fibrin and Shock--Septic

A well-established development of increasing disease severity leads from sepsis through systemic inflammatory response syndrome, septic shock, multiple organ dysfunction syndrome, and cellular and organismal death. Less commonly discussed are the equally well-established coagulopathies that accompany this. We argue that a lipopolysaccharide-initiated (often disseminated intravascular) coagulation is accompanied by a proteolysis of fibrinogen such that formed fibrin is both inflammatory and resistant to fibrinolysis. In particular, we argue that the form of fibrin generated is amyloid in nature because much of its normal α-helical content is transformed to β-sheets, as occurs with other proteins in established amyloidogenic and prion diseases. We hypothesize that these processes of amyloidogenic clotting and the attendant coagulopathies play a role in the passage along the aforementioned pathways to organismal death, and that their inhibition would be of significant therapeutic value, a claim for which there is considerable emerging evidence.

Topics: Fibrin; Humans; Multiple Organ Failure; Prions; Shock, Septic

Topics: Animals; Anticoagulants; Bacteria; Bacterial Infections; Blood Coagulation; Blood Coagulation Factor Inhibitors; Blood Coagulation Factors; Fibrin; Fibrinogen; Fibrinolysis; Hemostasis; Humans; Sepsis; Shock, Septic

The authors' and literature data on the liver changes at different types of shock are summarized with consideration of the role of etiology and pathogenetic factors. Three groups of similar liver alterations reflecting the severity of impairment of the reticulo-endothelial system (RES), microcirculation and parenchyma are distinguished. No clear-cut dependence between the liver morphological changes and the severity of shock is noted. At the same time the characteristic structural alterations for some forms of shock differing at their early stages by a predominance of neuro-reflectoral, hypovolemic or toxic component are revealed. A rapidly developing hydropic degeneration, the absence of the compensatory changes, signs of the RES deficiency with the progressing necrobiotic and necrotic processes in the liver are characteristic for a neuro-reflectoral shock. Endotoxic shock is associated with widespread intravascular thrombi, liver cell necrosis, combination of the destruction of reticuloendotheliocytes with the signs of their preceding activation, foci of a smooth cytoplasmic network hyperplasia of centrolobular hepatocytes; hypovolemic shock is characterized by activation of compensatory processes.

Topics: Animals; Crush Syndrome; Disseminated Intravascular Coagulation; Energy Metabolism; Fibrin; Kupffer Cells; Liver; Microcirculation; Microscopy, Electron; Mitochondria, Liver; Pain; Phagocytosis; Platelet Aggregation; Rabbits; Rats; Shock; Shock, Hemorrhagic; Shock, Septic

Topics: Acute Disease; Animals; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Disseminated Intravascular Coagulation; Embolism, Amniotic Fluid; Female; Fetal Death; Fibrin; Fibrinogen; Fibrinolysis; Hemoglobinometry; Humans; Postpartum Hemorrhage; Pregnancy; Pregnancy Complications, Hematologic; Puerperal Disorders; Shock, Septic; Thrombin

Septic shock patients are prone to altered fibrinolysis, which contributes to microthrombus formation, organ failure and mortality. However, characterisation of the individual patient's fibrinolytic capacity remains a challenge due to a lack of global fibrinolysis biomarkers. We aimed to assess fibrinolysis in septic shock patients using a plasma-based fibrin clot formation and lysis (clot-lysis) assay and investigate the association between clot-lysis parameters and other haemostatic markers, organ dysfunction and mortality.. This was a prospective cohort study including adult septic shock patients (. Three distinct clot-lysis profiles emerged in the patients: (1) severely decreased fibrin formation (flat clot-lysis curve), (2) normal fibrin formation and lysis and (3) pronounced lysis resistance. Patients with abnormal curves had lower platelet counts (. Septic shock patients showed distinct and abnormal clot-lysis profiles that were associated with markers of coagulation and organ dysfunction. Our results provide important new insights into sepsis-related fibrinolysis disturbances and support the importance of assessing fibrinolytic capacity in septic shock.

Topics: Aged; Aged, 80 and over; Cohort Studies; Female; Fibrin; Fibrin Clot Lysis Time; Fibrinolysis; Humans; Male; Middle Aged; Shock, Septic

The histological findings in the heart in cases of fatal sepsis can show myocytolysis, interstitial fibrosis, necrotic contraction band, mononuclear infiltrates, and interstitial edema, which can be used in post mortem diagnosis of sepsis. Septic myocardial calcification is a very rare condition, and only a few cases have been reported in the literature. In general, the pathogenesis of the myocardial calcification has not been well clarified, but two pathogenic mechanisms have been universally recognized: metastatic or dystrophic. We present a rare case of sepsis-related myocardial calcification. Here we report a case involving a 72-year-old white male who was admitted to a hospital for a polytrauma caused by a motorbike accident. On the 110th day of hospitalization, the patient was diagnosed with a septic process and a subsequent transesophageal echocardiogram revealed the presence of a calcification on the right atrial wall. According to the medical history of the patient there were no systemic factors predisposing to calcium crystals deposition in tissues. Patient died due to multi-organ failure in the course of multimicrobial septic shock during the 149th day. The autopsy revealed both the presence of a greenish-brown formation and a greater consistency of the right atrial wall. The histological investigation of the right atrium wall showed a wide calcification area localized at subendocardial level, which contained fibrin deposition and was surrounded by fibrotic tissue.

