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)

The liver is the primary site of synthesis for the majority of coagulation factors. There are published accounts of liver donor-to-recipient transmission of protein C deficiency with dysfibrinogenemia and factor XI deficiency. In this article, we report what we believe to be the first observation, of transmission of factor VII deficiency, a rare, autosomal recessive coagulation disorder, from an affected liver donor to a naive liver recipient. At 300 days after transplantation, the recipient remains with an isolated prolongation of the prothrombin time and a below-normal level of factor VII, and has had no bleeding complications.
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PMID:Transmission of factor VII deficiency through liver transplantation. 1046 Aug 74

We have investigated the influence of alterations in plasma coagulation factor levels between 50% and 150% of their mean values for prothrombin, factor X, factor XI, factor IX, factor VII, factor VIII, factor V, protein C, protein S, antithrombin III (AT-III), and tissue factor pathway inhibitor (TFPI) as well as combinations of extremes, eg, 50% anticoagulants and 150% procoagulants or 50% procoagulants and 150% anticoagulants in a synthetic "plasma" system. The reaction systems were constructed in vitro using purified, natural, and recombinant proteins and synthetic phospholipid vesicles or platelets with the reactions initiated by recombinant tissue factor (TF)-factor VIIa complex (5 pmol/L). To investigate the influence of the protein C system, soluble thrombomodulin (Tm) was also added to the reaction mixture. For the most extreme situations in which the essential plasma procoagulants (prothrombin, and factors X, IX, V, and VIII) and the stoichiometric anticoagulants (AT-III and TFPI) were collectively and inversely altered by 50%, a 28-fold difference in the total available thrombin generated was observed. Variations of most of these proteins 50% above and below the "normal" range, with the remainder at 100%, had only modest influences on the peak and total levels of thrombin generated. The dominant factors influencing thrombin generation were prothrombin and AT-III. When these 2 components were held at 100% and all other plasma procoagulants were reduced to 50%, there was a 60% reduction in the available thrombin generated. No increase in the thrombin generated was observed when the 150% level of all plasma procoagulants other than prothrombin was evaluated. When only prothrombin was raised to 150%, and all other factors were maintained at 100%, the thrombin generated increased by 71% to 121%. When AT-III was at 50% and all other constituents were at 100%, thrombin production was increased by 104% to 196%. The additions of protein C and protein S over the 50% to 150% ranges with Tm at 0.1 nmol/L concentration had limited influence on thrombin generation. Individual variations in factors VII, XI, and X concentrations had little effect on the duration of the initiation phase, the peak thrombin level achieved, or the available thrombin generated. Paradoxically, increases in factor IX concentration to 150% led to lowered thrombin generation, while decreases to 50% led to enhanced thrombin generation, most likely a consequence of factor IX as a competitive substrate with factor X for factor VIIa-TF. Reductions in factor V or factor VIII concentration led to prolongations of the initiation phase, while the reduction of TFPI to 50% led to shortening of this phase. However, none of these alterations led to significant changes in the available thrombin generated. Based on these data, one might surmise that increases in prothrombin and reductions in AT-III, within the normal range, would be potential risk factors for thrombosis and that algorithms that combine normal factor levels may be required to develop predictive tests for thrombosis.
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PMID:"Normal" thrombin generation. 1049 86

Factor XI (FXI) is the zymogen of a plasma serine protease (FXIa) that contributes to hemostasis by activating factor IX (FIX). This reaction appears to be important for sustaining thrombin production after initial fibrin formation, to consolidate and protect fibrin clots from degradation by fibrinolysis. Humans with congenital FXI deficiency have a variable propensity to bleed after trauma or surgery, but do not experience the "spontaneous" hemorrhage in joints and soft tissue characteristic of hemophilia (FVIII or FIX deficiency). Mice homozygous for a disruption of the FXI gene (FXI-/-) have prolonged activated partial thromboplastin times and no detectable plasma FXI activity. Like their human counterparts, FXI-/- animals are generally healthy, reproduce normally, and do not develop spontaneous hemorrhage. In tail bleeding time assays, FXI-/- animals may have slightly prolonged bleeding compared to FXI+/+ and FXI+/- animals, however, a consistent hemostatic deficit has not been identified. More impressive results are obtained when FXI-/- mice are crossed with protein C deficient mice. Severe FXI deficiency partially ameliorates the devastating hypercoagulable state associated with severe protein C deficiency, indicating that FXI plays a role in certain thrombotic conditions.
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PMID:Gene targeting in hemostasis. factor XI. 1117 49

