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)

After menopause the haemostatic balance shifts towards a latent hypercoagulable state. To evaluate the effects of two regimens of transdermal estradiol (E2) combined with progestin on the balance between procoagulant factors and inhibitors, 255 women in physiological menopause for 1-5 years were randomly allocated to 1 year of treatment with cyclic transdermal E2 (50 micrograms/day for 21 days) plus medroxyprogesterone acetate (MPA) (10 mg/day from days 10 to 21), continuous transdermal E2 (50 micrograms/day for 28 days) plus MPA (10 mg/day from days 14 to 25), or placebo. Fibrinogen, factor VII (FVII), factor VIII:C (FVIII:C), antithrombin III (ATIII), protein C, protein S, heparin cofactor II (HCII) and plasminogen activator inhibitor (PAI-1) levels were measured at baseline and after 6 and 12 cycles. 167 women who took the treatment for at least 6 cycles were evaluable. The continuous treatment group had significantly lower final values of fibrinogen, FVII, ATIII, protein S and HCII than the placebo group; the cyclic treatment reduced fibrinogen in comparison with placebo but the difference was not significant. In conclusion, both regimens produce a clinically relevant decrease of fibrinogen levels; the continuous regimen affects also the levels of FVII and inhibitors suggesting that the haemostatic balance is shifted to a more physiological state.
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PMID:Effects on haemostasis of hormone replacement therapy with transdermal estradiol and oral sequential medroxyprogesterone acetate: a 1-year, double-blind, placebo-controlled study. The Writing Group for the Estradiol Clotting Factors Study. 870 11

Blood coagulation proteins were determined in 285 healthy fetuses from 19 to 38 weeks' gestation and compared with those of 60 normal full-term newborns and 40 adult controls. Prolongation of the coagulation screening tests, prothrombin time, activated partial prothrombin time, and thrombin clotting time, in fetuses throughout intrauterine life was explained by low levels of vitamin K-dependent factors (II, VII, IX, and X), contact factors (XI, XII, prekallikrein, and high-molecular-weight kininogen), factor V, factor VIII, and fibrinogen. Low levels of antithrombin III, heparin cofactor II, protein C and protein S, and tissue factor pathway inhibitor were also found, and these probably contributed to a satisfactory hemostatic balance. Some of these parameters were evaluated by both immunologic and functional assays to detect possible "fetal" proteins. An increase in factor levels was observed after the thirty-fourth week of intrauterine life for most of the coagulation activators and inhibitors, but only factors V and VIII reached adult values at birth. This study therefore showed that fetal hemostasis is a dynamic system that evolves gradually toward the neonatal state and then toward the adult state.
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PMID:Evolution of blood coagulation activators and inhibitors in the healthy human fetus. 870 47

In a rat template bleeding model, depolymerized holothurian glycosaminoglycan (DHG) prolonged bleeding time at 30 mg/kg i.v. but unfractionated heparin (UFH) had the same effect at 1 mg/kg i.v., indicating that DHG is much less bleeding than UFH. To characterize this difference, we examined the affinity of DHG for plasma proteins by means of a glycosaminoglycan-conjugated cellulofine column in comparison with that of UFH. The DHG column strongly bound factor V, factor IX, protein S, histidine-rich glycoprotein, platelet factor 4 (PF4), beta-thromboglobulin, von Willebrand factor, fibronectin, and heparin cofactor II, but did not bind fibrinogen, prothrombin, factor VII, protein C, antithrombin III (ATIII), plasminogen or alpha 2-plasmin inhibitor. The profile of protein binding to the UFH column was almost the same as that of the DHG column except that ATIII showed affinity for UFH. One of the reasons why DHG caused much less bleeding than UFH is thus suggested to be the differences in their affinity for ATIII in plasma.
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PMID:Interaction of a new depolymerized holothurian glycosaminoglycan with proteins in human plasma. 884 Apr 67