Topics: Aged; Calcinosis; Fatal Outcome; Fibrin; Fibrosis; Heart Atria; Humans; Male; Multiple Organ Failure; Sepsis; Shock, Septic

Sepsis is a systemic inflammatory disorder with organ dysfunction and represents the leading cause of mortality in non-coronary intensive care units. A key player in septic shock is Tumor Necrosis Factor-alpha (TNF-α). Phospholipase (PL)D1 is involved in the regulation of TNF-α upon ischemia/reperfusion injury in mice. In this study we analyzed the impact of PLD1 in the regulation of TNF-α, inflammation and organ damage in experimental sepsis. PLD1 deficiency increased survival of mice and decreased vital organ damage after LPS injections. Decreased TNF-α plasma levels and reduced migration of leukocytes and platelets into lungs was associated with reduced apoptosis in lung and liver tissue of PLD1 deficient mice. PLD1 deficient platelets contribute to preserved outcome after LPS-induced sepsis because platelets exhibit an integrin activation defect suggesting reduced platelet activation in PLD1 deficient mice. Furthermore, reduced thrombin generation of PLD1 deficient platelets might be responsible for reduced fibrin formation in lungs suggesting reduced disseminated intravascular coagulation (DIC). The analysis of Pld1

Topics: Animals; Apoptosis; Blood Platelets; Cell Movement; Cells, Cultured; Disease Models, Animal; Fibrin; Immunity, Innate; Inflammation; Leukocytes; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Phospholipase D; Platelet Activation; Shock, Septic; Tumor Necrosis Factor-alpha

Sepsis induces hypercoagulability, hypofibrinolysis, microthrombosis, and endothelial dysfunction leading to multiple organ failure. However, not all studies reported benefit from anticoagulation for patients with severe sepsis, and time courses of coagulation abnormalities in septic shock are poorly documented. Therefore, the aim of this prospective observational cohort study was to describe the coagulation profile of patients with septic shock and to determine whether alterations of the profile are associated with hospital mortality.. Thirty-nine patients with septic shock on ICU admission were prospectively included in the study. From admission to day 7, analytical coagulation tests, thrombin generation (TG) assays, and thromboelastometric analyses were performed and tested for association with survival.. Patients with septic shock presented on admission prolongation of prothrombin time, activated partial thromboplastin time (aPTT), increased consumption of most procoagulant factors as well as both delay and deficit in TG, all compatible with a hypocoagulable state compared with reference values (P < 0.001). Time courses revealed a persistent hypocoagulability profile in non-survivors as compared with survivors. From multiple logistic regression, prolonged aPTT (P = 0.007) and persistence of TG deficit (P = 0.024) on day 3 were strong predictors of mortality, independently from disease severity scores, disseminated intravascular coagulation score, and standard coagulation tests on admission.. Patients with septic shock present with hypocoagulability at the time of ICU admission. Persistence of hypocoagulability assessed by prolonged aPTT and unresolving deficit in TG on day 3 after onset of septic shock is associated with greater hospital mortality.

Topics: Aged; Anticoagulants; Antithrombin III; Blood Coagulation Disorders; Blood Coagulation Factors; Female; Fibrin; Hospital Mortality; Humans; Intensive Care Units; Logistic Models; Longitudinal Studies; Male; Middle Aged; Partial Thromboplastin Time; Prospective Studies; Protein C; Prothrombin Time; Shock, Septic; Thrombin

Gram-negative sepsis is accompanied by a disproportionate innate immune response and excessive coagulation mainly induced by endotoxins released from bacteria. Due to rising antibiotic resistance and current lack of other effective treatments there is an urgent need for new therapies. We here present a new treatment concept for sepsis and endotoxin-mediated shock, based on host defense peptides from the C-terminal part of human thrombin, found to have a broad and inhibitory effect on multiple sepsis pathologies. Thus, the peptides abrogate pro-inflammatory cytokine responses to endotoxin in vitro and in vivo. Furthermore, they interfere with coagulation by modulating contact activation and tissue factor-mediated clotting in vitro, leading to normalization of coagulation responses in vivo, a previously unknown function of host defense peptides. In a mouse model of Pseudomonas aeruginosa sepsis, the peptide GKY25, while mediating a modest antimicrobial effect, significantly inhibited the pro-inflammatory response, decreased fibrin deposition and leakage in the lungs, as well as reduced mortality. Taken together, the capacity of such thrombin-derived peptides to simultaneously modulate bacterial levels, pro-inflammatory responses, and coagulation, renders them attractive therapeutic candidates for the treatment of invasive infections and sepsis.

Topics: Animals; Blood Coagulation; Cytokines; Disease Models, Animal; Endotoxins; Escherichia coli; Fibrin; Flow Cytometry; Humans; Inflammation; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Microscopy, Electron, Scanning; Peptides; Pseudomonas aeruginosa; Sepsis; Shock, Septic; Thrombin

Topics: Adult; Aged; Aged, 80 and over; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Humans; Male; Middle Aged; Shock, Septic; Young Adult

Platelet activation contributes to microvascular thrombosis and organ failure in systemic inflammation. We tested the hypothesis whether anti-platelet drugs might favourably affect outcome in patients at risk for organ failure as well as in a mouse model of endotoxin shock. Two hundred twenty-four consecutive patients who were admitted for community acquired pneumonia over a time period of 5 years to a University Hospital were enrolled; about 20% of whom received anti-platelet drugs (acetylsalicylic acid, thienopyridines) for secondary prevention of cardiovascular disease. Patients with anti-platelet drugs were about 12 years old but did not differ in SOFA score and routine laboratory parameters at admission. Logistic regression and 2 x 2 table analysis in age-matched subgroups indicated that anti-platelet drugs may reduce the need of intensive care treatment (odds ratio (OR) 0.32 [95% confidential interval: 0.10-1.00] and 0.19 [0.04-0.87], respectively). In age-matched subgroups, the use of anti-platelet drugs was also associated with a shorter stay in hospital (13.9 +/- 6.2 vs. 18.2 +/- 10.2 days; p < 0.02). In the animal model Balb/c mice were pre-treated with clopidogrel (added to drinking water) for 4 days prior to intraperitoneal (i.p.) administration of endotoxin (lipopolsaccharide (LPS) from Escherichia coli 0111:B4). Within the first 48 hours after LPS there were no differences between clopidogrel and control animals (n = 26 each) in macro-haemodynamics. However, clopidogrel abolished the LPS-induced drop in platelet count and reduced fibrin deposition in lung tissue. Using DNA microarray technology, we could show that clopidogrel suppressed endotoxin-induced up-regulation of inflammation-relevant genes, including arachidonate-5-lipoxygenase activating protein and leukotriene B4 receptor 1. According to our data a possible benefit of anti-platelet drugs in patients on risk for systemic inflammation and organ failure should be tested in a prospective trial.

