no difference in the rate of plasmin-induced clot lysis, platelet aggregation, or binding. Thus, increased levels of fibrinogen nitration may lead to a pro-thrombotic state via acceleration in formation of fibrin clots. The present results may account, in part, for the association between nitrative stress and risk for coronary artery disease.

Topics: Blood Coagulation; Coronary Artery Disease; Fibrin; Fibrinogen; Humans; Microscopy, Electron, Scanning; Protein Processing, Post-Translational; Reactive Nitrogen Species; Thrombosis

A family history of premature coronary artery disease (CAD) is an independent cardiovascular risk factor. Fibrin clots composed of dense fiber networks are found in young CAD patients and may occur in the relatives of such individuals.. The ex vivo fibrin structure of 100 healthy male relatives of patients with premature CAD and 100 age-matched control subjects was assessed by measurement of permeability (K(s)), fiber mass-length ratio ( micro ), and turbidity (lag phase and maximum absorbency [max DeltaAbs]). Scanning electron microscopy was performed on selected samples. Relatives and controls shared similar levels of conventional cardiovascular risk factors. K(s) was lower in relatives than in controls, 12.2 (11.1 to 13.3) versus 15.2 (14.0 to 16.5) x10(-9) cm(2) (P<0.001), associated with a smaller decrease in micro, 8.5 (7.7 to 9.2) versus 9.7 (8.9 to 10.5) x 10(13) Da/cm (P<0.05), respectively. Lag phase was shorter in relatives than in controls, 39 (37 to 41) versus 47 (44 to 50) seconds (P<0.001), and max DeltaAbs was higher in relatives, 0.78 (0.74 to 0.82) versus 0.71 (0.67 to 0.74) in controls (P=0.02), which indicates the presence of thicker fibers in relatives. After adjustment for fibrinogen levels, lag phase and K(s) remained significantly different between relatives and control subjects. Scanning electron microscopy images confirmed increased fiber diameter in relatives, possibly of reduced density. Factor XIII Val34Leu and fibrinogen Aalpha Thr312Ala and Bbeta -455 G/A showed no association with clot structure.. The male relatives of patients with premature CAD form fibrin clots that begin polymerization more quickly, have thicker fibers, and are less permeable than those of control subjects.

Topics: Adult; Blood Coagulation; Case-Control Studies; Coronary Artery Disease; Factor XIII; Family Health; Fibrin; Fibrinogen; Hemostatics; Humans; Male; Middle Aged; Permeability; Polymorphism, Genetic; Time Factors

We measured fibrin monomer (FM), soluble fibrin, as a marker of thrombin activity in plasma samples obtained in parallel with the first two routine samples for cardiac markers in 165 patients with acute chest pain admitted consecutively to our hospital. A reference limit of FM in a healthy population was set at 3.0 mg/l. Elevated plasma FM was observed in 48.8% of patients with acute coronary syndromes, in 42.3% of patients with specific non-coronary disease, in 31.5% of those with stable angina pectoris and in 18.2% of patients with non-specific chest pain. No significant difference was observed between sample 1 and sample 2 in patients not receiving thrombolytic treatment during the sampling period (P = 0.46). In patients with coronary artery disease, FM was significantly related to the level of cardiac troponin T (P = 0.001), but no correlation was observed between the individual plasma FM and cardiac troponin T values. Outcome analysis during the following 30 months after the index event in patients with acute coronary syndromes revealed higher FM levels in those with coronary re-events or death than in patients without new events (P = 0.001). This observation indicates a prognostic potential of FM in risk evaluation of patients with coronary artery disease.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Chest Pain; Cohort Studies; Coronary Artery Disease; Enzyme-Linked Immunosorbent Assay; Female; Fibrin; Humans; Male; Middle Aged; Prognosis; Reference Standards; Solubility; Thrombophilia; Troponin T

