Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation and inactivation of protein C during the clinical course of disseminated intravascular coagulation (DIC) was studied in three patients by qualitative (Western blotting) and quantitative (ELISA) analysis and the intensity of procoagulant activity monitored by the measurement of thrombin and factor Xa antithrombin III complexes. In one patient, inhibitor complexes of APC with protein C inhibitor (PCI) and alpha 1-antitrypsin (alpha 1-AT) were observed and the latter predominated at presentation. Both disappeared during the development of remission but the loss of alpha 1-AT complexes preceded PCI complexes which on Western blotting appeared to increase in intensity prior to disappearance. The two other patients bled to death from uncontrollable haemorrhage. In both cases, APC/inhibitor complexes with alpha 2-macroglobulin (alpha 2-M) in addition to PCI and alpha 1-AT were detected and persisted until death. Although PCI appeared to be the primary inhibitor in all three cases, alpha 1-antitrypsin and particularly alpha 2-macroglobulin appeared to assume greater roles in the two fatal cases. These data are similar to previous findings in an experimental animal model of DIC that suggested that alpha 2-macroglobulin and alpha 1-antitrypsin become more important inhibitors of APC as the primary inhibitor PCI is consumed in the face of a sustained procoagulant challenge.
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PMID:Activation of protein C and its distribution between its inhibitors, protein C inhibitor, alpha 1-antitrypsin and alpha 2-macroglobulin, in patients with disseminated intravascular coagulation. 768 92

This review has stressed the common hereditary and acquired blood protein defects associated with thrombosis. The most common of the hereditary defects appear to be antithrombin, protein C, and protein S deficiency, and the most common acquired defects are anticardiolipin antibodies and the lupus anticoagulant. Therefore, these are the defects which should first be searched for in an individual with unexplained thrombosis. If these more common defects are not found, the rarer defects, including HC-II, plasminogen, or TPA deficiency, dysfibrinogenemia, elevated PAI-1, or heterozygous homocystinemia should be looked for. The incidence of activated protein C co-factor deficiency (APC resistance) is not yet clear but may also represent a common defect. PAI-1 defects may, with time, be shown to be common. Finding these defects has important implications for therapy for the individual patient and for the institution of family studies to identify, inform, and possibly treat others at risk. It is expected that as knowledge of hemostasis expands, more hereditary and acquired defects, such as elevated lipoprotein(a) or defects of extrinsic (tissue factor) pathway inhibitor (EPI, TFPI), may be associated with enhanced risks for thrombosis.
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PMID:Blood protein defects associated with thrombosis. Laboratory assessment. 778 Dec 75

Venous thromboembolic diseases are of major importance with respect to morbidity and mortality. Therefore, efficient prophylaxis is essential. Indication for thromboprophylaxis has to be made individually: In high risk situations, especially in orthopedic surgery, every patient should receive medical prophylaxis, e.g. with heparin, in addition to other preventive measures such as the wearing of elastic stockings or physiotherapy until full mobilization. For high-risk patients having a history of recurrent venous thromboembolism or which are suffering from a thrombogenic disease (e.g. myeloproliferative disorder, especially polycythemia vera, paroxysmal nocturnal hemoglobinuria, systemic lupus erythematosus, homocystinuria) or a hereditary thrombophilia (e.g. deficiency of antithrombin III, protein S, protein C or APC resistance), prophylactic measures should be more generally applied. In these patients, risk factors (e.g. oral contraceptive medication) or risk situations (e.g. long-distance travelling by car or airplane) have to be avoided whenever possible. In inevitable risk situations (e.g. perioperative or peripartal period) prophylaxis is mandatory. It is generally limited to the period of elevated thrombogenic risk and is often effected by application of a low molecular weight heparin. Patients with a history of recurrent thromboembolic events despite elimination of all avoidable risk factors should get a lifelong prophylaxis, usually with oral anticoagulants.
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PMID:[Prevention of venous thromboembolism--in whom, when and how?]. 783 22

Resistance to activated protein C (RAPC) has been described recently as a cause of trombophilia; this may justify up to 50% of thromboembolic disease without predisposing cause in patients under 45 years. A 29 years-old male with a previous deep venous thrombosis (DVT) in the lower left limb three years earlier, developed a DVT in the right lower limb after a trauma of the knee that required immobilization, was associated to pulmonary thromboembolism diagnosed by gammagraphic methods. The phlebographic study showed femoro-iliaco-caval venous thrombosis. The proband's father and a younger brother had a previous history of thrombotic episodes. The following tests, were performed in the proband and relatives: prothrombin time, aPTT, thrombin time, fibrinogen, (Von Clauss), antithrombin III (chromogenic), protein C and protein S (coagulometry and ELISA), plasminogen (chromogenic) and lupus anticoagulant (ITT, dRVVT, aCL). RAPC was evaluated in two different samples. The proband study was performed under oral anticoagulation treatment (OAT). Control groups were: 21 blood donors and 12 OAT patients. The results showed a decreased response to APC in the proband (ratio 1.5) and relatives: father (1.4), brothers (1.5 and 1.5), while the mother was within the normal range (> or = 2). In normal controls and OAT patients the ratio was over 2. No other abnormalities were detected in the assays performed. It is concluded that RAPC is the cause of this familial trombophilia. RAPC should be included in the evaluation study of trombophilia.
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PMID:[Familial thrombophilia due to resistance to activated protein C]. 798 58