Topics: Adult; Aged; Animals; Cell Line; Clopidogrel; Female; Fibrin; Gene Expression Profiling; Hemodynamics; Humans; Infections; Intensive Care Units; Length of Stay; Leukocytes; Lung; Male; Mice; Mice, Inbred BALB C; Middle Aged; Oligonucleotide Array Sequence Analysis; Platelet Activation; Platelet Aggregation Inhibitors; Pneumonia; Retrospective Studies; Shock, Septic; Ticlopidine

To unravel the strategy by which Brucella abortus establishes chronic infections, we explored its early interaction with innate immunity.. Brucella did not induce proinflammatory responses as demonstrated by the absence of leukocyte recruitment, humoral or cellular blood changes in mice. Brucella hampered neutrophil (PMN) function and PMN depletion did not influence the course of infection. Brucella barely induced proinflammatory cytokines and consumed complement, and was strongly resistant to bactericidal peptides, PMN extracts and serum. Brucella LPS (BrLPS), NH-polysaccharides, cyclic glucans, outer membrane fragments or disrupted bacterial cells displayed low biological activity in mice and cells. The lack of proinflammatory responses was not due to conspicuous inhibitory mechanisms mediated by the invading Brucella or its products. When activated 24 h post-infection macrophages did not kill Brucella, indicating that the replication niche was not fusiogenic with lysosomes. Brucella intracellular replication did not interrupt the cell cycle or caused cytotoxicity in WT, TLR4 and TLR2 knockout cells. TNF-alpha-induction was TLR4- and TLR2-dependent for live but not for killed B. abortus. However, intracellular replication in TLR4, TLR2 and TLR4/2 knockout cells was not altered and the infection course and anti-Brucella immunity development upon BrLPS injection was unaffected in TLR4 mutant mice.. We propose that Brucella has developed a stealth strategy through PAMPs reduction, modification and hiding, ensuring by this manner low stimulatory activity and toxicity for cells. This strategy allows Brucella to reach its replication niche before activation of antimicrobial mechanisms by adaptive immunity. This model is consistent with clinical profiles observed in humans and natural hosts at the onset of infection and could be valid for those intracellular pathogens phylogenetically related to Brucella that also cause long lasting infections.

Topics: Animals; Bacteremia; Blood Coagulation; Brucella abortus; Brucellosis; Fibrin; Fibrinogen; Immunity, Innate; Leukocytes; Mice; Neutrophils; Platelet Aggregation; Sepsis; Shock, Septic

Topics: Animals; Disease Models, Animal; Fibrin; Fibrinolytic Agents; Humans; Lipopolysaccharides; Protein C; Pulmonary Alveoli; Shock, Septic; Swine

Topics: Anticoagulants; Enzyme Activation; Fibrin; Half-Life; Heparin; Humans; Meningococcal Infections; Protein C; Shock, Septic

The effects of a monoclonal antibody (mAb) to tumor necrosis factor-alpha (TNF-alpha) were examined in a rabbit model of endotoxic shock. Intravenous administration of lipopolysaccharide (100 microg/kg/hr) for 6 hours (n = 11) increased TNF-alpha levels. Fibrinogen was partially consumed, and fibrin deposits were seen in kidney and lungs at 24 hours. Mortality at 24 hours was 64%. Levels of interleukin-8 (aka CXCL-8) were notably increased. Mean arterial pressure (MAP) and leukocyte counts decreased, whereas creatinine levels were enhanced. The anti-TNF-alpha mAb (20 mg/kg i.v. bolus + 5 mg/kg/h i.v. for the first 90 minutes) (n = 10) efficiently inhibited the TNF-activity. Rabbits exhibited lower CXCL-8 levels; MAP improved, the decrease in leukocyte counts was partially prevented and creatinine levels were lower, but fibrinogen, fibrin deposits in kidneys and lungs and mortality, 55%, were similar to the LPS group. Rabbits that did not survive exhibited lower fibrinogen levels, more fibrin in kidneys and lungs and higher CXCL-8 and creatinine levels than survivors, while there were no differences in TNF-alpha, MAP and leukocytes. Thus, the inhibition of TNF-alpha, although beneficial through lowering CXCL-8 levels, is not enough to improve the outcome, which could be partly due to the inability to prevent the fibrin deposits formation in kidneys and lungs.

Topics: Animals; Antibodies, Monoclonal; Blood Pressure; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Fibrin; Fibrinogen; Interleukin-8; Kidney; Leukocytes; Lipopolysaccharides; Lung; Male; Rabbits; Shock, Septic; Survival Rate; Tumor Necrosis Factor-alpha

Activated protein C has recently been shown in a multicentre trial to significantly reduce mortality in patients with septic shock. There are also some case reports and minor studies demonstrating promising results with the unactivated form of protein C. However, in children with severe meningococcal infection, skin biopsies have demonstrated low expression of endothelial thrombomodulin and protein C receptors, suggesting low protein C activation capacity in severe meningococcal sepsis.. A patient with meningococcal septic shock was treated with two doses of the unactivated form of protein C, the first during intense activation of the coagulation system and the second during a phase of low grade or no activation. Repeated plasma samples were analysed for protein C concentration, which made it possible to compare pharmacokinetics and half-lives of the two administrations. A shorter half-life during intense coagulation was expected if there was an activation and consumption of the protein C administered.. The calculated half-lives of protein C during intense and low grade activation were 32 h and 19 h, respectively, a magnitude similar to that reported in protein C-deficient patients without infection.. The result indicates that whole body utilisation of the unactivated protein C was low. Endothelial impairment of protein C activation does not seem to be restricted to the skin vessels only.

