Clinical Pharmacokinetics of Heparin

Abstract

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.

ORG 10172: a low molecular weight heparinoid anticoagulant with a long half‐life in man.

“…bolus than that for ORG 10172. One interesting contrast is that nonlinear pharmacokinetic behaviour is now well established for heparin and an increasing halflife with increasing dose has been demonstrated in several species including man (Estes, 1980). Our data indicate that the ORG 10172 anti-Xa response in plasma is linearly dose-related and the kinetics of response to this material are apparently linear.…”

Antithrombin-heparin covalent complex reduces microemboli during cardiopulmonary bypass in a pig model

“…33 In order to subdue thrombi formation during CPB, ongoing heparin administration is maintained as a standard protocol. However, apart from limitations of a short intravenous half-life and variable anticoagulant response, 11,12 heparin's inability to inhibit clot-bound thrombin 13,14 reduces its capacity for microthrombi prevention. Application of large heparin dosing (usually 300-400 U/kg) and additional boluses to maintain suitable ACT response during CPB can potentially lead to bleeding complications during and after surgery.…”

“…UFH has a short, dose-dependent intravenous half-life and an unpredictable anticoagulant effect, mainly due to variable nonspecific plasma and cell surface protein binding. 11,12 UFH is also unable to inactivate surface-bound coagulation factors, such as fibrin-bound thrombin (protected from inactivation by the heparin/antithrombin [AT] complex), 13,14 and may activate platelets. 15 This inability to neutralize fibrin-bound thrombin makes UFH incapable of reducing fibrin-based thrombin generation leading to thromboemboli growth during CPB, since studies have shown that clot propagation is primarily due to the activity of clot-bound thrombin.…”

ECMO Biocompatibility: Surface Coatings, Anticoagulation, and Coagulation Monitoring

“…Heparin is cleared through two mechanisms. Low doses of heparin are rapidly cleared through a reticuloendothelial process, whereas higher doses which saturate these processes are cleared through the kidneys in a much slower fashion [57]. Additionally, heparin effects can be rapidly reversed through administration of a reversal agent, protamine sulfate, which is negatively charged and binds with UFH or LMWH to form a stable ionic pair preventing binding to AT3.…”