Heparin with plasma protein

Heparinoids and mucopolysaccharides react with, and modify, many of the plasma proteins. Heparin combines with fibrinogen, globulins and albumin. As judged by electrophoresis and various types of analysis and staining, the particular plasma protein components with which heparin combines are dependent upon the concentration of protein, concentration of heparin, pH value, and salts present. This explains the somewhat contradictory statements in literature about combinations of heparin with plasma proteins. The combination may result in change of solubility of the protein and reverse protein tests . Heparin can modify the murexide reaction for calcium in serum by affecting the calcium-protein-heparin complex. Many heparinoids... 

Heparin has been reported to complex with a variety of basic species, including biogenic amines and drugs for reviews, see Refs. 10 and 391. For its possible relevance to the pharmacological properties of heparin and complexed species, mention is made here of complexes with histamine392,393 and anthracycline antibiotics.394 C.d. studies on the interaction of basic homopolypeptides with heparin and other glycosaminogly-cans have shown that heparin is able to induce an ordered, helical conformation in the polypeptide.395 397 Similar, and even more dramatic, effects were observed with mixed basic polypeptides, presumed to represent better models for the biologically relevant interactions with plasma proteins.368... 

Hence, concerning the interaction with plasma proteins, covalently immobilized heparin performs identically to heparin in solution, and this results in the enrichment of the HCP surface with the most thrombogenic plasma components fibrinogen and thrombin. 

In this article it is shown that a completely antithrombogenic surface can be obtained from synthetic polymers without any help of bioactive polymers as heparin and urokinase. Such a surface has a diffuse structure, which essentially differs from that of so-called hydrogels which have a relatively low water content. There is no reason to suspect that the interaction of the polymer surface with plasma proteins initiates a series of complex biochemical events leading to thrombus formation. Rec i% it has been reported that even if proteins deposit on a material to a multilayer, the proteins at the outermost layer of multi-layered protein deposit might remain intact, which would eventually prevent platelet adhesion... 

Essentially as a result of its ability to bind to basic sites, heparin interacts with many proteins.398 Although most of these interactions (such as that with protamine, a basic protein frequently used to neutralize heparin399) are probably not of biological significance, binding to plasma proteins and to proteins exposed on the surface of endothelial cells has an important influence on the circulation system. 

The increased bioavailability of LMWHs together with their limited interactions with platelets and other plasma proteins lends itself to once-a-day dosing, in contrast to two or more injections needed with conventional heparin. Thus, unlike conventional heparin, which needs frequent monitoring with the activated partial... 

Heparin is a carbohydrate-based (glycosaminoglycan) anticoagulant associated with many tissues, but mainly found stored intracellularly as granules in mast cells that line the endothelium of blood vessels. Upon release into the bloodstream, heparin binds to and thereby activates an additional plasma protein, namely antithrombin. The heparin-antithrombin complex then binds a number of activated clotting factors (including Ha, IXa, Xa, XIa and Xlla), thereby inactivating them. The heparin now disassociates from the complex and combines with another antithrombin molecule, thereby initiating another turn of this inhibitory cycle. 

Table 7. Elution of heparin from the surface of polypropylene with the solutions of plasma proteins, 25 C, time of incubation 30 min65 ...

The more profound and extensive effect of immobilized heparin on the blood clotting system observed in the presence of immobilized trypsin is due to the tryptic lysis of the protein constituents of the complexes of immobilized heparin with the most thrombogenic plasma proteins (thrombin and fibrinogen) (Fig. 11). 

Heparin can be attached to a variety of surfaces by means of complex formation with quaternary ammonium salts. Depending on the method used to attach heparin, the resulting surfaces may or may not release heparin when contacted with blood plasma. The removal of heparin from surfaces by plasma protein fractions was studied and it was found that alpha-globulins removed greater amounts than any other fraction. Heparinized surfaces adsorb proteins when exposed to blood or plasma. However, with the possible exception of thrombin, there is no consistent pattern of protein adsorption which can be related to their nonthrombogenicity. 

An important factor in the interaction of foreign surfaces with blood is the rapid adsorption of plasma proteins onto such surfaces when they are exposed to blood (4). For this reason the adsorption of radioactively tagged blood components on heparinized and unheparinized surfaces was measured. Proteins were dissolved in approximate physiological concentrations in a buffered (pH 7.35) physiological saline solution and the solutions were exposed to the test surfaces for 2 hours at 37 °C. in a static system. After the exposure, the surfaces were rinsed with physiological saline and distilled water and then dried. The amount of protein on the surfaces was determined in a 27r-gas flow proportional counter (7). As shown in Table III, although both heparinized surfaces were nonthrombogenic, there is no consistent pattern of either increased or decreased adsorption of the proteins caused by the heparinization. In-... 

Pharmacokinetics. Heparin is poorly absorbed from the gastrointestinal tract and is given i.v. or S.C. once in the blood its effect is immediate. Heparin binds to several plasma proteins and to sites on endothelial cells it is also taken up by cells of the reticuloendothelial system and some is cleared by the kidney. Due to these factors, elimination of heparin from the plasma appears to involve a combination of zero-order and first-order processes, the effect of which is that the plasma biological effect alters disproportionately with dose, being 60 min after 75 units per kg and 150 min after 400 units per kg. 

Different high molecular mass affinity ligands were successfully immobilized to monolithic disks.Monolithic disks with immobilized heparin and collagen were used for the purification of membrane proteins and annexins. The heparin unit was also used in the quality control of the preparation of the plasma proteins Antithrombin 111 and clotting Factor IX. Purification of IgG was successfully performed by immobilizing Protein... 

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