Natural anticoagulant system

Defects in natural anticoagulants result in an increased risk of venous thrombosis. The most common defect in the natural anticoagulant system is a mutation in factor V (factor V Leiden), which results in resistance to inactivation by the protein C, protein S mechanism. 

The inherited disorders characterized by an tendency to form thrombi (thrombophilia) derive from either quantitative or qualitative abnormalities of the natural anticoagulant system. Deficiencies in the natural anticoagulants antithrombin, protein C, and protein S account for approximately 15% of selected patients with juvenile or recurrent thrombosis and 5-10% of unselected cases of acute venous thrombosis. Additional causes of thrombophilia include the factor V Leiden mutation, hyperhomocystinemia, and the prothrombin 20210 mutation that together account for the greater number of hypercoagulable patients. 

Plasma Inhibitors, In Vivo Anticoagulants. Fourteen naturally occurring compounds that normally exert an inhibiting effect on the activity of coagulation, platelet function, and fibrinolytic activity and complement systems have been identified within the circulating blood. 

The anticoagulant fondaparinux, a synthetic analogue of the terminal fragment of heparin, is synthesized using multiple protection/deprotection steps that result in a route of up to 50 steps. There is, as yet, no enzymatic system that approaches the capability to make such a molecule." As this modified pentasaccharide is a natural product, it should, in theory, be accessible through a series of biotransformations, but we currently lack the biocatalytic tools to achieve more than a few steps and would stiU need to use some protection steps to avoid multiple products. Enzymatic synthesis in vivo depends largely on the levels and selectivities of glycosylating enzymes to achieve multistep reactions, a situation that has been mimicked in vitro for simpler systems." ... 

In defining anticoagulants above, it was emphasized that heparin in concentrations of 0 1 mg/ml. and over, shows general inhibitory effects and this has led to much confusion in the literature. The important problem is the nature of the action of the heparin-cofactor complex which provides the unique high activity of heparin. In analysing the inhibitory effect of heparin in plasma systems, the essential constituent is the cofactor and its concentration is an unknown limiting variable in many investigations . 

Over the years, isolation and purification of natural sulfated polysaccharides responsible for anticoagulant activity from different seaweed species had been reported (De Zoisa et ah, 2008). The ability of sulfated polysaccharides to interfere with biological systems has a longstanding record, as illustrated with heparin (Huynh et ah, 2001). In addition, anticoagulant and antithrombotic activities are among the most widely studied properties of sulfated polysaccharides. 

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