Pharmacodynamics and Clinical Effectiveness of Heparin

Abstract

It has been generally assumed that the clinical use of heparin is simply an extension of the initial laboratory use to prevent blood coagulation in test tubes and cannulae. Here the effects of mixing heparin with blood appear to be the same in vivo and in vitro. Evidence was obtained early that this was an oversimplification of the situation and the large amount of data that has now accumulated calls for a reevaluation of this basic assumption in a number of aspects which bear on the clinical use of this important drug. DISSIMILARITY BETWEEN IN VIVO and IN VITRO EFFECTS OF HEPARINThe most clear-cut demonstration that the effects of heparin in vivo are not the same as those when this drag is added to blood in vitro is the appearance of enzymes in the general circulation which were not present in significant amounts before injection of the drug-e.g., lipoprotein lipase [70] and diamine oxidase [15], also known as histaminase. This dissimilarity was early indicated for the effect of heparin on thrombosis when compared with coagulation tests in vitro. Solandt and Best [103], in the initial paper to report the use of heparin in an extracorporeal circulation, measured the effectiveness of heparin in preventing platelet thrombi in glass chambers inserted in arteriovenous shunts in dogs. Immediately after the injection of heparin, the clotting time reached infinity (the blood became incoagulable), as was the case when a comparable amount of heparin was added to the blood outside the body. However, formation of thrombi was not prevented until 20-60 minutes after the injection. When the clotting time had again become measurable 2-7 hours later, thrombus formation did not occur. It was not for yet another hour (when the clotting time was essentially normal) that accumulation of platelets and formation of thrombi occurred again in the shunt. Hence, the anticoagulant effect and the prevention of thrombus formation appeared to be two distinct properties of heparin.

Endothelial Cell Physiology, Perturbations and Responses

“…This important anticoagulant is bound to the endothelial cell surface [109]. Its slow release from this storage site is the basis for the effectiveness of low dose heparin therapy.…”

Endogenous Heparin

“…In the Figure given on pp 304-6 by Jaques and Mahadoo [47] one can distinguish functionally three types of cells containing granules staining metachromatically with toluidine blue. These are (a) the normal basophils which contain chondroitins A/C, (b) tissue mast cells which probably contain approximately equal proportions of chondroitins A/C and heparin, (c) RES cells which contain heparin.…”

“…As indicated in the Figure just discussed, mast cell granules are little affected by the administration of heparin. When heparin is released from rat peritoneal mast cells, the metachromatic granules are taken up by macrophages and are rapidly digested [32,81], whereas commercial heparin is taken up by the reticuloendothelial system and remains there, being dealt with as are other electronegative colloids [47]. Endogenous heparin (released from mast cells) and exogenous commercial heparin are therefore treated differently.…”

“…The further different disposal of the mast cell granules by destruction of the granules in the macrophage must be due to the contents of the granule or due to activation of the macrophage. Macrophage activation occurs when commercial heparin is added to the tissue culture medium in which macrophages are growing [47,89]. It is possible that this is another activity which, like lipoprotein lipase activation, changes with molecular size, so that the macromolecular heparin released from the mast cell may result in a different activation.…”

“…It is possible that this is another activity which, like lipoprotein lipase activation, changes with molecular size, so that the macromolecular heparin released from the mast cell may result in a different activation. Metabolism and excretion of heparin appears to follow different routes, depending on the nature of binding; i.e., antithrombin-active chains combined with antithrombin undergo N-desulfation, etc., while inactive and active chains combined with other plasma proteins, such as fibrinogen, undergo O-desulfation [47]. When released from mast cell granules, heparin will probably remain combined with the basic proteins of the granules.…”