Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hereditary protein C deficiency, which is inherited as an autosomal-dominant trait, predisposes to venous thrombotic disease. Heterozygotes are at risk for superficial thrombophlebitis, deep venous thrombosis and/or pulmonary embolism, which may occur without apparent cause at a young age. Other manifestations are cerebral venous thrombosis and mesenteric vein thrombosis. In severe, often homozygous, protein C deficiency, a purpura fulminans syndrome may occur shortly after birth, resulting in death due to extensive thrombosis, if it is not adequately treated. The thrombotic manifestations in heterozygotes are effectively prevented by coumarin therapy. However, in the initial phase of oral anticoagulant therapy, the patients have an increased risk for the development of coumarin-induced haemorrhagic skin necrosis. The purpura fulminans syndrome can be treated with either replacement therapy or with coumarin therapy. Heparin appears to be ineffective in the prevention of both the purpura fulminans syndrome and the coumarin-induced skin necrosis.
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PMID:Hereditary protein C deficiency. 384 Jan 12

Major mesenteric venous thrombosis in a young man who had already had spontaneous thromboembolic accidents prompted the diagnosis in 1982 of 'Antithromin III' deficiency. The initial reduction of this inhibitor proved to be secondary to a consumption raised abnormally by Heparin. Research into the family antecedents made it possible in 1983 to discover a constitutional 'Protein C' deficiency without stopping the antivitamins K for this patient.
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PMID:[Antithrombin III deficiency induced by heparin and constitutional protein C deficiency. Apropos of a case]. 384 May 98

The response of components of the coagulation and fibrinolytic systems has been examined in patients undergoing minor and major elective surgery and receiving or not receiving subcutaneously administered prophylactic low molecular weight (LMW) heparin. Blood samples were withdrawn pre-operation (PO), post-anaesthesia (PA), during operation (DO) and 24 hours post-operation. Release of plasminogen activator occurred post anaesthesia at a time when factor VIII components were unchanged or decreased. Induction of anaesthesia decreased plasminogen (p less than 0.005) fibrinogen (p less than 0.02) ATIII (p less than 0.002) and fast a2-antiplasmin (p less than 0.005). During operation plasminogen activator release reached a peak in association with a moderate increase in factor VIII components. Heparin treatment produced a prolongation of APTT at DO (p less than 0.05) and at 24hr (p less than 0.002) stages, this prolongation being apparently unrelated to its concentration but did not prevent the rise of factor VIII components observed at 24 hr (p less than 0.02). Prekallikrein (p less than 0.05) and antithrombin III levels (p less than 0.05) were significantly higher whereas fast a2-antiplasmin (p less than 0.002) was significantly lower at 24 hours in patients undergoing major operation and treated with heparin. Protein C levels fell significantly at 24 hours in the untreated patient (p less than 0.014) and in the heparin treated group the fall was greater than the control group (p less than 0.007). At 24 hours other haemostatic and fibrinolytic components were unaffected by heparin treatment.
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PMID:The influence of LMW heparin on the coagulation and fibrinolytic response to surgery. 392 Jul 75

Thrombin activity was assayed on the aortic surface of rabbits after soft tissue trauma or endothelial injury caused by a balloon catheter. The animals were sacrificed by exsanguination 20 minutes or 3 hours after either type of trauma. Thrombin amidolytic activity on the luminal surface of the aorta was measured by exposing it to a synthetic chromogenic substrate. Thrombin activity appeared on the aortic endothelium 3 hours but not 20 minutes after soft tissue trauma. Heparin prevented the appearance of thrombin activity completely only if given just before the trauma. After endothelial injury, thrombin activity appeared on the vascular surface after 3 hours but not after 20 minutes. Thrombin activity appearing on the endothelium after soft tissue trauma may explain posttraumatic thrombotic events. The thrombin activity could, however, also be directed towards activation of protein C in which case an anticoagulant effect is obtained. Thrombin appearing after endothelial injury may enhance reactivity on the damaged vessel wall.
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PMID:Thrombin activity appearing on the vessel wall after trauma. 408 12

