Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A recent clinical sepsis trial reported a significant reduction in 90-day mortality by antithrombin (AT) exclusively in the subgroup of patients without simultaneous heparin prophylaxis. Patients additionally receiving heparin did not benefit from AT treatment. Herein, we studied the microhemodynamic and cellular mechanisms of this adverse effect of heparin on AT actions by the use of intravital microscopy and granulocyte culturing. In Syrian golden hamsters normotensive endotoxemia was induced by 2 mg/kg endotoxin (LPS, E. coli) i.v. In a first group of animals, AT (AT, 250 IU/kg i.v., n = 6) was given 5 min before LPS administration. A second group of animals (Heparin + AT, n = 5) received AT (250 IU/kg i.v.) combined with unfractionated heparin (sodium heparin, 100 IU/kg/24 h, i.v.). Additional animals (LMWH + AT, n = 5) received AT (250 IU/kg i.v.) combined with LMWH (nadroparin 47.5 IU anti-Xa/kg, s.c., 2 h before LPS). LPS-treated animals, which received only saline, served as controls (control, n = 6). Using dorsal skinfold fold preparations, LPS-induced microvascular leukocyte-endothelial cell interaction (LE) and alteration of functional capillary density (FCD) were studied by intravital video fluorescence microscopy. In controls, LPS induced a massive increase in LE with a maximum at 8 h and an impressive decrease in FCD over a 24-hour period. Both LPS effects were effectively prevented by AT treatment (p < 0.01), whereas Heparin + AT and LMWH + AT animals showed microcirculatory alterations comparable to that in controls. In additional in vitro chemotaxis assays. AT blocked neutrophil chemotaxis, an effect reversed by both unfractionated heparin and LMWH. Thus, our study elucidates a relevant in vivo and in vitro unfractionated heparin and LMWH adverse effect in the microcirculatory actions of AT during endotoxemia. These results indicate that heparin should be avoided to permit AT to modulate LPS-induced inflammatory responses.
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PMID:Adverse effect of heparin on antithrombin action during endotoxemia: microhemodynamic and cellular mechanisms. 1219 96

Hyperthrombinogenesis due to bacterial septicemia may aggravate the risk of irreversible septic shock. In 22 patients with septicemia complicating urinary or alimentary infections, daily assessment of hemostasis was performed throughout 1 week. Standard screening of hemostasis revealed significantly increased mean values of prothrombin time, fibrinogen, and fibrinogen degradation product (FDP) concentration. However, platelet counts, activated partial thromboplastin times (APTT), thrombin times, ethanol gelation tests, and antithrombin activity remained within the normal range. By contrast, except for insignificant changes in protein C activity and activated factor VII content, specific markers of plasma hypercoagulability, that is, thrombin-antithrombin (TAT) complexes, prothrombin activating factor F 1+2, activated factor XII (XIIa), and dimer D were all markedly increased. Pathologic levels of TAT and Xlla were found in 82% and 73% of all plasma samples, respectively. The augmentation of TAT correlated with prolongation of thrombin time and increases in F 1+2 levels. The increase in XIIa correlated with thrombocytopenia, prolongation of APTT, exhaustion of antithrombin, and accumulation of F 1+2 and FDP in the plasma. Moreover, a significant increase in XIIa, stronger positivity of the ethanol gelation test, a greater increase in FDP, and a more pronounced decrease in protein C activity were observed in 8 patients with fatal septic shock. This study suggests the usefulness of TAT and XIIa measurements in the early recognition of plasma hypercoagulation in serious infections.
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PMID:Plasma markers of hypercoagulability in patients with serious infections and risk of septic shock. 1236 Nov 99

