thromboplastin and Multiple-Organ-Failure

The pathobiology of the septic process includes a complex interrelationship between inflammation and the coagulations system. Antithrombin (AT) and tissue factor are important components of the coagulation system and have potential roles in the production and amplification of sepsis. Sepsis is associated with a decrease in AT levels, and low levels are also associated with the development of multiple organ failure and death. Treatment strategies incorporating AT replacement therapy in sepsis and septic shock have not resulted in an improvement in survival or reversal of disseminated intravascular coagulation.

Topics: Antithrombin III; Critical Illness; Humans; Multiple Organ Failure; Sepsis; Shock, Septic; Thromboplastin

Coagulopathy is common in acute sepsis and may range from subclinical activation of blood coagulation (hypercoagulability), which may contribute to venous thromboembolism, to acute disseminated intravascular coagulation, characterized by widespread microvascular thrombosis and consumption of platelets and coagulation proteins, eventually causing bleeding. The key event underlying this life-threatening complication is the overwhelming inflammatory host response to the pathogen leading to the overexpression of inflammatory mediators. The latter, along with the microorganism and its derivatives drive the major changes responsible for massive thrombin formation and fibrin deposition: (1) aberrant expression of tissue factor mainly by monocytes-macrophages, (2) impairment of anticoagulant pathways, orchestrated by dysfunctional endothelial cells (ECs), and (3) suppression of fibrinolysis because of the overproduction of plasminogen activator inhibitor-1 by ECs and thrombin-mediated activation of thrombin-activatable fibrinolysis inhibitor. Neutrophils and other cells, upon activation or death, release nuclear materials (neutrophil extracellular traps and/or their components such as histones, DNA, lysosomal enzymes, and High Mobility Group Box-1), which have toxic, proinflammatory and prothrombotic properties thus contributing to clotting dysregulation. The ensuing microvascular thrombosis-ischemia significantly contributes to tissue injury and multiple organ dysfunction syndromes. These insights into the pathogenesis of sepsis-associated coagulopathy may have implications for the development of new diagnostic and therapeutic tools.

Topics: Animals; Disease Models, Animal; Disseminated Intravascular Coagulation; Endothelium, Vascular; Endotoxemia; Extracellular Traps; Fibrinolysis; Humans; Immunity, Innate; Inflammation; Inflammation Mediators; Macrophages; Models, Biological; Monocytes; Multiple Organ Failure; Neutrophils; Protein C; Sepsis; Thrombophilia; Thromboplastin; Thrombotic Microangiopathies

Thrombocytopenia-associated multiple organ failure (TAMOF) is a clinical phenotype that encompasses a spectrum of syndromes associated with disseminated microvascular thromboses, such as the thrombotic microangiopathies thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) and disseminated intravascular coagulation (DIC). Autopsies findings in TTP, HUS, or DIC reveal specific findings that can differentiate these 3 entities. Von Willebrand factor and ADAMTS-13 play a central role in TTP. Shiga toxins and the complement pathway are vital in the development of HUS. Tissue factor is the major protease that drives the pathology of DIC. Acute kidney injury (AKI) is a common feature in patients with TAMOF.

Topics: Acute Kidney Injury; ADAM Proteins; ADAMTS13 Protein; Antibodies, Monoclonal, Humanized; Complement Inactivating Agents; Complement System Proteins; Disseminated Intravascular Coagulation; Hemolytic-Uremic Syndrome; Humans; Multiple Organ Failure; Purpura, Thrombotic Thrombocytopenic; Shiga Toxins; Thromboplastin; von Willebrand Factor

Sepsis is often associated with systemic intravascular activation of coagulation, potentially leading to widespread microvascular deposits of fibrin, and thereby contributing to multiple organ dysfunction. A complex interaction exists between activation of inflammatory systems and the initiating and regulating pathways of coagulation. A diagnosis of sepsis-associated disseminated intravascular coagulation can be made by a combination of routinely available laboratory tests, for which simple diagnostic algorithms have become available. Strategies to inhibit coagulation activation may theoretically be justified and are being evaluated in clinical studies.

Topics: Anticoagulants; Antithrombin III; Disseminated Intravascular Coagulation; Glycocalyx; Humans; Multiple Organ Failure; Plasma; Platelet Transfusion; Protein C; Sepsis; Thromboplastin

Tissue factor (TF) performs an essential role in the blood clotting system by activating the extrinsic coagulation pathway following vascular injury. In addition to this physiological hemostatic role for wound repair, TF also plays pivotal roles in organ dysfunction in trauma patients by triggering pathological disseminated thrombosis and inflammation. Constitutively expressed TF in subendothelial cells is released into the circulation following trauma and can be detected as slightly elevated TF levels in the plasma. Liberation of constitutive TF into the blood and inducible tissue factor expression on monocytes and the other cells may synergistically increase plasma TF levels to higher values at the early stage of posttrauma, especially in patients with disseminated intravascular coagulation (DIC) in association with sustained systemic inflammatory response syndrome. Marked TF generation not adequately balanced by physiological coagulation inhibitors such as tissue factor pathway inhibitor in posttrauma DIC patients has been observed. Based on these pieces of evidence, it has now been accepted that combined activation of TF-dependent coagulation inadequately regulated by anticoagulant mechanisms and inflammation may synergistically play important roles in the pathogenesis of posttrauma multiple organ dysfunction syndrome.

