fibrin and Endocarditis--Bacterial

Infective endocarditis is characterized by the formation of septic masses of platelets on the surfaces of heart valves and is most commonly caused by viridans streptococci. Streptococcal virulence in endocarditis involves factors that promote infectivity and pathogenicity. Adhesins and exopolysaccharide (glycocalyx) contribute to infectivity. Although many factors may contribute to pathogenicity, the platelet aggregation-associated protein (PAAP) of Streptococcus sanguis contributes directly to the development of experimental endocarditis. PAAP is synthesized as a rhamnose-rich glycoprotein of 115 kDa and contains a collagen-like platelet-interactive domain, pro-gly-glu-gln-gly-pro-lys. Expressed on the cell wall of platelet aggregation-inducing strains (Agg+) of S. sanguis, PAAP apparently interacts with a signal-transducing receptor complex on platelets, which includes a novel 175-kDa alpha 2-integrin-associated protein and a 65-kDa collagen-binding component. From available data, the role of PAAP in the pathogenesis of experimental endocarditis may be explained by a proposed mechanistic model. On injured heart valves, PAAP first enhances platelet accumulation into a fibrin-enmeshed thrombus (vegetation), within which S. sanguis colonizes. Colonizing bacteria must resist platelet microbicidal protein (PMPR). The aggregation of platelets on the heart valve may be potentiated by an ectoATPase expressed on the surface of the S. sanguis and platelet alpha-adrenoreceptors that respond to endogenous catecholamines. The expression of PAAP may be modified during infection. Collagen is exposed on damaged heart valves; fever (heat shock) occurs during endocarditis. In response to heat shock or collagen in vitro, PAAP expression is altered. After colonization, streptococcal exotoxin(s) may cause fever. Proteases and other enzymes from streptococci and host sources may directly destroy the heart valves. When PAAP is unexpressed or neutralized with specific antibodies, experimental endocarditis runs a milder course and vegetations are smaller. The data suggest strongly, therefore, that the role of PAAP may overlap the colonization function of putative adhesins such as FimA or SsaB. Finally, PAAP also contributes to the development of the characteristic septic mural thrombus (vegetation) of infective endocarditis and the signs of valvular pathology.

Topics: Adenosine Triphosphatases; Adhesins, Bacterial; Bacterial Proteins; Bacterial Toxins; beta-Thromboglobulin; Blood Platelets; Blood Proteins; Chemokines; Collagen; Endocarditis, Bacterial; Fibrin; Gene Expression Regulation; Glycoproteins; Heart Valves; Humans; Integrins; Platelet Aggregation; Polysaccharides, Bacterial; Receptors, Adrenergic, alpha; Rhamnose; Signal Transduction; Streptococcal Infections; Streptococcus; Streptococcus sanguis; Virulence

Topics: Animals; Antibodies, Bacterial; Bacteria; Blood Platelets; Coronary Disease; Endocarditis; Endocarditis, Bacterial; Endocarditis, Subacute Bacterial; Fibrin; Heart Failure; Heart Valves; Humans; Platelet Aggregation; Prognosis; Rupture, Spontaneous; Sepsis; Thrombosis

The experimental and clinical observations analyzed in this review suggest that the deposition of fibrin within glomeruli is an important pathogenic mechanism in the series of events leading to progressive destruction of glomerular capillaries. Neither the causal factors nor the consequences of this type of reaction are peculiar to the glomerulus. Fibrin deposits can occur in any injured blood vessel and, if not rapidly dealt with by fibrinolysis, will lead to endothelial changes and the development of organizing thrombi. It seems that glomerular capillaries are especially vulnerable; there are several reasons for this. First, some immunologic reactions are triggered within the glomeruli and thus produce a local inflammatory response, leading to fibrin deposition. Secondly, the glomerular filtration function allows a progressive local accumulation of potentially damaging particles, such as circulating fibrinogen derivatives (formed during generalized intravascular clotting), or phlogistic immune complexes (as a result of systemic antigen-antibody interaction); these too cause local injury and fibrin deposition. Finally, the glomerular obliteration resulting from the organization of such fibrin deposits leads to irreversible damage and so has more serious implications for the patient than if the lesions occurred elsewhere, where the formation of functionally useful new capillaries is often possible. It seems reasonable to propose, therefore, that the use of anticoagulant may be natural therapy in cases with the risk of rapid, massive, and continuous fibrin accumulation in glomeruli, where glomerular sclerosis and irreversible renal failure are likely.

