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

Increased thrombogenesis observed in systemic lupus erythematosus (SLE) is derived from multiple mechanisms, including: Enhanced coagulation factor VIII:VWf activity, lupus anticoagulants, anti-phospholipid antibodies, acquired deficiencies of natural anti-thrombotic mechanisms (protein C, protein S, anti-thrombin III), and impaired fibrinolytic mechanisms. We studied the fibrinolytic mechanisms of 18 patients with systemic lupus erythematosus, selected carefully to avoid other possible causes of abnormalities in the fibrinolytic activity. Despite the fact that the euglobulin lysis time in steady state was normal in all instances, disturbances in the tissue plasminogen activator/plasminogen activator inhibitor (TPA/PAI) system were found in all SLE patients: TPA activity was undetectable in all cases, whereas it was above 0.4 IU/ml in a control group. In 72 percent of patients, the undetectable TPA activity was correlated with abnormally high PAI activity; PAI levels were normal in all members of the control group, their mean value being 0.74 versus 8.63 IU/ml for SLE patients (P less than .01). Coagulation protein C deficiency was found in 3 patients (17%). Even though within normal range, fibrinogen levels were significantly higher in SLE than in normal controls (219 versus 192 mg/dl, P less than .01) and plasminogen levels were significantly higher in SLE than in controls (117 versus 78.2%, P less than .01). Cross-linked fibrin derivatives (D-D dimers) were negative in all patients with SLE. Sixty-eight percent of SLE patients had high levels of antiphospholipid antibodies, but no correlation with the disturbances of the TPA/PAI system was found. It is concluded that most patients with SLE display severe abnormalities in the TPA/PAI anti-thrombotic system and that these abnormalities may be related to the lupus thrombophilia, apparently multifactorial in its origin.
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PMID:Disturbances in the tissue plasminogen activator/plasminogen activator inhibitor (TPA/PAI) system in systemic lupus erythematosus. 190 23

Hemophilia A is caused by a defect in coagulation factor VIII, a protein that undergoes extensive proteolysis during its activation and inactivation. To determine whether some cases of hemophilia are caused by mutations in important cleavage sites, we screened patient DNA samples for mutations in these sites by a two-step process. Regions of interest were amplified from genomic DNA by repeated rounds of primer-directed DNA synthesis. The amplified DNAs were then screened for mutations by discriminant hybridization using oligonucleotide probes. Two cleavage site mutations were found in a survey of 215 patients. A nonsense mutation in the activated protein C cleavage site at amino acid 336 was discovered in a patient with severe hemophilia. In another severely affected patient, a mis-sense mutation results in a substitution of cysteine for arginine in the thrombin activation site at amino acid 1689. This defect is associated with no detectable factor VIII activity, but with normal levels of factor VIII antigen. The severe hemophilia in this patient was sporadic; analysis of the mother suggested that the mutation originated in her gametes or during her embryogenesis. The results demonstrate that this approach can be used to identify factor VIII gene mutations in regions of the molecule known to be important for function.
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PMID:Mutations of factor VIII cleavage sites in hemophilia A. 313 81

The effect of activated protein C on human coagulation factor VIII was evaluated by studying its effect on the intrinsic factor X activation using a system of purified coagulation factors (factor IXa, factor X, factor VIII, activated protein C). Activated protein C had no effect on the activation of factor X by factor IXa in the absence of factor VIII. In the presence of thrombin activated factor VIII the rate of factor X activation was decreased by activated protein C in a dose dependent way. The presence of factor IXa during the preincubation of factor VIII with activated protein C was found to protect the factor VIII against inactivation. The results suggest that activated protein C and factor IXa compete for the same part of the factor VIII molecule.
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PMID:Factor IXa protects activated factor VIII against inactivation by activated protein C. 643 1

