Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0012739 (disseminated intravascular coagulation)
 8,673 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Kunitz-type proteinase inhibitor, tissue factor pathway inhibitor (TFPI), is the only endogenous inhibitor of the tissue factor (TF)-mediated coagulation pathway that plays a dominant role in normal haemostasis. TFPI exerts its action by binding to factor Xa (FXa) forming a TFPI-FXa complex that then, in a second step, binds and effectively inhibits the TF-factor VIIa (FVIIa) complex. Both full-length TFPI and chemically modified forms (e.g., truncated, glycosylated or phosphorylated TFPI variants) exert various pharmacological effects. The anticoagulant and antiplatelet actions of TFPI, its potency in inhibiting thrombin and FXa generation, as well as its favourable antithrombotic effectiveness seen in different animal models of venous and arterial thrombosis make this inhibitor a promising agent that could be potentially useful in several clinical indications. The inhibitory action of TFPI is accelerated by heparin. Heparin, as well as low molecular weight heparin (LMWH) derivatives, release TFPI from the vascular endothelium, an effect which seems to contribute mainly to the antithrombotic effectiveness of these drugs. The clinical relevance of TFPI is still undefined. Based on the beneficial actions in animal studies, as well as on the results obtained in first clinical investigations, TFPI is expected to be effective in the treatment of various diseases, such as disseminated intravascular coagulation, sepsis, coronary syndromes, stroke and acute respiratory distress syndrome (ARD). Further clinical trials should clarify the role of TFPI and more importantly define its potential usefulness as a prophylactic and/or therapeutic agent.
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PMID:Recombinant TFPI and variants: potential implications in the treatment of cardiovascular disorders. 1599 20

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

Tissue factor (TF)-initiated coagulation plays a significant role in the pathophysiology of many diseases, including cancer and inflammation. Tissue factor pathway inhibitor (TFPI) is a plasma Kunitz-type serine protease inhibitor, which modulates initiations of coagulation induced by TF. In a factor (F) Xa-dependent feedback system, TFPI binds directly and inhibits the TF-FVII/FVIIa complex. Normally, TFPI exists in plasma both as a full-length molecule and as variably carboxy-terminal truncated forms. TFPI also circulates in complex with plasma lipoproteins. The levels and the dual inhibitor effect of TFPI on FXa and TF-FVII/FVIIa complex offers insight into the mechanisms of various pathological conditions triggered by TF. The use of selective pharmacological inhibitors has become an indispensable tool in experimental haemostasis and thrombosis research. In vivo administration of recombinant TFPI (rTFPI) in an experimental animal model prevents thrombosis (and re-thrombosis after thrombolysis), reduces mortality from E. coli-induced-septic shock, prevents fibrin deposition on subendothelial human matrix and protects against disseminated intravascular coagulation (DIC). Thus, TFPI may play an important role in modulating TF-induced thrombogenesis and it may also provide a unique therapeutic approach for prophylaxis and/or treatment of various diseases. In this review, we consider structural and biochemical aspects of the TFPI molecule and detail its inhibitory mechanisms and therapeutic implications in various disease conditions.
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PMID:Tissue factor pathway inhibitor: structure, biology and involvement in disease. 1626 34

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.
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PMID:Tissue factor in trauma and organ dysfunction. 1647 62

Tissue factor plays an essential role in the initiation of coagulation in vivo. In severe conditions, including sepsis and acute lung injury, increased expression of tissue factor may induce disseminated intravascular coagulation and fibrin deposition in organs, which are believed to have a determining impact on patient outcome. Tissue factor also acts as a signaling receptor and is involved in the systemic inflammatory response, as in cancer progression and atherosclerosis. Interventions aiming at limiting tissue factor activities have been evaluated in multiple experimental studies and the observed results have supported the potential benefits for coagulation disorders, inflammation, and survival. The effects of the main physiological inhibitor of tissue factor, tissue factor pathway inhibitor, have been evaluated in two large clinical trials in sepsis. Even though they are not associated with an improved outcome, the observed data support further clinical studies.
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PMID:Pharmacological inhibition of tissue factor. 1647 64

