Anticoagulants

Anticoagulants

To prevent inappropriate activation of the clotting cascade, natural inhibitors of the clotting system are present:


Antithrombin III is a protein produced by the liver which has inhibitory activity against factors IIa, VIIa, IXa, Xa, and XIa, especially in the presence of heparin so it is a protease inhibitor. It is has a weak inhibitory activity against thrombin and factor Xa. When antithrombin binds to heparin this inhibitory activity is markedly accelerated and this forms the basis of the anticoagulant of heparin. Congenital deficiency of antithrombin is associated with a predisposion to venous thromboembolism, such patients may be relatively resistant to anticoagulation with heparin because of the low level of antithrombin which is necessary for heparin to produce it is anticoagulant effect.
Protein C is a vitamin K dependant factor produced by the liver, when activated by interaction with protein S, it inhibits factor Va and VIIIa. Thus a deficiency of either protein C or S results in aprothrombotic state due to reduced inhibition of activated factor V and VIII.
A deficiency of either factor is usually inherited in an autosomal fashion .
These natural inhibitors are powerful control points in the positive feed back cascade of clotting, and abnormalities in their function result in a tendency to thrombosis.

Anticoagulant therapy

Heparin
Standard or unfractionated heparin (SH) produces its anticoagulant effect by potentiating the activity of antithrombin which inhibits the procoagulant enzymic activity of factors IIa,VIIa,IXa,Xa and XIa. The more recently developed low molecular weight heparins (LMWH) augment antithrombin activity especially against factor Xa . LMWH does not prolong the APTT unlike SH and if plasma level needs to be measured this is done by use of a specific anti-Xa based assay

Warfarin

Warfarin inhibits the vitamin K dependent carboxylation of factors II, VII, IX, X in the liver, these factors are rich in glutamic acid (GLa) residues which must be carboxylated to permit calcium-binding and association with phospholipids. The carboxylase enzyme responsible for this in the liver uses. Vitamin K as a cofactor, so they are called as vitamin K dependant factor. Vitamin K is converted to an epoxide in this reaction and must be regenerated to it is active form by a reductase enzyme. This reductase is inhibited by warfarin and this mechanism forms the basis of the anticoagulant effect of cumarins.











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