Today we known that the coagulation system of the neonate differs in many ways from that of the adult system. We see a general reduction of the coagulation factors II-XIII (except VIII), the fibrinogen and of the coagulation inhibitors ATIII, protein C and heparin cofactor II at the same time. In addition the newborns show different levels of the coagulation factors for premature and full-term infants. This situation necessitates the generation of not one, but several, reference ranges for the various components of the hemostatic system. While the above-mentioned factors of the coagulation and fibrinolytic system of the newborn are well studied, our knowledge of others is still lagging behind that of the adult. That applies to the vWF and PAI and even more to D-Dimer. Our aim was to collect some data for vWF, PAI and D-Dimer to complete the understanding of the physiology of the hemostatic system in the newborn. Therefore we used the blood samples from 59 newborns and their mothers to obtain a number of different components of the coagulation and fibrinolytic system. Besides some rheological parameters (erythrocyte aggregation, plasma viscosity) we measured the aPTT, PT and the plasma levels of ATIII, fibrinogen and protein C (PC). But we paid special attention to the plasma levels of von Willebrand factor (vWF), plasma activator inhibitor (PAI) and D-Dimer. The blood samples were collected from the umbilical cord and the cubital vein of the mother immediately after delivery, anti-coagulated, centrifuged and stored until measurement at -70 degrees C. ATIII, aPTT, PT and fibrinogen were measured by the clotting technique test on the Chromotimer (Behring, Marburg, Germany). D-Dimer, vWF and protein C were determined with a commercially available ELISA obtained from Boehringer Mannheim (Mannheim, Germany). PAI activity was measured by a two-stage amiolytic method (Behring, Marburg). Besides the known differences of the neonatal hemostatic components to their mothers, such as a prolonged aPTT (52.19 s +/- 13.4 newborn, 35.26 s +/- 4.2 mother), reduced PT (64.34 s +/- 20.15 vs. 91.03 s +/- 1.25), ATIII (83.36% +/- 24.42 vs. 92.58% +/- 11.43) and fibrinogen (156.05 mg/dl +/- 91.68 vs. 344 mg/dl +/- 55.25), we found some peculiarities. The newborns show a clear reduction in the vWF (97.79 ng/ml +/- 36.33 vs. 183.43 ng/ml +/- 16.03) as well as the PAI (0.846 U/ml +/- 1.44 vs. 7.652 U/ml +/- 0.764). D-Dimer levels in the umbilical cord samples (1514.02 ng/ml +/- 953.56) are clearly prolonged in contrast to the maternal levels (740.2 ng/ml +/- 139.68). We were also able to find a difference of these factors related to gestational age. Premature infants showed a clearly higher level of PAI (2.2 U/ml +/- 2.86 vs. 0.69 +/- 1.13; p = 0.0136) compared with full-term infants, as well as significantly lower levels of ATIII (48.8% +/- 23.19 vs. 86.62 +/- 22.04; p = 0.0006) and protein C (25.33% +/- 9.37 vs. 35.73 +/- 7.53; p = 0.0027). D-Dimer, vWF, fibrinogen and the rheological parameters are similar. This seems to show an increased tendency for bleeding with the premature infant. Newborns show a balance of the coagulation system solely on a lower level. This is due to the general reduction of the coagulation factors with a reduction of the coagulation inhibitors at the same time. The physiologically low level of the vitamin K dependent and other coagulation factors and ATIII leads to a prolonged aPTT and reduced PT of the newborn. As well as these differences, known from literature, we found the following specialities: lower vWF and PAI and higher D-Dimer levels of the newborn compared with their mothers.
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PMID:Maternal and cord blood hemostasis at delivery. 908 4

The haemostatic system and the use of heparin during cardiopulmonary bypass (CPB) have been studied extensively in adults but not in children. Results from adult trials cannot be extrapolated to children because of age-dependent physiologic differences in haemostasis. We studied 22 consecutive paediatric patients who underwent CPB at The Hospital for Sick Children, Toronto. Fibrinogen, factors II, V, VII, VIII, IX, XII, prekallikrein, protein C, protein S, antithrombin (AT), heparin cofactor II, alpha 2-macroglobulin, plasminogen, alpha 2-antiplasmin, tissue plasminogen activator (tPA), plasminogen activator inhibitor, thrombin-AT complexes (TAT), D-dimer, heparin (by both anti-factor Xa assay and protamine titration) and activated clotting time (ACT) were assayed perioperatively. The timing of the sampling was: pre heparin, post heparin, after initiation of CPB, during hypothermia, post hypothermia, post protamine reversal and 24 h post CPB. Plasma concentrations of all haemostatic proteins decreased by an average of 56% immediately following the initiation of CPB due to haemodilution. During CPB, the majority of procoagulants, inhibitors and some components of the fibrinolytic system (plasminogen, alpha 2 AP) remained stable. However, plasma concentrations of TAT and D-dimers increased during CPB showing that significant activation of the coagulation and fibrinolytic systems occurred. Mechanisms responsible for the activation of haemostasis are likely complex. However, low plasma concentrations of heparin (< 2.0 units/ml in 45% of patients) during CPB were likely a major contributing etiology. ACT values showed a poor correlation (r = 0.38) with heparin concentrations likely due to concurrent haemodilution of haemostatic factors, activation of haemostatic system, hypothermia and activation of platelets. In conclusion, CPB in paediatric patients causes global decreases of components of the coagulation and fibrinolytic systems, primarily by haemodilution and secondarily by consumption.
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PMID:Coagulation and fibrinolytic profile of paediatric patients undergoing cardiopulmonary bypass. 915 80