Several parameters of fibrinolytic and protein C pathways were evaluated in three groups of patients with high (HR), moderate (MR) and low (LR) postoperative thrombotic risk undergoing major gynaecological surgery. The HR and MR groups were subjected to low molecular weight heparin (LMW) prophylaxis. A significant increase in plasminogen activator inhibitor type 1 (PAI-1) antigen and activity levels was observed in the HR patient group in comparison with the MR and LR groups in the preoperative and early postoperative period. In all the groups studied, the maximum increase in the levels of PAI-1 was seen on day 1 after surgery. However, the D-dimeric levels reached the highest level on day 7. A significant increase in activated protein C:alpha 1 antitrypsin (APC:alpha 1AT) complex levels was observed in the HR group in comparison with the LR group, and a strong decrease in protein C inhibitor in the early postoperative period was detected in all the groups. In spite of heparin prophylaxis, 2 HR patients were diagnosed as deep vein thrombosis (DVT) during the postoperative period. Both patients showed pre-operative levels of PAI-1 antigen or activity and APC:alpha 1AT complexes above the mean + 1 SD of the pre-operative levels in the HR group. In conclusion, in HR patients a hypofibrinolytic and hypercoagulable state was detected in the pre-operative and early postoperative periods. The prophylactic LMW heparin dose used in the present report (20 mg/day x 7) was insufficient to prevent DVT in the HR group. At present our HR patients are given higher doses of LMW heparin (40 mg/day x 7).
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PMID:Alterations in fibrinolytic and protein C pathways in gynaecological surgery: low molecular weight heparin prophylaxis. 798 53

A mutant cDNA of recombinant (r)-human protein C (PC) encoding a Leu5-->Gln substitution ([Leu5-->Gln]r-PC) has been constructed and expressed in human 293 cells. A subpopulation of molecules was then purified that contained fully gamma-carboxylated [Leu5-->Gln]r-PC. Intrinsic fluorescence quenching studies with this mutant protein revealed a C50 for Ca2+ binding (0.24 mM) that was essentially the same as that of wild-type (wt) r-PC (0.35 mM). Additionally, the C50 for the Ca2+ dependence of binding of a Ca(2+)-specific monoclonal antibody to [Leu5-->Gln]r-PC, of 5.4 mM-6.5 mM, was similar to that of wtr-PC (4.5 mM). On the other hand, the anticoagulant activity of the activated form of this mutant ([Leu5-->Gln]r-APC) was only 2% of that of activated wtr-PC (wtr-APC), and the inactivation rate of human factor Va catalyzed by this same mutant enzyme was approximately 10% of that of wtr-APC, at maximal levels of Ca2+. This substantial loss of activity was reconciled with the apparent retention of the integrity of the Ca(2+)-dependent conformation of this mutant by the finding that this Ca(2+)-dependent conformation of [Leu5-->Gln]r-PC interacted poorly with mixed (60:40, w/w) phosphatidylcholine/phosphatidylserine (PL) vesicles. These results suggest that Leu5, a residue strictly conserved in vitamin K-dependent proteins, is required for functional binding of PC to PL vesicles. These findings lend support to recent observations that have shown the importance of hydrophobic interactions in the binding of coagulation factors to PL vesicles. This current work further implicates Leu5 as a possible key participant in this hydrophobic binding energy.
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PMID:The binding energy of human coagulation protein C to acidic phospholipid vesicles contains a major contribution from leucine 5 in the gamma-carboxyglutamic acid domain. 810 3

The dependence of the activity of recombinant activated human protein C (r-APC) on each of its nine gamma-carboxyglutamic (Gla) residues (sequence positions 6, 7, 14, 16, 19, 20, 25, 26, and 29) has been assessed in purified systems and in plasma using r-mutants in which each Gla residue of r-APC was individually altered to an Asp (D) residue. The assays employed included a factor Va inactivation assay in the prothrombinase system with purified components and in plasma. In addition, a factor VIII inactivation assay in the tenase system, also with purified components, was utilized. Compared to wild-type protein (wtr-APC), the r-mutants that possessed nearly full activity in all assays were the Gla6-->D variant ([Gla6D]r-APC]) as well as [Gla14D]r-APC and [Gla19D]r-APC. In addition, another mutant (Q32-->Gla) in which a Gla was substituted for Gln (Q) at position 32, a situation that exists with other vitamin-K-dependent clotting proteins (e.g., factor IX and prothrombin), displayed full activity in all assays. Those mutants that possessed very-low-to-no activity in all assays included [Gla16D]r-APC and [Gla26D]r-APC. The other mutants showed partial and, in some cases, differential activity in these assay systems, with [Gla25D]r-APC being the most remarkable example. In this case, the factor V/Va plasma assay and the plasma-based activated partial thromboplastin time assay yielded < 25% activity, whereas nearly full activity was observed for this variant in the prothrombinase and tenase assays with purified components.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The activities of recombinant gamma-carboxyglutamic-acid-deficient mutants of activated human protein C toward human coagulation factor Va and factor VIII in purified systems and in plasma. 811 Jul 90

