fibrin and Myocardial-Infarction

Fibrin is a topical haemostat, sealant and tissue glue, which consists of concentrated fibrinogen and thrombin. It has broad medical and research uses. Recently, several studies have shown that engineered patches comprising mixtures of biological or synthetic materials and progenitor cells showed therapeutic promise for regenerating damaged tissues. In that context, fibrin maintains cell adherence at the site of injury, where cells are required for tissue repair, and offers a nurturing environment that protects implanted cells without interfering with their expected benefit. Here we review the past, present and future uses of fibrin, with a focus on its use as a scaffold material for cardiac repair. Fibrin patches filled with regenerative cells can be placed over the scarring myocardium; this methodology avoids many of the drawbacks of conventional cell-infusion systems. Advantages of using fibrin also include extraction from the patient's blood, an easy readjustment and implantation procedure, increase in viability and early proliferation of delivered cells, and benefits even with the patch alone. In line with this, we discuss the numerous preclinical studies that have used fibrin-cell patches, the practical issues inherent in their generation, and the necessary process of scaling-up from animal models to patients. In the light of the data presented, fibrin stands out as a valuable biomaterial for delivering cells to damaged tissue and for promoting beneficial effects. However, before the fibrin scaffold can be translated from bench to bedside, many issues must be explored further, including suboptimal survival and limited migration of the implanted cells to underlying ischaemic myocardium. Copyright © 2016 John Wiley & Sons, Ltd.

Topics: Animals; Cell Transplantation; Cicatrix; Fibrin; Humans; Myocardial Infarction; Tissue Scaffolds

Treating a myocardial infarction (MI), the most frequent cause of death worldwide, remains one of the most exciting medical challenges in the 21st century. Cardiac tissue engineering, a novel emerging treatment, involves the use of therapeutic cells supported by a scaffold for regenerating the infarcted area. It is essential to select the appropriate scaffold material; the ideal one should provide a suitable cellular microenvironment, mimic the native myocardium, and allow mechanical and electrical coupling with host tissues. Among available scaffold materials, natural scaffolds are preferable for achieving these purposes because they possess myocardial extracellular matrix properties and structures. Here, we review several natural scaffolds for applications in MI management, with a focus on pre-clinical studies and clinical trials performed to date. We also evaluate scaffolds combined with different cell types and proteins for their ability to promote improved heart function, contractility and neovascularization, and attenuate adverse ventricular remodeling. Although further refinement is necessary in the coming years, promising results indicate that natural scaffolds may be a valuable translational therapeutic option with clinical impact in MI repair.

Topics: Alginates; Animals; Biocompatible Materials; Cell Transplantation; Cellular Microenvironment; Chitosan; Collagen; Drug Combinations; Fibrin; Gelatin; Glucuronic Acid; Hexuronic Acids; Humans; Hyaluronic Acid; Laminin; Materials Testing; Myocardial Infarction; Myocardium; Proteoglycans; Regeneration; Tissue Engineering; Tissue Scaffolds; Translational Research, Biomedical

Accumulating evidence indicates that accelerated formation of fibrin clots composed of compact, highly-branched networks with thin fibres which are relatively resistant to plasmin-mediated lysis can be commonly observed in patients with venous or arterial thrombosis. This review discusses characteristics of fibrin clot structure and function in patients with various thromboembolic manifestations, in particular myocardial infarction, ischaemic stroke and venous thromboembolism, based on the publications till December 2013. Moreover, factors will be presented that in vivo unfavourably determine altered fibrin clot properties in thrombotic disorders and modalities that can improve clot phenotype.

Topics: Animals; Blood Coagulation; Fibrin; Humans; Myocardial Infarction; Stroke; Thrombolytic Therapy; Venous Thromboembolism

Although, the first-generation drug eluting stents (DES) have significantly reduced rates of restenosis compared to bare metal stents (BMS), an increased risk of late stent thrombosis (LST) has emerged as a major concern. Pathologic studies of patients dying from late DES thrombosis demonstrates delayed arterial healing characterized by persistent fibrin deposition and poor endothelialization as the primary substrate. However, recent thorough investigations revealed additional mechanisms of stent thrombosis such as hypersensitivity reaction, excessive fibrin deposit with malapposition, or neoatherosclerosis, which are associated with device-specific components and the majority of very late stent thrombosis is likely associated with these abnormal vascular responses. Therefore, although the incidence of stent thrombosis following DES implantation is similar in each period, the underlying mechanisms of this complication may vary. In the current review, the mechanisms of stent thrombosis in the DES era will be discussed using the data from autopsy studies that have been published.

Topics: Adult; Atherosclerosis; Autopsy; Coronary Vessels; Drug-Eluting Stents; Female; Fibrin; Humans; Male; Middle Aged; Myocardial Infarction; Prevalence; Regeneration; Thrombosis; Time Factors

Several novel interventional and pharmacological therapeutic approaches have been examined in recent years for the prevention of ischemia/reperfusion injury in myocardial infarction; however, most approaches have failed to progress to clinical trials, and the underlying pathological mechanisms of ischemia/reperfusion injury remain poorly understood. The fibrin Bbeta chain-derived peptide FX-06, under development by Ikaria Holdings Inc, is a novel candidate in phase II trials for the prevention of ischemia/reperfusion injury. FX-06 competitively binds to vascular endothelial (VE)-cadherin, thereby inhibiting leukocyte transmigration and initiating VE-cadherin-mediated signaling, which tightens the endothelial barrier and reduces capillary leakage. The sequence of FX-06 resembles that of a physiological peptide, and the compound has been well tolerated in clinical trials. In a phase II trial in patients with acute ST-segment elevation myocardial infarction who were undergoing percutaneous coronary intervention, FX-06 significantly reduced the necrotic core zone compared with placebo. Whether FX-06 treatment can have a clinical benefit remains to be established. Nonetheless, the unique mechanism of action and short half-life that distinguish FX-06 from competitive pharmacological agents would allow its use in combination with other drugs, potentially contributing to a successful pharmacological therapy for the prevention of ischemia/reperfusion injury after decades of disappointing results.

Topics: Amino Acid Sequence; Angioplasty, Balloon, Coronary; Animals; Antigens, CD; Cadherins; Clinical Trials as Topic; Cohort Studies; Dose-Response Relationship, Drug; Fibrin; Fibrin Fibrinogen Degradation Products; Half-Life; Humans; Molecular Sequence Data; Myocardial Infarction; Peptide Fragments; Randomized Controlled Trials as Topic; Reperfusion Injury; Structure-Activity Relationship

Rapid reperfusion is the key treatment goal in patients with ST-segment elevation myocardial infarction (STEMI). The American College of Cardiology-American Heart Association (ACC-AHA) 2004 guidelines for the management of STEMI include recommendations for pharmacologic reperfusion with use of fibrinolytic agents. Fibrinolytic agents are the preferred pharmacologic class for the management of STEMI because of their ability to achieve reperfusion and to restore blood flow when administered within 12 hours of symptom onset. Four fibrinolytic agents are approved for the treatment of STEMI in the United States-streptokinase, alteplase, reteplase, and tenecteplase. Several clinical trials have demonstrated the beneficial effects of these therapies in reducing mortality rates in patients with suspected acute myocardial infarction. Alteplase is administered as an intravenous infusion. However, the relatively long half-lives of reteplase and tenecteplase enable bolus administration, which may be more convenient and less time consuming. Reteplase is administered as a double bolus, and dosing does not depend on the patient's weight; tenecteplase is administered as a single bolus, and dosing is weight based. Adherence to the ACC-AHA guidelines, as well as knowledge about the available fibrinolytic agents, is essential for physicians and pharmacists to make informed decisions regarding appropriate pharmacologic reperfusion strategies.

Topics: Angioplasty, Balloon, Coronary; Clinical Trials as Topic; Electrocardiography; Emergency Medical Services; Fibrin; Fibrinolytic Agents; Humans; Myocardial Infarction; Myocardial Reperfusion; Practice Guidelines as Topic

The occlusion of a coronary artery leads to ischemia of the myocardium, while permanent occlusion results in cell death and myocardial dysfunction. Early restoration of blood flow is the only means to reduce or prevent myocardial necrosis, but-paradoxically-reperfusion itself contributes to injury of the heart. In animal models, this phenomenon is well described, and there are many different unrelated approaches to reduce reperfusion injury. In humans, however, pharmacological interventions have so far failed to reduce myocardial reperfusion injury. We summarize the pathogenesis of reperfusion injury, detailing the role of fibrin(ogen) and its derivatives. Moreover, we introduce a new concept for fibrin derivatives as potential targets for reperfusion therapy.

Topics: Animals; Anti-Inflammatory Agents; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Humans; Inflammation; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium

Topics: Controlled Clinical Trials as Topic; Dose-Response Relationship, Drug; Fibrin; Fibrinolytic Agents; Hemorrhage; Humans; Metabolic Clearance Rate; Myocardial Infarction; Myocardial Reperfusion; Recombinant Proteins; Treatment Outcome

Optimal induction of coronary thrombolysis depends in part upon the nature of the specific plasminogen activator used. The two general classes of plasminogen activators available clinically differ in a fundamental respect delineated by the term, clot selectivity. Clot selective agents are less prone to induce plasminemia and consequent occult activation of the coagulation cascade than are non-selective agents. However, under clinical conditions, all plasminogen activators result in some activation of the cascade with consequent generation of thrombin. Accordingly, optimal therapy requires the use of conjunctive anticoagulation to preclude the deleterious effects of rebound generation of thrombin, which has been well documented biochemically. The potential value of antiplatelet agents that can attenuate the positive feedback loop between activation of platelets and markedly amplified generation of thrombin in the setting of coronary thrombolysis is under active exploration. With appropriate monitoring of the efficacy of such agents in vivo it should be possible to enhance even further the benefits that can be conferred by pharmacologically induced coronary thrombolysis.

Topics: Animals; Anticoagulants; Aspirin; Blood Coagulation; Dogs; Fibrin; Fibrinolysis; Fibrinolytic Agents; Humans; Myocardial Infarction; Plasminogen Activators; Rabbits; Terminology as Topic; Thrombin; Tissue Plasminogen Activator

When fibrin deposition and removal are properly balanced, the organism is protected from both a catastrophic loss of blood at the site of injury and the inappropriate loss of fluidity within the vascular system. When these activities are not properly balanced, however, severe bleeding or thromboses can occur. Myocardial infarction is a common and morbid consequence of the latter. The thrombin/thrombomodulin complex plays an essential role in regulating this balance because it generates both an anticoagulant substance, activated protein C, and an antifibrinolytic substance, activated TAFI (thrombin activatable fibrinolysis inhibitor, also known as plasma carboxypeptidase B or carboxypeptidase U). Thus, the coagulation and fibrinolytic cascades are explicitly linked by virtue of thrombin catalyzed activation of TAFI, either by the thrombin/thrombomodulin complex or, in the absence of thrombomodulin, by the massive amounts of thrombin generated through the factor XI-dependent pathway after clotting. Some potential targets for diagnosis, prognosis and therapy related to the balance between fibrin formation and removal include: development of a convenient global assay for plasma fibrinolytic potential; an assay for plasma or urine thrombomodulin that had been oxidized at methionine 388 and thereby has lost its capacity to stimulate activation of protein C but not TAFI; an assay for activated TAFI; discovery of a means for tapping the tremendous potential of the vasculature to acutely release tissue-type plasminogen activator; and an assessment of the potential role of polymorphisms in the TAFI gene which might influence TAFI levels or the properties TAFIa. In addition, a much fuller and quantitative understanding of the properties of the coagulation and tibrinolytic cascades is needed in order to optimize diagnosis, prognosis and therapy in disorders such as myocardial infarction that are related to the balance between fibrin formation and removal.

Topics: Blood Coagulation; Enzyme Activation; Fibrin; Fibrinolysis; Humans; Myocardial Infarction; Prognosis; Thrombin; Thrombomodulin

Topics: Coronary Disease; Fibrin; Fibrinolysis; Humans; Insulin Resistance; Myocardial Infarction; Plasminogen Activator Inhibitor 1; Polymorphism, Genetic; Risk Factors; Tissue Plasminogen Activator

Current thrombolytic therapy fails to induce early, complete, and sustained reperfusion in +/-50% of the patients with ST-segment elevation acute coronary syndromes. There are two complementary approaches to improve thrombolytic therapy: the development of new fibrinolytics with enhanced fibrin specificity and/or reduced plasma clearance and the coadministration of new antithrombotic agents. The results obtained so far suggest that single-bolus fibrinolytic therapy is likely to replace the current infusions in the near future. This may result in a significantly earlier (prehospital) treatment of patients. The concomitant intravenous administration of a glycoprotein IIb/IIIa receptor antagonist (in combination with a reduced dose of a fibrinolytic) appears to be able to further enhance the efficacy for clot lysis without increasing the risk for bleeding complications.

Topics: Coronary Disease; Fibrin; Fibrinolytic Agents; Hemorrhage; Humans; Injections, Intravenous; Metabolic Clearance Rate; Myocardial Infarction; Myocardial Reperfusion; Platelet Glycoprotein GPIb-IX Complex; Platelet Glycoprotein GPIIb-IIIa Complex; Platelet Membrane Glycoproteins; Receptors, Antigen, B-Cell; Receptors, Cell Surface; Substrate Specificity; Thrombolytic Therapy; Time Factors; Tissue Plasminogen Activator

Topics: Amino Acid Sequence; Fibrin; Metalloendopeptidases; Molecular Sequence Data; Myocardial Infarction; Recombinant Proteins; Thrombolytic Therapy; Tissue Plasminogen Activator

Topics: Adult; Aged; Aged, 80 and over; Animals; Clinical Trials as Topic; Dogs; Drug Evaluation, Preclinical; Female; Fibrin; Fibrinolytic Agents; Humans; Immunodominant Epitopes; Male; Metalloendopeptidases; Middle Aged; Multicenter Studies as Topic; Myocardial Infarction; Papio; Pilot Projects; Protein Engineering; Randomized Controlled Trials as Topic; Recombinant Proteins; Thromboembolism; Thrombolytic Therapy

Topics: Animals; Coronary Thrombosis; Fibrin; Fibrinolysis; Fibrinolytic Agents; Humans; Models, Biological; Myocardial Infarction; Plasminogen Activators; Thrombosis

It was only quite recently that the thrombotic component in myocardial infarction and sudden coronary death was generally acknowledged. When attention was eventually paid to it, interest initially centered primarily on platelet function. There is, of course, no doubt about the central role of platelet adhesion and aggregation in thrombogenesis, but still no generally accepted measure of platelet function has been shown to be associated with the later onset of ischemic heart disease (IHD). Epidemiologically, the assessment of coagulability has been more rewarding. Several prospective studies have now shown a strong relationship between the plasma fibrinogen level and the incidence of IHD and stroke. Epidemiologic and laboratory studies have also implicated factor VII and extrinsic pathway activity in the onset of IHD. Other components of the hemostatic system that are probably involved include factor VIII activity and the fibrinolytic system. It is increasingly clear that lipoproteins exert a major influence on coagulability as well as their better known role in atherogenesis. Any further polarization of hypotheses for IHD as being purely atherogenic or purely thrombogenic is therefore counterproductive. At the same time, antithrombotic measures for primary prevention need to be evaluated as thoroughly as lipid-lowering regimens. If thrombosis is seen as the final arterial event in virtually all major episodes of IHD, the indications for antithrombotic agents in primary prevention may be wider than those for lipid-lowering regimens. It is therefore necessary to establish as quickly as possible not only the preventive effectiveness of antithrombotic measures, including low-dose aspirin and low-intensity oral anticoagulation, but also the relative effectiveness and safety of antithrombotic and lipid-modifying regimens.

Topics: Blood Platelets; Fibrin; Hemostasis; Humans; Myocardial Infarction; Myocardial Ischemia; Thrombosis

The application of recombinant DNA methodology to clinical medicine offers the clinician a new generation of more potent and specific therapies. Recombinant methods offer great promise in the treatment of coronary artery thrombosis. This review focuses on the characterization of 1) molecules that activate plasminogen locally (in the vicinity of a thrombus) rather than systemically, and 2) molecules that offer new approaches to the inhibition of platelet activation and thrombin activity. We first describe the methods used to uncover these molecules and their characterization at the molecular level. The ways in which this knowledge can lead to the development of agents tailored to clinical needs are then explored.

Topics: Antibodies, Monoclonal; Coronary Thrombosis; Fibrin; Humans; Molecular Structure; Myocardial Infarction; Plasminogen Activators; Platelet Aggregation; Recombinant Proteins; Substrate Specificity

The concept of the haemostatic balance was reviewed, and its potential role in the regulation of tissue repair and the pathogenesis of thrombotic processes was surveyed. Physiological activation of coagulation appears to be dominated by effects of degenerated and injured cells of the vascular wall causing local release of thromboplastin and exposition of activating surfaces. Inhibition of coagulation impairs its progression and the non-thrombogenic nature of the normal endothelium is chiefly caused by the binding of inhibitory components (antithrombin-III, protein C) to specific receptor sites. Physiological activation of fibrinolysis appears to be triggered by and limited to the fibrin because of a specific affinity to fibrin of plasminogen and plasminogen activators. Systemic activation of fibrinolysis is prevented by primary (alpha 2-antiplasmin) and secondary (alpha 2-macroglobulin, alpha 1-antitrypsin) plasmin inhibitors. A plasminogen binding protein (histidine-rich glycoprotein), plasmin inhibitors and activator inhibitors appear to contribute to the regulation of the initial phase of fibrinolysis. A deviation from normal of the dynamic balance, regulating fibrin formation and resolution, may lead to a haemorrhagic and/or a thrombophilic state. Described were the optimization of selected methods for assessment of variables involved in the haemostatic balance. An overestimation of plasminogen concentrations in plasma may occur in patients with elevated levels of fibrinogen or fibrin degradation products, when using assays based on the activation of plasminogen by streptokinase followed by the hydrolysis of a synthetic chromogenic substrate. This source of error could be eliminated by presence of fibrinogen in excess in the plasminogen assay, thereby securing maximum stimulation of the plasminogen-streptokinase complex. The presence of cryoglobulin in plasma interferes with the assessment in euglobulins of plasminogen activator activities. Experiments indicate that tissue-type plasminogen activator adsorb cryoglobulins and that a cold-promoted activation of the factor XII-dependent proactivator system of fibrinolysis is related to the presence of cryoglobulins. Experiments supported the existence of an as yet not characterized factor XII-dependent proactivator. Strictly optimized procedures for the preparation of euglobulins for the accurate determination of plasminogen activators were recommended. The determination of plasminogen activator inhibitio

Topics: Antithrombin III; Antithrombin III Deficiency; Blood Coagulation; Coronary Disease; Coronary Thrombosis; Cryoglobulins; Fibrin; Fibrinolysis; Heparin Cofactor II; Humans; Myocardial Infarction; Plasminogen Activators; Protein C; Protein C Deficiency; Thrombophlebitis

Topics: Animals; Anistreplase; Fibrin; Fibrinolysis; Fibrinolytic Agents; Humans; Myocardial Infarction; Plasminogen; Streptokinase

Thrombolytic therapy has now become established as a useful therapeutic measure for the immediate treatment of an acute evolving transmural infarction. Nevertheless, several important and fundamental aspects of a pharmacologic nature remain to be resolved. Prominent among these is whether or not fibrin specificity of a thrombolytic agent provides important benefits, and whether heparin therapy as commonly employed to prevent rethrombosis has been effective. Review of the available data raises serious questions as to the validity of current views and the appropriateness of prevailing trends.

Topics: Fibrin; Fibrinolytic Agents; Heparin; Humans; Myocardial Infarction; Plasminogen Activators; Recurrence; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator

Acute myocardial infarction is caused by thrombotic occlusion of a coronary vessel. Mortality and quality of life are both determined by the extent of infarction. It is possible to interrupt the development of necrosis by early fibrinolytic therapy. If reperfusion is initiated within three to six hours, a significant reduction in mortality is likely. Currently available fibrin-unspecific plasminogen activators such as streptokinase and urokinase are effective thrombolytic agents but do not fulfill all the criteria of an ideal plasminogen activator. Recanalisation rates are relatively low after intravenous administration, since the agents are not fibrin-specific and because the effect is delayed. Serious hemorrhagic complications may occur, since therapeutically effective dosage results in a hemostatic defect. The possible advantages of reduction in blood viscosity for collateral circulation in the ischemic region and a possible antithrombotic effect have not been defined. A complex strategy is necessary for optimal treatment of acute myocardial infarction. Early intervention is decisive in regard to recanalisation rate, infarct size, left ventricular function and mortality, while delayed interventions serve to maintain the advantages of early recanalisation by limiting angina pectoris and preventing reinfarction. Therefore, a combination of early intravenous administration of a fibrinolytic agent with subsequent invasive intervention appears reasonable and advantageous. Progress in the treatment of acute myocardial infarction will depend on development of effective plasminogen activators capable of achieving rapid and complete recanalisation without major side effects after intravenous administration.

Topics: Coronary Circulation; Fibrin; Fibrinolytic Agents; Humans; Myocardial Infarction

Topics: Animals; Blood Coagulation Factors; Blood Coagulation Tests; Blood Platelets; Drug Evaluation; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolysin; Fibrinolytic Agents; Hemorrhage; Humans; Myocardial Infarction; Plasminogen Activators; Streptokinase; Thrombin; Thromboembolism

Topics: Animals; Clinical Enzyme Tests; Coronary Disease; Diagnosis, Differential; Dogs; Fibrin; Fibrin Fibrinogen Degradation Products; Heparin; Humans; Hypertension; Lung Diseases; Myocardial Infarction; Pulmonary Embolism; Solubility; Thrombophlebitis

The existence of a system in the human body capable of inducing the dissolution of endogenous pathologically formed thrombi was appreciated in ancient times. Considered in detail in this article are the data that have elucidated the physiologic regulation of which plasmin formation is dependent on, the plasma concentration of plasminogen, availability of activators of plasminogen in the plasma and surrounding tissue environment, the concentration of naturally present inhibitors, and the existence of fibrin in the circulation. Important in this rapidly progressive scientific discipline is consideration of the factors which control the synthesis of the components of this proteolytic enzyme system. Recently abundant information has indicated that this plasminogen-plasmin proteolytic enzyme system can be utilized therapeutically. Knowledge of the mechanisms of this system has permitted identification of agents that can be exogenously administered to releave thrombotic obstruction to blood flow in the venous (pulmonary emboli, deep vein thrombosis) and arterial (peripheral and central vessels) circulatory systems. Particularly important is the demonstration that thrombolytic agents can directly attack and alleviate the immediate cause of acute myocardial infarction. As a result of the innovations in the present decade, it is evident that the plasminogen system can be advantageously employed to reverse the pathologic effects of all thrombotic diseases.

Topics: alpha 1-Antitrypsin; alpha-2-Antiplasmin; alpha-Macroglobulins; Antifibrinolytic Agents; Antithrombin III; Arterial Occlusive Diseases; Arteriosclerosis; Complement C1 Inactivator Proteins; Disseminated Intravascular Coagulation; Fibrin; Fibrinogen; Fibrinolysin; Fibrinolysis; Fibrinolytic Agents; Humans; Kidney Diseases; Liver Diseases; Myocardial Infarction; Neoplasms; Plasminogen; Pulmonary Embolism; Thrombophlebitis

Topics: alpha-2-Antiplasmin; Anticoagulants; Catheterization; Coronary Disease; Drug Evaluation; Fibrin; Fibrinolysin; Fibrinolysis; Fibrinolytic Agents; Humans; Infusions, Intra-Arterial; Infusions, Parenteral; Myocardial Infarction; Plasminogen; Plasminogen Activators; Streptokinase; Thrombosis; Urokinase-Type Plasminogen Activator

Topics: alpha-2-Antiplasmin; Animals; Blood Vessels; Dogs; Endothelium; Fibrin; Fibrinolysis; Fibrinolytic Agents; Humans; Myocardial Infarction; Plasminogen Activators; Streptokinase; Thrombosis; Urokinase-Type Plasminogen Activator

Topics: Blood Coagulation Disorders; Blood Coagulation Factors; Blood Platelets; Blood Vessels; Cardiopulmonary Bypass; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Humans; Infant, Newborn; Kidney Diseases; Myocardial Infarction; Neoplasms; Pregnancy; Pulmonary Embolism; Syndrome; Thrombin; Thrombophlebitis; Thrombosis

Topics: Adenine Nucleotides; Animals; Anticoagulants; Blood Circulation; Blood Coagulation; Blood Coagulation Factors; Blood Platelets; Blood Vessels; Collagen; Diet; Endotoxins; Fibrin; Fibrinolytic Agents; Humans; Leukocytes; Microscopy, Electron; Myocardial Infarction; Oral Hemorrhage; Platelet Adhesiveness; Thromboembolism; Thrombosis; Wounds and Injuries

Atherothrombotic events are influenced by systemic hypercoagulability and fibrinolytic activity. The present study evaluated thrombogenicity indices and their prognostic implications according to disease acuity.. From the consecutive patients undergoing percutaneous coronary intervention (PCI), those with thrombogenicity indices (n = 2705) were grouped according to disease acuity [acute myocardial infarction (AMI) vs. non-AMI]. Thrombogenicity indices were measured by thromboelastography (TEG). Blood samples for TEG were obtained immediately after insertion of the PCI sheath, and TEG tracing was performed within 4 h post-sampling. Major adverse cardiovascular events (MACE, a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) were evaluated for up to 4 years. Compared with non-AMI patients, AMI patients had higher platelet-fibrin clot strength [maximal amplitude (MA): 66.5 ± 7.8 vs. 65.3 ± 7.2 mm, P < 0.001] and lower fibrinolytic activity [clot lysis at 30 min (LY30): 0.9 ± 1.8% vs. 1.1 ± 1.9%, P < 0.001]. Index AMI presentation was associated with MA [per one-mm increase: odds ratio (OR): 1.024; 95% confidence interval (CI): 1.013-1.036; P < 0.001] and LY30 (per one% increase: OR: 0.934; 95% CI: 0.893-0.978; P = 0.004). The presence of high platelet-fibrin clot strength (MA ≥68 mm) and low fibrinolytic activity (LY30 < 0.2%) was synergistically associated with MACE occurrence. In the multivariable analysis, the combined phenotype of 'MA ≥ 68 mm' and 'LY30 < 0.2%' was a major predictor of post-PCI MACE in the AMI group [adjusted hazard ratio (HR): 1.744; 95% CI: 1.135-2.679; P = 0.011], but not in the non-AMI group (adjusted HR: 1.031; 95% CI: 0.499-2.129; P = 0.935).. AMI occurrence is significantly associated with hypercoagulability and impaired fibrinolysis. Their combined phenotype increases the risk of post-PCI atherothrombotic event only in AMI patients. These observations may support individualized therapy that targets thrombogenicity for better outcomes in patients with AMI.. Gyeongsang National University Hospital (G-NUH) Registry, NCT04650529.

