Heparin and its derivatives are known to regulate a variety of pathophysiological events related to vascular biology. In the present manuscript we examine a variety of heparinomimetics biochemically (electrophoretic behavior and enzymatic degradation) and pharmacologically (in vitro
anticoagulant activity and in vivo hemorrhagic and antithrombotic tests) as well as their interactions with cells from the vessel wall using a time resolved fluorometric method and confocal microscopy. Data were determined for
unfractionated heparin (UFH),
enoxaparin, synthetic
heparin pentasaccharide, C3
heparin derived
oligosaccharides and phosphosulfomannan (PI-88). While being structurally distinct from UFH, all compounds exhibited
anticoagulant, antithrombotic and hemorrhagic activities. In addition, besides the pentasaccharide, they all stimulated the synthesis of an antithrombotic
heparan sulfate present at the cell surface and secreted by endothelial cells. Also, like UFH, they interacted with both endothelial and smooth muscle cells and dislodged UFH from its binding sites in a dose dependent manner but, with distinct saturable curves showing that the binding of polymeric structures to extracellular matrix (ECM)
proteins does not depend on a
glycosaminoglycan backbone. The data also suggest a common pathway, which does not depend on the presence of the conventionally accepted
antithrombin binding pentasaccharide, for ECM dependent activity of the heparinomimetic stimulated synthesis of antithrombotic
heparan sulfate. Notably, although of similar molecular weight as well as polymeric backbone, the synthetic
heparin pentasaccharide showed significant hemorrhagic action and negligible antithrombotic activity in a
venous thrombosis model, contrasting with C3, that displayed negligible hemorrhagic effect and potent antithrombotic action. These results provide evidence that structurally unrelated
polymers can elicit similar
hemostatic activities and show that polymeric sequence is not always crucial for certain activities. The results also suggest that non-GAG structures may provide an alternative route for the
pharmaceutical control of hemostasis.