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)

Measurement of Protein S in human plasma is clinically important because of deficiency of this protein, which functions as a cofactor of the naturally occurring anticoagulant activated Protein C, is a risk factor for venous thromboembolism. We describe a two-site, enzyme-linked immunosorbent assay (ELISA) for measuring Protein S in which a monoclonal IgG directed against the calcium-independent conformation of Protein S is the capture antibody. The range of detection for the assay was 10 to 160 ng of Protein S per milliliter. The coefficients of variation were 4.6%-7.3% within-assay and 7.7%-10.1% between-assay. We compared this assay with an ELISA involving a polyclonal anti-Protein S rabbit IgG as capture antibody (I) and with Laurell's electroimmunoassay (II) to measure Protein S in plasma from 32 normal subjects and 121 patients or individuals expected to have low concentrations of total Protein S (full-term newborns, pregnant women after the 18th week of gestation, patients with disseminated intravascular coagulation or liver cirrhosis, patients receiving therapy with warfarin, and patients with congenital Protein S deficiency). In general, the results obtained with the monoclonal antibody-based ELISA correlated well with those from I (r = 0.94), less well with those from II (r = 0.86).
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PMID:A monoclonal antibody to human protein S used as the capture antibody for measuring total protein S by enzyme immunoassay. 213 55

Activated protein C (APC) is inhibited by two major plasma inhibitors (PCIs). To find evidence for in vivo complexation of APC, immunoblotting studies were performed on plasmas of 85 patients with suspected disseminated intravascular coagulation (DIC). Samples from 62 of these patients contained 5% to 35% of protein C antigen in APC:inhibitor complexes, indicating that protein C activation and inhibition had occurred. In 24 normal plasmas, no detectable APC:PCI complexes were observed (less than 5%). Patients with higher levels of complexes had more abnormal coagulation test data for DIC. The major band of APC complexes detected by anti-protein C antibodies did not react with antibodies to the heparin-dependent protein C inhibitor (PCI-1) previously described. Rather, APC was complexed with another recently described plasma protein C inhibitor, PCI-2. Immunoblotting studies for protein S, the cofactor for APC, revealed that the majority of the DIC patient plasmas contained a higher than normal proportion of protein S in cleaved form, suggesting that protein S may have been proteolytically inactivated. Protein S total antigen levels were also found to be low in DIC patients, excluding those with malignancy. These studies support the hypothesis that the protein C pathway is activated during DIC.
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PMID:Activation and complexation of protein C and cleavage and decrease of protein S in plasma of patients with intravascular coagulation. 252

Proteins C and S are two vitamin K-dependent plasma proteins that work in concert as a natural anticoagulant system. Activated protein C is the proteolytic component of the complex and protein S serves as an activated protein C binding protein that is essential for assembly of the anticoagulant complex on cell surfaces. The anticoagulant activity is expressed through the selective inactivation of Factors Va and VIIIa. Many patients deficient in proteins C and S have been described and have an associated thrombotic tendency, but not all heterozygous protein C and S deficient individuals experience thrombotic complications. Multiple mechanisms and/or drugs can lead to acquired deficiencies of these proteins: oral anticoagulation, liver disease, DIC and in the case of protein S, lupus erythematosus, nephrotic syndrome, pregnancy and certain hormones. The anticoagulant activity of protein C decreases rapidly after administration of warfarin (i.e., with a time course similar to Factor VII). This rapid decrease may lead to a transient imbalance and contribute to coumarin induced skin necrosis. Protein S antigen levels do not decrease as rapidly, but protein S functional levels are often low in patients with an acute thrombus. The discrepancy between antigen and function results from elevations in C4b-binding protein, which complexes reversibly with protein S. Unlike free protein S, the complex does not function in the anticoagulant pathway. The available information all suggest that deficiency of protein C and protein S should be considered a risk factor contributing to recurrent thrombotic disease and that the function of these proteins is altered by many common clinical conditions which have associated an increased risk of thrombosis.
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PMID:Anticoagulation proteins C and S. 295 34

