fibrin and Coronary-Thrombosis

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

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

Topics: Arteriosclerosis; Catheterization; Coronary Thrombosis; Diagnosis, Differential; Fibrin; Fibrinolytic Agents; Humans; Platelet Activation; Platelet Aggregation Inhibitors; Prognosis; Stents; Thrombolytic Therapy; Tissue Plasminogen Activator

Although heparin is widely used to treat arterial thrombosis, it has limitations in this setting. These limitations reflect heparin's inability to inactivate fibrin-bound thrombin, a major stimulus for thrombus growth, and the fact that heparin is neutralized by platelet factor 4, large quantities of which are released from platelets at the site of plaque rupture. Heparin also has a propensity to bind non-specifically to other plasma proteins. Because plasma levels of these heparin-binding proteins vary from patient to patient, the anticoagulant response to heparin is unpredictable and careful laboratory monitoring is necessary to ensure that an adequate anticoagulant effect is achieved. Direct thrombin inhibitors, such as bivalirudin and hirudin, overcome many of the limitations of heparin. These agents inhibit fibrin-bound thrombin, as well as fluid-phase thrombin. Direct thrombin inhibitors also produce a more predictable anticoagulant response than heparin because they do not bind to plasma proteins and are not neutralized by platelet factor 4. Bivalirudin appears to have a wider therapeutic window than hirudin. Because this may permit administration of higher doses of bivalirudin, this agent may also have an efficacy advantage over hirudin. Differences observed between hirudin and bivalirudin demonstrate that not all direct thrombin inhibitors have the same risk-benefit profile.

Topics: Angioplasty, Balloon, Coronary; Antithrombins; Blood Coagulation; Coronary Thrombosis; Fibrin; Humans; Platelet Activation; Platelet Factor 4; Receptors, Thrombin; Thrombolytic Therapy

Percutaneous transluminal coronary angioplasty (PTCA) is increasingly extended to patients with complex stenosis morphology or acute coronary insufficiency syndromes. Especially these patients are at high risk to suffer thrombotic complications during PTCA. Thus an effective anticoagulant regimen is of great importance during PTCA. PTCA-induced damage of the arterial wall induces the formation of a platelet-rich thrombus. After adhesion of platelets to the arterial wall further platelet aggregation is stimulated mainly by activated thrombin, followed by fibrin formation stabilizing the growing thrombus. This article describes the pathophysiologic basis of coagulation and thrombus formation during PTCA and potential targets for a therapeutic intervention. The results of clinical studies regarding the currently available antithrombotic, antiplatelet, and thrombolytic therapies are described. Furthermore, the results are reported of clinical studies of newer anticoagulant strategies such as inhibition of the platelet glycoprotein receptor GP IIb/IIIa with monoclonal antibodies and direct inhibition of activated thrombin with hirudin analogues. At present an aggressive anticoagulant regimen with heparin is recommended during the PTCA procedure. Heparin should not be continued after the intervention unless a complication during the procedure has occurred. Already before PTCA patients should receive 100 mg aspirin daily. Thrombolytic therapy during PTCA has failed to demonstrate an improvement of clinical results. Thus its use should be limited to bail-out situations. First results with hirudin analogues and GP IIb/IIIa receptor antagonists are promising. Further studies are, however, warranted before a general use can be recommended.

Topics: Angioplasty, Balloon, Coronary; Antibodies, Monoclonal; Anticoagulants; Aspirin; Blood Platelets; Coronary Thrombosis; Fibrin; Heparin; Hirudin Therapy; Hirudins; Humans; Platelet Glycoprotein GPIIb-IIIa Complex; Thrombolytic Therapy

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

Thrombosis of a coronary artery is the most common cause of myocardial infarction. Thrombolytic therapy, when instituted timely, has been shown capable of reducing morbidity and mortality. However, the use of presently available thrombolytic agents is associated with a bleeding tendency and efficacy is not optimal. This article reviews one of several lines of investigation that are presently being pursued in order to improve efficacy and specificity of thrombolytic therapy. The chemical conjugation of a fibrin specific monoclonal antibody and urokinase or tissue plasminogen activator results in markedly enhanced thrombolytic potency, both in vitro and in vivo. Specificity of the conjugates is greater than that of the parent plasminogen activators as reflected by conservation of fibrinogen, plasminogen and alpha-2 antiplasmin. A bispecific antibody, with specificity for both, fibrin and tissue plasminogen activator, has the potential of concentrating endogenous tissue plasminogen activator at the site of a thrombus. In the presence of the bispecific antibody, efficacy and specificity of tissue plasminogen activator are markedly enhanced in vitro and in vivo. The tools of molecular biology are presently being applied in order to translate these findings into better thrombolytic therapy.

Topics: Antibodies, Monoclonal; Antibody Specificity; Coronary Disease; Coronary Thrombosis; Fibrin; Humans; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator

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

We describe the internal structure, spatial organization and dynamic formation of coronary artery thrombi from ST-segment elevation myocardial infarction patients. Scanning electron microscopy (SEM) revealed significant differences among four groups of patients (<2 hours; 2-6 hours; 6-12 hours, and >12 hours) related to the time of ischemia. Coronary artery thrombi from patients presenting less than 2 hours after the infarction were almost entirely composed of platelets, with small amounts of fibrin and red blood cells. In contrast, thrombi from late presenters (>12 hours) consisted of mainly platelets at the distal end, where clotting was initiated, with almost no platelets at the proximal end, while the red blood cell content went from low at the initiating end to more than 90% at the proximal end. Furthermore, fibrin was present mainly on the outside of the thrombi and older thrombi contained thicker fibers. The red blood cells in late thrombi were compressed to a close-packed, tessellated array of polyhedral structures, called polyhedrocytes. Moreover, there was redistribution from the originally homogeneous composition to fibrin and platelets to the outside, with polyhedrocytes on the interior. The presence of polyhedrocytes and the redistribution of components are signs of in vivo clot contraction (or retraction). These results suggest why later thrombi are resistant to fibrinolytic agents and other treatment modalities, since the close-packed polyhedrocytes form a nearly impermeable seal. Furthermore, it is of particular clinical significance that these findings suggest specific disparate therapies that will be most effective at different stages of thrombus development.