Fibrin deposits are found in and around the vessels in transplant coronary artery disease, in spontaneous atherosclerosis, and in the microvasculature of failing cardiac allografts. Fibrin is deposited due to a failure in anticoagulant pathways, one of the most important being the heparan sulfate proteoglycan-antithrombin (AT) natural anticoagulant pathway. A failure in this pathway results in a loss of AT binding in veins and arteries and increased fibrin deposition. This is associated with an increased risk of coronary artery disease and graft failure. Recovery of the previously lost vascular AT binding is associated with the development of a novel binding of AT by capillaries. The development of capillary AT binding is associated with significantly less coronary artery disease and improved survival. Understanding the mechanisms involved in the development of this unusual binding of AT by capillaries is important in developing new treatments directed to promote microvascular AT binding and reduce the deposition of fibrin.

Topics: Antithrombins; Blood Coagulation; Capillaries; Coronary Artery Disease; Endothelium, Vascular; Fibrin; Graft Survival; Heart Transplantation; Heparan Sulfate Proteoglycans; Humans; Muscle, Smooth, Vascular; Risk; Risk Factors; Time Factors; Transplantation, Homologous; Tunica Intima

Tissue factor (TF) initiates the extrinsic pathway of blood coagulation by acting as a cofactor for Factor VII. Inhibition of the Factor VIIa-TF complex is mediated by the tissue factor pathway inhibitor (TFPI), which is a serine protease inhibitor with three Kunitz-type domains. The localization of TF and TFPI protein has been examined immunohistochemically in various atherosclerotic lesions of coronary arteries from 22 autopsy cases and their messenger RNA expression has been confirmed by reverse transcription-polymerase chain reaction. Four types of atherosclerotic lesion (types I, II, III, and IV) were classified according to the method described by Stary et al. TF and TFPI were localized in endothelial cells, macrophages, macrophage-derived foam cells, and smooth muscle cells in the intimal lesions, medial smooth muscle cells, and endothelial cells of the microvessels in the adventitia. Immunohistochemical double staining revealed the co-localization of TF and TFPI in the endothelial cells and macrophages in four types of atherosclerotic lesions. In type III and IV lesions, the number of TF- and TFPI-positive cells was increased, accompanied by extracellular localization of TF and TFPI in the lipid core of atherosclerotic plaques. Fibrin deposition was found around TF- and TFPI-positive macrophages and in the lipid core of atherosclerotic plaques. TF and TFPI messenger RNA were detected more frequently in coronary arteries with type III and IV lesions than in those with type I and II lesions. The co-localization of TF and TFPI was demonstrated in various atherosclerotic lesions of coronary arteries and was shown to be intimately related to fibrin deposition in advanced atherosclerotic plaques. The co-localization of TF and TFPI may thus be closely associated with thrombogenicity in atherosclerotic lesions of coronary arteries.

Topics: Aged; Aged, 80 and over; Coronary Artery Disease; Coronary Vessels; Endothelium, Vascular; Female; Fibrin; Foam Cells; Humans; Immunohistochemistry; Lipoproteins; Macrophages; Male; Middle Aged; Muscle, Smooth, Vascular; Polymerase Chain Reaction; RNA, Messenger; Serine Proteinase Inhibitors; Thromboplastin