Topics: Blood Coagulation; Disseminated Intravascular Coagulation; Gene Expression Regulation; Humans; Inflammation; Multiple Organ Failure; Thromboplastin; Wounds and Injuries

Sepsis is caused by a dysregulated immune response to infection and, without intervention, can lead to septic shock and multiple organ failure. A leading cause of morbidity and mortality in intensive care units worldwide, severe sepsis is also associated with a considerable cost burden that places significant strain on global healthcare budgets. The development of an efficacious and cost-effective treatment strategy is therefore of vital importance to today's intensive care physicians. This paper will examine the pathophysiology of sepsis and multiple organ dysfunction before reviewing trials recently undertaken to investigate three potential anticoagulant therapies: antithrombin III, activated protein C, and tissue factor pathway inhibitor. Finally, other recent developments in the care of sepsis patients will be briefly examined.

Topics: Anticoagulants; Disease Management; Humans; Multiple Organ Failure; Sepsis; Thromboplastin; Treatment Outcome

To present and discuss the rationale and the results of clinical trials using supplementation with physiologic anticoagulants (Tissue Factor Pathway Inhibitor (TFPI), AntiThrombin (AT), and Protein C (PC) in patients with severe sepsis.. An early activation of the coagulation cascade occurs in severe sepsis. TFPI, AT, and PC are major inhibitors of the coagulation cascade, and additionally modulate inflammatory and vascular reactions. They are consumed or inhibited in the sepsis pathologic process. Therapeutic supplementation with these inhibitors could improve the sepsis-induced organ failures and mortality.. Randomized controlled studies were recently completed. No effect on the mortality rate could be documented after treatment with recombinant TFPI. AT concentrates neither improve mortality, but a biological interaction with heparin therapy could have biased the study results. Treatment with recombinant activated PC (alpha-drotrecogin) was associated with a significant reduction in the mortality rate of severely ill patients and received recently the approval from FDA and EC authorities in this indication. An increase in the rate of hemorrhagic adverse effects has been observed with these compounds, justifying a strict observance of contraindications and of patients selection. PROSPECTIVE: Additional studies are needed to give confirmation of the positive effects of activated PC supplementation in less severely ill patients, children and specific clinical situations. The effects of new anticoagulant compounds are currently evaluated in preclinical studies.

Topics: Anticoagulants; Antithrombins; Blood Coagulation Disorders; Drug Evaluation, Preclinical; Drug Interactions; Drug Monitoring; Heparin; Humans; Inflammation; Multiple Organ Failure; Patient Selection; Protein C; Randomized Controlled Trials as Topic; Recombinant Proteins; Sepsis; Severity of Illness Index; Thromboplastin; Treatment Outcome

In the pathogenesis of disseminated intravascular coagulation, dysfunctional natural anticoagulant pathways appear to play a pivotal role. In this article, we will address the mechanisms that contribute to this defect in the regulation of coagulation activation. Furthermore, we will explore the experimental and clinical evidence that restoration of these anticoagulant pathways results in clinical improvement.. We have searched and reviewed published articles on experimental studies of disseminated intravascular coagulation models in animals and clinical studies in patients with disseminated intravascular coagulation.. All three major anticoagulant pathways, that is, the antithrombin pathway, the protein C system, and tissue factor pathway inhibitor, are defective in sepsis and disseminated intravascular coagulation. Several mechanisms contribute to this defect. Restoration of these pathways, in principle, by administration of coagulation inhibitor concentrates or recombinant anticoagulant factors, appears to ameliorate the coagulation disorder and, more important, result in improvement of clinically relevant outcomes, such as a reduction of organ failure and mortality.. Restoration of disrupted physiologic anticoagulant pathways in disseminated intravascular coagulation is not only a logical point of impact in patients with sepsis and an activated coagulation system, but also is associated with an improved outcome in experimental and (initial) clinical studies.