Topics: Blood Coagulation; Blood Platelets; Coronary Thrombosis; Drug Resistance; Erythrocytes; Female; Fibrin; Fibrinolytic Agents; Humans; Male; Microscopy, Electron, Scanning; Middle Aged; ST Elevation Myocardial Infarction; Thrombectomy; Time Factors; Time-to-Treatment

Arterial thrombus formation is thought to be initiated by platelet adhesion to the subendothelial matrix, but ruptured atherosclerotic plaques are characterized by substantial reduction of matrix proteins compared with stable plaques. Intraplaque erythrocytes and/or fibrin have been reported in high-risk coronary plaques. The aims of the current study were to identify factors that provide scaffolds for platelets at the sites of ruptured coronary plaques and investigate depositions of iron and bilirubin as hemoglobin catabolites in the ruptured plaques. Histological characteristics of plaque components and the thrombus interface were examined in 73 acute coronary aspirated thrombi. Necrotic debris (95%), macrophages (95%), and cholesterin clefts (81%) were observed frequently at the ruptured plaque and thrombus interface. A fibrous matrix (47%), calcification (32%), and extracellular deoxyribonucleic acid (15%) were identified as small foci. Tissue factor was localized in the necrotic core and macrophages. Fibrin and von Willebrand factor were consistently deposited within the plaques and beneath platelet aggregations. The citrullinated histone H3-immunopositive area accounted for only 0.5% of the plaque area. Bilirubin and iron depositions were detected in approximately 20% of the plaques in addition to biliverdin reductase and ferritin expression in macrophages. Fibrin and von Willebrand factor rather than matrix proteins and neutrophil extracellular traps may be major adhesive molecules at the sites of ruptured plaques. Iron and bilirubin deposits may be markers for rupture-prone plaques.

Topics: Aged; Aged, 80 and over; Bilirubin; Blood Platelets; Coronary Thrombosis; Female; Fibrin; Humans; Iron; Male; Middle Aged; Plaque, Atherosclerotic; Platelet Aggregation; von Willebrand Factor

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its resultant clinical presentation, coronavirus disease 2019 (COVID-19), is an emergent cause of mortality worldwide. Cardiac complications secondary to this infection are common; however, the underlying mechanisms of such remain unclear. A detailed cardiac evaluation of a series of individuals with COVID-19 undergoing postmortem evaluation is provided, with 4 aims: (1) describe the pathological spectrum of the myocardium; (2) compare with an alternate viral illness; (3) investigate angiotensin-converting enzyme 2 expression; and (4) provide the first description of the cardiac findings in patients with cleared infection.. Study cases were identified from institutional files and included COVID-19 (n=15: 12 active, 3 cleared), influenza A/B (n=6), and nonvirally mediated deaths (n=6). Salient information was abstracted from the medical record. Light microscopic findings were recorded. An angiotensin-converting enzyme 2 immunohistochemical H-score was compared across cases. Viral detection encompassed SARS-CoV-2 immunohistochemistry, ultrastructural examination, and droplet digital polymerase chain reaction.. Male sex was more common in the COVID-19 group (. This detailed histopathologic, immunohistochemical, ultrastructural, and molecular cardiac series showed no definitive evidence of direct myocardial infection. COVID-19 cases frequently have cardiac fibrin microthrombi, without universal acute ischemic injury. Moreover, myocarditis is present in 33.3% of patients with active and cleared COVID-19 but is usually limited in extent. Histological features of resolved infection are variable. Cardiac amyloidosis may be an additional risk factor for severe disease.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme 2; Child; Child, Preschool; Coronary Thrombosis; COVID-19; Female; Fibrin; Gene Expression Regulation, Enzymologic; Humans; Immunohistochemistry; Infant; Male; Middle Aged; Myocardium; SARS-CoV-2

Topics: Biofilms; Coronary Thrombosis; Fibrin; Humans; Microscopy, Electron, Scanning; ST Elevation Myocardial Infarction; Suction; Surface Properties; Thrombectomy

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

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

Therapeutic fibrinolysis is ineffective in 40 % of ST-segment elevation acute myocardial infarction (STEMI) patients, but understanding of the mechanisms is incomplete. It was our aim to compare the composition of coronary thrombus in lysis-resistant STEMI patients with that of lysis-sensitive patients. Intracoronary thrombi (n=64) were obtained by aspiration in consecutive STEMI patients. Of them, 20 had received fibrinolysis and underwent rescue percutaneous coronary intervention (r-PCI, lysis-resistant patients) and 44 underwent primary PCI (p-PCI). Lysis-sensitivity was determined in vitro by clot permeability measurements and turbidimetric lysis in plasma of 44 patients undergoing p-PCI and 20 healthy donors. Clot-lysis sensitivity was defined as a clot-lysis time not greater than 1 SD over the mean of healthy donors. Coronary thrombus composition in 20 lysis-resistant and in 20 lysis-sensitive patients was analysed by immunofluorescence with confocal microscopy. Plasma biomarkers (P-selectin, VWF, PAI-1, t-PA, D-dimer, TF pathway markers, plasmin and CD34+) were measured simultaneously on peripheral blood. Lysis-resistant clots had higher levels of fibrin (p=0.02), P-selectin (p=0.03) and VWF (p=0.01) than lysis-sensitive clots. Among thrombi obtained ≤ 6 hours after onset of symptoms, those from lysis-resistant patients showed a higher content in fibrin than those from p-PCI patients (p=0.01). Plasma PAI-1 (p=0.02) and D-dimer levels were significantly higher (p=0.003) in lysis-resistant patients, whereas plasmin levels were lower (p=0.03). Multivariate analysis showed the content of fibrin and VWF within thrombus as predictors of thrombolysis resistance. In conclusion, coronary thrombi in STEMI patients resistant to fibrinolysis are characterised by higher fibrin, P-selectin and VWF content than lysis-sensitive thrombi.

