Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.6 (thromboplastin)
 13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This review summarises evidence supporting the view that the therapeutic anticoagulant properties of heparin are related to its physiological function in the organism, especially its activation of lipoprotein lipase and lecithinase. The conflicting results obtained from studies of the effect of heparin on platelet function are discussed, together with reasons for these differences of opinion. Finally, a hypothesis which links heparin, heparin-activated enzymes and platelet function is proposed, this hypothesis being complementary to the current views concerning the activation by heparin of the inhibitor of activated factor X.
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PMID:Heparin, heparin-activated enzymes and platelets. 32 21

Heparin is used as standard anticoagulant in the extracorporeal circuit of hemodialysis. Widespread use of this drug revealed several potentially adverse effects, such as release of lipoprotein lipase and hepatic lipase from the endothelial surface. Recently it was found that anticoagulatory potency and provocation of adverse effects are linked to different subfractions of heparin. A heparin subfraction of 4000 to 6000 Daltons rather specifically inhibits factor Xa and therefore has a very high antithrombotic potency. Its effects on release of lipases are minor. During a four year period five patients on maintenance hemodialysis were treated with this low molecular weight heparin (LMWH) subfraction. Additionally, another five patients successively received standard heparin, LMWH and again standard heparin. At all circumstances during treatment with LMWH there was a significant (0.001 less than P less than 0.05) reduction both of cholesterol and triglyceride blood concentrations. LMWH is efficient in avoiding clotting in extracorporeal circuit during hemodialysis in doses of 17 to 95 U/kg (initial dose) and 7 to 20 U/kg/hr (continuous dose).
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PMID:Reduced lipid concentrations during four years of dialysis with low molecular weight heparin. 166 3

In a double-blind study the dose-dependent effect of 10, 20, 40, and 70 mg of SSHA was tested in volunteers. Whereas only a minor prolongation of the aPTT was noted, a clear anti-factor Xa effect was proven (method of Yin), as well as the release of lipoprotein lipase. In a subsequent study, 12 volunteers were treated daily with a dose of 40 mg for 11 days. On the first day of treatment a dosage of 40 mg SC was administered three times every 90 min. There was no cumulative effect with this dose and a clear plateau effect was recorded daily after each application. Repeated administration therefore results in an identical reproducible effect. Thus, no tachyphylaxis occurred under long-term treatment with 40 mg SSHA.
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PMID:Study of a dose-dependent effect of the glycosaminoglycan polysulfate on various parameters of blood coagulation. 194 92

The risk of cardiovascular complications is reported to be several times higher in severe exercise than in daily activity. EPI-mediated inhibition of factor VIIa/thromboplastin enzymatic activity is believed to be an important modulator of blood coagulation during hemostasis. The plasma concentration of EPI, corrected for changes in plasma volume, was determined in healthy male subjects prior to, immediately after and at various time intervals after strenuous exercise of different duration. A slight, but significant decrease in EPI (7.5 +/- 2.8%, p less than 0.03) was found after a short term run (1.7 km), whereas no significant change was seen after a middle term run (4.8 km). In contrast, we observed a marked increase in EPI after a long term run (20.3 +/- 6.9%, p less than 0.03) and in a second group of athletes participating in the Norwegian championship of 30 km cross country skiing (39.9 +/- 10.3%, p less than 0.02). A peak value was reached 2 h after the run, and after that the curve started to approach baseline values. The rise in EPI might reflect a significant release of EPI from the endothelium that is greater than eventually any consumption. Another explanation for this enhancement in EPI might be that the increase in lipoprotein lipase activity after physical exercise causes a rise in the availability of EPI since EPI is known to be associated with lipoproteins in the circulation. It is hypothesized that mobilization of EPI during extensive physical exercise may suppress activation of the clotting system.
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PMID:Physical exercise enhances plasma levels of extrinsic pathway inhibitor (EPI). 227 17