Topics: Fibrin; Fibrinolysis; Humans; Myocardial Infarction; Percutaneous Coronary Intervention; Prognosis; Thrombophilia; Treatment Outcome

Remote ischemic preconditioning (RIPC) prior to surgery has recently been shown to reduce the risk of myocardial injury and myocardial infarction after hip fracture surgery. This study investigated whether RIPC initiated antithrombotic mechanisms in patients undergoing hip fracture surgery. This trial was a predefined sub-study of a multicentre randomized clinical trial. Adult patients with cardiovascular risk factors undergoing hip fracture surgery between September 2015 and September 2017 were randomized 1 : 1 to RIPC or control. RIPC was initiated before surgery with a tourniquet applied to the upper arm and it consisted of four cycles of 5 min of forearm ischemia followed by five minutes of reperfusion. The outcomes such as surgery-induced changes in thrombin generation, fibrinogen/fibrin turnover, tissue plasminogen activator, plasminogen activator inhibitor-1 and fibrin structure measurements were determined preoperatively (prior to RIPC) and 2 h postoperatively. One hundred and thirty-seven patients were randomized to RIPC (n = 65) or control (n = 72). There were no significant changes in thrombin generation, fibrinogen/fibrin turnover or fibrin structure measurements determined pre and postoperatively between patients in the RIPC and control groups. Subgroup analyses on patients not on anticoagulant therapy (n = 103), patients receiving warfarin (n = 17) and patients receiving direct oral anticoagulant therapy (n = 18) showed no significant changes between the RIPC-patients and controls. RIPC did not affect changes in thrombin generation, fibrin turnover or fibrin structure in adult patients undergoing hip fracture surgery suggesting that the cardiovascular effect of RIPC in hip fracture surgery is not related to alterations in fibrinogen/fibrin metabolism.

Topics: Adult; Fibrin; Humans; Ischemic Preconditioning; Myocardial Infarction; Tissue Plasminogen Activator; Treatment Outcome

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

To determine whether fibrin clot properties are associated with clinical outcomes following acute coronary syndrome (ACS).. Plasma samples were collected at hospital discharge from 4354 ACS patients randomized to clopidogrel or ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial. A validated turbidimetric assay was employed to study plasma clot lysis time and maximum turbidity (a measure of clot density). One-year rates of cardiovascular (CV) death, spontaneous myocardial infarction (MI) and PLATO-defined major bleeding events were assessed after sample collection. Hazard ratios (HRs) were estimated using Cox proportional hazards models. After adjusting for CV risk factors, each 50% increase in lysis time was associated with CV death/spontaneous MI [HR 1.17, 95% confidence interval (CI) 1.05-1.31; P < 0.01] and CV death alone (HR 1.36, 95% CI 1.17-1.59; P < 0.001). Similarly, each 50% increase in maximum turbidity was associated with increased risk of CV death (HR 1.24, 95% CI 1.03-1.50; P = 0.024). After adjustment for other prognostic biomarkers (leukocyte count, high-sensitivity C-reactive protein, high-sensitivity troponin T, cystatin C, N-terminal pro B-type natriuretic peptide, and growth differentiation factor-15), the association with CV death remained significant for lysis time (HR 1.2, 95% CI 1.01-1.42; P = 0.042) but not for maximum turbidity. These associations were consistent regardless of randomized antiplatelet treatment (all interaction P > 0.05). Neither lysis time nor maximum turbidity was associated with major bleeding events.. Fibrin clots that are resistant to lysis independently predict adverse outcome in ACS patients. Novel therapies targeting fibrin clot properties might be a new avenue for improving prognosis in patients with ACS.

Topics: Acute Coronary Syndrome; Aged; Blood Coagulation; Clopidogrel; Double-Blind Method; Female; Fibrin; Fibrin Clot Lysis Time; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Ticagrelor; Treatment Outcome

Enoxaparin was superior to unfractionated heparin (UFH), regardless of fibrinolytic agent in ST-elevation myocardial infarction (STEMI) patients receiving fibrinolytic therapy in ExTRACT-TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment - Thrombolysis in Myocardial Infarction 25) trial.. This post hoc analysis compared outcomes with streptokinase plus enoxaparin to the standard regimen of fibrin-specific lytic (FSL) plus UFH and to the newer combination of FSL plus enoxaparin.. In ExTRACT-TIMI 25, STEMI patients received either streptokinase or a FSL (alteplase, reteplase or tenecteplase) at the physician's discretion and were randomized to enoxaparin or UFH, stratified by fibrinolytic type. Thirty-day outcomes were adjusted for baseline characteristics, region, in-hospital percutaneous coronary intervention (PCI) and a propensity score for the choice of lytic.. The primary trial endpoint of 30-day death/myocardial infarction (MI) occurred in fewer patients in the streptokinase-enoxaparin cohort (n = 2083) compared with FSL-UFH (n = 8141) [10.2% vs 12.0%, adjusted odds ratio [OR(adj)] 0.76; 95% CI 0.62, 0.93; p = 0.008]. Major bleeding was significantly increased with streptokinase-enoxaparin compared with FSL-UFH (OR(adj) 2.74; 95% CI 1.81; 4.14; p < 0.001) but intracranial haemorrhage (ICH) was similar (OR(adj) 0.90; 95% CI 0.40, 2.01; p = 0.79). Net clinical outcomes, defined as either death/MI/major bleeding or as death/MI/ICH tended to favour streptokinase-enoxaparin compared with FSL-UFH (OR(adj) 0.88; 95% CI 0.73, 1.06; p = 0.17; and OR(adj) 0.77; 95% CI 0.63, 0.93; p = 0.008, respectively). Patients receiving FSL-enoxaparin (n = 8142) and streptokinase-enoxaparin therapies experienced similar adjusted rates of the primary endpoint (OR(adj) 1.08; 95% CI 0.87, 1.32; p = 0.49) and net clinical outcomes.. Our results suggest that fibrinolytic therapy with the combination of streptokinase and the potent anticoagulant agent enoxaparin resulted in similar adjusted outcomes compared with more costly regimens utilizing a FSL.

Topics: Adult; Aged; Angioplasty, Balloon, Coronary; Cohort Studies; Drug Therapy, Combination; Endpoint Determination; Enoxaparin; Female; Fibrin; Fibrinolytic Agents; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Plasminogen Activators; Recombinant Proteins; Streptokinase; Tenecteplase; Thrombolytic Therapy; Time Factors; Tissue Plasminogen Activator; Treatment Outcome; Young Adult

Patients with a recent myocardial infarction have an increased risk of recurrent ischaemic events. In the ESTEEM trial, the oral direct thrombin inhibitor ximelagatran reduced the risk of new ischaemic events when compared with placebo in aspirin treated post myocardial infarction patients. Ximelagatran persistently reduced markers of coagulation activity, i.e. prothrombin fragment 1 + 2 (F1 + 2) and D-dimer levels. The aim of this substudy was to evaluate the levels of these markers and activated thromboplastin time (APTT) in relation to new ischaemic events or bleeding.. In the substudy, 518 out of 1883 patients were included and within 14 days after a myocardial infarction randomized to ximelagatran or placebo for 6 months. The clinical endpoints death, myocardial infarction, severe recurrent ischaemia, ischaemic stroke, and bleeding were evaluated. The levels of F1 + 2, D-dimer, and APTT were analysed at randomization and in serial samples during the study. Ximelagatran treatment appeared to have a larger treatment effect in patients with F1 + 2 and D-dimer levels above the median at randomization with a reduction of ischaemic events from 18 to 9% (P = 0.03) for F1 + 2 and from 20 to 9% for D-dimer (P = 0.009). A reduction of D-dimer levels was found in 60% of the patients 1 week after randomization and these patients had less ischaemic events when compared with patients with unchanged or increased levels (P = 0.03) regardless of treatment. F1 + 2 and D-dimer levels were unrelated to bleeding risk. In the ximelagatran group, increased APTT was not related to ischaemic events but associated with a raised risk of bleeding.. A reduction of initially high coagulation activity, as measured by the D-dimer level, in patients with recent myocardial infarction identifies patients with a decreased risk of new ischaemic events, regardless whether the reduction occurs spontaneously or is induced by pharmacological means. Patients with higher initial coagulation activity seemed to benefit most from long-term treatment with ximelagatran.

Topics: Aged; Anticoagulants; Azetidines; Benzylamines; Blood Coagulation Disorders; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Humans; Male; Myocardial Infarction; Myocardial Ischemia; Partial Thromboplastin Time; Peptide Fragments; Protein Precursors; Prothrombin; Risk Factors; Thrombin

In the ESTEEM study, patients with a recent myocardial infarction were treated with aspirin and randomized to one of four doses (24-60 mg b.i.d) of the oral direct thrombin inhibitor ximelagatran or placebo for 6 months. Ximelagatran and aspirin reduced the risk of recurrent ischemic events compared with aspirin alone. In the present substudy we evaluated the different doses of ximelagatran on pharmacokinetics as measured by plasma concentration of the active compound melagatran and activated partial thromboplastin time (APTT) and pharmacodynamics as related by markers for coagulation activity, prothrombin fragment 1 + 2 (F1 + 2) and D-dimer.. Plasma samples from 518 patients were collected before, during and after the treatment period. There was a linear dose-concentration relation at peak and trough and a linear relation between concentration and APTT (P < 0.001). F1 + 2 and D-dimer were decreased by 25% and 52% at 1 week (P < 0.001) in the ximelagatran groups compared with the placebo group and the reductions were maintained during the 6 months treatment. There were no differences detected in F1 + 2 or D-dimer levels between the different ximelagatran dosages. There was no correlation between the melagatran concentration and the change in F1 + 2 and D-dimer levels. After cessation of ximelagatran F1 + 2 and D-dimer levels returned to the initial levels.. The dose of ximelagatran and APTT are linearly related to the plasma concentration of melagatran. Ximelagatran induces a sustained and stable reduction of thrombin generation and fibrin turnover without any relation to dose above 24 mg b.i.d. These properties indicate that long-term treatment with a low dose of ximelagatran may provide valuable depression of coagulation activity in aspirin treated post myocardial infarction patients.

Topics: Aged; Azetidines; Benzylamines; Biomarkers; Blood Coagulation; Dose-Response Relationship, Drug; Female; Fibrin; Glycine; Humans; Male; Myocardial Infarction; Partial Thromboplastin Time; Pharmacokinetics; Thrombin; Time Factors

In the Thrombosis Prevention Trial (TPT), low-intensity warfarin reduced the risk of first coronary events only when the achieved international normalized ratio (INR) was > or =1.4. To validate the likely mechanism of action of low-intensity warfarin we measured its effects on plasma markers of thrombin generation, fibrin turnover and low-grade inflammation in TPT participants. D-dimer and prothrombin fragment F1.2 levels were lower at INRs > or =1.4 (P = 0.02 and 0.03 respectively); levels fell as INR increased (P for trend 0.04 and 0.002 respectively). C-reactive protein did not vary with INR. The efficacy of warfarin is related to reductions in thrombin generation and fibrin turnover.

Topics: Anticoagulants; Coronary Thrombosis; Fibrin; Fibrin Fibrinogen Degradation Products; Humans; International Normalized Ratio; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Prothrombin; Risk Factors; Thrombin; Warfarin

Few data exist on the effects of n-3 polyunsaturated fatty acids (PUFAs) on the initiators and endstage products of coagulation following an acute myocardial infarction (MI). We assessed the long-term effects of n-3 PUFAs on postinfarct variations of tissue factor (TF), activated factor XII (FXIIa) and fibrin monomer (FM), and expected additional statin treatment to modify thrombogenicity. Acute MI patients (n = 300) were randomly allocated to a high dose of n-3 PUFAs or corn oil for at least one year. Plasma concentrations of TF, FXIIa and FM were unaffected by n-3 PUFAs as compared to corn oil, and were uninfluenced by additional statin treatment in subgroup analyses. TF decreased (p = 0.0001), while FXIIa increased during the first 6 weeks (p = 0.001). FM remained essentially unchanged during the entire observation period. In conclusion, TF, FXIIa and FM were unaffected by long-term treatment with high- dosed n-3 PUFAs and by additional statin treatment.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Blood Coagulation; Cholesterol; Corn Oil; Double-Blind Method; Factor XIIa; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Female; Fibrin; Humans; Lipid Metabolism; Male; Middle Aged; Models, Statistical; Myocardial Infarction; Prospective Studies; Random Allocation; Thromboplastin; Triglycerides

Thrombolytic therapy in patients with acute myocardial infarction is hampered by bleeding complications and procoagulant effects favoring early reocclusion. TNK-tPA was shown in vitro to have considerable fibrin specificity. We investigated the effects of tenecteplase (TNK-tPA) and alteplase (rt-PA) on the haemostasis and fibrinolytic system.. We enrolled 30 patients with AMI into the study. Twenty patients received front-loaded rt-PA up to 100 mg; 10 patients were given TNK-tPA in a single bolus up to 50 mg. All patients received aspirin and intravenous heparin. During the first 2 days, the following parameters were repetitively determined: thrombin-antithrombin III complexes (TAT), antithrombin III (ATIII), prothrombin fragment F 1 + 2 (F 1 + 2), kallikrein-like activity (KK), activated factor XII (FXIIa), plasmin alpha 2-antiplasmin complexes (PAP), fibrinogen, D-dimers (DD), tissue-type plasminogen activator (t-PA). A total of 75 healthy persons served as control group. TAT increased significantly after rt-PA but not after TNK-tPA (3 h: 38.1 +/- 29.4 versus 10.5 +/- 4.2 microg/l; p < 0.01), indicating paradoxical thrombin activation. F 1 + 2 increased transiently after rt-PA but not after TNK-tPA. Fibrinogen was significantly lower after rt-PA versus TNK-tPA (3 h: 163 +/- 27 versus 380 +/- 54 mg/dl; p < 0.05). KK activities in the rt-PA group were significantly (p < 0.01) increased over 48 h versus TNK-tPA. PAP and D-dimers were lower over the time course of 48 h in the tenecteplase group versus rt-PA.. This study indicates that tenecteplase has higher fibrin specificity not only in vitro but also in vivo versus alteplase. TNK-tPA consecutively has no paradoxical systemic procoagulant effect due to the lower extent of activation of the kallikrein-factor XII system than alteplase.

Topics: Aged; alpha-2-Antiplasmin; Anticoagulants; Antifibrinolytic Agents; Antithrombin III; Aspirin; Biomarkers; Enzyme Activation; Factor XIIa; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinolysin; Fibrinolysis; Fibrinolytic Agents; Hemostasis; Heparin; Humans; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Platelet Aggregation Inhibitors; Prothrombin; Recombinant Proteins; Substrate Specificity; Tenecteplase; Thrombin; Thrombolytic Therapy; Tissue Plasminogen Activator

Diagnosis of acute coronary syndromes (ACS) is a major challenge for emergency physicians. Because soluble fibrin (sF) has been suggested as a potential early marker of impending myocardial ischemia, we were interested whether a sF bedside test could help in early identification of patients with ACS in the emergency department.. We evaluated plasma coagulation markers, including a newly developed sF bedside test, prothrombin fragment (F(1+2)), sF, and D-dimer, in a cross-sectional trial with 184 patients suggestive of ACS.. Whereas 76% (13 of 17) of patients with unstable angina pectoris (UAP) had a positive sF bedside test, only 10 of 33 patients (30%) with non-ST-segment-elevation myocardial infarction and 10 of 44 patients (23%) with ST-elevation myocardial infarction tested positive. Three percent of controls (1 of 33) and 11% of patients (6 of 57) with preexisting stable angina had a positive sF bedside test (P <0.001 for noncardiac chest pain vs ACS), yielding an overall specificity of 92% and a sensitivity of 35%. The sensitivity of the established coagulation markers was significantly less to detect ACS (11% for F(1+2), 20% for thrombus precursor protein, and 18% for D-dimer; P <0.02 vs sF bedside test). The sF bedside test presented the earliest objective indicator of impending myocardial damage in the majority (10 of 13) of ACS patients with a normal or nondiagnostic electrocardiogram (ECG).. A sF bedside test offers a specific tool for early identification of patients with ACS in an emergency department setting, although its sensitivity seems sufficient only for the early identification of patients with UAP. A sF bedside test could be useful, particularly in UAP patients with a nondiagnostic ECG.

Topics: Acute Disease; Angina, Unstable; Biomarkers; Blood Coagulation Tests; Emergency Medical Services; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Point-of-Care Systems; Sensitivity and Specificity

In the current study, we investigated molecular markers of coagulation activity, ie, prothrombin fragment 1+2 (F1+2), thrombin-antithrombin (TAT) complex, soluble fibrin (SF), and D-dimer, and their relation to death, myocardial infarction, and refractory angina during and after anticoagulant treatment in unstable coronary artery disease. Patients with unstable coronary artery disease (N=320) were randomized to a 72-hour infusion with either inogatran, a low-molecular-mass direct thrombin inhibitor, or unfractionated heparin. During the 30-day follow-up, a 40% lower event rate was seen in patients with high compared with low baseline levels of TAT or SF. High baseline levels of coagulation activity were correlated with a larger decrease during treatment. Patients with decreased compared with raised F1+2 or TAT levels after 6 hours of treatment had a 50% lower event rate at 30 days (F1+2, P=0.04; TAT, P=0.02). At the cessation of antithrombin treatment, there was a clustering of cardiac events that tended to be related to a rise in the levels of TAT and the other markers. During long-term follow-up (median, 29 months), there was a relation between higher baseline levels of D-dimer (P=0.003) and increased mortality. High baseline levels of molecular markers of coagulation activity might identify patients with a thrombotic condition (as the major cause of instability) who are good responders to anticoagulant therapy, with a larger decrease in coagulation activity during treatment and a decreased risk of ischemic events. However, this early benefit is lost during long-term follow-up when high baseline levels of coagulation activity are associated with a raised risk of early reactivation and increased mortality.

Topics: Adult; Aged; Angina, Unstable; Anticoagulants; Antithrombin III; Antithrombins; Biomarkers; Blood Coagulation; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Follow-Up Studies; Glycine; Heparin; Humans; Kinetics; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Peptide Hydrolases; Piperidines; Prothrombin; Random Allocation; Treatment Outcome

This study was undertaken to compare the effects of reteplase and alteplase regimens on hemostasis and fibrinolysis in acute myocardial infarction (AMI). Thrombolytic treatment in patients with AMI is hampered by paradoxical procoagulant effects that favor early reocclusion. In vivo data comparing this effect and the fibrin specificity of double-bolus reteplase and front-loaded alteplase regimens are not available. In a prospective, randomized study, 50 patients with AMI were either treated with double bolus (10 + 10 U) reteplase or with front-loaded alteplase (up to 100 mg) within 6 hours of symptom onset. Thirty apparently healthy persons served as controls. Molecular markers of coagulation and fibrinolysis were serially examined for up to 5 days. Paradoxical thrombin activation at 3 hours after initiation of therapy was comparable between reteplase and alteplase. Reteplase (65 +/- 5 U/L) and alteplase (72 +/- 8 U/L) caused significantly elevated kallikrein activity at 3 hours after adminstration (p <0.01 vs controls 30 +/- 1 U/L). Fibrin specificity was less for reteplase (p <0.05) with a decrease in fibrinogen at 3 hours to 122 +/- 27 mg/dl versus 224 +/- 28 mg/dl for alteplase (p <0.01 and p <0.05 vs controls). D-Dimer levels at 3 hours were higher (p <0.05) after reteplase (5,459 +/- 611 ng/ml) versus alteplase (3,445 +/- 679 ng/ml) (both p <0.01 vs controls 243 +/- 17 ng/ml). Plasmin generation (plasmin-antiplasmin complexes) was significantly (p <0.01) increased at 3 hours with both regimens to 27,079 +/- 3,964 microg/L (reteplase) and 19,522 +/- 2,381 microg/L (alteplase). The data from 3 hours after start of thrombolytic therapy proved less marked fibrin specificity of the reteplase regimen (in vivo) compared with front-loaded alteplase. Both regimens have a moderate procoagulant effect without differences in activation of the kallikrein system.

Topics: Adult; Aged; Aged, 80 and over; Antithrombin III; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Fibrin; Fibrinolysin; Fibrinolysis; Fibrinolytic Agents; Hemostasis; Humans; Kallikreins; Male; Middle Aged; Myocardial Infarction; Peptide Hydrolases; Prospective Studies; Recombinant Proteins; Recurrence; Thrombin; Thrombolytic Therapy; Tissue Plasminogen Activator

A novel sensitive method for analyses of soluble fibrin monomer antigen was used to assess the predictive value of fibrin monomer when estimating mortality after acute myocardial infarction.. Fibrin monomer was measured in plasma samples from 293 patients enrolled in a randomized clinical trial of low molecular weight heparin (dalteparin) in acute myocardial infarction (the FRAMI trial). Samples taken on days 2 and 7 were analysed using the Enzymun-Test FM(R)(Boehringer Mannheim, Germany). Non-survivors had significantly higher fibrin monomer levels relative to survivors (day 2, median (min-max): 1.8 mg. l-1(<0.01-73.1) vs 0.4 mg. l-1(<0. 01-103.5), P<0.0001). Fibrin monomer levels were significantly associated with congestive heart failure (P<0.001), enzymatic infarct size (P<0.0001), dalteparin treatment (P<0.001), and thrombolytic therapy (P=0.016). The relationship between fibrin monomer and mortality remained statistically significant after adjustment for these variables. In logistic regression analyses, fibrin monomer levels, age and congestive heart failure were all independent predictors of fatal outcome.. Increased fibrin monomer level is an independent predictor of mortality in patients with myocardial infarction. It allows further risk stratification when combined with known risk factors such as age and presence of congestive heart failure.

Topics: Aged; Dalteparin; Double-Blind Method; Female; Fibrin; Fibrinolytic Agents; Humans; Immunoenzyme Techniques; Male; Middle Aged; Multicenter Studies as Topic; Myocardial Infarction; Risk Assessment

The native fibrin gel structure formed in vitro from plasma samples was examined by liquid permeation of hydrated fibrin gel networks in 38 unselected men who had suffered a myocardial infarction before the age of 45 years and in 88 age-matched population-based control men. Both the fibrin gel porosity (permeability coefficient, Ks) and the calculated fiber mass-length ratio varied considerably within the two groups, but were generally lower in the patients. Ks was 8.3 +/- 5.2 cm2 x 10(9) (mean +/- SD) in the patient group and 12.5 +/- 5.7 cm2 x 10(9) among controls (p < 0.001). The corresponding figures for fiber mass-length ratio were 13.1 +/- 7.7 and 16.5 +/- 7.5 Dalton/ cm x 10(-13), respectively (p < 0.01). Around 50% of the patients had Ks values below the 10th percentile of the control group. A strong inverse correlation was seen between plasma plasminogen activator inhibitor-1 (PAI-1) activity and Ks (r = -0.603, p < 0.001) or fiber mass-length ratio (r = -0.565, p < 0.001) in the patient group. Corresponding weaker associations of PAI-1 with fibrin gel properties were also present in the control group. In addition, inverse relationships of very low density lipoprotein (VLDL) triglyceride concentrations to Ks (r = -0.362, p < 0.001) and fiber mass-length ratio (r = -0.283, p < 0.01) were found among the controls. Proneness to formation of tight and rigid fibrin gel networks with abnormal architecture in vitro is in vivo associated with myocardial infarction at a young age. Impaired fibrinolytic function secondary to a raised plasma PAI-1 activity level is associated with abnormal fibrin gel structure.

Topics: Adult; Fibrin; Fibrinogen; Fibrinolysis; Gels; Humans; Lipoproteins; Logistic Models; Male; Multivariate Analysis; Myocardial Infarction; Plasminogen Activator Inhibitor 1

The aim of this study was to assess the hemorrhagic risk associated with fibrin-specific thrombolytic therapy and invasive procedures with acute myocardial infarction.. Successful coronary artery reperfusion has important prognostic implications. Because immediate coronary angiography is the only method proved to differentiate early fibrinolytic success from failure, its use may be important for selected patients.. Five hundred seventy-five patients were evaluated with six combined thrombolytic and catheterization strategies. Patients were randomized to intravenous urokinase alone, recombinant tissue-type plasminogen activator (rt-PA) alone, or both; simultaneously they were randomized to an immediate versus a deferred catheterization strategy. Hemorrhagic events were assessed. The correlation of hemorrhage with clinical and hemostatic variables was evaluated. Prespecified transfusion criteria were employed.. No difference in baseline characteristics or in hemorrhagic complications was noted among the three thrombolytic regimens. Although mild (< 250 ml) bleeding was more common in the group with immediate catheterization, no clinically significant difference among catheterization groups was seen in moderate to life-threatening hemorrhagic events. Most bleeding occurred at vascular access sites, yet severe and life-threatening hemorrhage occurred in < 1% of patients. Baseline and nadir fibrinogen levels, change in baseline fibrinogen levels and peak fibrin and fibrinogen degradation products did not correlate with bleeding risk. A clinical predisposition for bleeding was observed in women as well as older (> or = 65 years) and lighter (< or = 70 kg) patients. With prespecified transfusion criteria, only a minimal increase in blood product usage was noted with immediate catheterization.. Immediate cardiac catheterization can be accomplished without a clinically significant difference in bleeding risk. Fibrin specificity offers no clear advantage in reducing hemorrhagic risk. Bleeding risk correlates best with baseline patient characteristics. Finally, the amount of blood transfused can be reduced with lower transfusion criteria.

Topics: Cardiac Catheterization; Female; Fibrin; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Risk Factors; Thrombolytic Therapy; Time Factors; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator

Although low molecular weight heparins (LMWH) have been extensively investigated for the prophylaxis and treatment of venous thromboembolism in surgical environments, few data in acute myocardial infarction are available in the literature. In this study two dosages of a new LMWH, Parnaparin, and unfractionated heparin (UF) were investigated in 50 pts with acute myocardial infarction. 20 pts received UF (15.000 units, three subcutaneous injections, Group 1), 20 pts received Parnaparin (6.400 units, single injection, Group 2) and 10 pts received a higher dose of Parnaparin (12.800 units, single injection, Group 3). Similar fibrinopeptide A (FpA) levels were observed in Group 1 and Group 2. In Group 3 the dosage of Parnaparin resulted in a significant prolongation of the APTT and in lower FpA levels. Fibrin formation was decreased by Parnaparin in a concentration-dependent way, according to both the anti-Xa activity and the APTT ratio. Parnaparin did not result in a significant increase in free fatty acid concentration, in comparison with UF. Thus, Parnaparin may offer the advantage of a single subcutaneous injection in patients with acute myocardial infarction.