The cDNA encoding a chimeric human protein C (PC), in which its epidermal growth factor-(EGF) like regions have been replaced with equivalent structures from human factor IX (fIX), was constructed and the gene product was expressed in human 293 cells. A molecular subpopulation of the recombinant chimeric protein (r-[PC/delta EGF-1,2/delta fIXEGF-1,2]) was purified that contained the full complement (9 residues/mol) of gamma-carboxyglutamic acid (Gla). After conversion by thrombin to its activated form (r-[APC/delta EGF-1,2/delta fIXEGF-1,2]), this latter enzyme was found to possess approximately 10% of the activity of wild-type recombinant APC (wtr-APC) in an APTT assay. In assay systems employing purified components, the activity of the mutant enzyme toward prothrombinase cofactor Va (fVa) and tenase cofactor VIII (fVIII) was approximately 30% and < 10%, respectively, of that of wtr-APC. The chimeric protein displayed full reactivity with a Ca(2+)-dependent monoclonal antibody to the Gla domain of PC, yielding a C50 for Ca2+ that was very similar to that obtained with wtr-PC (ca. 3.7 mM). Titrations of the dependency on Ca2+ of the intrinsic fluorescence of r-[PC/delta EGF-1,2/delta fIXEGF-1,2] allowed calculation of a C50 value of 0.34 mM, again very similar to that of wtr-PC. As with wtr-PC, Ca2+ inhibited the thrombin-catalyzed activation of r-[PC/delta EGF-1,2/delta fIXEGF-1,2] with aKi of 148 microM, as compared to a Ki of 125 microM for wtr-PC. At a saturating level of Ca2+, activation of r-[PC/delta EGF-1,2/delta fIXEGF-1,2/] by the thrombin/thrombomodulin (thrombin/TM) complex occurred at approximately 70% of the rate of that of wtr-PC.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Construction, expression, and properties of a recombinant chimeric human protein C with replacement of its growth factor-like domains by those of human coagulation factor IX. 829 11

C4b-binding protein (C4BP) down-regulates the anticoagulant cofactor activity of protein S in the protein C pathway since free protein S but not the protein S:C4BP complex is anticoagulantly active. To identify beta chain residues responsible for binding protein S, synthetic overlapping pentadecapeptides covering the entire 1-235 sequence were tested as inhibitors of complex formation. The peptide comprising residues 31-45 (VCIKGYHLVGKKTLF) from the first short consensus repeat domain inhibited the binding of C4BP to protein S with half-maximal inhibition at 20-45 microM, and studies suggested the sequence of YxLVG was crucial. Peptide beta(31-45) specifically inhibited the APC cofactor activity of purified protein S in Xa-1-stage coagulation assays with 50% inhibition at 15 microM peptide. Peptide beta(31-45) and related peptides such as beta(34-42) inhibited the binding of protein S to an antipeptide monoclonal antibody made against residues 420-434 of protein S (monoclonal antibody LJ-56). Polyclonal anti-beta(31-45) peptide antibodies inhibited complex formation. Dose-dependent binding studies showed that protein S bound directly to immobilized peptide beta(31-45). These results show that residues 31-45 of the C4BP beta chain provide a binding site for protein S, and they suggest that the C4BP beta chain residues 34-42 are located near residues 420-434 of protein S in the protein S:C4BP complex.
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PMID:A protein S binding site on C4b-binding protein involves beta chain residues 31-45. 830 May 81

Thrombin generation is a pivotal function of plasma in haemostasis and thrombosis. Its mechanism is essentially the classical cascade, the velocity of which is governed by the availability of factors Va and VIIIa and that is confined to the surface of the procoagulant membranes which appear at the site of injury. There is no routine test that quantitatively renders the thrombin forming capacity of a plasma sample. Clotting times (PT-prothrombin time, APTT-activated partial tromboplastin time) do not reflect the over all thrombin generation and are insensitive to hypercoagulative states. The endogenous thrombin potential (ETP), i.e. the area under the thrombin generation curve, better represents this function. We developed a method to assess the ETP in the routine laboratory. The first results suggest that it is a sensitive indicator for every form of anticoagulation. It is increased in hypercoagulable states thus far studied, both congenital and acquired and can be designed to indicate deficiencies in protein C and S and APC (activated protein C) resistance.
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PMID:Thrombin generation in plasma: its assessment via the endogenous thrombin potential. 857 46


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