The incomplete penetrance of thrombosis in familial protein C deficiency suggests disease occurs when this deficit is combined with additional abnormalities in the hemostatic system. The pattern of inherited thrombophilia in the Vermont II kindred, which is affected by a clinically dominant type I protein C deficiency, provides strong evidence for a second unidentified gene that segregates independently of protein C deficiency and increases susceptibility to thrombosis. To test the second gene hypothesis, thirty-four candidate genes for proteins involved in hemostasis or inflammation were tested as the unknown defect, using highly polymorphic short tandem repeat (STR) markers in an informative subset (n = 31) of the kindred. The genes considered are; alpha-fibrinogen, beta-fibrinogen, gamma-fibrinogen, prothrombin, tissue factor, factor V, protein S, complement component 4 binding protein, factor XI, factor XII, factor XIIIa, factor XIIIb, histidine rich glycoprotein, high molecular weight kininogen, kallikrein, von Willebrands factor, platelet factor 4, thrombospondin, antithrombin III, alpha-1-antitrypsin, thrombomodulin, plasminogen, tissue plasminogen activator, urokinase plasminogen activator, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, protein C inhibitor, alpha-2-plasmin inhibitor, kallistatin, lipoprotein a, interleukin 6, interleukin 1, cystathionine-beta-synthase, and methylenetetrahydrofolate reductase. Mutations in many of these genes have been previously established as independent risk factors for thrombosis. However, linkage analysis provided no evidence to implicate any of the candidate genes as the second inherited factor that promotes thrombophilia in this kindred.
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PMID:Genetic screening of candidate genes for a prothrombotic interaction with type I protein C deficiency in a large kindred. 1120 93

Evaluation of inherited thrombophilia in patients with venous thromboembolism includes testing for functional activity of antithrombin, protein C and protein S, and resistance to activated protein C (factor V Leiden), which can be assessed with plasma and DNA-based assays. The antiphospholipid syndrome is an acquired disorder related to the development of antibodies against phospholipid-protein complexes. Testing for the antiphospholipid syndrome includes measurement of antibodies to phospholipid-protein complexes by immunoassay or by detecting interference of anti-phospholipid antibodies in sensitive phospholipid-based assays. Other genetic risk factors have been listed, including a common polymorphism in prothrombin gene (3'-untranslated region) related to an increase of prothrombin level (> 115%) and a common polymorphism in the methylene tetrahydrofolate reductase (enzyme involved in homocysteine metabolism) gene related to a mild increase of homocysteine blood level. More recently high plasmatic levels of factor VIII (> 150%) or factor XI (> 120%), not related so far to a molecular defect, have been identified as risk factors for deep vein thrombosis. As a candidate gene, factor XIII gene polymorphisms are under investigation. Beside the acquired or genetic risk factors involved in thrombophilia, the gene-environment interactions are of importance in the onset of thrombosis.
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PMID:[Laboratory testing for venous thromboembolism]. 1120 40

Eighty percent of patients with diabetes mellitus die a thrombotic death. Seventy-five percent of these deaths is due to cardiovascular complications, and the remainder is due to cerebrovascular events and peripheral vascular complications. Vascular endothelium, the primary defense against thrombosis, is abnormal in diabetes. Endothelial abnormalities undoubtedly play a role in the enhanced activation of platelets and clotting factors seen in diabetes. Coagulation activation markers, such as prothrombin activation fragment 1+2 and thrombin-anti-thrombin complexes, are elevated in diabetes. The plasma levels of many clotting factors including fibrinogen, factor VII, factor VIII, factor XI, factor XII, kallikrein, and von Willebrand factor are elevated in diabetes. Conversely, the level of the anticoagulant protein C (PC) is decreased. The fibrinolytic system, the primary means of removing clots, is relatively inhibited in diabetes due to abnormal clot structures that are more resistant to degradation and an increase in plasminogen activator inhibitor type 1 (PAI-1). Increased circulating platelet aggregates, increased platelet aggregation in response to platelet agonists, increased platelet contractile force (PCF), and the presence of higher plasma levels of platelet release products, such as beta-thromboglobulin, platelet factor 4, and thromboxane B(2), demonstrate platelet hyperactivity in diabetes. This constellation of findings supports the clinical observation that diabetes is a hypercoagulable state. This article briefly reviews the published evidence for this conclusion and the putative roles played by hyperglycemia and hyperinsulinemia in its development.
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PMID:Diabetes mellitus: a hypercoagulable state. 1125 26