Activated protein C is a vitamin K-dependent plasma protein which inhibits blood coagulation at the levels of factors V and VIII in the clotting cascade and which enhances blood clot lysis by raising the levels of circulating plasminogen activator. Activation of protein C occurs when thrombin binds to an endothelial cell associated cofactor, thrombomodulin. The thrombin-thrombomodulin complex rapidly activates the protein C. The activated protein C has a relatively long half-life in plasma and thus can serve as a circulating anticoagulant as well as elevate the levels of plasminogen activator. Heparin interacts with the protein C system in at least two distinct ways. First, the activation of protein C in vivo can be blocked by administration of low levels of heparin. The heparin brings about the inhibition of thrombin either before thrombin is bound to the cell-associated thrombomodulin or after the thrombin is complexed to the thrombomodulin. Secondly, activated protein C has its own unique inhibitor, activated protein C inhibitor. Inhibition of activated protein C by this inhibitor is stimulated by relatively high levels of heparin (5-10 u/ml). The physiologic significance of heparin-activated protein C inhibitor remains to be demonstrated.
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PMID:Heparin-protein C interaction. 608 2

Protein C is a vitamin K-dependent plasma protein. Activated protein C is a potent anticoagulant and enhances blood clot lysis. We have developed a functional assay for protein C in human plasma. The measurement of protein C is accomplished by the addition of thrombomodulin, an endothelial-cell-associated cofactor for protein C activation, and thrombin in a 1:1 molar complex. The activated protein C formed in the plasma is immunoadsorbed with goat anti-human protein C IgG-agarose. The immunoadsorbed activated protein C retains the ability to hydrolyze chromogenic substrates, and after unbound plasma proteins are removed by washing, the bound activated protein C is quantitated by incubation with the substrate H-D-phe-pip-arg-p-nitroanilide (S-2238). Normal individuals have functional protein C levels of 3.9-5.9 micrograms/ml, with a mean value of 4.8 micrograms/ml. Individuals undergoing warfarin anticoagulation and patients with advanced liver diseases have decreased levels, as do certain patients with evidence of intravascular clotting. Functional protein C levels correlate well with immunologic levels of the protein in the patient groups studied. Heparin enhances the rate of activated protein C inhibition, as monitored by recovery of activated protein C by immunoadsorption. A patient with recurrent venous thrombosis and abnormal functional protein C activity, but normal levels of antigen, has been identified.
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PMID:Determination of functional levels of protein C, an antithrombotic protein, using thrombin-thrombomodulin complex. 631 87

Thrombomodulin (TM) is an anionic (pI approximately 4) protein cofactor that promotes thrombin (THR) cleavage of protein C to generate activated protein C (APC), a potent anticoagulant. We find that the cationic platelet alpha-granule protein platelet factor 4 (PF4) stimulates 4-25-fold the cofactor activity of rabbit TM and two differentially glycanated versions of an extracellular domain human TM polypeptide in which the glycosaminoglycan (GAG) is either present (GAG+ TM) or absent (GAG- TM) with an ED50 of 3.3-10 micrograms/ml. No such stimulation occurs in response to beta-thromboglobulin or thrombospondin, or when protein C lacking its gamma-carboxyglutamic acid (Gla) domain is the substrate. Heparin and chondroitin sulfates A and E reverse PF4 stimulation. PF4 minimally affects the Kd for THR but decreases 30-fold (from 8.3 to 0.3 microM) the Km for protein C of APC generation by GAG+ TM. PF4 also strikingly transforms the [Ca2+] dependence profile of rabbit and GAG+ TM to resemble that of GAG- TM. A potential explanation for this is that PF4, like Ca2+, induces heparin-reversible alterations in native (but not Gla-domainless) protein C conformation as assessed by autofluorescence emission analysis. We conclude that PF4 stimulates TM APC generation by interacting electrostatically with both the TM GAG and the protein C Gla domain to enhance markedly the affinity of the THR.TM complex for protein C. By this mechanism, PF4 may play a previously unsuspected role in the physiologic regulation of clotting.
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PMID:Platelet factor 4 stimulates thrombomodulin protein C-activating cofactor activity. A structure-function analysis. 752 87

