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)

Current concepts of etiology and pathophysiology resulting in disseminated intravascular coagulation (DIC) form the basis of treatment of this hemostatic disorder. Due to the heterogeneous triggering diseases and different kinds of DIC, clinical symptoms such as predominant bleeding, thromboembolic complications or organ failure, clinical experience together with the profile of laboratory test results and their development over time provide the basis for the individually tailored treatment strategy. The guiding principle of therapy is to identify and vigorously treat the underlying cause of DIC without delay. Treatment options to correct the hemostatic defect and to dampen the intravascular clotting/fibrinolytic process include transfusion of blood products, heparin, antithrombin III, and antifibrinolytic agents. The availability of new drugs such as activated protein C, tissue factor pathway inhibitor, hirudin, or synthetic serine protease inhibitors, and the upcoming trials investigating the role of these and older treatment options will help us to more clearly recommend therapy in DIC of different etiology.
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PMID:Treatment options for clinically recognized disseminated intravascular coagulation. 951 80

In southern Brazil, envenomation by larvae of the moth Lonomia obliqua (Walker) may result in blood clotting factor depletion, leading to disseminated intravascular coagulation with subsequent haemorrhage and acute renal failure which may prove fatal. We have examined the effect of a crude extract of spicules from these caterpillars on in vitro hemostasis. The extract alone did not aggregate platelets and had no detectable effect on purified fibrinogen, suggesting that extract induces clot formation by triggering activation of the clotting cascade. In agreement with the presence of thrombin-mediated activity, hirudin prevented clot formation. The extract was found to activate both prothrombin and factor X, suggesting that the depletion of blood clotting factors results from the steady activation of factor X and prothrombin. Heating and diisopropylfluorophosphate abolished the procoagulant activity of the extract, indicating that the active component involved is a protein that may belong to the serine protease family of enzymes. The ability of hirudin to inhibit this coagulant activity suggests that this inhibitor could be beneficial in the treatment of patients envenomed by L. obliqua caterpillars.
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PMID:Lonomia obliqua caterpillar spicules trigger human blood coagulation via activation of factor X and prothrombin. 953 Oct 36

Nafamostat mesilate (FUT) was first reported by Fujii et al, in 1981 as a synthetic protease inhibitor. FUT has been reported as a drug for the treatments of DIC (disseminated intravascular coagulation) and acute pancreatitis and as an anticoagulant in extracorporeal circulation. FUT has a structure of ester conjugate of p-guanidinobenzoic acid and 6-amidino-2-naphthol. In in vivo, this ester site was found as the reaction center as well as the site for the catabolic changes. Plasma half life (t1/2 beta) of FUT was about 23.1 min, compared to about 55 seconds of the related compound, FOY. The inhibitory activity of FUT on the protease was found to be due to the mis-reading of serine protease in vivo.
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PMID:[Pharmacokinetics studies of nafamostat mesilate (FUT), a synthetic protease inhibitor, which has been used for the treatments of DIC and acute pancreatitis, and as an anticoagulant in extracorporeal circulation]. 1083 50

Although it has been suggested that some biological activities of platelet-activating factor (PAF) are mediated by, at least in part, reactive oxygen intermediates (ROI), the precise mechanisms underlying the interaction between the two remains to be elucidated. Antioxidants, such as alpha-tocopherol acid succinate, N-acetyl-L-Cysteine, pyrrolidinedithiocarbamate failed to inhibit PAF-induced immediate systemic reactions such as lethality, symptoms of disseminated intravascular coagulation, and histological changes such as pulmonary edema and hemorrhage in renal medullae 10 min following PAF injection. In contrast. antioxidants significantly inhibited both the in vivo and in vitro PAF-induced NF-kappaB activation and NF-kappaB-dependent TNF-alpha expression. The effects of the antioxidants were due to their inhibition of PAF-induced degradation of IkappaBalpha, a protein responsible for keeping NF-kappaB in an inactive form. A protein tyrosine kinase and N-tosyl-L-phenylalanine chloromethyl ketone sensitive serine protease were involved in both PAF- and H2O2-induced NF-kappaB activation. Collectively, these data indicate that the PAF-induced NF-kappaB activation is selectively mediated through the generation of ROI.
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PMID:Selective involvement of reactive oxygen intermediates in platelet-activating factor-mediated activation of NF-kappaB. 1092 4