Topics: Anticoagulants; Antigen-Antibody Complex; Antigen-Antibody Reactions; Basement Membrane; Blood Coagulation; Blood Coagulation Disorders; Disseminated Intravascular Coagulation; Endocarditis, Bacterial; Fibrin; Glomerulonephritis; Humans; Hyalin; Kidney Diseases; Kidney Glomerulus; Lupus Erythematosus, Systemic; Phagocytosis; Purpura

Infectious endocarditis (IE) remains one of the deadliest heart diseases with a high death rate, generally following thrombo-embolic events. Today, therapy is based on surgery and antibiotic therapy. When thromboembolic complications in IE patients persist, this is often due to our lack of knowledge regarding the pathophysiological development and organization of cells in the vegetation, most notably the primordial role of platelets and further triggered hemostasis, which is related to the diversity of infectious microorganisms involved. Our objective was to study the organization of IE vegetations due to different bacteria species in order to understand the related pathophysiological mechanism of vegetation development. We present an approach for ultrastructural analysis of whole-infected heart valve tissue based on scanning electron microscopy and energy-dispersive X-ray spectroscopy. Our approach allowed us to detect differences in cell organization between the analyzed vegetations and revealed a distinct chemical feature in

Topics: Aged; Aged, 80 and over; Blood Platelets; Endocarditis, Bacterial; Female; Fibrin; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Heart Valves; Humans; Inflammation; Male; Microscopy, Electron, Scanning; Middle Aged; Spectrometry, X-Ray Emission

The pathogenesis of endocarditis is not well understood resulting in unsuccessful attempts at prevention. Clinical observations suggest that Staphylococcus aureus infects either damaged or inflamed heart valves. Using a newly developed endocarditis mouse model, we therefore studied the initial adhesion of S. aureus in both risk states.. Using 3D confocal microscopy, we examined the adhesion of fluorescent S. aureus to murine aortic valves. To mimic different risk states we either damaged the valves with a surgically placed catheter or simulated valve inflammation by local endothelium activation. We used von Willebrand factor (VWF) gene-deficient mice, induced platelet and fibrinogen depletion and used several S. aureus mutant strains to investigate the contribution of both host and bacterial factors in early bacterial adhesion. Both cardiac valve damage and inflammation predisposed to endocarditis, but by distinct mechanisms. Following valve damage, S. aureus adhered directly to VWF and fibrin, deposited on the damaged valve. This was mediated by Sortase A-dependent adhesins such as VWF-binding protein and Clumping factor A. Platelets did not contribute. In contrast, upon cardiac valve inflammation, widespread endothelial activation led to endothelial cell-bound VWF release. This recruited large amounts of platelets, capturing S. aureus to the valve surface. Here, neither fibrinogen, nor Sortase A were essential.. Cardiac valve damage and inflammation predispose to S. aureus endocarditis via distinct mechanisms. These findings may have important implications for the development of new preventive strategies, as some interventions might be effective in one risk state, but not in the other.

Topics: Animals; Aortic Valve; Bacterial Adhesion; Blood Platelets; Coagulase; Disease Models, Animal; Endocarditis, Bacterial; Endothelium; Female; Fibrin; Inflammation; Male; Mice; Platelet Membrane Glycoproteins; Staphylococcal Infections; Staphylococcus aureus; von Willebrand Factor

Topics: Aged, 80 and over; Anti-Bacterial Agents; Catheter-Related Infections; Catheterization, Central Venous; Catheters, Indwelling; Central Venous Catheters; Device Removal; Echocardiography, Transesophageal; Endocarditis, Bacterial; Enterococcus faecalis; Female; Fibrin; Gram-Positive Bacterial Infections; Humans; Kidney Failure, Chronic; Predictive Value of Tests; Renal Dialysis; Thrombosis; Treatment Outcome

Bacterial endocarditis is a frequent infectious cardiac disease, especially in patients with congenital or acquired heart defects. It is characterized by bacterial colonization of the heart valves and the appearance of vegetations consisting of fibrin, blood cells, and bacteria. The glycoprotein Deleted in Malignant Brain Tumors 1 is a scavenger receptor cysteine-rich protein with functions in innate immunity and epithelial differentiation. Because of the aggregating capacity of Deleted in Malignant Brain Tumors 1, we hypothesized that an up-regulation in bacterial endocarditis may be linked to the development of vegetations.. Heart tissue of 19 patients with bacterial endocarditis and 10 controls without bacterial endocarditis was analyzed by immunohistochemistry. The effect of human recombinant Deleted in Malignant Brain Tumors 1 on erythrocyte aggregation was measured using an automated red blood cell aggregometer MA1. Binding of human recombinant Deleted in Malignant Brain Tumors 1 to erythrocyte membranes, platelets, fibrin, and fibrinogen was analyzed by Western blotting and enzyme-linked immunosorbent assay.. Deleted in Malignant Brain Tumors 1 expression was up-regulated in affected heart valves with bacterial endocarditis and limited to the colonizing bacteria on the heart valves and granulocyte-depleted fibrin/fibrinogen formations, and around localized atheromatosis. Patients with aggressive bacteria showed higher DMBT1 levels than patients with less aggressive bacteria. Human recombinant Deleted in Malignant Brain Tumors 1 aggregates erythrocytes and binds to erythrocyte membranes, platelets, and fibrin/fibrinogen.. Deleted in Malignant Brain Tumors 1 up-regulation at sites of bacterial endocarditis, its association with platelets and fibrin/fibrinogen, and its ability to aggregate erythrocytes through binding to their membranes indicate a potential role in the development of vegetations and thrombosis.