Topics: Aged; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Female; Fibrin; Heparin; Heparin, Low-Molecular-Weight; Humans; Injections, Subcutaneous; Lipolysis; Male; Middle Aged; Myocardial Infarction; Partial Thromboplastin Time

Fibrinopeptide A (FPA) and beta thromboglobulin (BTG) were measured in 42 patients with acute myocardial infarction (AMI) allocated on admission to one of three groups: 14 patients received a heparin bolus injection of 5000 IU intravenously followed by a 2-hour intravenous infusion (830 IU/hr) (group 1), 14 patients received a heparin bolus of 5000 IU subcutaneously (group 2), and the remaining 14 patients received no anticoagulant treatment (group 3). In group 1 the initially elevated FPA level of 5.8 +/- 1.8 ng/ml dropped to 2.0 +/- 1.5 ng/ml 30 minutes after the intravenous heparin bolus injection of 5000 IU (p less than 0.001) and returned to normal (1.9 +/- 0.8 ng/ml) in 8 of 14 patients. The initially elevated BTG level of 64 +/- 21 ng/ml did not change significantly during intravenous heparin treatment, whereas there was a rapid but only transitory increase in platelet factor 4, (PF4) from 25 +/- 9 to 74 +/- 16 ng/ml (p less than 0.01) after the intravenous heparin bolus. In group 2 the initial FPA of 5.0 +/- 2.3 ng/ml was similarly elevated as in group 1 and dropped to 2.7 +/- 1.7 and 3.3 +/- 1.5 ng/ml 2 and 4 hours after 5000 IU subcutaneously (p less than 0.05), whereas 6 and 8 hours after subcutaneous heparin bolus the mean FPA levels were 4.2 +/- 1.7 and 5.5 +/- 2.0 ng/ml and no more significantly different from the initial FPA values. BTG and PF4 did not change significantly after the subcutaneous heparin bolus. In group 3 the initially elevated mean FPA level of 4.9 +/- 2.4 ng/ml did not change significantly during the first 8 hours after admission, whereas the FPA level 24 hours after admission was 8.4 +/- 3.9 ng/ml and higher than the initial value (p less than 0.01). We conclude that heparin may reduce the elevated FPA level in plasma found in patients with AMI; however, neither subcutaneous nor intravenous heparin in a dosage frequently used is sufficient to consistently normalize the elevated rate of fibrin formation found in these patients.

Topics: Aged; Beta-Globulins; beta-Thromboglobulin; Blood Coagulation Tests; Female; Fibrin; Fibrinogen; Fibrinopeptide A; Heparin; Humans; Infusions, Parenteral; Injections, Subcutaneous; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation; Platelet Factor 4; Time Factors

Topics: Clinical Trials as Topic; Fibrin; Humans; Myocardial Infarction; Plasminogen Activators

Topics: Adult; Aged; Blood Coagulation; Blood Coagulation Tests; Clinical Trials as Topic; Coronary Disease; Electrocardiography; Fibrin; Fibrinogen; Fibrinolysis; Fibrinolytic Agents; Humans; Male; Middle Aged; Myocardial Infarction; Plasminogen; Stanozolol

Angiogenesis is essential for cardiac repair after myocardial infarction. Promoting angiogenesis has been demonstrated as an effective approach for myocardial infarction treatment. Several different strategies for inducing myocardial angiogenesis have been explored, including exogenous delivery of angiogenic genes, proteins, microRNAs, cells, and extracellular vesicles. Various types of injectable hydrogels have been investigated for cardiac tissue repair. One of the most promising injectable hydrogels in cardiac regeneration is a cardiac extracellular matrix hydrogel that is derived from decellularized porcine myocardium. It can be delivered minimally invasively

Topics: Animals; Extracellular Matrix; Fibrin; Heart; Human Umbilical Vein Endothelial Cells; Humans; Hydrogels; Myocardial Infarction; Neovascularization, Physiologic; Swine

Native myocardium exhibits well-organized cellular orientations and highly vascularized architectures, which is important for tissue survival and synchronic contraction activities. Mimicking such structural organizations to engineer functional cardiac constructs is a promising approach to treat myocardial infarction

Topics: Animals; Endothelial Cells; Fibrin; Myocardial Infarction; Myocytes, Cardiac; Printing, Three-Dimensional; Rats; Tissue Engineering; Tissue Scaffolds

Cardiac patch, a scaffold layered on the surface of the heart that can provide mechanical and regeneration support for damaged myocardium, has provided a promising solution to treat severe myocardial infarction (MI). In this work, a fibrin based cardiac patch loaded with neuregulin-1 (NRG-1) is developed to attach locally to the infract area of heart. The composite patch exhibited good biocompatibility and promoted cardiomyocyte proliferation in vitro via NRG-1/ErbB signaling. Moreover, implantation of this patch to the infracted border zone reduced cell apoptosis, promoted angiogenesis and inhibited fibrosis, which reduced infraction size and improved cardiac function consequently. Thus, the combination of natural biomaterial fibrin and bioactive factor NRG-1 might have a promising potential for clinical application of MI treatment.

Topics: Fibrin; Heart; Humans; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Neuregulin-1; Tissue Scaffolds

Myocardial infarction (MI) is a serious threat to public health. The early identification of MI is important to promote appropriate treatment strategies for patients. Recently, strategies targeting extracellular matrix (ECM) components have gained attention. Fibrin is an ECM protein involved after MI. In this work, we constructed fibrin-targeted nanoparticles (NPs) by co-assembling a fibrin-targeted peptide (CREKA) and indocyanine green (ICG) and used them to enhance photoacoustic (PA) imaging for noninvasive detection of the infarct region to help diagnose MI.. ICG NPs modified with CREKA were prepared (CREKA-ICG-LIP NPs). Then, the fundamental characteristics, stability, safety, and targeting ability of the NPs were detected. Finally, in an ischemia-reperfusion (IR) injury model, the performance of the NPs in detecting the infarct region in the model on PA imaging was evaluated.. CREKA-ICG-LIP NPs were successfully constructed and showed excellent basic characteristics, a high safety level, and an excellent targeting ability. After intravenous injection, the CREKA-ICG-LIP NPs accumulated in the injured region in the IR model. Then, the PA signal in the infarct region could be detected by the ultrasound transducer of the Vevo LAZR Photoacoustic Imaging System.. This work provides new insights for non-invasive, real-time imaging techniques to detect the region of myocardial injury and help diagnose MI based on a PA imaging system with high sensitivity in optical imaging and deep penetration in ultrasound imaging.

Topics: Animals; Cell Death; Cell Line, Tumor; Fibrin; Humans; Indocyanine Green; Myocardial Infarction; Myocardial Reperfusion Injury; Nanoparticles; Optical Imaging; Photoacoustic Techniques; Rats, Sprague-Dawley

The Coronavirus disease 2019 (COVID)-19 pandemic has already affected millions worldwide, with a current mortality rate of 2.2%. While it is well-established that severe acute respiratory syndrome-coronavirus-2 causes upper and lower respiratory tract infections, a number of neurological sequelae have now been reported in a large proportion of cases. Additionally, the disease causes arterial and venous thromboses including pulmonary embolism, myocardial infarction, and a significant number of cerebrovascular complications. The increasing incidence of large vessel ischemic strokes as well as intracranial hemorrhages, frequently in younger individuals, and associated with increased morbidity and mortality, has raised questions as to why the brain is a major target of the disease. COVID-19 is characterized by hypercoagulability with alterations in hemostatic markers including high D-dimer levels, which are a prognosticator of poor outcome. Together with findings of fibrin-rich microthrombi, widespread extracellular fibrin deposition in affected various organs and hypercytokinemia, this suggests that COVID-19 is more than a pulmonary viral infection. Evidently, COVID-19 is a thrombo-inflammatory disease. Endothelial cells that constitute the lining of blood vessels are the primary targets of a thrombo-inflammatory response, and severe acute respiratory syndrome coronavirus 2 also directly infects endothelial cells through the ACE2 (angiotensin-converting enzyme 2) receptor. Being highly heterogeneous in their structure and function, differences in the endothelial cells may govern the susceptibility of organs to COVID-19. Here, we have explored how the unique characteristics of the cerebral endothelium may be the underlying reason for the increased rates of cerebrovascular pathology associated with COVID-19.

Topics: Angiotensin-Converting Enzyme 2; Blood Coagulation; Brain; Brain Ischemia; COVID-19; Cytokines; Endothelial Cells; Fibrin; Fibrin Fibrinogen Degradation Products; Hemostasis; Humans; Hypoxia; Incidence; Inflammation; Ischemic Stroke; Myocardial Infarction; Pandemics; Prognosis

Coronary artery disease is associated with impaired clot structure. The aim of this study was to investigate acute phase myocardial infarction (AMI) and provide detailed quantitative analysis of clot ultrastructure.. Clot formation and breakdown, pore size, fiber density, fiber radius and protofibril packing were investigated in plasma clots from AMI patients. These data were compared to those from healthy controls.. Analysis on clot formation using turbidity showed increased lag time, suggesting changes in protofibril packing and increased fiber size for AMI patients compared to healthy controls. Additionally, increased average rate of clotting and decreased time to maximum absorbance in AMI patients suggest that clots formed more quickly. Moreover, we observed increased time from max OD to max rate of lysis. Increased fibrinogen and decreased plasminogen in AMI patients were accounted for in represented significant differences. AMI samples showed increased time to 25% and 50% lysis, but no change in 75% lysis, representative of delayed lysis onset, but expediated lysis once initiated. These data suggest that AMI patients formed less porous clots made from more densely packed fibers with decreased numbers of protofibrils, which was confirmed using decreased permeation and increased fiber density, and decreased turbidimetry.. AMI plasma formed clots that were denser, less permeable, and lysed more slowly than healthy controls. These findings were confirmed by detailed analysis of clot ultrastructure, fiber size, and protofibril packing. Dense clot structures that are resistant to lysis may contribute to a prothrombotic milieu in AMI.

Topics: Blood Coagulation; Fibrin; Fibrin Clot Lysis Time; Fibrinolysis; Humans; Myocardial Infarction; Radius; Thrombosis

 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

 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

Topics: Adaptive Immunity; Angiogenesis Inducing Agents; Animals; Biomechanical Phenomena; Cicatrix; Fibrin; Heart; Humans; Hydrogels; Injections; Myocardial Infarction; Neovascularization, Physiologic; Rats, Sprague-Dawley; Vascular Endothelial Growth Factor A

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

Layering a regenerative polymer scaffold on the surface of the heart, termed as a cardiac patch, has been proven to be effective in preserving cardiac function after myocardial infarction (MI). However, the placement of such a patch on the heart usually needs open-chest surgery, which is traumatic, therefore prevents the translation of this strategy into the clinic. We sought to device a way to apply a cardiac patch by spray painting in situ polymerizable biomaterials onto the heart with a minimally invasive procedure. To prove the concept, we used platelet fibrin gel as the "paint" material in a mouse model of MI. The use of the spraying system allowed for placement of a uniform cardiac patch on the heart in a mini-invasive manner without the need for sutures or glue. The spray treatment promoted cardiac repair and attenuated cardiac dysfunction after MI.

Topics: Animals; Biocompatible Materials; Blood Platelets; Fibrin; Heart; Male; Mice; Myocardial Infarction; Myocytes, Cardiac; Paintings; Rats; Rats, Sprague-Dawley; Regeneration

The combination of mesenchymal stem cells and tissue-engineered fibrin patches improves the therapeutic efficacy of stem cells. In vivo cardiac magnetic resonance (4.7 Tesla) and ex vivo high-spatial resolution CMR were used to track the fate of human bone marrow-derived mesenchymal stem cell (BMSC) delivered on an epicardial scaffold and more specifically assess their potential intramyocardial migration. Fifty-seven nude rats underwent permanent coronary artery ligation. Two months later, those with a left ventricular ejection fraction ≤55% were randomly allocated to receive a patch loaded with human BMSC (BMSC-P, n = 10), a patch loaded with BMSCs labelled with iron oxide nanoparticles (BMSC*-P, n = 12), an acellular patch (A-P, n = 8) or to serve as sham-operated animals (SHAM, n = 7). BMSC secretion of cytokines and growth factors was evaluated with flow-cytometry. Cardiac functional parameters of cell-treated groups (BMSC*-P and BMSC-P) yielded significantly better outcomes than the SHAM group (p = 0.044 and p = 0.026, respectively, for ejection fraction). Angiogenesis was higher in the cell-patch than in control groups (e.g. BMSC*P vs. SHAM: p = 0.007). No BMSCs were identified into the myocardium on cardiac magnetic resonance or histological sections, although persisting BMSCs were identified on the epicardial surface 21 days post-transplantation in 10% of rats hearts (Lamin A/C and CD90 positive). Cytokine and growth factor profiling demonstrated an increase in their release by cells seeded in patches. The absence of stem cell migration into the myocardium and the persistence of stem cells on the epicardial surface suggest that fibrin patches are likely to act predominantly as reservoirs of paracrine factors. Copyright © 2017 John Wiley & Sons, Ltd.

Topics: Animals; Bone Marrow Cells; Cytokines; Female; Fibrin; Flow Cytometry; Heart Function Tests; Humans; Immunohistochemistry; Magnetic Resonance Imaging; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Myocardial Infarction; Paracrine Communication; Pericardium; Rats, Nude

Cardiac cells are subjected to mechanical and electrical forces, which regulate gene expression and cellular function. Therefore, in vitro electromechanical stimuli could benefit further integration of therapeutic cells into the myocardium. Our goals were (a) to study the viability of a tissue-engineered construct with cardiac adipose tissue-derived progenitor cells (cardiac ATDPCs) and (b) to examine the effect of electromechanically stimulated cardiac ATDPCs within a myocardial infarction (MI) model in mice for the first time. Cardiac ATDPCs were electromechanically stimulated at 2-millisecond pulses of 50 mV/cm at 1 Hz and 10% stretching during 7 days. The cells were harvested, labeled, embedded in a fibrin hydrogel, and implanted over the infarcted area of the murine heart. A total of 39 animals were randomly distributed and sacrificed at 21 days: groups of grafts without cells and with stimulated or nonstimulated cells. Echocardiography and gene and protein analyses were also carried out. Physiologically stimulated ATDPCs showed increased expression of cardiac transcription factors, structural genes, and calcium handling genes. At 21 days after implantation, cardiac function (measured as left ventricle ejection fraction between presacrifice and post-MI) increased up to 12% in stimulated grafts relative to nontreated animals. Vascularization and integration with the host blood supply of grafts with stimulated cells resulted in increased vessel density in the infarct border region. Trained cells within the implanted fibrin patch expressed main cardiac markers and migrated into the underlying ischemic myocardium. To conclude, synchronous electromechanical cell conditioning before delivery may be a preferred alternative when considering strategies for heart repair after myocardial infarction. Stem Cells Translational Medicine 2017;6:970-981.

Topics: Adult Stem Cells; Animals; Cell Differentiation; Cell Movement; Cell Survival; Fibrin; Gene Expression Regulation; Heart Function Tests; Humans; Mice, SCID; Myocardial Infarction; Myocardium; Neovascularization, Physiologic; Prosthesis Implantation; Recovery of Function; Stem Cell Transplantation; Tissue Engineering; Ventricular Remodeling

There is still no standard large animal model for evaluating the effectiveness of potential thrombolytic therapies. Here, we aimed to develop a new beagle model with ST-elevation myocardial infarction (STEMI) by injecting autologous emboli with similar components of coronary thrombus.. 18 male beagles were included and divided into three groups: red embolus group (n = 6), white embolus group (n = 6) or white embolus + rt-PA group (n = 6). Autologous emboli were infused into the mid-distal region of the left anterior descending coronary artery. The composition of embolus was examined by scanning electron microscope (SEM). Coronary angiography was performed to verify the status of embolism. Myocardial infarct size was measured by 2, 3, 5- triphenyltetrazolium chloride (TTC) staining.. Red thrombus was characteristic of loose reticular structure of erythrocytes under SEM, while the white embolus had compacted structure that mainly consisted of a dense mass of fibrin. Coronary angiography showed the recanalization rate was 2/6 in the red embolus group versus 0/6 in the white embolus group in three hours after occlusion. Arrhythmia, resolution of ST-segment elevation and lower T wave on the electrocardiogram appeared in the red embolus group but not in the white embolus group. Another six dogs with white thrombi were treated with rt-PA. Five out of six dogs exhibited coronary recanalization after two hours of therapy, compared to zero dogs without rt-PA treatment. The size of myocardial infarction in rt-PA group reduced significantly compared with white embolus group using TTC staining method.. The white embolism model was more convenient experimentally and had a higher uniformity, stability and success rate. The major innovation of our study is that we applied fibrin-rich white thrombi to establish beagle model possessing features of clinically observed coronary thrombi in time window of intravenous thrombolysis of STEMI. This model can be used to evaluate new thrombolytic drugs for the treatment of STEMI.

Topics: Animals; Cellulose; Coronary Angiography; Coronary Thrombosis; Disease Models, Animal; Dogs; Electrocardiography; Erythrocytes; Fibrin; Fibrinolytic Agents; Male; Microscopy, Electron, Scanning; Myocardial Infarction; Thrombolytic Therapy; Tissue Plasminogen Activator

It is widely known that myocardial damage is not immediately terminated after the elimination of epicardial occlusion in cases of myocardial infarction. In situ thrombosis during epicardial occlusion might contribute to poor myocardial perfusion after reperfusion of an occluded epicardial artery. In the current study, we sought to determine the effects of ischemia and reperfusion on microvascular thrombotic occlusion.. Thirty male Wistar rats were included in the study. After the rats had been anesthetized and thoracotomized, the left coronary artery was occluded for 30 minutes in the first group, and it was occluded for 30 minutes and reperfused for an additional 20 minutes in the second group. Ten rats were used as a sham-operated control group. After completion of the study protocol, excised heart preparations were analyzed by immunohistochemistry and electron microscopy.. A significant difference was found between the infarction plus reperfusion group and the other 2 groups, with respect to microvascular fibrin and thrombocyte deposition in immunohistochemistry analysis. These results were confirmed by morphological examination with electron microscopy.. In situ fibrin formation accompanies microvascular obstruction in acute myocardial infarction. Our results indicate that additional therapeutic approaches are needed in order to achieve better tissue perfusion in contemporary treatment of acute myocardial infarction after successful reopening of the infarct-related artery.

Topics: Animals; Arterial Occlusive Diseases; Coronary Vessels; Fibrin; Male; Myocardial Infarction; Rats; Rats, Wistar; Thrombosis

Stem cells and biomaterials have been studied for therapeutic cardiac repair. Previous studies have shown the beneficial effects of platelet fibrin gel and cardiac stem cells when cotransplanted into rodent hearts with myocardial infarction (MI). We hypothesized that matrix metalloproteinases (MMPs) play an important role in such protection. Thus, the present study is designed to elucidate the effects of MMP inhibition on the therapeutic benefits of intramyocardial injection of platelet fibrin gel spiked with cardiac stem cells (cell-gel) in a rat model of acute MI. In vitro, broad-spectrum MMP inhibitor GM6001 undermines cell spreading and cardiomyocyte contraction. In a syngeneic rat model of myocardial infarction, MMP inhibition blunted the recruitment of endogenous cardiovascular cells into the injected biomaterials, therefore hindering de novo angiogenesis and cardiomyogenesis. Echocardiography and histology 3 weeks after treatment revealed that metalloproteinase inhibition diminished the functional and structural benefits of cell-gel in treating MI. Reduction of host angiogenesis, cardiomyocyte cycling, and MMP-2 activities was evident in animals treated with GM6001. Our findings suggest that MMPs play a critical role in the therapeutic benefits of platelet fibrin gel spiked with cardiac stem cells for treating MI.. In this study, the effects of matrix metalloproteinase inhibition on the performance of platelet gel spiked with cardiac stem cells (cell-gel) for heart regeneration are explored. The results demonstrate that matrix metalloproteinases are required for cell-gel to exert its benefits in cardiac repair. Inhibition of matrix metalloproteinases reduces cell engraftment, host angiogenesis, and recruitment of endogenous cardiovascular cells in rats with heart attack.

Topics: Animals; Blood Platelets; Dipeptides; Disease Models, Animal; Echocardiography; Fibrin; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Myocardial Infarction; Myocytes, Cardiac; Rats; Regeneration; Stem Cell Transplantation

Topics: Animals; Drug Delivery Systems; Fibrin; Humans; Molecular Targeted Therapy; Myocardial Infarction; Oligopeptides; Protein Binding; Rats; Regenerative Medicine; Stem Cell Transplantation; Stem Cells

Utilizing a fast 31P magnetic resonance spectroscopy (MRS) 2-dimensional chemical shift imaging (2D-CSI) method, this study examined the heterogeneity of creatine kinase (CK) forward flux rate of hearts with postinfarction left ventricular (LV) remodeling. Immunosuppressed Yorkshire pigs were assigned to 4 groups: 1) A sham-operated normal group (SHAM, n = 6); 2) A 60 minutes distal left anterior descending coronary artery ligation and reperfusion (MI, n = 6); 3) Open patch group; ligation injury plus open fibrin patch over the site of injury (Patch, n = 6); and 4) Cell group, hiPSCs-cardiomyocytes, -endothelial cells, and -smooth muscle cells (2 million, each) were injected into the injured myocardium pass through a fibrin patch (Cell+Patch, n = 5). At 4 weeks, the creatine phosphate (PCr)/ATP ratio, CK forward flux rate (Flux PCr→ATP), and k constant of CK forward flux rate (kPCr→ATP) were severely decreased at border zone myocardium (BZ) adjacent to MI. Cell treatment results in significantly increase of PCr/ATP ratio and improve the value of kPCr→ATP and Flux PCr→ATP in BZ myocardium. Moreover, the BZ myocardial CK total activity and protein expression of CK mitochondria isozyme and CK myocardial isozyme were significantly reduced, but recovered in response to cell treatment. Thus, cell therapy results in improvement of BZ bioenergetic abnormality in hearts with postinfarction LV remodeling, which is accompanied by significantly improvements in BZ CK activity and CK isozyme expression. The fast 2D 31P MR CSI mapping can reliably measure the heterogeneity of bioenergetics in hearts with post infarction LV remodeling.

Topics: Animals; Biomarkers; Cell Differentiation; Cell Lineage; Creatine Kinase; Endothelial Cells; Energy Metabolism; Fibrin; Humans; Induced Pluripotent Stem Cells; Magnetic Resonance Spectroscopy; Metabolic Flux Analysis; Mitochondria; Myocardial Contraction; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Myocytes, Smooth Muscle; Stem Cell Transplantation; Sus scrofa; Ventricular Remodeling

The presence and amount of the proteins within a plasma clot may influence clot properties, like susceptibility to fibrinolysis, however, the clot proteome has not yet been extensively described. The aim of the study was to investigate the protein composition of clots of four patients with acute myocardial infarction (AMI) in two time points: in the acute ischemic phase and two months later during the standard therapy.. Shotgun proteomic method (2DLC-MS/MS) was used to investigate time-dependent protein composition changes of clots prepared ex vivo from citrated plasma of the peripheral blood of patients with AMI.. Proteomic analysis revealed a total number of 62 proteins identified in all 8 samples grouping into several distinct functional clusters (e.g. cholesterol transporter activity, immunoglobulin binding and peptidase regulatory activity). The protein signatures of clots differed significantly depending on time after ACS, showing 30% greater variability in protein composition of the clots prepared in the plasma two months after the onset of AMI. Several proteins potentially involved in clot formation and resolution showed an interesting pattern of changes over time.. We provided the first qualitative analysis of proteomes of fibrin clots generated ex vivo in plasma taken from patients with AMI showing differences between clots generated in the acute ischemic phase and those prepared two months later. It might be hypothesized that differences involving proteins of potential influence on within-clot fibrinolysis and clot stability may partially explain time-dependent changes in the clots structure and firmness in patients with AMI.

Topics: Acute Disease; Fibrin; Humans; Middle Aged; Myocardial Infarction; Proteomics

Determinants of intracoronary thrombus (ICT) composition in patients with ST-elevation myocardial infarction (STEMI) are largely unknown. We sought to investigate whether plasma fibrin phenotype and platelet reactivity affect ICT ultrastructure. We assessed the content of fibrin, platelets and erythrocytes including polyhedrocytes by scanning electron microscopy on the surface and inside ICT aspirated from 80 STEMI patients within 12 hours since chest pain onset. Plasma fibrin clot permeability (Ks), which indicates the average pore size, lysis time (t50 %), platelet reactivity index (PRI) and ADP-induced platelet aggregation (ADP5, 20µM) were evaluated on admission. All patients received aspirin and 45 (56.3 %) 600 mg of clopidogrel, 80 (60-120) min prior to aspiration. Higher content of fibrin (61.6 vs 34.3 %, P< 0.0001) and platelets (8.2 vs 4.8 %, P=0.018) and lower erythrocyte content (15.8 vs 42.9 %, P< 0.0001) were found on ICT surface compared with its inner part. After adjustment for fibrinogen, in both ICT parts fibrin content was correlated with Ks (r≤-0.55, P< 0.0001) and t50 % (r≥ 0.29, P≤ 0.02) but not with PRI and ADP5,20µM. Polyhedrocytes were observed in 16 (20 %) patients and their large amount expressed as ≥ 50 % fields of view covered by polyhedrocytes was associated with the lower PRI values (40 vs 69 %, P=0.015), but not Ks or t50 %. By multivariate regression, Ks (β=-0.62, P< 0.0001), clopidogrel pretreatment (β=-0.36, P< 0.001), ischemia time (β=0.19, P=0.044) and family history (β=0.18, P=0.049) independently predicted fibrin content in the whole ICT (R²=0.65, P< 0.0001). Formation of denser plasma fibrin clots is independently associated with high fibrin content within the ICT in STEMI.