Topics: Adult; Aged; Biomarkers; Coronary Thrombosis; Cross-Sectional Studies; Female; Fibrin; Humans; Male; Middle Aged; P-Selectin; Percutaneous Coronary Intervention; ST Elevation Myocardial Infarction; Thrombectomy; Thrombolytic Therapy; Time Factors; Treatment Failure; von Willebrand Factor

Coronary stent thrombosis is a devastating complication of percutaneous coronary intervention (PCI). Multiple factors underlie the pathophysiological mechanisms of stent thrombosis. Previous studies demonstrated that patients with stent thrombosis, compared to control PCI patients, formed denser fibrin clots in vitro which were more resistant to fibrinolysis, suggesting that altered fibrin clot properties may contribute to the pathophysiology of stent thrombosis. We assessed the plasma fibrin clot formation and fibrinolysis of patients with and without stent thrombosis.. Cases (patients with stent thrombosis) and matched controls (patients without stent thrombosis) were included for a matched case-control study. Matching was performed on indication and time of the index PCI (initial stent implantation) from the cases. Fibrin clot formation and fibrinolysis were assessed in vitro by turbidimetric assays, with human thrombin to initiate fibrin polymerization and tissue type plasminogen activator to initiate fibrinolysis. Lag time, maximal absorbance and clot lysis time were determined by these assays.. In total, 27 cases and 27 controls were included. No significant differences were observed between cases and controls in lag time (173 vs. 162s, p=0.18), maximal absorbance (0.78 vs. 0.83, p=0.36), and clot lysis time (69 vs. 71min, p=0.78). Fibrin clot formation and fibrinolysis were not associated with stent thrombosis.. Plasma fibrin clot formation and fibrinolysis were not significantly different between patients with stent thrombosis and matched control patients, suggesting that fibrin clot formation and fibrinolysis play no significant role in the pathophysiology of stent thrombosis.

Topics: Aged; Case-Control Studies; Coronary Thrombosis; Female; Fibrin; Fibrin Clot Lysis Time; Fibrinolysis; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Stents

Although it is known that in-stent restenosis (ISR) patterns appear homogeneous or nonhomogeneous by optical coherence tomography (OCT), interpretations of the ISR inflammatory response, of the OCT image, and its pathological implications are unclear. The aim of this study was to use OCT to characterize ISR and its inflammatory index in patients after coronary stenting.. OCT was performed at follow-up in 100 angiographic ISR lesions. ISR lesions were divided into two groups: (a) homogeneous (n=48) and (b) nonhomogeneous (n=52) image groups. We assessed the ISR images produced by OCT for tissue heterogeneity and neo-intimal hyperplasia using the normalized standard deviation of OCT signal-intensity (OCT-NSD) observed in neo-intimal hyperplasia tissue. In some patients with a nonhomogeneous OCT image, we collected pathological tissue.. The prevalence of drug-eluting stents was 48% in the nonhomogeneous group and 29% in the homogeneous group (P=0.05). The OCT-NSD value in the nonhomogeneous group (0.223±0.019) was significantly higher than that in the homogeneous group (0.203±0.025; P<0.0001). Pathological tissue showed fibrin thrombi with infiltrating macrophage in 12 cases of nonhomogeneous ISR. The area under the receiver operating characteristic curve for the prediction of a nonhomogeneous image was 0.73 for OCT-NSD (95% confidence interval: 0.62-0.83: P<0.0001). The odds ratio for the prediction of a nonhomogeneous image was 3.47 (95% confidence interval: 1.18-10.2: P=0.02) for smoking by logistic regression analysis.. Nonhomogeneous ISR visualized by OCT showed a high OCT-NSD value, which was a useful predictor for nonhomogeneous images. Moreover, the nonhomogeneous ISR image visualized by OCT may show chronic inflammation and fibrin thrombi.

Topics: Aged; Area Under Curve; Biomarkers; Biopsy; Chi-Square Distribution; Coronary Angiography; Coronary Restenosis; Coronary Thrombosis; Coronary Vessels; Drug-Eluting Stents; Female; Fibrin; Humans; Hyperplasia; Immunohistochemistry; Inflammation; Logistic Models; Male; Middle Aged; Multivariate Analysis; Neointima; Observer Variation; Odds Ratio; Percutaneous Coronary Intervention; Predictive Value of Tests; Prosthesis Design; Reproducibility of Results; Risk Factors; ROC Curve; Smoking; Tomography, Optical Coherence; Treatment Outcome

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

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

Cardiac lymphomas are rare, and the spectrum of pathologic features is not well defined. We encountered an unusual case of cardiac lymphoma residing within a presumed thrombus. To place such cases in context, we reviewed all cardiac lymphomas presenting to a large US cardiovascular medicine referral center during a 30-year period. A total of 14 cardiac lymphomas were identified, and these included 6 primary cardiac lymphomas (PCLs) and 8 lymphomas secondarily involving cardiac structures. Upon review, 3 of the PCLs were confirmed to be diffuse large B-cell lymphoma, not otherwise specified, involving the myocardium. The other 3 cases of PCL lacked myocardial invasion and showed lymphoma cells embedded in fibrin thrombus. Acute inflammation was not evident. These lymphomas presented in immunocompetent male individuals and involved either a prolapsed myxomatous mitral valve, a pseudomyxoma from the left atrium, or a thrombus arising in a synthetic aortic root graft. All 3 consisted of large atypical lymphocytes expressing a nongerminal center B-cell immunophenotype. Two cases were positive for Epstein-Barr virus (latency type III), but none demonstrated human herpes virus-8 latent nuclear antigen. No systemic disease was found at presentation or during follow-up. In our experience, fibrin-associated large B-cell lymphoma arising in the heart represents a substantial proportion of PCL. These lymphomas appear to represent an underrecognized variant of diffuse large B-cell lymphoma with favorable outcome. Further study is needed to understand their natural history.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Coronary Thrombosis; Epstein-Barr Virus Infections; Female; Fibrin; Heart Neoplasms; Herpesvirus 4, Human; Humans; Immunocompetence; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Myocardium; Treatment Outcome

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

Because fibrin is transparent and almost invisible by any conventional imaging methodologies, clinical examinations of coronary fibrin thrombus have been ignored, and little is known about its role in the genesis of acute coronary syndrome (ACS). The present study was performed to visualize coronary fibrin thrombus and to examine its role in ACS.. Dye-staining coronary angioscopy using Evans blue dye, which selectively stains fibrin blue but does not stain blood corpuscles, was performed for observation of globular coronary thrombi in 111 ACS patients. The thrombi were aspirated for histological examination. The thrombi were classified by visual appearance into 8 transparent, 3 light-red, 2 frosty glass-like and membranous, 32 white, 8 brown, 34 red, and 19 red-and-white in a mosaic pattern. Transparent thrombi that were not visible by conventional angioscopy were visualized as a blue structure by dye-staining angioscopy, and they were observed in patients with unstable angina (UA) and non-ST elevation myocardial infarction (NSTEMI). The thrombi caused total or subtotal coronary occlusion. The aspirated thrombi were composed of fibrin alone by histology. Fibrin-rich thrombi were visualized using dye-staining angioscopy in 60% of 50 patients with UA+NSTEMI and in 29% of 61 patients with ST-elevation myocardial infarction. By histology of the aspirated thrombi, fibrin-rich thrombi were observed in 71% of 33 patients with UA+NSTEMI and in 28% of 35 patients with ST-elevation myocardial infarction.. Fibrin-rich coronary thrombi were frequently observed by both dye-staining angioscopy and histology in ACS patients. Rarely, fibrin itself formed a globular thrombus and caused coronary occlusion.