Systemic activation of coagulation leading to disseminated intra-vascular coagulation (DIC) is an important feature in patients with severe sepsis. Tissue factor has been shown to play a primary role in this pathological response, as revealed by the use of specific inhibitors and antagonists of the tissue factor/factor VIIa pathway. This class of agents has been demonstrated to attenuate the coagulation response in human volunteers with induced low-grade endotoxemia and to reduce mortality in primate models of Gram-negative sepsis. The efficacy of these agents in attenuating the activation of coagulation and formation of microvascular thrombosis in sepsis may depend on the mechanism of inhibition. Here we demonstrate the efficacy of recombinant nematode anticoagulant protein c2 (rNAPc2) that specifically inhibits the tissue factor/factor VIIa complex by a novel mechanism, in a model of endotoxin-induced coagulation activation in chimpanzees. Administration of a low dose of Gram-negative endotoxin induced marked increases of thrombin generation as measured by plasma levels of prothrombin activation fragment F(1+2) and thrombin-antithrombin complexes, which were completely blocked by rNAPc2. In chimpanzees receiving rNAPc2 alone, there was a significant reduction in the activation of factor X but not factor IX, compared to animals receiving placebo. In contrast to the effect of rNAPc2 on thrombin generation, there was no effect of this inhibitor on the well known enhanced systemic fibrinolytic response induced by endotoxin. In conclusion, the recombinant peptide rNAPc2 is an effective inhibitor of tissue factor-driven thrombin generation during low grade endotoxemia. These results suggest that rNAPc2 may be a promising therapeutic option to inhibit coagulation activation in patients with sepsis.
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PMID:Recombinant nematode anticoagulant protein c2, a novel inhibitor of tissue factor-factor VIIa activity, abrogates endotoxin-induced coagulation in chimpanzees. 1236 34

There are global coagulation tests and hemostatic molecular markers in the diagnosis of disseminated intravascular coagulation (DIC). In the global coagulation tests, the sensitivity of prothrombin time ratio and fibrinogen for the diagnosis of DIC is low, but their specificity is high. In platelet count and FDP, the sensitivity for the diagnosis of DIC is good, but the specificity is low. Fibrinogen may be unsuitable for the diagnosis of DIC, because it increases of the inflammatory reaction. It is possible to theoretically diagnose DIC by increased tissue factor production. It is currently considered that hemostatic molecular marker should be utilized to diagnose DIC. Thrombin-antithrombin complex and soluble fibrin are reflected to hypercoagulable state, thrombomodulin to vascular endothelial cell injuries, and plasminogen activator inhibitor-I to hypofibrinolytic state. In leukemia with DIC, hyperfibrinolysis and marked bleeding symptoms are often observed. In septicemia with DIC, hypofibrinolysis and severe organ failure often occur. Early diagnosis and treatment of DIC are important to improve the prognosis, and hemostatic molecular markers should be useful for that purpose.
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PMID:[Hemostatic abnormalities in DIC]. 1237 12