Systemic inflammation can induce blood hypercoagulability, even disseminated intravascular coagulation (DIC), and "cross talk" exists between inflammatory and coagulation system. So anticoagulation should be helpful in the treatment of systemic inflammatory response syndrome (SIRS) or sepsis. The success in the use of recombinant human activated protein C (rhAPC) is a strong evidence to support anticoagulation strategy in the treatment of sepsis. Unexpectedly, other two anticoagulation studies, KyberSept and OPTIMIST, respectively with antithrombin and tissue factor pathway inhibitor (TFPI) failed to show improvement in 28-day survival rate. Blame had been laid on the combined use of heparin or low molecular weight heparin (LMWH), as it might interfere with efficacy of antithrombin and TFPI. However, no compelling evidence was found to support this hypothesis, as there was no significant difference in result between the patients with and without heparin or LMWH in the treatment groups in these two studies. Contrarily, significant differences in outcome were found between patients with and without heparin or LMWH in control groups, and the survival rate of patients with heparin or LMWH in control groups was higher than that of the treatment groups. These results strongly suggested heparin or LMWH could be effective in the treatment of sepsis. It is our understanding that any anticoagulant should have some potential effect in treatment of sepsis. Therefore, it seems to be necessary to explore the efficacy of traditional anticoagulant, and compare the effects between the new and old drugs.
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PMID:[Highlighting the potential of heparin in the treatment of sepsis in view of failure of KyberSept and OPTIMIST projects]. 1737 63

Adrenomedullin (ADM) is a vasodilator peptide that has a variety of effects, including antithrombotic activities and resistant roles to lipopolysaccharide (LPS)-induced septic shock. During sepsis, LPS triggers the development of disseminated intravascular coagulation (DIC) via the tissue factor-dependent pathway of coagulation. It is unknown whether the antithrombotic activities of ADM contribute to its resistance to sepsis. In the present study, we investigated the effects of ADM on tissue factor pathway inhibitor (TFPI) (primary anticoagulant factor) expression in human umbilical vein endothelial cells (HUVECs) exposed to LPS, and the possible underlying mechanism for these effects. Exposure of HUVECs to LPS for 12 hours caused significant decrease of TFPI protein activities and mRNA expression. These effects were abolished by treatment with ADM (10(-10) to 10(-6) M), cAMP analogue and calcium antagonist. Accordingly, cAMP antagonist inhibited the counteraction effect of ADM on LPS in TFPI expression. Electrophoresis mobility shift assay (EMSA) and Western blot analysis showed that the protein level of GATA-2 and SP1 transcriptional factors and their binding to the corresponding regulatory sequences decreased by LPS treatment. And these effects of LPS were antagonized by ADM. Promoter-reporter assays and mutational analysis also confirmed the roles of GATA-2 and SP1 motifs from -1247 to -381 bp promoter sequence in TFPI inducible expression. Taken together, these results indicate that ADM antagonizes the effect of LPS on TFPI expression, which is mediated by affecting transcriptional factor GATA-2 and SP1 through cAMP and calcium signaling pathway.
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PMID:Crucial roles of GATA-2 and SP1 in adrenomedullin-affected expression of tissue factor pathway inhibitor in human umbilical vein endothelial cells exposed to lipopolysaccharide. 1747 96

