Binding of heparin to plasma proteins and endothelial surfaces is inhibited by covalent linkage to antithrombin.
Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are used for prophylaxis and treatment of thrombosis. However, UFH has a short plasma half-life and variable anticoagulant response in vivo due to plasma or vessel wall protein binding and LMWH has a decreased ability to inactivate thrombin, the pivotal enzyme in the coagulation cascade. Covalent linkage of antithrombin to heparin gave a complex (ATH) with superior anticoagulant activity compared to UFH and LMWH, and longer intravenous half-life compared to UFH. We found that plasma proteins bound more to UFH than ATH, and least to LMWH. Also, UFH bound significantly more to endothelial cells than ATH, with 100% of UFH and 94% of ATH binding being on the cell surface and the remainder was endocytosed. Competition studies with UFH confirmed that ATH binding was likely through its heparin moiety. These findings suggest that differences in plasma protein and endothelial cell binding may be due to available heparin chain length. Although ATH is polydisperse, the covalently-linked antithrombin may shield a portion of the heparin chain from association with plasma or endothelial cell surface proteins. This model is consistent with ATH's better bioavailability and more predictable dose response.
Chan
Anthony K C
AK
Henderson Research Centre, 711 Concession Street, Hamilton, ON, L8V 1C3, Canada. achan@thrombosis.hhscr.org
Paredes
Nethnapha
N
Thong
Bruce
B
Chindemi
Paul
P
Paes
Bosco
B
Berry
Leslie R
LR
Monagle
Paul
P
D000328:Adult; D000990:Antithrombin III / Q000378:metabolism*; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005312:Fetal Blood; D006493:Heparin / Q000378:metabolism*; D006495:Heparin, Low-Molecular-Weight / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D011485:Protein Binding
D001798:Blood Proteins; D006495:Heparin, Low-Molecular-Weight; D000990:Antithrombin III; D006493:Heparin