Topics: Aged; Aspirin; Blood Platelets; Chi-Square Distribution; Clopidogrel; Coronary Thrombosis; Coronary Vessels; Drug Therapy, Combination; Erythrocytes; Female; Fibrin; Fibrinolysis; Humans; Male; Microscopy, Electron, Scanning; Middle Aged; Multivariate Analysis; Myocardial Infarction; Percutaneous Coronary Intervention; Permeability; Phenotype; Platelet Aggregation; Platelet Aggregation Inhibitors; Porosity; Suction; Thrombectomy; Ticlopidine; Time Factors

Treatment of ischemia through therapeutic angiogenesis faces significant challenges. Growth factor (GF)-based therapies can be more effective when concerns such as GF spatiotemporal presentation, bioactivity, bioavailability, and localization are addressed. During angiogenesis, vascular endothelial GF (VEGF) is required early to initiate neovessel formation while platelet-derived GF (PDGF-BB) is needed later to stabilize the neovessels. The spatiotemporal delivery of multiple bioactive GFs involved in angiogenesis, in a close mimic to physiological cues, holds great potential to treat ischemic diseases. To achieve sequential release of VEGF and PDGF, we embed VEGF in fibrin gel and PDGF in a heparin-based coacervate that is distributed in the same fibrin gel. In vitro, we show the benefits of this controlled delivery approach on cell proliferation, chemotaxis, and capillary formation. A rat myocardial infarction (MI) model demonstrated the effectiveness of this delivery system in improving cardiac function, ventricular wall thickness, angiogenesis, cardiac muscle survival, and reducing fibrosis and inflammation in the infarct zone compared to saline, empty vehicle, and free GFs. Collectively, our results show that this delivery approach mitigated the injury caused by MI and may serve as a new therapy to treat ischemic hearts pending further examination.

Topics: Angiogenesis Inducing Agents; Animals; Becaplermin; Cell Proliferation; Cells, Cultured; Chemistry, Pharmaceutical; Chemotaxis; Delayed-Action Preparations; Disease Models, Animal; Drug Carriers; Drug Combinations; Fibrin; Fibrosis; Gels; Heparin; Human Umbilical Vein Endothelial Cells; Humans; Kinetics; Male; Myocardial Infarction; Myocardium; Myocytes, Smooth Muscle; Neovascularization, Physiologic; Papio; Proto-Oncogene Proteins c-sis; Rats, Sprague-Dawley; Recovery of Function; Solubility; Vascular Endothelial Growth Factor A; Ventricular Function, Left

Fibrin is an extracellular matrix protein that is responsible for maintaining the structural integrity of blood clots. Much research has been done on fibrin in the past years to include the investigation of synthesis, structure-function, and lysis of clots. However, there is still much unknown about the morphological and structural features of clots that ensue from patients with disease. In this research study, experimental techniques are presented that allow for the examination of morphological differences of abnormal clot structures due to diseased states such as diabetes and sickle cell anemia. Our study focuses on the preparation and evaluation of fibrin clots in order to assess morphological differences using various experimental assays and confocal microscopy. In addition, a method is also described that allows for continuous, real-time calculation of lysis rates in fibrin clots. The techniques described herein are important for researchers and clinicians seeking to elucidate comorbid thrombotic pathologies such as myocardial infarctions, ischemic heart disease, and strokes in patients with diabetes or sickle cell disease.

Topics: Anemia, Sickle Cell; Blood Chemical Analysis; Factor XIIIa; Fibrin; Fibrinogen; Fibrinolysis; Humans; Microscopy, Confocal; Myocardial Infarction; Myocardial Ischemia; Stroke; Thrombin; Thrombosis

Considerable research has been dedicated to restoring myocardial cell slippage and limiting ventricular remodeling after myocardial infarction (MI). We examined the ability of a three-dimensional (3D) engineered fibrin patch filled with human umbilical cord blood-derived mesenchymal stem cells (UCBMSCs) to induce recovery of cardiac function after MI. The UCBMSCs were modified to coexpress luciferase and fluorescent protein reporters, mixed with fibrin, and applied as an adhesive, viable construct (fibrin-cell patch) over the infarcted myocardium in mice (MI-UCBMSC group). The patch adhered well to the heart. Noninvasive bioluminescence imaging demonstrated early proliferation and differentiation of UCBMSCs within the construct in the postinfarct mice in the MI-UCBMSC group. The implanted cells also participated in the formation of new, functional microvasculature that connected the fibrin-cell patch to both the subjacent myocardial tissue and the host circulatory system. As revealed by echocardiography, the left ventricular ejection fraction and fractional shortening at sacrifice were improved in MI-UCBMSC mice and were markedly reduced in mice treated with fibrin alone and untreated postinfarction controls. In conclusion, a 3D engineered fibrin patch composed of UCBMSCs attenuated infarct-derived cardiac dysfunction when transplanted locally over a myocardial wound.

Topics: Animals; Cell Differentiation; Fetal Blood; Fibrin; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Myocardial Infarction

The murine MI model is widely recognized in the field of cardiovascular disease, and has consistently been used as a first step to test the efficacy of treatments in vivo. The traditional, established protocol has been further fine-tuned to minimize the damage to the animal. Notably, the pectoral muscle layers are teased away rather than simply cut, and the thoracotomy is approached intercostally as opposed to breaking the ribs in a sternotomy, preserving the integrity of the ribcage. With these changes, the overall stress on the animal is decreased. Stem cell therapies aimed to alleviate the damage caused by MIs have shown promise over the years for their pro-angiogenic and anti-apoptotic benefits. Current approaches of delivering cells to the heart surface typically involve the injection of the cells either near the damaged site, within a coronary artery, or into the peripheral blood stream. While the cells have proven to home to the damaged myocardium, functionality is limited by their poor engraftment at the site of injury, resulting in diffusion into the blood stream. This manuscript highlights a procedure that overcomes this obstacle with the use of a cell-encapsulated hydrogel patch. The patch is fabricated prior to the surgical procedure and is placed on the injured myocardium immediately following the occlusion of the left coronary artery. To adhere the patch in place, biocompatible external fibrin glue is placed directly on top of the patch, allowing for it to dry to both the patch and the heart surface. This approach provides a novel adhesion method for the application of a delicate cell-encapsulating therapeutic construct.

Topics: Animals; Biocompatible Materials; Disease Models, Animal; Female; Fibrin; Hydrogels; Mice; Mice, Inbred C57BL; Myocardial Infarction; Stem Cell Transplantation

The balance between hyper- and hypocoagulable states is critical after coronary artery surgery both with (coronary artery bypass grafting [CABG]) and without (off-pump coronary artery bypass [OPCAB]) cardiopulmonary bypass to prevent thrombotic or bleeding complications. We aimed to quantify novel parameters of coagulation, fibrinolysis, and overall hemostasis ≤6 months after CABG and OPCAB and to determine the influences on these parameters.. A total of 63 patients (30 CABG, 33 OPCAB) had blood collected before and at various points ≤6 months after surgery. Fibrin and fibrinolysis time curves were generated by measuring the absorption of 405 nm each minute for 100 minutes after the addition of tissue factor and tissue plasminogen activator to cell-free plasma. The parameters were compared with those from a group of healthy controls.. The patients' preoperative prothrombotic assay parameters were compared with those from healthy controls. Both CABG and OPCAB patients were hypercoagulable until at least day 10 after surgery, with elevation of fibrin generation (CABG, peak day 3, +28.9%; OPCAB, peak day 1, +16.3% vs preoperative baseline) and impairment of fibrinolysis capacity (CABG, day 1, -58.4%; OPCAB, day 1, -22.6%). Surgical revascularization resulted in resolution of preoperative hypercoagulability by 6 months postoperatively. Patients with preoperative myocardial infarction (MI) had prolonged hypercoagulability after surgery that was most exaggerated after CABG (overall hemostatic potential day 5, no MI, +64.1% vs with MI, +128.9% compared with baseline; P = .013).. Patients will be vulnerable to thrombotic events for ≤6 weeks after coronary surgery yet will have resolution of hypercoagulability by 6 months. Preoperative factors, such as MI, could require individualized management of thrombosis prophylaxis in the postoperative period.

Topics: Biomarkers; Blood Coagulation; Blood Coagulation Tests; Case-Control Studies; Coronary Artery Bypass; Coronary Artery Bypass, Off-Pump; Fibrin; Fibrinolysis; Humans; Myocardial Infarction; Postoperative Hemorrhage; Risk Factors; Thrombophilia; Thrombosis; Time Factors; Treatment Outcome

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

We tested the hypothesis that plasma fibrin clot structure/function is unfavourably altered in patients with antiphospholipid syndrome (APS). Ex vivo plasma clot permeability, turbidity and susceptibility to lysis were determined in 126 consecutive patients with APS enrolled five months or more since thrombotic event vs 105 controls. Patients with both primary and secondary APS were characterised by 11% lower clot permeability (p<0.001), 4.8% shorter lag phase (p<0.001), 10% longer clot lysis time (p<0.001), and 4.7% higher maximum level of D-dimer released from clots (p=0.02) as compared to the controls. Scanning electron microscopy images confirmed denser fibrin networks composed of thinner fibres in APS. Clots from patients with "triple-antibody positivity" were formed after shorter lag phase (p=0.019) and were lysed at a slower rate (p=0.004) than in the remainder. Clots from APS patients who experienced stroke and/or myocardial infarction were 8% less permeable (p=0.01) and susceptible to lysis (10.4% longer clot lysis time [p=0.006] and 4.5% slower release of D-dimer from clots [p=0.01]) compared with those following venous thromboembolism alone. Multivariate analysis adjusted for potential confounders showed that in APS patients, lupus anticoagulant and "triple-positivity" were the independent predictors of clot permeability, while "triple-positivity" predicted lysis time. We conclude that APS is associated with prothrombotic plasma fibrin clot phenotype, with more pronounced abnormalities in arterial thrombosis. Molecular background for this novel prothrombotic mechanism in APS remains to be established.

Topics: Adult; Antiphospholipid Syndrome; Autoantibodies; Biomarkers; Blood Coagulation Tests; Case-Control Studies; Chi-Square Distribution; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Humans; Linear Models; Male; Microscopy, Electron, Scanning; Middle Aged; Multivariate Analysis; Myocardial Infarction; Poland; Predictive Value of Tests; Prognosis; Risk Factors; Stroke; Thrombosis; Time Factors; Venous Thromboembolism

This study tested whether adipose-derived mesenchymal stem cells (ADMSC) embedded in platelet-rich fibrin (PRF) scaffold is superior to direct ADMSC implantation in improving left ventricular (LV) performance and reducing LV remodeling in a rat acute myocardial infarction (AMI) model of left anterior descending coronary artery (LAD) ligation.. Twenty-eight male adult Sprague Dawley rats equally divided into group 1 [sham control], group 2 (AMI only), group 3 (AMI+direct ADMSC implantation), and group 4 (AMI+PRF-embedded autologous ADMSC) were sacrificed on day 42 after AMI.. LV systolic and diastolic dimensions and volumes, and infarct/fibrotic areas were highest in group 2, lowest in group 1 and significantly higher in group 3 than in group 4, whereas LV performance and LV fractional shortening exhibited a reversed pattern (p<0.005). Protein expressions of inflammation (oxidative stress, IL-1β, MMP-9), apoptosis (mitochondrial Bax, cleaved PARP), fibrosis (Smad3, TGF-β), and pressure-overload biomarkers (BNP, MHC-β) displayed a pattern similar to that of LV dimensions, whereas anti-inflammatory (IL-10), anti-apoptotic (Bcl-2), and anti-fibrotic (Smad1/5, BMP-2) indices showed a pattern similar to that of LV performance among the four groups (all p<0.05). Angiogenesis biomarkers at protein (CXCR4, SDF-1α, VEGF), cellular (CD31+, CXCR4+, SDF-1α+), and immunohistochemical (small vessels) levels, and cardiac stem cell markers (C-kit+, Sca-1+) in infarct myocardium were highest in group 4, lowest in group 1, and significantly higher in group 3 than in group 2 (all p<0.005).. PRF-embedded ADMSC is superior to direct ADMSC implantation in preserving LV function and attenuating LV remodeling.

Topics: Adipose Tissue; Animals; Blood Platelets; Fibrin; Male; Mesenchymal Stem Cell Transplantation; Myocardial Infarction; Random Allocation; Rats; Rats, Sprague-Dawley; Tissue Scaffolds; Treatment Outcome

Cell-based angiogenic therapy for ischemic heart failure has had limited clinical impact, likely related to low cell retention (<1%) and dispersion. We developed a novel, tissue-engineered, hydrogel-based cell-delivery strategy to overcome these limitations and provide prolonged regional retention of myocardial endothelial progenitor cells at high cell dosage.. Endothelial progenitor cells were isolated from Wistar rats and encapsulated in fibrin gels. In vitro viability was quantified using a fluorescent live-dead stain of transgenic enhanced green fluorescent protein(+) endothelial progenitor cells. Endothelial progenitor cell-laden constructs were implanted onto ischemic rat myocardium in a model of acute myocardial infarction (left anterior descending ligation) for 4 weeks. Intramyocardial cell injection (2 × 10(6) endothelial progenitor cells), empty fibrin, and isolated left anterior descending ligation groups served as controls. Hemodynamics were quantified using echocardiography, Doppler flow analysis, and intraventricular pressure-volume analysis. Vasculogenesis and ventricular geometry were quantified. Endothelial progenitor cell migration was analyzed by using endothelial progenitor cells from transgenic enhanced green fluorescent protein(+) rodents.. Endothelial progenitor cells demonstrated an overall 88.7% viability for all matrix and cell conditions investigated after 48 hours. Histologic assessment of 1-week implants demonstrated significant migration of transgenic enhanced green fluorescent protein(+) endothelial progenitor cells from the fibrin matrix to the infarcted myocardium compared with intramyocardial cell injection (28 ± 12.3 cells/high power field vs 2.4 ± 2.1 cells/high power field, P = .0001). We also observed a marked increase in vasculogenesis at the implant site. Significant improvements in ventricular hemodynamics and geometry were present after endothelial progenitor cell-hydrogel therapy compared with control.. We present a tissue-engineered, hydrogel-based endothelial progenitor cell-mediated therapy to enhance cell delivery, cell retention, vasculogenesis, and preservation of myocardial structure and function.

Topics: Animals; Cell Culture Techniques; Cell Movement; Cell Survival; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Fibrin; Fibrosis; Green Fluorescent Proteins; Hemodynamics; Hydrogels; Male; Myocardial Infarction; Myocardium; Neovascularization, Physiologic; Rats; Rats, Wistar; Stem Cell Transplantation; Time Factors; Tissue Engineering; Tissue Scaffolds; Transfection; Ventricular Function, Left; Ventricular Pressure

Human induced pluripotent stem cells (hiPSCs) hold promise for myocardial repair following injury, but preclinical studies in large animal models are required to determine optimal cell preparation and delivery strategies to maximize functional benefits and to evaluate safety. Here, we utilized a porcine model of acute myocardial infarction (MI) to investigate the functional impact of intramyocardial transplantation of hiPSC-derived cardiomyocytes, endothelial cells, and smooth muscle cells, in combination with a 3D fibrin patch loaded with insulin growth factor (IGF)-encapsulated microspheres. hiPSC-derived cardiomyocytes integrated into host myocardium and generated organized sarcomeric structures, and endothelial and smooth muscle cells contributed to host vasculature. Trilineage cell transplantation significantly improved left ventricular function, myocardial metabolism, and arteriole density, while reducing infarct size, ventricular wall stress, and apoptosis without inducing ventricular arrhythmias. These findings in a large animal MI model highlight the potential of utilizing hiPSC-derived cells for cardiac repair.

Topics: Acute Disease; Animals; Apoptosis; Cell Differentiation; Cell Lineage; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Fibrin; Heart Ventricles; Humans; Induced Pluripotent Stem Cells; Insulin-Like Growth Factor I; Microspheres; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Myocytes, Smooth Muscle; Recovery of Function; Stem Cell Transplantation; Swine

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

Adipose tissue-derived progenitor cells (ATDPCs) isolated from human cardiac adipose tissue are useful for cardiac regeneration in rodent models. These cells do not express cardiac troponin I (cTnI) and only express low levels of PECAM-1 when cultured under standard conditions. The purpose of the present study was to evaluate changes in cTnI and PECAM-1 gene expression in cardiac ATDPCs following their delivery through a fibrin patch to a murine model of myocardial infarction using a non-invasive bioluminescence imaging procedure.. Cardiac and subcutaneous ATDPCs were doubly transduced with lentiviral vectors for the expression of chimerical bioluminescent-fluorescent reporters driven by constitutively active and tissue-specific promoters (cardiac and endothelial for cTnI and PECAM-1, respectively). Labeled cells mixed with fibrin were applied as a 3-D fibrin patch over the infarcted tissue. Both cell types exhibited de novo expression of cTnI, though the levels were remarkably higher in cardiac ATDPCs. Endothelial differentiation was similar in both ATDPCs, though cardiac cells induced vascularization more effectively. The imaging results were corroborated by standard techniques, validating the use of bioluminescence imaging for in vivo analysis of tissue repair strategies. Accordingly, ATDPC treatment translated into detectable functional and morphological improvements in heart function.. Both ATDPCs differentiate to the endothelial lineage at a similar level, cardiac ATDPCs differentiated more readily to the cardiomyogenic lineage than subcutaneous ATDPCs. Non-invasive bioluminescence imaging was a useful tool for real time monitoring of gene expression changes in implanted ATDPCs that could facilitate the development of procedures for tissue repair.

Topics: Animals; Cell Differentiation; Cell Transplantation; Cells, Cultured; Disease Models, Animal; Endothelium, Vascular; Female; Fibrin; Humans; Luminescent Measurements; Mice; Mice, SCID; Myocardial Infarction; Myocardium; Platelet Endothelial Cell Adhesion Molecule-1; Stem Cell Transplantation; Stem Cells; Subcutaneous Fat

There are few histologic studies of intracoronary stents found at autopsy. We studied histologic findings of 87 intracoronary stents from 45 autopsy hearts. There were 40 patients with chronically implanted stents and five shorter than 30 days. Of five patients with recent stent placement, the cause of death was related to the stent (in-stent thrombosis) in one case. Of the 40 patients with chronic stents, there were 16 sudden coronary deaths and 24 noncoronary deaths (controls). There were no late stent thromboses in the coronary deaths. In the coronary deaths, 26% of stents showed restenosis versus 11% in controls (p = 0.1). The rate of healed infarcts and cardiomegaly was similar in the coronary and noncoronary groups, and acute thrombi in native arteries were seen only in three hearts in the coronary group. We conclude that the cause of death is rarely impacted by in-stent findings at autopsy, especially in chronically implanted stents.

Topics: Cardiomegaly; Case-Control Studies; Coronary Occlusion; Coronary Restenosis; Coronary Thrombosis; Coronary Vessels; Death, Sudden, Cardiac; Female; Fibrin; Forensic Pathology; Giant Cells; Humans; Male; Middle Aged; Myocardial Infarction; Myocardium; Neointima; Prospective Studies; Stents

Bone marrow mononuclear cells (BMMNCs) can be used to treat patients with myocardial infarction, since BMMNCs can differentiate in vitro toward cardiomyogenic lineages when treated with transforming growth factor-β1 (TGF-β1). However, the in vitro cardiomyogenic differentiation culture process is costly and laborious, and the patients should wait during the culture period. In this study, we hypothesize that BMMNCs implanted in cardiomyogenically undifferentiated state to myocardial infarction site would differentiate cardiomyogenically in situ when exogenous TGF-β1 is delivered to the cell implantation site. Heparin-conjugated poly(lactic-co-glycolic acid) nanospheres (HCPNs) suspended in fibrin gel were used as a TGF-β1 delivery system. BMMNCs were labeled with a green fluorescent dye (PKH67) and implanted into the infarction border zone of rat myocardium using fibrin gel containing HCPNs and TGF-β1. BMMNC implantation using fibrin gel and HCPNs without TGF-β1 served as a control. Four weeks after implantation, the expression of cardiomyogenic marker proteins by the implanted BMMNCs was dramatically greater in the TGF-β1 delivery group than in the control group. This method can significantly improve the stem cell therapy technology for myocardial regeneration, since it can remove in vitro cell culture step for cardiomyogenic differentiation prior to cell implantation.

Topics: Animals; Bone Marrow Cells; Bone Marrow Transplantation; Cell Differentiation; Cells, Cultured; Drug Delivery Systems; Fibrin; Leukocytes, Mononuclear; Myocardial Infarction; Myocytes, Cardiac; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta1

We assessed whether abnormality of haemostasis measured by a newly developed global method is associated with risk of a first myocardial infarction (MI). The global markers coagulation activation profile (Cp), fibrinolysis activation profile (Fp) and sum of fibrin optical density over time (Fibrin OD-sum) were determined in plasma from 800 MI cases and 1,123 controls included in the Stockholm Heart Epidemiology Program. Clot lysis time (CLT) was also determined based on raw data of fibrin OD from the global assay. Odds ratios (OR) of MI with 95% confidence intervals (CI) were calculated using logistic regression. A Fp value <10th percentile value in controls was significantly associated with increased MI risk; OR after multivariate adjustments for conventional cardiovascular risk factors 1.66 (95% CI 1.22-2.27). For an abnormally long CLT (>90th percentile value in controls) the adjusted OR of MI was 2.62 (95% CI 1.87-3.66) and for a high Fibrin OD-sum value (>90th percentile in controls) it was 1.86 (95% CI 1.37-2.53). A high Cp value was not significantly associated with MI. In conclusion, we found that abnormal haemostasis in platelet-poor plasma, reflected either as an attenuated fibrinolytic capacity or the resulting increase of fibrin formation, was associated with increased MI risk.

Topics: Aged; Biomarkers; Blood Coagulation Tests; Chi-Square Distribution; Female; Fibrin; Fibrinolysis; Humans; Logistic Models; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Odds Ratio; Predictive Value of Tests; Retrospective Studies; Risk Assessment; Risk Factors; Sweden; Up-Regulation

Administration of a recombinant peptide of Periostin (rPN) has recently been shown to stimulate cardiomyocyte proliferation and angiogenesis after myocardial infarction (MI) [1]. However, strategies for targeting the delivery of rPN to the heart are lacking. Intrapericardial administration of drug-eluting hydrogels may provide a clinically viable strategy for increasing myocardial retention, therapeutic efficacy, and bioactivity of rPN and to decrease systemic re-circulation.. We investigated the ability of intrapericardial injections of drug-eluting hydrogels to deliver and prolong the release of rPN to the myocardium in a large animal model of myocardial infarction. Gelfoam is an FDA-approved hemostatic material commonly used in surgery, and is known to stimulate fibrin clot formation. We show that Gelfoam disks loaded with rPN, when implanted within the pericardium or peritoneum of mammals becomes encapsulated within a non-fibrotic fibrin-rich hydrogel, prolonging the in vitro and in vivo release of rPN. Administration into the pericardial cavity of pigs, following a complete occlusion of the left anterior descending artery, leads to greater induction of cardiomyocyte mitosis, increased cardiomyocyte cell cycle activity, and enhanced angiogenesis compared to direct injection of rPN alone.. The results of this study suggest that intrapericardial drug delivery of Gelfoam, enhanced by triggered clot formation, can be used to effectively deliver rPN to the myocardium in a clinically relevant model of myocardial infarction. The work presented here should enhance the translational potential of pharmaceutical-based strategies that must be targeted to the myocardium.

Topics: Animals; Cell Adhesion Molecules; Coronary Vessels; Delayed-Action Preparations; Female; Fibrin; Gelatin Sponge, Absorbable; Hemostatics; Humans; Mice; Myocardial Infarction; Myocytes, Cardiac; Neovascularization, Physiologic; Peptides; Pericardium; Recombinant Proteins; Swine

The mechanism by which endogenous progenitor cells contribute to functional and beneficial effects in stem cell therapy remains unknown.. Utilizing a novel (31)P magnetic resonance spectroscopy-2-dimensional chemical shift imaging method, this study examined the heterogeneity and bioenergetic consequences of postinfarction left ventricular (LV) remodeling and the mechanisms of endogenous progenitor cell contribution to the cellular therapy.. Human embryonic stem cell-derived vascular cells (hESC-VCs) that stably express green fluorescent protein and firefly luciferase (GFP(+)/Luc(+)) were used for the transplantation. hESC-VCs may release various cytokines to promote angiogenesis, prosurvival, and antiapoptotic effects. Both in vitro and in vivo experiments demonstrated that hESC-VCs effectively inhibit myocyte apoptosis. In the mouse model, a fibrin patch-based cell delivery resulted in a significantly better cell engraftment rate that was accompanied by a better ejection fraction. In the swine model of ischemia-reperfusion, the patch-enhanced delivery of hESC-VCs resulted in alleviation of abnormalities including border zone myocardial perfusion, contractile dysfunction, and LV wall stress. These results were also accompanied by a pronounced recruitment of endogenous c-kit(+) cells to the injury site. These improvements were directly associated with a remarkable improvement in myocardial energetics, as measured by a novel in vivo (31)P magnetic resonance spectroscopy-2-dimensional chemical shift imaging technology.. The findings of this study demonstrate that a severely abnormal heterogeneity of myocardial bioenergetics in hearts with postinfarction LV remodeling can be alleviated by the hESC-VCs therapy. These findings suggest an important therapeutic target of peri-scar border zone and a promising therapeutic potential for using hESC-VCs together with the fibrin patch-based delivery system.

Topics: Adenosine Triphosphate; Animals; Apoptosis; Cell Line; Cell Movement; Cell Tracking; Coronary Circulation; Disease Models, Animal; Embryonic Stem Cells; Endothelial Cells; Energy Metabolism; Female; Fibrin; Green Fluorescent Proteins; Humans; Hypertrophy, Left Ventricular; Luciferases, Firefly; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred NOD; Mice, SCID; Myocardial Contraction; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Myocytes, Smooth Muscle; Phosphocreatine; Proto-Oncogene Proteins c-kit; Recovery of Function; Stem Cell Transplantation; Stroke Volume; Swine; Time Factors; Tissue Scaffolds; Transfection; Ventricular Function, Left; Ventricular Remodeling

Aspiration thrombectomy is used in primary percutaneous coronary interventions, but the importance of thrombus constituency has been scarcely investigated. The objective of this study was to evaluate thrombus constituency and its association with clinical, laboratory, and angiographic findings in patients with ST-segment elevation myocardial infarction.. From April 2010 to May 2011, 562 patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary interventions were considered for inclusion, and information on thrombi characteristics was available for 113 patients. Thrombus material were obtained and classified as white or red based on its constituency. Samples were analyzed by 3 independent pathologists blinded to clinical characteristics.. The mean age of patients was 58.6 ± 12.7 years, and 69% were men. White thrombi were present in 31% of cases, and red thrombi, in 69%. Patients with white thrombi had smaller vessels and lower ischemic times. All other clinical, angiographic, and laboratory characteristics did not differ. White thrombi were smaller and associated with fibrin infiltration, whereas red thrombi were associated with red blood cell infiltration. Thirty-day death rates were lower in patients with white thrombi than red (0% vs 10.1%, respectively; P = .05), as were 30-day major adverse cardiac event rates (4.2% vs 13.9%; P = .10). Total ischemic time was well correlated with fibrin infiltration (R = -0.30; P < .01), red blood cell infiltration (R = 0.27; P < .01), and thrombus volume (R = 0.22; P = .02).. White thrombi were present in one-third of cases and were associated with lower ischemic times, higher fibrin infiltration, smaller thrombus volume, and lower mortality. These findings suggest that thrombus constituency may be a useful prognostic tool in this setting.