Topics: Adult; Anticoagulants; Blood Coagulation Factors; Disseminated Intravascular Coagulation; Female; Fibrin; Half-Life; Humans; Meningococcal Infections; Protein C; Shock, Septic

Hemorrhagic shock due to major trauma predisposes to the development of acute respiratory distress syndrome. Because lung fibrin deposition is one of the hallmarks of this syndrome, we hypothesized that resuscitated shock might predispose to the development of a net procoagulant state in the lung. A rodent model of shock/resuscitation followed by low-dose intratracheal lipopolysaccharide (LPS), a clinically relevant "two-hit" model, was used to test this hypothesis. Resuscitated shock primed the lungs for an increased tissue factor and plasminogen activator (PA) inhibitor-1 gene expression in response to LPS, while the fibrinolytic PA was reduced. These alterations were recapitulated in isolated alveolar macrophages, suggesting their role in the process. LPS-induced tumor necrosis factor (TNF) was also augmented in animals after antecedent shock/resuscitation, and studies using anti-TNF antibodies revealed that TNF expression was critical to the induction of the procoagulant molecules and the reduction in PA. By contrast, TNF did not appear to play an important role in neutrophil sequestration in this model, inasmuch as anti-TNF had no effect on lung neutrophil accumulation or chemokine expression. However, treatment prevented albumin leak by preventing alveolar neutrophil activation. The inclusion of the antioxidant N-acetyl-cysteine in the resuscitation fluid resulted in prevention of both the development of the net procoagulant state and lung neutrophil sequestration, suggesting a role for upstream oxidant effects in the priming process. These studies provide a cellular and molecular basis for lung fibrin deposition after resuscitated shock and demonstrate a divergence of pathways responsible for fibrin generation and neutrophil accumulation.

Topics: Acetylcysteine; Animals; Antioxidants; Blood Coagulation Disorders; Bronchoalveolar Lavage Fluid; Capillary Leak Syndrome; Disseminated Intravascular Coagulation; Fibrin; Fibrinolysis; Gene Expression Regulation; Lipopolysaccharides; Lipoproteins; Macrophage Activation; Macrophages, Alveolar; Male; Models, Biological; Neutrophils; NF-kappa B; Oxidative Stress; Plasminogen Activator Inhibitor 1; Pulmonary Alveoli; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Respiratory Distress Syndrome; Shock, Hemorrhagic; Shock, Septic; Thromboplastin; Transcription, Genetic; Tumor Necrosis Factor-alpha

To assess the effect of a combined antithrombin III and C1-esterase inhibitor treatment on intravascular organ fibrin deposition and cardiorespiratory changes following intravenous Escherichia coli endotoxin (lipopolysaccharide [LPS] 80 microg/kg i.v.) exposure.. Prospective, randomized trial.. Research laboratory of a university medical center.. Anesthetized, instrumented and mechanically ventilated rabbits ([Chbb:CH); n = 40).. Endotoxin was given to 30 animals. Ten animals received no inhibitor (endotoxin control group). The other animals were either treated by high-dose (300 units/kg; n = 10) or low-dose (100 units/kg; n = 10) combined antithrombin III and C1-esterase inhibitor administration. Ten rabbits (time control group) were given placebo (sodium chloride 0.9%). Cardiorespiratory variables were assessed at baseline, 120 mins, and 240 mins after endotoxin or placebo administration. Four hours after endotoxin injection, liver, lung, and kidney tissue samples were examined for intravascular fibrin deposition by light microscopy.. Inhibitor treatment significantly decreased clot formation in lungs and livers without, however, demonstrating a clear dose-dependent effect. Combined antithrombin III/C1-esterase treatment attenuated the decrease of mean arterial pressure and cardiac output observed following endotoxin injection. Blood pressure improvement was significantly dependent on dosage administered.. Combination of antithrombin III and C1-esterase inhibitor treatment during early endotoxin shock decreased organ fibrin deposition and improved cardiovascular stability.

Topics: Animals; Antithrombin III; Antithrombins; Complement C1 Inactivator Proteins; Disseminated Intravascular Coagulation; Dose-Response Relationship, Drug; Drug Combinations; Endotoxins; Escherichia coli Infections; Fibrin; Hemodynamics; Infusions, Intravenous; Injections, Intravenous; Leukocyte Count; Male; Rabbits; Random Allocation; Shock, Septic

Previous work has shown that pre-treatment with the thrombin inhibitor recombinant desulfato-hirudin prevented fibrin formation and respiratory dysfunction in porcine lipopolysaccharide shock. We examined the effects of delayed administration of recombinant desulfato-hirudin in bacterial lipopolysaccharide shock. Miniature pigs were studied under anaesthesia and ventilation, and received a bacterial lipopolysaccharide infusion (2 microg/kg/h) for 7 h; recombinant desulfato-hirudin was started 1 h after bacterial lipopolysaccharide in 10 animals (bolus 12.9 nmol/kg; continuous infusion 6.5 nmol/ kg/h); 10 randomised control animals received saline instead of recombinant desulfato-hirudin. Fibrin and thrombin-antithrombin complex levels in plasma were significantly lower in bacterial lipopolysaccharide+recombinant desulfato-hirudin animals than in controls. Both groups displayed a similar rise in pulmonary vascular resistance and other parameters of lung dysfunction; only lung tissue wet/dry ratio was lower in recombinant desulfato-hirudin-treated than in control animals. Both groups had similar circulatory alterations. Recombinant desulfato-hirudin interrupted coagulation activation during ongoing bacterial lipopolysaccharide-induced shock in pigs even when administered with a delay of one hour after start of the bacterial lipopolysaccharide infusion. A protective effect of delayed recombinant desulfato-hirudin administration on bacterial lipopolysaccharide-induced acute lung injury and alterations in the systemic circulation could not be demonstrated in this experiment.