Interactions between standard heparin and the physiological anticoagulant plasma protein, activated protein C (APC) were studied. The ability of heparin to prolong the activated partial thromboplastin time and the factor Xa- one-stage clotting time of normal plasma was markedly enhanced by addition of purified APC to the assays. Experiments using purified clotting factors showed that heparin enhanced by fourfold the phospholipid-dependent inactivation of factor V by APC. In contrast to factor V, there was no effect of heparin on inactivation of thrombin-activated factor Va by APC. Based on SDS-PAGE analysis, heparin enhanced the rate of proteolysis of factor V but not factor Va by APC. Coagulation assays using immunodepleted plasmas showed that the enhancement of heparin action by APC was independent of antithrombin III, heparin cofactor II, and protein S. Experiments using purified proteins showed that heparin did not inhibit factor V activation by thrombin. In summary, heparin and APC showed significant anticoagulant synergy in plasma due to three mechanisms that simultaneously decreased thrombin generation by the prothrombinase complex. These mechanisms include: first, heparin enhancement of antithrombin III-dependent inhibition of factor V activation by thrombin; second, the inactivation of membrane-bound FVa by APC; and third, the proteolytic inactivation of membrane-bound factor V by APC, which is enhanced by heparin.
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PMID:Anticoagulant synergism of heparin and activated protein C in vitro. Role of a novel anticoagulant mechanism of heparin, enhancement of inactivation of factor V by activated protein C. 916 95

Several human genetic linkage maps have been constructed as part of the Human Genome Project. These maps show the positional order of closely linked, highly informative AC-repeat polymorphisms on each human chromosome, and are extremely useful in genetic linkage analysis of inheritable diseases. For a candidate gene approach the current linkage maps are less useful, since they consist mainly of anonymous markers rather than of specific genes. This situation also applies for inheritable disorders of blood coagulation. Numerous genes are involved in the blood coagulation cascade and its regulation, and can be considered as candidate genes for unexplained haemophilia and thrombophilia. We have selected 29 candidate genes that seem to be the ones most likely to be involved in thrombophilia. For 19 genes genotype data were already present in the CEPH database (version 7.0). We typed 7 additional genes in the CEPH reference families, i.e. the factor V, factor XII, protein C, protein S, prothrombin, thrombomodulin, and heparin cofactor II gene. The genotype data were used to integrate these 26 genes in the current genetic linkage map, and to identify closely linked AC-repeat polymorphisms. This information will benefit the investigation of inheritable disorders of blood coagulation, especially thrombophilia.
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PMID:Location on the human genetic linkage map of 26 genes involved in blood coagulation. 918 95

Meizothrombin and meizothrombin(desF1) are intermediates formed during the conversion of prothrombin to thrombin by factor Xa, factor Va, phospholipids, and Ca2+ (prothrombinase). These intermediates are active toward synthetic peptide substrates but have limited ability to interact with platelets or macromolecular substrates such as fibrinogen. Meizothrombin and meizothrombin(desF1) activate protein C, however, and may exert primarily an anticoagulant effect. In this study, we investigated the inhibition of meizothrombin and meizothrombin(desF1) by two glycosaminoglycan-dependent protease inhibitors, heparin cofactor II (HCII) and antithrombin (AT). Purified recombinant meizothrombin and meizothrombin(desF1) were inhibited by HCII in the presence of dermatan sulfate with maximal second-order rate constants of 8 x 10(6) M-1.min-1 and 1.8 x 10(7) M-1.min-1, respectively, but were inhibited less than one-tenth as fast by AT in the presence of heparin. Similarly, the products of the prothrombinase reaction were inhibited in situ more effectively by HCII than by AT. When HCII and dermatan sulfate were present continuously during the prothrombinase reaction, meizothrombin was trapped as a sodium dodecyl sulfate-stable complex with HCII and no amidolytic activity could be detected with a thrombin substrate. Our findings indicate that HCII is an effective inhibitor of meizothrombin and meizothrombin(desF1) and, therefore, might regulate the anticoagulant activity of these proteases.
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PMID:Inhibition of meizothrombin and meizothrombin(desF1) by heparin cofactor II. 935 33

The nature of the relationship between inherited abnormalities of the clotting system and the occurrence of cerebrovascular accidents in young subjects is controversial. To evaluate the risk of cerebrovascular disease associated with such abnormalities, we analyzed a series of 23 consecutive patients in a case-control study with ischemic stroke proven by computerised tomography and aged below 45 years at admission, and a control group of 115 age- and sex-matched controls from the general population. No differences in antithrombin, protein C, protein S, heparin cofactor II, plasminogen or response to activated protein C were observed between cases and controls. None of the patients had a history of personal or familial thrombosis, and none had a reduction in the considered clotting factor below the reference range. We conclude that abnormalities of the clotting system are not associated with the occurrence of cerebrovascular abnormalities in the young and that routine screening for inherited thrombophilia is not appropriate in young patients with cerebrovascular disease.
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PMID:Inherited abnormalities of blood coagulation in juvenile stroke. A case-control study. 939 20

We have established a system for etiological analysis of thrombophilia which includes assays of antithrombin III, protein C, protein S, plasminogen, fibrinogen, heparin cofactor II and lupus anticoagulants as well as gene analysis. The analysis conducted on 115 patients with venous thrombosis, arterial thrombosis and small vessel thrombosis revealed that forty-one patients(36% of the examined patients) were accompanied with decreased activities of protein S, protein C, antithrombin III and plasminogen. Eleven candidate causal mutations were found by gene analysis. These studies indicate that a comprehensive examination is instrumental in identifying and confirming the etiology in patients with thrombophilia.
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PMID:[Etiological analysis of thrombophilia]. 939 41


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