Topics: Coronary Angiography; Coronary Thrombosis; Erythrocytes; Female; Fibrin; Humans; Male; Middle Aged; Myocardial Infarction; Pigmentation; Thrombectomy

Control over cell engraftment, survival, and function remains critical for heart repair. We have established a tissue engineering platform for the delivery of human mesenchymal progenitor cells (MPCs) by a fully biological composite scaffold. Specifically, we developed a method for complete decellularization of human myocardium that leaves intact most elements of the extracellular matrix, as well as the underlying mechanical properties. A cell-matrix composite was constructed by applying fibrin hydrogel with suspended cells onto decellularized sheets of human myocardium. We then implanted this composite onto the infarct bed in a nude rat model of cardiac infarction. We next characterized the myogenic and vasculogenic potential of immunoselected human MPCs and demonstrated that in vitro conditioning with a low concentration of TGF-β promoted an arteriogenic profile of gene expression. When implanted by composite scaffold, preconditioned MPCs greatly enhanced vascular network formation in the infarct bed by mechanisms involving the secretion of paracrine factors, such as SDF-1, and the migration of MPCs into ischemic myocardium, but not normal myocardium. Echocardiography demonstrated the recovery of baseline levels of left ventricular systolic dimensions and contractility when MPCs were delivered via composite scaffold. This adaptable platform could be readily extended to the delivery of other reparative cells of interest and used in quantitative studies of heart repair.

Topics: Animals; Disease Models, Animal; Extracellular Matrix; Fibrin; Humans; Hydrogels; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Myocardial Infarction; Myocardium; Neovascularization, Physiologic; Rats; Rats, Nude; Tissue Engineering; Tissue Scaffolds; Transforming Growth Factor beta; Transplantation, Heterologous; Ventricular Function, Left

It is unknown how to use human embryonic stem cell (hESC) to effectively treat hearts with postinfarction left ventricular (LV) remodeling. Using a porcine model of postinfarction LV remodeling, this study examined the functional improvement of enhanced delivery of combined transplantation of hESC-derived endothelial cells (ECs) and hESC-derived smooth muscle cells (SMCs) with a fibrin three-dimensional (3D) porous scaffold biomatrix. To facilitate tracking the transplanted cells, the hESCs were genetically modified to stably express green fluorescent protein and luciferase (GFP/Luc). Myocardial infarction (MI) was created by ligating the first diagonal coronary artery for 60 minutes followed by reperfusion. Two million each of GFP/Luc hESC-derived ECs and SMCs were seeded in the 3D porous biomatrix patch and applied to the region of ischemia/reperfusion for cell group (MI+P+C, n = 6), whereas biomatrix without cell (MI+P, n = 5), or saline only (MI, n = 5) were applied to control group hearts with same coronary artery ligation. Functional outcome (1 and 4 weeks follow-up) of stem cell transplantation was assessed by cardiac magnetic resonance imaging. The transplantation of hESC-derived vascular cells resulted in significant LV functional improvement. Significant engraftment of hESC-derived cells was confirmed by both in vivo and ex vivo bioluminescent imaging. The mechanism underlying the functional beneficial effects of cardiac progenitor transplantation is attributed to the increased neovascularization. These findings demonstrate a promising therapeutic potential of using these hESC-derived vascular cell types and the mode of patch delivery.

Topics: Animals; Cell Differentiation; Coronary Vessels; Disease Models, Animal; Embryonic Stem Cells; Endothelial Cells; Fibrin; Humans; Mice; Myocardial Infarction; Myocytes, Smooth Muscle; Neovascularization, Physiologic; Stem Cell Transplantation; Swine; Ventricular Function, Left; Ventricular Remodeling

Topics: Acute Coronary Syndrome; Aged; Angina, Unstable; Angioscopy; Coronary Angiography; Coronary Thrombosis; Coronary Vessels; Female; Fibrin; Humans; Male; Middle Aged; Myocardial Infarction

In this study, we analyzed whether transplantation of cardiac fibroblasts (CFs) expressing vascular endothelial growth factor (VEGF) mitigates cardiac dysfunction after myocardial infarction (MI) in rats. First, we observed that the transgene expression lasts longer (45 vs 7 days) when fibroblasts are used as vectors compared with myoblasts. In a preventive protocol, induction of cardiac neovascularization accompanied by reduction in myocardial scar area was observed when cell transplantation was performed 1 week before ischemia/reperfusion and the animals analyzed 3 weeks later. Finally, the therapeutic efficacy of this approach was tested injecting cells in a fibrin biopolymer, to increase cardiac retention, 24 h post-MI. After 4 weeks, an increase in neovascularization and a decrease in myocardial collagen were observed only in rats that received cells expressing VEGF. Basal indirect or direct hemodynamic measurements showed no differences among the groups whereas under pharmacological stress, only the group that received cells expressing VEGF showed a significant reduction in end-diastolic pressure and improvement in stroke volume and cardiac work. These results indicate that transplantation of CFs expressing VEGF using fibrin biopolymer induces neovascularization and attenuates left ventricle fibrosis and cardiac dysfunction in ischemic heart.

Topics: Animals; Fibrin; Fibroblasts; Genetic Therapy; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Neovascularization, Physiologic; Rats; Rats, Inbred Lew; Transgenes; Vascular Endothelial Growth Factors

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

Using scanning electron microscopy we analyzed thrombotic material removed from coronary bypass grafts in a 57-year-old woman with multilevel atherosclerosis presenting with acute myocardial infarction (AMI). A white thrombotic material removed from the marginal branch bypass that contained large amounts of activated platelets displaying pseudopodia clearly visible at a higher magnification with a relatively low amount of fibrin. The other thrombus obtained from the right posterior descendent branch (RPD) bypass showed a highly organized fibrin structure composed of thicker fibers with low amounts of cellular components. Our findings indicate that the thrombus structure is different in AMI patients in whom the infarct-related vessel is vein anastomosis compared to those with a native coronary artery occluded. These findings help explain resistance of such thrombi to fibrinolysis and faster plaque growth related to fibrin accumulation.

Topics: Atherosclerosis; Cell Shape; Coronary Artery Bypass; Female; Fibrin; Humans; Microscopy, Electron, Scanning; Middle Aged; Myocardial Infarction; Platelet Activation; Pseudopodia; Thrombosis

Blood neutrophils provide the first line of defense against pathogens but have also been implicated in thrombotic processes. This dual function of neutrophils could reflect an evolutionarily conserved association between blood coagulation and antimicrobial defense, although the molecular determinants and in vivo significance of this association remain unclear. Here we show that major microbicidal effectors of neutrophils, the serine proteases neutrophil elastase and cathepsin G, together with externalized nucleosomes, promote coagulation and intravascular thrombus growth in vivo. The serine proteases and extracellular nucleosomes enhance tissue factor- and factor XII-dependent coagulation in a process involving local proteolysis of the coagulation suppressor tissue factor pathway inhibitor. During systemic infection, activation of coagulation fosters compartmentalization of bacteria in liver microvessels and reduces bacterial invasion into tissue. In the absence of a pathogen challenge, neutrophil-derived serine proteases and nucleosomes can contribute to large-vessel thrombosis, the main trigger of myocardial infarction and stroke. The ability of coagulation to suppress pathogen dissemination indicates that microvessel thrombosis represents a physiological tool of host defense.

Topics: Animals; Blood Coagulation; Blood Coagulation Factors; Cathepsin G; Fibrin; Immunity, Innate; Leukocyte Elastase; Lipoproteins; Mice; Mice, Knockout; Models, Biological; Myocardial Infarction; Neutrophils; Nucleosomes; Protein Processing, Post-Translational; Serine Proteases; Signal Transduction; Stroke

Cardiac cell transplantation is compromised by low cell retention and poor graft viability. Here, the effects of co-injecting adipose tissue-derived stem cells (ASCs) with biopolymers on cell cardiac retention, ventricular morphometry and performance were evaluated in a rat model of myocardial infarction (MI).. 99mTc-labeled ASCs (1x10(6) cells) isolated from isogenic Lewis rats were injected 24 hours post-MI using fibrin a, collagen (ASC/C), or culture medium (ASC/M) as vehicle, and cell body distribution was assessed 24 hours later by gamma-emission counting of harvested organs. ASC/F and ASC/C groups retained significantly more cells in the myocardium than ASC/M (13.8+/-2.0 and 26.8+/-2.4% vs. 4.8+/-0.7%, respectively). Then, morphometric and direct cardiac functional parameters were evaluated 4 weeks post-MI cell injection. Left ventricle (LV) perimeter and percentage of interstitial collagen in the spare myocardium were significantly attenuated in all ASC-treated groups compared to the non-treated (NT) and control groups (culture medium, fibrin, or collagen alone). Direct hemodynamic assessment under pharmacological stress showed that stroke volume (SV) and left ventricle end-diastolic pressure were preserved in ASC-treated groups regardless of the vehicle used to deliver ASCs. Stroke work (SW), a global index of cardiac function, improved in ASC/M while it normalized when biopolymers were co-injected with ASCs. A positive correlation was observed between cardiac ASCs retention and preservation of SV and improvement in SW post-MI under hemodynamic stress.. We provided direct evidence that intramyocardial injection of ASCs mitigates the negative cardiac remodeling and preserves ventricular function post-MI in rats and these beneficial effects can be further enhanced by administering co-injection of ASCs with biopolymers.

Topics: Adipose Tissue; Animals; Biopolymers; Cell Survival; Cells, Cultured; Collagen; Female; Fibrin; Heart; Injections; Myocardial Infarction; Myocardium; Rats; Rats, Inbred Lew; Stem Cell Transplantation; Stem Cells

Cell therapy approaches for biologic cardiac repair hold great promises, although basic fundamental issues remain poorly understood. In the present study we examined the effects of timing and routes of administration of bone marrow cells (BMC) post-myocardial infarction (MI) and the efficacy of an injectable biopolymer scaffold to improve cardiac cell retention and function.. (99m)Tc-labeled BMC (6 x 10(6) cells) were injected by 4 different routes in adult rats: intravenous (IV), left ventricular cavity (LV), left ventricular cavity with temporal aorta occlusion (LV(+)) to mimic coronary injection, and intramyocardial (IM). The injections were performed 1, 2, 3, or 7 days post-MI and cell retention was estimated by gamma-emission counting of the organs excised 24 hs after cell injection. IM injection improved cell retention and attenuated cardiac dysfunction, whereas IV, LV or LV* routes were somewhat inefficient (<1%). Cardiac BMC retention was not influenced by timing except for the IM injection that showed greater cell retention at 7 (16%) vs. 1, 2 or 3 (average of 7%) days post-MI. Cardiac cell retention was further improved by an injectable fibrin scaffold at day 3 post-MI (17 vs. 7%), even though morphometric and function parameters evaluated 4 weeks later displayed similar improvements.. These results show that cells injected post-MI display comparable tissue distribution profile regardless of the route of injection and that there is no time effect for cardiac cell accumulation for injections performed 1 to 3 days post-MI. As expected the IM injection is the most efficient for cardiac cell retention, it can be further improved by co-injection with a fibrin scaffold and it significantly attenuates cardiac dysfunction evaluated 4 weeks post myocardial infarction. These pharmacokinetic data obtained under similar experimental conditions are essential for further development of these novel approaches.

Topics: Animals; Biopolymers; Bone Marrow Cells; Bone Marrow Transplantation; Cell- and Tissue-Based Therapy; Fibrin; Heart Diseases; Hemodynamics; Humans; Male; Myocardial Infarction; Rats; Rats, Inbred Lew; Technetium; Time Factors

Current efforts to treat myocardial infarction include the delivery of cells and matrix scaffolds. Bone marrow-derived mesenchymal stem cells (BM-MSCs) are multipotent stem cells that secrete angiogenic growth factors, and fibrin has been shown to be a biomaterial that provides structural support to cells and tissues. The objective of this study was to characterize the attachment and viability of BM-MSCs in fibrin in vitro, and then to assess the efficacy of treatment with BM-MSCs in fibrin for promoting neovascularization in the chronically infarcted myocardium.. BM-MSCs were cultured in fibrin and assessed for cell attachment and viability by using immunofluorescence staining for actin filaments and Live/Dead((R)) viability assays, respectively. To determine the efficacy of BM-MSCs in fibrin in vivo, chronically infarcted rat hearts were treated with either cells, cells in fibrin, fibrin or saline (n = 9). After 5 weeks, the infarct scar tissues were assessed for neovascularization.. BM-MSCs exhibited robust cell attachment and viability when cultured in fibrin in vitro. Furthermore, when injected together into the infarcted tissue, BM-MSCs in fibrin could enhance neovasculature formation by increasing capillary density, in comparison to treatment by cells or fibrin separately. Concomitant to significant improvement in capillary density was an increase in the levels of VEGF in the infarct scar.. This study demonstrates the angiogenic potential of the combined delivery of BM-MSCs and fibrin, and highlights the advantage of stem cell-matrix approaches for myocardial repair.

Topics: Animals; Bone Marrow Cells; Cell Adhesion; Cell Culture Techniques; Cell- and Tissue-Based Therapy; Fibrin; Fluorescent Antibody Technique; Humans; Mesenchymal Stem Cells; Myocardial Infarction; Neovascularization, Physiologic; Rats

Topics: Aged; Autopsy; Blood Coagulation; Fibrin; Humans; Male; Myocardial Infarction; Tomography, Optical Coherence

The long-term safety of drug-eluting stents (DES) for acute myocardial infarction (AMI) remains uncertain. Using autopsy data, we evaluated the pathological responses of the stented segment in patients treated with DES for AMI and compared with patients with stable angina.. From the CVPath Registry of 138 DES autopsies, we identified 25 patients who presented with AMI and had an underlying necrotic core with a ruptured fibrous cap. Twenty-six patients who had stable angina with thick-cap fibroatheroma treated by DES were selected as controls. Histomorphometric analysis was performed in patients with >30-day stent duration. We compared the response to stenting at the culprit site in these 2 groups and to nonculprit sites within each stent. Late stent thrombosis was significantly less frequent in stable (11%) than in AMI (41%; P=0.04) patients. Although neointimal thickness in the AMI culprit site was significantly less (median, 0.04 mm; interquartile range [IQR], 0.02 to 0.09 mm), the prevalence of uncovered struts (49%; IQR, 16% to 96%), fibrin deposition (63+/-28%), and inflammation (35%; IQR, 27% to 49%) were significantly greater compared with the culprit site in stable patients (neointimal thickness: 0.11 mm [IQR, 0.07 to 0.21 mm], P=0.008; uncovered struts: 9% [IQR, 0% to 39%], P=0.01; fibrin: 36+/-27%, P=0.008; inflammation, 17% [IQR, 7% to 25%], P=0.003) and the nonculprit site within each stent.. Vessel healing at the culprit site in AMI patients treated with DES is substantially delayed compared with the culprit site in patients receiving DES for stable angina, emphasizing the importance of underlying plaque morphology in the arterial response to DES. Our data suggest an increased risk of thrombotic complications in patients treated with DES for AMI.

Topics: Adult; Aged; Angina Pectoris; Autopsy; Coronary Vessels; Drug-Eluting Stents; Female; Fibrin; Humans; Inflammation; Male; Middle Aged; Myocardial Infarction; Prosthesis Implantation; Retrospective Studies; Thrombosis; Time Factors; Treatment Outcome

Topics: Blood Vessels; Constriction, Pathologic; Drug-Eluting Stents; Fibrin; Humans; Hypersensitivity; Myocardial Infarction; Patient Selection; Platelet Aggregation Inhibitors; Prosthesis Design; Risk Factors; Thrombosis; Wound Healing

Increased levels of microparticles exposing tissue factor circulate in the blood of patients with coronary heart disease, possibly disseminating their pro-thrombotic and pro-inflammatory potential. Because diets rich in n-3 (polyunsaturated) fatty acids have been associated with reduced incidence of coronary heart disease-related events, we investigated the in vivo effects of treatments with n-3 fatty acids on levels of circulating microparticles and their tissue factor- dependent procoagulant activity in patients with a previous myocardial infarction.. Forty-six post-myocardial infarction patients were assigned to receive either 5.2 g of n-3 fatty acids daily (n=23) or an olive oil placebo (n = 23) for 12 weeks. Circulating microparticles were isolated from peripheral blood. The number of microparticles, their cellular source and tissue factor antigen were determined by flow cytometry, and their procoagulant potential assayed by a fibrin generation test.. The total number of microparticles, endothelium-derived microparticles and microparticle tissue factor antigen were not significantly different between the two groups. However, the number of platelet-derived microparticles [from a median of 431 (126-1796, range) x 10(6)/L to a median of 226 (87-677, range)] x 10(6)/L and monocyte-derived microparticles [from a median of 388 (9-1681, range) x 10(6)/L to a median of 265 (7-984, range) x 10(6)/L] in plasma were significantly (p < 0.05) decreased by n-3 fatty acids, while they were unchanged in the placebo group. Total microparticle tissue factor-procoagulant activity was also reduced in the n-3 fatty acid group compared to that in the placebo group.. Treatment with n-3 fatty acids after myocardial infarction exerts favorable effects on levels of platelet- and monocyte-derived microparticles, thus possibly explaining some of the anti-inflammatory and anti-thrombotic properties of these natural compounds.

Topics: Aged; Blood Platelets; Coronary Disease; Endothelium, Vascular; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Female; Fibrin; Humans; Male; Middle Aged; Myocardial Infarction; Placebos; Thromboplastin; Thrombosis

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

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

Acute coronary reperfusion is accomplished pharmacologically with intravenous thrombolytic therapy or mechanically with primary percutaneous coronary intervention (PCI).. We have determined the immediate effects of the main coronary reperfusion procedures on the plasma concentrations of myeloperoxidase (MPO), pregnancy-associated plasma protein A (PAPP-A), fibrin monomer (FM) and D-dimer (DD). We studied a total of 38 patients admitted for ST-segment elevation infarct (STEMI). 18 patients were given thrombolytic therapy with tenecteplase and 20 were treated with primary PCI.. The plasma concentrations of PAPP-A increased by a factor of six to eight times (p<0.001) following both reperfusion therapies. No significant increase was observed for MPO by either procedure. DD and FM concentrations both increased significantly following thrombolytic therapy, p=0.000, whereas only minor increases, although statistically significant for FM (p=0.013), were noted after PCI. DD and FM were highly correlated prior to the two treatment regimens (R=0.91), and were still highly correlated after PCI (R=0.94) and thrombolytic therapy (R=0.86). No correlation was demonstrated between PAPP-A and markers of activated coagulation.. This is the first report of a significant rise in the plasma concentration of PAPP-A after PCI as compared to thrombolytic treatment (p=0.002) and may indicate a greater impact of PCI than that of thrombolytic therapy on target coronary plaques.

Topics: Adult; Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; Enoxaparin; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinolytic Agents; Humans; Male; Middle Aged; Myocardial Infarction; Peroxidase; Pregnancy; Pregnancy-Associated Plasma Protein-A; Solubility; Tenecteplase; Tissue Plasminogen Activator; Treatment Outcome

Fibrinogen gamma', a fibrinogen gamma-chain variant generated via alternative mRNA processing, has been associated with susceptibility to thrombotic disease.. The present case-control study searched for potential determinants of the plasma fibrinogen gamma' concentration and examined the relationship between this variant and risk of myocardial infarction (MI).. The Stockholm Coronary Artery Risk Factor study, comprising 387 postinfarction patients and 387 healthy individuals, was employed. The fibrinogen gamma (FGG) 9340T > C [rs1049636], fibrinogen alpha (FGA) 2224G > A [rs2070011] and fibrinogen beta (FGB) 1038G > A [rs1800791] polymorphisms were determined. The plasma fibrinogen gamma' concentration was measured by enzyme-linked immunosorbent assay. The multifactor dimensionality reduction method was used for interaction analyses on risk of MI.. The FGG 9340T > C and FGA 2224G > A polymorphisms, total plasma concentrations of fibrinogen, insulin and high-density lipoprotein, and gender appeared to be independent determinants of plasma fibrinogen gamma' concentration in patients, and the corresponding determinants in controls included FGG 9340T > C and FGA 2224G > A polymorphisms and plasma fibrinogen concentration. An elevated plasma fibrinogen gamma' concentration proved to be an independent predictor of MI [adjusted odds ratio (OR) (95% CI): 1.24 (1.01, 1.52)]. The plasma fibrinogen gamma' concentration was involved in a high-order interaction with total plasma fibrinogen and the FGG 9340T > C and FGA 2224G > A polymorphisms, associated with a further increased risk of MI [OR (95% CI): 3.22 (2.35, 4.39)].. Plasma fibrinogen gamma' concentration influences the risk of MI, and this relationship seems to be strengthened by the presence of an elevated total plasma fibrinogen concentration and the FGG 9340T and FGA 2224G alleles.

Topics: Female; Fibrin; Fibrinogen; Genetic Predisposition to Disease; Humans; Male; Models, Genetic; Myocardial Infarction; Peptide Fragments; Polymorphism, Genetic; Protein Isoforms; Risk; Risk Factors; RNA, Messenger

Cardiac tumors other than myxomas are rare. We report a series of 10 intracavitary polypoid myofibroblastic proliferations in children and young adults emphasizing gross, histologic, and clinical features. There were 6 females and 4 males, with a mean age of 10 years (range 5 wk to 21 y). All lesions were endocardial-based, located in the right atrium (1), right ventricular inflow/tricuspid valve (1), right ventricular outflow (3), mitral valve (3), aortic valve/left coronary sinus (1), and left ventricular free wall (1). Symptoms included shortness of breath or dyspnea (3), syncope (2), chest pain (1), transient ischemic attacks (1), and fever with myalgias (1). All tumors were surgical resections, except 1 tumor that resulted in sudden coronary death and that was diagnosed at autopsy, and 1 tumor that embolized into the coronary artery and was treated by cardiac transplant. Two tumors, present in the aortic and mitral valves, respectively, caused cardiac ischemia. The tumors were polypoid or filiform and histologically resembled inflammatory myofibroblastic tumors of extracardiac sites, with loose spindle cell growth with sparse inflammation. Although there were frequent collagen bundles interspersed among the tumor cells, there were no large areas of dense fibrosis. Surface fibrin was present on the polypoid projections in 7 cases. Symptoms resulted from prolapse into coronary ostia or embolization, but no patient developed metastasis. Long-term follow-up in 2 patients demonstrated no evidence of disease or recurrence. Although metastatic potential was not identified, these tumors may result in serious symptoms, including myocardial infarct, syncope, and sudden death. These cardiac myofibroblastic tumors are readily distinguished from other endocardial-based cardiac tumors, including papillary fibroelastoma and myxoma, which may present clinically in the same manner.

Topics: Adolescent; Adult; Biomarkers; Child; Child, Preschool; Death, Sudden; Female; Fibrin; Granuloma, Plasma Cell; Heart Diseases; Humans; Infant; Male; Myocardial Infarction; Retrospective Studies; Syncope

We assessed the relationship between fibrin clot properties and the no-reflow phenomenon after primary coronary intervention (PCI).. Epicardial blood flow was assessed by TIMI scale and corrected TIMI frame count (cTFC), and perfusion by TIMI Myocardial Perfusion Grade (TMPG) after PCI during ST-segment elevation myocardial infarction (STEMI). Fibrin clot permeability (K(s)) and susceptibility to lysis in assays using exogenous thrombin (t(50%)) and without thrombin (t(TF)) were determined in 30 no-reflow patients (TIMI < or = 2) and in 31 controls (TIMI-3) after uneventful 6 to 14 months from PCI. Patients with TIMI < or = 2 had lower K(s) by 18% (P<0.0001) and prolonged fibrinolysis by 33% for t(50%) (P<0.0001) and by 45% for t(TF) (P<0.0001). cTFC was correlated with K(s) (r=-0.56, P<0.0001), t(50%) (r=0.49, P<0.001), and t(TF) (r=0.54, P<0.001). K(s) increased in a stepwise fashion with TIMI flow (P<0.0001) and TMPG (P<0.0001), whereas both fibrinolysis times decreased with TIMI flow (P<0.0001 for both) and TMPG (P<0.01 for both). Multiple regression models showed that only K(s) and fibrinogen were independent predictors of cTFC (P<0.05 for both), TIMI < or = 2 flow (P<0.05 for both) and TMPG-0/1 (P<0.05 for both).. Survivors of myocardial infarction with a history of the no-reflow after PCI are characterized with more compact fibrin network and its resistance to lysis.

Topics: Aged; Angioplasty, Balloon, Coronary; Case-Control Studies; Coronary Angiography; Coronary Circulation; Coronary Thrombosis; Electrocardiography; Female; Fibrin; Fibrinolysis; Follow-Up Studies; Humans; Linear Models; Male; Middle Aged; Myocardial Infarction; Permeability; Research Design; Risk Assessment; Severity of Illness Index; Time Factors; Treatment Outcome

The rapid closure of coronary arteries due to occlusive thrombi is the major cause of acute myocardial infarction. However, the mechanisms of coronary thrombus formation have not been elucidated. We immunohistochemically assessed the localizations and their changes over time of glycoprotein IIb/IIIa, fibrin, von Willebrand factor (vWF), and tissue factor (TF), after the onset of chest pain (<4, 4 to 6, or 6 to 12 hours), in fresh coronary thrombi causing acute myocardial infarction. The occlusive thrombi were consistently composed of platelets, fibrin, vWF, and TF from the early phase of onset, and glycoprotein IIb/IIIa and fibrin were closely associated with vWF and TF, respectively. vWF and/or TF may contribute to occlusive thrombus formation and be novel therapeutic candidates for treating patients with coronary thrombosis.