As a result of advanced technology, dramatic developments in the area of new anticoagulant and antithrombotic drugs appear to have made a profound impact on the use of LMWHs. Furthermore, because porcine mucosal heparin is used for the preparation of these agents, it is likely that alternative drugs with comparable pharmacologic and clinical efficacy are sought. Antithrombin drugs such as argatroban and hirudin are already approved for alternative management of heparin-compromised patients. Their efficacy in other indications is less superior. The development of specific anti-Xa drugs is slow. Although these agents may inhibit factor Xa and thrombin generation, none of them are capable of mimicking the polytherapeutic effects of LMWHs and thus can only be given in drug combinations. Synthetic and recombinant protein-derived anti-tissue factor agents have also been developed. These drugs only inhibit the tissue factor-mediated process and are limited in their therapeutic spectrum. Plasma-derived and recombinant serine protease inhibitors (serpins) are also available for the management of thrombotic and inflammatory disorders, but these agents cannot be given subcutaneously. Furthermore, because they are proteins, antibodies to these agents are generated. Nucleic acid derivatives (natural and synthetic aptomers) are developed for intravenous administration, but they are relatively weak antithrombotic agents. Dermatans, heparans, and chondroitin sulfates represent nonheparin GAGs, and, in mono-compositional and polycompositional form, these drugs are mainly used for the intravenous management of DVT prophylaxis. They can be given to patients who are heparin compromised. Synthetic heparinomimetics include heparin consensus-binding oligosaccharides and synthetic oligosaccharides with non-serpin affinity. In addition, binding oligosaccharides are conjugated with antithrombin agents to mimic the anti-Xa/anti-IIa activities of heparin. Biotechnology using bacterial and yeast cultures, aqua cultures for marine products, and plant carbohydrates have been the focus of developing heparin analogues. Development of these agents is in the early phase; however, it is likely that this approach may provide a reasonable alternative to LMWHs. Despite these developments, it is unlikely that any of these drugs will have a profound impact on the use of LMWHs in the near future. Unfractionated heparin and LMWHs collectively represent an important group of polypharmacologic drugs without which the management of thrombosis and vascular disorders would not be possible. The continual development of LMWHs in expanded indications did not comprise the use of unfractionated heparin in surgical and interventional cardiovascular indications. Ever since their introduction in the 1980s, the use of LMWHs has continually increased. This is primarily because of expanded indications and growing awareness among the clinicians. It is likely that once an antidote is developed and additional information is available on the mechanism of action of LMWHs, these drugs may gradualty be used for surgery patients. Despite these developments, it is likely that unfractionated heparin will continue to be used for specific indications. Drug combinations with heparins may necessitate dose adjustments, but it is unclear whether unilateral reduction of heparins will be optimal. The coming years will provide useful clinical and applied data on the improved use of unfractionated heparin. LMWHs, and pentasaccharide in the management of thrombotic and cardiovascular disorders. In addition, use of these drugs will be extended to many conditions, including cancer, inflammation, sepsis, and autoimmune diseases. Polytherapeutic approaches emphasizing LMWHs as primary and secondary drugs will also have an impact on the management of thrombotic and nonthrombotic disorders. Ultra-LMWHs and synthetic heparinomimetics, such as fondaparinux, that exhibit a narrow pharmacologic spectrum will only be useful in specific indications and in combination with other drugs.
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PMID:Heparin, low-molecular-weight heparins, and heparin pentasaccharide: basic and clinical differentiation. 1262 73

Disseminated intravascular coagulation (DIC) is characterized by systemic activation of the haemostasis. In many instances the release of inflammatory cytokines and tissue factor trigger the system in septic or traumatic conditions. Initially, the increased activation of haemostasis can be compensated by natural inhibitor systems. As release of the triggers persists, inhibitors (e.g. antithrombin and protein C) will be consumed leading to intravascular clotting. In this process many coagulation factors, most notably fibrinogen and platelets are consumed too, resulting in a failure of haemostasis system and in a diffuse bleeding (decompensated DIC). Fresh frozen plasma, blood transfusion, and fibrinogen concentrate correct the bleeding, if needed, in the case of traumatic (obstetric) DIC. Arrest of the activated haemostasis by heparin and natural anticoagulants (antithrombin or/and protein C) is recommended, mainly in septic conditions with systemic inflammatory reactions. A case of stercoral sepsis usefully treated by recombinant human activated protein C is reported.
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PMID:[Disseminated intravascular coagulation syndrome and protein C]. 1268 50

In neonates and infants numerous clinical and environmental conditions such as the use of central lines, cardiac diseases and polycythemia, renal diseases such as congenital nephrotic syndrome and neonatal hemolytic uremic syndrome, peripartal asphyxia, infants of diabetic mothers, dehydration, septicemia, necrotizing enterocolitis, acute respiratory distress syndrome, and extracorporeal membrane oxygenation lead to elevated thrombin generation and subsequent thrombus formation. Genetic prothrombotic defects [protein C, protein S and antithrombin deficiency, mutations of coagulation factor V and factor II, elevated lipoprotein (a)] have been established as risk factors for thromboembolic events. The interpretation of laboratory results relies on age-dependent normal reference values. Because appropriate clinical trials are missing in these age groups, treatment recommendations are adapted from small-scale studies in neonates and infants and from guidelines relating to adult patient protocols. Secondary long-term anticoagulation should be administered on an individual basis.
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PMID:Neonatal thromboembolism. 1270 27

