fibrin and Respiratory-Distress-Syndrome

The pathomechanisms of hypoxemia and treatment strategies for type H and type L acute respiratory distress syndrome (ARDS) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced coronavirus disease 2019 (COVID-19) have not been elucidated.. SARS-CoV-2 mainly targets the lungs and blood, leading to ARDS, and systemic thrombosis or bleeding. Angiotensin II-induced coagulopathy, SARS-CoV-2-induced hyperfibrin(ogen)olysis, and pulmonary and/or disseminated intravascular coagulation due to immunothrombosis contribute to COVID-19-associated coagulopathy. Type H ARDS is associated with hypoxemia due to diffuse alveolar damage-induced high right-to-left shunts. Immunothrombosis occurs at the site of infection due to innate immune inflammatory and coagulofibrinolytic responses to SARS-CoV-2, resulting in microvascular occlusion with hypoperfusion of the lungs. Lung immunothrombosis in type L ARDS results from neutrophil extracellular traps containing platelets and fibrin in the lung microvasculature, leading to hypoxemia due to impaired blood flow and a high ventilation/perfusion (VA/Q) ratio. COVID-19-associated ARDS is more vascular centric than the other types of ARDS. D-dimer levels have been monitored for the progression of microvascular thrombosis in COVID-19 patients. Early anticoagulation therapy in critical patients with high D-dimer levels may improve prognosis, including the prevention and/or alleviation of ARDS.. Right-to-left shunts and high VA/Q ratios caused by lung microvascular thrombosis contribute to hypoxemia in type H and L ARDS, respectively. D-dimer monitoring-based anticoagulation therapy may prevent the progression to and/or worsening of ARDS in COVID-19 patients.

Topics: Anticoagulants; Biomarkers; Blood Platelets; COVID-19; COVID-19 Drug Treatment; Extracellular Traps; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Hemostasis; Humans; Hypoxia; Lung; Microvessels; Phenotype; Respiratory Distress Syndrome; SARS-CoV-2; Thromboinflammation; Thrombosis

Enhanced intrapulmonary fibrin deposition as a result of abnormal broncho-alveolar fibrin turnover is a hallmark of acute respiratory distress syndrome (ARDS), pneumonia and ventilator-induced lung injury (VILI), and is important to the pathogenesis of these conditions. The mechanisms that contribute to alveolar coagulopathy are localized tissue factor-mediated thrombin generation, impaired activity of natural coagulation inhibitors and depression of bronchoalveolar urokinase plasminogen activator-mediated fibrinolysis, caused by the increase of plasminogen activator inhibitors. There is an intense and bidirectional interaction between coagulation and inflammatory pathways in the bronchoalveolar compartment. Systemic or local administration of anticoagulant agents (including activated protein C, antithrombin and heparin) and profibrinolytic agents (such as plasminogen activators) attenuate pulmonary coagulopathy. Several preclinical studies show additional anti-inflammatory effects of these therapies in ARDS and pneumonia.

Topics: Animals; Anticoagulants; Fibrin; Fibrinolytic Agents; Hemostasis; Humans; Inflammation Mediators; Pneumonia; Pulmonary Alveoli; Respiratory Distress Syndrome; Ventilator-Induced Lung Injury

Disturbed alveolar fibrin turnover is intrinsic to acute lung injury/acute respiratory distress syndrome (ALI/ARDS) and pneumonia and is important to its pathogenesis. Recent studies also suggest disturbed alveolar fibrin turnover to be a feature of ventilator-induced lung injury (VILI). The mechanisms that contribute to alveolar coagulopathy are localized tissue factor-mediated thrombin generation, impaired activity of natural coagulation inhibitors, and depression of bronchoalveolar urokinase plasminogen activator-mediated fibrinolysis, caused by the increase of plasminogen activator inhibitors. Administration of anticoagulant agents (including activated protein C, antithrombin, tissue factor-factor VIIa pathway inhibitors, and heparin) and profibrinolytic agents (including plasminogen activators) attenuate pulmonary coagulopathy. Several preclinical studies show additional anti-inflammatory effects of these therapies in ALI/ARDS and pneumonia. In this article, we review the involvement of coagulation and fibrinolysis in the pathogenesis of ALI/ARDS pneumonia and VILI and the potential of anticoagulant and profibrinolytic strategies to reverse pulmonary coagulopathy and pulmonary inflammatory responses.

Topics: Acute Lung Injury; Bronchi; Cytokines; Fibrin; Fibrinolysis; Hemostasis; Humans; Plasminogen Activators; Pulmonary Alveoli; Receptors, Thrombin; Respiratory Distress Syndrome; Thrombin

To review: a) the role of extravascular fibrin deposition in the pathogenesis of acute lung injury; b) the abnormalities in the coagulation and fibrinolysis pathways that promote fibrin deposition in the acutely injured lung; and c) the pathways that contribute to the regulation of the fibrinolytic system via the lung epithelium, including newly recognized posttranscriptional and urokinase-dependent pathways. Another objective was to determine how novel anticoagulant or fibrinolytic strategies may be used to protect against acute inflammation or accelerated fibrosis in acute lung injury.. Published medical literature.. Alveolar fibrin deposition is characteristic of diverse forms of acute lung injury. Intravascular thrombosis or disseminated intravascular coagulation can also occur in the acutely injured lung. Extravascular fibrin deposition promotes lung dysfunction and the acute inflammatory response. In addition, transitional fibrin in the alveolar compartment undergoes remodeling leading to accelerated pulmonary fibrosis similar to the events associated with wound healing, or desmoplasia associated with solid neoplasms. In acute lung injury, alveolar fibrin deposition is potentiated by consistent changes in endogenous coagulation and fibrinolytic pathways. Procoagulant activity is increased in conjunction with depression of fibrinolytic activity in the alveolar compartment. Initiation of the procoagulant response occurs as a result of local overexpression of tissue factor associated with factor VII. Depression of fibrinolytic activity occurs as a result of inhibition of urokinase plasminogen activator (uPA) by plasminogen activators, or series inhibition of plasmin by antiplasmins. Locally increased amplification of plasminogen activator inhibitor-1 (PAI-1) is largely responsible for this fibrinolytic defect. Newly described pathways by which lung epithelial cells regulate expression of uPA, its receptor uPAR, and PAI-1 at the posttranscriptional level have been identified. These pathways operate by cis-trans interactions between mRNA binding proteins; regulatory sequences within these mRNAs control their stability. The regulatory mechanisms seem to involve multiple protein-mRNA interactions, and the phosphorylation state of the proteins appears to determine whether complex formation of, or dissociation from, the regulatory sequences occurs. uPA is capable of inducing its own expression in lung epithelial cells as well as that of uPAR and PAI-1-the effects involve posttranscriptional regulatory components. These and related observations have led to the implementation of anticoagulant or fibrinolytic strategies to protect the lung against acute lung injury. The success of new fibrinolytic strategies to block pleural loculation suggests that a similar approach might be used to prevent accelerated pulmonary fibrosis, which can occur in association with many forms of acute lung injury.. Disordered coagulation and fibrinolysis promote extravascular fibrin deposition in acute lung injury. It is this deposition that characterizes acute lung injury and repair. Expression of uPA, uPAR, and PAI-1 by the lung epithelium, as well as the ability of uPA to induce other components of the fibrinolytic system, involves posttranscriptional regulation. These pathways may contribute to disordered fibrin turnover in the injured lung. The success of anticoagulant or fibrinolytic strategies designed to reverse the abnormalities of local fibrin turnover in acute lung injury supports the inference that abnormalities of coagulation, fibrinolysis, and fibrin deposition have a critical role in the pathogenesis of acute lung injury.

Topics: Animals; Anticoagulants; Blood Coagulation; Fibrin; Fibrinolysis; Gene Expression Regulation; Humans; Respiratory Distress Syndrome; Respiratory Mucosa; Urokinase-Type Plasminogen Activator

To review the involvement of coagulation and fibrinolysis in the pathogenesis of acute lung injury during severe infection. To review the cross-talk between coagulation and inflammation that may affect this response.. Published articles on experimental and clinical studies of coagulation and fibrinolysis during infection, inflammation, acute lung injury, and evolving acute respiratory distress syndrome.. Fibrin deposition is an important feature of pulmonary infection or severe inflammation. The mechanisms that contribute to this fibrin deposition are bronchoalveolar tissue factor-mediated thrombin generation and localized depression of urokinase plasminogen activator-mediated fibrinolysis, caused by the increase of plasminogen activator inhibitors. These effects on pulmonary coagulation and fibrinolysis are regulated by various proinflammatory cytokines. Rather than being a unidirectional relationship, the interaction between inflammation and coagulation involves significant cross-talk. Coagulation and fibrinolytic proteins may have an additional role beyond fibrin turnover and inflammation, e.g., in mechanisms mediating cell recruitment and migration.

