Coagulants and Anticoagulants

Coagulation Process:
The main coagulation reactions are divided into the intrinsic and
extrinsic systems. Activation of factor XII on contact with a negatively charged surface initiates
the intrinsic coagulation system. (The activated form of the factor is indicated by "a.") The
extrinsic coagulation system induces the formation of a complex composed of factor VII and
tissue factor, which is released after tissue injury. Some of these reactions depend on calcium
ions. Thrombin is formed by an enzyme complex called prothrombinase, composed of factor X,
factor V, negatively charged phospholipids, and calcium ions. Intrinsic and extrinsic activation
of the coagulation cascade leads to the generation of thrombin, the activation of fibrinogen, the
release of fibrinopeptides, the formation of soluble fibrin, and finally, the formation of factor
XIII-mediated, cross-linked, insoluble fibrin. The main fibrinolytic reactions involve the
inhibition of fibrinolysis by plasminogen-activator inhibitor type 1 (PAI-1) and {alpha}2-
antiplasmin. Fibrinolysis is initiated by tissue plasminogen activator (t-PA), urinary-type
plasminogen activator (u-PA), and plasmin. Plasmin bound to the surface of fibrin initiates the
lysis of insoluble, cross-linked fibrin, with the subsequent generation of fibrin-degradation
products. Plasmin bound to the surface of fibrin is better protected from inhibition by {alpha}2-
antiplasmin than is plasmin generated in the fluid phase.
Anticoagulants:
Drugs that help prevent the clotting (coagulation) of blood are called
anticoagulants. Coagulation will occur instantaneously once a blood vessel has been severed.
Blood begins to solidify to prevent excessive blood loss and to prevent invasive substances from
entering the bloodstream.

Classification:
1. Anticoagulants.
2. Thrombolytic agents.
3. Antiplatelet agents.

Anticoagulants:

1. Parenteral
 Heparin Sulphate.
 Danaparoid.
 Lepirudin.
 Hirudin
 Argatroban

Mechanism of action: (Heparin)

• Heparin binds to AT-III and causes a conformational change thereby activating AT-III
• Enhances the action of Antithrombin III (AT-III) (plasma protease inhibitor) 1000 fold ↑
activity
• Antithrombin III inhibits clotting factor proteases,Thrombin (IIa), IXa, Xa, XIa and XIIa,
by forming stable complexes

Mechanism: (Lepirudin)
• One molecule of lepirudin binds to one molecule of thrombin
• Resulting in blockage of the thrombogenic activity of thrombin

2. Oral
 Warfarin sodium.
 Dicumarol.
 Rivaroxaban
 Anisindione.

Mechanism of action:
• Some clotting factors need a carboxyl group added to their carboxyl-terminal glutamates
after synthesis in the liver in order to be able to bind Ca++ during coagulation activation
[these are called Vitamin K dependent clotting factors]
• This γ-carboxylation reaction requires reduced Vitamin K, which leaves the reaction as a
Vitamin K epoxide.
 • Vitamin K epoxide is then converted back to its reduced form via the enzyme vitamin K
epoxide reductase and NADH
• The Vitamin K antagonists inhibit the action of the reductase enzyme

Thrombolytic agents.
 Alteplase (Activase)
 Streptokinase (Streptase, Kabikinase)

Mechanism: (Alteplase)
• Work by activating the enzyme plasminogen
• Clears the cross-linked fibrin mesh
• Makes the clot soluble
• Followed by proteolysis
• Blood flow in the occluded blood vessels is therefore restored.

Mechanism: (Streptokinase)
• Forms an active one-to-one complex with plasminogen
• This enzymatically active complex converts uncomplexed plasminogen to the active
enzyme
plasmin
• Also catalyzes the degradation of fibrinogen as well as clotting Factors V and VII

Antiplatelet agents:
 Aspirin
 Clopidogrel (Plavix)
 Ticlopidine
 Tirofiban

Mechanism: (Aspirin)
• Aspirin inhibits the synthesis of TxA by irreversible acetylation of the enzyme
cyclooxygenase
• The platelet can not manufacture new enzyme during its 10-day lifetime.
• Prolong the bleeding time.

Mechanism: (Ticlopidine and Clopidogrel)

• Inhibit the binding of ADP to its receptors on platelet
• Thus inhibit the activation of the GP IIb/IIIa receptors required for platelets to bind to
fibrinogen and to each other

Mechanism: (Tirofiban)
• Blocking the GP IIb/IIIa receptor
 • Binds to GP IIb/IIIa at the site that interacts with the arginine-glycine-aspartic acid
sequence of fibrinogen

Coagulants:
Coagulants are the drugs which promote coagulation of blood to prevent blood loss.

 Vitamin- K
 Fibrinogen
 Plasma fractions
 Fibrinolytic inhibitors (aminocaproic acid)
 Serine protease inhibitors: aprotinin

Mechanism: (aminocaproic acid)

• Inhibit plasminogen activation

Mechanism: (Protamine sulfate)

• Positively charged protamine interacts with the negatively charged heparin
• Form a stable complex without anticoagulant activity

Mechanism: (Vitamin- K)
• Act antagonist to warfarin
• Activate coagulation factors

Mechanism: (Aprotinin)
• Stops bleeding by blocking plasmin
• Can inhibit streptokinase
References:
 Lippincott's Illustrated Reviews: Pharmacology, edi. 4th by Richard Finkel, 2009, pp
364-393.