Heparins and heparinoids: occurrence, structure and mechanism of antithrombotic and hemorrhagic activities.
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.
Nader
Helena B
HB
Departamento de Bioquímica, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua 3 de Maio 100, 4 andar,04044-020 São Paulo, SP, Brazil. hbnader.bioq@epm.br
Lopes
Carla C
CC
Rocha
Hugo A O
HA
Santos
Elizeu A
EA
Dietrich
Carl P
CP
D000818:Animals; D000925:Anticoagulants / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D006470:Hemorrhage / Q000139:chemically induced*; D006493:Heparin / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D006496:Heparinoids / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D013329:Structure-Activity Relationship; D013927:Thrombosis / Q000517:prevention & control
D000925:Anticoagulants; D005343:Fibrinolytic Agents; D006496:Heparinoids; D006493:Heparin