THE VARIABLE ANTICOAGULANT RESPONSE TO UNFRACTIONATED HEPARIN IN-VIVOREFLECTS BINDING TO PLASMA-PROTEINS RATHER THAN CLEARANCE

The anticoagulant response to fixed doses of unfractionated heparin is variable in patients with acute illness, and some patients with venou s thromboembolism require high doses of heparin to achieve a therapeut ic anticoagulant response. To investigate the mechanism responsible fo r the variable anticoagulant response to heparin in acute illness, hep arin clearance and nonspecific protein binding were compared in contro l and endotoxin-treated rabbits. The plasma half-life (t(1/2)) of radi olabeled heparin increased in a dose-dependent fashion. At all doses o f heparin studied, the t(1/2) of radiolabeled heparin was unaffected b y experimental endotoxemia when compared with control animals. In cont rast, the amount of heparin recovered was lower in the plasma of endot oxemic animals because of increased binding to plasma proteins. A chem ically modified heparin with low affinity for antithrombin ill was add ed ex vivo or in vivo to displace heparin bound nonspecifically to pla sma proteins. The proportion of heparin bound to plasma proteins was s ignificantly greater in the plasma of endotoxemic animals than in cont rols. These findings indicate that acute inflammation alters heparin r ecovery but does not affect heparin clearance. The variability of the anticoagulant response to heparin seen in patients with thromboembolis m may, in pad, be due to this effect of the underlying disease process .