Topics: Bronchoalveolar Lavage Fluid; Cytokines; Endotoxemia; Fibrin; Fibrinolysis; Humans; Pneumonia; Respiratory Distress Syndrome; Thromboplastin

The adult respiratory distress syndrome (ARDS) is a form of acute lung injury that is characterized by florid extravascular fibrin deposition. Thrombosis in the pulmonary vasculature and disseminated intravascular coagulation have also been observed in association with ARDS. Fibrin deposition does not occur in the normal lung but is virtually universal in acute lung injury induced by disparate insults. A large body of basic and preclinical evidence further implicates abnormalities of pathways of fibrin turnover in the pathogenesis of acute inflammation and fibrotic repair. Coagulation is locally upregulated in the injured lung, while fibrinolytic activity is depressed. These abnormalities occur concurrently and favor alveolar fibrin deposition. The systemic derangements of fibrin turnover in sepsis are similar to those that occur in the injured lung. Recent clinical trials demonstrate that interventions using selective anticoagulation can provide a mortality advantage and that selective anticoagulants differ in their ability to provide clinical benefit. Preclinical trials in primates with sepsis-induced ARDS now indicate that anticoagulant interventions that block the extrinsic coagulation pathway can protect against the development of pulmonary fibrin deposition as well as lung dysfunction and acute inflammation. These observations provide proof of principle that key steps in the coagulation cascade are appropriate therapeutic targets to prevent the development of acute lung injury in ARDS. Ongoing studies and prior publications also support the hypothesis that reversal of the fibrinolytic defect in ARDS could protect against the development of acute lung injury. In all, these studies suggest that fibrin deposition in the injured lung as well as abnormalities of coagulation and fibrinolysis are integral to the pathogenesis of ARDS. The ability of selective anticoagulants to effectively and safely alter clinical outcome in ARDS remains to be determined.

Topics: Adult; Anticoagulants; Blood Coagulation; Fibrin; Fibrinolysis; Humans; Respiratory Distress Syndrome; Respiratory Mucosa

To review derangements of pathways of fibrin turnover that promote pathologic fibrin deposition in the acute respiratory distress syndrome and to review the contribution of the endothelium and parenchymal lung cells to the derangements. In addition, to review how these pathways can be exploited in specific clinical circumstances, including sepsis and acute lung injury. Lastly, to review newly recognized posttranscriptional and urokinase-dependent pathways by which the fibrinolytic system is regulated in the lung.. Medical literature published in English from 1966 to present.. Local abnormalities of fibrin turnover in the injured lung recapitulate the systemic changes observed in sepsis. In both circumstances, the procoagulant response is increased, whereas fibrinolytic activity is concurrently depressed. The increased procoagulant activity is related to tissue factor associated with factor VII/VIIa. Fibrinolytic activity in the vasculature is mainly attributable to tissue plasminogen activator, whereas extravascular fibrinolytic activity in the lung is mainly attributable to urokinase plasminogen activator (uPA). Depressed fibrinolytic activity is in large part attributable to plasminogen activator inhibitor-1. In sepsis, activated protein C is also deficient, potentiating the inflammatory response, coagulopathy, and depressed fibrinolysis. Recombinant human activated protein C (drotrecogin alfa [activated]) was successful as an intervention for sepsis in a recent phase 3 clinical trial (PROWESS). Recently, novel posttranscriptional pathways that regulate expression of uPA, its receptor (uPAR), and plasminogen activator inhibitor-1 have been identified. The responsible mechanisms involve cis-trans interactions between newly recognized messenger RNA (mRNA) binding sequences and mRNA binding proteins. A 51 nucleotide mRNA binding sequence within the coding region of uPAR mRNA interacts with a novel 50-kDa mRNA binding protein to destabilize the message. Sequences within the 3' untranslated region of uPA or plasminogen activator inhibitor-1 mRNA interact with 30- and 60-kDa proteins, respectively, to regulate message stability. All of these pathways operate in lung epithelial cells, and endothelial cells regulate uPA expression through a similar pathway. In addition, uPA itself is capable of inducing expression of other components of the fibrinolytic system, including uPAR. This observation defines another feedback loop that could amplify local fibrinolysis and other uPA- or uPAR-mediated cellular responses, including cellular proteolysis, proliferation, and directed cellular migration.. Novel posttranscriptional pathways regulate expression of uPA, uPAR, and plasminogen activator inhibitor-1. uPA itself is capable of inducing other components of the fibrinolytic system. Some or all of these newly recognized pathways are operative in endothelial and parenchymal lung cells and may influence disordered fibrin turnover in the injured lung.

Topics: Endothelium, Vascular; Fibrin; Fibrinolysis; Humans; Lung Neoplasms; Plasminogen Activator Inhibitor 1; Respiratory Distress Syndrome; Urokinase-Type Plasminogen Activator

To review the dual characteristics of disseminated intravascular coagulation (DIC), as both a contributor to multiple organ failure as well as a symptom of severe underlying disease associated with systemic vascular changes.. Published literature data and unpublished results from the authors.. Clinical and experimental studies strongly suggest that DIC contributes to multiple organ failure and death in patients with severe systemic disorders such as sepsis. DIC is evoked by systemic cytokine activity, and the inflammatory response aggravates vascular permeability, inflammation, and cell damage in tissues. In addition to intravascular fibrin formation, thrombin and fibrin generation in tissues is also an important aspect of DIC. An example of DIC at the organ level is adult respiratory distress syndrome, where fibrin in the lung is a characteristic feature. Intravascular fibrin formation and occlusion may elicit a hypoxic response with induction of hypoxia related transcription factors. The resulting ischemic preconditioning may offer protective effects to the involved organ(s).. Overall, the beneficial or harmful effects of activated coagulation and fibrin formation for organ pathology and recovery from DIC remain to be explored. This may be a critical element in the assessment of ischemia-reperfusion effects of specific anticoagulant therapy.

Topics: Anticoagulants; Capillary Permeability; Cytokines; Disseminated Intravascular Coagulation; Endothelium, Vascular; Fibrin; Humans; Inflammation; Microcirculation; Multiple Organ Failure; Respiratory Distress Syndrome; Sepsis; Thrombin

Topics: Animals; Disease Models, Animal; Disease Progression; Drug Evaluation, Preclinical; Fibrin; Fibrinolysis; Humans; Lipoproteins; Multiple Organ Failure; Protein C; Respiratory Distress Syndrome; Sepsis; Treatment Outcome

Extravascular fibrin deposition is characteristic of the acute inflammatory response and is, for example, prominent in the alveolar compartment of patients with the adult respiratory distress syndrome. Fibrin deposition in the injured lung is regulated by a balance of locally expressed pathways of coagulation and fibrin clearance, called fibrinolysis. These pathways comprise part of the interactive network of responses that influence local inflammatory cell traffic, microvascular permeability, and repair mechanisms. In this sense, fibrin turnover in the lung extends beyond traditional hemostasis and may influence the acute inflammatory response and resolution. Within the injured alveolar compartment, fibrin deposition is initiated by increased activity of the extrinsic coagulation pathway-tissue factor associated with factor VII. Activation of the contact and intrinsic coagulation pathways also occurs. Local fibrinolysis is generally impaired, which may potentiate extravascular fibrin deposition. Fibrin turnover in the adult mammalian lung is similarly disrupted in several forms of injury but differs from the injury that occurs in the lungs of premature infants with respiratory distress.

Topics: Animals; Blood Coagulation; Fibrin; Fibrinolysis; Humans; Hyaline Membrane Disease; Infant, Newborn; Lung; Respiratory Distress Syndrome

Pulmonary microembolism results in lung vascular injury characterized by an increase in the transport of the pulmonary micro- vascular barrier into proteins. The increase in lung vascular permeability is a primary factor responsible for the protein-rich oedema associated with pulmonary microembolism. The microembolism can result from a variety of causes, but an essential feature of it is the "plugging" of pulmonary microvessels with thrombi; that is, the entrapment of fibrin and blood-formed elements in pulmonary microvessels. Neutrophil-derived products released subsequent to neutrophil activation are primary mediators of lung vascular injury. The attachment of neutrophils to the endothelial cell is a requisite for the development of endothelial injury. Fibrin itself plays another important role in that fibrin promotes neutrophil adhesiveness and releases factors such as fibrin degradation products which may increase endothelial permeability. Therefore, pulmonary microembolism is a determinant of acute lung microvascular injury and is a factor in the pathogenesis of the adult respiratory distress syndrome. Neutrophils are important effector cells mediating lung microvascular injury, although the factors that are responsible for neutrophil sequestration and activation remain unclear.

Topics: Animals; Blood Platelets; Capillary Permeability; Fibrin; Free Radicals; Humans; Lung; Macrophages; Neutrophils; Pulmonary Circulation; Pulmonary Embolism; Respiratory Distress Syndrome

Topics: Blood Platelets; Complement Activation; Endothelium; Fibrin; Humans; Lung; Multiple Organ Failure; Neutrophils; Respiratory Distress Syndrome; Sepsis; Shock, Traumatic

Topics: Biomechanical Phenomena; Blood Platelets; Fibrin; Fibrin Fibrinogen Degradation Products; Humans; Infant; Infant, Newborn; Oxygen; Platelet Activating Factor; Pulmonary Surfactants; Respiratory Distress Syndrome

Clinical and autopsy studies have shown an association between clotting, microembolism, and inhibition of fibrinolysis and respiratory distress after trauma or sepsis. Prophylaxis and treatment with the aim of decreasing the deposition of fibrin in the lungs were associated with a large decrease in the incidence and death rate of this syndrome. Small fibrin degradation products (peptides) are accumulated in the lungs and are only slowly cleared from this organ, especially during states of inhibition of fibrinolysis. These peptides may contribute to the pulmonary damage in several ways. As well as having a direct effect on the endothelium, they act by interfering with other vasoactive substances as bradykinin, histamine, and products of the arachidonic acid cascade. Products of the cyclooxygenase pathway such as thromboxane A2 play a major role in early microembolism, whereas lipoxygenase products seem to be involved in later stages. Pulmonary microembolism thus seems to be one important, but certainly not the only, pathogenetic factor in acute "idiopathic" respiratory failure. Other factors, such as pulmonary contusion, aspiration of gastric contents or blood, or oxygen toxicity, might well be contributory in some cases. Pulmonary microemboli containing fibrin and leukocytes are probably also involved as contributory agents in some cases in the large group of acute respiratory failures due to "known factors."