Topics: Acute Coronary Syndrome; Aged; Angioscopy; Coloring Agents; Coronary Thrombosis; Female; Fibrin; Humans; Male; Middle Aged; Platelet Aggregation

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

We sought to test the prognostic performance of thrombus precursor protein (TpP) in patients presenting with an acute coronary syndrome (ACS).. Because thrombus formation is a critical step in the development of ACS, a measurement of activated coagulation could yield important information. Thrombus precursor protein is a biomarker that is used to measure soluble fibrin polymers, which are the penultimate products in fibrin formation.. We measured the levels of TpP in 284 healthy volunteers and in 2,349 patients with ACS.. Median TpP concentrations were 3.6 mug/ml (interquartile range 2.6 to 5.5) in the volunteers and 8.9 mug/ml (interquartile range 4.9 to 15.9) in the ACS patients (p < 0.001). Patients with ACS who had elevated TpP were older, more likely to be women, and more likely to have diabetes and pre-existing CAD (p < 0.02 for each). Thrombus precursor protein levels greater than the median were associated with a significantly increased risk for the composite of death, myocardial infarction (MI), or recurrent ischemia leading to rehospitalization or urgent revascularization through 10 months (hazard ratio [HR] 1.45, p < 0.001), as well as death or MI (HR 1.42, p = 0.02). We found that TpP correlated only weakly with cardiac troponin I, B-type natriuretic peptide, and high-sensitivity C-reactive protein (|r| <0.15 for each). After adjusting for clinical characteristics, cardiac troponin I, high-sensitivity C-reactive protein, and B-type natriuretic peptide, we found that patients with TpP levels greater than the median remained at significantly increased risk for the composite outcome (adjusted HR 1.51, p = 0.001) and death or MI (adjusted HR 1.58, p = 0.02).. In patients with ACS, increased levels of TpP are associated with an increased risk of death or ischemic complications. The incorporation of a marker of activated coagulation, such as TpP, with established cardiovascular risk factors may offer valuable complementary insight into risk assessment in ACS.

Topics: Acute Coronary Syndrome; Adult; Biomarkers; Blood Coagulation; C-Reactive Protein; Case-Control Studies; Coronary Thrombosis; Female; Fibrin; Humans; Male; Middle Aged; Myocardial Ischemia; Odds Ratio; Prognosis; Risk Assessment; Treatment Outcome; Troponin I

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

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

Haemodialysis patients are at an increased risk of cardiovascular (CV) morbidity and mortality. Both end-stage renal disease (ESRD) and thromboembolic coronary events have been shown to be associated with the formation of dense fibrin clots resistant to fibrinolysis. The aim of the present study was to investigate the effect of long-term haemodialysis on clot structure/function and analyse an influence of markers of inflammation, oxidative stress and lipoprotein(a). We sought also to investigate if clot features might be related to CV events and mortality in haemodialysis patients. Subjects and methods. In 33 patients (19 males, 14 females), aged 27 to 89 years, on long-term haemodialysis and 33 age- and sex-matched apparently healthy controls, we investigated fibrin clot properties and susceptibility to lysis using recombinant tissue plasminogen activator by using permeation and turbidity assays.. Haemodialysis patients produced fibrin clots that had less porous structure (P < 0.0001) were less susceptible to fibrinolysis (P < 0.0001), began fibrin protofibril formation more quickly (P < 0.0001) and showed increased overall fibre thickness (P < 0.0001) compared with controls. Clot permeability and lysis time correlated with F2-isoprostanes (P < 0.01), Lp(a) (P < 0.0001) and fibrinogen (P < 0.01). None of the clot variables showed associations with the duration of haemodialysis treatment or the cause of ESRD. During a 36-month follow-up, 10 CV deaths were recorded. Mortality was associated with reduced clot permeability (P < 0.0001), prolonged lysis time (P < 0.0001), faster fibrin protofibril formation (P = 0.0004), thicker fibres (P < 0.0001) and increased fibrin clot mass (P < 0.0001).. Unfavourably altered clot properties can be detected in haemodialysis patients and may be associated with increased CV mortality.

Topics: Adult; Aged; Aged, 80 and over; Blood Coagulation; Cardiovascular Diseases; Case-Control Studies; Cohort Studies; Coronary Thrombosis; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinolytic Agents; Humans; Kidney Failure, Chronic; Long-Term Care; Male; Middle Aged; Nephelometry and Turbidimetry; Permeability; Probability; Reference Values; Renal Dialysis; Risk Assessment; Statistics, Nonparametric; Survival Analysis

The present study was performed to characterize the functional properties of RGD-SAK, a novel mutant of staphylokinase (SAK). Biochemical analysis indicated that RGD-SAK maintained the similar structure and the fibrinolytic function of SAK. Measurement of platelet binding activity in vitro demonstrated that RGD-SAK had a much higher affinity with platelets than SAK. In vitro platelet-rich clot lysis assay demonstrated that the engineered mutant outperformed the non-manipulated SAK. The time required for 50% platelet-rich clot lysis was reduced significantly across different concentrations of RGD-SAK comparing with SAK. Meanwhile, RGD-SAK was found to inhibit ADP-induced platelet aggregation in a concentration-dependent manner while SAK had negligible effect on platelet aggregation. In concordance, further study in a porcine coronary balloon injury model demonstrated the efficacy of RGD-SAK for the lysis of platelet-rich coronary blood clots and for the prevention of reocclusion after thrombolysis. These results suggested that RGD-SAK may serve as a potential thrombolytic agent with platelet-targeted fibrinolysis and antiplatelet aggregation activities.