The anticoagulant, lipolytic and protamine reversible effects of high doses of low molecular weight (LMW) heparin 21-23 and unfractionated heparin were compared in man. 7,500 units of each heparin were applied, which corresponds to 90 mg LMW heparin and 48 mg unfractionated heparin. The anticoagulant properties of the LMW heparin are characterized by a doubled half life of factor Xa activity, smaller influence on aPTT and thrombin after intravenous (i.v.) and subcutaneous (s.c.) injection, and higher bioavailability of factor Xa activity after s.c. administration (90% versus 15%). Protamine chloride completely neutralizes the effect on aPTT and thrombin and reduces the anti factor Xa activity by 60%. The bleeding time is prolonged by both normal and LMW heparin by 20%. This effect is normalized by protamine chloride, too. Thrombelastography with recalcified whole blood demonstrates that protamine chloride shortens but not completely normalizes the coagulation time in presence of either unfractionated or LMW heparin. The half life of lipoprotein lipase (LPL) activity is 60 min after i.v. administration of unfractionated heparin and 120 min with LMW heparin. Although the release of lipases (LPL and HTGL) is higher after i.v. and s.c. administration of the LMW heparin they do not induce higher releases of free fatty acids. This indicates that the lipolytic activity of this LMW heparin and unfractionated heparin is similar. The results show an improved anticoagulant pharmacological profile of this LMW heparin as compared to unfractionated heparin. Protamine normalizes the anticoagulant effects of LMW heparin with exception of a residual anti factor Xa activity and normalizes the changes of bleeding time and thrombelastography.
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PMID:The pharmacological profile of the low molecular weight heparin 21-23 in man: anticoagulant, lipolytic and protamine reversible effects. 248 15

Intravenous fat tolerance was tested in two groups of patients given a continuous i.v. infusion of heparin for several days. One group of 11 patients with deep vein thrombosis (DVT) of the leg was given 25,000-35,000 IU heparin daily for 4-5 days. The other group comprised 10 patients who had central venous catheters (CVC) for total parenteral nutrition. These patients were given 20,000 IU heparin daily for 6 days as prophylaxis against CVC-related thrombosis. In the DVT group heparinization was associated with a 44% decrease in plasma fat removal capacity (P less than 0.05). This reduction persisted for 2 days after the discontinuation of heparin therapy. In the CVC group the plasma fat removal capacity decreased by 29% during heparinization (P greater than 0.05, NS). During heparinization activated partial thromboplastin time was more than three times the basal value in the DVT group but less than twice those in the CVC group. One week after the heparin therapy the serum triglyceride levels were higher in both groups compared with initial values (DVT group: 1.2 +/- 0.2 s.e. mean vs. 1.7 +/- 0.3 mmol/l; P less than 0.05. CVC group: 1.0 +/- 0.1 vs. 1.4 +/- 0.2 mmol/l; NS). The possibility that full-dose heparinization reduces plasma fat removal capacity and that this may be due to a partial depletion of lipoprotein lipase stores is discussed.
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PMID:Plasma clearance of fat emulsion during continuous heparin infusion. 310 29

Lipoprotein lipases from human, bovine or guinea-pig milk were purified, judged for domain relationships by characterization of sites sensitive to proteases, and structurally compared. The subunit of human lipoprotein lipase migrated slightly slower than those of bovine or guinea-pig lipoprotein lipases on sodium dodecyl sulfate/polyacrylamide gel electrophoresis. Bovine lipoprotein lipase is known to be a dimer of two non-covalently linked subunits of equal size, and the lipases from all three sources now yielded homogeneous N-terminal amino acid sequences (followed for 15-27 residues). The results indicate that the two subunits are identical. Bovine lipoprotein lipase had two additional N-terminal residues, Asp-Arg, compared to the human and guinea-pig enzymes, and the next two positions revealed residue differences, but further on homologies were extensive between all three enzymes as far as presently traced. Exposure of bovine lipoprotein lipase to trypsin led to production of three fragments (T1, T2a, and T2b), suggesting cleavage at exposed segments delineating domain borders. Time studies gave no evidence for precursor-product relationships between the fragments, and prolonged digestion did not lead to further cleavage. Fragments T2a and T2b had the same N-terminal sequence as intact lipase. Fragment T1 revealed a new sequence, and represents the C-terminal half of the molecule. Plasmin caused a similar cleavage as trypsin, whereas thrombin, factor Xa, and tissue plasminogen activator did not cleave the enzyme. Chymotrypsin cleaved off a relatively small fragment from the C-terminal of the molecule, after which exposure to trypsin still resulted in cleavage at the same sites as in intact lipase. Tryptic cleavage of guinea-pig lipoprotein lipase yielded two fragments. One had a similar size as bovine fragment T2b; the other had a similar size as bovine fragment T1 and an N-terminal sequence homologous with that of T1. Thus, trypsin recognizes the same unique site in guinea-pig lipoprotein lipase as in the bovine enzyme. This confirms the conclusion that this segment is the border between two domains in the subunit. The binding site for heparin was retained after both tryptic and chymotryptic cleavages and was identified as localized in the C-terminal part of the molecule.
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PMID:Lipoprotein lipases from cow, guinea-pig and man. Structural characterization and identification of protease-sensitive internal regions. 353 11