Topics: Albumins; Animals; Clinical Trials as Topic; Dextrans; Dogs; Fibrin; Fibrinolysis; Hemostasis; Heparin; Humans; Lung; Pulmonary Embolism; Random Allocation; Rats; Respiratory Distress Syndrome; Syndrome; Thrombin; Time Factors

Septic pulmonary injury remains a significant cause of morbidity and mortality among hospitalized patients today and is likely to increase in prevalence as advances in medical technology allow the salvage of more critically ill and immunocompromised hosts. Treatment of the host's underlying disease and even of the infection itself has appeared to redeem septic patients only to have them succumb in increasing numbers to the pulmonary injury reaction. Our understanding of the mechanisms and mediators of lung dysfunction in sepsis is in a rapidly expanding phase. Currently we recognize the contributions of several blood elements, lipids, and peptides to pulmonary injury, although the relative importance and points of interaction and interdependence of these mediators remain to be established. It is hoped that a more complete understanding of the process of pulmonary injury in sepsis will suggest effective means of intervention at a stage in which damage may be reversed or minimized.

Topics: Animals; Cell Aggregation; Complement System Proteins; Fibrin; Humans; Leukotriene B4; Lung; Neutrophils; Platelet Aggregation; Prostaglandins; Respiratory Distress Syndrome; Sepsis; SRS-A

The authors describe the pathophysiology of disseminated intravascular coagulation and the coagulopathy of utilization. The clinical and laboratory data on different types of shock are described. The efficacy of different antithrombotic agents in shock with disseminated intravascular coagulation is shown.

Topics: Blood Coagulation Disorders; Blood Platelets; Cyclic AMP; Disseminated Intravascular Coagulation; Fibrin; Fibrinolysis; Hemostasis; Humans; Microcirculation; Respiratory Distress Syndrome; Shock; Thrombocytopenia; Thrombosis

Topics: Animals; Blood Platelets; Blood Preservation; Blood Transfusion; Cell Aggregation; Disease Models, Animal; Dogs; Fibrin; Humans; Leukocytes; Micropore Filters; Papio; Platelet Aggregation; Postoperative Complications; Pulmonary Embolism; Respiratory Distress Syndrome; Transfusion Reaction

COVID-19 pneumonia is associated with the development of acute respiratory distress syndrome (ARDS) displaying some typical histological features. These include diffuse alveolar damage with extensive pulmonary coagulation activation. This results in fibrin deposition in the microvasculature, leading to the formation of hyaline membranes in the air sacs. Well-conducted clinical trials have found that nebulised heparin limits pulmonary fibrin deposition, attenuates progression of ARDS, hastens recovery and is safe in non-COVID ARDS. Unfractionated heparin also inactivates the SARS-CoV-2 virus and prevents entry into mammalian cells. Nebulisation of heparin may therefore limit fibrin-mediated lung injury and inhibit pulmonary infection by SARS-CoV-2. Based on these findings, we designed the CHARTER-Ireland Study, a phase 1b/2a randomised controlled study of nebulised heparin in patients requiring advanced respiratory support for COVID-19 pneumonia.. This is a multi-centre, phase 1b/IIa, randomised, parallel-group, open-label study. The study will randomise 40 SARs-CoV-2-positive patients receiving advanced respiratory support in a critical care area. Randomisation will be via 1:1 allocation to usual care plus nebulised unfractionated heparin 6 hourly to day 10 while receiving advanced respiratory support or usual care only. The study aims to evaluate whether unfractionated heparin will decrease the procoagulant response associated with ARDS up to day 10. The study will also assess safety and tolerability of nebulised heparin as defined by number of severe adverse events; oxygen index and respiratory oxygenation index of intubated and unintubated, respectively; ventilatory ratio; and plasma concentration of interleukin (IL)-1β, IL6, IL-8, IL-10 and soluble tumour necrosis factor receptor 1, C-reactive protein, procalcitonin, ferritin, fibrinogen and lactate dehydrogenase as well as the ratios of IL-1β/IL-10 and IL-6/IL-10. These parameters will be assessed on days 1, 3, 5 and 10; time to separation from advanced respiratory support, time to discharge from the intensive care unit and number tracheostomised to day 28; and survival to days 28 and 60 and to hospital discharge, censored at day 60. Some clinical outcome data from our study will be included in the international meta-trials, CHARTER and INHALE-HEP.. This trial aims to provide evidence of potential therapeutic benefit while establishing safety of nebulised heparin in the management of ARDS associated with SARs-CoV-2 infection.. ClinicalTrials.gov NCT04511923 . Registered on 13 August 2020. Protocol version 8, 22/12/2021 Protocol identifier: NUIG-2020-003 EudraCT registration number: 2020-003349-12 9 October 2020.

Topics: Acute Lung Injury; Animals; COVID-19; Fibrin; Heparin; Humans; Interleukin-10; Ireland; Mammals; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Respiratory Distress Syndrome; SARS-CoV-2

Adequate linezolid blood concentrations have been shown to be associated with an improved clinical outcome. Our goal was to assess new predictors of inadequate linezolid concentrations often observed in critically ill patients. Fifty-two critically ill patients with severe infections receiving standard dosing of linezolid participated in this prospective observational study. Serum samples (median, 32 per patient) were taken on four consecutive days, and total linezolid concentrations were quantified. Covariates influencing linezolid pharmacokinetics were identified by multivariate analysis and a population pharmacokinetic model. Target attainment (area under the concentration-time curve over 12 h [AUC12]/MIC ratio of >50; MIC = 2 mg/liter) was calculated for both the study patients and a simulated independent patient group (n = 67,000). Target attainment was observed for only 36% of the population on both days 1 and 4. Independent covariates related to significant decreases of linezolid concentrations included higher weight, creatinine clearance rates, and fibrinogen and antithrombin concentrations, lower concentrations of lactate, and the presence of acute respiratory distress syndrome (ARDS). Linezolid clearance was increased in ARDS patients (by 82%) and in patients with elevated fibrinogen or decreased lactate concentrations. In simulated patients, most covariates, including fibrinogen and lactate concentrations and weight, showed quantitatively minor effects on target attainment (difference of ≤9% between the first and fourth quartiles of the respective parameters). In contrast, the presence of ARDS had the strongest influence, with only ≤6% of simulated patients reaching this target. In conclusion, the presence of ARDS was identified as a new and strong predictor of insufficient linezolid concentrations, which might cause treatment failure. Insufficient concentrations might also be a major problem in patients with combined alterations of other covariate parameters. (This study has been registered at ClinicalTrials.gov under registration number NCT01793012.).

Topics: Aged; Anti-Bacterial Agents; Body Weight; Creatinine; Critical Illness; Drug Administration Schedule; Drug Dosage Calculations; Female; Fibrin; Fibrinogen; Humans; Lactic Acid; Linezolid; Male; Middle Aged; Models, Statistical; Multivariate Analysis; Prospective Studies; Respiratory Distress Syndrome; Risk Factors

Deposition of fibrin in the alveolar space is a hallmark of acute lung injury (ALI). Plasminogen activator inhibitor-1 (PAI-1) is an antifibrinolytic agent that is activated during inflammation. Increased plasma and pulmonary edema fluid levels of PAI-1 are associated with increased mortality in adults with ALI. This relationship has not been examined in children. The objective of this study was to test whether increased plasma PAI-1 levels are associated with worse clinical outcomes in pediatric patients with ALI.. We measured plasma PAI-1 levels on the first day of ALI among 94 pediatric patients enrolled in two separate prospective, multicenter investigations and followed them for clinical outcomes. All patients met American European Consensus Conference criteria for ALI.. A total of 94 patients were included. The median age was 3.2 years (range 16 days-18 years), the PaO(2)/F(i)O(2) was 141 +/- 72 (mean +/- SD), and overall mortality was 14/94 (15%). PAI-1 levels were significantly higher in nonsurvivors compared to survivors (P < 0.01). The adjusted odds of mortality doubled for every log increase in the level of plasma PAI-1 after adjustment for age and severity of illness.. Higher PAI-1 levels are associated with increased mortality and fewer ventilator-free days among pediatric patients with ALI. These findings suggest that impaired fibrinolysis may play a role in the pathogenesis of ALI in pediatric patients and suggest that PAI-1 may serve as a useful biomarker of prognosis in patients with ALI.