Topics: Animals; Coronary Thrombosis; Fibrin; Fibrinolysis; Humans; Metalloendopeptidases; Mutation; Plasminogen; Platelet Aggregation; Platelet Aggregation Inhibitors; Swine

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

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

The role of a hypercoagulable microvasculature in the development of cardiac allograft vasculopathy (CAV) after heart transplantation in humans is not well understood. The aim of this study was to identify an animal model by which to further evaluate the role of coagulation in the pathogenesis of CAV.. Adult male PVG (RT-1(c)) rats were transplanted into ACI (RT-1(av1)) recipients (n = 29). ACI donors into ACI recipients (n = 31) and rats with a sham operation (n = 33) served as controls. All rats received cyclosporine (10 mg/kg/day) on Days 0 to 9 after surgery. Grafts and native hearts were harvested at 10 days to 3 months after surgery. Hearts were processed for immunohistochemistry and light microscopy. A hypercoagulable microvasculature was defined as presence of microvascular fibrin and capillary antithrombin. CAV was defined as the presence of concentric intimal proliferation and chronic inflammatory infiltrate in the arterial intima, and assessed by computer-assisted image analysis.. Donor and recipient hearts from PVG-ACI rats showed high levels of fibrin (donors 7.5% to 21.9%, recipients 5.1% to 20.2%) and antithrombin (donors 5.2% to 27.9%, recipients 3.3% to 20.8%) at 10 days to 3 months post-transplant. ACI-ACI donor and recipient hearts had lower deposition of fibrin (donors 0.9% to 9.9%, recipients 0% to 4.0%) and antithrombin (donors 1.4% to 15.2%, recipients 0.8% to 4.5%). Hearts from sham-operated rats had negligible amounts of fibrin (0% to 1.5%) and antithrombin (0% to 2.8%). There was a strong association (p < 0.001) between presence of fibrin and capillary antithrombin and development of CAV.. A hypercoagulable microvasculature in a rat model of heart transplantation was associated with development of CAV, as found in humans.

Topics: Animals; Antithrombins; Capillaries; Coronary Disease; Coronary Thrombosis; Coronary Vessels; Disease Models, Animal; Fibrin; Heart Transplantation; Immunohistochemistry; Male; Microcirculation; Myocardium; Rats; Rats, Inbred Strains; Transplantation, Heterotopic; Transplantation, Homologous

The differential diagnosis of acute chest pain is challenging, especially in patients with normal ECG findings, and may include coronary thrombosis or pulmonary emboli. The aim of this study was to investigate the novel fibrin-specific contrast agent EP-2104R for molecular targeted MR imaging of coronary thrombosis and pulmonary emboli.. Fresh clots were engineered ex vivo from human blood and delivered in the lungs and coronary arteries of 7 swine. Subsequent molecular MR imaging was performed with a navigator-gated free-breathing and cardiac-triggered 3D inversion-recovery black-blood gradient-echo sequence before and after systemic administration of 7.5 micromol/kg EP-2104R. Two swine served as the control group. MR images were analyzed by 2 investigators, and contrast-to-noise ratio and gadolinium concentration in the clots were assessed. Before contrast media application, no thrombi were visible. After contrast administration, all 32 pulmonary emboli, 3 emboli in the right heart, and 5 coronary thrombi were selectively visualized as white spots with a mean contrast-to-noise ratio of 32+/-19. The average gadolinium concentration from all 3 types of thrombi was 144+/-79 micromol/L.. Molecular MR imaging with the fibrin-targeted contrast-agent EP-2104R allows selective visualization of acute coronary, cardiac, and pulmonary thrombi.

Topics: Angiography; Animals; Chest Pain; Contrast Media; Coronary Thrombosis; Diagnosis, Differential; Fibrin; Gadolinium; Humans; Magnetic Resonance Imaging; Peptides; Pulmonary Embolism; Sus scrofa; Tomography, Spiral Computed

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

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

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

The advent of fibrin-binding molecular magnetic resonance (MR) contrast agents and advances in coronary MRI techniques offers the potential for direct imaging of coronary thrombosis. We tested the feasibility of this approach using a gadolinium (Gd)-based fibrin-binding contrast agent, EP-2104R (EPIX Medical Inc), in a swine model of coronary thrombus and in-stent thrombosis.. Ex vivo and in vivo sensitivity of coronary MR thrombus imaging was tested by use of intracoronarily delivered Gd-DTPA-labeled fibrinogen thrombi (n=6). After successful demonstration, in-stent coronary thrombosis was induced by x-ray-guided placement of thrombogenic-coated, MR-lucent stents (n=5). After stent placement, 60 micromol of EP-2104R was injected via the left main coronary artery. Free-breathing, navigator-gated 3D coronary MR angiography and thrombus imaging were performed (1) before and after stent placement and (2) before and after EP-2104R. Thrombi were confirmed by x-ray angiography and autopsy. Fibrinogen thrombi: 5 of 6 intracoronarily delivered Gd-labeled fibrinogen clots (approximately 250 micromol/L Gd) were visible on MRI and subsequently confirmed by x-ray angiography. In-stent thrombi: in-stent thrombosis was observed in all stents after EP-2104R. Four of 5 thrombi were confirmed by x-ray angiography. Chemical analysis of 2 thrombi demonstrated 99 to 147 micromol/L Gd.. We demonstrate the feasibility of MRI of coronary thrombus and in-stent thrombosis using a novel fibrin-binding molecular MR contrast agent. Potential applications include detection of coronary in-stent thrombosis or thrombus burden in patients with acute coronary syndromes.

Topics: Animals; Contrast Media; Coronary Thrombosis; Coronary Vessels; Feasibility Studies; Female; Fibrin; Fibrinogen; Injections, Intra-Arterial; Magnetic Resonance Angiography; Pentetic Acid; Sensitivity and Specificity; Stents; Sus scrofa

This study evaluated the role of circulating tissue factor (TF) in mediating thrombus formation on stents in an in vitro model of stent perfusion.. The traditional view of coagulation has recently been challenged by the demonstration that TF is present in circulating blood. The potential contribution of this intravascular pool of TF to thrombus formation on stents is not known.. Coronary stents were placed in parallel silicone tubes connected to a roller pump that was set to pump blood at a flow rate of 10 ml/min. Stents were then exposed to heparinized blood from healthy volunteers for 120 min.. The presence of the stent in the circuit caused a significant increase in monocyte TF expression, but only monocytes with attached platelets stained positive for TF. Thrombi formed on stents and the thrombi stained positive for TF. Pretreatment of blood with a monoclonal antibody against TF (cH36) caused a 56% reduction in (125)I-fibrin(ogen) deposition on stents compared with controls (p = 0.002). Monocyte depletion of blood reduced (125)I-fibrin(ogen) deposition by 45% (p = 0.01) and TF staining in the thrombus by 83% (p = 0.01). Pretreatment of blood with a monoclonal antibody against P-selectin reduced (125)I-fibrin(ogen) deposition by 24% (p = 0.04). Perfusion of stents with leukocyte-reduced platelet-rich plasma (PRP) produced small thrombi and treatment of PRP with cH36 reduced (125)I-fibrin(ogen) deposition by 43% (p = 0.01).. Circulating TF plays a pivotal role in thrombus formation on stents. Monocytes appear to be the main, but not only, source of TF depositing in the thrombus.