Topics: Animals; Ascites; Cardiovascular System; Fibrin; Fibrinolytic Agents; Hirudin Therapy; Hirudins; Kidney; Lipopolysaccharides; Lung; Peritoneal Cavity; Recombinant Proteins; Shock, Septic; Swine; Swine, Miniature; Time Factors

The present study compared the activities of recombinant tissue-type plasminogen activator (t-PA) and a plasminogen activator inhibitor-1 (PAI-1)-resistant variant t-PA (Kt-PA, KHRR 296-299 AAAA) in preventing renal fibrin deposition in rabbits with elevated PAI-1 activity. In this model, all rabbits were infused with endotoxin (10 micrograms/kg), followed by initiation of thrombin (130 U/kg) 4 hours later, when plasma PAI-1 activity was greater than 200 arbitrary units (AU)/mL (baseline, < 3 AU/mL). Thirty minutes after completion of the 1-hour thrombin infusion, rabbits were killed and the kidneys fixed and stained for identification of fibrin deposition. Rabbits received one of the following treatments initiated 30 minutes before thrombin and continued during the 1-hour thrombin infusion: (1) saline (n = 7); (2) low-dose t-PA (17 micrograms/kg, n = 4); (3) higher-dose t-PA (170 micrograms/kg, n = 4); or (4) low-dose Kt-PA (17 micrograms/kg, n = 6). Fibrin deposition occurred in 86% and 100% of the rabbits receiving saline or low-dose t-PA, respectively. Fibrin deposition did not occur in any of the rabbits receiving low-dose Kt-PA or higher-dose t-PA. Low-dose Kt-PA and higher dose t-PA also caused a reduction in fibrin deposition when infused after thrombin administration had been completed. The data provide in vivo evidence that Kt-PA is more effective than t-PA in preventing fibrin deposition in an animal model that combines thrombogenic stimulation with increased PAI-1 activity.

Topics: Animals; Binding Sites; Endotoxins; Fibrin; Fibrinolytic Agents; Kidney; Mutagenesis, Site-Directed; Plasminogen Activator Inhibitor 1; Rabbits; Shock, Septic; Thrombin; Tissue Plasminogen Activator

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

Tissue factor pathway inhibitor (TFPI) plays a key role in modulating tissue factor-dependent blood coagulation. This study was done to determine not only the inhibitory effects of recombinant human TFPI (rTFPI) on thrombus formation in rat models with disseminated intravascular coagulation (DIC), but also to identify the distribution of exogenous TFPI in vivo. Disseminated intravascular coagulation was induced by administering a priming dose of carrageenan 10 mg/kg body weight and was followed 24 hours later by a provocative dose of lipopolysaccharide (LPS) 500 mg/kg body weight. The rTFPI was administered intravenously at a dose of either 1 or 4 mg/kg body weight immediately after LPS treatment. Exogenous rTFPI at a dose of 4 mg/kg significantly inhibited the consumption of fibrinogen, platelets and factor VIIa (P < .05) and also reduced the number of fibrin thrombi formed in the liver, lungs, kidneys, and spleen (P < .05), whereas rTFPI at a dose of 1 mg/kg had no significant inhibitory effect on these DIC parameters. Recombinant human rTFPI activity was rapidly cleared from the plasma; however, a significant amount of the inhibitor was still present in tissues even 3 to 6 hours after intravenous administration. Exogenous TFPI was mainly identified in Kupffer cells, macrophages, and on the microvascular endothelial lining of different organs. In the kidney, rTFPI was identified on both the abluminal surface of the renal tubules and the luminal surface of the proximal convoluted tubules. No rTFPI, however, was detected in the hepatocytes. Tissue factor was mainly expressed by monocytes/macrophages. These findings suggest that TFPI plays an important role in modulating TF-dependent thrombogenesis. The elucidation of the rTFPI distribution and interactions in vivo might thus provide valuable insight into its inhibitory mechanisms as well as its therapeutic implications in DIC.

Topics: Animals; Anticoagulants; Carrageenan; Disease Models, Animal; Disseminated Intravascular Coagulation; Fibrin; Humans; Immunohistochemistry; Lipoproteins; Male; Rats; Rats, Wistar; Recombinant Proteins; Shock, Septic; Survival Rate; Thromboplastin; Thrombosis; Tissue Distribution

The dissolution by the fibrinolytic agent saruplase of microthrombi due to disseminated intravascular coagulation (DIC) has been studied in anesthetized rats. The intravenous infusion of E. coli lipopolysaccharide (endotoxin) for 4 hours (total dose: 25 mg/kg) induced marked thrombocytopenia and hypofibrinogenemia. DIC-related microthrombosis, detected as increased deposition of 125I-labelled human fibrin, was found in the liver and the kidneys, but not in the lungs, the heart, the mesenterium, the spleen and the M. rectus abdominis of endotoxemic rats. Treatment with 1-20 micrograms/kg.min saruplase, that was infused concomitantly with endotoxin, dose-dependently and significantly reduced endotoxin-induced microthrombosis in the liver and the kidneys by 85 resp. 88%. When saruplase (20 micrograms/kg.min) was administered only during the last two hours of endotoxin infusion, liver microthrombosis was still significantly dissolved by 69%, whereas renal microthrombosis was insignificantly reduced by 34%. The inhibition of endotoxin-induced microthrombosis took place in the same dosage range as the shortening of the euglobulin clot lysis time in normal rats by saruplase as a measure of its fibrinolytic activity. Saruplase did not modify thrombocytopenia and hypofibrinogenemia in endotoxemic rats. Saruplase per se did not affect plasma fibrinogen levels. Thus, in a fibrin-selective dose range saruplase is able to dissolve microthrombosis associated with DIC in endotoxemic rats.