Topics: Acute Lung Injury; Child; Child, Preschool; Female; Fibrin; Humans; Infant; Infant, Newborn; Male; Plasminogen Activator Inhibitor 1; Prospective Studies; Pulmonary Alveoli; Respiratory Distress Syndrome; Survival Rate; Treatment Failure

Clinical and autopsy studies have shown an association between clotting, microembolism, and inhibition of fibrinolysis and respiratory distress after trauma or sepsis. Prophylaxis and treatment with the aim of decreasing the deposition of fibrin in the lungs were associated with a large decrease in the incidence and death rate of this syndrome. Small fibrin degradation products (peptides) are accumulated in the lungs and are only slowly cleared from this organ, especially during states of inhibition of fibrinolysis. These peptides may contribute to the pulmonary damage in several ways. As well as having a direct effect on the endothelium, they act by interfering with other vasoactive substances as bradykinin, histamine, and products of the arachidonic acid cascade. Products of the cyclooxygenase pathway such as thromboxane A2 play a major role in early microembolism, whereas lipoxygenase products seem to be involved in later stages. Pulmonary microembolism thus seems to be one important, but certainly not the only, pathogenetic factor in acute "idiopathic" respiratory failure. Other factors, such as pulmonary contusion, aspiration of gastric contents or blood, or oxygen toxicity, might well be contributory in some cases. Pulmonary microemboli containing fibrin and leukocytes are probably also involved as contributory agents in some cases in the large group of acute respiratory failures due to "known factors."

Topics: Albumins; Animals; Clinical Trials as Topic; Dextrans; Dogs; Fibrin; Fibrinolysis; Hemostasis; Heparin; Humans; Lung; Pulmonary Embolism; Random Allocation; Rats; Respiratory Distress Syndrome; Syndrome; Thrombin; Time Factors

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is a common clinical problem, leading to significant morbidity and mortality, and no effective pharmacotherapy exists. The problem of ARDS causing mortality became more apparent during the COVID-19 pandemic. Biotherapeutic products containing multipotent mesenchymal stromal cell (MMSC) secretome may provide a new therapeutic paradigm for human healthcare due to their immunomodulating and regenerative abilities. The content and regenerative capacity of the secretome depends on cell origin and type of cultivation (two- or three-dimensional (2D/3D)). In this study, we investigated the proteomic profile of the secretome from 2D- and 3D-cultured placental MMSC and lung fibroblasts (LFBs) and the effect of inhalation of freeze-dried secretome on survival, lung inflammation, lung tissue regeneration, fibrin deposition in a lethal ALI model in mice. We found that three inhaled administrations of freeze-dried secretome from 2D- and 3D-cultured placental MMSC and LFB protected mice from death, restored the histological structure of damaged lungs, and decreased fibrin deposition. At the same time, 3D MMSC secretome exhibited a more pronounced trend in lung recovery than 2D MMSC and LFB-derived secretome in some measures. Taking together, these studies show that inhalation of cell secretome may also be considered as a potential therapy for the management of ARDS in patients suffering from severe pneumonia, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), however, their effectiveness requires further investigation.

Topics: Acute Lung Injury; Animals; Cell Culture Techniques; COVID-19; Female; Fibrin; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Pandemics; Placenta; Pneumonia; Pregnancy; Proteomics; Respiratory Distress Syndrome; SARS-CoV-2; Secretome

Acute lung injury (ALI) as a model of acute respiratory distress syndrome is characterized by inflammation, complex coagulation, and hematologic abnormalities which result in the formation of fibrin-platelet microthrombi in the pulmonary vessels with the rapid development of progressive respiratory dysfunction. We hypothesize that a nebulized fibrinolytic agent, non-immunogenic staphylokinase (nSta), may be useful for ALI therapy. First, the effect of the nebulized nSta (0.2 mg/kg, 1.0 mg/kg, or 2.0 mg/kg) on the coagulogram parameters was studied in healthy rats. ALI was induced in mice by nebulized administration of lipopolysaccharide (LPS) at a dose of 10 mg/kg. nSta (0.2 mg/kg, 0.4 mg/kg or 0.6 mg/kg) was nebulized 30 min, 24 h, and 48 h after LPS administration. The level of pro-inflammatory cytokines was determined in the blood on the 8th day after LPS and nSta administration. The assessment of lung damage was based on their weighing and microscopic analysis. Fibrin/fibrinogen deposition in the lungs was determined by immunohistochemistry. After nSta nebulization in healthy rats, the fibrinogen blood level as well as activated partial thromboplastin time and prothrombin time did not change. In the nebulized ALI model, the mice showed an increase in lung weight due to their edema and rising fibrin deposition. An imbalance of proinflammatory cytokines was also found. Forty percent of mice with ALI without nSta nebulization had died. Nebulized nSta at a dose of 0.2 mg/kg reduced the severity of ALI: a decrease in interstitial edema and inflammatory infiltration was noted. At a dose of 0.4 mg/kg of nebulized nSta, the animals showed no peribronchial edema and the bronchi had an open clear lumen. At a dose of 0.6 mg/kg of nebulized nSta, the manifestations of ALI were completely eliminated. A significant dose-dependent reduction of the fibrin-positive areas in the lungs of mice with ALI was established. Nebulized nSta had a normalizing effect on the proinflammatory cytokines in blood- interleukin (IL)-1α, IL-17A, IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF). These data showed the effectiveness of nebulized nSta and the perspectives of its clinical usage in COVID-19 patients with acute respiratory distress syndrome (ARDS).

Topics: Acute Lung Injury; Animals; COVID-19; Disease Models, Animal; Fibrin; Fibrinogen; Lipopolysaccharides; Lung; Metalloendopeptidases; Mice; Rats; Respiratory Distress Syndrome

The use of fibrinolytic therapy has been proposed in severe acute respiratory distress syndrome (ARDS). During the COVID-19 pandemic, anticoagulation has received special attention due to the frequent findings of microthrombi and fibrin deposits in the lungs and other organs. Therefore, the use of fibrinolysis has been regarded as a potential rescue therapy in these patients. In this prospective meta-analysis, we plan to synthesise evidence from ongoing clinical trials and thus assess whether fibrinolytic therapy can improve the ventilation/perfusion ratio in patients with severe COVID-19-caused ARDS as compared with standard of care.. This protocol was registered in PROSPERO. All randomised controlled trials and prospective observational trials that compare fibrinolytic therapy with standard of care in adult patients with COVID-19 and define their primary or secondary outcome as improvement in oxygenation and/or gas exchange, or mortality will be considered eligible. Safety outcomes will include bleeding event rate and requirement for transfusion. Our search on 25 January 2022 identified five eligible ongoing clinical trials. A formal search of MEDLINE (via PubMed), Embase, CENTRAL will be performed every month to identify published results and to search for further trials that meet our eligibility criteria.. This could be the first qualitative and quantitative synthesis summarising evidence of the efficacy and safety of fibrinolytic therapy in critically ill patients with COVID-19. We plan to publish our results in peer-reviewed journals.. CRD42021285281.

Topics: Adult; Anticoagulants; COVID-19; Critical Illness; Fibrin; Humans; Meta-Analysis as Topic; Observational Studies as Topic; Pandemics; Prospective Studies; Respiratory Distress Syndrome; SARS-CoV-2; Thrombolytic Therapy; Treatment Outcome

As one of the most important endogenous chemotactic factors for neutrophils, the chemokine CXCL8 (IL-8) is involved in the pathogenesis of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), characterized by massive neutrophil infiltration in the lung. Since neutralization of CXCL8 with polyclonal antibody has been shown to reduce the severity of ALI/ARDS in animal models, we explored the potential of humanized anti-CXCL8 antibody as a preventive or therapeutic agent for ALI. We used a 'two-hit' protocol to induce ALI in rabbits that showed extensive edema in the alveolar lumina, marked infiltration of neutrophils in the lung tissue, fibrin deposition in alveolar space, and destruction of pulmonary architecture, culminating in severe hypoxemia. Concomitant challenge with endotoxin after priming with oleic acid (OA) induced a marked elevation of CXCL8 level in bronchoalveolar lavage fluid. Treatment of the rabbits with a humanized anti-CXCL8 antibody prevented neutrophil infiltration in the lung in association with alleviated ALI syndrome. Our results indicate a promising future for utilization of humanized anti-CXCL8 antibody in the prevention and treatment of ALI and ARDS in human.

Topics: Acute Lung Injury; Animals; Antibodies, Monoclonal; Bronchoalveolar Lavage; Capillary Permeability; Edema; Endotoxins; Female; Fibrin; Hypoxia; Interleukin-1; Interleukin-8; Lung; Male; Mice; Neutrophils; Oleic Acid; Rabbits; Respiratory Distress Syndrome; Tumor Necrosis Factor-alpha

Topics: Acute Lung Injury; Animals; Fibrin; Humans; Mice; Plasminogen Activator Inhibitor 1; Protein C; Rats; Respiratory Distress Syndrome

Critically ill patients are commonly associated with systemic inflammatory response syndrome (SIRS) and are at a greater risk of developing acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Under these conditions, large amounts of various cytokines are produced, which either directly or indirectly induce tissue injury and finally organ dysfunctions, through the activation of neutrophils and as a result of release of cytotoxic molecules, especially neutrophil elastase (NE). In the present study, we determined plasma neutrophil elastase-alpha-1 antitrypsin complex (NE-AT) and elastase digests of cross-linked fibrin (e-XDP) in critically ill patients to elucidate the significance of NE in the initiation and progression of ALI and ARDS in the presence or absence of SIRS. We found significantly increased levels of plasma NE-AT in the patients with ARDS, especially when the definition of SIRS was met. Among ALI/ARDS groups, plasma NE-AT, but not e-XDP, correlated significantly with the decrease in PaO(2)/FIO(2) ratio and the duration of ALI/ARDS. Furthermore, NE-AT, but not e-XDP, significantly increased in subgroups whose PaO(2)/FIO(2) ratio decreased by more than 20%. Such correlations and differences between the subgroups were not observed in the non-ALI patients. From these results, we speculate that NE-AT, but not e-XDP, may be predictive of progressive lung injury in the early stage of ALI and ARDS.