Topics: Adult; Coronary Thrombosis; Equipment Failure Analysis; Female; Fibrin; Fibrinogen; Flow Cytometry; Humans; Immunoenzyme Techniques; In Vitro Techniques; Male; Models, Cardiovascular; Monocytes; Platelet Count; Prosthesis Design; Risk Factors; Stents; Thromboplastin

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

Disorders of hemostasis lead to vascular pathology. Endothelium-derived gene products play a critical role in the formation and degradation of fibrin. We sought to characterize the importance of these locally produced factors in the formation of fibrin in the cardiac macrovasculature and microvasculature. This study used mice with modifications of the thrombomodulin (TM) gene, the tissue-type plasminogen activator (tPA) gene, and the urokinase-type plasminogen activator (uPA) gene. The results revealed that tPA played the most important role in local regulation of fibrin deposition in the heart, with lesser contributions by TM and uPA (least significant). Moreover, a synergistic relationship in fibrin formation existed in mice with concomitant modifications of tPA and TM, resulting in myocardial necrosis and depressed cardiac function. The data were fit to a statistical model that may offer a foundation for examination of hemostasis-regulating gene interactions.

Topics: Animals; Cells, Cultured; Coronary Thrombosis; Disease Models, Animal; Endothelium, Vascular; Fibrin; Fibrosis; Genetic Predisposition to Disease; Genotype; Hemostasis; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microcirculation; Myocardium; Thrombomodulin; Tissue Plasminogen Activator; Ultrasonography; Urokinase-Type Plasminogen Activator; Ventricular Dysfunction, Left

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

Superficial and intramural thrombosis are reproducible histopathological features of the porcine coronary oversized stent injury model. Fibrin and its degradation products are chemotactic for mononuclear leukocytes, and promote the proliferation and migration of vascular smooth muscle cells (VSMC) in vitro. The goal of this study was to quantitate the serial histomorphologic evolution of thrombosis, leukocyte infiltration, VSMC proliferation and collagen accumulation following porcine coronary artery stent placement in a porcine model.. Twenty-four normocholesterolemic swine underwent oversized balloon (3.5-4.0 mm) coronary angioplasty and tantalum metal stent placement. Twenty-six different arterial sites were injured, followed by serial sacrifice at day 4 (n = 6), 8 (n = 6), 14 (n = 6), and 28 (n = 6). Quantitative analysis of the neointima was performed using a high resolution video-microscopy interface and a validated histomorphometric software program. Alpha actin-positive VSMC density (per 10(4) micro(2) neointimal area) and collagen-specific picro-sirius red fluorescence (percent of neointima) were quantitated at sites adjacent to and distant from coronary artery stent placement.. The percent of total neointimal area occupied by resolving thrombus material was greater at days 4-8 compared to 14-28 days (59-63% vs. 1-2%; P = 0.001). Mononuclear leukocytes were also significantly increased at days 4 and 8 (92 +/- 1 and 70 +/- 8%) compared to days 14-28 (both 3 +/- 3%; P = 0.001), as a percentage of the total neointimal cellularity. Total neointimal cell density did not change (20 +/- 10, 12 +/- 6, 23 +/- 7 and 20 +/- 3 cells/10(4) micro(2); P-value, NS), despite progressive cross-sectional vascular area stenosis reduction from 7 +/- 3% at day 4 to 72 +/- 14% at day 28 (P = 0.001). Percent neointimal fibrinoid thrombus content and mononuclear leukocyte cellularity were correlated in this model (R = 0.81; P < 0.001). Peri-stent neointimal collagen staining exceeded that at vascular sites distant from porcine coronary stent placement by 14 days (29 +/- 6 vs. 15 +/- 3%), and remained greater at 28 days (35 +/- 11 vs. 16 +/- 12%) (both P < 0.05).. Quantitative serial histomorphometry of porcine coronary vascular stent delivery sites demonstrates early (4-8 day) neointimal mononuclear leukocyte infiltration which is histomorphologically and temporally related to intramural fibrinoid thrombosis. Significant vascular stenosis and collagen deposition occurs by 14-28 days at these vascular injury sites. These data suggest a local interaction between thrombotic and inflammatory elements in porcine coronary neointima following oversized stent injury.

Topics: Angioplasty, Balloon; Animals; Cell Division; Cell Movement; Collagen; Coronary Thrombosis; Coronary Vessels; Disease Models, Animal; Fibrin; Leukocytes, Mononuclear; Male; Microscopy, Video; Muscle, Smooth, Vascular; Stents; Swine; Tunica Intima

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

The in vivo pharmacological profile of SK&F 106760 [N alpha-acetyl-cyclo(S,S)-cysteinyl-N alpha-methylarginyl-glycyl-aspartyl-penicillamine-amide], a novel, potent glycoprotein IIb/IIIa (GPIIb/IIIa) antagonist has been investigated. In conscious dogs, SK&F 106760 (0.3-3 mg/kg i.v.) produced a dose-related inhibition of ex vivo whole blood platelet aggregation induced by collagen (5 micrograms/ml) with complete inhibition being produced for 5, 90 and 165 min after administration of 0.3, 1 and 3 mg/kg i.v., respectively. Plasma levels of SK&F 106760 were measured by high-performance liquid chromatography after i.v. bolus administration of 1 mg/kg. An initial alpha-disposition phase with a T1/2 of 11 +/- 6 min was followed by a longer terminal beta-elimination phase with a T1/2 of 66 +/- 12 min, which accounted for 79 +/- 9% of the total area under the plasma concentration-time curve. The apparent steady-state volume of distribution was 259 +/- 26 ml/kg and the plasma clearance was 3.4 +/- 0.8 ml/min/kg. The plasma concentration of SK&F 106760 at which collagen-induced ex vivo whole blood aggregation was inhibited by 50% was estimated to be 593 +/- 52 nM. After intraduodenal and intrajejunal administration of 3 mg/kg, SK&F 106760 had a bioavailability of 3 to 6% and produced a peak inhibition of ex vivo platelet aggregation of 40 to 50%. In anesthetized dogs, SK&F 106760 (0.3-3.0 mg/kg i.v.) produced a complete inhibition of platelet-dependent coronary artery thrombosis, with a dose-related duration of action.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Platelets; Coronary Thrombosis; Dogs; Fibrin; Male; Peptides, Cyclic; Platelet Aggregation Inhibitors; Platelet Membrane Glycoproteins; Streptokinase