Topics: Adult; Aged; Aged, 80 and over; Aortic Valve; Bacteria; Blood Platelets; Calcium-Binding Proteins; DNA-Binding Proteins; Endocarditis, Bacterial; Erythrocyte Aggregation; Erythrocyte Membrane; Female; Fibrin; Fibrinogen; Humans; Immunohistochemistry; In Vitro Techniques; Male; Middle Aged; Mitral Valve; Receptors, Cell Surface; Recombinant Proteins; Tricuspid Valve; Tumor Suppressor Proteins; Up-Regulation

We adopted an in vitro infective endocarditis model (IVIEM) to compare the efficacy of vancomycin (VAN), arbekacin (ABK), and gentamicin (GEN) alone or in combination. Using two strains of clinically isolated methicillin-resistant Staphylococcus aureus, one GEN susceptible (GS171) and one GEN resistant (GR153), fibrin clots were prepared and suspended in the IVIEM. Antibiotics were given as boluses every 6 h (q6h), q12h, or q24h or by continuous infusion with VAN, q12h or q24h with ABK, and q8h or q24h with GEN. For combination treatment, VAN q12h plus ABK q24h and VAN q12h plus GEN q24h were given. Fibrin clots were removed from each model at 0, 8, 24, 32, 48, and 72 h, and the bacterial densities were determined. The number of colonies within the fibrin clot was significantly decreased in all study groups compared with control groups (P<0.001). When VAN and ABK were administered alone, the number of colonies was significantly lower in GS171 than in GR153 by 8 h after administration (P=0.02) and was lowest in GS171 when ABK was administered q12h (P=0.01). At 72 h, ABK or VAN alone produced equivalent bacterial reductions regardless of dosing frequency and GEN resistance. In GR153, VAN plus ABK showed an additive effect till 24 h, although VAN plus GEN showed indifference. Our data suggest that ABK could be used as an alternative to VAN in GEN-resistant staphylococcal endocarditis. An additive effect was seen when VAN and ABK were used together in GEN-resistant strains until 24 h; however, further studies are warranted for the clinical application of this combination.

Topics: Aminoglycosides; Anti-Bacterial Agents; Area Under Curve; Blood Coagulation; Colony Count, Microbial; Dibekacin; Drug Therapy, Combination; Endocarditis, Bacterial; Fibrin; Gentamicins; Methicillin Resistance; Microbial Sensitivity Tests; Models, Biological; Staphylococcal Infections; Staphylococcus aureus; Vancomycin

Intravascular infection with Staphylococcus aureus, Staphylococcus epidermidis, or Streptococcus sanguis can initiate fibrin formation on endocardial tissue, causing bacterial endocarditis. The ability of these bacteria to injure intact endothelial cells (ECs) and to aggravate tissue factor (TF)-dependent coagulation in the presence of blood leukocytes was investigated. Cytolysis of ECs occurred after infection with S. aureus and, with membrane-bound monocytes or granulocytes present, also after infection with S. sanguis or S. epidermidis. Monocytes that subsequently bound to the resultant bacteria-infected subcellular EC matrix (ECM) elicited TF mRNA, TF antigen, and TF activity (TFA). This was most pronounced in ECM prepared after the cytolysis of ECs by infection with S. aureus or S. epidermidis. We demonstrate that monocytes continue and intensify fibrin formation after lysis of bacteria-infected ECs, which suggests that, during the course of intravascular infection, early fibrin formation shifts from being mediated by EC-derived TFA to being mediated by TFA of monocytes bound to bacteria-infected ECM.

Topics: Blood Coagulation; Cell Adhesion; Cells, Cultured; Endocarditis, Bacterial; Endothelium, Vascular; Extracellular Matrix; Fibrin; Flow Cytometry; Gene Expression Regulation; Humans; Monocytes; Staphylococcus; Thromboplastin

Infectious endocarditis is a microbial infection of the endothelial lining of the heart that typically occurs on damaged or prosthetic heart valves. The characteristic lesion seen with infective endocarditis, termed "the vegetation," is composed of bacteria surrounded by a platelet/fibrin layer attached to the underlying endothelium. The vegetation has long been believed to exclude or hinder host defenses from clearing bacteria, although formal demonstration of mechanisms by which this occurs are lacking. This study investigated the ability of the vegetation to exclude host antibodies specific for the bacterial surface protein aggregation substance in vivo during experimental endocarditis caused by Enterococcus faecalis. The results demonstrate that, once the vegetation encloses bacteria, they are no longer accessible to high-titer bacterial-specific host antibodies, establishing a mechanism by which the vegetation functions to protect the bacteria from the humoral immune response.

