Interactions of Heparins in the Vascular Environment

Abstract

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 constitutent 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. In addition, the ability of immobilised heparin to bind fibronectin, vitronectin and fibrinogen in a plasma milieu may increase the exposure of these adhesive ligands and stimulate interaction with activated platelets through the α_IIb/β₃-integrin.

Influence of prolonged dalteparin treatment on coagulation, fibrinolysis and inflammation in unstable coronary artery disease

“…The biological mechanisms underlying the association of elevated tPA/PAI-1 or vWF and LMW heparin treatment are yet unknown. A possible explanation is direct effects on platelets and endothelial cells, both of which have binding sites for heparins [39]. The high levels of these markers might thus be related to the gradually decreasing efficacy after the 6 weeks of prolonged dalteparin treatment in the non-revascularized patients in the FRISC-II study [18].…”

Regulation of Urokinase/Urokinase Receptor Interaction by Heparin-like Glycosaminoglycans

“…We think that this apparent discrepancy may be explained on the basis of the privileged location of membrane-or ECM-associated HS. Indeed, on the cell surface and within the ECM, HP-like repeats of HS have the chance to interact not only with u-PA, but also with ␤ 1 integrins (40 -44), leukocyte integrin Mac-1 (45), fibronectin and laminin (46), collagens (47), and VN (48). Many of these proteins are essential components of the focal adhesions (49), where also u-PAR has been shown to be preferentially located (50).…”

Unfractionated Heparin: Multitargeted Therapy for Delayed Neurological Deficits Induced by Subarachnoid Hemorrhage

“…Similarly, the antiproliferative activity of heparin on smooth muscle is maximal in its high molecular weight component [130]. LMWHs have lower affinities than unfractionated heparin for all cell receptors studied and are less likely to exert their effects through cellular interactions [131, 132]. Rats subjected to temporary focal cerebral ischemia and that received unfractionated heparin show significantly better outcomes compared to animals receiving an equivalent dose of LMWH [133].…”