Tissue factor pathway inhibitor (TFPI) controls activation of blood coagulation while antithrombin (AT) regulates the final stage. Both inhibitors inhibit the intermediate stage of activation. Subnormal levels of TFPI increase the risk of disseminated intravascular coagulation (DIC) in septic conditions, and the risk of occlusive thrombi over damaged vascular intima or fissured arteriosclerotic plaques. The risk of venous thrombosis is increased by subnormal AT or subnormal activity of the protein C system. In contrast, TFPI may be little involved in the control of deep venous thrombosis. Heparin strongly accelerates AT and releases TFPI to the blood. Both these effects may contribute to the antithrombotic effect of heparin. In septic DIC, heparin may contribute little to quench activation of coagulation. Once hereditary deficiency of TFPI is described, its biological role will be better understood.
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PMID:Relative roles of tissue factor pathway inhibitor and antithrombin in the control of thrombogenesis. 764 20

Thrombomodulin (TM) is an endothelial cell membrane glycoprotein which neutralizes thrombin procoagulant activity and accelerates the thrombin-catalyzed activation of protein C. We expressed recombinant human soluble TM (rhs-TM) in Chinese hamster ovary cells and compared the effects of rhs-TM and heparin on endotoxin-induced experimental disseminated intravascular coagulation (DIC) in rats. Experimental DIC was induced by a continuous intravenous infusion of endotoxin for four hours. rhs-TM or heparin was infused simultaneously with endotoxin. Treatment with rhs-TM significantly reversed the endotoxin-induced changes in significantly reversed the endotoxin-induced changes in following parameters: platelet count, fibrinogen level and fibrinogen and fibrin degradation products. Furthermore, glomerular fibrin deposits elevated by endotoxin treatment were reduced by the rhs-TM administration. Heparin showed the similar effects to rhs-TM. Activated partial thromboplastin time (APTT) in rats receiving rhs-TM were slightly longer than APTT in endotoxin-treated rats, but rats receiving heparin had much more prolonged APTT. From these results, we concluded that rhs-TM may be useful for the clinical treatment of DIC while having only minor adverse effects on APTT.
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PMID:Antithrombotic effect of recombinant human soluble thrombomodulin on endotoxin-induced disseminated intravascular coagulation in rats. 823 61

In a previous report, we described the molecular cloning, expression, and partial characterization of a second human tissue factor pathway inhibitor (TFPI), which we designated as TFPI-2 [Sprecher, C. A., et al. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 3353-3357]. Recombinant TFPI-2 inhibited the amidolytic activity of trypsin as well as that of factor VIIa in complex with tissue factor. TFPI-2 recently has been shown to be identical to placental protein 5 (PP5), a glycoprotein originally isolated from placenta that exhibits serine protease inhibitory activity. In the present study, we have examined TFPI-2/PP5 for its ability to inhibit a number of serine proteases involved in blood coagulation and fibrinolysis, inasmuch as TFPI-2/PP5 prolonged the coagulation time of human plasma induced by either tissue factor or contact activation in a dose-dependent manner. In addition to its ability to inhibit the amidolytic and proteolytic activities of the factor VIIa-tissue factor complex, TFPI-2/PP5 strongly inhibited the amidolytic activities of human factor XIa, human plasma kallikrein, and human plasmin with Ki values of 15, 25, and 3 nM, respectively. TFPI-2/PP5 was also a weak inhibitor of the activation of factor X by a complex of human factor IXa and poly(lysine) with an apparent Ki of 410 nM. Heparin markedly enhanced the ability of TFPI-2/PP5 to inhibit factor VIIa-tissue factor both in the solution phase and on cell surfaces. In addition, heparin augmented the inhibition of human factor Xa amidolytic activity at relatively high levels (10-100 nM) of TFPI-2/PP5. No significant inhibition of glandular kallikrein, urinary plasminogen activator, tissue plasminogen activator, human activated protein C, human factor Xa, human thrombin, or leukocyte elastase was observed when these proteases were incubated with TFPI-2 in the absence of heparin.
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PMID:Inhibitory properties of a novel human Kunitz-type protease inhibitor homologous to tissue factor pathway inhibitor. 855 84


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