Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.5 (thrombin)
 33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human fibrinogen exposed to protease III from Crotalus atrox venom is cleaved near the NH2 terminus of the B beta chain yielding a species of Mr 325,000 (Fg325) with impaired thrombin clottability. The derivative was compared with intact fibrinogen in a number of ways to determine whether the functional defect resulted from a conformational change or from the loss of a polymerization site. NH2-terminal amino acid sequencing of isolated A alpha, B beta, and gamma chains showed that Fg325 contained intact A alpha and gamma chains, but differed from fibrinogen by the absence of the first 42 residues of the B beta chain. Fibrinopeptide A was present and was cleaved at the same rate in both fibrinogen and Fg325. The rate and extent of A alpha and gamma cross-linking by factor XIIIa was also indistinguishable. In contrast, the thrombin-catalyzed coagulation of Fg325 was 46% less in extent and 180-fold slower than observed for intact fibrinogen. A conformational comparison of Fg325 and fibrinogen was made using immunochemical and spectroscopic approaches. Antisera specific for different regions of the fibrinogen molecule were used to characterize the epitopes in Fg325. The only significant differences were found in the NH2-terminal region of the B beta chain, probed with antiserum to B beta 1-118. The conformational similarity of Fg325 and fibrinogen was confirmed by the identity of both near and far UV CD spectra of the two proteins. Structural, functional, and immunochemical results imply that cleavage of 42 NH2-terminal residues from the B beta chain is not accompanied by a measurable conformational change. The residues of this B beta chain segment, which are evidently located on the surface of the molecule, in conjunction with the NH2-terminal part of the A alpha chain appear to play an important role in the expression of a fibrin polymerization site.
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PMID:Conservation of human fibrinogen conformation after cleavage of the B beta chain NH2 terminus. 257 73

Fibrinopeptide A (FPA) levels were determined in 40 consecutive patients admitted to the coronary care unit with a typical history of chest pain: in 24 of them a diagnosis of acute myocardial infarction (AMI) and in 16 a diagnosis of angina was made. Seven of the patients with AMI suffered from recurrent episodes of early post-infarctional angina. FPA levels were determined in each patient on admission and every 4 h for 48 h. On admission in patients with both angina and AMI the FPA levels were significantly higher than in normal controls; these levels were higher in patients with AMI than in those with angina, but this difference was not significant. In patients with angina the values decreased progressively after 12 h to baseline values, while in those with AMI the high levels of FPA persisted throughout the 48-hour observation period. In many instances, particularly after 24 h, the differences between the two groups were statistically significant. In patients with early post-infarctional angina the episode of angor was preceded by or corresponded to a new great elevation of FPA levels. These data suggest that the thrombin generation is higher and more prolonged in patients with AMI than in those with angina; the determination of FPA levels, which are an index of 'in vivo' thrombin generation, can be useful to follow the clinical course of ischaemic heart disease.
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PMID:Fibrinopeptide A levels in patients with acute ischaemic heart disease. 274 31

In vivo study of blood coagulation and fibrinolysis activities in non insulin dependent diabetes mellitus. The aim of the study was to investigate in vivo blood coagulation and fibrinolysis activities in a group of diabetic patients NIDDM with and without vascular complications. For this purpose we determined two sensitive indicators in vivo of blood coagulation and fibrinolytic activities such as fibrinopeptide A and B beta 15-42 respectively. Moreover, we computed the ratio between B beta 15-42 and fibrinopeptide A in order to investigate a possible imbalance in vivo between blood coagulation and fibrinolysis. Control groups were 15 healthy subjects and 28 non diabetic patients affected by atherosclerotic disease. Fibrinopeptide A and B beta values were significantly higher in the diabetic patients than controls but there was no difference between the former group and the atherosclerotic patients. Also, no correlation was found for FPA, B beta, B beta/FPAr and HbAlc, fructosamine and blood glucose levels. There was no difference in B beta, FPA and B beta/FPAr values for patients treated with insulin and for those treated with either hypoglycemic agents or diet. Our data indicate that in diabetic patients fibrinolysis activity is increased, but it cannot counterbalance thrombin activity which appears much more enhanced. Finally, the lack of correlation for FPA, B beta, B beta/FPAr and HbAlc, fructosamine and blood glucose suggests that blood coagulation and fibronolysis abnormalities are not related to the degree of blood glucose control.
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PMID:[Activity of the coagulation and fibrinolysis in non-insulin-dependent diabetes mellitus. In vivo study]. 277 95

