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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Disseminated intravascular coagulation (DIC) constitutes a part of the multiple organ failure (MOF) syndrome seen with such disorders as trauma and sepsis. Early detection of increased coagulation and fibrinolytic activity is important. The dynamic changes in some markers for early detection of the activation of these cascade systems are presented in relation to two patients with brain trauma. The clinical status and the severity of the disease were assessed by an established scoring method (APACHE II). The coagulation activation was noted by the appearance of increased end products of the coagulation cascade, such as soluble fibrin, thrombin-antithrombin complex, and prothrombin fragment 1 + 2. Fibrinolytic activation and an increased secondary inhibition of fibrinolysis were detected by increased levels of D-dimer and plasminogen activator inhibitor-1. Leukocyte activation was indicated by a rise in elastase. The laboratory results normalized with clinical improvement. These new methods seem to detect DIC earlier than traditional methods and may also be of value for monitoring treatment.
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PMID:Disseminated intravascular coagulation in neurosurgical patients: diagnosis by new laboratory methods. 1581 52

Coagulation activation with intravascular fibrin formation is a general finding in patients with sepsis. Low coagulation factors may be caused by disseminated intravascular coagulation, as well as by loss of plasma and impaired hepatic synthesis in the course of sepsis. The leading clinical symptom in consumption coagulopathy is bleeding. Therefore, treatment mainly consists of substitution of coagulation factors and platelets. Meningococcal and pneumococcal, as well as some other infections may lead to sepsis-induced purpura fulminans, a condition associated with microvascular thrombosis, necrosis, and haemorrhage. A typical laboratory sign is a very low plasma protein C level. Treatment with protein C concentrate or recombinant activated protein C (Drotrecogin alfa, activated) has been shown to be beneficial in sepsis-induced purpura fulminans. Unfractionated heparin or low molecular weight heparin has been recommended for prophylaxis of venous thrombosis, but there are no clinical studies specifically on patients with sepsis. Antithrombin concentrate is used in patients with antithrombin deficiency treated with heparin for acute venous thrombosis or embolism, extracorporeal circulation procedures or other invasive procedures. There is no indication for general use of antithrombin concentrate in patients with sepsis even in patients with low plasma antithrombin levels. Drotrecogin alfa, activated, is used for treatment of patients with severe sepsis. Its use is not limited to patients with sepsis-induced disseminated intravascular coagulation, although these patients appear to benefit especially from this therapy.
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PMID:[Sepsis-associated coagulation disorders]. 1592 56

Based on the increasing knowledge of defects in haemostasis in patients with sepsis as well as on the non-conclusive results of studies which tried to increase the prognosis by modulating cytokine response of the patients, in the last years the impact of therapeutic modulation of coagulation in sepsis has been investigated. In contrast to the results of phase III studies with the coagulation inhibitors antithrombin and tissue factor pathway inhibitor recombinant human activated protein C (rhAPC) resulted in a significant reduction in mortality for the whole study population. Data analyses showed, that treatment with rhAPC was clinically beneficial especially in patient groups who showed a high mortality in the placebo arm. Inhibition of thrombus formation due to the therapy with natural coagulation inhibitors resulted in an increase of sepsis-imminent haemorrhage, which became significant in some studies. Treatment with antithrombin and heparin resulted in a considerable increase in bleeding complications and on the other hand, may have antagonized the expected effect of antithrombin on the patient's prognosis. Some results suggesting beneficial effects of heparin on patient prognosis in the placebo arms and on the other hand negative effects of heparin in the verum arms -- especially with antithrombin or tissue factor pathway inhibitor -- let to a controversial discussion of the risk/benefit relation of heparin, given in prophylactic doses to patients with severe sepsis. Whereas the impact and optimal application of heparin to patients with severe sepsis needs to be clarified study results with rhAPC resulted in the approval of this therapy and the implementation in the guidelines of the treatment of patients with severe sepsis.
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PMID:[Therapeutic modulation of coagulation in sepsis]. 1592 57