Protein C is the zymogen of an anticoagulant serine protease and is converted to its active form (activated protein C: APC) by thrombin in the presence of thrombomodulin. APC plays an important role in regulating coagulation and fibrinolysis by inactivating not only blood coagulation factors Va and VIIIa but also type-1 plasminogen activator inhibitor (PAI-1). The aim of the present study was to examine the effect of a human APC product (designated as CTC-111), compared with that of heparin, on the disseminated intravascular coagulation (DIC) induced by lipopolysaccharide (LPS) in rats. LPS (1 mg/kg/h) infusion was performed through a femoral vein for 4 h. One-fifth amount of the total dosage of CTC-111 or heparin was injected into the other femoral vein, followed by a 4-h infusion of the remainder. Both CTC-111 (10,000-100,000 U/kg) and heparin (400-800 IU/kg) inhibited the decrease in platelet count and fibrinogen level equally. The prolonged activated partial thromboplastin time and prothrombin time observed in DIC rats were further elongated in both CTC-111- and heparin-treated rats. But, this prolongation was less in CTC-111-treated rats than in the heparin-treated ones. Heparin inhibited the increase in fibrin and fibrinogen degradation products more prominently than CTC-111. On the other hand, CTC-111 strongly inhibited the increase in PAI-1 activity but heparin did not. These results suggest that CTC-111 may enhance fibrinolysis through its direct inhibitory effect on PAI-1. The parameters for liver or renal damage, i.e., plasma glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), creatinine (Cre) and blood urea nitrogen (BUN), were significantly increased by LPS infusion. Both CTC-111 (100,000 U/kg) and heparin (800 IU/kg) decreased the increase in GOT and GPT levels significantly, whereas neither affected the increase in Cre or BUN. From these results, the activation of the blood coagulation system might partially contribute to the progression of liver damage caused by LPS, and might be less involved in the progression of renal damage in this model. In conclusion, CTC-111 showed both anticoagulant and profibrinolytic activity in the LPS-induced DIC model without excessive prolongation of coagulation time. From these results, CTC-111 is expected to be a useful remedy for DIC without the risk of bleeding.
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PMID:Effect of activated human protein C on disseminated intravascular coagulation induced by lipopolysaccharide in rats. 1105 Jun 97

Hepsin is a type II transmembrane serine protease abundantly expressed on the surface of hepatocytes. Biochemical studies have shown that hepsin is an enzyme of 51 kDa with the trypsin-like substrate specificity. Several in vitro studies have suggested that hepsin may play a role in blood coagulation, hepatocyte growth, and fertilization. To determine the functional importance of hepsin, hepsin-deficient mice were generated by homologous recombination. Homozygous hepsin-/- mice were viable and fertile, and grew normally. When analyzed in hemostasis assays, such as tail bleeding time and plasma clotting times, and in vivo modes, such as disseminated intravascular coagulation, septic shock, and acute liver regeneration, hepsin-/- mice had similar phenotypes as wild-type controls. Liver weight and serum concentrations of liver-derived proteins or enzymes were also similar in hepsin-/- and wild-type mice. No abnormalities were identified in major organs in hepsin-/- mice in histological examinations. These results indicate that hepsin is not an essential enzyme for normal hemostasis, embryogenesis, and maintenance of normal liver function. Unexpectedly, serum concentrations of bone-derived alkaline phosphatase were approximately two-fold higher in both male and female hepsin-/- mice than those in wild-type controls. The underlying mechanism for this phenotype and long-term effects of hepsin deficiency remain to be determined.
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PMID:Gene targeting in hemostasis. Hepsin. 1117 58

Increasing occurrence of hemorrhagic syndrome in man, caused by contact with Lonomia obliqua caterpillars, has been reported in Southern Brazil in the past 10 years. The L. obliqua venom causes a severe consumptive coagulopathy, which can lead to hemorrhagic syndrome. L. obliqua prothrombin activator protease (Lopap) is a 69-kDa prothrombin activator serine protease isolated from L. obliqua caterpillar bristle extract, which is able to evoke thrombus formation, unclottable blood, and fibrinogen depletion when injected into the blood stream of rats. The purified protein generated thrombin from prothrombin, able to clot purified human fibrinogen and plasma. A decrease in platelet count and inhibition of collagen-induced platelet aggregation were observed, as well as leukocyte infiltration in the lungs. In addition, we observed congestion and hemorrhage in renal glomeruli and necrosis in renal distal tubules. These data support the hypothesis that Lopap contributes to the clinical syndrome caused by human contact with L. obliqua, most probably through prothrombin activation, resulting in a consumption coagulopathy.
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PMID:In vivo characterization of Lopap, a prothrombin activator serine protease from the Lonomia obliqua caterpillar venom. 1139 29