Topics: alpha 1-Antitrypsin; Critical Illness; Female; Fibrin; Humans; Leukocyte Elastase; Male; Middle Aged; Protein Binding; Respiratory Distress Syndrome; Systemic Inflammatory Response Syndrome

Acute respiratory distress syndrome (ARDS) is characterized by the presence of fibrin-rich inflammatory exudates in the intra-alveolar spaces and the extensive migration of neutrophils into alveoli of the lungs. Tissue factor (TF)-dependent procoagulant properties of bronchoalveaolar lavage fluid (BALF) obtained from ARDS patients favor fibrin deposition, and are likely the result of cross-talk between inflammatory mediators and hemostatic mechanisms. However, the regulation of these interactions remains elusive. Prompted by previous findings suggesting that neutrophils, under certain inflammatory conditions, can express functional TF, we investigated the contribution of intra-alveolar neutrophils to the procoagulant properties of BALF from patients with ARDS. Our results confirm that the procoagulant properties of BALF from ARDS patients are the result of TF induction, and further indicate that BALF neutrophils are a main source of TF in intra-alveolar fluid. We also found that BALF neutrophils in these patients express significantly higher levels of TF than peripheral blood neutrophils. These results suggest that the alveolar microenvironment contributes to TF induction in ARDS. Additional experiments indicated that the ability of BALF to induce TF expression in neutrophils from healthy donors can be abolished by inhibiting C5a or TNF-alpha signaling, suggesting a primary role for these inflammatory mediators in the up-regulation of TF in alveolar neutrophils in ARDS. This cross-talk between inflammatory mediators and the induction of TF expression in intra-alveolar neutrophils may be a potential target for novel therapeutic strategies to limit ARDS-associated disturbances of coagulation.

Topics: Adult; Aged; Bronchoalveolar Lavage Fluid; Complement C5a; Cytokines; Fibrin; Humans; Middle Aged; Neutrophils; Respiratory Distress Syndrome; Thromboplastin; Tumor Necrosis Factor-alpha

The hypothesis that the expression of protease-activated receptors (PARs) protein is regulated at the level of transcription and that PAR isoforms, PAR-1, PAR-2, PAR-3, and PAR-4, in lung tissue show different patterns of expression in lipopolysaccharide (LPS)-induced acute lung injury (ALI) was tested. Male Wistar rats were rendered endotoxemic by intra-peritoneal injection of LPS (15 mg/kg body weight). We examined the expression of protein and mRNA and the immunohistochemical localization of PAR isoforms in lung tissues 1, 3, 6, and 10 h after LPS administration. Induction of ALI by LPS was confirmed based on histopathological changes. LPS administration induced significant increases in the expression of PAR isoforms (protein) at the level of transcription in ALI. While the time course of PAR-1 and -2 expressions were different, those of PAR-3 and -4 were almost similar. An immunohistochemical analysis showed localization of PAR isoforms in the vascular endothelium, alveolar epithelium, and alveolar macrophages. However, the cellular distribution patterns of PAR isoforms were different. We conclude that LPS induces increase in protein expression of PAR isoforms at the level of transcription in rats with ALI. The differential expression patterns (over a time course) and distribution of PAR isoforms suggests a distinct role for each isoform in the pathogenesis of LPS-induced ALI.

Topics: Animals; Blood Pressure; Blotting, Western; Disease Models, Animal; Endothelial Cells; Epithelial Cells; Fibrin; Immunohistochemistry; Lipopolysaccharides; Lung; Macrophages, Alveolar; Male; Nitric Oxide Synthase Type II; Oxygen; Pulmonary Alveoli; Rats; Rats, Wistar; Receptor, PAR-1; Receptor, PAR-2; Receptors, Proteinase-Activated; Receptors, Thrombin; Respiratory Distress Syndrome; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors; Transcription, Genetic; Tumor Necrosis Factor-alpha

Reopening the injured lung with deep inflation (DI) and positive end-expiratory pressure (PEEP) likely depends on the duration and severity of acute lung injury (ALI), key features of which include increased alveolar permeability and fibrin accumulation. We hypothesized that the response to DI and PEEP would worsen as ALI evolves and that this would correspond with increasing accumulation of alveolar fibrin. C57BL/6 mice were anesthetized and aspirated 75 microl of HCl (pH 1.8) or buffered normal saline. Subgroups were reanesthetized 4, 14, 24, and 48 h later. Following DI, tissue damping (G) and elastance (H) were measured periodically at PEEP of 1, 3, and 6 cmH(2)O, and air within the lung (thoracic gas volume) was quantified by microcomputed tomography. Following DI, G and H increased with time during progressive lung derecruitment, the latter confirmed by microcomputed tomography. The rise in H was greater in acid-injured mice than in controls (P < 0.05) and also increased from 4 to 48 h after acid aspiration, reflecting progressively worsening injury. The rise in H was reduced by PEEP, but this effect was significantly blunted by 48 h (P < 0.05), also confirmed by thoracic gas volume. Lung permeability and alveolar fibrin also increased over the 48-h study period, accompanied by increasing levels and transcription of the fibrinolysis inhibitor plasminogen activator inhibitor-1. Lung injury worsens progressively in mice during the 48 h following acid aspiration. This injury manifests as progressively increasing alveolar instability, likely due to surfactant dysfunction caused by increasing levels of alveolar protein and fibrin.

Topics: Animals; Biomarkers; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Disease Progression; Female; Fibrin; Fibrinolysis; Hydrochloric Acid; Lung Volume Measurements; Mice; Mice, Inbred C57BL; Pneumonia, Aspiration; Positive-Pressure Respiration; Respiratory Distress Syndrome; Severity of Illness Index

Hemostatic parameters were examined before and during 102 courses of chemotherapy in 42 patients with malignant lymphoma with high risk for infection. The white blood cell count was significantly reduced in all patients at days 1 and 3, but significantly increased at days 7 and 9, compared to before chemotherapy. At day 7 of chemotherapy, tissue factor (TF) mRNA levels in leukocytes were significantly increased in all patients, especially those with infection. Plasma concentrations of granulocyte elastase derived-XDP (GE-XDP) levels correlated with D-dimer levels during chemotherapy in patients with malignant lymphoma, suggesting that the elevated D-dimer is fibrin products degraded by granulocyte elastase. GE-XDP, C-reactive protein (CRP), GE-XDP and D-dimer were significantly higher in patients with infection, disseminated intravascular coagulation (DIC) and acute respiratory distress syndrome (ARDS) than those without. In patients with DIC or ARDS, TF mRNA correlated with D-dimer, and GE-XDP correlated with leukocyte count, CRP and D-dimer, suggesting that inflammatory changes due to thrombosis may cause the activation of leukocytes in patients with malignant lymphoma during chemotherapy. Activated leukocytes and granulocyte elastase may elicit a hypercoagulable state and ARDS in patients with malignant lymphoma during chemotherapy.

Topics: Aged; Antineoplastic Agents; C-Reactive Protein; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Hemostasis; Humans; Infections; Leukocyte Count; Leukocyte Elastase; Leukocytes; Lymphoma; Male; Middle Aged; Prospective Studies; Respiratory Distress Syndrome; RNA, Messenger; Thromboplastin; Time Factors

Topics: Fibrin; Fibrinolytic Agents; Humans; Lung; Pneumonia; Pulmonary Fibrosis; Respiratory Distress Syndrome; Thrombosis; Time Factors

In acute lung injury (ALI), a coagulation/fibrinolysis imbalance leads to fibrin deposition, persistence of which contributes to fibrotic evolution. Our study evaluated the effects of early inhibition of coagulation in Pseudomonas aeruginosa (Pa)-induced ALI through the use of recombinant human antithrombin (rhAT). The study was conducted in vivo on a murine model of Pa-induced ALI. Intravenous rhAT was administered simultaneously with intratracheal Pa. Four experimental groups were compared: CTR, intratracheal saline (0.5 mL/kg)/intravenous saline (1 mL); PNP, intratracheal Pa (0.5 mL/kg of 2 x 10(9) cfu)/intravenous saline; AT, intratracheal saline/intravenous rhAT (500 IU/kg); ATPNP, intratracheal Pa/intravenous rhAT. Epithelial and endothelial permeabilities were evaluated with radiolabeled albumin flux across the alveolar barrier (125I- and 131I-labeled albumin). Thrombin-antithrombin (TAT) complexes levels were used as markers of coagulation activation in blood samples and in BAL fluid. Epithelial and endothelial protein permeability were increased in Pa-induced ALI versus control. Intravenous rhAT administration led to further permeability disorders. Administration of rhAT in Pa ALI led to a rise in TAT complexes in ATPNP blood serum and BAL fluids compared with the other groups. In Pa-induced ALI the administration intravenous rhAT leads to major histologic damage, alveolar capillary barrier injury, and permeability increase. Such effects of the inhibition of thrombin activation by rhAT lead to the hypothesis of a probable beneficial role of early coagulation activation in ALI as a factor limiting both the extent of injury and permeability disorders. Our study suggests that inhibition of this initial procoagulative imbalance is potentially dangerous.