The contributions to functional phospholipid (PL) binding of the cluster of amino acid side chains of human protein C (PC) comprising F4, L5, and L8 have been assessed by construction of mutants of PC and activated protein C (APC) designed wherein a hydrophilic side chain replaced the wild-type hydrophobic groups at these positions. The PL-dependent plasma-based anticoagulant activities of [F4Q]-r-APC and [L8Q]r-APC were severely reduced to 5% and < 2%, respectively, of wild-type r-APC. Activity losses of the mutants toward inactivation of coagulation factor VIII, measured in the complete in vitro tenase system, have also been observed. As evidenced through Ca(2+)-induced intrinsic fluorescence changes, both [F4Q]r-PC and [L8Q]r-PC were able to adopt Ca(2+)-dependent conformations that appeared similar to that of wtr-PC, ruling out shortcomings associated with such Ca(2+)-induced transitions as the basis for their anticoagulant activity losses. However, despite this, [L8Q]r-PC showed greatly defective macroscopic binding properties to PL vesicles, as did to a lesser extent [F4Q]r-PC. These findings were similar to those reported previously for [L5Q]r-PC/APC [Zhang, L., & Castellino, F. J. (1994) J. Biol. Chem. 269, 3590-3595]. We thus propose that the PL-dependent activity losses of these mutants are related to their suboptimal binding to PL or to their misorientation on the PL surface leading to poor alignment of the active sites of the r-APC mutants with the complementary cleavage sites on fVIII/fVIIIa and fV/fVa.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hydrophobic amino acid residues of human anticoagulation protein C that contribute to its functional binding to phospholipid Vesicles. 765 91

The purpose of the study was to find a model to study the effect of endogenous oestradiol on haemostasis. Hormones and haemostatic variables were therefore measured before and after in vitro fertilization and egg replacement therapy in 14 women with tubal infertility. The differences between the levels of the haemostatic variables at minimum and maximum levels of oestradiol and progesterone were evaluated. A significant increase in the plasma levels of coagulation factor VIII, von Willebrand factor and fibrinogen was found between samples drawn before stimulation and at the highest oestradiol levels (P < 0.002, P < 0.002 and P < 0.015, respectively). However, coagulation factor VII activity and antigen decreased significantly (P < 0.001 and P = 0.009, respectively). The levels of the coagulation inhibitors protein C and antithrombin decreased (P < 0.003 and P = 0.008, respectively), while that of free protein S increased (P = 0.039). No significant changes were observed in the fibrinolytic variables or in those reflecting thrombin activity (prothrombin fragment 1 + 2, thrombin-antithrombin complexes, soluble fibrin and D-dimers). In conclusion, the increase in the levels of factor VIII, von Willebrand factor, fibrinogen and the decrease in the levels of antithrombin and protein C may, if coagulation is triggered, contribute to a hypercoagulable state. The depressed factor VII levels and the tendency to elevated free protein S levels may constitute a protective mechanism that modulates the coagulation system when levels of oestradiol become extremely high.
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PMID:Do lowered factor VII levels at extremely high endogenous oestradiol levels protect against thrombin formation? 805 52

A chimeric cDNA, encoding residues 1-46 (the gamma-carboxyglutamic acid module and its trailing helical stack) of human coagulant factor (f) VII, bound to residues 47-419 of human anticoagulant protein C (PC), was constructed and expressed. The resulting protein, r-[delta GD-HSPC/[symbol: see text] GD-HSfVII]PC, was properly processed with regard to signal/propeptide release, cleavage of the K156R dipeptide, Gla and Hya contents, and the presence of glycosylation. The mutant protein displayed normal dependencies on Ca2+ for adoption of its metal ion-dependent conformation and for binding to acidic phospholipid vesicles. The chimera failed to recognize a monoclonal antibody (MAb) specific for the Ca(2+)-induced conformation of the Gla domain (GD) of PC, but did react with another MAb directed in part to the Ca(2+)-dependent conformation of the GD of fVII. Further, this chimeric protein possessed similar steady state constants as wild-type r-PC toward activation by thrombin and thrombin/thrombomodulin. The activated form of the chimera was very similar to that of its wild-type counterpart in its whole plasma anticoagulant activity, as well as its activity toward inactivation of coagulation factor VIII. The chimeric protein did not bind to the fVII cofactor, tissue factor, showing that the GD/HS domain region of fVII is insufficient for that particular interaction. The results demonstrate that the GD/HS of fVII, when present in the PC and APC background, serves to maintain the Ca2+/PL-related functions of these latter proteins, and suggest that the Ca2+ and PL-dependent interactions of the GD-HS of PC are sufficiently general in nature such that the GD-HS regions of other proteins of this type can satisfy most of the requirements of PC and APC. The data presented also offer support for the independent nature of the domain unit consisting of the GD/HS module.
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PMID:Properties of a recombinant chimeric protein in which the gamma-carboxyglutamic acid and helical stack domains of human anticoagulant protein C are replaced by those of human coagulation factor VII. 918 4

