Heparin mechanisms

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... 

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. 

Protamine. Protamine, whose use to reverse heparin anticoagulation has increased over the last two decades, has also been incriminated. Reactions may involve a number of mechanisms including IgE, IgG and complement. The incidence of anaphylactic reactions is estimated at 0.19% (retrospective studies) and 0.69% (prospective studies), respectively [27]. 

All patients with a mechanical prosthetic heart valve should receive concomitant unfractionated heparin or a low molecular weight heparin in combination with warfarin pharmacotherapy until the INR is therapeutic and stable for two consecutive days... 

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. 

A major portion of TFPI is bound to the endothelial surface and can be released from the cells by heparin (28). Platelets contain very small amounts of TFPI, which are released when platelets are activated (29). Figure 6 illustrates the mechanism of inhibition by TFPI. 

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. 

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

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... 

Edelberg (E2-E4) extensively describes the interaction of Lp(a) with tPA-mediated plasminogen activation and the influence of heparin on this mechanism. Lp(a) inhibits this mechanism analogous to the direct activation of plasminogen by tPA on fibrin(ogen) by displacing heparin from the binding sites. 

Figure 3.19. Proposed mechanism for template-directed excimer formation, (a) No heparin (b) minimal heparin (CHEQ) (c) excess heparin (CHEF). (Reproduced from Ref. 25. Copyright 1990 American Chemical Society.)...

The syndecan family of heparin sulfate proteoglycans (HSPGs) plays critical roles in several signal transduction pathways, and syndecan 3 intramembrane proteolysis is presenilin/y-secretase dependent (357). COX2 and COXl potentiate ABP formation through mechanisms that involve y-secretase activity. Sulindac sulfide and other NSAIDs (ibuprofen, indomethacin, R-flurbiprofen) selectively decrease the secretion of ABP independently of COX activity, probably via y-secretase inhibition (358-360). Pepstatin A methylester, sulfonamides, and benzodiazepines can also act as potent, noncompetitive, y-secretase inhibitors (335). These are but a few examples of the potential repercussions and biochemical consequences that the pharmacological manipulation of secretases in AD may bring about. 

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