Topics: Animals; Anticoagulants; Cytokines; Disease Models, Animal; Disseminated Intravascular Coagulation; Humans; Multiple Organ Failure; Protein C; Sepsis; Thrombin; Thromboplastin; Treatment Outcome

Septic shock-induced disseminated intravascular coagulopathy (DIC) contributes to multiple organ failure. Mechanisms governing vascular responses to open occurrence of DIC have not yet been established. Circulating plasma microparticles (MPs), released upon cell stress, constitute a catalytic procoagulant surface and are surrogates of vascular cell activation/injury. Herein, MPs were assessed as possible markers of haemostatic and vascular dysfunction in the DIC time course.. One hundred patients with septic shock from three ICUs were enrolled and their haemostatic status evaluated at admission (D1), D2, D3 and D7. Circulating procoagulant MPs were isolated, quantified by prothrombinase assay and their cellular origin determined. DIC diagnosis was made according to the JAAM 2006 score.. Ninety-two patients were analysed and 40 had DIC during the first 24 h. Routine clotting times and factor/inhibitor activity did not allow assessing vascular cell involvement. At admission, thrombin generation and fibrinolysis were observed in both groups while impaired fibrin polymerisation was evidenced only in DIC patients. Sustained thrombin generation persisted over time in both groups at D7. While total microparticle concentrations were in the same range regardless of DIC diagnosis, specific phenotypes were already detected at admission in DIC patients. Endothelial- and leucocyte-derived MPs were higher in DIC while an increased soluble glycoprotein V/platelet ratio was delayed, underscoring the first involvement of endothelial cells and leucocytes whereas platelet activation was delayed. Endothelium-derived CD105-MPs (OR 6.55) and CD31-MPs (OR 0.49) were strongly associated with early DIC in multivariate analysis.. Endothelial-derived microparticles are relevant biomarkers of septic shock-induced DIC and could be used to evaluate early vascular injury.

Topics: Biomarkers; Cell-Derived Microparticles; Disseminated Intravascular Coagulation; Endothelial Cells; Female; Humans; Male; Middle Aged; Multiple Organ Failure; Shock, Septic; Thromboplastin; Young Adult

To elucidate the effects of serum of patients with multiple organ dysfunction syndrome (MODS) on tissue factor (TF) and Plasminogen activator inhibitor-1 (PAI-1) secretion of human vascular endothelial cells(HUVEC)during continuous renal replacement therapy (CRRT).. Sixteen patients who diagnosed MODS involved were divided into two groups randomly, eight patients treated with CRRT without heparin and the others with heparin for 8 hours. The blood was collected from patients at 0 min, 15 min, 60 min, 120 min and 480 min during CRRT. Serum TNF-alpha, IL-1beta were measured by ELISA.TF and PAI-1 secretion of HUVEC stimulated with serum of patients with MODS undergoing CRRT were detected. TF and PAI-1 expression level were assayed by RT-PCR.. TF and PAI-1 secretion were significantly increased in HUVEC stimulated with serum of patients with MODS, but the levels were decreased after CRRT. There are significant positive correlation between TF or PAI-1 secretion of HUVEC and corresponding serum TNFalpha level in the group without heparin, the coefficient correlation is 0.902 and 0.939(P<0.05)respectively. But there are not significant correlation(P>0.05)in the group with heparin.. Serum of patients with MODS promote the secretion of TF and PAI-1 in HUVEC.The dysfunction of HUVEC induced by serum of patients with MODS may be related to mediators of inflammation. CRRT can clean up the component which injure HEVEC and improve endothelial cell functions.

Topics: Adult; Anticoagulants; Cells, Cultured; Combined Modality Therapy; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Female; Heparin; Humans; Interleukin-1beta; Male; Multiple Organ Failure; Plasminogen Activator Inhibitor 1; Renal Replacement Therapy; Reverse Transcriptase Polymerase Chain Reaction; Serum; Thromboplastin; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

To evaluate the pathogenetic role of tissue factor (TF), tissue factor pathway inhibitor (TFPI), and neutrophil elastase in acute respiratory distress syndrome (ARDS), as well as to test the hypothesis that TFPI levels modified by neutrophil activation are not sufficient to prevent TF-dependent intravascular coagulation, leading to sustained systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS), which determine the prognosis of these patients.. The study subjects consisted of 55 patients with trauma and sepsis who were divided into three groups according to the Lung Injury Score. Ten normal healthy volunteers served as control. Plasma levels of TF, TFPI, and neutrophil elastase were measured on the day of injury or the day of diagnosis of sepsis (day 0) and days 1 through 4. The number of SIRS criteria that the patient met and the disseminated intravascular coagulation (DIC) score is determined daily.. Patients (15) developed ARDS, 23 were at risk for but did not develop the syndrome, and 17 patients were without risk for ARDS. TF and neutrophil elastase levels in ARDS patients were persistently higher than those in other two groups and control subjects. However, the TFPI levels showed no difference among the three groups, which retained normal or slightly elevated levels compared to the control subjects. DIC scores did not improve and SIRS continued during the study period in patients with ARDS. The ARDS patients showed higher numbers of dysfunctioning organs and associated with poorer outcome than the other two groups.. Systemic activation of the TF-dependent pathway not adequately balanced by TFPI is one of the aggravating factors of ARDS. High levels of neutrophil elastase released from activated neutrophils may explain the imbalance of TF and TFPI. Persistent DIC and sustained SIRS contribute to MODS, determining the prognosis of ARDS patients.