The use of lipid-lowering drugs has been shown to have beneficial effects in primary and secondary prevention of cardiovascular disease. Gemfibrozil has shown beneficial effects as a lipid lowering agent; however, some proactivating effects on platelet function in vitro have been described. We have studied in a porcine model of atherosclerosis if gemfibrozil could prevent the early vascular effects of a cholesterol-rich diet without inducing platelet activation and, hence, mural thrombosis. Pigs were fed for 50 days with a diet rich in saturated fat and cholesterol (cho). The longitudinal follow-up study showed that in control animals LDL-cho increased significantly up to 181.9 +/- 34.2 mg/dl or 79% of total-cho, while HDL-cho was reduced to 19% of total-cho. Gemfibrozil, at average therapeutic plasma levels (peak levels of 28 micrograms/ml) [corrected], induced a significant reduction in the relative amount of LDL (P < 0.05) and increased HDL (P < 0.05). The increase in fibrinogen plasma levels observed in the control group due to the dietary intervention (+25%) was prevented in the treated animals (-5%). In treated animals, vascular lesions were significantly less severe, platelet deposition upon exposure of damaged vessel wall was unchanged and the fibrin layer deposited on the damaged vessel wall was significantly reduced over control animal values. This short term pharmacologic lipid lowering intervention has been able to slow down lesion development and to reduce fibrin formation onto lesioned disrupted vascular substrates without increasing platelet mural thrombosis.

Topics: Animals; Cholesterol, HDL; Cholesterol, LDL; Coronary Artery Disease; Coronary Vessels; Fibrin; Gemfibrozil; Hypolipidemic Agents; Immunohistochemistry; Platelet Activation; Platelet Adhesiveness; Platelet Aggregation; Risk Factors; Swine; Thrombosis

The native fibrin gel structure formed in vitro from plasma samples was examined by liquid permeation of the hydrated fibrin gel networks in 18 men who had suffered a myocardial infarction before the age of 45 years and in 20 control subjects. Patients with an elevated plasma fibrinogen concentration had a considerably lower fibrin gel porosity (permeability coefficient, Ks) compared with patients with a normal plasma fibrinogen level and with controls. The calculated fiber mass-length ratio of the fibrin gel networks was decreased in both patient groups. Gel porosity differed markedly between individuals at a given plasma fibrinogen concentration. Fairly strong inverse correlations were found between plasma orosomucoid level on the one hand and Ks (r = -0.617, p less than 0.01) or fiber mass-length ratio (r = -0.499, p less than 0.05) on the other. The low density lipoprotein (LDL) cholesterol concentration also correlated inversely with Ks (r = -0.471, p less than 0.05) and fiber mass-length ratio (r = -0.522, p less than 0.05). Significant inverse relations, which were independent of plasma fibrinogen and lipoprotein concentrations, were detected between Ks (r = -0.519, p less than 0.05) and calculated fiber mass-length ratio (r = -0.723, p less than 0.001) and number and severity of coronary artery stenoses determined by angiography. A proneness to formation of tight, rigid and space-filling fibrin network structures with small pores thus appears to be associated with premature coronary artery disease.

Topics: Acute-Phase Proteins; Adult; Coronary Artery Disease; Coronary Disease; Fibrin; Fibrinogen; Gels; Humans; In Vitro Techniques; Lipoproteins; Male; Molecular Structure; Myocardial Infarction; Polymers

The incorporation of the stable isotope 15N in plasma proteins and blood cells after oral application of 3 g 15NH4Cl (95 At% 15N) per 70 kg body weight was followed up in 11 patients with ischemic heart disease or peripheral arteriosclerosis and in 7 healthy control subjects. Preliminary results indicate that the turnover of plasma protein, especially fibrin, is elevated in patients with arteriosclerosis. Investigations of platelets intimate a decreased turnover of platelet protein in patients with arteriosclerosis as compared to control subjects. Possible reasons for these alterations are discussed.

Topics: Arteriosclerosis; Blood Platelets; Blood Proteins; Coronary Artery Disease; Fibrin; Humans; Male; Middle Aged; Nitrogen Radioisotopes; Reference Values

Following Skelton's procedure with unilateral adrenonephrectomy, contralateral adrenal enucleation and application of 1% NaCl with drinking fluid, normal rats develop hypertension and generalized severe arteriosclerosis within 7 weeks, experimental group I. Thereby the mean systolic blood pressure increased from 108 +/- 10 to 223 +/- 12 mm Hg, and 90 arteriosclerotic blood vessels could be counted in 100 histological sections (10 from each animal) of the hearts. Following Skelton's procedure and admixture of flunarizine with the food (40 mg flunarizine per kg for 8 weeks, started 1 week before the operation; mean plasma flunarizine value: 336 +/- 136 ng/ml at the end of the experiment), experimental group II, all rats developed hypertension too, whereby the mean systolic blood pressure increased from 109 +/- 10 to 214 +/- 16 mm Hg, but in contrast to experimental group I, only one artery with sclerosis could be observed in 100 comparable histological sections of the hearts. The untreated control rats, experimental group III, remained normotensive, and no arteriosclerotic blood vessels could be observed. The findings presented show that the calcium-antagonist flunarizine with the dosage used does not reduce hypertension, but almost completely suppresses hypertension-induced arteriosclerosis of the myocardial blood vessels without lowering the high blood pressure.

Topics: Animals; Blood Pressure; Cardiomegaly; Coronary Artery Disease; Coronary Vessels; Endothelium, Vascular; Fibrin; Flunarizine; Hypertension; Male; Muscle, Smooth, Vascular; Organ Size; Rats; Rats, Inbred Strains

A histopathological study was performed on 36 patients (60 grafts) who had undergone aorto-coronary bypass graft (ACBG) surgery 0 to 99 months prior to death. The following pathologic changes were found: 1) The thickness of diffuse intimal proliferation in the ACBG progressed with time from graft surgery to death. 2) The media became atrophic and the adventitia was increased slightly in thickness. 3) Fibrin deposits were found in 20 patients on/in the intimal thickenings of the vein graft walls and 7 patients showed incorporated fibrin in the thickened intima even one month after surgery. 4) Atherosclerosis, identified as intimal foam cell accumulation or frank plaques, was seen in only 3 patients 4 years after surgery. Fibrointimal proliferation occurred with relatively greater frequency in patients with fibrin deposits (P less than 0.001). Although it is well known that mural thrombi in vein grafts manifest fibrointimal proliferation, our results suggest that fibrin deposits might be responsible for intimal thickening even one month after graft surgery.

Topics: Aged; Autopsy; Coronary Artery Bypass; Coronary Artery Disease; Female; Fibrin; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Myocardium; Retrospective Studies; Saphenous Vein

Topics: Animals; Coronary Artery Disease; Coronary Vessels; Dogs; Endothelium, Vascular; Fibrin; Fibrinogen; Microscopy, Electron, Scanning

Two groups of male patients with CHD were examined. The first group (30 persons) was treated with a 30-day therapeutic course of physical training on a bicycle ergometer, the second group received nitrates of prolonged action and beta-blocking agents. Eleven healthy men receiving a course of physical training were entered into the control group. The content of fibrinogen, soluble fibrin and fibrinogen degradation products in the blood plasma was investigated prior to and after a therapeutic course. An analysis of the blood plasma protein spectrum was performed using gel-filtration on a chromatographic column as well as separate disk-electrophoresis of the blood plasma proteins and isolated fractions in polyacrylamide gel. Regular physical training of the CHD patients resulted in a significant decrease in the content of fibrinogen, soluble fibrin and fibrin degradation products in the blood that might be conducive to the improvement of microcirculation and hence to lessening the number of angina attacks in these patients.

Topics: Adult; Angina Pectoris; Blood Protein Electrophoresis; Chromatography, Gel; Coronary Artery Disease; Coronary Disease; Exercise Therapy; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Humans; Male; Middle Aged; Myocardial Infarction; Physical Exertion

Topics: Blood; Blood Coagulation; Coronary Artery Disease; Coronary Disease; Diet; Fibrin; Fibrinolysis; Humans; Nutritional Physiological Phenomena; Nutritional Sciences

Topics: Blood Coagulation; Coronary Artery Disease; Coronary Disease; Coronary Thrombosis; Fibrin; Fibrinolysis; Heart; Humans; Sclerosis