Individuals with hemophilia A require frequent infusion of preparations of coagulation factor VIII. The activity of factor VIII (FVIII) as a cofactor for factor IXa in the coagulation cascade is limited by its instability after activation by thrombin. Activation of FVIII occurs through proteolytic cleavage and generates an unstable FVIII heterotrimer that is subject to rapid dissociation of its subunits. In addition, further proteolytic cleavage by thrombin, factor Xa, factor IXa, and activated protein C can lead to inactivation. We have engineered and characterized a FVIII protein, IR8, that has enhanced in vitro stability of FVIII activity due to resistance to subunit dissociation and proteolytic inactivation. FVIII was genetically engineered by deletion of residues 794-1689 so that the A2 domain is covalently attached to the light chain. Missense mutations at thrombin and activated protein C inactivation cleavage sites provided resistance to proteolysis, resulting in a single-chain protein that has maximal activity after a single cleavage after arginine-372. The specific activity of partially purified protein produced in transfected COS-1 monkey cells was 5-fold higher than wild-type (WT) FVIII. Whereas WT FVIII was inactivated by thrombin after 10 min in vitro, IR8 still retained 38% of peak activity after 4 hr. Whereas binding of IR8 to von Willebrand factor (vWF) was reduced 10-fold compared with WT FVIII, in the presence of an anti-light chain antibody, ESH8, binding of IR8 to vWF increased 5-fold. These results demonstrate that residues 1690-2332 of FVIII are sufficient to support high-affinity vWF binding. Whereas ESH8 inhibited WT factor VIII activity, IR8 retained its activity in the presence of ESH8. We propose that resistance to A2 subunit dissociation abrogates inhibition by the ESH8 antibody. The stable FVIIIa described here provides the opportunity to study the activated form of this critical coagulation factor and demonstrates that proteins can be improved by rationale design through genetic engineering technology.
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PMID:Characterization of a genetically engineered inactivation-resistant coagulation factor VIIIa. 934 26

Cranial dural arteriovenous fistulae (DAVF) may occur post-traumatic or sporadic. The physiopathologic mechanisms of sporadic DAVF are still unclear. A dural sinus thrombosis followed by an increase in venous pressure and/or an increased procoagulatory activity of the coagulation system are associated at least with some DAVF. The objective of this study was to investigate the coagulation profile in patients with DAVF. Thus the association of thrombophilic abnormalities, sinus thrombosis and DAVF should be analyzed. A total of 15 patients with cranial DAVF were included in this study. Blood samples were analyzed for 20210A mutation of the prothrombin gene, resistance to activated protein C and factor V Leiden mutation. Fibrinogen (Fib), Textarin time (TT), antithrombin (AT), protein C and protein S activity, von Willebrand factor antigen (vWF:Ag), Ristocetin cofactor activity (vWF:RCo), D-Dimer (DD) and coagulation factor VIII-activity (F VIII) were determined in all patients. Blood was screened for the occurrence of lupus antiphospholipid antibodies and cardiolipin antibodies. Thrombophilic risk factors were found in 5 (33%) of the 15 patients with cranial DAVF. Four patients had a heterozygote 20210A mutation of the prothrombin gene and one patient had a heterozygote FV Leiden mutation. Sinus thrombosis was detected in two patients with grade 2b DAVF and was associated with a 20210A mutation of the prothrombin gene in both patients. Additionally, one patient had deficient protein C activity and screening for cardiolipin antibodies was positive in three patients. In the current series the frequency of prothrombin Gene 20210A mutation was higher in patients with DAVF compared to the general population, whereas the incidence of Factor V Leiden mutation was not. Therefore in patients with cranial DAVF thrombophilic abnormalities should be considered in the post-operative/post-interventional management.
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PMID:Increased incidence of thrombophilic abnormalities in patients with cranial dural arteriovenous fistulae. 1457 93