Topics: Animals; Disseminated Intravascular Coagulation; Endotoxins; Fibrin; Fibrinogen; Male; Organ Specificity; Platelet Count; Rats; Rats, Wistar; Recombinant Proteins; Shock, Septic; Specific Pathogen-Free Organisms; Thrombolytic Therapy; Tissue Distribution; Urokinase-Type Plasminogen Activator

Disseminated intravascular coagulation (DIC) was induced in 84 rabbits by intravenous infusion of 20 micrograms/kg/h of endotoxin during 6 hours. The following treatments were administered simultaneously with endotoxin: heparin, 5, 10 and 20 UI/kg/h, antithrombin III (AT III), 10, 20 and 40 U/kg/h or as a 240 U/kg bolus dose, and heparin (10 UI/kg/h) plus AT III (20 U/kg/h). Blood samples were taken before endotoxin and 2 and 6 hours after endotoxin to perform screening coagulation assays, factors V, VIII and XII, AT III, fibrin monomers and fibrinogen degradation products. All treatments were able to modify some of the parameters related to DIC, but only AT III bolus dose and heparin plus AT III significantly reduced fibrin deposition in kidneys (p less than 0.05). All the therapeutic schedules significantly diminished the mortality rate. We conclude that AT III bolus dose and heparin plus AT III are useful in the treatment of endotoxin-induced intravascular coagulation in rabbits.

Topics: Animals; Antithrombin III; Disseminated Intravascular Coagulation; Drug Therapy, Combination; Fibrin; Heparin; Male; Rabbits; Shock, Septic

Endotoxin-treated rabbits produce high levels of plasminogen activator inhibitor-1 (PAI-1), which inhibits fibrinolysis by neutralizing endogenous tissue-type plasminogen activator (t-PA). These animals will develop renal fibrin deposition when infused with ancrod, an enzyme that acts directly on fibrinogen. In normal rabbits with an intact fibrinolytic system, ancrod induces hypofibrinogenemia without fibrin deposition. Rabbit PAI-1 activity can be neutralized by recombinant human t-PA or by bovine activated protein C. The present study determined the efficacy of these two agents used alone or in combination in neutralizing increased PAI-1 activity and in preventing renal fibrin deposition in a rabbit model. Male New Zealand rabbits first received intravenous endotoxin to increase PAI-1 activity. Ancrod was infused intravenously during hour 4 to 5, and the kidneys were examined at hour 5.5. Renal fibrin deposition occurred in 100% (6 out of 6) of the endotoxin-treated rabbits that received ancrod; this was reduced to 14% (1 out of 7) for rabbits receiving t-PA (170 micrograms/kg) before and during the ancrod infusion. Fibrin deposition occurred in only 12% (1 out of 8) of the rabbits that received a 10-fold lower dose of t-PA (17 micrograms/kg) combined with activated protein C (1 mg/kg) before and during the ancrod. Activated protein C at this dose completely neutralized plasma PAI-1 activity. However, low-dose t-PA and activated protein C did not prevent fibrin deposition when used as single agents, with fibrin deposition occurring in 75% and 100% of rabbits, respectively. The data indicate that activated protein C can neutralize plasma PAI-1 activity in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Ancrod; Animals; Fibrin; Fibrinolysis; In Vitro Techniques; Kidney; Plasminogen Inactivators; Protein C; Rabbits; Recombinant Proteins; Shock, Septic; Thrombosis; Tissue Plasminogen Activator

The use of tampons and surgical gauze pads and colonization with Staphylococcus aureus have been established as risk factors for the development of toxic shock syndrome. To elucidate the role of blood factors in the mediation of staphylococcal adherence to fibers used in tampons and surgical packing, an adherence assay with cotton fibers was developed. Results demonstrated that cotton disks precoated with fibrinogen in the presence of human serum albumin bound a significant percentage of the inoculum for both staphylococcal strains tested when compared to human serum albumin controls. Likewise, fibers pretreated with plasma or defibrinated blood containing a small amount of fibrin revealed comparable staphylococcal adherence to that of fibrinogen. In contrast, fibers pretreated with serum, fibronectin, or vitronectin did not exhibit significant augmentation in staphylococcal attachment in comparison to human serum albumin controls. The attachment of staphylococci to fibrinogen and/or fibrin appeared to be specific and is blocked by goat anti-human fibrinogen antibody, but not fibronectin, vitronectin, or nonimmune goat IgG. Thus, our data indicate that fibrinogen/fibrin is the dominant blood component in the mediation of staphylococcal adherence to fibers used in tampons and surgical gauze pads.

Topics: Animals; Antibodies; Bacterial Adhesion; Fibrin; Fibrinogen; Goats; Gossypium; Humans; Shock, Septic; Staphylococcal Infections; Staphylococcus aureus

30 rabbits received an infusion of lipopolysaccharide B (75 micrograms/kg.h) over 4 hours (groups E, EI, EA; n = 10 each). Saline was given to a control group (C; n = 8). In group EI, prostacyclin (PGI2; 500 ng/kg.min) was given simultaneously to endotoxin. Into group EA animals, aspirin (20 mg/kg) was injected before the endotoxin infusion was started. PGI2 and aspirin both improved survival of animals (6/10 each vs. 2/10 in group E). The drop of platelet counts was significantly reduced by PGI2, while leukocyte depletion was similar in all endotoxin groups. PGI2 preserved the functional capacity of platelets as indicated by collagen stimulated aggregation and thromboxane formation. PGI2 but not aspirin significantly reduced renal fibrin deposition.

