Coagulants and Antithrombotics BY:DR/AZZA BARAKA

ANTICOAGULANTS (Drugs that prevent coagulation)

These

are drugs which interfere with the coagulation of blood. They are used clinically to: 1- Prevent the extension of an existing thrombus (therapy) and 2- stop formation of new thrombi in the vascular bed (prophylaxis).

Classification of anticoagulants
According to their route of administration: A. Parenteral anticoagulants: Heparin. Low molecular weight heparin (LMWH). B. Oral anticoagulants: Warfarin Sodium Oral anticoagulants: inhibits clotting factor synthesis Parenteral anticoagulants inhibits activity of certain activated factors.

A. Parenteral Anticoagulants
[1] HEPARIN (Unfractionated heparin,UFH) Natural mucopolysaccharide of large molecular size. Mechanism of action of heparin on blood coagulation: The anticoagulant effect of heparin is immediate . It acts indirectly by markedly increasing(1000 times) the activity of a heparin co-factor (antithrombin-III). Antithrombin III is an globulin and a protease inhibitor that inactivates several activated clotting factors, namely Xlla, Xla, Xa, lla and Xllla.

Dosage & routes of administration of heparin

I- Intravenous administration: II- Subcutaneous administration: Can be used for long term prophylaxis of patients in whom oral anticoagulants are contraindicated e.g. in pregnancy, also to prevent deep vein thrombosis & thromboembolism. N.B: Intramuscular injection is contraindicated because it causes painful haematoma. It is not absorbed when given orally because of its high negative charge & large molecular size.

Control of therapy
Heparin therapy is monitored by the activated partial thromboplastin time (aPTT). During therapy the aPTT should be twice the control value.

Side effects and toxicity

These are mainly caused by overdosage: 1. Spontaneous hemorrhages 2. Thrombocytopenia: results from heparin-induced platelet aggregation or from formation of antiplatelet antibodies due to binding of heparin to platelets. 3. Hypersensitivity reactions may occur because heparin is obtained from animal sources. A test dose should be given to patients with allergic history. 4. Osteoporosis may occur after prolonged use of large doses.( Due to heparin-induced stimulation of osteoclasts 5. Elevation of liver transaminases. 6. Heparin can inhibit synthesis of aldosterone(toxic to zona glomerulosa cells) and causes hyperkalemia.

Reversal of Anticoagulant effects of heparin

1.
2.

3.

Discontinuation of the drug. The specific heparin antagonist (antidote) is protamine sulphate, (a strongly basic protein which forms an inactive complex with heparin).1 mg I.V. is required to antagonize each 100 units of heparin. Transfusion of fresh whole blood controls hemorrhage and replaces lost blood.

2] Low Molecular Weight Heparins (LMWHs)

Mechanism of action Anticoagulant activity: Both heparin and LMWHs exert their anticoagulant activity by activating antithrombin III. But unlike heparin which has an equivalent activity against factor Xa and thrombin, LMWH has greater activity against factor Xa.

Drug Characteristic Mechanism of action

Heparin Activating antithrombin-III with equivalent activity against factor Xa and thrombin

LMWH Activating antithrombin III with greater activity against factor Xa

Half life

Two hours

Four hours ( Less binding to macrophages & endothelial cells)

Predictable (Less binding to plasma proteins)

Anti-coagulant response

variable

Bioavailability
Thrombocytopenia Risk of bleeding Osteoporosis Specific antagonist Setting for therapy

20%
Frequent Frequent bleeding More Protamine sulphate Hospital

90%((Less binding to tissue proteins)

Less frequent(Less binding to platelets) Less frequent bleeding Less --------------------Hospital &Outpatient

Laboratory monitoring

Needed

Not needed

B- Oral anticoagulants
Synthetic drugs similar to vitamin K in structure. They are given orally as they are absorbed from the gut.

Oral Anticoagulants
Coumarin derivatives: Warfarin MOA: Interfere with the formation of prothrombin and clotting factors VII, IX and X by the liver leading to an anticoagulant effect . During the formation of these clotting factors in the liver, vitamin K is converted to a biologically inactive metabolite (epoxide form), that is then reduced back to the active vitamin by the enzyme epoxide reductase. The oral anticoagulants (e.g warfarin): are structurally similar to vitamin K. they act as competitive inhibitors of this enzyme and thus decrease the active form of the vitamin that form the clotting factors.

A latent period is always present before their anticoagulant action is manifested, this is due to: - The slow removal of prothrombin and factors VII & IX already present in the circulation.

Control of therapy
1-Prothrombin time (PT) adjusted to be double the normal value. 2-International Normalized Ratio (INR) = Patients Prothrombin time Normal control value Its value should be adjusted to 2- 2.5 normal

Side effects and toxicity

1-Spontaneous hemorrhage from different sites. 2-Teratogenic.

Treatment of warfarin-induced bleeding: 1. Stopping the drug. 2. The antidote is Vitamin K1 3. Transfusion of fresh whole blood (it controls haemorrhage and replaces lost blood).

Therapeutic uses of anticoagulant drugs

Anticoagulation is usually initiated by heparin and maintained by warfarin. 1. Therapeutically to prevent clot extension after: a. Myocardial infarction (coronary thrombosis). b. Deep venous thrombosis. c. Pulmonary embolism. d. Long standing atrial fibrillation. 2. Prophylactically to prevent clot formation : a- Following major surgery. b- Cardiopulmonary bypass c- Dialysis d-Cardiac prosthesis