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)

Recent studies on the mechanism of initiation and regulation of blood coagulation are reviewed. In the intrinsic blood coagulation pathway, factor XII, prekallikrein (or factor XI) and high molecular weight kininogen from a complex on an anionic surface, such as exposed subendothelium at the site of vascular trauma. In complex, zymogen factor XII activates prekallikrein (or factor XI) by limited proteolysis to initiate the coagulation cascade. A similar initiating mechanism may be operative in the extrinsic pathway, where zymogen factor VII, complexed with a lipoprotein (tissue factor) and calcium ions, converts factor X to factor Xa. Factor Xa converts prothrombin to thrombin which converts soluble fibrinogen to an insoluble fibrin network which physically arrests the flow of blood from the damaged vasculature. In addition, thrombin converts protein C to activated protein C. Activated protein C functions as a negative regulator in the coagulation process by degrading factor VIIIa and factor Va.
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PMID:Enzymological aspects of blood coagulation. 668 3

In the last few years, plasma fractionation has been subjected to major technological changes which have contributed to improve the viral safety and overall purity of plasma derivatives. New viral inactivation treatments, primarily solvent-detergent and pasteurization, have been introduced in the manufacturing processes of plasma derivatives to ensure the inactivation of major plasma-borne viruses, including HIV and hepatitis B and C viruses. Concurrently, new highly purified products obtained by chromatographic methods (mainly ion exchange and/or immunopurification) have been developed in the last five years and have replaced former preparations, providing a significantly higher safety level in terms of purity and viral risks. For an example, the new generation of Factor VIII and Factor IX concentrates (to treat hemophilia A and hemophilia B, respectively), which have been introduced in the last five years, are purified over 10,000- to 20,000-fold from plasma, as compared to only 50- to 100-fold for the former products. Similarly, new, standardized, clotting factor or protease inhibitor concentrates have been made available, thus permitting to carry out selective hemotherapy of specific diseases. Examples include the development of von Willebrand factor, factor XI, protein C, or alpha 1-antitrypsin concentrates for the substitutive therapy of congenital or acquired deficiencies. In addition, the concept of good manufacturing practices has been implemented, whereas carefully controlled, validated processes are contributing to the consistency in the quality of those products. Current major problems in plasma fractionation relate to the potential occurrence of new pathogenic agents that could resist present viral inactivation treatments and to the potential effect of given purification technologies on the development of immunogenic properties of proteins. Current trends indicate that significant progress in viral safety of plasma derivatives (for example through the introduction of new concept such as viral filtration) are to be expected very soon. Further research in this very important field is mandatory as plasma should remain the starting material of important therapeutic products in the coming years.
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PMID:[Plasma fractionation. Progress, problems and perspectives]. 799 59

The important roles of thrombin in the development and propagation of thrombosis are well recognized. In addition to being the enzyme for clotting fibrinogen (the major protein component of blood clots), thrombin accelerates its own generation by activating factor V, factor VIII, factor XI and platelets. It accelerates the stabilization of clots by activating factor XIII to factor XIIIa, the enzyme which crosslinks fibrin. There are probably two major pathways for regulating the availability of thrombin in vivo: inactivation of thrombin (by antithrombin III/vessel wall heparan sulfate and perhaps by other endogenous antithrombins) and the inactivation of factor Va and factor VIIIa by activated protein C. Factor Va and factor VIIIa accelerate the production of thrombin. However, when thrombin becomes bound to fibrin (in clots or possibly on cell surfaces), the ability of antithrombin III/heparin to inactivate thrombin is then reduced significantly. Impairment by fibrin of thrombin inhibition by antithrombin III may account in part for the inability of unfractionated heparin to prevent post-operative deep vein thrombosis in up to 20% of patients who undergo major elective orthopaedic surgery, and may also explain the need for oral anticoagulants after unfractionated and low molecular weight heparins are used to initiate the treatment of established deep vein thrombi. The ineffectiveness of the antithrombin III/heparin pathway for inhibiting thrombin under some circumstances has been a contributory factor for the development, evaluation and identification of other inhibitors of thrombin which are more able than antithrombin III/heparin to inactivate thrombin when the enzyme is bound to fibrin. The focus of this review is to detail how these synthetic agents, by directly or indirectly inactivating thrombin, can also effectively inhibit prothrombin activation in vitro.
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PMID:Mechanisms for the anticoagulant effects of synthetic antithrombins. 815 38