The present study was designed to test the hypothesis that the direct thrombin hirudin is more efficient than heparin in reducing thrombus formation after coronary stenting.. Despite aggressive anticoagulation, subacute thrombosis of coronary stents is a major complication associated with these new devices.. In 19 minipigs indium-111-labeled thrombocytes and iodine-125-labeled fibrinogen were injected 14 to 19 h before coronary implantation of tantalum balloon-expandable stents. In group 1 (n = 6, seven stents), a bolus of heparin (100 U/kg body weight) was given before stenting. Group 2 (n = 6, 11 stents) received both dextran (500 ml) and heparin (a 100-U/kg bolus followed by a continuous infusion of 50 U/kg per h). In group 3 (n = 7, 13 stents), hirudin (recombinant desulphatohirudin HV 1 [CGP 39393] [1 mg/kg]) was given before stent implantation, followed by an infusion of 1 mg/kg per h. All animals were pretreated with aspirin (250 mg intravenously).. Activated partial thromboplastin time was prolonged to > 1.8 times control values in groups 2 and 3. Histologic examination after perfusion fixation 12 h after stenting showed a variable extent of thrombus on all stents. Medial tear was observed in three stents in group 1, six stents in group 2 and six stents in group 3. The number of platelets on all stents averaged 116.2 (range 22 to 522) x 10(6) in group 1, 64.3 (range 11 to 169) x 10(6) in group 2 and 19.7 (range 9 to 38) x 10(6) in group 3 (p < 0.05 vs. group 1 and vs. group 2). The increase in platelet deposition, associated with medial tear in all groups, was lowest in the hirudin group. Similarly, fibrin deposition was lowest on stents in hirudin-treated animals.. Recombinant hirudin significantly reduces platelet and fibrin deposition on coronary stents compared with the reduction achieved with combined heparin, dextran and aspirin.

Topics: Angioplasty, Balloon, Coronary; Animals; Aspirin; Coronary Thrombosis; Dextrans; Drug Evaluation, Preclinical; Drug Therapy, Combination; Female; Fibrin; Heparin; Hirudin Therapy; Hirudins; Indium Radioisotopes; Male; Platelet Aggregation; Recombinant Proteins; Stents; Swine; Swine, Miniature; Time Factors

Although intracoronary thrombosis often occurs after angioplasty and may affect its outcome, the accuracy of arteriography for identification of mural thrombi is unclear. This study analyzed the relationship between arteriographic abnormalities immediately before death and the histologic extent of thrombosis in 77 dogs submitted to balloon injury of intact left anterior descending coronary arteries. Survival time after angioplasty was 120 min. The incidence of mural thrombosis, defined on serial histologic sections, was 65.0 percent. A positive diagnosis of intracoronary thrombus at arteriography (AT+) was based on the presence of any of the following signs: filling defects, retention of contrast material, and slowed or interrupted flow. Seventeen dogs were AT+, and 60 were AT-. The overall sensitivity of arteriography was 34 percent, and the specificity was 100 percent. Even considering as significant only thrombi greater than 25.0 percent of the arterial lumen area, 11 of 27 dogs were AT- despite thrombus sizes between 27 percent and 75 percent of lumen area (sensitivity, 59 percent); arteriography consistently missed smaller thrombi (22 of 23 dogs were AT-). Arterial diameters and balloon-induced injury were similar between AT- and AT+ dogs. Scanning electron microscopy depicted a fibrin-poor thrombus in 14 of 19 AT+ dogs and a fibrin-rich thrombus in five, whereas all seven AT+ dogs had fibrin-rich thrombi. Logistic regression analysis showed a correlation between thrombus size and arteriographic positivity, whereas the presence of fibrin and slowed flow of contrast material did not independently predict positive arteriographic results. Thus, arteriography is inaccurate for identification of mural thrombosis after angioplasty, mostly because of its poor sensitivity.

Topics: Angioplasty, Balloon, Coronary; Animals; Blood Platelets; Cineradiography; Coronary Angiography; Coronary Thrombosis; Coronary Vasospasm; Coronary Vessels; Dogs; Erythrocytes; Female; Fibrin; Fluoroscopy; Male; Microscopy, Electron, Scanning; Regional Blood Flow; Sensitivity and Specificity

Factor Xa is a central procoagulant enzyme, linking the intrinsic and extrinsic activation mechanisms to the final common pathway of coagulation. To assess its contribution to pathologic thrombosis, studies were performed in a canine coronary thrombosis model. Thrombus formation was initiated by the application of electric current via a needle electrode placed in the lumen of the left circumflex coronary artery. When 50% occlusion of the vessel developed, the current was stopped and animals received an intravenous bolus of either saline, bovine glutamyl-glycinyl-arginyl-factor Xa (Xai), a competitive inhibitor of factor Xa assembly into the prothrombinase complex, Factor X, or heparin. Animals infused with saline or factor X (300 micrograms/kg) developed total occlusion of the vessel due to a fibrin/platelet thrombus in 70 +/- 11 minutes (36 of 36 animals) and 74 +/- 13 minutes (8 of 8 animals), respectively. In contrast, infusion of Xai prevented thrombus formation completely at a dose of 300 micrograms/kg (8 of 8 animals). As the dose of Xai was decreased, its antithrombotic effect was diminished, with a patency rate of only 2 of 6 animals at a dose of 90 micrograms/kg. Xai at 300 micrograms/kg prevented the accumulation of 125I-fibrinogen/fibrin at the site of the coronary thrombus by approximately 63% and decreased deposition of 111In-labeled platelets by approximately 57%. Hemostatic parameters of animals infused with Xai demonstrated prolongation of the PT and dose-dependent increased extravascular bleeding tendency. These data indicate that factor Xa has a comparably important role in thrombus formation and extravascular hemostasis, and contrast with previous results in this same animal model in which IXai selectively prevented clotting in the coronary vasculature.

