Abstract
We investigated the effect of histidine-rich glycoprotein (HRG) and platelet factor 4 (PF4) on the antithrombin III (ATIII) cofactor action of parnaparin sodium (LHG), a type of low molecular weight heparin (LMWH), and unfractionated heparin. The anti-Xa actvity of both LHG and heparin was inhibited by these proteins, but the degree of inhibition was significantly less in case of LHG. In contrast, the anti-thrombin actvity of both LHG and heparin was inhibited to almost the same degree by these heparin-neutralizing proteins. Moreover, studies with crossed immunoelectrophoresis of ATIII revealed that both HRG and PF 4 more strongly inhibited the complex formation between heparin and ATIII compared to that of LHG and ATIII. These findings show that HRG and PF 4 inhibit the ATIII cofactor activity of larger size heparin molecules. In addition, the inhibitory action of HRG and PF 4 on the anti-Xa activity of the fraction of LHG with high affinity for ATIII (HA-LHG) was reduced by the low-affinity fraction (LA-LHG). Therefore, this shows that while the LA-LHG itself is “inactive”, it plays an important role in protecting the “active” molecules from heparin neutralizing proteins. LHG has a longer half-life compared to heparin and has been demonstrated to possess sustained anticoagulant activity. Since LHG is less affected by proteins like HRG and PF 4 compared to heparin, the anticoagulant activity can probably be thought of as one of its results.