Topics: Disseminated Intravascular Coagulation; Female; Humans; Leukocyte Elastase; Lipoproteins; Male; Middle Aged; Multiple Organ Failure; Respiratory Distress Syndrome; Risk Assessment; Statistics as Topic; Systemic Inflammatory Response Syndrome; Thromboplastin

Sepsis, a leading cause of death worldwide, involves widespread activation of inflammation, massive activation of coagulation, and lymphocyte apoptosis. Calpains, calcium-activated cysteine proteases, have been shown to increase inflammatory reactions and lymphocyte apoptosis. Moreover, calpain plays an essential role in microparticle release.. We investigated the contribution of calpain in eliciting tissue damage during sepsis.. To test our hypothesis, we induced polymicrobial sepsis by cecal ligation and puncture in wild-type (WT) mice and transgenic mice expressing high levels of calpastatin, a calpain-specific inhibitor.. In WT mice, calpain activity increased transiently peaking at 6 hours after cecal ligation and puncture surgery. Calpastatin overexpression improved survival, organ dysfunction (including lung, kidney, and liver damage), and lymphocyte apoptosis. It decreased the sepsis-induced systemic proinflammatory response and disseminated intravascular coagulation, by reducing the number of procoagulant circulating microparticles and therefore delaying thrombin generation. The deleterious effect of microparticles in this model was confirmed by transferring microparticles from septic WT to septic transgenic mice, worsening their survival and coagulopathy.. These results demonstrate an important role of the calpain/calpastatin system in coagulation/inflammation pathways during sepsis, because calpain inhibition is associated with less severe disseminated intravascular coagulation and better overall outcomes in sepsis.

Topics: Animals; Apoptosis; Calcium-Binding Proteins; Calpain; Cell-Derived Microparticles; Cytokines; Disease Models, Animal; Disseminated Intravascular Coagulation; Lymphocytes; Mice; Mice, Inbred C57BL; Mice, Transgenic; Multiple Organ Failure; NF-kappa B; Sepsis; Thromboplastin

Being a central link between inflammation and coagulation, tissue factor (TF) and its inhibitor (TFPI) might be associated with the severity of acute pancreatitis (AP) and the development of organ failure (OF).. The study comprises 9 severe AP patients with OF and 24 reference patients (11 mild AP and 13 severe AP without OF). Plasma samples were collected on admission. TF-induced thrombin generation in plasma samples was studied using the thrombogram method. In vivo thrombin generation was estimated by prothrombin fragment F1+2. Free and total TFPI levels were measured. To evaluate coagulation status the activated partial thromboplastin time, prothrombin time, platelet count, D-dimer, fibrinogen, antithrombin (AT) 3 and protein C (PC) were determined.. There was no significant difference in F1+2 levels between the patient groups. Patients with severe AP tended to show low platelet counts, PC and AT3 levels, and high D-dimer levels. In 11 patients the standard TF stimulation did not trigger thrombin generation in the thrombogram. All deaths occurred in these patients. Free TFPI levels and free/total TFPI ratios were significantly higher in these patients and in non-survivors.. Failure of TF-initiated thrombin generation in the thrombogram assay explained by high levels of circulating free TFPI may be associated with OF and mortality in AP. and IAP.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Biomarkers; Blood Coagulation; Blood Coagulation Tests; Cells, Cultured; Female; Finland; Humans; Lipoproteins; Male; Middle Aged; Multiple Organ Failure; Pancreatitis; Platelet Count; Survival Rate; Thrombin; Thromboplastin

In acute pancreatitis (AP), disorders of the coagulation-fibrinolysis system are closely related to the severity of the AP and to organ dysfunctions. We previously reported that plasma tissue factor (TF) levels were elevated in patients with AP, particularly in cases of alcoholic AP with pancreatic necrosis. Tissue factor pathway inhibitor (TFPI) is a key regulator of the extrinsic coagulation pathway, but plasma TFPI levels in AP have not yet been determined.. Plasma TFPI concentrations were measured by enzyme-linked immunosorbent assay in 44 patients with AP on admission. The relationships between AP severity, pancreatic necrosis, organ dysfunction, infection, and prognosis were analyzed.. Plasma TFPI levels were increased in AP patients compared with healthy volunteers. Plasma TFPI levels in severe AP were greater than those in mild AP. Plasma TFPI levels significantly correlated with Ranson score, APACHE II score, and Japanese severity score. Plasma TFPI levels in patients with pancreatic necrosis were greater than those in patients without pancreatic necrosis. Plasma TFPI levels in patients with organ dysfunction were greater than those in patients without organ dysfunction. In patients with pancreatic necrosis, the TF/TFPI ratios in non-survivors were lower than those in survivors. Moreover, the mortality rates in patients with TF/TFPI ratios > or = 2.0 were lower than those in patients with TF/TFPI ratios < 2.0.. Plasma TFPI levels were significantly increased in patients with AP, and the elevation was markedly related to the severity, pancreatic necrosis and organ dysfunctions. The imbalance of TF and TFPI may influence the disease state and thereby the prognosis in AP.

