INDUCTION OF THE ACUTE-PHASE REACTION INCREASES HEPARIN-BINDING PROTEINS IN PLASMA

We have previously demonstrated that the nonspecific binding of unfrac tionated heparin (UFH) to plasma proteins has a marked modulating effe ct on its anticoagulant activity. Since some heparin-binding proteins are also acute-phase-reactant proteins, we explored the possibility th at the induction of the acute-phase response can increase the plasma c oncentrations of heparin-binding proteins. The recovery of a fixed amo unt of UFH or low-molecular-weight heparin (LMWH) added in vitro to ra t plasma samples obtained at various time intervals after the administ ration of intravenous endotoxin or subcutaneous turpentine was compare d with that of saline-treated control animals. The anti-factor Xa acti vity was measured in the plasma samples before and after the addition of a chemically modified low-affinity heparin (LAH) to displace the pr oportion of the added heparin that is reversibly bound to plasma prote ins. Our results show that at 6 hours post-endotoxin and at 24 hours p ost-turpentine treatment, virtually no anti-factor Xa activity could b e measured in the plasma samples, while the expected levels were obtai ned for control plasma. After the addition of LAH to displace protein- bound UFH, essentially the same anti-factor Xa levels were measured in the plasma from all three treatment groups. These results indicate th at induction of the acute-phase reaction can dramatically increase the levels of heparin-binding proteins in rat plasma. In addition, we com pared the anti-factor Xa recovery of UFH with that uf an LMWH from the plasma of endotoxin-and saline-treated rats and demonstrated that LMW H binds less to plasma proteins than UFH, even in plasma in which the levels of heparin-binding proteins are markedly elevated. The recovery of a fixed amount of UFH added in vitro to human plasma from septic p atients was also reduced, but not to the same extent as seen In rat pl asma. Removal of candidate heparin-binding and acute-phase proteins by immunodepletion indicated that vitronectin plays an important role in the nonspecific binding of UFH in patient plasma.