A previous study of neurosurgical patients demonstrated an imbalance between thrombin and plasmin action following surgery. The present study was designed to determine the effect of intermittent pneumatic calf compression on postoperative enzyme activity. Fibrinopeptide A (FPA) and B beta 1-42 levels, reflecting thrombin and plasmin action respectively, were measured daily in patients undergoing elective craniotomy. Two of 9 patients not receiving calf compression developed positive fibrinogen leg scans, while none of 5 patients receiving prophylaxis had positive scans. Calf compression was associated with a markedly altered pattern of changes in the fibrinopeptide values following surgery. Without compression, there was perturbation of the balance between thrombin and plasmin action on the day after surgery as reflected by an increase in the FPA/B beta 1-42 ratio. In contrast, in those receiving prophylaxis there was no change in this ratio on the first postoperative day. Calf compression both blunted the mean postoperative increase in the FPA level (1.8 nM vs 4.7 nM; p less than .05) and augmented the mean B beta 1-42 value (3.0 nM vs 0.2 nM; p less than .05) so that the mean increase in the FPA/B beta 1-42 ratio was only 0.1 with calf compression as compared to 2.2 without it (p less than .05). Systemic modulation of both the coagulation and fibrinolytic pathways thus occurred in association with calf compression.
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PMID:Effects of intermittent pneumatic calf compression on postoperative thrombin and plasmin activity. 294 90

Acute exposure to hypoxia causes acceleration of activated partial thromboplastin time (aPTT) and a rise in factor VIII precoagulant activity (F VIII:C). To determine whether this activation of coagulation leads to in vivo fibrin formation we investigated 15 army pilots before and at the end of 21 min (range 14-29) of hypobaric hypoxia. Mean final pressure in the decompression chamber was 283 (250-310) mm Hg causing a fall in oxygen saturation to 61.5% (53-69). Hypobaric hypoxia caused acceleration of thrombin time (p less than 0.05), aPTT (p less than 0.01), and euglobulin lysis time (p = 0.05), as well as a rise of F VIII:C (p less than 0.05), beta-thromboglobulin (p less than 0.005), fibrin(ogen) degradation products E (p less than 0.005) and B beta 15-42 (p less than 0.001), as well as lactate (p less than 0.001). Fibrinopeptide A, a marker of in vivo fibrin formation, did not change significantly. It is concluded that severe hypoxemia due to rapid decompression going to the limit of tolerance does not lead to fibrin formation, whereas the rise in fibrin(ogen) degradation products demonstrates activation of the fibrinolytic system.
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PMID:Fibrinogenolysis in the absence of fibrin formation in severe hypobaric hypoxia. 296 86

To investigate the effect of blood glucose concentration on thrombin generation and fibrinolytic activity, six Type 1 patients had the blood glucose concentration maintained for 1 h at 5, 15, and 25 mmol l-1, and 8 patients underwent hypoglycaemia of 20 min duration after the blood glucose had been kept at 8 mmol l-1 for 1 h. During hyperglycaemia plasminogen activator activity rose from 214 (11-625) (median, range) to 478 (18-772) units (p less than 0.05) at a blood glucose of 5 mmol l-1 and to 511 (89-816) (p less than 0.05) and 535 (33-976) (p less than 0.05) units at a blood glucose of 15 and 25 mmol l-1, respectively. Cross-linked fibrin degradation products (FDP) were 45 and 53 micrograms l-1 at a blood glucose of 5 mmol l-1 and remained unchanged at higher glucose levels. Fibrinopeptide A was 1.3 (0.6-2.8) nmol l-1 at a blood glucose of 5 mmol l-1, and remained unchanged with hyperglycaemia, being 1.3 (0.9-1.3) nmol l-1 after 1h at 25 mmol l-1. During hypoglycaemia, plasminogen activator activity rose from 155 to 745 units (p less than 0.05) while both fibrinopeptide A and cross-linked FDP remained unchanged. The results indicate that acute fluctuations in blood glucose concentration do not lead to thrombin generation. Additionally, increased fibrinolytic activity measured in vitro is not associated with an increase in cross-linked FDP. This suggests that short-term hyper- and hypoglycaemia do not affect the end-products of the coagulation and fibrinolytic pathways.
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PMID:Acute changes in blood glucose concentration do not promote thrombin generation or fibrin breakdown in type 1 diabetes. 297 49