Topics: Animals; Aspirin; Blood Coagulation; Blood Platelets; Blood Pressure; Carbon Dioxide; Epoprostenol; Fibrin; Fibrinogen; Lactates; Lactic Acid; Leukocyte Count; Oxygen; Partial Thromboplastin Time; Platelet Aggregation; Platelet Count; Prothrombin Time; Rabbits; Shock, Septic; Survival Analysis; Thromboxane B2

Topics: Aged; Aged, 80 and over; Blood Cell Count; Blood Coagulation; Blood Pressure; Blood Proteins; Complement System Proteins; Endotoxins; Female; Fibrin; Fibrinolysis; Humans; Kinins; Male; Middle Aged; Shock, Septic

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Epoprostenol; Fibrin; Kidney Glomerulus; Lipopolysaccharides; Platelet Aggregation; Platelet Count; Rabbits; Shock, Septic; Thromboxane B2

Topics: Animals; Aprotinin; Fibrin; Gabexate; Guanidines; Lidocaine; Methylprednisolone; Rabbits; Shock, Septic

This study was performed on patients (n = 18) suffering from strictly defined hyperdynamic septic shock. Plasma factors (C-reactive protein, acid alpha 1-glycoprotein, fibrinogen, fibrinopeptide A, fibrinogen-fibrin split products, factor XIII, antithrombin III, complement factors C3 and C4, inter-alpha-trypsin-inhibitor and alpha 2-macroglobulin) measured during hyperdynamic septic shock were highly abnormal. The activation and consumption of clotting, fibrinolytic and complement factors due to system-specific proteinases (such as thrombokinase or plasminogen activators) seemed to be intensified by the nonspecific proteolytic activity of granulocytic proteinases probably released by the action of endotoxins. Possible therapeutic measures to maintain the endogeneous defence mechanism against enhanced proteolysis during septic shock are discussed.

Topics: Alpha-Globulins; alpha-Macroglobulins; Antithrombin III; Blood Coagulation Factors; Blood Proteins; Complement System Proteins; Female; Fibrin; Humans; Leukocytes; Leukocytosis; Leukopenia; Male; Prospective Studies; Protease Inhibitors; Shock, Septic; Trypsin Inhibitors

Intravascular hemolysis and ultrastructure of erythrocytes from liver sinusoids were studied during and after infusion of Escherichia coli endotoxin in Labrador retriever dogs. Endotoxin infusion caused hemoconcentration, and induced disseminated intravascular coagulation (DIC), characterized by a rapid drop of platelet numbers, a gradual consumption of coagulation factors and activation of fibrinolysis. Advanced DIC and circulatory shock gradually developed, and the animals died after 7-15 h. Plasma hemoglobin concentrations did not rise for several hours, but late in the experimental period a significant intravascular hemolysis was constantly found. Circulating adenosine diphosphate (ADP) did not appear. During shock, liver biopsies revealed accumulation of erythrocytes often disintegrated within distended sinusoidal lumina. In advanced shock the fragmented erythrocyte seemed to form occlusive masses within the vessels. A fibrin-like material frequently appeared adjacent to the red cells. However, it did not have the periodicity characteristic for fibrin, and the ultrastructure of the material was very similar to that inside the erythrocytes. None of these changes were induced by saline infusion in control animals. The lack of fibrin formation and the late development of intravascular hemolysis indicate that red cell breakdown was of little importance for the initiation and progress of DIC.

Topics: Animals; Blood Coagulation Factors; Blood Pressure; Disseminated Intravascular Coagulation; Dogs; Erythrocytes; Escherichia coli; Fibrin; Fibrinolysis; Hematocrit; Hemoglobins; Hemolysis; Microscopy, Electron; Platelet Count; Shock, Septic

Topics: Animals; Escherichia coli; Fibrin; Haplorhini; Kidney; Kidney Function Tests; Lactates; Liver; Lung; Myocardium; Papio; Potassium; Shock, Septic; Thrombosis

In this study, an attempt was made to elucidate further the role of intravascular fibrin formation in the pathogenesis of sepsis in the primate. It was found that injected live Escherichia coli caused death in primates within four to 11 hours as a result of microcirculatory failure and acidosis. Pretreatment with Arvin did not prolong the survival rate, probably because of an overloading of the reticuloendothelial system with fibrin degradation products. This study does not support an obligatory role for intravascular coagulation or fibrin formation in primate sepsis and coincides with an earlier report (6) from this laboratory on cats. Vascular damage and malfunction, secondary to mediators released by platelets, leukocytes, red cells or Hageman factor, are not ruled out.

Topics: Ancrod; Animals; Blood; Blood Coagulation; Blood Pressure; Carbon Dioxide; Cardiac Output; Disease Models, Animal; Escherichia coli Infections; Female; Fibrin; Haplorhini; Heart Rate; Hemodynamics; Hydrogen-Ion Concentration; Lactates; Oxygen; Oxygen Consumption; Papio; Shock, Septic

Endotoxin shock was induced in dogs by slow administration of a lethal dose of Escherichia coli endotoxin. During the 3-hour infusion period a state of disseminated intravascular coagulation (DIC) was noted. The drop in platelets and leukocytes was the most rapid and pronounced effect of the infusion, while consumption of coagulation factors occurred more slowly. Activation of the extrinsic and intrinsic pathways of coagulation appeared to be closely parallel. Concomitantly increasing amounts of fibrin(ogen) degradation products were detected, while soluble fibrin monomers were observed only inconstantly. Intravascular hemolysis was slight and occurred in the late stages of shock, and could not have influenced the development of DIC.

Topics: Animals; Blood Cell Count; Blood Coagulation; Blood Coagulation Tests; Blood Platelets; Blood Pressure; Disseminated Intravascular Coagulation; Dogs; Endotoxins; Escherichia coli; Factor XII; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Hematocrit; Hemoglobins; Infusions, Parenteral; Leukocytes; Male; Shock, Septic

Topics: Animals; Arteries; Arterioles; Brain; Endoplasmic Reticulum; Endothelium; Escherichia coli; Fibrin; Neurotoxins; Platelet Adhesiveness; Platelet Aggregation; Ribosomes; Shock, Septic; Spinal Cord; Swine

In previous studies we have presented morphological evidence that the terminal shock-like phase of fatal meningococcemia is caused by the occlusion of the pulmonary microcirculation with thrombi composed of platelets, leukocytes, and fibrin. We have also shown that in experimental meningococcemia, pretreatment of rabbits with heparin sodium prevents fibrin formation but does not influence the cellular pulmonary thrombi and does not prolong survival. If our theory is correct, drugs that inhibit platelet aggregation and leukocyte adhesion in rabbits should prolong life. The present experiment demonstrates that pretreatment with a small dose of aspirin doubles the survival time without altering the mortality.