Topics: Animals; Antibodies, Bacterial; Antibody Specificity; Bacterial Proteins; Bacterial Vaccines; Blood Platelets; Endocarditis, Bacterial; Enterococcus faecalis; Fibrin; Gram-Positive Bacterial Infections; Immunization; Immunohistochemistry; Rabbits

Since Staphylococcus aureus expresses multiple pathogenic factors, studying their individual roles in single-gene-knockout mutants is difficult. To circumvent this problem, S. aureus clumping factor A (clfA) and fibronectin-binding protein A (fnbA) genes were constitutively expressed in poorly pathogenic Lactococcus lactis using the recently described pOri23 vector. The recombinant organisms were tested in vitro for their adherence to immobilized fibrinogen and fibronectin and in vivo for their ability to infect rats with catheter-induced aortic vegetations. In vitro, both clfA and fnbA increased the adherence of lactococci to their specific ligands to a similar extent as the S. aureus gene donor. In vivo, the minimum inoculum size producing endocarditis in > or =80% of the rats (80% infective dose [ID80]) with the parent lactococcus was > or =10(7) CFU. In contrast, clfA-expressing and fnbA-expressing lactococci required only 10(5) CFU to infect the majority of the animals (P < 0.00005). This was comparable to the infectivities of classical endocarditis pathogens such as S. aureus and streptococci (ID80 = 10(4) to 10(5) CFU) in this model. The results confirmed the role of clfA in endovascular infection, but with a much higher degree of confidence than with single-gene-inactivated staphylococci. Moreover, they identified fnbA as a critical virulence factor of equivalent importance. This was in contrast to previous studies that produced controversial results regarding this very determinant. Taken together, the present observations suggest that if antiadhesin therapy were to be developed, at least both of the clfA and fnbA products should be blocked for the therapy to be effective.

Topics: Adhesins, Bacterial; Amino Acid Sequence; Animals; Bacterial Adhesion; Bacterial Proteins; Blood Platelets; Carrier Proteins; Coagulase; Disease Models, Animal; Endocarditis, Bacterial; Female; Fibrin; Fibrinogen; Fibronectins; Gene Expression; Humans; Lactococcus lactis; Molecular Sequence Data; Rats; Rats, Wistar; Staphylococcus aureus

In Streptococcus sanguinis (sanguis) induced experimental endocarditis, we sought evidence that the development of aortic valvular vegetation depends on the availability of fibrin. Endocarditis was induced in New Zealand white rabbits by catheter placement into the left ventricle and inoculation of the bacteria. Fibrin was localized in the developing vegetation with 99mTechnetium (Tc)-labeled anti-fibrin antibody one or three days later. When rabbit anti-fibrin antibody was given intravenously on day 1, the mass of aortic valvular vegetation was significantly reduced at day 3; infusion of non-specific rabbit IgG showed no effect. The 99mTc-labeled anti-fibrin antibody also labeled kidneys that showed macroscopic subcapsular hemorrhage. To learn if the deposition of fibrin in the kidneys was a consequence of endocarditis required a comparison of farm-bred and specific pathogen-free rabbits before and after the induction of endocarditis. Before induction, the kidneys of farm-bred rabbits were labeled, but specific pathogen-free rabbits were free of labeling and signs of macroscopic hemorrhage. After 3 days of endocarditis, kidneys of 10 of 14 specific pathogen-free rabbits labeled with 99mTc-labeled anti-fibrin antibody and showed hemorrhage. Kidney lesions were suggested to be a frequent sequellae of S. sanguinis infective endocarditis. For the first time, fibrin was shown to be required for the continued development of aortic valvular vegetations.

Topics: Animals; Antibodies; Aortic Valve; Disease Models, Animal; Endocarditis, Bacterial; Fibrin; Kidney; Rabbits; Streptococcal Infections; Streptococcus sanguis; Technetium

The model of experimental endocarditis can be used for the investigation of the different steps in the physiopathologic process leading to the formation of the infected cardiac vegetation. It has also greatly contributed to the knowledge of the characteristics of the infected vegetation. These data allow a better understanding of the therapeutic consequences (both preventive and curative) of the physiopathologic process.

Topics: Animals; Antibiotic Prophylaxis; Bacterial Adhesion; Disease Models, Animal; Endocarditis, Bacterial; Endothelium; Fibrin; Heart Valves; Humans; Rabbits; Streptococcal Infections; Streptococcus; Thrombosis

Topics: Blood Bactericidal Activity; Blood Platelets; Endocarditis, Bacterial; Fibrin; Gene Expression; Genes, Bacterial; Genetic Vectors; Humans; In Vitro Techniques; Models, Biological; Promoter Regions, Genetic; Streptococcus; Streptococcus sanguis; Virulence

The spectrum of organisms causing native valve endocarditis is changing. Despite an increasing incidence of infections caused by gram-negative organisms, they remain a rare cause of native valve endocarditis. Escherichia coli is especially uncommon. We describe the case of a 47-year-old man with no previous history of cardiac problems, who presented with culture-positive E coli endocarditis of his native aortic valve. His complicated clinical course necessitated emergent valve replacement, emphasizing the virulence of this organism. The high mortality rate and significant morbidity associated with this entity necessitates aggressive medical management and early surgical intervention.