Topics: Acute Disease; APACHE; Biomarkers; Blood Coagulation; Case-Control Studies; Female; Humans; Lipoproteins; Male; Middle Aged; Multiple Organ Failure; Necrosis; Pancreatitis; Prognosis; Severity of Illness Index; Thromboplastin

To determine if neurally adjusted ventilatory assist (NAVA) that delivers pressure in proportion to diaphragm electrical activity is as protective to acutely injured lungs (ALI) and non-pulmonary organs as volume controlled (VC), low tidal volume (Vt), high positive end-expiratory pressure (PEEP) ventilation.. Prospective, randomized, laboratory animal study.. Twenty-seven male New Zealand white rabbits.. Anesthetized rabbits with hydrochloric acid-induced ALI were randomized (n = 9 per group) to 5.5 h NAVA (non-paralyzed), VC (paralyzed; Vt 6-ml/kg), or VC (paralyzed; Vt 15-ml/kg). PEEP was adjusted to hemodynamic goals in NAVA and VC6-ml/kg, and was 1 cmH2O in VC15-ml/kg.. PaO2/FiO2; lung wet-to-dry ratio; lung histology; interleukin-8 (IL-8) concentrations in broncho-alveolar-lavage (BAL) fluid, plasma, and non-pulmonary organs; plasminogen activator inhibitor type-1 and tissue factor in BAL fluid and plasma; non-pulmonary organ apoptosis rate; creatinine clearance; echocardiography. PEEP was similar in NAVA and VC6-ml/kg. During NAVA, Vt was lower (3.1 +/- 0.9 ml/kg), whereas PaO2/ FiO2, respiratory rate, and PaCO2 were higher compared to VC6-ml/kg (p<0.05 for all). Variables assessing ventilator-induced lung injury (VILI), IL-8 levels, non-pulmonary organ apoptosis rate, and kidney as well as cardiac performance were similar in NAVA compared to VC6-ml/kg. VILI and non-pulmonary organ dysfunction was attenuated in both groups compared to VC15-ml/kg.. In anesthetized rabbits with early experimental ALI, NAVA is as effective as VC6-ml/kg in preventing VILI, in attenuating excessive systemic and remote organ inflammation, and in preserving cardiac and kidney function.

Topics: Acute Lung Injury; Analysis of Variance; Animals; Bronchoalveolar Lavage Fluid; Diaphragm; Disease Models, Animal; Electrophysiological Phenomena; Feedback, Physiological; Interleukin-8; Male; Multiple Organ Failure; Plasminogen Activator Inhibitor 1; Positive-Pressure Respiration; Prospective Studies; Rabbits; Random Allocation; Respiration, Artificial; Statistics, Nonparametric; Thromboplastin; Tidal Volume; Ventilator-Induced Lung Injury

Severe sepsis is associated with an exacerbated procoagulant state with protein C (PC) system impairment. In contrast, the inflammatory and coagulation status of nonseptic patients with organ failure (OF) is less documented.. To compare coagulation activation, focusing on the PC system, and inflammatory status in septic and nonseptic patients with OF.. Thirty patients with severe sepsis and 30 nonseptic patients were recruited at the onset of OF and compared with 30 matched healthy subjects. We performed an extensive analysis of the PC pathway, including plasma protein measurements and quantification of leukocyte expression of PC system receptors. In addition, we analyzed the inflammatory status, based on inflammation-related gene leukocyte expression.. We observed coagulation activation, reflected by a similar increase in tissue factor mRNA expression, in the two patient groups when compared with the healthy subjects. Soluble thrombomodulin levels were higher in septic patients than in healthy control subjects, whereas PC, protein S, and soluble endothelial cell PC receptor levels were lower. Similar results were obtained in nonseptic patients with OF. Monocyte thrombomodulin overexpression, together with increased circulating levels of activated PC, suggests that the capacity for PC activation is at least partly preserved in both settings. No difference in the inflammatory profile was found between septic and nonseptic patients.. The pathogenesis of OF in critical care patients is characterized by an overwhelming systemic inflammatory response and by exacerbated coagulation activation, independently of whether or not infection is the triggering event. Clinical trial registered with www.clinicaltrials.gov (NCT 00361725).