ORG 10172 is a heparinoid with mean molecular weight 6500 daltons. Intravenous bolus injections of ORG 10172 were compared with placebo and heparin injections in 91 separate studies in 83 healthy male subjects. 6400 units ORG 10172 produced a mean maximum change of 14.7 s in kaolin cephalin time (c.f. greater than 120 s for 5000 units heparin). Changes in prothrombin time were minimal (1.6 s for 6400 units ORG 10172 and 4.5 s after 5000 units heparin). A dose-related increase in bleeding time occurred after ORG 10172 and at high doses (greater than 3200 units) some secondary bleeding, which was never serious, occurred at between 1 and 4 h after incision. A dose-dependent reduction in ex vivo platelet adhesiveness was found at 10 min after ORG 10172 injection. ORG 10172 promoted a much smaller release of lipoprotein lipase as compared with heparin. The effect of ORG 10172 on plasma factor Xa activity (one measure of its action) was described by a biexponential decay with a mean distribution half-life of 2.34 (s.e. mean 0.16) h and mean disposition half-life of 17.6 (s.e. mean 1.1) h. It thus has a much longer duration of effect than heparin. There was a linear relationship of plasma anti-Xa response to increasing dose although there was some variability only partly explained by differences in body weight or surface area. ORG 10172 administration by bolus intravenous injection was well tolerated and there was no evidence of adverse effects on clinical chemistry or haematology tests.
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PMID:ORG 10172: a low molecular weight heparinoid anticoagulant with a long half-life in man. 360 28

Low molecular weight heparin (LMWH) and standard heparin were given intravenously to six healthy subjects receiving a continuous infusion of Intralipid. After infusion, antifactor Xa, antithrombin II and coagulation activity (Normotest) were the same for both heparins. Activated partial thromboplastin time increased significantly, but the increase was much higher after standard heparin (+473%) than after LMWH (+48%). The increase in lipoprotein lipase activity was less pronounced after LMWH infusion. This resulted in a smaller decrease in Intralipid-triglyceride concentration and a smaller increase in both plasma FFA concentration and Intralipid fractional removal rate compared to standard heparin. This study shows that the plasma lipolytic potential of LMWH is weaker than that of standard heparin when given in doses with equipotent anticoagulation. LMWH may therefore be preferable to standard heparin as an antithrombotic agent in clinical situations where a high plasma lipolytic activity may be disadvantageous.
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PMID:Lipolytic and anticoagulant activities of a low molecular weight fragment of heparin. 393 Feb 57

Fluorescein-labelled sulodexide pharmacokinetics and urinary excretion were studied in the rat after intravenous administration. The compound showed a pharmacokinetic pattern similar to that of heparin and the plasmatic levels were linearly correlated with anti-factor Xa activity and logarithmically with lipoprotein lipase activation. The compound is well eliminated by urinary route; the urinary recovery was 50% in 24 h and 67% 48 h after administration. The results obtained indicate that fluorescein labelling of glycosaminoglycans may be a valid tool for pharmacokinetics and distribution studies in the laboratory animals.
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PMID:Pharmacokinetics and distribution of a fluoresceinated glycosaminoglycan, sulodexide, in rats. Part I: Pharmacokinetics in rats. 407 5


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