Topics: Animals; Antithrombins; Blood Coagulation; Blood Pressure; Bronchoalveolar Lavage Fluid; Female; Fibrin; Fibrinolysis; Humans; Lung; Lung Injury; Oxygen; Pseudomonas aeruginosa; Pseudomonas Infections; Pulmonary Alveoli; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome; Thrombin; Time Factors

Changes in the alveolar hemostatic balance in severe pneumonia were compared with those in the acute respiratory distress syndrome (ARDS). Analysis was performed in bronchoalveolar lavage fluids (BALF) of patients with ARDS triggered by nonpulmonary underlying events in the absence of lung infection (ARDS; n = 25), pneumonia demanding mechanical ventilation (PNEU-vent; n = 114), spontaneously breathing patients with pneumonia (PNEU-spon; n = 40), and ARDS in combination with lung infection (ARDS+PNEU; n = 43); comparison with healthy control subjects (n = 35) was performed. In all groups of patients, BALF total procoagulant activity was increased by nearly two orders of magnitude, being largely attributable to the tissue factor pathway of coagulation. Concomitantly, markedly reduced overall fibrinolytic capacity (fibrin plate assay) was noted in the lavage fluids of all patients. BALF levels of urokinase-type plasminogen activator were significantly reduced throughout, whereas the lavage concentrations of tissue-type plasminogen activator did not differ from those in control subjects. In addition, markedly enhanced levels of plasminogen activator- inhibitor I and alpha(2)-antiplasmin were noted in ARDS, ARDS+PNEU, and PNEU-vent, but not in PNEU-spon. In all groups of patients, the changes in the lavage enzymatic activities were paralleled by manifold increased BALF concentrations of fibrinopeptide A and D-dimer, reflecting in vivo coagulation processes. Within the overall number of patients with pneumonia, changes in the alveolar hemostatic balance were more prominent in alveolar and interstitial pneumonia than in bronchopneumonia. Acute inflammatory lung injury, whether triggered by nonpulmonary systemic events or primary lung infection, is thus consistently characterized by both enhanced procoagulant and depressed fibrinolytic activities in the alveolar lining layer, with the appearance of fibrin formation in this compartment. Profile and extent of changes in severe pneumonia demanding respirator therapy are virtually identical to those in ARDS, whereas somewhat less prominent alterations of the alveolar hemostatic balance are noted in spontaneously breathing patients with pneumonia.

Topics: Adolescent; Adult; Aged; Bronchoalveolar Lavage Fluid; Critical Care; Diagnosis, Differential; Female; Fibrin; Fibrinolysis; Humans; Male; Middle Aged; Pneumonia, Bacterial; Pulmonary Alveoli; Respiration, Artificial; Respiratory Distress Syndrome

Topics: Acute Disease; Animals; Antithrombin III; Blood Coagulation Disorders; Complement Activation; Cytokines; Disseminated Intravascular Coagulation; Endotoxemia; Fibrin; Gene Expression Regulation; Hemorrhage; Humans; Lipoproteins; Lung Injury; Primates; Protein C; Reactive Oxygen Species; Respiratory Distress Syndrome; Sepsis; Thromboplastin; Transcription, Genetic; Tumor Necrosis Factor-alpha

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

Extravascular coagulation and fibrin deposition coupled with perturbations of intravascular coagulation occurs in association with acute respiratory distress syndrome (ARDS). To evaluate the pathogenetic role of an extrinsic coagulation pathway in the intravascular coagulation of ARDS patients and to explore the time course of the changes of tissue factor levels, platelet counts, and disseminated intravascular coagulation (DIC), we performed a prospective cohort study.. The study subjects consisted of 113 patients: 27 patients with ARDS, 31 patients at risk for but not developing the syndrome, and 55 patients without ARDS. According to the underlying disease, the patients were further subdivided into two groups: patients with trauma (n = 76) and patients with sepsis (n = 37). Ten normal healthy volunteers served as control subjects. Plasma tissue factor antigen (tissue factor) levels and platelet counts were measured on the day of admission and on days 1 through 4 after admission. Simultaneously, the DIC scores were determined.. The values of tissue factor in the patients with ARDS were significantly more elevated than those measured in the other two groups (p < 0.001) and control subjects (p < 0.001) on the day of admission. The values continued to be markedly high up to day 4 of admission. On the day of admission, the platelet counts in the ARDS patients showed significantly lower values (p < 0.05) than those in the other two groups. The incidence of DIC and the DIC scores in ARDS patients were significantly higher than those in the other two groups. The tissue factor levels (r(s) = 0.428, p < 0.0001) and DIC scores (r(s) = 0.357, p < 0.0002) correlated significantly with Lung Injury Score. When the patients were subdivided into two subgroups, i.e., trauma and sepsis, some differences of the tissue factor levels were noted between the two groups.. We demonstrated that tissue-factor dependent coagulation pathway of plasma is extensively activated in patients with ARDS, followed by intravascular coagulation and platelet consumption. We further provide precise information on the time course of tissue factor levels and DIC in patients with ARDS and those at risk for developing this syndrome.

Topics: Analysis of Variance; APACHE; Blood Coagulation; Case-Control Studies; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrinogen; Humans; Male; Middle Aged; Multiple Trauma; Platelet Count; Prospective Studies; Prothrombin Time; Respiratory Distress Syndrome; Risk Factors; Sepsis; Thromboplastin; Time Factors

Fibrosis results when myofibroblasts invade the wound fibrin provisional matrix. Extracellular matrix receptors on the cell surface mediate cell adhesion, migration, and invasion. Recent work with transformed cells indicates that these cells use the cell surface matrix receptor CD44 for migration and invasion. In this study, we examine whether lung fibroblasts, isolated from patients dying with acute alveolar fibrosis, use CD44 to invade a fibrin matrix. Consistent with a role for CD44 in mediating fibroblast invasion and subsequent tissue fibrosis, immunohistochemical analysis of lung tissue from patients who died from acute alveolar fibrosis after lung injury reveals CD44-expressing mesenchymal cells throughout newly formed fibrotic tissue. PCR, Western, and immunoprecipitation analysis demonstrate that the 85-kD CD44 isoform is expressed by acute lung injury fibroblasts. Consistent with a role in mediating matrix adhesion and migration ultrastructurally, CD44 was found uniformly over the cell surface and was found densely labeling filopodia and lamellipodia, highly motile structures involved in cell migration. To determine if lung injury fibroblasts use CD44 to invade fibrin, a fibrin gel model of fibrosis was used. By blocking the function of CD44 with monoclonal antibodies, fibroblast invasion into a fibrin matrix was inhibited. To examine the mechanism by which CD44 mediates fibroblast invasion, the role of CD44 in fibroblast migration and adhesion was evaluated. Anti-CD44 antibody blocked fibroblast migration on the provisional matrix proteins fibronectin, fibrinogen, and hyaluronic acid. Additionally, fibroblast CD44 mediated adhesion to the provisional matrix proteins fibronectin, fibrin, and hyaluronic acid, but not to laminin, a component of the basement membrane. These findings support the hypothesis that fibroblast CD44 functions as an adhesion receptor for provisional matrix proteins and is capable of mediating fibroblast migration and invasion of the wound provisional matrix resulting in the formation of fibrotic tissue.

Topics: Cell Adhesion; Cell Movement; Cells, Cultured; Fibrin; Fibroblasts; Humans; Hyaluronan Receptors; Hyaluronic Acid; Immunohistochemistry; Pulmonary Fibrosis; Respiratory Distress Syndrome; RNA, Messenger

Topics: Adult; Animals; Bronchoalveolar Lavage Fluid; Fetal Organ Maturity; Fibrin; Hemostasis; Humans; Infant, Newborn; Lung; Papio; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn

In order to determine if the Adult Respiratory Distress Syndrome (ARDS) is associated with a shortage of pulmonary surfactant, we have examined a series of 155 undiluted tracheal aspirates obtained from 23 patients with ARDS and from 30 patients without ARDS, all 53 needing ventilatory support. The unfixed and unstained specimens were examined by polarized light microscopy for the presence of pulmonary surfactant. Free surfactant particles were present in the aspirates of 50 patients (95%). Within minutes of obtaining the specimen, in addition to showing surfactant, the examination of these undiluted, unfixed tracheal aspirates by light microscopy showed the presence of bacterial and fungal infection. As fibrinogen/fibrin inactivates surfactant, the undiluted aspirates of 21 patients with ARDS and of 30 patients without ARDS were stained for the presence of these proteins by a new slide method using 0.01 ml of tracheal aspirate. Fibrinogen/fibrin was found in the aspirates from 20 of 21 patients with ARDS and in only five of 30 patients without ARDS; these five had bronchopneumonia. The method has a sensitivity of 0.95 and a specificity of 0.83. The role of plasma proteins and of neutrophil leucocytes in causing ARDS is discussed.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Colony Count, Microbial; Female; Fibrin; Fibrinogen; Humans; Leukocyte Count; Male; Middle Aged; Pulmonary Surfactants; Respiratory Distress Syndrome