Topics: Adult; Aged; Antigens, CD; Blood Coagulation; Case-Control Studies; Endothelial Protein C Receptor; Female; Humans; Male; Middle Aged; Multiple Organ Failure; Protein C; Protein S; Receptors, Cell Surface; RNA, Messenger; Sepsis; Thrombomodulin; Thromboplastin

We measured the plasma level of fibrinogen in 560 patients with disseminated intravascular coagulation (DIC) and evaluated its relationship with outcome and with other hemostatic markers. Forty-seven percent of patients had >200 mg/dL of plasma fibrinogen and 24% had <100 mg/dl of plasma fibrinogen, suggesting that plasma fibrinogen level is not a sensitive marker for DIC. In our analysis of outcome and plasma fibrinogen levels, the rate of death was high in leukemia/lymphoma patients with high fibrinogen concentration, but no significant difference in outcome was observed in relation to plasma fibrinogen concentration in non-leukemia/lymphoma patients with DIC. Among patients with leukemia/lymphoma, the frequency of organ failure was markedly high in patients with high plasma levels of fibrinogen. Among patients without leukemia/lymphoma, the frequency of organ failure increased concomitantly with the increase in plasma fibrinogen levels. The international normalized ratio was significantly increased in leukemia/lymphoma patients with low fibrinogen. FDP levels were slightly increased in patients with low fibrinogen. Platelet count was significantly low in patients without leukemia/lymphoma with high fibrinogen. DIC score increased concomitantly with the reduction in plasma fibrinogen levels. Plasma levels of thrombomodulin and tissue factor were significantly high in patients with high fibrinogen levels. Plasma levels of antiplasmin and plasminogen were significantly decreased in patients with low fibrinogen. Plasma levels of plasmin plasmin-inhibitor complex and tissue type plasminogen activator/plasminogen activator inhibitor-1 complex (PAI-I) were significantly higher in patients with low fibrinogen than in those with high fibrinogen. Plasma levels of PAI-I and IL-6 were significantly higher in patients with high fibrinogen than in those with low fibrinogen. Patients with high fibrinogen levels showed less activation of secondary fibrinolysis, which might explain the occurrence of organ failure and poor outcome.

Topics: Adult; Aged; alpha-2-Antiplasmin; Antifibrinolytic Agents; Antithrombin III; Biomarkers; Disseminated Intravascular Coagulation; Female; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolysin; Fibrinolysis; Hematologic Neoplasms; Hemorrhage; Humans; Infections; Interleukin-1; Interleukin-6; International Normalized Ratio; Male; Middle Aged; Multiple Organ Failure; Neoplasms; Peptide Hydrolases; Plasminogen; Plasminogen Activator Inhibitor 1; Platelet Count; Prognosis; Thrombomodulin; Thromboplastin; Thrombosis; Tissue Plasminogen Activator

To determine the precise relationship among tissue factor, tissue factor pathway inhibitor (TFPI), and neutrophil elastase in sepsis, as well as to test the hypothesis that low TFPI concentrations are not sufficient to prevent tissue factor-dependent intravascular coagulation, leading to multiple organ dysfunction syndrome and death.. Prospective, cohort study.. General intensive care unit of tertiary care emergency department.. Thirty-one consecutive patients with sepsis, classified as 15 survivors and 16 nonsurvivors. Ten normal, healthy volunteers served as controls.. None.. Tissue factor antigen concentration (tissue factor), TFPI, neutrophil elastase, and global variables of coagulation and fibrinolysis were measured on the day of diagnosis of sepsis, severe sepsis, and septic shock and days on 1-4 after diagnosis. The number of systemic inflammatory response syndrome criteria that patients met and the disseminated intravascular coagulation score were determined simultaneously. The results of these measurements were compared between the survivors and the nonsurvivors. In the nonsurvivors, significantly higher concentrations of tissue factor and neutrophil elastase were found compared with the survivors and control subjects. However, the TFPI values showed no difference between the two groups. No correlation was found between the peak concentrations of tissue factor and TFPI. Disseminated intravascular coagulation scores and numbers of the SIRS criteria met by the survivors significantly decreased from day 0 to day 4, but those of the nonsurvivors did not improve during the study period. The nonsurvivors showed thrombocytopenia and higher numbers of dysfunctioning organs than did the survivors.. We systematically elucidated the relationship between tissue factor and TFPI in patients with sepsis, severe sepsis, and septic shock. Activation of tissue factor-dependent coagulation pathway not adequately balanced by TFPI has important roles in sustaining DIC and systemic inflammatory response syndrome, and it contributes to multiple organ dysfunction syndrome and death. High concentrations of neutrophil elastase released from activated neutrophils may explain, in part, the imbalance of tissue factor and TFPI in sepsis.

Topics: Adult; Anticoagulants; Cohort Studies; Disseminated Intravascular Coagulation; Female; Humans; Incidence; Japan; Leukocyte Elastase; Lipoproteins; Male; Middle Aged; Multiple Organ Failure; Platelet Count; Prognosis; Prospective Studies; Respiratory Distress Syndrome; Sepsis; Serine Proteinase Inhibitors; Survival Analysis; Thromboplastin; Treatment Outcome

Topics: Anticoagulants; Antithrombin III; Blood Coagulation; Heparin; Humans; Inflammation; Multiple Organ Failure; Protein C; Thromboplastin

Sepsis and septic shock are very complex and dynamic clinical syndromes. A systemic response to an infection or other triggers can induce a cascade consisting of toxins--leukocytes--cytokines--mediators of inflammation--endothelial cell dysfunction--activation of blood coagulation--intravascular fibrin deposition--alteration of microcirculation, resulting in a damage of organs. Multi organ failure and sepsis are therefore tightly connected. The associated disturbances of blood coagulation range between a simple activation of coagulation with a transient increase of activation markers (i.e. D-dimer), similar to an acute-phase reaction and full blown disseminated intravascular coagulation with consumption coagulopathy. This article summarizes these pathophysiological mechanisms, shows available diagnostic tools and differential diagnoses, and discusses therapeutic options for sepsis and multi organ failure.