Topics: Aged; Blood Platelets; Coronary Thrombosis; Female; Fibrin; Humans; Immunohistochemistry; Male; Middle Aged; Myocardial Infarction; Platelet Glycoprotein GPIIb-IIIa Complex; Thromboplastin; von Willebrand Factor

Detailed histochemical analysis of coronary thrombi obtained freshly from acute phase of myocardial infarction patients may provide information necessary to understand the mechanism of coronary occlusive thrombus formation.. Coronary thrombi causing myocardial infarction were obtained from 10 consecutive patients of myocardial infarction in the acute phase, using a newly developed aspiration catheter. All the fixed specimens of coronary thrombi, by hematoxylin and eosin staining, were found to contain three major constituents, namely, platelets, densely packed fibrin and inflammatory cells, including polymorphonuclear and mononuclear cells, although their distribution in each specimen is totally heterogeneous. Immunohistochemical staining revealed the prominent presence of von Willebrand factor (VWF) at the sites of platelet accumulation, presence of tissue factor and platelets at the sites of deposition of fibrin fibrils. It also revealed the presence of CD16-, CD45- and CD34-positive cells, yet the functional roles of these cells have still to be elucidated. There are weak positive correlation between the number of inflammatory cells involved in the unit area of coronary thrombi specimen and the time of collection of the specimens after the onset of chest pain.. In spite of various limitations, our results contain information suggesting the possible role of VWF in platelet-thrombus formation, possible important role played by tissue factor and activated platelets in the formation of fibrin fibrils, and the positive relationship between inflammatory cells migration and the formation of occlusive thrombi in human coronary arteries.

Topics: Adult; Aged; Aged, 80 and over; Biopsy, Needle; Blood Platelets; Coronary Thrombosis; Female; Fibrin; Humans; Immunohistochemistry; Inflammation; Male; Middle Aged; Myocardial Infarction; Thromboplastin; von Willebrand Factor

Topics: Aged; Angioplasty, Balloon, Coronary; Blood Platelets; Coronary Angiography; Coronary Thrombosis; Electrocardiography; Erythrocytes; Fibrin; Humans; Male; Microscopy, Electron, Scanning; Myocardial Infarction; Stents; Time Factors

Extracellular matrix proteins not only provide structural support, but also modulate cellular behavior by activating signaling pathways. Healing of myocardial infarcts is associated with dynamic changes in the composition of the extracellular matrix; these changes may play an important role in regulating cellular phenotype and gene expression. We examined the time course of extracellular matrix deposition in a canine and mouse model of reperfused infarction. In both models, myocardial infarction resulted in fragmentation and destruction of the cardiac extracellular matrix, extravasation of plasma proteins, such as fibrinogen and fibronectin, and formation of a fibrin-based provisional matrix providing the scaffold for the infiltration of granulation tissue cells. Lysis of the plasma-derived provisional matrix was followed by the formation of a cell-derived network of provisional matrix composed of cellular fibronectin, laminin, and hyaluronic acid and containing matricellular proteins, such as osteopontin and osteonectin/SPARC. Finally, collagen was deposited in the infarct, and the wound matured into a collagen-based scar with low cellular content. Although the canine and mouse infarcts exhibited a similar pattern of extracellular matrix deposition, deposition of the provisional matrix was more transient in the mouse infarct and was followed by earlier formation of a mature collagen-based scar after 7-14 days of reperfusion; at the same timepoint, the canine infarct was highly cellular and evolving. In addition, mature mouse infarcts showed limited collagen deposition and significant tissue loss leading to the formation of a thin scar. In contrast, dogs exhibited extensive collagen accumulation in the infarcted area. These species-specific differences in infarct wound healing should be taken into account when interpreting experimental infarction studies and when attempting to extrapolate the findings to the human pathological process.

Topics: Animals; Dogs; Extracellular Matrix; Extracellular Matrix Proteins; Female; Fibrin; Male; Mice; Mice, Inbred C57BL; Myocardial Infarction; Myocardial Reperfusion; Species Specificity

A potential therapy for myocardial infarction is to deliver isolated mesenchymal stem cells (MSCs) to the infarcted site. A key issue with this technology is the development of a suitable system for MSC delivery. Our delivery system of interest is a fibrin-based patch used to entrap cells during polymerization. This delivery vehicle has many advantages; however the mechanical properties and the limited capacity for tailoring cell response may restrict its application. We have developed a PEGylated fibrin patch for MSC transplantation by modifying fibrinogen (Fgn) with the benzotriazole carbonate derivative of PEG to create secondary crosslinking. In this study, the chemical PEGylation of fibrinogen was verified by both amine group quantification and SDS-PAGE. The clotting characteristics and physical properties were compared between the fibrin patch and PEGylated fibrin patch. After seeding with porcine MSCs, the cell viability, morphology, and motility in the novel patch were observed. Phenotypic changes in the embedded MSCs were examined using immunohistochemistry and RT-PCR. The optimal molar ratio (PEG:Fgn = 10:1) was determined for loading MSCs in vitro into the PEGylated fibrin patch. The results suggest that our PEGylated fibrin patch increases MSC viability. Furthermore, the PEGylated fibrin causes phenotypic changes in MSCs consistent with endothelial cells.

Topics: Animals; Cell Differentiation; Cells, Cultured; Fibrin; Fibrinogen; Mesenchymal Stem Cells; Myocardial Infarction; Polyethylene Glycols; Stem Cell Transplantation; Swine; Time Factors; Triazoles

An intricate interplay between the genes encoding fibrinogen gamma (FGG), alpha (FGA) and beta (FGB), coagulation factor XIII (F13A1) and interleukin 6 (IL6) and environmental factors is likely to influence plasma fibrinogen concentration, fibrin clot structure and risk of myocardial infarction (MI). In the present study, the potential contribution of SNPs harboured in the fibrinogen, IL6 and F13A1 genes to these biochemical and clinical phenotypes was examined. A database and biobank based on 387 survivors of a first MI and population-based controls were used. Sixty controls were selected according to FGG 9340T > C [rs1049636] genotype for studies on fibrin clot structure using the liquid permeation method. The multifactor dimensionality reduction method was used for interaction analyses. We here report that the FGA 2224G > A [rs2070011] SNP (9.2%), plasma fibrinogen concentration (13.1%) and age (8.1%) appeared as independent determinants of fibrin gel porosity. The FGA 2224G > A SNP modulated the relation between plasma fibrinogen concentration and fibrin clot porosity. The FGG-FGA*4 haplotype, composed of the minor FGG 9340C and FGA 2224A alleles, had similar effects, supporting its reported protective role in relation to MI. Significant epistasis on plasma fibrinogen concentration was detected between the FGA 2224G > A and F13A1 Val34Leu [rs5985] SNPs (p < 0.001). The FGG 9340T > C and FGB 1038G > A [rs1800791] SNPs appeared to interact on MI risk, explaining the association of FGG-FGB haplotypes with MI in the absence of effects of individual SNPs. Thus, epistatic and pleiotropic effects of polymorphisms contribute to the variation in plasma fibrinogen concentration, fibrin clot structure and risk of MI.

Topics: Environment; Epistasis, Genetic; Factor XIII; Fibrin; Fibrinogen; Gels; Genetic Markers; Genetic Predisposition to Disease; Humans; Middle Aged; Models, Genetic; Myocardial Infarction; Polymorphism, Single Nucleotide; Porosity; Risk Factors

Topics: Adult; Aged; C-Reactive Protein; Case-Control Studies; Fibrin; Fibrinogen; Humans; Lipids; Lipoprotein(a); Male; Middle Aged; Myocardial Infarction

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

We have developed a robust rat model of myocardial infarction (MI). Here we describe the step-by-step protocol for creating an ischemia-reperfusion rat model of MI. We also describe how to deliver therapeutic injections of mesenchymal stem cells (MSCs) together with fibrin, to show an application of this model. In addition, to confirm the presence of fibrin and cells in the infarct, visualization of MSCs and fibrin by histological techniques are also described. The ischemia-reperfusion MI model can be modified and generalized for use with various injectable polymers, cell types, drugs, DNA and combinations thereof. The model can be created in 7 days or less, depending on the timing of therapeutic intervention.

Topics: Animals; Cell- and Tissue-Based Therapy; Disease Models, Animal; Fibrin; Histological Techniques; Mesenchymal Stem Cell Transplantation; Myocardial Infarction; Rats; Reperfusion Injury

Neovascularization may improve cardiac function and prevent further scar tissue formation in infarcted myocardium. A number of studies have demonstrated that bone marrow-derived cells have the potential to induce neovascularization in ischemic tissues. In this study, we hypothesized that implantation of bone marrow mononuclear cells (BMMNCs) using injectable fibrin matrix further enhances neovascularization in infarcted myocardium compared to BMMNC implantation without matrix. To test this hypothesis, infarction was induced in rat myocardium by cryoinjury. Three weeks later, rat BMMNCs were mixed with fibrin matrix and injected into the infarcted myocardium. Injection of either BMMNCs or medium alone into infarcted myocardium served as controls. Eight weeks after the treatments, histological analyses indicated that implantation of BMMNCs using fibrin matrix resulted in more extensive tissue regeneration in the infarcted myocardium compared to BMMNC implantation without matrix. Examination with fluorescence microscopy revealed that cells labeled with a fluorescent dye prior to implantation survived in the infarcted myocardium at 8 weeks of implantation. Importantly, implantation of BMMNCs using fibrin matrix resulted in much more extensive neovascularization in infarcted myocardium than BMMNC implantation without matrix. The microvessel density in infarcted myocardium was significantly higher (p < 0.05) when BMMNCs were implanted using fibrin matrix (350 +/- 22 microvessels/mm2) compared to BMMNC implantation without matrix (262 +/- 13 microvessels/mm2) and medium injection (76 +/- 9 microvessels/mm2). In addition, average internal diameter of microvessels was significantly larger (p < 0.05) in BMMNC implantation with fibrin matrix group (14.6 +/- 1.2 microm) than BMMNC implantation without matrix group (10.2 +/- 0.7 microm) and medium injection group (7.3 +/- 0.5 microm). These results suggest that fibrin matrix could serve as a cell implantation matrix that enhances neovascularization efficacy for myocardial infarction treatment.

Topics: Animals; Biomimetic Materials; Bone Marrow Transplantation; Cell Culture Techniques; Cell Survival; Extracellular Matrix; Fibrin; Injections; Microcirculation; Monocytes; Myocardial Infarction; Neovascularization, Physiologic; Rats; Rats, Sprague-Dawley; Treatment Outcome

Topics: Coronary Thrombosis; Female; Fibrin; Humans; Middle Aged; Myocardial Infarction; Radiography

Current therapies for heart failure due to transmural left ventricular (LV) infarction are limited. We have developed a novel patch method for delivering autologous bone marrow stem cells to sites of myocardial infarction for the purpose of improving LV function and preventing LV aneurysm formation. The patch consisted of a fibrin matrix seeded with autologous porcine mesenchymal stem cells labeled with lacZ. We applied this patch to a swine model of postinfarction LV remodeling. Myocardial infarction was produced by using a 60-min occlusion of the left anterior descending coronary artery distal to the first diagonal branch followed by reperfusion. Results were compared between eight pigs with stem cell patch transplantation, six pigs with the patch but no stem cells (P), and six pigs with left anterior descending coronary artery ligation alone (L). Magnetic resonance imaging data collected 19 +/- 1 days after the myocardial infarction indicated a significant increase of LV systolic wall thickening fraction in the infarct zone of transplanted hearts compared with P or L hearts. Blue X-gal staining was observed in the infarcted area of transplanted hearts. PCR amplification of specimens from the X-gal-positive area revealed the Ad5 RSV-lacZ vector fragment DNA sequence. Light microscopy demonstrated that transplanted cells had differentiated into cells with myocyte-like characteristics and a robust increase of neovascularization as evidenced by von Willebrand factor-positive angioblasts and capillaries in transplanted hearts. Thus this patch-based autologous stem cell procedure may serve as a therapeutic modality for myocardial repair.

Topics: Animals; Cell Differentiation; Cell Movement; Cells, Cultured; Fibrin; Mesoderm; Myocardial Infarction; Myocytes, Cardiac; Neovascularization, Physiologic; Phenotype; Stem Cell Transplantation; Stem Cells; Swine; Transduction, Genetic; Transplantation, Autologous; Wound Healing

A method has been developed for accurately and precisely measuring the activity of a range of plasminogen activators (PAs) used as thrombolytic agents, including streptokinase, tissue plasminogen activator (tPA) and variants, and urokinase (uPA), both single and two chain forms. Plasminogen activation is monitored in a transparent, solid fibrin matrix but uses chromogenic substrate hydrolysis, rather than changes in fibrin, to quantitate the activity of PAs. The method has been tested in two recent international collaborative studies involving tPA and streptokinase where it has been shown to perform very well. Furthermore, the method is based on sound enzymological principles and once correction for the competitive inhibition of fibrin(ogen) is made, the generation of plasmin can be determined in molar terms and hence the activity of PAs can be expressed and compared in SI units (rate of increase in molar concentration of plasmin) as well as International Units. The assay is also arranged in such a way to reflect the behavior of PAs in vivo during thrombolytic therapy and it is shown that the specific activity of streptokinase and tPA in this system reflects plasmin generation capacity of these thrombolytics for doses given in infusions for treatment of myocardial infarction. The method would make a suitable reference method for PAs and provides a rigorous means of studying and modeling the enzymology of fibrinolysis and will be helpful in the rational design of third generation thrombolytic agents.

Topics: Fibrin; Fibrinogen; Fibrinolysin; Fibrinolysis; Fibrinolytic Agents; Humans; International System of Units; Kinetics; Laboratories; Models, Chemical; Myocardial Infarction; Plasminogen Activators; Receptors, Cell Surface; Receptors, Urokinase Plasminogen Activator; Reference Standards; Reproducibility of Results; Streptokinase; Thrombolytic Therapy; Tissue Plasminogen Activator

Elevated circulatory levels of many blood coagulation factors are known to be a risk factor for deep vein thrombosis in humans. Here we report the first direct demonstration of a close association between elevated circulatory factor IX levels in mice with thrombosis as well as myocardial fibrosis. Transgenic mice overexpressing human factor IX at persistently high levels died at much younger ages than their cohorts expressing lower levels, or nontransgenic control animals. The median survival age of animals was inversely related to the circulatory levels of human factor IX. Prematurely dying animals had focal fibrotic lesions predominantly present in the left ventricular myocardium, and vasculatures in these lesions showed fibrin deposition. Thromboemboli were also present in other organs, including lung and brain. These observations support the hypothesis that persistently high circulatory levels of factor IX are a risk factor not only for thrombosis and/or thromboembolism, but also for myocardial fibrosis mimicking human myocardial infarction.

Topics: Animals; Coronary Thrombosis; Disease Models, Animal; Factor IX; Female; Fibrin; Fibrosis; Gene Expression Regulation; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardial Infarction; Myocardium; Recombinant Fusion Proteins; Risk Factors; Thromboembolism; Thrombophilia

We evaluated assay systems for detection of in vivo thrombin activity in patients with acute myocardial infarction. The study included 31 consecutive patients with acute myocardial infarction treated either with fibrinolytic therapy (FLT), or acute PTCA. Blood samples were drawn at admission, after 30 min, 1 h, 3 h, 6 h, 12 h, 24, and 48 h. Assays related to the enzymatic action of thrombin included fibrinopeptide A ELISA, a novel latex-enhanced photometric immunoassay for soluble fibrin complexes, fibrin monomer antigen, D-dimer antigen, and soluble platelet glycoprotein V, which is released from the platelet surface by thrombin cleavage. The soluble fibrin assay displayed a high degree of correlation with fibrinopeptide A, and no correlation with D-dimer antigen, indicating that this parameter allows monitoring of in vivo thrombin activity in patients with acute myocardial infarction. Fibrin monomer antigen, and D-dimer antigen, were influenced by FLT, indicating cross-reactivity with proteolytic fragments of fibrin. No significant changes in soluble glycoprotein V were observed. The results show that the novel soluble fibrin assay appears to be a promising method for measurement of in vivo fibrin formation in patients with acute myocardial infarction, irrespective of the primary treatment decision for FLT or acute PTCA.

Topics: Angioplasty, Balloon, Coronary; Biomarkers; Cardiovascular Agents; Drug Therapy, Combination; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinolytic Agents; Fibrinopeptide A; Humans; Myocardial Infarction; Platelet Glycoprotein GPIb-IX Complex; Solubility; Thrombin; Time Factors

Fibrinogen B beta polymorphisms, such as the -455 G/A and the Arg448Lys amino acid substitution, have been shown to increase the risk of atherothrombotic disease. Although these polymorphisms are related to fibrinogen concentrations, their effect on fibrin clot structure has not been extensively studied. We examined the frequency of the fibrinogen B beta -455 G/A polymorphism in a group of myocardial infarction (MI) patients. There was no association between this polymorphism and MI. However, we found that patients homozygous for the rare -455 A allele had a higher average age at first MI. A similar result was found for individuals homozygous for the B beta 448 Lys allele who also had a higher age at first MI. We subsequently studied the clotting properties of purified Arg448 and Lys448 fibrinogens in vitro and found that these fibrinogens did not significantly differ in their polymerisation, fibrinolysis kinetics or in their clot permeation properties. Mass spectrometry analysis of endoproteinase Asp-N digests of B beta chains revealed that the Lys(448) and the Arg(448) chains were expressed in approximately equal proportions in a heterozygote Arg448Lys individual. Our results demonstrate that the fibrinogen B beta -455 G/A polymorphism is not associated with myocardial infarction and further-more the closely linked B beta Arg448Lys protein coding variation does not have an influence on the function nor the structure of the protein in a purified system.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Coagulation; Case-Control Studies; Female; Fibrin; Fibrinogen; Fibrinolysis; Gene Frequency; Genotype; Humans; Male; Middle Aged; Myocardial Infarction; New Zealand; Permeability; Polymorphism, Genetic; Smoking

Topics: Alleles; Amino Acid Substitution; Case-Control Studies; Fibrin; Fibrinogen; Humans; Male; Myocardial Infarction; Polymorphism, Genetic; Thromboembolism

Functional inhibition of tissue factor (TF) has been shown to improve coronary blood flow after myocardial ischemia/reperfusion (I/R) injury. TF initiates the coagulation protease cascade, resulting in the generation of the serine protease thrombin and fibrin deposition. Thrombin can also contribute to an inflammatory response by activating various cell types, including vascular endothelial cells. We used a rabbit coronary ligation model to investigate the role of TF in acute myocardial I/R injury. At-risk areas of myocardium showed increased TF expression in the sarcolemma of cardiomyocytes, which was associated with a low level of extravascular fibrin deposition. Functional inhibition of TF activity with an anti-rabbit TF monoclonal antibody administered either 15 minutes before or 30 minutes after coronary ligation reduced infarct size by 61% (P = 0.004) and 44% (P = 0.014), respectively. Similarly, we found that inhibition of thrombin with hirudin reduced infarct size by 59% (P = 0.014). In contrast, defibrinogenating the rabbits with ancrod had no effect on infarct size, suggesting that fibrin deposition does not significantly contribute to infarct size. Functional inhibition of thrombin reduced chemokine expression and inhibition of either TF or thrombin reduced leukocyte infiltration. We propose that cardiomyocyte TF initiates extravascular thrombin generation, which enhances inflammation and injury during myocardial I/R.

Topics: Animals; Antibodies, Monoclonal; Antithrombins; Cell Movement; Chemokines; Fibrin; Fibrinogen; Hirudins; Microscopy, Electron; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocarditis; Myocardium; Neutrophils; Rabbits; Thrombin; Thromboplastin

Achieving early, complete, and sustained reperfusion after acute myocardial infarction does not occur in approximately 50% of patients, even with the most potent established thrombolytic therapy. Bleeding is observed with increased concentrations of thrombolytics as well as with adjunctive antithrombotic and antiplatelet agents. A novel approach to enhance thrombolytic therapy is to inhibit the activated form of thrombin-activatable fibrinolysis inhibitor (TAFI), which attenuates fibrinolysis in clots formed from human plasma. Identification of TAFI in rabbit plasma facilitated the development of a rabbit arterial thrombolysis model to compare the thrombolytic efficacy of tissue-plasminogen activator (tPA) alone or with an inhibitor, isolated from the potato tuber (PTI), of activated TAFI (TAFIa). Efficacy was assessed by determining the time to patency, the time the vessel remained patent, the maximal blood flow achieved during therapy, the percentage of the original thrombus, which lysed, the percentage change in clot weight, the net clot accreted, and the release of radioactive fibrin degradation products into the circulation. The results indicate that coadministration of PTI and tPA significantly improved tPA-induced thrombolysis without adversely affecting blood pressure, activated partial thromboplastin time, thrombin clotting time, fibrinogen, or alpha-2-antiplasmin concentrations. The data indicate that inhibitors of TAFIa may comprise novel and very effective adjuncts to tPA and improve thrombolytic therapy to achieve both clot lysis and vessel patency.

Topics: Animals; Carboxypeptidase B2; Carboxypeptidases; Drug Evaluation, Preclinical; Drug Synergism; Drug Therapy, Combination; Fibrin; Fibrinolysis; Humans; Male; Myocardial Infarction; Partial Thromboplastin Time; Plant Proteins; Protease Inhibitors; Rabbits; Specific Pathogen-Free Organisms; Thrombolytic Therapy; Tissue Plasminogen Activator

This study investigates the association between the concentration and function of plasma fibrinogen molecules measured at the time of hospital admission in patients with acute myocardial infarction (AMI), with reference to the risk of new coronary ischemic events during a three-day follow-up period of. Before starting fibrinolytic and anticoagulant treatment plasma fibrinogen, high molecular weight fibrinogen (HMW-fibrinogen), fibrin formation rate (FbFR) and phosphorous content in fibrinogen were determined in 90 AMI patients. During a three-day follow-up period 12 patients suffered new ischemic events. The 12 patients with coronary ischemia had higher concentrations of plasma fibrinogen (312+/-23 vs. 270+/-73 mg/dl, p<0.05) and HMW-fibrinogen (246+/-35 vs. 189+/-23 mg/dl, p<0.001) and a higher FbFR (65+/-30 vs. 40+/-25, p<0.001) than patients without these events. No association was found between the phosphorous content in fibrinogen and new coronary ischemic events. We conclude that after myocardial infarction an elevated plasma level of HMW-fibrinogen and a high FbFR value at the time of hospital admission are associated with new coronary ischemic events during a three-day follow-up period.

Topics: Aged; Biomarkers; Convalescence; Coronary Thrombosis; Female; Fibrin; Fibrinogen; Fibrinopeptide A; Follow-Up Studies; Humans; Male; Middle Aged; Molecular Weight; Myocardial Infarction; Phosphorus; Phosphorylation; Protein Processing, Post-Translational; Recurrence

Thrombolytic therapy in acute myocardial infarction (AMI) is hampered by a considerable reocclusion rate. Thrombin activity is enhanced, and contact-system activation via plasminemia might be possible. Prospectively we examined the contact phase and the kallikrein-kinin system and additional molecular markers of hemostasis and fibrinolysis in AMI. In 22 patients with AMI, blood sampling was performed at admission and < or =10 days afterward. Eleven patients received 1.5 Mio U streptokinase (group A) and were compared with 11 AMI patients without thrombolytic therapy (group B). All patients had systemic heparinization (5,000 IU bolus, i.v.; 1,000 IU/h, i.v.). In group A (vs. group B), the kallikrein-factor XII system was significantly activated (3 h after start of therapy): kallikrein activity 140 +/- 41 (vs. 43 +/- 8) U/L (p < 0.05); kallikrein inhibition 87 +/- 9 (vs. 113 +/- 7%; p < 0.05), and factor XII 70 +/- 14 (vs. 94 +/- 6%). C1 inhibitor and factor XII inhibition were decreased. High-molecular-weight kininogen consumption indicating bradykinin generation was enhanced (p < 0.01). In group A, thrombin activity (TAT) was increased, and a hypercoagulative state with increased fibrin degradation products (d-dimer) was found. Plasmin activation in group A was reflected by decreased plasminogen and antiplasmin levels (p < 0.01). The findings indicate that streptokinase induces activation of the contact phase-kinin system in vivo associated with a consecutive increase of thrombin and bradykinin generation. Activation of this pathway might substantially contribute to reocclusion after initially successful thrombolytic therapy and to hypotensive reactions observed after streptokinase.

Topics: Acute Disease; Aged; Analysis of Variance; Factor XII; Female; Fibrin; Humans; Kallikrein-Kinin System; Kallikreins; Male; Middle Aged; Myocardial Infarction; Prospective Studies; Streptokinase; Thrombin

Transmyocardial laser revascularization is an investigational technique for revascularizing ischemic myocardium in patients with inoperable coronary arterial disease. This study tests the hypothesis that laser revascularization prevents left ventricular functional deterioration and aneurysm formation after acute anteroapical myocardial infarction.. An ultrasonic ascending aortic flow probe and snares around the distal left anterior descending and second diagonal coronary arteries were placed in 26 Dorsett hybrid sheep. Ten to 14 days later, snared arteries were occluded to produce an anteroapical infarction of 23% of left ventricular mass. Before infarction 14 animals had 34 +/- 4 transmyocardial perforations in the area of the anticipated infarction made with a carbon dioxide laser. Twelve animals served as controls. Hemodynamic measurements and transdiaphragmatic quantitative echocardiograms were obtained before, immediately after, and 2, 5, and 8 weeks after infarction. Eighteen sheep completed the protocol.. All animals had large anteroapical left ventricular aneurysms with massive ventricular enlargement. Immediately after infarction the anterior wall became thinner and dyskinetic in all sheep. At 8 weeks aneurysmal size and shape were indistinguishable between groups. Two days after infarction, laser holes were filled with fibrin. At 5 and 8 weeks the infarct consisted of dense collagen, fibroblasts, scattered calcifications, myocyte fragments, neutrophils, macrophages, and no laser holes. There were no significant differences at any time between groups for cardiac pressures or output, ventricular volumes, ejection fraction, stroke work, and the stroke work-left ventricular end-diastolic pressure index.. Transmyocardial laser perforations do not revascularize acute myocardial infarction in sheep.

Topics: Animals; Echocardiography; Fibrin; Heart Aneurysm; Heart Ventricles; Hemodynamics; Laser Therapy; Myocardial Infarction; Myocardial Revascularization; Myocardium; Sheep; Treatment Failure; Ventricular Dysfunction, Left

Recently, increases in the plasma concentration of soluble fibrin (SF) have been suggested to be sensitive and specific for myocardial infarction (MI). However, the relationship between elevations in the SF concentration and the onset of symptoms and clinical course of MI is unknown. In addition, there are no data regarding the relationship between SF concentrations and concentrations of other markers of procoagulant (fibrinopeptide A [FPA]) and fibrinolytic (cross-linked fibrin degradation products [XL-FDPs]) activity in patients with MI. In this study, concentrations of SF were measured with a novel antigen-based assay for 93 MI patients and 29 control subjects, and the relationship between SF concentrations and those of XL-FDPs and FPA was determined. Increases in SF, FPA, and XL-FDP concentrations were documented in 55.9%, 45.2%, and 73.9%, respectively, of patients with MI, but there was no relationship between the concentrations of these markers. Increases in the concentration of SF or XL-FDPs did not show a relationship to increases in the concentration of FPA. Concentrations of XL-FDPs but not of SF were elevated to a greater extent in patients with MI complications (defined as death, ventricular arrhythmia, severe congestive heart failure, or mural thrombus). Increases in SF and XL-FDPs were not sensitive enough for the diagnosis of MI, but increased concentrations of XL-FDPs appear to predict those patients who are at higher risk for MI-related complications.