Protein C (PC) is the zymogen form of a serine protease, activated protein C (APC), a naturally occurring anticoagulant. In control of the coagulation of blood, APC functions by attenuating thrombin formation. It serves this role through inactivation, by limited proteolysis, of two important cofactors for overall clot formation, one of which, Factor Va (FVa), stimulates prothrombin activation, and another, Factor VIIIa (FVIIIa), enhances activation of coagulation Factor X (FX). In maintaining the fluidity of blood, APC also indirectly functions in fibrinolysis, in one manner by directly inactivating an inhibitor of plasminogen activation, plasminogen activation inhibitor-1 (PAI-1), and in another manner via its role in attenuating thrombin production, with the resulting effect of limiting production of another thrombin-dependent fibrinolytic inhibitor, thrombin activatable fibrinolysis inhibitor (TAFI). PC, and other components of the PC anticoagulant pathway, e.g., protein S (PS), thrombomodulin (Tm), and endothelial cell protein C receptor (EPCR), also can serve as anti-inflammatory mediators, through a number of different thrombin-dependent and thrombin-independent mechanisms. A large number of symptomatic and asymptomatic mutations occur in PC in humans, which express a variety of phenotypes. Generation and characterization of a murine model of a total PC gene inactivation has demonstrated that while an untreated total PC deficiency results in neonatal death through DIC-related abnormalities, a valuable resource is now available to study phenotypes of less severe deficiencies of this protein. Such studies will lead to advances in an understanding of the relative role of this protein system in the various pathways in which it has an influence.
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PMID:Gene targeting in hemostasis: protein C. 1143 41

A serine protease, prostasin, has been shown to stimulate the activity of amiloride-sensitive sodium channels (ENaC). Prostasin is a glycosylphosphatidylinositol-anchored protein that is found free in physiologic fluids and tissue culture medium, but the mechanism by which prostasin is secreted from the cells has not been elucidated. The current studies found that serine protease inhibitor aprotinin blocked the secretion of prostasin in a mouse cortical collecting duct (CCD) cell line (M-1 cells). A synthetic serine protease inhibitor, nafamostat mesilate (NM), which is commonly used for the treatment of pancreatitis and disseminated intravascular coagulation in Japan, also inhibited the secretion of prostasin in M-1 cells. Continuous infusion of NM into rats resulted in a substantial decrease in urinary prostasin and urinary sodium excretion. p-guanidinobenzoic acid and 6-amidino-2-naphtol, catalytically inactive metabolites of NM, had no effect on prostasin secretion both in M-1 cells and in rats. These findings suggest that a serine protease-sensitive mechanism is involved in the secretion of prostasin in vitro as well as in vivo. Potassium secretion in the CCD is tightly linked to sodium reabsorption through EnaC; therefore, NM-induced decrease in prostasin secretion and subsequent inhibition of ENaC activity could account for the side effects of hyponatremia and/or hyperkalemia that are found sometimes in patients treated with NM. The results indicate an important role for prostasin in sodium reabsorption in the kidney under pathophysiologic conditions.
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PMID:Inhibition of prostasin secretion by serine protease inhibitors in the kidney. 1250 33

Tissue factor (also known as tissue thromboplastin or CD142) is the protein that activates the blood clotting system by binding to, and activating, the plasma serine protease, factor VIIa, following vascular injury. Because of its essential role in hemostasis, tissue factor plays a role in pathology associated with hemostasis, triggering the coagulation system in many thrombotic diseases and the coagulopathies associated with sepsis and other forms of disseminated intravascular coagulation. Recent research has also implicated tissue factor in a variety of nonhemostatic roles, including cell signaling, inflammation, vasculogenesis, and tumor growth and metastasis. This review focuses on both the well-known roles of tissue factor in hemostasis and thrombosis and the newer concepts of tissue-factor biology including how it functions as a signaling receptor and the possible role of blood-borne tissue factor in thrombosis.
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PMID:Tissue factor: a key molecule in hemostatic and nonhemostatic systems. 1500 35


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