Heparin molecules

Polysaccharides can regulate weak interactions between protein molecules. A recent example is the effect of low molecular weight heparin molecules on the weak dimerisation of the plasminogen growth factor NKl, or at least a mutant thereof [135]. 

Fig. 20 Modular resilin-like polypeptide containing domains conferring elastomeric properties, heparin molecule interaction, cell adhesion, and matrix metalloproteinase (MMP) proteolysis. Lysine residues are encoded periodically to permit crosslinking...

The anticoagulant effect of UFH is mediated through a specific pentasaccharide sequence on the heparin molecule that binds to antithrombin, provoking a conformational change. The UFH-antithrombin complex is 100 to 1,000 times more potent as an anticoagulant than antithrombin alone. 

Fondaparinux sodium is the first of a new class of direct-acting antithrombin agents. The anticoagulant activity of heparin depends on the binding of ATIII to a critical pentasaccharide sequence within the heparin molecule. This results in a change in the conformation of AITII. This leads to the inhibitory effect of ATIII on factor Xa, which activates the conversion of prothrombin to thrombin. Fondaparinux is a synthetic pentasaccharide identical to the ATIII-binding site of heparin. 

Heparin is most tightly bound to a polymeric material when immobilized via covalent bonding. The heparin molecules contain hydroxy, carboxy, sulfate, and amino groups which are all suitable for this purpose. However, heparin is soluble in water and form-amide only and is insoluble in organic solvents which presents a significant restriction for covalent conjugation of heparin. 

It seemed reasonable to anticipate that the synergism of these two features (high heparin content and stability of the resultant materials) would result in long-term thromboresistant polymers. The in vivo tests revealed, however, their extremely low thromboresistance as compared to the ionically bound heparin-containing polymers, in particular. The effect is assumed to be caused by a lack of sufficient mobility of the polymer-bound heparin molecules, which prevents the performance of the intrinsic anticoagulant properties of heparin. 

In all of the reported cases, anticoagulant activity of immobilized heparin, as was already stressed above, was less than the activity of heparin in solution, which was attributed to the low accessibility of heparin molecules for physiological substrates. Increasing the porosity of the polymer, i.e., increasing the accessibility of the immobilized heparin led to an increase in its anticoagulant activity 100). 

The permanency of the bonded heparin on a number of selected polymer systems has been measured using radiolabeled heparin (35S). It has been found that the loss of heparin after prolonged exposure to distilled water and isotonic saline at 37 °C. is almost negligible for heparinized polypropylene, silicone rubber, and Hydrin rubber. On the other hand, polypropylene loses 70% of its originally bound heparin after exposure to plasma for three hours. Hydrin rubber and silicone rubber lose only from 0 to 5%. The loss of heparin on the polypropylene may be attributed to displacement of the heparin molecules by a protein or combination of proteins. A series of experiments was performed in which... 

In order that the heparin remain biologically active after fixation to a polymer substrate, the covalent bond must be achieved via functional groups on the heparin molecule, which are non-essential for its biological activity. Further, the binding reaction should be performed under reaction conditions which themselves do not cause loss of the antithrombogenic character of the heparin. 

The drug danaparoid consists mostly of the heparinoid heparan sulfate. Its chains are composed of a part of the heparin molecule (indicated by blue color underlay). Its effect is mediated by AT III. 

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