Topics: Adult; Aged; Cross-Linking Reagents; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinolysin; Fibrinolysis; Hospitalization; Humans; Male; Middle Aged; Myocardial Infarction; Thrombosis; Time Factors

Increases in thrombin activity occur in patients treated with streptokinase, but conjunctive therapy with intravenous heparin does not appear to improve either the rate of early infarct artery patency or survival in patients with acute myocardial infarction. In a recent study we found that concentrations of fibrinopeptide A, a marker of thrombin-mediated fibrin formation, were lower in the first 3 h in patients treated with intravenous heparin (5000 U bolus followed by a fixed-dose 1000 U/h infusion, n = 14) compared with subcutaneous (12,500 U every 12 h, started 4 h after streptokinse, n = 14) administration, but were increased in both groups of patients, consistent with persistent thrombin activity. To determine whether the differential effects of the intensity of heparinization on thrombin formation were reflected in differences in fibrin degradation, we measured cross-linked fibrin degradation products (XL-FDP) before and 1, 2, 3, 8, 12, and 24 h after streptokinase in the same cohort of patients, with a new ELISA with a D-dimer-specific capture antibody (MAb 3B6) and a fibrin-specific tag antibody (MAb 1D2, Agen, Brisbane, Australia). The incidence of early coronary recanalization assessed by creatine-kinase MM isoforms (increase in activity > or = 0.18%/min), was similar in both groups (79 vs 86%). Concentrations of XL-FDP were similar in patients with and without recanalization, but were lower in patients treated with intravenous compared with subcutaneous heparin at 8 h, but the results did not reach statistical significance (627 +/- 151 ng/ml versus 1007 +/- 157 ng/ ml, p = 0.06), and were significantly lower at 12 h (327 +/- 72 versus 781 +/- 162 ng/ml, p = 0.03 at 12 h) (mean +/- SEM). Concentrations of cross-linked fibrin degradation products were also lower in patients in whom the activated partial thromboplastin time was greater than two times the control, compared with those with inadequate anticoagulation (498 +/- 105 versus 1084 +/- 179 ng/ml; p = 0.02) (mean +/- SEM). Thus, more effective inhibition of thrombin with conjunctive intravenous heparin therapy results in less cross-linked fibrin turnover in the first 12 h after thrombolysis with streptokinase. This probably reflects decreased fibrin formation with therapeutic anticoagulation.

Topics: Cohort Studies; Cross-Linking Reagents; Fibrin; Fibrin Fibrinogen Degradation Products; Heparin; Humans; Injections, Intravenous; Myocardial Infarction; Streptokinase; Thrombin

During episodes of dental bacteremia, viridans group streptococci encounter platelets. Among these microorganisms, certain Streptococcus sanguis induce human and rabbit platelets to aggregate in vitro. In experimental rabbits, circulating streptococci induced platelets to aggregate, triggering the accumulation of platelets and fibrin into the heart valve vegetations of endocarditis. At necropsy, affected rabbit hearts showed ischemic areas. We therefore hypothesized that circulating S. sanguis might cause coronary thrombosis and signs of myocardial infarction (MI). Signs of MI were monitored in rabbits after infusion with platelet-aggregating doses of 4 to 40 x 10(9) cells of S. sanguis 133-79. Infusion resulted in dose-dependent changes in electrocardiograms, blood pressure, heart rate, and cardiac contractility. These changes were consistent with the occurrence of MI. Platelets isolated from hyperlipidemic rabbits showed an accelerated in vitro aggregation response to strain 133-79. Cultured from immunosuppressed children with septic shock and signs of disseminated intravascular coagulation, more than 60% of isolates of viridans streptococci induced platelet aggregation when tested in vitro. The data are consistent with a thrombogenic role for S. sanguis in human disease, contributing to the development of the vegetative lesion in infective endocarditis and a thrombotic mechanism to explain the additional contributed risk of periodontitis to MI.

Topics: Animals; Bacteremia; Bacterial Physiological Phenomena; Blood Platelets; Blood Pressure; Cells, Cultured; Child; Coronary Thrombosis; Disseminated Intravascular Coagulation; Electrocardiography; Endocarditis, Bacterial; Fibrin; Heart Diseases; Heart Rate; Humans; Hyperlipidemias; Immunocompromised Host; Mouth; Myocardial Contraction; Myocardial Infarction; Myocardial Ischemia; Periodontitis; Platelet Aggregation; Rabbits; Shock, Septic; Streptococcus sanguis; Thrombosis

Thrombin activation of the soluble plasma protein fibrinogen is vital for successful haemostasis. Thrombin is generated from prothrombin by the prothrombinase complex which also includes factor Xa, factor Va, Ca2+ and a procoagulant membrane surface. Factor X activation is catalysed in a complex including either factor VIIa and tissue factor, or factor IXa and factor VIIIa. Factor IXa can be generated either by the factor VIIa/tissue factor complex or by factor XIa which is in turn produced by the contact phase reactions in vitro. Once activated, fibrinogen develops into the fibrin polymeric matrix at the site of injury. It is not known to what extent the properties of this haemostatic plug are sensitive to the pathway leading up to thrombin generation. Here static human plasma is studied in vitro using magnetically induced birefringence. It is shown that the contact phase/factor XIa pathway gives rise to linear fibrin assembly process curves whereas the factor VIIa/ tissue factor activation of factor X provokes largely sigmoid assembly. The latter pathway also causes the formation of significantly thicker fibres even though assembly is more rapid. This result is the inverse of that anticipated from the study of simple model systems. Whilst the streptokinase activated lysis both types of clot exhibits similar biphasic kinetics, an exponential main phase followed by a sigmoidal tailing off, the data suggest that clots produced by the contact phase/factor XIa pathway are more recalcitrant to lysis. These results demonstrate that the profile of thrombin generation not only determines the kinetics of assembly but also influences the rate of lysis and structure of the haemostatic plug.

Topics: Birefringence; Blood Coagulation; Blood Coagulation Factors; Blood Coagulation Tests; Enzyme Activation; Fibrin; Fibrinogen; Fibrinolysis; Gels; Hemophilia A; Humans; Myocardial Infarction; Plasma; Prothrombin; Thrombin; Thromboplastin

The incidence of early reocclusion is reported to be higher in patients who receive fibrin-specific thrombolytic agents than nonspecific ones. The reason has yet to be clarified. In the present study, we focused on the difference in duration of fibrinolytic activity. The hemostatic parameters of 7 consecutive patients suffering from acute myocardial infarction treated with a fibrin-nonspecific thrombolytic agent (urokinase) were compared with 9 patients who received a fibrin-specific agent (tissue plasminogen activator, t-PA). The plasma concentrations of alpha 2-plasmin inhibitor (alpha 2-PI), plasmin alpha 2-PI complex (PLC), fibrin degradation products E fragment (FDP-E), and D-D dimer (D-dimer) were measured before, soon after, 1, 2, 3, 4, and 6 h and 2, 3, 4, and 7 days after thrombolytic therapy to estimate the hemostatic and fibrinolytic state. A significant decrease in alpha 2-PI (less than the lowest measurable level) with a simultaneous increase in FDP-E and D-dimer was induced soon after the administration of urokinase. FDP-E and D-dimer decreased, with a significant increase in alpha 2-PI, more than 6 h after thrombolytic therapy. In contrast, a less significant decrease in alpha 2-PI with a lesser amount and shorter duration of fibrinolysis were observed in patients who received t-PA. The amount of PIC soon after drug administration was not different between the two groups. Our data suggested that fibrinolytic activities induced by fibrin-nonspecific urokinase persisted longer than expected by its plasma half-life.The fibrinolytic activities might be terminated by the production of alpha 2-PI.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; alpha-2-Antiplasmin; Fibrin; Fibrinolysis; Hemostasis; Humans; Male; Middle Aged; Myocardial Infarction; Recombinant Proteins; Recurrence; Thrombolytic Therapy; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator

Pharmacokinetics and fibrin specificity of alteplase (recombinant tissue-type plasminogen activator) were determined in 10 patients with acute myocardial infarction undergoing an accelerated infusion regimen during the alteplase/anistreplase patency study (TAPS). Fifteen milligrams of alteplase was administered as an intravenous bolus injection, followed by infusions of 50 mg over 30 min and 35 mg over a further 60 min. Mean steady state plasma concentrations of alteplase during the initial 30 min were 3.2 +/- 0.84 micrograms/ml, measured immunochemically, and 2.1 +/- 0.23 micrograms/ml, measured using a functional activity assay. These values were 45% and 51% higher, respectively, than those during the standard infusion schedule (p less than 0.01). However, the predominant plasma half-life determined by model fitting based on either assay (3.3 to 3.5 min) was unaltered compared with the standard regimen. Maximal concentrations of fibrin and fibrinogen degradation products were 5.1 +/- 2.2 and 1.9 +/- 1.1 micrograms/ml, respectively. Plasminogen decreased to 70% and alpha 2-antiplasmin to 35% of values before infusion. The results indicate that 1) improved coronary patency rates during "front-loaded" infusions can be rationalized in terms of higher plasma concentrations of both free and immunoreactive alteplase, 2) kinetic variables are comparable with those of other dosing strategies, and 3) fibrin specificity is not diminished relative to that of the standard infusion regimen.

Topics: Aged; alpha-2-Antiplasmin; alpha-Macroglobulins; Female; Fibrin; Fibrinogen; Fibrinolysin; Hemostasis; Humans; Infusions, Intravenous; Male; Middle Aged; Myocardial Infarction; Plasminogen; Substrate Specificity; Time Factors; Tissue Plasminogen Activator

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

In a majority of instances, both unstable angina and acute myocardial infarction occur secondary to plaque disruption and thrombus formation. Although the pathogenetic substrates are similar the clinical presentations are quite different. It is hypothesized in this editorial review that the amount of acute thrombus formation and specifically fibrin deposition is greater in myocardial infarction than in unstable angina. Both angiographic studies and studies analyzing the response to thrombolytic agents suggest more thrombus in myocardial infarction than in unstable angina. These data have recently been substantiated by angioscopic observations in these acute syndromes suggesting that more platelet-rich (whitish) thrombus occurs in unstable angina and more red thrombus in myocardial infarction. The red thrombus presumably would be more responsive to thrombolytic agents. Furthermore, it is proposed that these differences between syndromes in acute thrombus formation can be explained by the interplay of vessel wall injury, coagulation variables or stasis of blood flow occurring at or after the time of presentation. Therefore, acute myocardial infarction is associated with occlusive, fibrin-rich thrombus, whereas in unstable angina, the thrombus is nonocclusive, mural and possibly more platelet-rich. However, the clinical syndrome that ultimately develops after plaque disruption is dependent not only on the amount of acute thrombus formation but on the net result of all factors that influence the balance between coronary blood supply and myocardial oxygen demand.

Topics: Angina, Unstable; Blood Platelets; Coronary Angiography; Coronary Thrombosis; Endoscopy; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinopeptide A; Humans; Myocardial Infarction; Plasminogen Inactivators; Thrombolytic Therapy

Thrombotic occlusion is the major cause of myocardial infarction (MI), and fibrin accumulation appears to play a significant role in development of atherosclerotic lesions. Any factor that reduces the lysis of fibrin may thus increase the risk of MI, and it has been suggested that this accounts for the atherogenicity of the lipoprotein variant Lp(a). The characteristic feature of Lp(a) is an apoprotein which is homologous with part of the plasminogen molecule, and experiments in vitro suggest that it interferes with uptake and activation of plasminogen on cell surfaces and fibrin. The presence of Lp(a) also seemed to offer an explanation for the apparent absence of plasminogen from 70-80% of intimal samples. We have compared the levels of Lp(a) and plasminogen in normal intima and atherosclerotic lesions. In aortic intima there was no relation between Lp(a) and plasminogen, which was absent in some samples with no Lp(a), and present in others with high levels. In intravascular thrombi plasminogen was present at a rather constant concentration (16.3 +/- 4.6 micrograms/100 mg wet tissue), whereas Lp(a) varied over a 100 fold range (0-104 micrograms/100 mg). Plasminogen binds to fibrin and is activated on the fibrin clot, so levels in extracts may not fully represent Lp(a)/plasminogen interactions. After extraction the residual tissues and thrombi were treated with 1 M epsilon-aminocaproic acid (epsilon-aca) to elute lysine-bound components. Lp(a) was eluted from all but one intimal sample, confirming previous findings on its binding to fibrin in lesions, but there was no relation between the amounts of Lp(a) and plasminogen in the tissue eluates. Paradoxically, in the thrombi there was a weak positive correlation between Lp(a) and plasminogen in epsilon-aca eluates (r = 0.504, P = 0.05). These results do not support the hypothesis that Lp(a) displaces plasminogen in vivo, but the large amount of Lp(a) eluted by epsilon-aca suggests that its atherogenicity resides in preferential binding to fibrin, leading to increased lipid accumulation in lesions.

Topics: Adult; Aged; Aorta; Aortic Diseases; Arteriosclerosis; Binding, Competitive; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Humans; Lipoprotein(a); Lipoproteins; Lipoproteins, LDL; Male; Middle Aged; Myocardial Infarction; Plasminogen; Thrombosis

Distribution of fibrinogen/fibrin and fibronectin in regions of experimental myocardial infarction were studied by the immunofluorescence technique. Distinct from normal myocardium 3 and 12 to 24 h after coronary artery ligation infiltration of necrotized cardiomyocytes by fibrinogen/fibrin and plasma fibronectin was detected. Fibrinogen/fibrin and plasma fibronectin constitute "primary matrix" of granulation tissue. On the third day after experimental infarction, synthesis of cellular fibronectin begins. Its content in the extracellular matrix (ECM of granulation tissue significantly increases on days 7 to 15. The amount of fibronectin in the ECM of developing scar tissue dramatically decreases 30 days after infarction, Fibrinogen/fibrin was continually identified in granulation tissue in zones of myocardial infarction. However, its amount in the ECM of developing scar tissue gradually decreased.

Topics: Animals; Antibodies; Antibodies, Monoclonal; Arteries; Chronic Disease; Coronary Aneurysm; Coronary Vessels; Epitopes; Fibrin; Fibrinogen; Fibronectins; Fluorescent Antibody Technique; Granulation Tissue; Ligation; Male; Myocardial Infarction; Myocardium; Rats; Rats, Inbred Strains

In this study the concentration of plasma breakdown products of cross-linked fibrin (XDP), serum fibrinogen-fibrin degradation products (FDP), and plasma fibrinogen were measured before and at the end of the administration of single-chain recombinant tissue-type plasminogen activator (rt-PA, 100 mg IV over three hours) or streptokinase (1.5 million units over one hour), respectively, in two groups, each composed of 22 patients with acute myocardial infarction. The XDP concentration was not statistically different between the two groups at the end of thrombolytic treatment, whereas FDP and fibrinogen concentrations were significantly different (FDP: streptokinase 396 +/- 287 vs rt-PA 177 +/- 222 micrograms/mL, p less than 0.01; fibrinogen: streptokinase 71 +/- 43 vs rt-PA 181 +/- 49 mg/dL, p less than 0.001). These results indicate that the two drugs have equipotent thrombolytic activity at this administration regimen but that rt-PA causes a markedly more selective lysis of fibrin in comparison with streptokinase.

Topics: Adult; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolysis; Humans; Male; Middle Aged; Myocardial Infarction; Recombinant Proteins; Streptokinase; Thrombolytic Therapy; Tissue Plasminogen Activator

1) The incidence of myocardial infarction, as well as thrombosis, has been increasing recently in the consecutive autopsy cases over 40 years old in Kyushu University, but is still less frequent than those in the autopsy cases in Boston around 1960. Increased fat intake might play a significant role in the increasing frequency of myocardial infarction in Japanese. 2) In a nationwide cooperative study of atherosclerosis in young Japanese, atherosclerotic changes were observed to begin developing in childhood. Primary prevention of atherosclerosis should be initiated in the pediatric age group. We should pay more attention to subclinical atherosclerosis. Age, serum cholesterol, and blood pressure were significantly and positively correlated with SI and AI of aortas and coronary arteries. Serum cholesterol was more strongly correlated with the extent of fatty streaks than was mean blood pressure and vice versa with that of fibrous plaques. Atherosclerosis of cerebral arteries, however, showed a significant correlation only with the factor of mean blood pressure. Therefore the susceptibility to risk factors varies with the artery in the case of early lesions of atherosclerosis in young people. More attention should be paid to the fact that atherosclerosis is a multifactoral disease. 3) Deposition of fibrinogen in the intima might precede LDL deposition and possibly play a more important role than LDL in the development of atherosclerotic lesions in the cerebral arteries, especially in their early stage. 4) The proliferation of smooth muscle cells is stimulated by fibrin and later inhibited by FDP, as produced by fibrinolytic activity of smooth muscle cells. The metabolism of fibrin in the arterial wall may be of importance in the regulation of smooth muscle cell proliferation, and the coagulation-fibrinolysis system may play a significant role in atherosclerosis with the effect of other risk factors such as cholesterol and hypertension.

Topics: Adolescent; Adult; Arteriosclerosis; Child; Child, Preschool; Female; Fibrin; Humans; Incidence; Infant; Japan; Male; Myocardial Infarction; Risk Factors

The mean levels of fibrinopeptide A (FPA), thrombin-antithrombin complex (TAT), and soluble fibrin (tPA method) in cancer patients (n = 32) were intermediate between those of patients with cerebral infarction and pancreatitis who had the most abnormal results and patients with myocardial infarction and pneumonia who had the least abnormal results. Patients with disseminated malignancies (n = 16) had significantly higher mean levels of FPA (10.6 vs. 5.3 nmol/l) and TAT (11.0 vs. 4.4 pmol/l) than patients with limited malignancies (n = 16). The difference in soluble fibrin (fibrin monomer, FM; 22.1 vs. 18.0 nmol/l) was not significant. The values of FPA, FM, and TAT in the patient population correlated significantly. There was a negative correlation between the level of antithrombin and test results for FPA (-0.69), FM (-0.48), and TAT (-0.38) in the cancer patients. Even cancer patients with locally limited disease may have elevated FPA, FM, and TAT test results, indicating a state of definite hypercoagulation.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Antithrombin III; Blood Coagulation Disorders; Blood Coagulation Tests; Cerebral Infarction; Female; Fibrin; Fibrinopeptide A; Humans; Male; Middle Aged; Myocardial Infarction; Neoplasms; Pancreatitis; Peptide Hydrolases; Pneumonia; Predictive Value of Tests; Reference Values

Fibrinopeptide A (FPA) is a very sensitive marker of fibrin generation in vivo. Because an imbalance between thrombogenic and thrombolytic forces may be responsible for the failure to recanalize and for reocclusion of coronary arteries, such a marker could be of eminent value during thrombolytic treatment of acute myocardial infarction. Thirty-four consecutive patients with acute myocardial infarction (peak creatine kinase level, 1,869 +/- 1,543 IU/l) were treated with 100 mg recombinant tissue-type plasminogen activator (rt-PA) 3.1 +/- 1.1 hours after onset of chest pain. Angiography 12.5 +/- 6.1 days later revealed an 81% patency rate of the infarct-related vessel. FPA plasma levels (normal, 1.9 +/- 0.5 ng/ml) were 34 +/- 46 ng/ml on admission and 93 +/- 86 ng/ml (538 +/- 674% with respect to each patient's admission level) after 90 minutes of rt-PA infusion (p less than 0.01). In patients without evidence of reocclusion (including three primary failures), FPA levels fell under continuous heparin infusion to 6.7 +/- 9.7 ng/ml (24 +/- 33%, p less than 0.01) within 30 minutes and were 3.1 +/- 2.2 ng/ml (15 +/- 15%, p less than 0.01), 1.6 +/- 1.1 ng/ml (8 +/- 10%, p less than 0.01), and 2.5 +/- 3.0 ng/ml (12 +/- 16%, p less than 0.01) 30 minutes, 9 hours, and 21 hours, respectively, after completion of rt-PA therapy. Five patients sustained intermittent or permanent coronary reocclusion after primary thrombolytic success. Their early postlytic FPA levels (13-51 ng/ml) remained high or increased again despite adequate anticoagulation. FPA allows the monitoring of fibrin generation during acute myocardial infarction and thrombolytic therapy. Despite successful recanalization, fibrin generation is increased under rt-PA administration before anticoagulation. Patients under anticoagulation with postlytic FPA levels less than 5 ng/ml or below their admission value seem to be at low risk of reocclusion for several days. FPA levels that are persistently high or that increase again despite adequate anticoagulation indicate ongoing fibrin generation. However, whether FPA can indeed be considered a useful marker of reocclusion remains to be confirmed in a larger population of patients with acute myocardial infarction.

Topics: Coronary Angiography; Female; Fibrin; Fibrinogen; Fibrinopeptide A; Heparin; Humans; Male; Middle Aged; Myocardial Infarction; Radioimmunoassay; Recombinant Proteins; Recurrence; Time Factors; Tissue Plasminogen Activator

Topics: Amino Acid Sequence; Fibrin; Fibrinolysis; Humans; Molecular Sequence Data; Myocardial Infarction; Plasminogen; Tissue Plasminogen Activator

Coronary spasm is the mechanism most often postulated to explain the rare combination of myocardial infarction and angiographically normal coronary arteries, although the reported evidence for its role is circumstantial rather than conclusive. Whereas the importance of thrombosis in myocardial infarction is uncontested in the presence of significant coronary artery disease, there is little in vivo evidence for thrombosis in angiographically normal coronary arteries. Among 11 consecutive patients with acute myocardial infarction undergoing thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) 3.2 +/- 0.7 h after onset of chest pain, and angiography 10.2 +/- 4.5 days later, three young men had normal coronary arteries. Their cases are documented electrocardiographically, enzymatically and angiographically. Mean plasma levels of fibrinopeptide A (FPA) and beta-thromboglobulin (BTG) were clearly elevated before and during rtPA therapy: FPA 52 +/- 41 ng ml-1, BTG 257 +/- 46 ng ml-1. They did not differ significantly from corresponding mean plasma levels in the eight patients with severe coronary artery disease: FPA 67 +/- 66 ng ml-1, BTG181 +/- 75 ng ml-1. We conclude that fibrin formation and platelet activation are probably equally important in the early hours of myocardial infarction, whether or not significant coronary artery disease is present.

Topics: Adult; Angiography; Arteries; beta-Thromboglobulin; Blood Platelets; Coronary Vasospasm; Coronary Vessels; Fibrin; Fibrinopeptide A; Humans; Male; Myocardial Infarction; Platelet Factor 4; Tissue Plasminogen Activator

The content of fibrinogen/fibrin, plasma and cellular fibronectin, the 1st type collagen, laminin and skeletal muscle myosin in the zone of experimental myocardial infarction was studied by the immunofluorescent method. The infiltration of the necrotized cardiomyocytes with fibrinogen/fibrin and plasma fibronectin was observed 3 hours and later after coronary artery ligation. Fibrinogen/fibrin and plasma fibronectin form a "primary matrix" of the granulation tissue in which the fibers of the 1st type collagen are being formed. Cellular fibronectin starts to be synthesized 3 days after the infarct development and its content in the extracellular matrix (ECM) of the granulation tissue increases 7-15 days after the infarction. The amount of the fibronectin in ECM of the scar tissue decreases 30 days after the infarct. Fibrinogen/fibrin is always found in the granulation tissue replacing the myocardial infarction but its content in ECM decreases during the scar formation.

Topics: Animals; Fibrin; Fibrinogen; Fibronectins; Fluorescent Antibody Technique; Granulation Tissue; Heart Aneurysm; Myocardial Infarction; Rats

In order to define some of the determinants of successful thrombolysis and reocclusion during fibrinolytic therapy for acute myocardial infarction (AMI), specific molecular markers of fibrin metabolism were serially measured in 15 patients with AMI treated with tissue-type plasminogen activator (t-PA). Fibrin formation was assessed by measurement of fibrinopeptide A (FpA) and fibrinolysis by assay of B-beta peptides 1-42 and 15-42 and crosslinked fibrin degradation products (XDP). At baseline, FpA levels were high while markers of fibrinolysis were near normal. Following a 90-minute infusion of t-PA (0.5-1.1 mg kg-1 hr-1), all markers of fibrinolysis increased. Levels of FpA remained elevated despite heparin at the initiation of cardiac catheterization. None of these markers discriminated between patients with successful reperfusion from those without. At 4 hours, B-beta 15-42 peptide and XDP levels remained elevated suggesting persistence of fibrinolysis beyond the short circulatory half-life of t-PA. FpA levels at 4 hours were lower in patients who underwent acute coronary angioplasty compared to those who received additional low dose t-PA (12.3 +/- 4.5 vs. 30.4 +/- 5.5 ng/ml, p less than 0.05). By 48 hours, markers of fibrinolysis had returned toward normal except in 2 patients with persistently elevated B-beta 15-42 peptide levels who suffered reocclusion on days 5 and 6 (75 and 44 vs. 29 +/- 3 nM, p less than 0.005). In conclusion, molecular markers of fibrin metabolism during fibrinolytic therapy may provide clinically relevant data.

Topics: Angioplasty, Balloon; Catheterization; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinolysin; Fibrinopeptide A; Fibrinopeptide B; Humans; Myocardial Infarction; Peptide Fragments; Recombinant Proteins; Reproducibility of Results; Thrombin; Time Factors; Tissue Plasminogen Activator

The frequency and clinical significance of platelet/fibrin microemboli in the microcirculation were investigated in 24 patients whose deaths (before and during hospital admission) were associated with acute myocardial infarction. An acute coronary thrombus was present in all the hearts. In nine hearts an acute thrombus was found in more than one major epicardial coronary artery. A total of 35 acute thrombi were found in the 24 hearts. Platelet/fibrin microemboli were found in 19 (79%) hearts. Eighteen patients died in hospital. The hearts of 16 of these cases showed microemboli; 16 had important arrhythmias or various forms of heart block; 13 showed acute pathological changes in the conduction system. Fourteen of the deaths in hospital were primarily the result of cardiogenic shock and four were primarily caused by arrhythmia. Six of the deaths that occurred before admission to hospital were regarded as being arrhythmic in origin. Three of these showed microemboli and the other three had acute pathological changes in the conduction system. Microemboli were found in two (24%) of 12 control hearts. Coronary thrombosis was found in most deaths caused by acute myocardial infarction and platelet/fibrin microemboli were present in the majority of such hearts. These may arise from the coronary thrombus in the larger upstream vessel supplying the microcirculation.