Topics: Aortic Valve; Echocardiography; Endocarditis, Bacterial; Escherichia coli; Escherichia coli Infections; Fibrin; Humans; Male; Middle Aged; Necrosis

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 "Streptococcus milleri" (SMG) group have been shown to possess factors in vitro that may be involved in pathogenesis. All SMG strains are able to bind fibronectin via a cell-surface protein; the binding ranged from 12 to 198 mol/cell. Strains also bound to platelet-fibrin or fibrin clots and fibrinogen, giving maximum adhesion values of 16.5%, 21.8% and 151 mol/cell respectively. Members of the species S. constellatus produced thrombin-like activity. Lancefield group C SMG aggregated rat platelets, a bacterial cell-surface protein acting as mediator in the reaction. Most of the in-vitro factors did not correlate with each other, an indication that SMG strains possess a wide variety of pathogenic properties that may be involved in the production of abscesses or endocarditis. However, there was a correlation between the binding of large amounts of fibrinogen ( > 100 mol/cell) and the ability to aggregate platelets. This suggests that fibrinogen binding may aid in platelet aggregation.

Topics: Abscess; Animals; Bacterial Adhesion; Blood Platelets; Endocarditis, Bacterial; Fibrin; Fibrinogen; Fibronectins; Platelet Aggregation; Rats; Serotyping; Streptococcal Infections; Streptococcus; Surface Properties

The coagulation system plays a major role in the formation of the infected endocardial vegetation in bacterial endocarditis. Since monocytes can express tissue factor (TF) on their surfaces, they are thought to be responsible for the extrinsic activation of the coagulation cascade during this disease. The present study used an in vitro model in which fibrin plates, isolated adherent monocytes, and Streptococcus sanguis were used as an analog for endocardial vegetations. Adherence to fibrin by itself was found to stimulate TF expression on the monocytes, but stimulation by S. sanguis significantly increased TF expression, which was found to be maximal at a bacterium-to-monocyte ratio of 9 or more.

Topics: Blood Coagulation; Cell Adhesion; Endocarditis, Bacterial; Fibrin; Humans; Models, Biological; Monocytes; Streptococcus sanguis; Thromboplastin

Heterogeneous diffusion of some antibiotics into fibrin rich infectious processes is one explanation of the difficulty to cure infections such as endocarditis. Ceftriaxone is a beta lactam antibiotic, potentially useful due to a broad spectrum of activity and its long elimination half-life. We investigated by means of autoradiography the diffusion of labelled ceftriaxone into large infected cardiac vegetations obtained in a rabbit model of endocarditis. Ten d after infection 250 microCi 14C ceftriaxone was injected over 30 min. Thirty min after the end of infusion (T30) vegetation/blood radioactivity ratio was 0.58 +/- 0.4 (n = 3). At T200, radioactivity decreased approximatively 3-fold, in blood and in vegetations simultaneously. Autoradiography showed that at T30, ceftriaxone was 20-30 times more concentrated at the periphery of vegetation than in the core. Autoradiography obtained at T200 showed a progressive diffusion toward the core. The diffusion gradient may explain the fact that high local concentrations are necessary to sterilize vegetations. The pattern of diffusion of antibiotics in fibrin is an important pharmacokinetic parameter for predicting in vivo activity.

Topics: Animals; Autoradiography; Carbon Radioisotopes; Ceftriaxone; Diffusion; Drug Evaluation, Preclinical; Endocarditis, Bacterial; Extracellular Matrix; Female; Fibrin; Myocardium; Rabbits

A case of infective endocarditis which was complicated with hemorrhagic fibrinous pericarditis was reported. The hemorrhagic fibrinous pericarditis is a rare complication of infective endocarditis of the aortic root and is observed massive hemorrhage into the pericardial space. These patients should be considered for the aortic valve replacement early in the course of the disease.

Topics: Aortic Valve; Aortic Valve Insufficiency; Endocarditis, Bacterial; Fibrin; Heart Valve Prosthesis; Hemorrhage; Humans; Male; Middle Aged; Pericarditis

Topics: Adult; Aged; Aortic Valve; Bioprosthesis; Endocarditis, Bacterial; Female; Fibrin; Heart Valve Diseases; Heart Valve Prosthesis; Humans; Male; Microscopy, Electron, Scanning; Middle Aged; Mitral Valve; Postoperative Complications; Prosthesis Design; Prosthesis Failure; Thrombosis

The penetration of ceftazidime, administered in a dose of 100 mg/kg intramuscularly, into cardiac vegetations and subcutaneously implanted fibrin clots was compared in rabbits with experimental Staphylococcus aureus endocarditis. Significant pharmacokinetic differences between the time-concentration curves for the two compartments were observed. Concentrations of ceftazidime in vegetations peaked at 30 min after dosing at a level slightly lower than that in plasma and thereafter declined in parallel with concentrations in plasma throughout the 8-h sampling period. Concentrations in fibrin clots increased more slowly than those in plasma and vegetations, reaching a maximum at 120 min. This was followed by a slow elimination phase yielding concentrations in excess of concurrent plasma and vegetation levels and a greater area under the curve. These features were observed for both large (2-ml volume) and small (0.1-ml volume) clots. Contrary to previous reports, these observations suggest that fibrin clots do not provide an accurate model for predicting antibiotic concentrations in cardiac vegetations produced in endocarditis and that concentrations of antimicrobial agents in vegetations can be predicted more accurately from concomitant plasma levels.