Protein C (PC), a 62,000-molecular weight vitamin K-dependent serine protease zymogen, is a natural anticoagulant that occurs in plasma at 4 mg/L. Activated PC inactivates clotting factors V and VIII and is also profibrinolytic. Activated PC is enhanced in its anticoagulant activity by protein S (PS), another vitamin K-dependent protein. Protein S is found in platelets and endothelial cells as well as in plasma. Inherited PC deficiency and PS deficiency have been associated with venous thrombosis. Both heterozygous PC and PS deficiency appear to be inherited in an autosomal dominant manner in some families. Homozygous PC deficiency presents as neonatal purpura fulminans and results in massive venous thrombosis of the skin and other organs within the first few days of life. Symptomatic heterozygous PC deficiency and PS deficiency have been treated with oral anticoagulants, successfully minimizing recurrence of thrombosis. Coumarin-induced skin necrosis, a rare complication of oral anticoagulant therapy usually seen within three to five days of initiation of therapy, has also been associated with heterozygous PC deficiency. The short half-life of PC (six to eight hours) compared with most of the vitamin K-dependent clotting factors (greater than 30 hours) is the probable reason for this paradoxical response to oral anticoagulants in some PC-deficient patients, since a transient imbalance of procoagulant and anticoagulant factors may exist during initiation of oral anticoagulant therapy. Acquired deficiency of the PC pathway occurs in disseminated intravascular coagulation and possibly other diseases such as those associated with a lupus anticoagulant.
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PMID:Coumarin necrosis, neonatal purpura fulminans, and protein C deficiency. 296 8

Protein C is a potent inhibitor of blood coagulation, and, in addition, appears to be a profibrinolytic agent. In a first step, protein C must be converted to a serine protease. This activation is catalyzed by a complex formed between thrombin and thrombomodulin, an endothelial cell surface protein. Activated protein C exhibits its anticoagulant activity through the proteolytic inactivation of two blood coagulation cofactors, factors Va and VIIIa. This reaction requires phospholipids, originating from platelets or endothelial cells, and a cofactor protein, protein S. Protein S enhances the binding of activated protein C to phospholipids. In addition, activated protein C stimulates fibrinolysis, through the inactivation of the tissue plasminogen activator (tPA) inhibitor. An isolated constitutional, quantitative or qualitative, protein C or protein S deficiency increases the risk of thrombosis, the clinical features are different in the rare cases of homozygous protein C deficiency (neonatal purpura fulminans) or in the heterozygous patients (recurrent venous thrombosis in young adults). Acquired deficiency in protein C and S had been observed in liver disease, during vitamin K antagonists or L-Asparaginase treatment, and in disseminated intravascular coagulation.
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PMID:[Protein C, protein S]. 303 76

Protein S, an important cofactor of activated protein C, and C4b-binding protein were purified from human plasma. Specific antibodies against the purified proteins were raised in rabbits and used for the development of immunologic assays for these proteins in plasma: an immunoradiometric assay for protein S (which measures both free protein S and protein S complexed with C4b-binding protein) and an electroimmunoassay for C4b-binding protein. Ranges for the concentrations of these proteins were established in healthy volunteers and patients using oral anticoagulant therapy. A slight decrease in protein S antigen was observed in patients with liver disease (0.78 +/- 0.25 U/ml); no significant decrease in protein S was observed in patients with DIC (0.95 +/- 0.25 U/ml). Criteria were developed for the laboratory diagnosis of an isolated protein S deficiency.
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PMID:Determination of plasma protein S--the protein cofactor of activated protein C. 316 Dec 6

Protein S is a vitamin K-dependent plasma protein which serves as the cofactor for activated protein C. Protein S circulates in both an active, free form and in an inactive complex with C4b-binding protein. To elucidate the role of protein S in disease states and during oral anticoagulation, we developed a functional assay for protein S that permits evaluation of the distribution of protein S between free and bound forms and permits determination of the specific activity of the free protein S. In liver disease, free protein S antigen is moderately reduced and the free protein S has significantly reduced specific activity. In disseminated intravascular coagulation, reduced protein S activity occurs due to a redistribution of protein S to the inactive bound form. During warfarin anticoagulation, reduction of free protein S antigen and the appearance of forms with abnormal electrophoretic mobility significantly decrease protein S activity. After the initiation of warfarin, the apparent half-life of protein S is 42.5 h. In patients with thromboembolic disease, transient protein S deficiency occurs due to redistribution to the complexed form. Caution should be exercised in diagnosing protein S deficiency in such patients by use of functional assays.
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PMID:Acquired deficiencies of protein S. Protein S activity during oral anticoagulation, in liver disease, and in disseminated intravascular coagulation. 328 13