The carbohydrate-deficient glycoprotein (CDG) syndromes are a newly recognized group of inherited metabolic diseases. We report a Japanese brother and sister with a CDG syndrome. Both patients showed decreased activities of blood coagulation Factor XI and of the coagulation inhibitor protein C. In one of them there was also a somewhat decreased activity of Factor IX and of antithrombin III. Isoelectric focusing of antithrombin III revealed a decrease of negatively charged fractions and an increase of more cathodal bands. Furthermore, there was a discrepancy between activity and antigen level of Factor VIII and protein C. The patients had an incidental deficiency of factor XII. This is the first detailed report on blood coagulation systems in the CDG syndromes. These blood coagulation abnormalities may explain at least in part the thrombotic or haemorrhagic complications of the CDG syndromes.
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PMID:Decreased blood coagulation activities in carbohydrate-deficient glycoprotein syndrome. 841 4

The carbohydrate-deficient glycoprotein syndromes are a recently individualized group of genetic multisystemic disorders. A predominant feature is a severe involvement of the central and peripheral nervous system resulting in psychomotor retardation, seizures, ataxia, and, mostly after infancy, stroke-like episodes. The hallmark biochemical feature is a carbohydrate deficiency in a large number of serum glycoproteins. Because coagulation factors and inhibitors are also glycoproteins, we performed a systematic study of these factors and inhibitors in nine patients with carbohydrate-deficient glycoprotein syndrome. All showed a decreased activity of factor XI and of the coagulation inhibitors antithrombin III and protein C. In five of seven patients more than 1 y old, there was also a (less pronounced) decrease of protein S and of heparin cofactor II. This combined coagulation inhibitor deficiency could explain the stroke-like episodes occurring in these children.
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PMID:A unique pattern of coagulation abnormalities in carbohydrate-deficient glycoprotein syndrome. 851 Oct 30

Carbohydrate-deficient glycoprotein (CDG) syndrome type I is an autosomal recessive disease with multisystemic manifestations. During childhood the patients may suffer from hemorrhages, which may be lethal, venous thromboses and stroke-like episodes. In this study 15 patients with CDG syndrome type I were examined from the levels and isoform patterns of coagulation factors and inhibitors and fibrinolysis parameters. The screening assays APTT and PTC were unaffected in most cases. In spite of this reduced levels were found particularly for factors II, V, X and XI and for antithrombin and protein C. Low values tended to be associated with elevated liver enzyme levels in serum. The values were at potential clinical risk levels for protein C and/or antithrombin in more than half of the patients, and for factor V and/or factor XI in one third of them. There were no current differences in values between patients who had previously displayed clinical symptoms of coagulation disturbance and those without such symptoms. Partially carbohydrate-deficient isoforms were demonstrated in antithrombin, protein C, protein S and in alpha 2-antiplasmin, but not in factors II, X and fibrinogen. Abnormal isoforms did not appear to reduce the functional activity of the respective glycoproteins. Analysis of individual hemostatic parameters is recommended in these patients in connection with clinical symptoms or elective surgery. The observed variability of the carbohydrate defect in glycoproteins in this disease may be a clue to its pathogenesis.
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PMID:Complex functional and structural coagulation abnormalities in the carbohydrate-deficient glycoprotein syndrome type I. 873

This paper continues our study (see Part I) where we modeled the spatio-temporal dynamics of the intrinsic pathway of blood coagulation. Here, we analyzed this model and showed that it describes the threshold behavior of coagulation. When activation is subthreshold (which produces not more than 0.07 nM factor XIa at saturating free calcium concentrations of 2 mM or higher), the concentration of generated thrombin remains below 0.01 nM. At the abovethreshold activation corresponding to factor XIa exceeding 0.07 nM, the concentration of thrombin explosively increases and then abruptly decreases. The peak concentration of thrombin reaches hundreds nM. With respect to free calcium concentration, the system also behaves in a threshold manner. For activation corresponding to 0.3 nM factor XIa, the threshold concentration of free calcium where the outburst of explosive thrombin generation occur is equal to 0.21 mM. The model simulations are in a good agreement with the experimentally recorded kinetics of thrombin generation at different concentrations of free calcium (1). Analysis of the spatial dynamics of coagulation showed that if activation exceeded the threshold level at a certain point, the concentration wave of thrombin arises and propagates at a high speed from the activation zone. The parameters of this wave depends mainly on the efficiency of the feedback loops. The feedback loops through the backbone factors of the intrinsic pathway (autoactivation of factor X or activation of factor XI by thrombin) has a potential for the unlimited propagation of the thrombin wave. With increasing activity of activated protein C (the effect equivalent to that of thrombomodulin), oscillating regimes arise in the model. The first thrombin wave is followed by several secondary running waves. The amplitudes of secondary waves increases to the periphery of the clot consolidating its surface layer.
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PMID:A mathematical model for the spatio-temporal dynamics of intrinsic pathway of blood coagulation. II. Results. 894 60

Great progress has been made within the past 10 years in characterizing, assaying, and describing mechanism(s) of action in vitro of antiphospholipid antibodies (a-PL Abs); three prominent members are reagin, anticardiolipin antibodies (a-CL Abs), and the lupus anticoagulants (LAC). The major focus of this review is on basic and current biochemical and immunologic research. First, the biochemistry, structural composition, and sources of anionic and dipolar ionic (zwitterionic) phospholipids are discussed together with several serum antibodies directed to these phospholipids. Cardiolipin, the most acidic phospholipid (net negative charge of 2 at pH 7.0) has been historically important as an antigen for testing reagin in syphilis serology, and currently is part of the antigenic composition used in the Venereal Disease Research Laboratory (VDRL) tests. In this connection, the chronic biological false-positive test for syphilis and the LAC are discussed in association with autoimmune disorders such as systemic lupus erythematosus. Second, a naturally occurring plasma anticoagulant in vitro and a critical cofactor for binding of purified autoimmune a-CL Abs to cardiolipin is considered, the beta 2-glycoprotein I (beta 2-gpI). This single-chain plasma polypeptide is highly glycosylated, has 326 amino acids, a molecular weight of 50 kD, and is characterized by repeating amino acid motifs or domains that structurally resemble multiple loops. The highly cationic C-terminal fifth domain binds to anionic phospholipids. The beta 2-gpI is a member of the short consensus repeat superfamily of proteins, and is compared with other proteins with similar domains. Third, experiments are detailed for defining LAC and distinguishing it from other a-CL Abs. Cofactors are also associated with LAC and include beta 2-gpI, prothrombin, protein C, protein S, tissue factor, and factor XI. Thus, LAC antibodies are heterogeneous, and no individual assay can detect all LACs. Because patients with syphilis and other infectious diseases have no cofactor associated with a-CL Abs, their plasma LACs are negative. The a-CL Abs found in infection are not associated with the clinical features of the antiphospholipid syndrome. LAC assays are important because of the pathogenetic association with clinical observations of venous and arterial thrombosis, thrombocytopenia, and recurrent fetal loss. Finally, reports leading to development of currently used direct solid-phase enzyme-linked immunosorbent assays (ELISA) for testing a-PL Abs are outlined; these developments have greatly increased understanding of the basic immunology of target antigens and their respective antibodies. Of significance, a-CL Abs cross-react with other anionic phospholipids. Additionally, the results of these assays led to the realization that high levels of circulating a-PL Abs over long periods are associated with a number of clinical problems now known collectively as the antiphospholipid syndrome.
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PMID:Antiphospholipid antibodies: basic immunology and assays. 914 49

Abetalipoproteinaemia is a rare disorder of apolipoprotein B metabolism associated with extremely low plasma concentrations of triglyceride. To discover whether the general positive association between factor VII and triglyceride levels extends to this condition, 5 patients were compared with 18 controls. All patients had a triglyceride below 100 micromol/l. Plasma unesterified fatty acid concentration was normal. Although factor IX activity was only slightly reduced (mean 88% standard) and factor IX antigen was normal, mean activated factor VII in patients was strikingly reduced to 34% of that in controls, a level similar to that found in haemophilia B. The patients' mean factor VII activity and factor VII antigen were also significantly reduced to 54% and 63% of those in controls, respectively. Mean factor XI activity and tissue factor pathway inhibitor activity were reduced in patients to 70% and 75% of control values respectively, while factor XII, factor XI antigen, factor X, prothrombin and protein C were normal.
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PMID:Very low activated factor VII and reduced factor VII antigen in familial abetalipoproteinaemia. 971 44

The carbohydrate-deficient glycoprotein syndromes are a group of recently described autosomal recessive, metabolic defects affecting multiple systems. The disorder is caused by inefficient posttranslational glycosylation of glycoproteins. Patients with the syndrome present early in life with psychomotor retardation, seizures, hypotonia, and stroke-like episodes. They also have dysmorphic features including almond-shaped eyes, constant squint, inverted nipples, and buttock fat pads. One of the features of the syndrome is coagulopathy, and we report here a patient who presented with a prolonged activated partial thromboplastin time, and was subsequently diagnosed with the carbohydrate-deficient glycoprotein syndrome. We also summarize the results of five previously published studies of the coagulation system in these patients. Most of the reported patients are deficient in factor XI, protein C, antithrombin III, and protein S. Other coagulation proteins are less frequently affected. Both bleeding and thrombosis have been observed, yet the cause of the stroke-like episodes remains speculative. The carbohydrate-deficient glycoprotein syndrome is an increasingly recognized multisystem disorder affecting hemostasis, and thus will involve clinical hematologists as part of a multidisciplinary team caring for patients with the syndrome.
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PMID:Coagulation abnormalities in the carbohydrate-deficient glycoprotein syndrome: case report and review of the literature. 988 8


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