Topics: Amino Acid Sequence; Animals; Binding Sites; Blood Coagulation; Blood Platelets; Cattle; Coronary Thrombosis; Disease Models, Animal; Dogs; Factor X; Factor Xa; Factor Xa Inhibitors; Fibrin; Fibrinogen; Hemostasis; Heparin; Microscopy, Electron; Molecular Sequence Data

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

The thrombolytic properties of a novel modified human tissue plasminogen activator (E6010), in which cystein 84 in the epidermal growth factor domain is replaced by serine and that has a prolonged biological half-life, were examined. The thrombolytic efficacies of E6010 and recombinant human tissue plasminogen activator (rt-PA) on the duration of coronary artery thrombus were evaluated in a canine model (123 anesthetized dogs) with copper coil-induced left anterior descending coronary artery thrombus. Thrombi established for periods of 1, 3, or 6 h, as documented by coronary arteriography, were employed. A single bolus i.v. injection of E6010 or rt-PA and an i.v. infusion of rt-PA over 60 min were compared (n = 6). Thrombolytic efficacy was evaluated by three criteria: time to reperfusion (TR), reperfusion rate at 60 min (RR), and reocclusion rate at 60 min after reperfusion (OR). With a bolus i.v. injection of E6010 at a dose of 0.2 mg/kg or an i.v. infusion of rt-PA at a dose of 0.6 mg/kg/h, these parameters were as follows: TR, 30.0 +/- 15.3 and 27.5 +/- 4.8 min; RR, 100 and 100%; OR, 17 and 33% for 1-h aged thrombi; TR, 30.0 +/- 9.5 and 35.0 +/- 8.2 min; RR, 83 and 50%; OR, 20 and 67% for 6-h aged thrombi. These data indicate that a bolus injection of E6010 is almost equally efficacious in lysing thrombi aged both 1 and 6 h. On the other hand, in the case of rt-PA, the thrombi aged 6 h were lysed significantly less than the thrombi aged 1 h. Plasma half-lives of E6010 were t1/2 alpha, 4.8 +/- 0.95 (estimated by antigen level) and 3.0 +/- 0.78 min (estimated by activity), and t1/2 beta, 51 +/- 5.4 (antigen level) and 22 +/- 7.0 min (activity). The half-lives of rt-PA were t1/2 alpha, 3.6 +/- 0.23 (antigen level) and 2.1 +/- 0.61 min (activity), and t1/2 beta, 36 +/- 2.3 (antigen level) and 7.0 +/- 3.5 min (activity). We conclude that a bolus injection of E6010 may have a more potent and longer-lasting effect than i.v.-infused rt-PA in clot lysis therapy.

Topics: Aging; alpha-2-Antiplasmin; Amino Acid Sequence; Animals; Coronary Thrombosis; Dogs; Fibrin; Fibrinogen; Humans; Infusions, Intravenous; Injections, Intravenous; Molecular Sequence Data; Plasminogen; Recombinant Proteins; Tissue Plasminogen Activator

Since currently available thrombolytics still show disadvantages, such as administration by infusion, occurrence of intracranial hemorrhage, major hemorrhagic complications, allergic reactions, and high price, a novel tissue plasminogen activator has been developed. BM 06.022 is a t-PA mutant produced in Escherichia coli by DNA technology. It has no oligosaccharide side-chains and comprises the kringle 2- and protease domains of t-PA. Like t-PA, the enzymatic activity of BM 06.022 can be stimulated by fibrin. However, BM 06.022 binds to neither endothelial cells nor fibrin. Despite this, BM 06.022 demonstrates the same fibrin selectivity in vivo as t-PA. Investigation of the pharmacokinetic properties in rats, rabbits, dogs, and primates reveals, depending on species, a 4.5- - 10.4-fold longer dominant half-life and 3- - 8.4-fold slower plasma clearance than t-PA (alteplase). In spite of its lower specific activity in vitro, BM 06.022 has a thrombolytic potency which is 4.6 - 11.5 times higher in vivo than that of alteplase in the rabbit model of venous thrombosis and the canine model of coronary artery thrombosis. BM 06.022 achieves reperfusion significantly more rapid than long-acting anistreplase. Therefore, because of its improved pharmacokinetic properties, BM 06.022 might be administered to infarct patients by i.v. injection in the pre-hospital phase to achieve rapid lysis. Due to its lack of fibrin- and endothelial-cell-binding, combined with retained fibrin selectivity, BM 06.022 further promises to induce fewer hemorrhagic complications than either t-PA or streptokinase.

Topics: Animals; Coronary Disease; Coronary Thrombosis; Dogs; Escherichia coli; Fibrin; Fibrinolytic Agents; Humans; Mutation; Rabbits; Recombinant Proteins; Tissue Plasminogen Activator

To evaluate the thrombolytic effects of the native tissue-type plasminogen activator (t-PA), the authors used a thrombus model simulating clinical situations. The native t-PA (AK-124) was obtained from human-derived normal cells. Experimental canine coronary thrombosis was produced by partial constriction and endothelial denudation of the vessel. In 19 dogs, coronary occlusive thrombus was produced. Three hours after total occlusion of the coronary artery with thrombus, the authors attempted the thrombolytic therapy in 16 dogs. Histologically, three-hour thrombus was composed of a mixture of platelet aggregates, fibrin, and blood cells. They infused 0.375 mg/kg t-PA intravenously in 7 dogs and 20,000 IU/kg urokinase (UK) in 9. Coronary recanalization was achieved in 5 (71%) with t-PA infusion and 6 (67%) with UK infusion. Plasma fibrinogen levels decreased to 76% of preinfusion value in the dogs with t-PA infusion and to 34% in those with UK infusion. Coronary reocclusion occurred in 2 dogs with t-PA and 3 with UK. Thus, the native t-PA (AK-124) can provide coronary thrombolysis without severe depletion of plasma fibrinogen levels.

Topics: Animals; Coronary Disease; Coronary Thrombosis; Dogs; Fibrin; Fibrinogen; Humans; Platelet Aggregation; Recurrence; Tissue Plasminogen Activator; Urokinase-Type 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

Topics: Blood; Castration; Coronary Disease; Coronary Thrombosis; Fibrin; Heart; Humans; Male; Orchiectomy

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