Alveolar fibrin deposition is prominent in diffuse alveolar damage, the morphologic hallmark of the adult respiratory distress syndrome. To determine if a persistent abnormality of fibrin clearance occurs in the alveolar compartment during evolving diffuse alveolar damage, we characterized abnormalities of fibrin turnover in serial bronchoalveolar lavage specimens from two baboon models: a) diffuse alveolar damage induced by 80% oxygen and bronchoscopic seeding of Pseudomonas aeruginosa; and b) a more fulminant form of diffuse alveolar damage induced by bronchoscopic seeding of Pseudomonas and the infusion of oleic acid.. Lavage procoagulant activity, due mainly to tissue factor associated with Factor VII, was increased and exceeded regulation by extrinsic pathway inhibitor in both models. Fibrinolytic activity was transiently diminished in baboons with evolving diffuse alveolar damage induced by oleic acid/Pseudomonas, but was preserved after 80% oxygen/Pseudomonas. Concentrations of plasminogen activator inhibitor-2 did not increase in lavage specimens obtained during evolving diffuse alveolar damage. Concentrations of alpha 2 antiplasmin and plasminogen activator inhibitor-1 tended to be higher in the lavage of oleic acid/Pseudomonas baboons with low fibrinolytic activity. Immunohistochemical analyses showed that tissue factor was distributed along the alveolar surface of controls and baboons with diffuse alveolar damage. Alveolar fibrin deposition was increased, by morphometric analyses, in both models.. These data indicate that while increased procoagulant activity is characteristic of evolving diffuse alveolar damage and favors alveolar fibrin deposition, fibrinolytic activity may be transiently diminished or remain intact during evolving diffuse alveolar damage in baboons.

Topics: alpha-2-Antiplasmin; Animals; Bronchoalveolar Lavage Fluid; Bronchoscopy; Disease Models, Animal; Evaluation Studies as Topic; Fibrin; Fibrinolysis; Immunohistochemistry; Metabolic Clearance Rate; Oleic Acid; Oleic Acids; Oxygen; Papio; Plasminogen; Plasminogen Activator Inhibitor 1; Plasminogen Activator Inhibitor 2; Pseudomonas aeruginosa; Pulmonary Fibrosis; Respiratory Distress Syndrome; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator

We studied the changes of coagulation and fibrinolysis in bronchoalveolar lavage (BAL) and plasma obtained serially at intervals after the onset of adult respiratory distress syndrome (ARDS). BAL procoagulant activity was increased at 3 days and tended to decrease thereafter. Tissue factor associated with factor VII was the major BAL procoagulant. Fibrinopeptide A was increased, indicating increased thrombin-mediated conversion of fibrinogen to fibrin. Fibrinolytic activity was usually undetectable in BAL at 3 days post-ARDS and remained depressed for up to 14 days despite unchanged concentrations of urokinase and variably detectable tissue plasminogen activator. Depressed fibrinolytic activity was associated with increased antiplasmin activity and plasminogen activator inhibitor 1 (PAI-1) while PAI-2 concentrations approximated those of control samples and did not change during evolving ARDS. Evidence of systemic coagulopathy and increased systemic fibrin degradation were commonly found in serial ARDS plasma samples, consistent with accelerated vascular and/or extravascular fibrin deposition in these patients. The data indicate that intra-alveolar as well as systemic derangements of fibrin turnover are common features of evolving ARDS. Concurrent local abnormalities of both coagulation and fibrinolytic pathways favor persistence of alveolar fibrin for up to 14 days after clinical recognition of ARDS.

Topics: Adult; Aged; Blood Coagulation; Bronchoalveolar Lavage Fluid; Fibrin; Fibrinogen; Fibrinolysis; Humans; Middle Aged; Proteins; Respiratory Distress Syndrome; Thrombin

Abundant deposition of bronchoalveolar fibrin and fibronectin occurs during the exudative phase of the adult respiratory distress syndrome (ARDS), promoting hyaline-membrane formation and subsequent alveolar fibrosis. To explore the mechanisms that account for the persistence of bronchoalveolar fibrin and fibronectin, we compared the activity of urokinase, which is necessary for plasminogen activation and fibrin degradation, in cell-free bronchoalveolar-lavage fluid from 8 patients with ARDS, 9 patients with acute pulmonary diseases other than ARDS, and 10 normal subjects. The mean level of urokinase activity in the lavage fluid from the patients with ARDS was 0.003 IU per milliliter of fluid (range, 0 to 0.008), which was significantly lower (P = 0.001) than the level in the fluid from either the patients with pulmonary diseases other than ARDS (0.118 IU per milliliter [range, 0.032 to 0.295]) or the normal subjects (0.129 IU per milliliter [range, 0.045 to 0.198]). The lavage fluid from all the patients with ARDS also had antiplasmin activity, which would promote the persistence of fibrin. A true decrease in urokinase activity was confirmed by the failure of the lavage fluid from the patients with ARDS to convert [125I]plasminogen to plasmin. Despite the low urokinase activity, immunochemical assays revealed normal levels of urokinase antigen in the fluid from the patients with ARDS, suggesting the presence of urokinase inhibitors. Inhibitors were demonstrated directly by a fibrin gel-underlay assay that detects complexes of urokinase with inhibitors. Plasminogen-activator inhibitor type 1 was the principal inhibitor identified. We conclude that increased antifibrinolytic activity due to both urokinase inhibitors and antiplasmins in the bronchoalveolar compartment of patients with ARDS contributes to the formation and persistence of hyaline membranes, a key component of alveolar histopathology in ARDS.

Topics: Adult; alpha-2-Antiplasmin; Antigens; Bronchoalveolar Lavage Fluid; Female; Fibrin; Fibronectins; Humans; Lung Diseases; Male; Middle Aged; Respiratory Distress Syndrome; Urokinase-Type Plasminogen Activator

Topics: Fibrin; Humans; Respiratory Distress Syndrome; Respiratory System

To determine the possible mechanism(s) promoting alveolar fibrin deposition in the adult respiratory distress syndrome (ARDS), we investigated the initiation and regulation of both fibrinolysis and coagulation from patients with ARDS (n = 14), at risk for ARDS (n = 5), and with interstitial lung diseases (ILD) (n = 8), and normal healthy individuals (n = 13). Bronchoalveolar lavage (BAL) extrinsic pathway inhibitor activity was increased in ARDS BAL compared with patients at risk for ARDS (P = 0.0146) or normal controls (P = 0.0013) but tissue factor-factor VII procoagulant activity was significantly increased in ARDS BAL compared with all other groups (P less than 0.001). Fibrinolytic activity was not detectable in BAL of 10 of the 14 patients with ARDS and low levels of activity were found in BAL of the other four ARDS patients. Depressed fibrinolysis in ARDS BAL was not due to local insufficiency of plasminogen; rather, there was inhibition of both plasmin and plasminogen activator. Plasminogen activator inhibitor 1 was variably detected and low levels of plasminogen activator inhibitor 2 were found in two ARDS BAL samples, but plasminogen activator inhibitor 2 was otherwise undetectable. ARDS BAL antiplasmin activity was, in part, due to alpha 2-antiplasmin. We conclude that abnormalities that result in enhanced coagulation and depressed fibrinolysis, thereby predisposing to alveolar fibrin deposition, occur in the alveolar lining fluids from patients with ARDS.

Topics: Adult; Antithrombin III; Blood Coagulation; Bronchoalveolar Lavage Fluid; Factor X; Fibrin; Fibrinolysis; Glycoproteins; Humans; Middle Aged; Plasminogen Activators; Plasminogen Inactivators; Pulmonary Alveoli; Respiratory Distress Syndrome

Decreased angiotensin converting enzyme (ACE) activity is a common finding in patients with adult respiratory distress syndrome and in animal models of lung injury. The nature of this effect is unknown. Intravascular fibrin, also a common finding in lung injury, is degraded to small peptides by proteolytic enzymes. Peptide 6A, corresponding to amino acid residues 43 to 47 of the B beta chain of fibrin(ogen), is produced by plasmin degradation of fibrin and has been shown to inhibit ACE in vitro. We investigated the effect of this peptide on the pulmonary hydrolysis of a synthetic ACE substrate, benzoyl-phenylalanyl-alanyl-proline, in anesthetized rabbits and in isolated, perfused rabbit lungs. Peptide 6A caused a reversible, dose-dependent inhibition of benzoyl-phenylalanyl-alanyl-proline hydrolysis. It also potentiated the increase in pulmonary arterial pressure and the decrease in systemic arterial pressure due to bradykinin (BK), as well as the increase in pulmonary artery pressure due to BK in isolated lungs. The amount of BK needed to increase pulmonary arterial pressure was about 1000-fold larger in the isolated lung than in the intact animal. Peptides of this type might contribute to decreased ACE activity in patients with adult respiratory distress syndrome and may potentiate BK-mediated hemodynamic changes in these patients.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bradykinin; Dose-Response Relationship, Drug; Fibrin; Lung; Peptide Fragments; Rabbits; Respiratory Distress Syndrome

