Heparin action

The agents like protamine sulfate react with the strongly acidic groups of heparin and can abolish its anticoagulant activity. Approximately 1 mg of protamine sulfate neutralizes 80 to 100 units of heparin. It is used only in severe bleeding or when heparin action needs to be terminated rapidly e.g. after cardiac or vascular surgery. 

Some Approaches to Increase the Efficiency of Immobilized Heparin Action... 

Adverse effects. When bleeding is induced by heparin, the heparin action can be instantly reversed by protamine. Against fractionated heparins and fondaparinux, protamine is less or not effective. Heparin-induced thrombocytopenia type II (HIT II) is a dangerous complication. It results from formation of antibodies that precipitate with bound heparin on platelets. The platelets aggregate and give rise to vascular occlusions. Because of the thrombocytopenia, hemorrhages may occur. Fondaparinux is also contraindicated in HIT II. 

It must be emphasized that the relationships between anticoagulant activities and r" (Fig 4) and activation entropy (Fig 5) are strictly empirical. Nevertheless, the existence of an underlying physical basis is consistent with models of heparin action. As summarized by Laurent and coworkers (I.) heparin promotes the interaction between thrombin and antithrombin which are bound to the same heparin chain. In this respect the heparin can be considered as a catalyst, and, as discussed above, its role in this process and fluorescence fading may well be quite analogous. A number of authors have shown that heparin Induces conformational changes in antithrombin or, possibly, in the serine proteases of the coagulant cascade, and that this leads to an increase in the rate of inactivation of the serine protease by antithrombin. Our... 

In viw PAI and antithrombin are stabilized in their active forms by binding to vitronectin and heparin, respectively. These two serpins seem to have evolved what Max Perutz has called "a spring-loaded safety catch" mechanism that makes them revert to their latent, stable, inactive form unless the catch is kept in a loaded position by another molecule. Only when the safety catch is in the loaded position is the flexible loop of these serpins exposed and ready for action otherwise it snaps back and is buried inside the protein. This remarkable biological control mechanism is achieved by the flexibility that is inherent in protein structures. 

Hirsh J, Warkentin TE, Shaughnessy SG et al (2001) Heparin and low-molecular-weight heparin mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 119(Suppl.) 64S-94S... 

Discuss the uses, general drug actions, adverse reactions, contraindications, precautions, and interactions of warfarin, heparin preparations, and the thrombolytic drugs. 

Heparin and warfarin are widely used in the treatment of thrombotic and thromboembolic conditions, such as deep vein thrombosis and pulmonary embolus. Heparin is administered first, because of its prompt onset of action, whereas warfarin takes several days to reach full effect. Their effects are closely monitored by use of appropriate tests of coagulation (see below) because of the risk of producing hemorrhage. 

The multiple effects of UFH on the coagulation cascade may increase its potential to cause hemorrhage." Anticoagulants with more specific sites of action may confer a better safety profile. Two such anticoagulants are low-molecular-weight heparin (LMWH) and heparinoids. 

Mechanism of action of unfractionated heparin, low-molecular-weight heparin (LMWH), and fondaparinux. (Reproduced from Haines ST, Zeolla M, Witt DM. Venous thromboembolism. In DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy ... 

The concept that different structural domains on the heparin chains are principally involved for optimal activity in the foregoing interactions could not be perceived in early work on structure-activity correlations, because the activity of heparin has been most frequently evaluated only with whole-blood-clotting tests (such as the U.S.P. assay). Development of assays for specific clotting-factors (especially Factor Xa and thrombin) has permitted a better insight into the mechanism of action of heparin at different levels of the coagulation cascade. 

Rosenberg R. D., Damus P. S. The purification and mechanism of action of human antithrom-bin-heparin co-factor. J Biol Chem 1973 248,6490-505. 