Sepsis, a systemic inflammatory syndrome, is a response to infection and when associated with multiple organ dysfunction is termed severe sepsis. It remains a leading cause of mortality in the critically ill. The response to the invading microorganisms may be considered as a balance between a pro-inflammatory and an anti-inflammatory reaction. While an inadequate pro-inflammatory reaction and a strong anti-inflammatory response could lead to overwhelming infection and the death of the patient, a strong and uncontrolled pro-inflammatory response, manifested by the release of pro-inflammatory mediators may lead to microvascular thrombosis and multiple organ failure. Endotoxin triggers sepsis via the release of various mediators such as tumour necrosis factor-alpha and interleukin-1 (IL-1). These cytokines activate the complement and coagulation systems, release adhesion molecules, prostaglandins, leukotrienes, reactive oxygen species and nitric oxide. Other mediators involved in the sepsis syndrome include IL-1, -6 and -8; arachidonic acid metabolites; platelet activating factor; histamine; bradykinin; angiotensin; complement components and vasoactive intestinal peptide. These pro-inflammatory responses are counteracted by IL-10. Most of the trials targeting the different mediators of the pro-inflammatory response have failed due to a lack of correct definition of sepsis. Understanding the exact pathophysiology of the disease will enable more advanced treatment options. Targeting the coagulation system with various anticoagulant agents including, activated protein C, and tissue factor pathway inhibitor (TFPI) is a rational approach. Many clinical trials have been conducted to evaluate these agents in severe sepsis. While trials on antithrombin and TFPI were not so successful, the double-blind, placebo-controlled, Phase III trial of recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) was successful, creating a significant decrease in mortality when compared to the placebo group. A better understanding of the pathophysiologic mechanism of severe sepsis will provide better treatment options, and combination antithrombotic treatment may provide a multipronged approach for the treatment of severe sepsis.
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PMID:Antithrombotic agents in the treatment of severe sepsis. 1598 40

The endogenous plasma anticoagulant proteins tissue factor pathway inhibitor (TFPI) and antithrombin (AT) have both been extensively studied in large, multinational phase III clinical trials in patients with severe sepsis. The TFPI and AT trials failed to result in significant reductions in the 28-day, all-cause mortality rates in their respective study populations. However, there appear to be definable patient populations within each study that may have benefited from TFPI or AT. Drug-drug interactions and dosing issues were observed in both trials. The similarities and differences of each anticoagulant and the lessons learned from the recent phase III clinical trials are examined in this review.
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PMID:Tissue factor pathway inhibitor and antithrombin trial results. 1599 66

Bacterial porins enhance the thrombin activity upon chromogen substrate chromozym. Should porin-dependent enhancement of thrombin activity take place also upon fibrinogen in vivo, this might greatly increase the fibrin production which, in turn, might lead to blood vessel obstruction. In this study, we demonstrate fibrin hyperproduction in a simplified coagulative system, consisting of fibrinogen and thrombin-pure molecules, in the presence of bacterial porins. In particular, bacterial porins, in the presence of thrombin, significantly increased the fibrin production compared with thrombin alone. Also, fibrin hyperproduction took place even in the presence of the thrombin inhibitors antithrombin III (AT III) or alpha2 macroglobulin (alpha2M). However, the thrombin-fibrinogen reaction in the presence of AT III or alpha2M did not generate fibrin, unless porins were present. In conclusion, porins not only enhance thrombin activity but also inhibit the antithrombin activity exerted by AT III or alpha2M. We hypothesize that, because of porins activity, fibrin is largely generated due to thrombin hyperactivation. Moreover, further fibrin is produced by thrombin, which is not blocked by two serpins for the presence of porins. These results might be relevant as to the occurrence of disseminated intravascular coagulation in sepsis by gram-negative bacteria, which are known to produce porins.
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PMID:Hyperproduction of fibrin and inefficacy of antithrombin III and alpha2 macroglobulin in the presence of bacterial porins. 1604 46