Fibrin is often seen occluding the lung vessels of patients dying from ARDS and is surrounded by regions of lung necrosis. To learn if we could observe increased or focal fibrin deposition and assess the kinetics of plasma fibrinogen turnover during severe acute respiratory failure, we injected technetium 99m-labeled human purified fibrinogen (Tc-HF) and used gamma camera scanning for as long as 12 h in 13 sequential patients as soon as possible after ICU admission. The fibrinogen uptake rates were determined by calculating the lung:heart radioactivity ratios at each time point. Slopes of the lung:heart ratio versus time were compared between ARDS and mild acute respiratory failure (ARF). The slope of the lung:heart Tc-HF ratio of the 9 patients with ARDS (2.9 +/- 0.4 units) was markedly higher (p less than 0.02) than the slope of the 4 patients with mild ARF (1.1 +/- 0.4) and the 3 patients studied 5 to 9 months after recovery from respiratory failure (0.7 +/- 0.07). In the 1 patient with ARDS and the 2 patients with mild ARF studied both during acute lung injury and after recovery, the lung:heart Tc-HF ratio had decreased at recovery. To compare the pulmonary uptake of Tc-HF to 99mTc-labeled human serum albumin (Tc-HSA), 5 patients were injected with 10 mCi of Tc-HSA, and scanning of the thorax was performed with a similar sequential imaging protocol 24 h after conclusion of the Tc-HF study.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aged; Female; Fibrin; Fibrinogen; Hemodynamics; Humans; Lung; Male; Middle Aged; Organotechnetium Compounds; Pulmonary Artery; Pulmonary Embolism; Radiography; Radionuclide Imaging; Respiratory Distress Syndrome; Technetium; Technetium Tc 99m Aggregated Albumin; Time Factors

Products of blood coagulation and fibrinolysis, which are generated by limited proteolysis are able to effect the pulmonary circulation and gas exchange by biochemically mediated actions. Thrombin, fibrin and its degradation products provoke functional and morphological changes in the vessel wall. Fibrinopeptides, fibrin monomers and fibrin (ogen) degradation products induce vasoconstriction and vascular leakage. The vasoconstricting action of fibrin monomers is mediated by thromboxane A2 (TXA2) which is synthetized in the lung tissue itself. Thromboxane synthesis is stimulated by fibrin monomers only in the pulmonary circulation and not in the systemic circulation. Besides their vascular effects, fibrin monomers disturb the function of the surfactant components and increase the surface tension in surfactant monolayers. Proteinase inhibition as a general prophylactic and therapeutic concept with adult respiratory distress syndrome (ARDS) has to include the system of blood coagulation and fibrinolysis predominantly to prevent or stop the generation of products which are able to induce pulmonary vasoconstriction, vascular leakage and impairment of pulmonary gas exchange.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Blood Coagulation; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolysis; Humans; Protease Inhibitors; Pulmonary Circulation; Pulmonary Gas Exchange; Respiratory Distress Syndrome

Many authors have advocated glucocorticoids for prophylaxis against or treatment of Adult Respiratory Distress Syndrome (ARDS) or post-traumatic pulmonary microembolism. One of the theories underlying this advocacy is that the activation of the complement system possibly is preventable by pharmacologic doses of corticosteroids. Studies on traumatized patients are difficult to standardize, and clinical observations are correspondingly difficult to evaluate. Animal models for study of the microembolism syndrome have often comprised too short a time and most have greatly differed from the clinical situation. We have earlier evolved an experimental model by means of which changes identical to the microembolism syndrome can be induced from a reproducible musculo-skeletal trauma in pigs observed under long-term anesthesia under standardized conditions. In this study, early and long-term effects of corticosteroids on the course of post-traumatic microembolism was evaluated by following the pulmonary function and X-ray appearance, pulmonary trapping of platelets and fibrin and histologic changes in pigs, using this standardized trauma model. Methylprednisolone sodium succinate (30 mg/kg bw) was given to 9 pigs one hour after trauma and thereafter every 8th hour during a 72 hour observation period. Two other groups of animals were used for comparison, 13 traumatized, non-treated and 15 non-traumatized, non-treated pigs. Intrapulmonary microembolism was measured quantitatively by repeated external detection of labelled platelets (51Cr) and fibrinogen (125I), sequential chest X-rays and morphologic examination of the lungs post mortem.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Drug Administration Schedule; Female; Fibrin; Fibrinogen; Hemodynamics; Lung; Male; Methylprednisolone; Methylprednisolone Hemisuccinate; Oxygen; Oxygen Consumption; Platelet Count; Pulmonary Embolism; Respiratory Distress Syndrome; Shock, Traumatic; Swine

A new experimental model is described in which pulmonary changes identical with the adult respiratory distress syndrome (ARDS) can be induced by reproducible musculoskeletal trauma in anesthetized pigs. The pigs were studied in maintained anesthesia for 3 days after the trauma under standardized conditions. The intrapulmonary aggregation of platelets and fibrin was monitored by external detection of radioactivity arising from pretrauma intravenous injection of 51Cr-labeled platelets and 125I-labeled fibrinogen. Pulmonary trapping of platelets and fibrin was significantly greater in the traumatized pigs than in nontraumatized but otherwise identically handled controls. Radiologic and morphologic changes corresponding to ARDS developed in the traumatized animals, but not in the controls. The experimental model offers new possibilities for study of factors influencing the occurrence and development of ARDS. After further experimental evaluation, the procedure for registering pulmonary microembolism by external detection may be useful in the clinical management of ARDS.

Topics: Animals; Blood Platelets; Disease Models, Animal; Female; Femoral Fractures; Fibrin; Fractures, Ununited; Lung; Male; Platelet Aggregation; Radiography; Respiratory Distress Syndrome; Swine; Wounds, Nonpenetrating

Pulmonary megakaryocytes and fibrin microthrombi were counted in lung sections from 22 patients dying from extensive burns. There was a significant correlation between numbers of megakaryocytes and fibrin microthrombi, supporting a relationship between disseminated intravascular coagulation (DIC) and numbers of pulmonary megakaryocytes. No correlation was found between antemortem platelet counts and either fibrin microthrombi or megakaryocytes. Possible explanations for this are forwarded and the nature of pulmonary megakaryocytes discussed.

Topics: Adult; Aged; Burns; Cell Count; Disseminated Intravascular Coagulation; Fibrin; Humans; Lung; Megakaryocytes; Middle Aged; Pulmonary Embolism; Respiratory Distress Syndrome

Injection of human alpha 2-antiplasmin resulted in delayed elimination of fibrin from the lungs in rats with thrombin-induced intravascular coagulation. The amount of alpha 2-antiplasmin injected was chosen so as to simulate the posttraumatic increase of this inhibitor in man. By injecting trace amounts only of radiolabelled alpha 2- antiplasmin a specific uptake of this protein in the lungs was noted after the thrombin-induced coagulation. The results may indicate that the posttraumatic increase in alpha 2-antiplasmin is of significance for the delayed elimination of fibrin seen in patients following trauma.

Topics: alpha-2-Antiplasmin; Animals; Disseminated Intravascular Coagulation; Fibrin; Lung; Male; Rats; Respiratory Distress Syndrome

Topics: Animals; Capillary Permeability; Dogs; Fibrin; Humans; Peptides; Pulmonary Embolism; Respiratory Distress Syndrome

Topics: Animals; Blood Coagulation Factors; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrinolysis; Hyalin; Male; Metaproterenol; Oxygen; Rabbits; Respiratory Distress Syndrome; Tranexamic Acid

Following severe multiple trauma, decreases were observed in a) Free cholesterol, b) Cholesteryl esters, c) Total phospholipids, and d) Lysolecithin. Comparatively slight changes in coagulation parameters did not differ regardless of whether pulmonary complications developed. In contrast, increased fibrin lipid complexing was more closely correlated with clinical data, because: a) Plasmatic lipids, particularly triglycerides complexed with fibrins, were elevated severalfold in patients with adult respiratory distress and fat embolism syndromes when compared with multiple trauma patients without pulmonary complications. This was independent of plasma lipid levels. b) Plasmatic triglycerides complexed with fibrins were significantly higher in patients who died than in those who survived. The considerable changes in the plasma lipid pattern following severe trauma suggest the presence of an abnormal lipoprotein with increased affinity to fibrin, thereby inhibiting fibrinolysis. This might well be one pathogenic mechanism in the development of post-traumatic respiratory distress syndrome.

Topics: Adult; Blood Coagulation Factors; Cholesterol; Cholesterol Esters; Fibrin; Humans; Lipids; Lipoproteins; Lysophosphatidylcholines; Phospholipids; Respiratory Distress Syndrome; Wounds and Injuries

Topics: Blood Preservation; Fibrin; Humans; Leukocytes; Micropore Filters; Platelet Aggregation; Respiratory Distress Syndrome; Transfusion Reaction

Topics: Animals; Fetus; Fibrin; Fibrinolysin; Guinea Pigs; Histocytochemistry; Humans; Hyaline Membrane Disease; Infant; Infant, Newborn; Infant, Premature; Physiology; Plasminogen; Research; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn