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)

Recurrent phlebothromboses in young patients with subsequent severe postthrombotic syndrome and chronic venous leg ulcers may be caused by underlying hereditary disorders of hemostasis or may occur as part of other congenital syndromes. The most common hereditary disorders of hemostasis in this respect appear to be deficiencies of antithrombin III, protein C, and protein S, and activated protein C resistance (mutations of factor V). Less frequently, dysfibrinogenemia, increased plasminogen activator inhibitor levels, or deficiencies of tissue plasminogen activator or heparin cofactor II may be found. Klinefelter's syndrome and homocystinuria are prime examples of those rare congenital disorders indirectly associated with an elevated risk of thrombosis in young individuals. Early diagnosis of these disorders will allow timely treatment, preventive care and counselling of patients as well as family members.
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PMID:[Recurrent thrombophlebitis and ulcera crurum as manifestations of hereditary blood coagulation disorders and Klinefelter syndrome. Discussion based on 4 case examples]. 941 Aug 47

The aim of the present study was to determine plasma levels of protein C antigen (PC:Ag) and activity (PC:Act), tissue factor pathway inhibitor (TFPI), protein S (PS), antithrombin (AT), heparin cofactor II (HCII), and resistance to activated protein C (APCR) before, during and after elective gastric surgery in order to compare patients with and without gastric malignancy. Blood was collected from a forearm vein of two age-matched patient groups undergoing elective gastric surgery, 9 patients with and 9 patients without gastric malignancy. The plasma levels of the parameters were determined preoperatively, intraoperatively, and on days 1 and 7 postoperatively. On the 1st and 7th postoperative day, plasma levels of HCII were significantly lower in patients operated for gastric malignancy than in those operated for benign disorders, but levels of TFPI, PC:Act, PC:Ag, AT, PS and APCR did not differ in the postoperative period. The day-to-day variation was also rather similar in the two patient groups.
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PMID:Determination of coagulation inhibitor levels and resistance to activated protein C in patients undergoing gastric surgery for benign and malignant disorders. 948 69

The objective of this article is to evaluate the plasma levels of coagulation and fibrinolysis parameters in the third trimester of gestation and 72 hr postdelivery. Antithrombin III (ATIII), thrombin-antithrombin III complexes (TAT), heparin cofactor II (HCII), protein C (PC), protein S (PS), tissue plasminogen activator (t-PA), D-dimer, and plasminogen activator inhibitors (PAI-1 and PAI-2) levels in uncomplicated pregnancies and in pregnancies complicated by intrauterine growth retardation (IUGR) have been determined. Normal pregnant women (n = 63) and women whose was complicated by IUGR (n = 10) formed the study population. Coagulation and fibrinolysis parameters were estimated using commercial tests. There were no differences in ATIII, HCII, and PS levels between normal and IUGR pregnancies. TAT, t-PA, and D-dimer levels were higher in IUGR pregnancy than in the uncomplicated pregnancy group. PAI-1 and PAI-2 were found depressed in IUGR pregnancy when compared with normal pregnancy. Changes in coagulation and fibrinolytic systems occur in plasma of women with pregnancies complicated by IUGR. The results suggest an activation of the coagulation system in pregnancies complicated by IUGR. Reduced PAI-2 and high TAT levels correlate with birth weight. In IUGR pregnancies a hypercoagulative state with hyperfibrinolytic compensatory mechanisms is suggested.
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PMID:Coagulation and fibrinolytic parameters in normal pregnancy and in pregnancy complicated by intrauterine growth retardation. 951 30

Hypercoagulable states are a group of conditions associated with increased predisposition to thromboembolic events. Most of the inherited abnormalities recognized to date are associated with venous thromboembolism (VTE) rather than arterial thrombosis. The well-recognized inherited hypercoagulable states are the deficiencies of antithrombin, protein C and protein S, and the resistance to APC (factor V Leiden). These entities represent aberrations in the natural anticoagulant systems that exist in plasma. Other causes of inherited thrombophilia include abnormalities in the proteins of the fibrinolytic system, dysfibrinogenemias, deficiency of heparin cofactor II, abnormal thrombomodulin, elevated levels of histidine-rich glycoprotein, and the recently described variation in the prothrombin gene. One entity that has become firmly established as a predisposing factor for recurrent VTE is hyperhomocysteinemia. About half of VTE episodes in patients with inherited thrombophilias occur in relation to events that are generally recognized as predisposing states, such as surgery, pregnancy (particularly puerperium) and immobilization. In this review, the risks of VTE associated with inherited risk factors are discussed, and guidelines for the diagnosis and management are presented.
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PMID:Inherited hypercoagulable states. 957 5

Several studies have demonstrated a higher risk of thrombosis in carriers of anticoagulant deficiencies than in non-deficient individuals from families with thrombophilia. The prevalences in Spain were established in a multicenter study (the EMET study) and all the deficient individuals were invited to recruit all available family members to be screened for the same deficiency in order to establish the risk of thrombosis in deficient individuals. Five-hundred-and-eighty-three individuals from 114 families with natural anticoagulant deficiencies were analysed. Propositi and relatives with a history of thrombosis were asked about the localization and the age at the first episode and whether or not it was spontaneous. Three families with antithrombin deficiency, 35 with protein C, 60 with protein S, four with plasminogen, four with heparin cofactor II, seven with combined deficiencies and one family with dysfibrinogenemia were included in the analysis. The risk of thrombosis was increased for individuals deficient in antithrombin (adjusted odds ratio 21.23; 95% confidence interval 5.71-78.94), protein C (adjusted odds ratio 12.62; 95% confidence interval 4.75-33.51), protein S type I (adjusted odds ratio 19.95; 95% confidence interval 7.40-53.82), protein S type III (adjusted odds ratio 8.11; 95% confidence interval 2.66-21.99) or in protein C plus protein S (adjusted odds ratio 8.99; 95% confidence interval 2.79-28.93), but not for those deficient in plasminogen or heparin cofactor II. The thrombosis-free survival was shortened for deficient individuals in antithrombin (median 30 years), protein C (median 46 years), protein S type-I (median 48 years), protein S type III (median 61 years) and combined protein C and S (median 40 years). In conclusion, individuals carrying anticoagulant deficiencies have an increased risk of thrombosis, especially those with antithrombin, protein C or type I protein S deficiencies.
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PMID:Increased risk of venous thrombosis in carriers of natural anticoagulant deficiencies. Results of the family studies of the Spanish Multicenter Study on Thrombophilia (EMET study). 960 21

Protein C inhibitor (PCI) is a heparin-binding serine protease inhibitor (serpin) that regulates hemostatic proteases such as activated protein C (APC) and thrombin. The work described here provides further evidence that the PCI H helix, but not the D helix, has a major role in heparin-accelerated inhibition of APC and thrombin. We previously identified Arg-269 and Lys-270 of the H helix [R269A/K270A "H1" recombinant PCI (rPCI)] as important residues both for heparin-accelerated inhibition of thrombin and APC and for heparin-Sepharose binding (Shirk, R. A., Elisen, M. G. L. M., Meijers, J. C. M., and Church, F. C. (1994) J. Biol. Chem. 269, 28690-28695). H1 rPCI was used as a template for Ala-scanning mutagenesis of other H helix basic residues (H1-K266A, H1-K273A, and H1-K266A/K273A) and of the D helix basic residues (H1-K82A, H1-K86A, H1-R90A, and H1-K82A/K86A/R90A). Compared to wild-type rPCI/heparin (k2 = 2.2 x 10(7) M-1 min-1 for thrombin), heparin-accelerated thrombin inhibition was decreased 2.4-fold by H1 rPCI, 4.4-fold by H1-K266A rPCI, and 8-fold by H1-K273A rPCI. H1-K266A/K273A rPCI thrombin inhibition was essentially not accelerated by heparin. A similar trend was found for APC-heparin inhibition using these H helix rPCI mutants. In contrast, the D helix rPCI mutants did not have further reduced heparin-stimulated thrombin or APC inhibition compared to H1 rPCI. Interestingly, all of the H and D helix rPCI mutants had reduced heparin-Sepharose binding activity (ranging from 180 to 360 mM NaCl) compared to wild-type rPCI and H1 rPCI, which eluted at 650 and 430 mM NaCl, respectively. These data suggest that all four basic residues (Lys-266, Arg-269, Lys-270, Lys-273) in the H helix of PCI form a heparin binding site. Our results also imply that while the D helix basic residues (Lys-80, Lys-86, and Arg-90) contribute to overall heparin binding, they are not necessary for heparin-accelerated activity. We conclude that the primary heparin binding site of PCI is the H helix and not the D helix as found in other homologous heparin-binding serpins such as antithrombin III, heparin cofactor II, and protease nexin 1.
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PMID:Contribution of basic residues of the D and H helices in heparin binding to protein C inhibitor. 964 72

The changes in coagulation and fibrinolysis parameters during pregnancy, delivery and 3 days after delivery were evaluated in normotensive and gestational diabetes pregnant women. Normal pregnant women (n = 60) and pregnant women with gestational diabetes (n = 15) formed the study population. Coagulation and fibrinolysis parameters were estimated using commercial tests. Antithrombin III, thrombin-antithrombin III complexes, heparin cofactor II, protein C, protein S, tissue plasminogen activator, (t-PA) D-dimer and plasminogen activator inhibitor (PAI-1 and PAI-2) activities in normal and gestational diabetes pregnancies were determined. Thrombin-antithrombin III complexes increased and coagulation inhibitors decreased in gestational diabetes. Plasminogen activator inhibitors remained unchanged and t-PA levels increased in gestational diabetes.
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PMID:Coagulation and fibrinolysis parameters in normal pregnancy and in gestational diabetes. 978 46

Thrombophilic states are a group of conditions associated with increased predisposition to thromboembolic events. The well-recognized inherited thrombophilic states include resistance to activated protein C (APC) (Factor V Leiden) and deficiencies of plasma antithrombin, protein C, and protein S. These entities are aberrations in the natural anticoagulant systems that exist in plasma and at the endothelial cell level. Other causes of inherited thrombophilia include hyperhomocysteinemia, abnormalities in the proteins of the fibrinolytic system, dysfibrinogenemias, deficiency of heparin cofactor II, abnormal thrombomodulin, and the recently described variation in the prothrombin gene. Most of the inherited abnormalities recognized to date are associated with venous thromboembolism (VTE) rather than arterial thrombosis. Approximately half of VTE episodes in patients with inherited thrombophilias occur in relation to events that are generally recognized as predisposing states, such as surgery, pregnancy, and immobilization. In this review, the risks of VTE associated with inherited risk factors are discussed, and guidelines for the diagnosis and management are presented.
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PMID:Inherited thrombophilic states. 984 Jun 87

Vascular occlusion has a central role in the pathophysiology of sickle cell disease (SCD) and, although there is little evidence that thrombosis alone is responsible, patients with sickle cell disease are known to have an ill-defined but increased thrombotic risk. The most serious complication of this in childhood is stroke which occurs in 7-10% of children and a further 14% have asymptomatic cerebrovascular disease (CVD) on imaging. We have performed a comprehensive profile of coagulation inhibitors and markers of thrombin generation in 96 children (83 nontransfused [NTx] and 13 transfused [Tx]) with steady-state SCD and 18 healthy sibling controls. The levels of protein S (free and total) and heparin cofactor II were reduced in both the NTx and Tx groups compared to controls and protein C and APC resistance ratios were reduced in the NTx group only. Antithrombin levels were not different from controls. Thrombin-antithrombin complexes and prothrombin fragment F1+2 were increased in both patient groups. In the NTx subgroups with or without CVD there were no differences for any of the parameters measured except for lower haemoglobin levels and higher white cell counts in those with asymptomatic CVD. We conclude that children with SCD have a reduction in levels of the majority of the coagulation inhibitors and increased thrombin generation in the steady-state and these are only partially reversed by transfusion. However, these abnormalities do not appear to play a primary role in the development of cerebrovascular disease.
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PMID:Prothrombotic changes in children with sickle cell disease: relationships to cerebrovascular disease and transfusion. 988 16

The normal aging process alters blood coagulation system in humans; this may be of great concern in the view of the known association of vascular disease with advancing age. The plasma concentration of several coagulation factors, namely fibrinogen, factor VII, factor VIII, factor IX, high molecular-weight kininogen, and prekallikrein, increase in healthy humans, paralleling the physiological aging process. Plasma parameters of clotting activation in vivo, such as prothrombin fragment 1 + 2, fibrinopeptide A, thrombin-antithrombin III complex, and D-dimer, are positively correlated with age. Nevertheless, among centenarians, biochemical signs of marked hypercoagulability are associated with a healthy state. Natural anticoagulants, including antithrombin III, heparin cofactor II, protein C, protein S, and tissue factor pathway inhibitor, can modulate the reactions of blood coagulation system. The occurrence of menopause is accompanied by a significant increase in antithrombin III plasma level; the mean antithrombin III levels in older women exceed levels in male contemporaries. In healthy elderly subjects heparin cofactor II plasma concentrations are lower than in young subjects, independently of gender. Protein C levels raise with age in both sexes, as well as free protein S levels. In women, statistically significant increases in the plasma concentration of the tissue factor pathway inhibitor have been observed, whereas no significant age-related change has been found in men. The fact that many subjects with congenital defects of natural anticoagulants do not undergo thromboembolic events in young age suggests that in healthy individuals a raise in natural anticoagulants can balance the age-related increase of procoagulant factors.
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PMID:Natural anticoagulants, aging, and thromboembolism. 995 32


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