Some active materials are carriers for drugs (drug delivery systems), some have immobilized peptides to enable cell adhesion or migration, some are degradable by hydrolysis or by specific enzyme action. Some contain bioactive agents (e.g., heparin, thrombomodulin) to prevent coagulation or platelet activation while others incorporate bioactive groups to enhance osteo-conduction. Many include polyethylene oxide to retard protein adsorption and this is perhaps the closest we have come to a kind of inertness. 

A 39-year-old pregnant female requires heparin for thromboembolic phenomena What is the mechanism of action of heparin ... 

Capacitative Ca2+ entry is the predominant mode of regulated Ca2+ entry in nonexcitable cells but it also occurs in a number of excitable cell types. This pathway of Ca2+ entry is usually associated with the activation of phospholipase C, which mediates the formation of IP3 (see Ch. 20). Intracellular application of IP3 mimics the ability of hormones and neurotransmitters to activate calcium ion entry, and activation of calcium ion entry by hormones and neurotransmitters can be blocked by intracellular application of low-molecular-weight heparin, which potently antagonizes IP3 binding to its receptor. There is considerable evidence for the presence of an IP3 receptor in the plasma membrane of some cells types. 1(1,3,4,5)P4, a product of IP3 phosphorylation, has been shown in some cells to augment this action of IP3 in activating PM calcium ion entry, but in others IP3 alone is clearly sufficient. 

However, the current view of the regulation of calcium ion entry into the cytoplasm by PLC-linked stimuli holds that activation occurs not as a direct result of the action of IP3 on the plasma membrane but indirectly, as a result of depletion of calcium ions from an intracellular store by IP3 [14]. In the context of this capacitative model , the actions of intracellularly applied IP3 and heparin reflect the effects of these maneuvers on intracellular release process from ER into cytosol, rather than via the plasma membrane. The reported actions of I(1,3,4,5)P4, if in fact they do represent physiological control mechanisms, may reflect an ability of I(1,3,4,5)P4 to augment the calcium-releasing ability of IP3, rather than a distinct and... 

The use of full-dose unff actionated heparin in the acute stroke period has not been proven to positively affect stroke outcome, and it significantly increases the risk of intracerebral hemorrhage. Trials of low-molecular-weight heparins and heparinoids have been largely negative and do not support their routine use in stroke patients. 

Bulbring E, T omita T 1969 Effect of calcium, barium and manganese on the action of adrenaline in the smooth muscle of the guinea-pig taenia coli. Proc R Soc Lond B Biol Sci 172 121-136 Marchant JS, Taylor CW 1998 Rapid activation and partial inactivation of inositol trisphosphate receptors by inositol trisphosphate. Biochemistry 37 11524-11533 Somlyo AV, Horiuti K, Trentham DR, Kitazawa T, Somlyo AP 1992 Kinetics of Ca2+ release and contraction induced by photolysis of caged D-myo-inositol 1,4,5-trisphosphate in smooth muscle the effects of heparin, procaine, and adenine nucleotides. J Biol Chem 267 22316-22322... 

The cholinesterase-inhibiting activity of the phosphorofluoridates was compared quantitatively with that of eserine sulphate thus. To 0-2 ml. of heparinized human plasma was added 05 ml. of a solution containing either eserine or the phosphorofluoridate in varying concentrations then the mixture was kept at room temperature for 10 min. before 1 /tg. of acetylcholine in 1 c.c. saline solution was added. After 5 min. at room temperature, the mixture was made up to 10 ml. with frog saline containing eserine 1/100,000, which at once stopped the action of any cholinesterase not yet inactivated. The solution was then assayed for acetylcholine on the frog rectus-muscle preparation. 

It is likely that the predominantly positively charged amino acids of TAT and other CPPs will interact with anionic components on the surface of the cell membrane (85). This idea is supported by the observation that cell association with CPP liposomes in glycosaminoglycan-deficient Chinese hamster ovary (CHO) cells is greatly reduced and is competitively inhibited by the presence of heparin (88,93). Furthermore, the removal of the heparan sulfate chains by the action of glycosaminoglycan lyase also suppressed the transduction of the TAT protein (94). 

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