Hyperactivity of coagulation factor VIII (fVIII) marks hypercoagulation. FVIII enhances activity of factor IX and their combination activates factor X, which is of primary importance in prothrombin transformation into thrombin, on the phospholipid membrane. The activity of fVIII was studied in 28 patients (26 women, 2 men, mean age 49.6 +/- 7.8 years) with Sneddon's syndrome (SS). SS manifests clinically similarly to primary antiphospholipid syndrome (PAS). The leading of them are ischemic disorders of cerebral circulation (IDCC) and advanced livedo present in all the examinees. Hyperactivity of fVIII was registered in 21 (75%) of 28 patients. Most of thrombosis-related symptoms occurred more frequently in patients with high than normal activity of fVIII: ischemic strokes (91% vs 57%, p > 0.05), repeated strokes (71% vs 0%, p = 0.0014), transient IDCC (76% vs 57%, p > 0.05), vascular dementia (43% vs 0%, p > 0.05), ischemic heart disease (43% vs 0%, p > 0.05), thickening of heart valves according to echocardiography (91% vs 57%, p > 0.05), peripheral venous thromboses (24% vs 0%, p > 0.05). In high fVIII activity cardiolipin antibodies occurred more rarely (24% vs 43%, p > 0.05) but lupus anticoagulant was seen more often (47% vs 14%, p > 0.05). High fVIII activity was in 8 of 12 aPL-negative patients. It is demonstrated that elevated fVIII activity is an essential mechanism of thrombosis development in SS. The cause of this enhanced activity is suggested to be special aPL in interaction with which fVIII becomes insensitive to inactivation with protein C. The activity of protein C was normal in all the cases.
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PMID:[Clotting factor VIII in Sneddon syndrome]. 1459 91

Inherited and acquired thrombophilia are associated with recurrent pregnancy loss. Recently, an increased risk for thromboembolic disease was described for patients with elevated coagulation factor VIII, but it is unknown whether there is also an association to early pregnancy loss. We therefore evaluated the relation between recurrent early pregnancy loss and levels of coagulation factor VIII. We enrolled 49 unrelated Caucasian women with a history of 2-6 early pregnancy losses and 48 healthy controls, who had delivered at least one term infant and had never experienced pregnancy loss. We determined factor V Leiden-, G20210A prothrombin-, MTHFR C677T- and A1298C-gene mutations, levels of antithrombin, protein C, protein S, factor VIII, C-reactive protein and antiphospholipid antibodies. There was a significantly higher rate of pregnancy losses in women with Antiphospholipid Syndrome (p = 0.043). Furthermore, plasma levels of coagulation factor VIII were significantly higher in cases than in controls (130.5 IU/dl +/- 25.4 vs 119.5 IU/dl +/- 24.1; p = 0.032) and appeared independent of C-reactive protein (R = 0.146, p = 0.323 in cases; R = -0.028, p = 0.850 in controls). The relative risk for recurrent pregnancy loss in women with factor VIII levels above 151 IU/dl (90(th) percentile of controls) was 2.5 (0.7 - 8.9, 95 percent confidence interval), for levels above 156 IU/dl (95(th) percentile of controls) 3.9 (0.8 - 20.0, 95 percent confidence interval). Elevated maternal plasma levels of coagulation factor VIII tend to be associated with an increased risk for recurrent early pregnancy loss.
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PMID:Elevated coagulation factor VIII and the risk for recurrent early pregnancy loss. 1504 30


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