The carbohydrate deficient glycoprotein (CDG) syndrome is a newly described disorder characterized by impaired glycosylated molecules. It has been reported that transient stroke-like episodes appear in half of the patients. We performed hemostatic studies on three CDG syndrome patients belonging to two unrelated families. The most characteristic findings were decreases in antithrombin III (AT III), protein C and alpha 2 plasmin inhibitor to nearly half normal levels. Protein S was reduced in two (siblings) patients. Isoelectric focusing of AT III in native plasma revealed decreased intensity of the major band and increased intensity of a minor cathodal band. These minor AT III molecules were considered to lack an oligosaccharide sidechain. A 12-year-old girl defective not only for AT III but also protein C and protein S developed disseminated intravascular coagulation accompanied by arterial thrombosis in her left hand following dyspnea associated with bronchial asthma. These findings suggest that thrombotic predisposition in patients with CDG syndrome is due to decreased levels of major coagulation inhibitors, particularly as a result of impaired glycosylation of AT III.
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PMID:Hemostatic studies in patients with carbohydrate-deficient glycoprotein syndrome. 786 68

Protein C, Protein S and Antithrombin III were screened in one hundred patients admitted for abruptio placentae and one hundred women who delivered normally in Dakar university hospital. We found a reduction of Protein S at normal delivery which is linked to hypercoagulation activity during this process. PC and PS were significantly decreased during abruptio placentae in relation with the disseminated intravascular coagulation which was found in our study. We recommend to include these tests to explore aetiologies of abruptio placentae and to confirm their congenital deficit two months after delivery.
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PMID:[Protein C, protein S and antithrombin III at normal delivery and during abruptio placentae]. 1079 88

Recently, basic and clinical advances have provided insights into the molecular events that link inflammation with blood coagulation and thrombosis. At least in cell culture, the inflammatory cytokines, especially tumour necrosis factor alpha (TNF) and interleukin 1-beta (IL-1), are major mediators that can elicit changes in cell phenotype. With respect to coagulation, one of the clot-promoting and one of the inhibitory pathways seem especially prone to modulation by these cytokines. Whenever Tissue Factor contacts the blood, coagulation is initiated rapidly. These cytokines can elicit Tissue Factor production on endothelium and monocytes. Thus, the cytokines elaborate Tissue Factor formation intravascularly. This contrasts with the normal situation in which Tissue Factor is located exclusively in the extravascular space, largely on fibroblasts, where it is expressed constitutively. Furthermore, cytokines, especially interleukin 6 (IL-6), can stimulate new platelet formation, and the new platelets responding to IL-6 have increased sensitivity to thrombin activation and increased procoagulant activity. Regulating the clotting process are a large number of anticoagulant and fibrinolytic mechanisms. The three major anticoagulant mechanisms appear to involve antithrombin-heparin, Tissue Factor pathway inhibitor (TFPI) and the Protein C pathway. Of these, the Protein C pathway appears to be the primary target for cytokine action. The Protein C pathway is initiated when thrombin binds to thrombomodulin (TM). TM is expressed constitutively on endothelium. In tissue culture, TNF, IL-1 or endotoxin lead to a slow loss of TM and endothelial cell Protein C receptor (EPCR) from the cell surface. In addition, Protein S levels decrease in patients with disseminated intravascular coagulation (DIC). Taken together, these results suggest that cytokines should elicit massive thrombotic responses when administered systemically. At near toxic levels, TNF fails to elicit an overt DIC or thrombotic response in patients, although sensitive markers of coagulation do detect changes in coagulation in response to TNF. In baboons, very high levels of TNF also fail to elicit fibrinogen or platelet consumption. However, if the Protein C pathway is blocked, these cytokines can elicit either DIC or deep-vein thrombosis, depending on the conditions. Thrombus formation is potently potentiated by impeding flow and/or by catheterization. DIC is facilitated by providing membrane surfaces, possibly mimicking complement mediated platelet activation/damage that occurs in shock. Thus, available evidence suggests important roles for inflammatory cytokines in DIC and thrombosis, but they seem insufficient by themselves to elicit overt thrombotic responses without secondary stimuli. Current data suggest that anti-inflammatory drugs are a viable candidate to blocking DIC or thrombosis without impairing the haemostatic balance.
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PMID:Possible involvement of cytokines in diffuse intravascular coagulation and thrombosis. 1085 74


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