Heparins and Heparinoids: Occurrence, Structure and Mechanism of Antithrombotic and Hemorrhagic Activities

Abstract

The correlation between structure, anticlotting, antithrombotic and hemorrhagic activities of heparin, heparan sulfate, low molecular weight heparins and heparin-like compounds from various sources that are in used in clinical practice or under development is briefly reviewed. Heparin-like molecules composed exclusively of iduronic acid 2-O-sulfate residues have weak anticlotting activities, whereas molecules that contain both iduronic acid 2-O sulfate, iduronic acid and small amounts of glucuronic acid, such as heparin, or mixed amounts of glucuronic and iduronic acids (mollusk heparins) possess high anticlotting and anti-Xa activities. These results also suggest that a proper combination of these elements might produce a strong antithrombotic agent. Heparin isolated from shrimp mimics the pharmacological activities of low molecular weight heparins. A heparan sulfate derived from bovine pancreas and a sulfated fucan from brown algae have a potent antithrombotic activity in arterial and venous thrombosis model "in vivo" with a negligible activity upon the serine-proteases of the coagulation cascade "in vitro". These and other results led to the hypothesis that antithrombotic activity of heparin and other antithrombotic agents is due at least in part by their action on endothelial cells stimulating the synthesis of an antithrombotic heparan sulfate. All the antithrombotic agents derived from heparin and other heparinoids have hemorrhagic activity. Exceptions to this are a heparan sulfate from bovine pancreas and a sulfated fucan derived from brown algae, which have no hemorrhagic activity but have high antithrombotic activities "in vivo". Once the structure of these compounds are totally defined it will be possible to design an ideal antithrombotic.

A Catalytic Role of Heparin within the Extracellular Matrix

“…Studies on the ability of heparin to facilitate thrombin inactivation by antithrombin have also suggested that heparin possesses catalytic properties (11,(53)(54)(55)(56). In this case, heparin appears to act as a scaffold that brings together the two proteins to facilitate the formation of the complex.…”

“…Some studies suggest that mast cell heparin promotes mitosis and migration of endothelial cells (10). Moreover, the anticoagulant properties of heparin prevent the formation of thrombi in the newly formed vessels (11). Other studies show that heparin has the ability to inhibit tumor growth and metastasis (12)(13)(14)(15), and there is some evidence that it may do so through an indirect mechanism, by interfering with the interaction between fibroblasts and the adjacent tumor cells (16).…”

Structural and Hemostatic Activities of a Sulfated Galactofucan from the Brown Alga Spatoglossum schroederi

“…The sulfated galactofucan is 2-fold more potent than heparin. In addition, this effect was only observed for heparan sulfate synthesis similar to the effect of heparin (4,36,39,56). Because the synthesis of the heparan sulfate by endothelial cells in culture exposed to the fucan requires ϳ4 -6 h for the full effect (results not shown), it explains the delay to detect the antithrombotic effect of the algal polysaccharide on the experimental model of thrombosis.…”

Biological activities of the sulfated polysaccharide from the vascular plant Halodule wrightii

“…Sulfated polysaccharides (SP) are compounds which posses several biological activities like as anticoagulant, antiviral, antioxidant, antitumor, antiprotozoal, anti-inflammatory, anticomplementary, antipeptic (Nader et al, 2004, Pomin, 2010. They occur in a great variety of animals, including the sulfated glycosaminoglycans found in vertebrates and invertebrates animals (Nader et al, 2004).…”

“…They occur in a great variety of animals, including the sulfated glycosaminoglycans found in vertebrates and invertebrates animals (Nader et al, 2004). Furthermore, marine invertebrate species are also rich sources of sulfated polysaccharides with novel structures such as sulfated fucans and galactans (Pomin, 2010).…”