Heparin binds reversibly to its target sites of action, antithrombin and the other serine proteases involved in coagulation, especially activated factor X. It also binds to other plasma proteins, including fibrinogen, plasmin, albumin, and lipases. The volume of distribution of heparin is then, under most circumstances, limited to the plasma volume. Heparin has a very short half-life, about 1.5 hours, which is dose-dependent and varies with the assay method employed for its measurements. It is not eliminated enzymatically nor by glomerular filtration or renal tubular secretion. In all likelihood, the anticoagulant is transferred to reticuloendothelial cells, which may also provide the means for its degradation. Many of the difficulties inherent in assessing the kinetic properties of heparin, as well as its clinical efficacy, may be attributed to: (1) its molecular heterogeneity; (2) its wide spectrum of binding sites and their respective kinetic properties and dissociation constants; (3) differences among methods for measuring heparin effect and concentration; (4) the dose dependence of the drug's half-life; (5) variation in patient response to heparin; (6) the specific cation associated with it; and (7) the presence of hypercoagulation syndromes associated with deficits of antithrombin. Neither renal nor hepatic disease, nor the biological tissues from which heparins are extracted commercially, seem to influence the drug's kinetic properties as much as variations in clearance and response to heparin among individual patients. Many comparisons among available studies are difficult because of the wide variation in the assay methods employed in them. It would appear that optimum therapy with heparin can be achieved only when the individual patient's response to, and rate of elimination of, heparin are taken into account concurrently.

SYNOPSIS Difficulties in evaluating the anticoagulant effect of heparin led to studies of the rate of disappearance of its effect on the whole body partial thromboplastin time, and of its simultaneously bioassayed plasma concentration. The slope of the anticoagulant's dose-effect curve varied with each subject's baseline coagulation status, which probably accounts for the wide range of clinically observed responses to the drug. The mean rate of disappearance of bioassayed heparin was less than the mean rate of disappearance of the drug's effect on the clotting time, probably because of heparin's extensive binding to the plasma proteins which comprise its site of action. That these two kinds of rate of disappearance were found not to be correlated may also reflect the proteinbinding capacity of heparin.

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