When fibrin deposition and removal are properly balanced, the organism is protected from both a catastrophic loss of blood at the site of injury and the inappropriate loss of fluidity within the vascular system. When these activities are not properly balanced, however, severe bleeding or thromboses can occur. Myocardial infarction is a common and morbid consequence of the latter. The thrombin/thrombomodulin complex plays an essential role in regulating this balance because it generates both an anticoagulant substance, activated protein C, and an antifibrinolytic substance, activated TAFI (thrombin activatable fibrinolysis inhibitor, also known as plasma carboxypeptidase B or carboxypeptidase U). Thus, the coagulation and fibrinolytic cascades are explicitly linked by virtue of thrombin catalyzed activation of TAFI, either by the thrombin/thrombomodulin complex or, in the absence of thrombomodulin, by the massive amounts of thrombin generated through the factor XI-dependent pathway after clotting. Some potential targets for diagnosis, prognosis and therapy related to the balance between fibrin formation and removal include: development of a convenient global assay for plasma fibrinolytic potential; an assay for plasma or urine thrombomodulin that had been oxidized at methionine 388 and thereby has lost its capacity to stimulate activation of protein C but not TAFI; an assay for activated TAFI; discovery of a means for tapping the tremendous potential of the vasculature to acutely release tissue-type plasminogen activator; and an assessment of the potential role of polymorphisms in the TAFI gene which might influence TAFI levels or the properties TAFIa. In addition, a much fuller and quantitative understanding of the properties of the coagulation and tibrinolytic cascades is needed in order to optimize diagnosis, prognosis and therapy in disorders such as myocardial infarction that are related to the balance between fibrin formation and removal.
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PMID:Myocardial infarction and the balance between fibrin deposition and removal. 1166 89

Affinity chromatography is a powerful technique for the purification of many proteins in human plasma. Applications cover the isolation of proteins for research purposes but also, to a large extent, for the production of therapeutic products. In industrial plasma fractionation, affinity chromatography has been found to be particularly advantageous for fine and rapid capture of plasma proteins from industrial plasma fractions pre-purified by ethanol fractionation or by ion-exchange chromatography. To date, affinity chromatography is being used in the production of various licensed therapeutic plasma products, such as the concentrates of Factor VIII, Factor IX, von Willebrand Factor, Protein C, Antithrombin III, and Factor XI. Most commonly used ligands are heparin, gelatin, murine antibodies, and, to a lesser extent, Cu(2+). Possible development of the use of affinity chromatography in industrial plasma fractionation should be associated to the current development of phage display and combinatorial chemistry. Both approaches may lead to the development of tailor-made synthetic ligands that would allow implementation of protein capture technology, providing improved productivity and yield for plasma products.
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PMID:Affinity chromatography in the industrial purification of plasma proteins for therapeutic use. 1169 3

The serine proteases, cofactors and cell-receptor molecules that comprise the haemostatic mechanism are highly conserved modular proteins that have evolved to participate in biochemical reactions in blood coagulation, anticoagulation and fibrinolysis. Blood coagulation is initiated by exposure of tissue factor, which forms a complex with factor VIIa and factor X, which results in the generation of small quantities of thrombin and is rapidly shutdown by the tissue factor pathway inhibitor. The generation of these small quantities of thrombin then activates factor XI, resulting in a sequence of events that lead to the activation of factor IX, factor X and prothrombin. Sufficient thrombin is generated to effect normal haemostasis by converting fibrinogen into fibrin. The anticoagulant pathways that regulate blood coagulation include the protein C anticoagulant mechanism, the serine protease inhibitors in plasma, and the Kunitz-like inhibitors, tissue factor pathway inhibitor and protease nexin 2. Finally, the fibrinolytic mechanism that comprises the activation of plasminogen into plasmin prevents excessive fibrin accumulation by promoting local dissolution of thrombi and promoting wound healing by reestablishment of blood flow.
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PMID:Proteases in blood clotting. 1246 64

As hormone replacement therapy is associated with an early excess risk of venous thrombosis, we investigated the effect of different oral hormone replacement therapies on resistance to activated protein C, and on levels of factor VIII antigen (FVIII:Ag) and factor XI antigen (FXI:Ag). In a prospective, randomized, placebo-controlled 12-week study, 60 healthy post-menopausal women daily received either placebo (n = 16) or 2 mg of micronized 17beta-oestradiol, either alone (E2, n = 16) or sequentially combined with dydrogesterone 10 mg (E2 + D, n = 14) or trimegestone 0.5 mg (E2 + T, n = 14). Medication was given orally. Normalized activated protein C sensitivity ratios (nAPCsr) were determined by quantifying the effect of activated protein C on the endogenous thrombin potential. FVIII:Ag and FXI:Ag were determined by enzyme-linked immunosorbent assay. Compared with baseline and placebo, the nAPCsr increased (92% to 142%; all P < 0.001) in all active treatment groups after both 4 and 12 weeks. Compared with placebo, hormone replacement therapy was not associated with significant changes in FVIII:Ag. After 4 and 12 weeks, FXI:Ag levels were significantly decreased in the E2 group (mean percentage changes from baseline versus placebo: -15.0%, P = 0.001 at 4 weeks and -16.6%, P = 0.003 at 12 weeks) and in the E2 + D group (-10.4%, P = 0.02 and -10.4%, P = 0.02). In conclusion, all hormone replacement regimens were associated with a large increase in resistance to activated protein C. In contrast, hormone replacement therapy had no effect on FVIII:Ag. Oral E2 and E2 + D had a small, favourable effect on FXI:Ag.
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PMID:Increased resistance to activated protein C after short-term oral hormone replacement therapy in healthy post-menopausal women. 1247 83


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