PubMed · 72924
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K W Denson, C W Redman. 1977-11-12. Heparin-induced decrease in circulating antithrombin-III.. https://doi.org/10.1016/s0140-6736(77)92924-5
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Blanket serial controls are not necessary in low-dosage heparin treatment. It would, in any case, be difficult under normal clinical conditions and would run counter to the whole conception of low-dose heparin treatment. However, in problem cases with an increased thrombo-embolic risk, sensitive methods for monitoring the heparin effect are recommended. A study on 150 patients has indicated that the most sensitive method is the use of chromogenic substrates. Thrombin time, using low-concentration thrombin solution of 1.5 NIH units/ml, thrombelastogram and activated partial thromboplastin time are less sensitive. Antithrombin III levels should be determined in all cases of increased heparin tolerance. With reduced antithrombin III levels and higher body weight an increase of the standard dose from 5000 U.S.P. units heparin t. i. d. subcutaneously to 7500 U.S.P. units t. i. d. should be considered.
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Preparations of low molecular weight porcine heparin with an average specific anticoagulant activity of 94 units/mg were fractionated into "active" and "relatively inactive" forms of the mucopolysaccharide of approximately 6000 daltons each. The active fraction was further subdivided into various species with descending but significant affinities for the protease inhibitor as well as decreasing but substantial anticoagulatn potencies. "Highly active" heparin (approximately 8% of the low molecular weight pool) possesses a specific anticoagulant activity of 350 +/- 10 units/mg. The relatively inactive fraction (67% of the low molecular weight pool) exhibits a specific anticoagulant activity of 4 +/- 1 units/mg. The binding of highly active heparin to antithrombin is accurately described by a single-site binding model with a KHep-ATDISS of approximately 1 X 10(-7) M. Variations in this binding parameter secondary to changes in environmental variables indicate that charge-charge interactions as well as an increase in entropy are critical to the formation of the highly active heparin-antithrombin complex. The interaction of relatively inactive heparin with the protease inhibitor is characterized by an apparent KHep-ATDISS of 1 X 10(-4) M. In large measure, this is due to small amounts of residual active mucopolysaccharide (0.5%). The ability of the highly active heparin to accelerate the thrombin-antithrombin interaction was also examined. We were able to demonstrate that the mucopolysaccharide acts as a catalyst in this process and is able to initiate multiple rounds of enzyme-inhibitor complex formation. The rate of enzyme neutralization is increased to a maximum of 2300-fold as the concentration of heparin is raised until the inhibitor is saturated with mucopolysaccharide. Further increases in heparin concentration result in a reduction in the speed of enzyme neutralization. This appears to be due to the formation of thrombin-heparin complexes. A mathematical model is given which provides a relationship between the initial velocity of enzyme neutralization and reactant concentrations.