Severe sepsis in children or adults may cause a life-threatening coagulopathy, with widespread consumption of activated protein C (APC); recombinant human APC (rhAPC) is a promising candidate anticoagulant treatment. We investigated the effects of rhAPC and other anticoagulants on coagulation triggered by adding small quantities of lipidated tissue factor to human umbilical-cord plasma in vitro. rhAPC, unfractionated heparin (UH), and melagatran (a direct thrombin inhibitor) were studied individually, and in combinations of rhAPC with either UH or melagatran. rhAPC alone dose-dependently prolonged the activated partial-thromboplastin time (aPTT) but not the prothrombin time (PT), and dose-dependently suppressed two indices of thrombin generation, namely prothrombin fragment F 1.2 (F 1.2) generation and thrombin-antithrombin (TAT) complex formation. UH alone dose-dependently prolonged the aPTT but not the PT, while melagatran alone dose-dependently prolonged both the aPTT and the PT. Adding either UH or melagatran dose-dependently augmented the capacity of rhAPC to suppress F 1.2 generation (with addition of UH showing a greater effect) and TAT formation (with addition of melagatran showing a greater effect). Both the capacity of UH to prolong the aPTT and the capacity of melagatran to prolong the aPTT and the PT were augmented by adding rhAPC. In our in-vitro study, adding either UH or melagatran augmented the capacity of rhAPC to suppress thrombin generation in human umbilical-cord plasma, with the anticoagulant effect of melagatran being more predictable than that of UH. Hence, combining rhAPC with melagatran might be a valuable therapeutic option in patients with severe sepsis.
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PMID:Additive effects of anticoagulants: recombinant human activated protein C and heparin or melagatran, in tissue factor-activated umbilical-cord plasma. 1611 86

Experimental studies in ischemia-reperfusion and sepsis indicate that activated protein C (APC) has direct anti-inflammatory effects at a cellular level. In vivo, however, the mechanisms of action have not been characterized thus far. Intravital multifluorescence microscopy represents an elegant way of studying the effect of APC on endotoxin-induced leukocyte-endothelial-cell interaction and nutritive capillary perfusion failure. These studies have clarified that APC effectively reduces leukocyte rolling and leukocyte firm adhesion in systemic endotoxemia. Protection from leukocytic inflammation is probably mediated by a modulation of adhesion molecule expression on the surface of leukocytes and endothelial cells. Of interest, the action of APC and antithrombin in endotoxin-induced leukocyte-endothelial-cell interaction differs in that APC inhibits both rolling and subsequent firm adhesion, whereas antithrombin exclusively reduces the firm adhesion step. The biological significance of this differential regulation of inflammation remains unclear, since both proteins are capable of reducing sepsis-induced capillary perfusion failure. To elucidate whether the action of APC and antithrombin is mediated by inhibition of thrombin, the specific thrombin inhibitor hirudin has been examined in a sepsis microcirculation model. Strikingly, hirudin was not capable of protecting from sepsis-induced microcirculatory dysfunction, but induced a further increase of leukocyte-endothelial-cell interactions and aggravated capillary perfusion failure when compared with nontreated controls. Thus, the action of APC on the microcirculatory level in systemic endotoxemia is unlikely to be caused by a thrombin inhibition-associated anticoagulatory action.
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PMID:Microcirculatory alterations in ischemia-reperfusion injury and sepsis: effects of activated protein C and thrombin inhibition. 1616 73

Disseminated intravascular coagulation is a frequent complication of sepsis. Coagulation activation, inhibition of fibrinolysis, and consumption of coagulation inhibitors lead to a procoagulant state resulting in inadequate fibrin removal and fibrin deposition in the microvasculature. As a consequence, microvascular thrombosis contributes to promotion of organ dysfunction. Recently, three randomized, double-blind, placebo-controlled trials investigated the efficacy of antithrombin, activated protein C (APC), and tissue factor pathway inhibitor, respectively, in sepsis patients. A significant reduction in mortality was demonstrated in the APC trial. In this article, we first discuss the physiology of coagulation and fibrinolysis activation. Then, the pathophysiology of coagulation activation, consumption of coagulation inhibitors, and the inhibition of fibrinolysis leading to a procoagulant state are described in more detail. Moreover, therapeutic concepts as well as the three randomized, double-blind, placebo-controlled studies are discussed.
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PMID:Disseminated intravascular coagulation in sepsis. 1623 64

As the pivotal phase III randomized controlled clinical trial on antithrombin concentrate in patients with severe sepsis did not show a beneficial effect of antithrombin treatment on 28-day mortality, the interest in the potential use of this treatment modality in sepsis has diminished. However, recent data on the effect of antithrombin administration on coagulation in combination with recent analyses from the clinical trials that were aimed to restore physiological anticoagulant pathways in patients with sepsis may revitalize the interest in antithrombin concentrate for the treatment of severe sepsis.
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PMID:Antithrombin in sepsis revisited. 1628 58


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