Topics: Animals; Blood Coagulation Tests; Disseminated Intravascular Coagulation; Endothelium, Vascular; Fibrinolysis; Humans; Inflammation Mediators; Multiple Organ Failure; Platelet Activation; Shock, Septic; Systemic Inflammatory Response Syndrome; Thromboplastin

Cytokines increase endothelial tissue factor (TF) and tissue plasminogen activator inhibitor type-1 (PAI-1) expression in vitro. Tissue factor interacts with factor VII to facilitate thrombosis and PAI-1 inhibits fibrinolysis by endogenous plasminogen activators. Because cytokine release is increased in children with sepsis-induced multiple organ failure (MOF), we hypothesized a cytokine associated increase in circulating TF and PAI-1 antigen release, and systemic activity in these patients.. One hundred and seven consecutive children, who met the criteria for sepsis, and 10 critically ill children without sepsis, were enrolled in the study. Plasma TF and PAI-1 antigen and activity levels, Interleukin-6 antigen levels (IL-6), nitrite + nitrate levels (marker of nitric oxide production) and number of organs failing were measured on days 1-3 of sepsis.. Increased TF and PAI-1 antigen, and PAI-1 activity levels were associated with increasing IL-6 and nitrite + nitrate levels (p <0.05), the development of MOF (p <0.05), and mortality (p <0.05). Increased systemic PAI-1 activity was associated with cardiovascular, renal. and hepatic failure (p <0.05). Increased systemic TF activity was associated with the development of coagulopathy (p <0.05) and tended to be associated with mortality (p = 0.06, power .77). A shift to an anti-fibrinolytic endothelium phenotype characterizes children who develop sepsis-induced MOF and mortality. Children with coagulopathy have a shift to a pro-coagulant phenotype. These findings support potential therapeutic roles for PAI-1 and TF pathway inhibitors in reversal of this devastating pathophysiologic process.

Topics: Adolescent; Child; Child, Preschool; Cytokines; Endothelium, Vascular; Female; Fibrinolysis; Humans; Infant; Infant, Newborn; Interleukin-6; Male; Multiple Organ Failure; Nitrates; Nitrites; Pennsylvania; Plasminogen Activator Inhibitor 1; Prospective Studies; Sepsis; Thrombophilia; Thromboplastin

To determine the precise relationship between tissue factor and tissue factor pathway inhibitor (TFPI) after trauma, as well as to test the hypothesis that low TFPI levels are not sufficient to prevent tissue factor-dependent intravascular coagulation, leading to multiple organ dysfunction syndrome (MODS).. Prospective, observational cohort study.. Emergency room and intensive care unit in a university hospital.. Thirty-three trauma patients, 18 with disseminated intravascular coagulation (DIC) and 15 without DIC were studied. Ten normal, healthy volunteers served as control subjects.. None.. Antigen concentration of tissue factor and TFPI, and global parameters of coagulation and fibrinolysis were measured on the day of admission, and on days 1-4 after admission. The number of systemic inflammatory response syndrome (SIRS) criteria that patients met and the DIC score were determined, simultaneously. The results of these measurements, incidence of MODS, and outcome were compared between the DIC patients and those without DIC. In the DIC patients, significantly higher tissue factor levels (p =.0049) and lower platelet counts (p =.0016) were found compared with the non-DIC patients and control subjects. However, the TFPI values remained at normal levels during the study period. No correlation was found between the peak levels of tissue factor and TFPI. The mean duration of SIRS and the maximum number of the SIRS criteria being met by the patients in the DIC group were statistically longer and higher than those in the non-DIC patients. The incidence of MODS and the number of the dysfunctioning organs were higher in the DIC patients compared with those in the non-DIC patients, and the DIC patients had a poor outcome.. We systematically elucidated the relationship between tissue factor and TFPI in post-trauma patients. Highly activated tissue factor-dependent coagulation pathway is not sufficiently prevented by the normal TFPI levels in patients with DIC. The DIC associated with thrombotic and inflammatory responses causes MODS, and leads to poor outcome in post-trauma patients.