We describe the coagulopathy of a 65-year-old woman with a thrombotic disorder associated with dysfibrinogenemia and lupus anticoagulant (LA). The patient's prothrombin time (PT), partial thromboplastin time (PTT), thrombin time (TT), and batroxobin time were prolonged and could not be corrected by mixing with equal volumes of normal plasma. Fibrinogen quantitation showed approximately twice as much immunoreactive as thrombin-clottable protein. The batroxobin and thrombin clotting times of the patient's isolated fibrinogen were prolonged and could not be corrected by mixture with normal fibrinogen. Turbidimetrically assessed fibrin monomer aggregation in response to thrombin, ancrod, or batroxobin and fibrin monomer reaggregation experiments disclosed clearly delayed onset and a lower maximum opacity. In other turbidimetric and clotting-time experiments, the patient's fibrinogen displayed a dose-dependent inhibition of the reaggregation of normal fibrin. Fibrinopeptide A and B release rates and sialic acid content were normal. Assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of reduced samples, the subunit structure of the patient's fibrinogen and its fully cross-linked fibrin was normal. The presence of LA was established by two techniques, the blood thromboplastin inhibition test and the platelet neutralization procedure (PNP). A positive PNP could not be produced by mixing afibrinogenemic plasma with the patient's purified fibrinogen. The patient's inactivated serum and her isolated IgG prolonged the PT and PTT of normal plasma but showed no inhibitory effect on the clotting of purified normal fibrinogen.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dysfibrinogenemia and lupus anticoagulant in a patient with recurrent thrombosis. 311 49

Fibrinopeptide A (FPA) is the first peptide released from fibrinogen upon thrombin action. Plasma FPA is cleared rapidly with a first order kinetics and therefore its level reflects the rate of thrombin cleavage of fibrinogen. A prospective study was undertaken to establish normal values of FPA during pregnancy. The mean FPA for the pregnant group (n = 136) was 2.8 ng/ml (SD = 3.3) while it was 1.24 ng/ml (SD = 0.4) for a nonpregnant control group of healthy women (n = 30). The median FPA for the pregnant group was 2.2 ng/ml and 1.4 ng/ml for the nonpregnant group (Wilcoxon test P less than 0.0001). Plasma FPA levels increased with gestational age. The median value was 1.5 ng/ml in the first trimester (n = 18), 1.8 ng/ml in the second trimester (n = 40), and 2.5 ng/ml in the third trimester (n = 78). Plasma FPA concentrations in the third trimester were significantly higher than in the first and second trimester. These findings suggest increased thrombin activity and fibrin generation during the course of normal pregnancy.
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PMID:Fibrinopeptide A during normal pregnancy. 325 91

