Heparin binding properties of human histidine-rich glycoprotein. Mechanism and role in the neutralization of heparin in plasma.
Human histidine-rich glycoprotein was found to interact strongly with heparin both in purified systems and in plasma, resulting in neutralization of the anti-coagulant activity of heparin. In purified systems, histidine-rich glycoprotein and heparin react with apparent 1:1 stoichiometry to form a complex with a dissociation constant of 7 nM. Covalent heparin-antithrombin complex still reacts with histidine-rich glycoprotein to form a complex with a dissociation constant of 29 nM. The interaction between a Mr = 4300-heparin fragment and histidine-rich glycoprotein appeared to be more complex. The mechanism of the interaction between histidine-rich glycoprotein and heparin appeared to be different from that between antithrombin III and heparin, since the former is abolished by EDTA and occurs both with heparin molecules having a high affinity or a low affinity for antithrombin III. In plasma, histidine-rich glycoprotein efficiently counteracts the anticoagulant activity of heparin. Both the thrombin times and the activated factor X inhibition following addition of heparin are markedly prolonged in the absence of histidine-rich glycoprotein and shortened by addition of purified histidine-rich glycoprotein. Low affinity heparin was found to efficiently compete with high affinity heparin for binding to histidine-rich glycoprotein but not to antithrombin III. This results in an increased anticoagulant activity of high affinity heparin in the presence of low affinity heparin. Since the effect of histidine-rich glycoprotein on the anticoagulant properties of heparin is clearly demonstrated in normal plasma, it may be of clinical significance.
D001798:Blood Proteins; D002413:Cations, Divalent; D006493:Heparin / Q000097:blood*; D006801:Humans; D007123:Immunoelectrophoresis, Two-Dimensional; D007700:Kinetics; D011485:Protein Binding; D011506:Proteins / Q000302:isolation & purification; D000099053:Histidine-Rich Glycoprotein
D001798:Blood Proteins; D002413:Cations, Divalent; D011506:Proteins; D000099053:Histidine-Rich Glycoprotein; D006493:Heparin