Topics: Animals; Ceftazidime; Endocarditis, Bacterial; Female; Fibrin; Half-Life; Kinetics; Myocardium; Rabbits; Staphylococcal Infections; Time Factors

Infectious endocarditis (IE) develops following bacteremic episodes during which bacteria may attach to sterile thrombotic vegetations. Such thrombotic vegetations result from the deposition of platelets and fibrin on lesioned endothelium. These sterile vegetations are the most susceptible to infection in the left side of the heart, since this localization is found in as much as 80% of the patients with IE. Any circulating bacterial or mycotic organism may induce endocarditis, but streptococci are most often responsible, possibly because of their high capacity to adhere to thrombotic vegetations. The host cell defenses apparently cannot penetrate the dense network of platelet and fibrin in the vegetation, and humoral immunity (antibodies and complement) are of no help against gram-positive cocci. Thus, the infected vegetation has been compared to a localized agranulocytic focus, permitting the survival of infection and allowing bacteria to be released freely and continuously into the circulation (hence the constant bacteremia, a hallmark of IE). In the subacute and chronic evolution of IE, the clinical findings are mainly due to immunization of the host against the infecting microbe, resulting in antigen-antibody-complex-mediated vasculitis, and in nonspecific symptoms. Only positive blood cultures at this stage will confirm the clinical suspicion of endocarditis. Embolism may occur in any organ and falsify the diagnosis because of focal signs. Local complications of IE are the major cause of mortality in this disease, and are due to valve perforation, paravalvular abscesses, cardiac metastatic abscesses etc. If these complications occur early in the course of IE, the course may be acute.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Agranulocytosis; Endocarditis, Bacterial; Endocarditis, Subacute Bacterial; Fibrin; Humans; Platelet Aggregation; Sepsis; Streptococcal Infections; Streptococcus

Eighteen percent of heart specimens with isolated ventricular septal defect also had a floppy mitral valve. There was no statistical difference in the incidence of floppy mitral valve in the three age groups considered (less than 1 year, 1 to 16 years and 17 to 91 years). In no patient was a floppy mitral valve considered to be the cause of death. Complications of floppy mitral valve (ruptured chordae tendineae, bacterial endocarditis, mitral regurgitation and fibrin deposits at the mitral valve-left atrial angle) occurred at approximately the same frequency as that reported in autopsy studies of isolated floppy mitral valve. In the specimens with floppy mitral valve and ventricular septal defect, 63% also had floppiness of the tricuspid valve, 16% of the pulmonary valve and 5% of the aortic valve. The anatomic basis for floppy mitral valve was considered to be spongiosal invasion and disruption of the fibrosa of the valve leaflet. In this study, spongiosal invasion of the fibrosa was fully developed by 3 months of age and there was no evidence that the incidence or severity of spongiosal invasion increased between the ages of 3 months and 88 years. These data suggest that the floppy mitral valve is a congenital lesion that reaches full anatomic expression in infancy. No evidence was found that ventricular septal defect and floppy mitral valve share a common etiology.

Topics: Adolescent; Adult; Age Factors; Aged; Child; Child, Preschool; Chordae Tendineae; Endocarditis, Bacterial; Female; Fibrin; Heart Diseases; Heart Septal Defects, Ventricular; Humans; Infant; Male; Middle Aged; Mitral Valve; Mitral Valve Insufficiency; Mitral Valve Prolapse; Rupture, Spontaneous

Bacterial adherence as a result of specific surface properties may be a contributory factor in the pathogenesis of bacterial endocarditis giving certain types of bacteria a selective advantage to cause this disease. Adherence could interact with other pathogenetic mechanisms, and this interaction could promote or hamper the development of endocarditis. Dextran production by streptococci, the activation of the clotting system by monocyte tissue thromboplastin, and phagocytic removal of bacteria from the vegetational surface by granulocytes and monocytes are examples of interacting mechanisms that could contribute to the pathogenesis of bacterial endocarditis.

Topics: Adhesiveness; Animals; Aortic Valve; Bacterial Infections; Bacterial Physiological Phenomena; Dogs; Endocarditis, Bacterial; Etoposide; Fibrin; Humans; In Vitro Techniques; Mechlorethamine; Rabbits; Staphylococcus; Streptococcus; Virulence; Warfarin

Bacterial adhesion to the constituents of nonbacterial thrombotic endocarditis (NBTE) is important in the pathogenesis of endocarditis. Subinhibitory concentrations (subMIC) of some antibiotics decrease bacterial adhesion to epithelial cells in vitro. We utilized an in vitro assay system to study the effect of subMIC of various antibiotics on streptococcal adhesion to a fibrin-platelet matrix (simulating NBTE). The results were (a) bacterial adhesion of Streptococcus sanguis and Streptococcus faecalis to NBTE was significantly reduced by vancomycin, penicillin, tetracycline, chloramphenicol and streptomycin (P less than 0.01 vs. controls) but not rifampin or trimethoprimsulfametrole; (b) the effect was dose-dependent and increased with duration of exposure to antibiotic; (c) reduction in bacterial adhesion did not correlate with altered retention by hydrophobic-interaction chromatography. This reduction in adhesion correlated with a diminished capacity of subMIC exposed Streptococcus sanguis (1/4 vancomycin minimum inhibitory concentration (MIC) X 4 h) to produce endocarditis in vivo. After intravenous inoculation of 10(6) colony-forming units of preincubated organisms into rabbits with traumatized aortic valves, 6 of 22 developed endocarditis vs. 17 of 22 controls (P = 0.03). These results may be relevant to prophylaxis of endocarditis since exposure of bacteria to subMIC of various antibiotics may reduce bacterial adherence both, to mucosal surfaces, and to damaged cardiac valves.