Polymerization of bovine fibrinogen acted upon by thrombin is accompanied by binding of Ca2+ and a concomitant decrease of the free Ca2+ concentration. The latter can be recorded by a Ca2+-selective electrode as a shift in the electrode potential. The shift shows marked dependence on the initial free Ca2+ concentration, being maximal at about 10(-4.1) M and decreasing sharply on either side of this. Thus, the effect is limited to the 10(-3)-10(-5) M free Ca2+ concentration range. From the initial and the final value of the electrode potential during a clotting experiment, the amount of Ca2+ bound to fibrinogen and fibrin, respectively, can be calculated. The difference between the two, plotted against free Ca2+ concentration, gives a bell-shaped curve. This indicates that the reason for the Ca2+ binding is a shift of the pK of some groups from a lower to higher value. The recordings can be used for evaluation of the kinetics of the Ca2+ uptake. However, they have to be corrected for the effect of the continuous shift in the free Ca2+ concentration during the experiment. The reaction does not follow simple kinetics, showing a lag period. Therefore, rates were estimated from inverse half-reaction times. Half-times of the corrected curves show that the reaction is first order with respect to thrombin. Moreover, the rate of Ca2+ uptake is identical with that of the conformational change seen in differential scanning calorimetry [Donovan, J.W., & Mihalyi, E. '1985) Biochemistry 24, 3434]. The inverse rate and the final corrected Ca2+ uptake increase linearly with the initial fibrinogen concentration. Concomitant estimates of fibrinopeptide A and B release showed that the Ca2+ uptake runs parallel to the release of fibrinopeptide B. Fibrinopeptide A was released largely during the lag period of the Ca2+ uptake. In agreement with this, clotting with Ancrod, an enzyme that liberates only fibrinopeptide A, was not accompanied by binding of Ca2+. Thus, polymerization is not sufficient for the Ca2+ uptake to occur; liberation of fibrinopeptide B seems to be obligatory. Further support for this was obtained with experiments with the polymerization inhibitor Gly-Pro-Arg-Pro. The tetrapeptide inhibits polymerization and also, proportional to this, release of fibrinopeptide B [Hurlet-Jensen, A., Cummins, H.Z., Nossel, H.L., & Liu, C.Y. (1982) Thromb. Res. 27, 419; Lewis, S.D., Shields, P.P., & Shafer, J.A. (1985) J. Biol. Chem. 260, 10192]. Calcium uptake was also depressed by the tetrapeptide in a way similar to its effect upon fibrinopeptide B release.
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PMID:Clotting of bovine fibrinogen. Calcium binding to fibrin during clotting and its dependence on release of fibrinopeptide B. 336 73

Fibrinopeptide A (FPA) levels as an indicator of thrombin activity in the cerebrospinal fluid (CSF) and plasma of 25 patients with subarachnoid haemorrhage (SAH) were measured serially by radioimmunoassay (RIA). FPA levels in CSF were extremely high on days 0-1 (1253 +/- 269 ng/ml, mean +/- standard error) but decreased rapidly (11.3 +/- 3.9 ng/ml on days 2-4, 10.7 +/- 5.9 ng/ml on days 5-7, and 6.3 +/- 1.5 ng/ml on days 8-14). In the controls the FPA concentration in CSF was 1.2 +/- 0.9 ng/ml (mean +/- standard deviation). Plasma FPA levels in patients with SAH showed no statistically significant changes with time. The bradykinin (BK) concentration in CSF and plasma in 27 patients with SAH was measured serially by RIA. The concentrations in CSF were 122.7 +/- 22.7 pg/ml (mean +/- standard error) on day 0, 38.6 +/- 6.1 pg/ml on day 1, 22.7 +/- 6.3 pg/ml on day 2, and 17.1 +/- 3.0 pg/ml or less thereafter. Plasma BK levels in patients with SAH were higher than those in the control group, but there was no statistically significant change over time. From the measurement of FPA it was apparent that the coagulation system in the subarachnoid space is strongly activated in the early stage of SAH. The formation of BK in CSF after SAH is thought to be due to the contact activation of Hageman factor (intrinsic factor) in the subarachnoid space. Trabeculae as collagen bundles in the subarachnoid space were considered to have a possible role in activating the Hageman factor of the coagulation system in SAH.
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PMID:Activation of the coagulation system in the subarachnoid space after subarachnoid haemorrhage: serial measurement of fibrinopeptide A and bradykinin of cerebrospinal fluid and plasma in patients with subarachnoid haemorrhage. 340 55


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