Reduced concentration of tissue factor pathway inhibitor is a risk factor for development of deep venous thrombosis, whereas elevated concentrations of tissue factor pathway inhibitor are observed in patients with acute myocardial infarction and disseminated intravascular coagulation. Presently, we studied the association between inflammation, endothelial cell perturbation, fibrin degradation and the concentration of tissue factor pathway inhibitor in patients suspected for acute deep venous thrombosis. We determined the tissue factor pathway inhibitor -33T/C polymorphism, free and total tissue factor pathway inhibitor, C-reactive protein, von Willebrand factor and D-Dimer in 160 consecutive patients admitted to hospital with a tentative diagnosis of acute deep venous thrombosis. Deep venous thrombosis was identified in 57 patients (18 distal and 39 proximal). The distribution of the tissue factor pathway inhibitor genotypes between patients with and without deep venous thrombosis showed a trend toward significant deviation (P = 0.08). The concentrations of free and total tissue factor pathway inhibitor, C-reactive protein, von Willebrand factor and D-Dimer were significantly higher in patients with deep venous thrombosis than in patients without deep venous thrombosis (P < 0.001 for all quantities). The significant relationship between free and total tissue factor pathway inhibitor and deep venous thrombosis persisted when adjusted for the tissue factor pathway inhibitor -33T/C polymorphism, C-reactive protein, von Willebrand Factor and potentially confounding clinical conditions (P < or = 0.004), but disappeared when adjusted for D-Dimer (P > or = 0.10). We conclude that patients suffering from acute deep venous thrombosis express significantly higher concentrations of tissue factor pathway inhibitor than patients without deep venous thrombosis. The significant relationship is not associated with the -33T/C polymorphism, inflammation or endothelial cell perturbation, but is most likely related to release of tissue factor pathway inhibitor from fibrin deposits.
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PMID:Tissue factor pathway inhibitor relates to fibrin degradation in patients with acute deep venous thrombosis. 1860 90

The immune response to infection includes activation of the blood clotting system, leading to extravascular fibrin deposition to limit the spread of invasive microorganisms. Some bacteria have evolved mechanisms to counteract this host response. Pla, a member of the omptin family of Gram-negative bacterial proteases, promotes the invasiveness of the plague bacterium, Yersinia pestis, by activating plasminogen to plasmin to digest fibrin. We now show that the endogenous anticoagulant tissue factor pathway inhibitor (TFPI) is also highly sensitive to proteolysis by Pla and its orthologs OmpT in Escherichia coli and PgtE in Salmonella enterica serovar Typhimurium. Using gene deletions, we demonstrate that bacterial inactivation of TFPI requires omptin expression. TFPI inactivation is mediated by proteolysis since Western blot analysis showed that TFPI cleavage correlated with loss of anticoagulant function in clotting assays. Rates of TFPI inactivation were much higher than rates of plasminogen activation, indicating that TFPI is a better substrate for omptins. We hypothesize that TFPI has evolved sensitivity to proteolytic inactivation by bacterial omptins to potentiate procoagulant responses to bacterial infection. This may contribute to the hemostatic imbalance in disseminated intravascular coagulation and other coagulopathies accompanying severe sepsis.
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PMID:Proteolytic inactivation of tissue factor pathway inhibitor by bacterial omptins. 1898 66

Inflammation and coagulation occur concomitantly in sepsis. Thrombin activates platelet that leads to P-selectin translocation, which upregulate tissue factor (TF) generation. Tissue factor pathway inhibitor (TFPI) is an anticoagulant that modulates coagulation induced by TF. The term non-overt disseminated intravascular coagulation (DIC) refers to a state of affairs prevalent before the occurrence of overt DIC. It was suggested that an initiation of treatment in non-overt DIC has better outcome than overt DIC. This study investigated the role of TFPI level, P-selectin, and thrombin activation markers in non-overt and overt DIC induced by sepsis and its relationship to outcome and organ dysfunction as measured by the Sequential Organ Failure Assessment (SOFA) score. It included 176 patients with sepsis. They were admitted to the pediatric intensive care unit (ICU).They included 144 cases of non-overt DIC and 32 cases of overt DIC. There was a significant difference in hemostatic markers, platelet count, partial thromboplastin time (PTT), P-selectin, thrombin activation markers, TFPI, and DIC score between overt and non-overt DIC in both groups. It was noticed that P-selectin was positively correlated with DIC score, fibrinogen consumption, fibrinolysis (D-dimer), thrombin activation markers, and TFPI. Tissue factor pathway inhibitor was significantly correlated with fibrinolysis, DIC score, and prothrombin fragment 1+2. Sequential Organ Failure Assessment score was correlated with DIC score and other hemostatic markers in patients with overt DIC. To improve the outcome of patients with DIC, there is a need to establish more diagnostic criteria for non-overt-DIC. Plasma levels of TFPI and P-selectin may be helpful in this respect.
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PMID:Tissue factor pathway inhibitor and P-selectin as markers of sepsis-induced non-overt disseminated intravascular coagulopathy. 1968 98


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