Topics: Animals; Anti-Bacterial Agents; Blood Platelets; Endocarditis, Bacterial; Enterococcus faecalis; Fibrin; Rabbits; Streptococcus sanguis; Vancomycin

The effect of immunization with whole organisms on the development of Streptococcus pneumoniae endocarditis was examined by in vivo and in vitro methods. Immunization protected rabbits from pneumococcal endocarditis when the in vivo catheterization model was used. The inoculum size that caused endocarditis in 50% of the unimmunized rabbits was 1.1 X 10(5) colony-forming units, whereas 1.2 X 10(7) colony-forming units were required for infecting 50% of the immunized rabbits (P less than 0.001). Investigations were carried out to determine the mechanism which enabled immunization to prevent the development of pneumococcal endocarditis; they indicated that a reduction in bacterial adherence could not explain this phenomenon. In vitro studies showed that subagglutinating quantities of antibody increased the adherence (P less than 0.05) of pneumococci to rabbit aortic valve cusps. The adherence ratio of pneumococci to fibrin-platelet clots was at least doubled by the presence of subagglutinating dilutions of immune sera (P less than 0.001). Further studies showed that immunoglobulin G in the immune sera accounted for this increased in vitro adherence. However, further in vivo studies showed that immunized rabbits were able to clear live pneumococci from their bloodstreams within 4.5 h, whereas unimmunized rabbits failed to clear the organism within 24 h.

Topics: Adhesiveness; Animals; Aortic Valve; Blood Platelets; Endocarditis, Bacterial; Fibrin; Immune Sera; Immunization; Pneumococcal Infections; Rabbits; Streptococcus pneumoniae

Topics: Adhesiveness; Animals; Antibodies, Bacterial; Blood Platelets; Dextrans; Disease Models, Animal; Endocarditis, Bacterial; Fibrin; Immunization; In Vitro Techniques; Rabbits; Streptococcus sanguis

As part of a study of the development of infective endocarditis in ncarcotic addicts, we sought to establish the feasibility of using scanning electron microscopy (SEM) to view the surface characteristics of human heart valves obtained at autopsy. Normal and infected heart valves from humans and animals were obtained at autopsy, fixed in formalin, and processed for SEM. Parallel samples from immediately adjacent regions were processed for light microscopy. Active and healed endocarditis were readily recognizable by SEM, and the observations correlated well with those made by light microscopy. The advantage of SEM in the study of endocarditis is that it provides significant information about damage to the endocardial surface across the entire valve. The relative proportions of fibrin, platelets, leukocytes, exposed stromal connective tissue and bacteria on the surface of a lesion can easily be analysed. SEM may prove particularly useful in the study of the pathogenesis of the early lesions of infective endocarditis on previously "undamaged" valves.

Topics: Animals; Collagen; Endocarditis, Bacterial; Endocardium; Fibrin; Haplorhini; Heart Valves; Humans; Intercellular Junctions; Microscopy, Electron, Scanning; Staphylococcal Infections; Substance-Related Disorders

The deposition of fibrin on infected vegetations and the presence of mononuclear phagocytes that have phagocytized bacteria are remarkabe features in experimental bacterial endocarditis. In a study in vitro, we show that phagocytosis of bacteria by human monocytes enhances thromboplastin generation by these cells. Maximal enhancement of the generation of thromboplastin by monocytes was about six times compared with that in the control experiment without bacteria, and it was obtained by preincubation of the monocytes with 5 to 10 bacteria per monocyte. No quantitative difference was observed between Staphylococcus epidermidis and Streptococcus sanguis as to the enhancement of the monocyte thromboplastin generation. An enhancement of the procoagulant activity generation was also observed after addition of bacteria to human or rabbit whole blood. Probably, this generation was also due to synthesis of thromboplastin by monocytes. It is conceivable that fibrin deposition on infected vegetations during bacterial endocarditis is mediated by thromboplastin synthesis by monocytes.

Topics: Animals; Endocarditis, Bacterial; Fibrin; Humans; In Vitro Techniques; Monocytes; Phagocytosis; Protein Biosynthesis; Rabbits; Staphylococcus; Streptococcus sanguis; Thromboplastin

The fungicidal effect of amphotericin B and 5-fluorocytosine (5-FC) on fungi incorporated into blood and fibrin clots was investigated. Amphotericin B was ineffective against fungi incorporated into blood clots, but effective in the eradication of fungi in fibrin clots. 5-FC was ineffective both against fungi incorporated in blood clots as well as in fibrin clots. The combination of 5-FC and amphotericin B was likewise ineffective against fungi incorporated into blood clots. The failure of these drugs to penetrate blood clots may explain the treatment failure in fungal endocarditis.

Topics: Amphotericin B; Blood; Blood Platelets; Candida; Cytosine; Embolism; Endocarditis, Bacterial; Fibrin; Flucytosine; Humans; Models, Biological

The role of dextran in the pathogenesis of bacterial endocarditis was investigated by studying the adherence of dextran producing oral streptococci to the constituents of nonbacterial thrombotic endocarditis (NBTE) in vitro and in vivo. The adherence of Streptococcus sanguis to fibrin and platelets was determined in an in vitro assay system simulating nonbacterial thrombotic endocarditis. Adherence was increased when the organisms were grown in sucrose-supplemented media (adherence ratio X 10(4), 177 +/- 6 in 5% sucrose vs. 140 +/- 7 in 0.5% sucrose, P less than 0.001), and decreased by incubating the organisms in dextranase (adherence ratio X 10(4), 117 +/- 16, P less than 0.001), an effect which was nullified by heat inactivating this enzyme (adherence ratio X 10(4), 192 +/- 7, P less than 0.001). The amount of dextran produced in broth by three different oral streptococci correlated directly with the adherence observed to fibrin and a fibrin-platelet matrix in vitro (P less than 0.001). These organisms adhered more readily to a fibrin-platelet matrix than to fibrin alone (adherence ratio X 10(4), 455 +/- 30 vs. 177 +/- 6, respectively, P less than 0.001). The role of dextran formation was also examined in vivo in rabbits with preexisting NBTE. After injection of 10(7) S. sanguis, 12 of 17 animals developed endocarditis. In contrast, when the organisms were pretreated with dextranase (an enzyme that removes dextran from the bacterial cell surface), the same inoculum resulted in endocarditis in only 5 of 19 animals (P less than 0.05). In addition, a fresh strain of S. sanguis that produced high levels of dextran (1,220 +/- 50 microgram/ml) and adhered avidly to fibrin (adherence ratio X 10(4), 220 +/- 11) produced endocarditis in 12 of 18 rabbits after injection of 10(7) organisms. Another isolate of the same strain that had been passed repeatedly in the laboratory produced less dextran (400 +/- 30 microgram/ml), adhered poorly to fibrin (adherence ratio X 10(4), 140 +/- 7), and produced endocarditis in only 3 of 14 rabbits under identical conditions (P less than 0.05). This study demonstrates that dextran production is important in the adherence of oral streptococci to the constituents of NBTE and may play a role in the pathogenesis of bacterial endocarditis by oral streptococci.

Topics: Animals; Blood; Blood Platelets; Cell Adhesion; Dextranase; Dextrans; Endocarditis, Bacterial; Fibrin; Microscopy, Electron, Scanning; Rabbits; Streptococcus; Time Factors

The vegetations of experimental sterile and bacterial endocarditis in rabbits were studied using light, immunofluorescent and electron microscopy. At an early stage, both lesions were composed chiefly of masses of platelets supported in a scaffolding of fibrin strands. In previous studies, this structure has often been described merely as "fibrin". After i.v. injection of Thorotrast, sterile vegetations showed remarkable accumulations of mononuclear phagocytes containing this substance, on surfaces projecting into the bloodstream. Sections fixed 30 min. after i.v. injection of streptococci also showed these phagocytes, which contained large numbers of bacteria. The possibility that BE is initiated by phagocytosis of circulating bacteria has been raised. Smaller numbers of circulating streptococci reached the vegetation by direct adhesion to exposed surfaces. In contrast, a majority of Proteus and Staphylococcus albus adhered directly to vegetations, without phagocytosis. Subsequently, these first settlers multiplied rapidly to form rounded colonies surrounded by capsules of fibrin, which apparently provided protection from phagocytosis. The vegetations grew by accretion of layers of fibrin and platelets, with colonies sandwiched between them. This suggested that a cycle of thrombosis and reseeding by circulating bacteria was a factor in their growth. Colonies showed morphological changes consistent with ageing after two days. Healing occurred by endothelialisation and organisation, and was greatly accelerated by penicillin treatment.

Topics: Animals; Blood; Cell Membrane; Endocarditis, Bacterial; Fibrin; Injections, Intravenous; Leukocytes; Macrophages; Penicillins; Phagocytes; Phagocytosis; Rabbits; Streptococcus; Thorium Dioxide

Topics: Animals; Blood; Cardiac Catheterization; Endocarditis, Bacterial; Fibrin; Injections, Intravenous; Rabbits; Sepsis; Streptococcus; Time Factors

Topics: Animals; Aortic Valve; Dogs; Endocarditis, Bacterial; Fibrin; Heart Valve Prosthesis; Mitral Valve; Suture Techniques; Transplantation, Homologous; Tricuspid Valve