Drugs Used in Coagulation Disorders November 2013 Thrombus

Drugs Used in Coagulation Disorders November 2013

Thrombus formation at the site of the damaged vascular wall (EC, endothelial cell) and the role of platelets and clotting factors. Platelet membrane receptors include the glycoprotein (GP) Ia receptor, binding to collagen (C); GP Ib receptor binding von Willebrand factor (v. WF), and GP IIb/IIIa, which binds fibrinogen and other macromolecules. Antiplatelet prostacyclin (PGI 2) is released from the endothelium. Aggregating substances released from the degranulating platelet include adenosine diphosphate (ADP), thromboxane A 2 (TXA 2), and serotonin (5 -HT).

A model of blood coagulation. With tissue factor (TF), factor VII forms an activated complex (VIIa-TF) that catalyzes the activation of factor IX to factor IXa. Activated factor XIa also catalyzes this reaction. Tissue factor pathway inhibitor (TFPI) inhibits the catalytic action of the VIIa-TF complex. The cascade proceeds as shown, resulting ultimately in the conversion of fibrinogen to fibrin, an essential component of a functional clot. The two major anticoagulant drugs, heparin and warfarin (an oral anticoagulant), have very different actions. Heparin, acting in the blood, directly activates anticlotting factors, specifically antithrombin, which inactivates the factors enclosed in rectangles. Warfarin, acting in the liver, inhibits the synthesis of the factors enclosed in circles. Proteins C and S exert anticlotting effects by inactivating activated factors Va and VIIIa.

Anticoagulants n Heparin ¨ UFH (Unfractionated Heparin) ¨ LMWH n n (Low Molecular Weight Heparins) Deltaprin Enoxaprin ¨ Fondaparinux (synthetic pentasaccharide) n Varfarin

Subunit structure of heparin. The small polymer section shown illustrates the repeating disaccharide units typical of heparin. The sequence shows the critical pentasaccharide portion required for binding to antithrombin. In addition to those shown, other saccharides occur. Heparin is a strongly acidic molecule because of its high content of anionic sulfate and carboxylic acid groups. (Glc. N, glucosamine; Id. UA, iduronic acid; Glc. UA, glucuronic acid. The same five residues with the terminal groups shown in parentheses, constitute fondaparinux. )

Heparin n Binds and activates antithrombin III which inactivates the active forms of the coagulation factors IIa, IXa, and Xa.

Vitamin K cycle (metabolic interconversions of vitamin K associated with the synthesis of vitamin K-dependent clotting factors. Vitamin K 1 or K 2 is activated by reduction to the hydroquinone form (KH 2). Stepwise oxidation to vitamin K epoxide (KO) is coupled to prothrombin carboxylation by the enzyme carboxylase. The reactivation of vitamin K epoxide is the warfarin-sensitive step (warfarin). The R on the vitamin K molecule represents a 20 carbon phytyl side chain in vitamin K 1 and a 30 - to 65 carbon polyprenyl side chain in vitamin K 2.

Trombolytics Streptokinase n Urokinase n tissue plasminogen activators (t-PAs) n Anistreplase n

Schematic representation of the fibrinolytic system. • Plasmin is the active fibrinolytic enzyme. • Several clinically useful activators are shown on the left in bold. • Anistreplase is a combination of streptokinase and the proactivator plasminogen. • Aminocaproic acid (right) inhibits the activation of plasminogen to plasmin and is useful in some bleeding disorders. (t-PA, tissue plasminogen activator. )

Antiplatelet Drugs n n n n Asprin Dipyridamole Clopidogrel Ticlopidine Abciximab, Eptifibatide Tirofiban

Thrombus formation at the site of the damaged vascular wall (EC, endothelial cell) and the role of platelets and clotting factors. Platelet membrane receptors include the glycoprotein (GP) Ia receptor, binding to collagen (C); GP Ib receptor binding von Willebrand factor (v. WF), and GP IIb/IIIa, which binds fibrinogen and other macromolecules. Antiplatelet prostacyclin (PGI 2) is released from the endothelium. Aggregating substances released from the degranulating platelet include adenosine diphosphate (ADP), thromboxane A 2 (TXA 2), and serotonin (5 -HT).