Topics: Animals; Aspirin; Female; Fibrin; Kidney Glomerulus; Kidney Tubular Necrosis, Acute; Lung; Meningococcal Infections; Rabbits; Sepsis; Shock, Septic

Topics: Animals; Blood Coagulation; Brain; Disseminated Intravascular Coagulation; Fibrin; Haplorhini; Hematocrit; Kidney; Liver; Myocardium; Papio; Pulmonary Edema; Shock, Hemorrhagic; Shock, Septic; Spleen

Blood clearance by phagocytosis, predominantly by the liver, presents an important mechanism for the elimination and detoxification of endotoxin. However, its effectiveness alone does not determine the outcome of an experimentally induced standardized endotoxin shock. Consequently other effects elicited by endotoxin--for instance, those on the coagulation mechanism or on an endotoxin-detoxifying enzyme system in plasma--must also play an important role in determining the ultimate fate of this condition, for it is now abundantly clear that interrupting such effects with heparin provides considerable protection.

Topics: Animals; Blood Coagulation; Endotoxins; Fibrin; Heparin; Liver; Lung; Metabolic Clearance Rate; Phagocytosis; Rats; Shock, Septic; Spleen

In a post mortem study of shock-induced changes in the bone marrow, marrow from six different parts of the skeletal system was examined in a total of 109 patients. The comparison of a group of 64 subjects deceased in shock conditions with a control group of 25 deceased without shock showed: In 76,6% of all patients with shock, fibrin networks were found in the sinus and perisinoidal interstice of bone marrow. This can be demonstrated abundantly in every fourth patient with shock. Microthrombi and emboli occluding vessels in the marrow were seen in only 6.3% of the shock cases (controls 0%). The different forms of fibrin precipitates appear most commonly after shock caused by infection. Platelet aggregates in the vessels are seen in 28.2% of all cases with shock (controls 8%). 5% of the cases with shock showed infarction-like necroses of the bone marrow and a further 23% necroses of small cell groups. In every fifth patient with shock, a great number of nucleated blood cells and their precursors were found in the marrow sinus (controls 8%). In a third group of 20 patients with serious illness alledgedly without shock, 45 per cent had a fibrin network when compared with the control group. When several of these findings are present simultaneously, one can apply the term "shock marrow".

Topics: Adult; Aged; Autopsy; Bone Marrow; Bone Marrow Examination; Female; Fibrin; Humans; Male; Middle Aged; Platelet Aggregation; Shock; Shock, Septic; Thromboembolism

Topics: Animals; Autopsy; Blood Cell Count; Blood Coagulation Tests; Blood Pressure; Disseminated Intravascular Coagulation; Dogs; Endotoxins; Factor V; Factor VII; Factor VII Deficiency; Factor X; Fibrin; Fibrinogen; Plasminogen; Prothrombin; Shock, Septic; Staining and Labeling; Thrombosis

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Factor IX; Factor V; Factor VII; Factor VIII; Factor X; Fibrin; Humans; Infections; Kidney Diseases; Phospholipids; Shock, Septic

Topics: Animals; Blood Coagulation; Endotoxins; Fibrin; Granulocytes; Leukocytes; Shock, Septic

Topics: Animals; Aorta; Blood Cell Count; Blood Pressure; Central Venous Pressure; Dogs; Endotoxins; Female; Fibrin; Hemodynamics; Histocytochemistry; Infusions, Parenteral; Leukocyte Count; Renal Artery; Renal Veins; Shock, Septic; Venous Pressure

Topics: Animals; Blood Vessels; Endothelium; Endotoxins; Fibrin; Heparin; Leukocytes; Microscopy, Electron; Platelet Adhesiveness; Rabbits; Sepsis; Shock, Septic; Vascular Diseases

Topics: Abortion, Septic; Animals; Blood Coagulation Disorders; Disseminated Intravascular Coagulation; Female; Fibrin; Heparin; Humans; Pregnancy; Rabbits; Shock, Septic

Topics: Coronary Circulation; Disseminated Intravascular Coagulation; Erythrocyte Aggregation; Fibrin; Fibrinogen; Humans; Microcirculation; Shock; Shock, Septic

Topics: Abortion, Septic; Adolescent; Adult; Anticoagulants; Antithrombins; Blood; Blood Coagulation Disorders; Blood Coagulation Factors; Child; Disseminated Intravascular Coagulation; Encephalitis; Encephalitis Viruses; Female; Fibrin; Fibrinogen; Fibrinolysis; Hemorrhagic Disorders; Humans; Liver; Male; Necrosis; Pituitary Gland; Pregnancy; Prostatic Neoplasms; Prothrombin; Sepsis; Shock, Septic; Spleen; Streptokinase

Topics: Animals; Blood Coagulation Disorders; Blood Pressure; Body Temperature; Carbon Dioxide; Diuresis; Endotoxins; Escherichia coli; Female; Fibrin; Hemodynamics; Histocytochemistry; Hydrogen-Ion Concentration; Injections, Intravenous; Kidney; Kidney Cortex Necrosis; Kidney Function Tests; Kidney Glomerulus; Lactates; Liver; Lung; Osmolar Concentration; Rabbits; Respiration; Shock, Septic; Spleen

Topics: Animals; Blood Pressure; Capillaries; Cardiac Output; Dogs; Electrocardiography; Escherichia coli Infections; Fibrin; Heart Rate; Hypotension; Microscopy, Electron; Respiration; Shock, Hemorrhagic; Shock, Septic; Shock, Traumatic

Topics: Animals; Blood Platelets; Endotoxins; Fibrin; Haplorhini; Jejunum; Kidney; Leukocytes; Liver; Lung; Microscopy; Microscopy, Electron; Myocardium; Shock, Septic; Spleen; Thrombosis