Topics: Analysis of Variance; APACHE; Case-Control Studies; Disseminated Intravascular Coagulation; Female; Humans; Incidence; Inflammation; Lipoproteins; Male; Middle Aged; Multiple Organ Failure; Multiple Trauma; Platelet Count; Prognosis; Prospective Studies; Systemic Inflammatory Response Syndrome; Thromboplastin; Time Factors; Treatment Outcome

To determine the roles of tissue factor and thrombin on the systemic inflammatory response syndrome (SIRS) in posttrauma patients, as well as to investigate the relationship between SIRS and sepsis.. Prospective, cohort study.. General intensive care unit of a tertiary care emergency department.. Forty trauma patients were classified into subgroups, according to the duration of SIRS: non-SIRS patients (n = 9); patients with SIRS for < 2 days (n = 15); and patients with SIRS for > 3 days (n = 16).. None.. Tissue factor antigen concentration, prothrombin fragment F1+2, thrombin antithrombin complex, fibrinopeptide A, and cross-linked fibrin degradation products (D-dimer) were measured on the day of admission, and on days 1 through 4 after admission. Simultaneously, the number of SIRS criteria that the patients met and the disseminated intravascular coagulation score were determined. The results of these measurements, frequency of acute respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome, sepsis, and outcome were compared among the groups. The values of all five hemostatic molecular markers in the patients with SIRS for > 3 days were significantly more increased than those molecular marker values measured in the other groups on the day of admission. These values continued to be markedly high up to day 4 of admission. The occurrence rates of disseminated intravascular coagulation in these patient groups were significantly higher than those rates in the other two groups (p = .0001), and the disseminated intravascular coagulation scores did not improve during the study period. The occurrence rates of ARDS (p < .05) and multiple organ dysfunction syndrome (p < .01) were higher in patients with SIRS for > 3 days compared with those rates in the other groups, and the patients with SIRS for > 3 days had a poor outcome. No significant difference was noted in the frequency of sepsis among the groups.. Sustained SIRS is the main determinant for ARDS, multiple organ dysfunction syndrome, and outcome in posttrauma patients. Disseminated intravascular coagulation associated with massive thrombin generation and its activation is involved in the pathogenesis of sustained SIRS. Sepsis has a small role in early posttrauma multiple organ dysfunction syndrome.

Topics: Abbreviated Injury Scale; Adult; Analysis of Variance; Anticoagulants; Blood Coagulation Factors; Disseminated Intravascular Coagulation; Female; Humans; Male; Middle Aged; Multiple Organ Failure; Prospective Studies; Respiratory Distress Syndrome; Systemic Inflammatory Response Syndrome; Thrombin; Thromboplastin; Wounds and Injuries

We have evaluated the quantitative relationship between lipopolysaccharide (LPS, endotoxin), fibrinopeptide A (FPA), antithrombin (AT), protein C (PC) and extrinsic pathway inhibitor (EPI) in plasma from 39 consecutively admitted patients with systemic meningococcal disease (SMD). The most severely ill patients with fulminant meningococcal septicemia (n = 13, 6 dead) had significantly (p less than 0.01) higher plasma levels of LPS and FPA and lower levels of PC and AT on admission as compared with the less severe clinical presentations (n = 26, 1 dead). The levels of EPI on admission were significantly (p less than 0.05) higher in nonsurvivors vs survivors with fulminant septicemia. As the disease progressed, the levels of LPS, FPA, AT and PC declined, while the levels of EPI increased. Three of six nonsurviving septicemic patients had levels of EPI greater than 200% within 16 hours of admission vs two of 30 survivors (p = 0.02). The results suggest that increasing levels of LPS in SMD elicit increasing consumption coagulopathy, contributing to the organ pathophysiology. The kinetics of EPI, inhibiting the thromboplastin-FVIIa-FXa complex, differs markedly from the kinetics of AT and PC i.e. increases as opposed to decreases.

Topics: Antithrombin III; Disseminated Intravascular Coagulation; Endotoxins; Factor VII; Fibrinogen; Fibrinopeptide A; Humans; Lipopolysaccharides; Lipoproteins; Meningitis, Meningococcal; Meningococcal Infections; Multiple Organ Failure; Neisseria meningitidis; Protein C; Sepsis; Thromboplastin

Hyperthromboplastinemia in rats and dogs was induced by the infusion of xenogenic or allogenic brain suspension or extract. The suspension caused fatal blood coagulation due to fibrin-platelet isolation of cytolemma fractions. The infusion of extracts produced hypotension, caused by hyperkininemia, and primary hypocoagulation due to simultaneous fibrin-formation and fibrinolysis. Severe hepatic, renal and myocardial lesions were discovered 3-4 min after the allogenic brain extract infusion. Xenogenic brain infusion caused inverse changes. The mechanism of this phenomenon is unknown. The organs were affected by lysosomal enzymes activated not by hypoxia but by thrombin- and plasmin-induced glycocalix destruction.

Topics: Animals; Blood Coagulation Disorders; Dogs; Female; Hypoxia; Kinins; Male; Multiple Organ Failure; Nerve Tissue; Rats; Thromboplastin; Time Factors; Transplantation, Heterologous; Transplantation, Homologous