Topics: Adult; Aged; Aged, 80 and over; Blood Platelets; Coronary Disease; Coronary Thrombosis; Female; Fibrin; Humans; Male; Middle Aged; Myocardial Infarction; Myocardium

Topics: Coronary Disease; Coronary Thrombosis; Coronary Vessels; Fibrin; Fibrinolytic Agents; Humans; Infusions, Intravenous; Myocardial Infarction; Plasminogen; Recombinant Proteins; Time Factors; Tissue Plasminogen Activator

Thrombin cleaves fibrinopeptides from fibrinogen, converting it to fibrin monomer, and activates factor XIII, which catalyzes the formation of intermolecular epsilon-(gamma-glutamyl)-lysine bonds to stabilize the fibrin polymer. The formation of factor XIIIa-catalyzed fibrin polymers during clotting of plasma and purified fibrinogen in vivo was followed by a sodium dodecyl sulfate agarose gel technique, and an increase in both amount and size of gamma-chain cross-linked polymers was demonstrated before visible clot formation. Plasma from patients presenting with acute myocardial infarction showed increases in the plasma concentration of fibrin polymer and in the proportion of total fibrinogen present as polymer, as determined by a quantitative adaptation of the electrophoretic technique. The plasma concentration in patients with subendocardial or transmural myocardial infarction showed significant (p less than .005) increases to 4.0 +/- 1.0% and 3.6 +/- .8%, respectively, as compared with the concentration in normal plasma (0.8 +/- 0.1%). There was no difference in plasma concentration in samples from patients with transmural compared with those with subendocardial myocardial infarction. This study provides the first demonstration of factor XIIIa cross-linked fibrin polymers in thrombotic disease and indicates the presence of increased activity of both thrombin and factor XIIIa in patients with acute myocardial infarction.

Topics: Blood Coagulation; Electrophoresis, Agar Gel; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Humans; Myocardial Infarction; Polymers; Thrombosis; Time Factors

Topics: Antibodies, Monoclonal; Epitopes; Fibrin; Fibrinolysis; Humans; Myocardial Infarction; Thrombophlebitis; Tissue Plasminogen Activator

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: Animals; Coronary Circulation; Coronary Disease; Fibrin; Fibrinolysis; Humans; Myocardial Infarction; Plasminogen; Recombinant Proteins; Urokinase-Type Plasminogen Activator

The fibrinolytic capacity was assessed in 18 healthy subjects and in 8 patients each with non-idiopathic venous thrombosis, idiopathic venous thrombosis and myocardial infarction after intravenous administration of 1-deamino-8-D-arginine vasopressin (DDAVP) (0.4 microgram/kg) in comparison to venous occlusion. In healthy subjects the results obtained by either stimulus were approximately in agreement. Compared to the control group, in patients with non-idiopathic venous thrombosis the fibrinolytic capacity was not changed either after venous occlusion or after administration of DDAVP. In 5 out of 8 patients with idiopathic venous thrombosis the capacity was significantly reduced both after venous occlusion and after administration of DDAVP. In 4 out of 8 patients with myocardial infarction the capacity was significantly below the limit after administration of DDAVP while it was not after venous occlusion. In determining the fibrinolytic capacity DDAVP proved to be superior to venous occlusion.

Topics: Adult; Blood Coagulation Tests; Deamino Arginine Vasopressin; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolysis; Humans; Middle Aged; Myocardial Infarction; Prognosis; Thrombophlebitis; Thrombosis

Normal human plasma contains fibrinogens of different molecular weight. To quantitate these fibrinogens, plasma was clotted at pH 6.4 with 7.5 NIH U/ml thrombin in the presence of 8 mM EDTA. The clots were dissolved in 6.6 M urea and submitted to SDS electrophoresis on gels containing 3% polyacrylamide/0.5% agarose, and the fractions quantitated by densitometric scanning. The reproducibility of this method was high with variation coefficient 1.5%. Three main fibrinogen fractions were found: High molecular weight fibrinogen (HMW, mw 340 000), low molecular weight fibrinogen (LMW, mw 300 000) and LMW' (mw 280 000). In addition 5 weak bands could be seen. In plasma from 123 healthy subjects of both sexes, aged 1-93 years, HMW constituted 69.7% +/- 5.1, LMW 26.5% +/- 4.8 and LMW' 3.8% +/- 1.8 of the total fibrinogen. Women and older subjects displayed a small, but statistically significant reduction in the relative amounts of HMW (2-4%). Following surgery and extensive acute myocardial infarction the HMW/LMW ratio changed. The substantial increase in total fibrinogen regularly recorded was mainly due to HMW that reached maximal values after 3-4 days. LMW remained unchanged the first 2 days and then displayed a slight increase with a delayed maximum (8-11 days).

Topics: Adolescent; Adult; Age Factors; Aged; Blood Protein Electrophoresis; Child; Child, Preschool; Edetic Acid; Female; Fibrin; Fibrinogen; Hip Prosthesis; Humans; Infant; Male; Middle Aged; Molecular Weight; Myocardial Infarction; Postoperative Period; Sex Factors

The presence of extravasated erythrocytes (EE), iron (I), and fibrin (F) within coronary atherosclerotic plaques and their relation to intraluminal coronary thrombus was determined in 2958 five-mm segments of 224 major epicardial coronary arteries in 57 patients with fatal coronary heart disease and in 1290 five-mm segments of 103 coronary arteries in 27 control (c) subjects. Intraplaque EE were present in 10% of the segments (controls [c] = 1%), in 35% of the arteries (c = 5%), and in 84% of the patients (c = 19%); I was present in 4% of the segments (c = less than 1%), in 14% of the arteries (c = 4%), and in 57% of the patients (c = 22%); intraplaque F was present in 2% of the segments (c = less than 1%), in 17% of the arteries (c = 3%), and in 63% of the patients (c = 7%). Intraluminal thrombus, present only in the patients with acute myocardial infarction and in none of the controls, occurred in 3% of the segments, in 8% of the arteries and in 26% of the patients. Intraplaque hemorrhage or EE occurred usually in the absence of intraluminal thrombus and conversely intraluminal thrombus occurred more frequently without than with underlying plaque hemorrhage. The frequency of intraplaque EE, I, and F was proportional to the amount of coronary atherosclerotic plaque present. Intraplaque I and F infrequently were observed in the absence of EE. The significance of extravasated erythrocytes, iron, and fibrin in atherosclerotic plaques remains unclear.

Topics: Adult; Aged; Autopsy; Coronary Disease; Coronary Vessels; Erythrocytes; Female; Fibrin; Humans; Iron; Male; Middle Aged; Myocardial Infarction

Plasma fibrinogen, soluble fibrin monomer complexes (FMM) in plasma and fibrin degradation products (FDP) in serum were studied in 31 patients with acute myocardial infarction (MI) during their stay in hospital. The ECGs of 15 patients indicated a high risk of recurrent MI. Seven patients had a recurrent MI within three months. No correlation could be found between plasma fibrinogen or FMM and reinfarction, but FDP was increased in six of the seven patients with reinfarction compared to six of the 24 without (p less than 0.01).

Topics: Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Humans; Myocardial Infarction; Prospective Studies; Recurrence; Risk

The activity of the inhibitor of activated Stuart factor (anti-Xa) was evaluated together with the activity of the antiactivator of plasminogen (antiplasminogen) and the amount and nature of the fibrinogen/fibrin degradation products (FDP), as indicators of the existence of the risk for hypercoagulability in patients with acute and recent myocardial infarction (AMI and RMI, respectively). The activity of anti-Xa was diminished in the AMI group with a p less than 0.001. The antiplasminogen activity was increased in both groups with a p less than 0.001; on the other hand, the amount of FDP was increased in the AMI patients and they were of the 'early' type, while in the RMI group the increase was not as marked, but the FDP were of the 'late' type. In both groups the euglobulin lysis time was very prolonged, while the plasminogen did not vary significantly. The tests described appear to be valuable tools for studying the status of the cardiovascular system during cardiac rehabilitation.

Topics: Acute Disease; Anticoagulants; Factor X; Factor Xa; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Humans; Male; Myocardial Infarction; Plasminogen; Serum Globulins

Platelet aggregation and serotonin-release in vitro and some coagulation and fibrinolysis parameters were studied closely in 12 patients with non-complicated acute transmural myocardial infarction from the very beginning, for 3 weeks. The aggregability with ADP, epinephrine and collagen and the serotonin-release was significantly reduced the first days. Significantly increased aggregability and serotonin-release developed after a week, with peak activity on days 14-16. Most patients still exhibited increased activity at the discharge on days 21-22. Positive ethanol gelation tests developed after day 1 in most patients with a peak at day 5, contemporary with peak activities of factor VIII and negatively correlated to factor XIII activity, quantitated biologically. These values were normalized on discharge. Antithrombin III (Xa) remained unchanged, normal to slightly elevated. The fibrinolytic activity decreased after day 1 with lowest activity on day 5, contemporary with peak activity of antiplasmin. Around 50% of the patients showed decreased activity on discharge.

Topics: Adenosine Diphosphate; Adult; Aged; alpha-2-Antiplasmin; Antithrombin III; Blood Coagulation; Blood Platelets; Collagen; Epinephrine; Factor VIII; Factor XIII; Female; Fibrin; Fibrinogen; Fibrinolysis; Humans; Male; Middle Aged; Myocardial Infarction; Partial Thromboplastin Time; Serotonin; Serum Globulins; Time Factors

Topics: Adult; Aged; Female; Fibrin; Humans; Male; Middle Aged; Myocardial Infarction; Solubility

The blood content of soluble fibrin and D and E fibrinogen fragments, the protamine sulfate test and the activity of plasmin and plasminogen activator were studied in patients with macrofocal myocardial infarction. It was established that the content of soluble fibrin in blood considerably increases in the first days of the disease, and the level of products of fibrinogen D and E disintegrationand the value of the protamine sulfate test increase in the 2nd--3rd week of the disease. The appearance in the blood of fibrinogen derivates was attended by low activity of plasmin and plasminogen activator in blood. The highest content of fibrinogen derivates and low activity of plasmin and plasminogen activator were noted in patients with arrhythmias and congestive circulatory insufficiency. It is suggested that the appearance in circulation of high-molecular fibrinogen compounds is important in the development of rheological disorders.

Topics: Adult; Aged; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolysis; Humans; Male; Middle Aged; Myocardial Infarction; Plasminogen Activators; Solubility

Coronary artery bypass graft surgery has been available and widely successful for the symptomatic treatment of ischemic heart disease. Despite its widespread use, there is little information available on the pathological consequences of this procedure on the human heart. In this article, morphological consequences of coronary artery bypass graft surgery is reviewed. Intimal changes occurring within the vein graft itself consist predominately of fibrous initimal proliferation, which in some patients may progress to from an occlusive plaque. Most occlusions, however, occur at the coronary artery bypass graft anastomosis site and the mechanisms of occlusion include compression of the vascular lumen, thrombosis, and dissection of the coronary artery. Most graft failure occurs in the setting of too small a native coronary artery lumen. The myocardium is also at risk for alterations as a result of the bypass operation. Contraction band or reperfusion necrosis is the type of injury most commonly seen, and it appears to occur most often in the distribution of patent grafts. Accelerated atherosclerosis in vein grafts and the myocardial injury associated with revascularization require further detailed morphological studies, but these are important areas for pathological exploration since they bear on important and yet unanswered questions about coronary bypass surgery: can it in the long run perserve myocardium and prolong life?

Topics: Adult; Aged; Coronary Artery Bypass; Coronary Vessels; Female; Fibrin; Humans; Male; Middle Aged; Myocardial Infarction; Myocardium; Necrosis; Postoperative Complications; Saphenous Vein; Thrombosis; Time Factors; Transplantation, Autologous

Following myocardial infarction, soluble fibrin in plasma is often elevated as a sign of an activated plasmatic coagulation system. Soluble fibrin in plasma is most pronounced in shock patients under catecholamine administration. With the improvement of the clinical situation the fibrin concentration declines to normal. Following incubation with N-ethylmaleimide an increased production of prostaglandin endoperoxides is observed in the platelets of patients after myocardial infarction compared to normal platelets. Plasma of patients exhibits an endoperoxide-producing effect on normal platelets. The stimulating effect of patient plasma diminishes together with the fall of soluble plasma fibrin. These phenomena may be considered as signs of a relation between the plasmatic and thrombocytic coagulation system.

Topics: Blood Coagulation; Blood Platelets; Ethylmaleimide; Fibrin; Humans; Malondialdehyde; Myocardial Infarction; Prostaglandin Endoperoxides; Solubility

The article discusses advantages of the so-called fuchsinorrhagic method offered by Lie et al. in 1971. Areas of the necrotized muscle obtained at autopsy of 11 individuals who had died of myocardial infarction of various periods of duration, 12 biopsy specimens of the myocardium obtained during the operation for correction of congenital heart defects of the type of Fallot's tetrad and isolated defects of the septum with various periods of extracorporeal circulation and hearts of 35 male Wistar rats with a damaged myocardium (lesions being induced by intro-abdominal injection of noradrenalin in a dose of 2.5 mg/kg), which were sacrified 6 hours following the exposure to noradrenalin, were studied. The method of staining with HBFP makes it possible to detect both ischemic and noncoronarogenic lesions of the myocardium; moreover, in this method erythrocytes, fibrin, and connective structures get also stained, which makes a complex study of morphology of the myocardium feasible.

Topics: Animals; Connective Tissue; Connective Tissue Cells; Erythrocytes; Fibrin; Hematoxylin; Humans; Myocardial Infarction; Myocardium; Picrates; Rats; Rosaniline Dyes; Staining and Labeling

Topics: Chromatography, Affinity; Disseminated Intravascular Coagulation; Electrophoresis, Disc; Fibrin; Fibrinogen; Fractional Precipitation; Humans; Myocardial Infarction; Solubility

Topics: Chromatography, Affinity; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrinogen; Genital Neoplasms, Female; Humans; Myocardial Infarction; Solubility

In patients with angina pectoris and acute myocardial infarction different signs of disseminated intravascular coagulation were found, their intensity depending on the severity of the clinical course. In myocardial infarction with a complicated course and, especially, in shock signs of disseminated intravascular microthrombus formation were revealed, its criteria including, according to the author's data, reduced platelets count, factor V activity, shortening of platelets life and period of labelled fibrinogen circulation, appearance of large quantities of the fibrin-monomer complex.

Topics: Adult; Aged; Blood Coagulation; Blood Platelets; Cell Count; Cell Survival; Disseminated Intravascular Coagulation; Factor V; Female; Fibrin; Fibrinogen; Humans; Male; Middle Aged; Myocardial Infarction

Topics: Acute Disease; Alpha-Globulins; Antithrombin III; Antithrombins; Biological Assay; Blood Coagulation Tests; Disseminated Intravascular Coagulation; Fibrin; Fibrinogen; Heparin; Hexadimethrine Bromide; Humans; Liver Cirrhosis; Methods; Myocardial Infarction; Spectrophotometry; Thrombin

Compared with streptokinase, thrombolytic treatment with urokinase has the advantages of being better tolerated and of practically unlimited applicability. Its disadvantage is the high cost. A good lytic action can be obtained with a dosage of 150,000 Ploug Units/12 hours for a duration of lysis of 8-14 days combined with heparin, the therapy being monitored by determination of the products of fibrinolysis. This dosage is not possible if the time factor plays a decisive role in the success of the treatment, e.g. in myocardial infarction. Urokinase is indicated when streptokinase cannot be used, or if continuation of the streptokinase therapy is necessary because of extensive thromboses.

Topics: Adult; Costs and Cost Analysis; Drug Therapy, Combination; Endopeptidases; Female; Femoral Vein; Fibrin; Fibrinolysin; Heparin; Humans; Male; Middle Aged; Myocardial Infarction; Pelvis; Streptococcal Infections; Streptokinase; Thrombosis; Time Factors; Urokinase-Type Plasminogen Activator; Venae Cavae

The effect of temporary myocardial ischaemia (x 52 mins) and reperfusion (x 23 hrs 8 mins) on myocardial tissue fibrinolysis and 125I fibrinogen incorporation into fibrin was investigated in nine baboons. Fibrinolytic activity was reduced by 54% in the endocardium of the ischaemic reperfused myocardium and the 125I fibrinogen activity was elevated by 480%. The reduction in myocardial fibrinolytic activity following ischaemia and reperfusion may be due to endothelial damage.

Topics: Animals; Coronary Circulation; Endocardium; Fibrin; Fibrinogen; Fibrinolysis; Haplorhini; Ischemia; Myocardial Infarction; Papio

Topics: Arteriosclerosis; Blood Specimen Collection; Cardiac Catheterization; Coronary Disease; Coronary Vessels; Electric Countershock; Enzyme Activation; Enzyme Repression; Fibrin; Fibrinogen; Fibrinolysin; Fibrinolysis; Heparin; Humans; Hypertension; Myocardial Infarction; Plasminogen; Radiography

Topics: Acute Kidney Injury; Aged; Blood Coagulation Tests; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrinogen; Heparin; Humans; Kidney; Male; Middle Aged; Myocardial Infarction; Shock, Cardiogenic

Topics: Age Factors; Blood Coagulation; Blood Coagulation Tests; Fibrin; Fibrinogen; Fibrinolysis; Globulins; Humans; Leukocytes; Myocardial Infarction; Prognosis

Topics: Adult; Aged; Animals; Antibodies; Aspartate Aminotransferases; Bronchitis; Bronchopneumonia; Erythrocytes; Female; Fibrin; Fibrinogen; Humans; Injections, Intravenous; Iodine Radioisotopes; Leg; Male; Middle Aged; Myocardial Infarction; Sheep; Thrombophlebitis

Topics: Aged; Aspartate Aminotransferases; Creatine Kinase; Female; Fibrin; Fibrinogen; Humans; L-Lactate Dehydrogenase; Male; Middle Aged; Myocardial Infarction; Prognosis

Topics: Abortion, Spontaneous; Allergy and Immunology; Chorionic Gonadotropin; Decidua; Endometritis; Environment; Estriol; Estrogens; Female; Fibrin; Genetics; Hematoma; Humans; Maternal-Fetal Exchange; Myocardial Infarction; Placenta; Placenta Diseases; Pregnancy; Pregnancy, Prolonged; Staining and Labeling; Thrombosis; Trophoblasts

Topics: Age Factors; Aged; Disseminated Intravascular Coagulation; Fibrin; Fibrinogen; Humans; Iodine Isotopes; Middle Aged; Myocardial Infarction; Prognosis; Thrombosis

Topics: Animals; Assisted Circulation; Blood Cells; Blood Platelets; Cattle; Cell Adhesion; Dextrans; Erythrocytes; Fibrin; Heparin; Humans; Leukocytes; Microscopy, Electron, Scanning; Myocardial Infarction; Shock, Cardiogenic; Surface Properties; Thrombosis; Time Factors

Topics: Animals; Barbiturates; Buffers; Cattle; Chromatography, Gel; Clot Retraction; Fibrin; Fibrinogen; Fibrinolytic Agents; Humans; Hydrogen-Ion Concentration; Immune Sera; Immunoelectrophoresis; Methods; Myocardial Infarction; Phosphates; Prothrombin Time; Rabbits

Topics: Animals; Blood Coagulation; Chromatography, DEAE-Cellulose; Fibrin; Fibrinogen; Fibrinolytic Agents; Glycine; Heparin; Humans; Hydrogen-Ion Concentration; Myocardial Infarction; Peptide Hydrolases; Prothrombin Time; Rabbits; Snakes; Thrombin; Venoms

Topics: Aspartate Aminotransferases; Blood Sedimentation; Fibrin; Fibrinogen; Humans; L-Lactate Dehydrogenase; Myocardial Infarction; Time Factors

Topics: Acute Disease; Age Factors; Aged; Fibrin; Fibrinogen; Humans; Middle Aged; Myocardial Infarction; Serologic Tests; Thrombophlebitis

Topics: Aminocaproates; Animals; Blood Coagulation; Blood Coagulation Disorders; Chlorides; Densitometry; Disseminated Intravascular Coagulation; Dogs; Endotoxins; Fibrin; Fibrinogen; Fibrinolysin; Fibrinolysis; Humans; Mercury; Methods; Myocardial Infarction; Protamines; Rabbits; Sulfates; Thromboembolism

Topics: Adult; Anticoagulants; Blood Cell Count; Blood Platelets; Ethyl Biscoumacetate; Ethylestrenol; Female; Fibrin; Fibrinogen; Fibrinolysis; Fluorescent Antibody Technique; Heparin; Humans; Male; Middle Aged; Myocardial Infarction; Neutrophils; Phagocytosis; Phenformin; Phlebography; Platelet Adhesiveness; Pulmonary Embolism; Pyrazoles; Thrombophlebitis; Time Factors

Topics: Adult; Aged; Arteriosclerosis; Coronary Disease; Coronary Vessels; Fibrin; Fibrinolysis; Humans; Male; Middle Aged; Myocardial Infarction

Topics: Arrhythmias, Cardiac; Burns; Diabetic Coma; Fibrin; Fibrinogen; Heart Failure; Humans; Intensive Care Units; Lung Diseases, Obstructive; Myocardial Infarction; Poisoning; Shock, Cardiogenic; Tetanus

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

Topics: Acute Disease; Arteriosclerosis; Blood Platelets; Cardiac Output; Coronary Disease; Death, Sudden; Erythrocytes; Fibrin; Humans; Leukocytes; Myocardial Infarction

Topics: Adult; Aged; Arteriosclerosis; Autopsy; Blood Platelets; Calcinosis; Cholesterol; Coronary Disease; Coronary Vessels; Embolism; Erythrocytes; Female; Fibrin; Heart Ventricles; Hemorrhage; Humans; Leukocytes; Male; Middle Aged; Myocardial Infarction; Myocardium; Thrombosis; Time Factors

Topics: Acute Disease; Adult; Agar; Aged; Female; Fibrin; Fibrinolysis; Humans; Male; Middle Aged; Myocardial Infarction; Racial Groups

Topics: Blood Platelets; Coronary Disease; Coronary Vessels; Erythrocytes; Fibrin; Fibrinolytic Agents; Humans; Myocardial Infarction; Thrombosis

Topics: Acute Disease; Adult; Aged; Blood Coagulation Tests; Diagnosis, Differential; Female; Fibrin; Humans; Male; Middle Aged; Myocardial Infarction; Sex Factors; Shock, Cardiogenic; Time Factors

Topics: Adult; Arteriosclerosis; Coronary Disease; Diagnosis, Differential; Fibrin; Fibrinogen; Fibrinolysis; Humans; Middle Aged; Myocardial Infarction; Prognosis; Protamines; Serum Globulins

Topics: Acute Disease; Blood Coagulation Disorders; Chromatography; Fibrin; Fibrinogen; Humans; Myocardial Infarction; Thrombosis

Topics: Acute Disease; Blood Coagulation; Blood Platelets; Chronic Disease; Female; Fibrin; Fibrinolysis; Humans; Male; Myocardial Infarction; Thrombin

Topics: Anticoagulants; Blood Coagulation Disorders; Blood Vessels; Capillaries; Fibrin; Heart Massage; Humans; Kidney; Kidney Glomerulus; Lung; Myocardial Infarction; Staining and Labeling; Time Factors

Topics: Adult; Agglutination Tests; Arthritis, Rheumatoid; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Contraceptives, Oral; Erythrocytes; False Negative Reactions; False Positive Reactions; Female; Fibrin; Fibrinogen; Fibrinolysin; Fibrinolysis; Hemagglutination Inhibition Tests; Hodgkin Disease; Humans; Immunoassay; Immunodiffusion; Kidney Diseases; Liver Cirrhosis; Lymphoma, Non-Hodgkin; Male; Methods; Middle Aged; Myocardial Infarction; Neoplasms; Plasminogen; Staphylococcus

Topics: Accidents, Traffic; Adolescent; Adult; Aged; Asphyxia Neonatorum; Brain Abscess; Capillaries; Child; Child, Preschool; Fibrin; Heart Arrest; Heart Failure; Humans; Infant; Infant, Newborn; Lung; Macrophages; Meningitis; Microcirculation; Middle Aged; Myocardial Infarction; Pancreatic Diseases; Postoperative Complications; Proteins; Pulmonary Alveoli; Pulmonary Atelectasis; Pulmonary Circulation; Pulmonary Edema; Respiration, Artificial; Respiratory Insufficiency; Shock, Traumatic; Suicide; Tetanus

Topics: Adult; Aged; Angina Pectoris; Aorta; Arteriosclerosis; Coronary Disease; Female; Fibrin; Fluorescent Antibody Technique; Humans; Immune Sera; Male; Microtomy; Middle Aged; Myocardial Infarction

Topics: Adult; Female; Fibrin; Fibrinogen; Humans; Immunoassay; Myocardial Infarction; Pulmonary Embolism

Topics: Fibrin; Fibrinolysis; Fluorescent Antibody Technique; Follow-Up Studies; Humans; Myocardial Infarction; Neutrophils; Phagocytosis

Topics: Arteriosclerosis; Blood Chemical Analysis; Blood Sedimentation; Coronary Disease; Female; Fibrin; Glycoproteins; Haptoglobins; Humans; Lipoproteins; Male; Myocardial Infarction

Topics: Brain Diseases; Brain Edema; Fibrin; Kidney Cortex Necrosis; Kidney Diseases; Kidney Glomerulus; Myocardial Infarction; Necrosis; Pathology; Pulmonary Embolism; Shwartzman Phenomenon; Thrombosis

Topics: Electrocardiography; Fibrin; Fibrinolysis; Histocytochemistry; Myocardial Infarction; Pathology; Plasminogen; Rats; Research; Thrombolytic Therapy

Topics: Fibrin; Humans; Myocardial Infarction; Syndrome

Topics: Aspartate Aminotransferases; Cardiovascular Diseases; Fibrin; Myocardial Infarction; Myocardium; Potassium; Transaminases

Topics: Cardiovascular Diseases; Fibrin; Fibrinolysis; Humans; Myocardial Infarction

Topics: Blood Proteins; Blood Sedimentation; C-Reactive Protein; Fibrin; Glycoproteins; Hematologic Tests; Humans; Myocardial Infarction

Topics: Fibrin; Fibrinolysis; Humans; Myocardial Infarction; Thrombosis

Topics: Coronary Disease; Fibrin; Fibrinogen; Humans; Myocardial Infarction; Plasma