Activation of protein C by thrombin bound to thrombomodulin is enhanced by endothelial protein C receptor. This pathway may inhibit inflammation. We investigated effects of protein C and activated protein C on neutrophils as well as whether an endothelial protein C receptor is involved in mediating protein C effects. Neutrophils were from venous blood of healthy donors. Cell migration, respiratory burst, phagocytic activity, and apoptosis were studied by micropore filter assays and fluorometry. Receptor expression was investigated by reverse transcriptase-polymerase chain reaction (PCR) for mRNA, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and autoradiography of immunoprecipitated receptor protein, and fluorescence-activated cell-sorter scanner (FACS) analysis using the anti-endothelial protein C receptor antibody RCR-252. Neither protein C nor activated protein C induced migration, yet both of them inhibited neutrophil chemotaxis triggered by interleukin-8, formyl-Met-Leu-Phe, antithrombin, or C5a. A protein C activation-blocking antibody against endothelial protein C receptor diminished inhibitory effects of protein C or activated protein C on migration. No effect of either protein C preparation was seen in neutrophil's respiratory burst, bacterial phagocytosis, or apoptosis assays. Endothelial protein C receptor immunoreactivity was confirmed on neutrophils by FACS. De novo synthesis is suggested by endothelial protein C receptor mRNA expression as demonstrated by reverse transcriptase PCR and immunoprecipitation SDS-PAGE analyses. Data suggest that an endothelial protein C receptor is expressed by human neutrophils whose active site ligation with either protein C or activated protein C arrests directed cell migration. Inhibitory effects of these components of the protein C pathway on neutrophil function may play a role in the protein C-based treatment of severe sepsis.
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PMID:Expression and function of the endothelial protein C receptor in human neutrophils. 1271 92

Sepsis and septic shock represent a frequent cause of mortality in Intensive Care Units, despite of the progress in antibiotic therapy and in the hemodynamic and respiratory support. The most frequent cause of death is the Multi Organ Dysfunction Syndrome (MODS), which is the clinical manifestation of the irreversibile damage of the microvascular bed. During sepsis and septic shock both activation of coagulation /fibrinolysis and release of mediators of inflammation contribute to the pathogenesis of disseminated intravascular coagulation (DIC); in particular the formation of fibrin in the microvascular bed is the pathological substrate of the clinical development of MODS. The rationale for employing antithrombin (AT) concentrates in the treatment of DIC associated to sepsis is based on the consideration that AT plasma levels are always decreased in patients with sepsis or septic shock; furthermore, the degree of the decrease is directly proportional to the severity of the disease and the prognosis and low AT plasma activities correlate with high mortality. AT has a double function: anticoagulant and anti-inflammatory. The most important mechanism responsible of the anti-inflammatory properties of AT is the binding to the glycosaminoglycans of the endothelial cells and the consequent release of prostacyclin. During sepsis and septic shock, treatment with AT was able, especially in animal models but also in clinical studies, to decrease plasma levels of mediators of inflammation and in some case to preserve organ failure and to reduce mortality.
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PMID:[Antithrombin: prospects in clinical practice. Sespsi: anticoagulant or anti-inflammatory agents?]. 1276 69

OBJECTIVE: To report successful treatment of three patients admitted with purpura fulminans. DESIGN: Three cases with purpura fulminans: clinical presentation, laboratory findings, treatment, and outcome. SETTING: A seven-bed medical and general surgical Intensive therapy unit in a district general hospital. PATIENTS: Three young patients with clinical and laboratory findings of severe meningococcal sepsis and purpura. INTERVENTIONS: Early replacement therapy with antithrombin concentrate after a single initial plasma exchange, together with conventional antibiotic and supportive treatment. MEASUREMENTS AND MAIN RESULTS: All three cases had abnormal coagulation profile consistent with disseminated intravascular coagulation, adult respiratory distress syndrome, impaired renal function, and severe hemodynamic instability requiring inotropic support. Plasma antithrombin levels were measured in all cases. All patients survived and made a good recovery. CONCLUSIONS: We consider that correction of antithrombin to supranormal levels may have a beneficial effect on survival and outcome in purpura fulminans despite sustained low levels of protein C.
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PMID:Antithrombin concentrate with plasma exchange in purpura fulminans. 1281 93


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