Biomedical subjects
Publications and source records attributed to T C Laurent.
The inactivation of thrombin and factor Xa by antithrombin was determined in the presence of heparin fractions of different molecular weights and with high affinity for antithrombin. The ability to potentiate the inactivation of either coagulation factor increased with increasing length of the polysaccharide chain.
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It is proposed that the anti-coagulant activity of heparin is related to the probability of finding, in a random distribution of different disaccharides, a dodecasaccharide with the sequence required for binding to antithrombin. It is shown that this probability is a function of the degree of polymerization of heparin. The hypothesis has been been tested with a series of narrow-molecular-weight-range fractions ranging from 5,600 to 36,000. The fractions having mol.wts. below 18,000 (comprising 85% of the original preparation) followed the predicted probability relationship as expressed by the proportion of molecules capable of binding to antithrombin. The probability that any randomly chosen dodecasaccharide sequence in heparin should bind to antithrombin was calculated to 0.022. The fraction with mol.wt. 36,000 contained proteoglycan link-region fragments, which may explain the deviation of the high-molecular-weight fractions from the hypothetical relationship. The relationship between anti-coagulant activity and molecular weight cannot be explained solely on the basis of availability of binding sites for antithrombin. The activity of high-affinity heparin (i.e. molecules containing high-affinity binding sites for antithrombin), determined either by a whole-blood clotting procedure or by thrombin inactivation in the presence of antithrombin, thus remained dependent on molecular weight. Possible explanations of this finding are discussed. One explanation could be a requirement for binding of thrombin to the heparin chain adjacent to antithrombin.
It is demonstrated that exclusion phenomena appear to dominate the interaction of dextran with albumin in aqueous solution. The enthalpic contribution to the interaction coefficient describing dextran/albumin mixtures is small, although its determination was subject to considerable error. These results support the earlier assumptions of the type of interaction between the two polymers. The conclusions are primarily based on the interpretation of the temperature-dependence of the interaction coefficient, as measured by light-scattering in the temperature range 6--33 degrees C. Enthalpy of dilution measurements of dextran/albumin mixtures by microcalorimetry were in qualitative agreement with the light-scattering data.
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Insoluble collagen from human dermis was equilibrated in a physiological medium with mixtures of 3H2O and fluorescein-conjugated dextrans of different molecular weights. Dextrans of mol.wts. greater than 10(5) were excluded from a volume of 3.82+/-0.87 ml(S.D.) per g of collagen; dextrans of lower molecular weight occupied a larger volume. The apparent excluded volume was proportional to the weight of the collagen. Dansylated albumin behaved similarly to dextran; the polymeric collagen from rat skin exhibited a much larger excluded volume than the insoluble collagen. These results indicated that the volume available to the plasma proteins in human dermis was limited by insoluble collagen as well as by the glycosaminoglycans of the tissue.
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A free-diffusion method has been developed for the determination of the intradiffusion coefficient ('self-diffusion coefficient') of a polymer in highly concentrated solutions. A fraction of the polymer is labelled with a small amount of light-absorbing substituent. The diffusion of this labelled species, present in low concentration, is followed in the presence of a high concentration of unlabelled material with the aid of absorption optics in the analytical ultracentrifuge. The diffusion proceeds over a boundary at which the difference in concentration of unlabelled material is varied. The average concentration of total polymer and the concentration of the labelled material are, however, constant. From theoretical considerations it is shown that by extrapolation of the diffusion coefficient so obtained to zero concentration difference of total material, the intradiffusion coefficient of the polymer at that concentration is obtained. The procedure also permits the ordinary translational diffusion coefficient to be estimated. The method has been applied to two dextran fractions with weight-average molecular weights of 19000 and 150000, which were labelled with fluorescein groups. As expected, the intradiffusion coefficient decreases with increasing polymer concentration, the decrease being more pronounced for the high-molecular-weight material. This decrease in the diffusion rate of dextran is, however, less than the corresponding decrease in the sedimentation rate which proteins with similar hydrodynamic parameters experience in dextran solutions. This agrees with the hypothesis that flexible linear polymers move through a network as chains rather than as hydrodynamic spheres. By combining measurements of the ordinary diffusion coefficient and the intradiffusion coefficient, it is possible to calculate the thermodynamic properties (as expressed by the virial expansion) of the system. This method is of particular importance in studies on concentrated solutions of high-molecular-weight polymers.
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A method is reported for the measurement of the diffusion coefficients in water of some sparingly soluble gases. The results obtained for the diffusion coefficients of oxygen and nitrogen gas through water at 25 degrees C are 2.12. 10-5 and 2.61 . 10-5 cm-2 . s-1, respectively. A check on the accuracy of the teachnique using tritiated water as the diffusing substance gave a value of 2.15 . 10-5 cm-2 . s-1 which agrees within 3% with recent values from the literature. The method was applied to the measurement of oxygen, nitrogen, and tritiated water diffusion coefficients through agarose gels and through agarose gels containing hyluronate. The results indicate that the hyaluronate had only a small effect as a barrier to the diffusion of such low molecular weight substance.