Interactions of heparins in the vascular environment.
Heparins are exposed in vivo to a complex environment containing heparin-binding proteins in solution, on the surface of cells and in the extracellular matrix. However, most studies of heparin binding have been carried out in simplified systems which fail to address the competition for binding resulting both from the different concentrations of constituent proteins and their relative affinities for heparin. In the blood heparin binds to platelets in a saturable, specific and reversible interaction which occurs in the presence of competing plasma proteins and which may be prothrombotic. Similar binding to monocytes and endothelial cells occurs but has not yet been confirmed in whole blood. Such interactions could inhibit coagulation resulting from generation of tissue factor activity and modulate endothelial responses which affect coagulation, fibrinolysis and cell growth as well as representing a physiologically significant anti-inflammatory function of heparin. Low-molecular-weight (LMW) heparins have lower affinities than unfractionated heparin for all cell receptors studied and are less likely to exert their effects through cellular interactions. In whole plasma in the absence of platelet release, antithrombin III was the most abundant protein bound to therapeutic doses of unfractionated heparin, and histidine-rich glycoprotein its only effective competitor, while both histidine-rich glycoprotein and vitronectin were potentially important modulators of LMW heparin activity. Sequestration of vitronectin and complement factor H by immobilised heparins could promote an effective defence against complement-mediated prothrombotic activity and cell damage under physiological conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
Dawes
J
J
Heart Research Institute, Sydney, Australia.
D000818:Animals; D001760:Bleeding Time; D001773:Blood Cells / Q000187:drug effects / Q000378:metabolism*; D001798:Blood Proteins / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D006493:Heparin / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007275:Injections, Intravenous; D010973:Platelet Adhesiveness / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000378:metabolism
D001798:Blood Proteins; D006495:Heparin, Low-Molecular-Weight; D011956:Receptors, Cell Surface; C037680:heparin receptor; D006493:Heparin