ANTICOAGULANTS

ANTICOAGULANTS

These agents are employed to inhibit homeostasis at different stages till the stage of fibrinolysis. Homeostasis involves the interplay of three procoagulant phases (vascular, platelet, and coagulation) that promote blood clotting to prevent blood loss. The fibrinolytic system prevents propagation of clotting beyond the site of vascular injury and is involved in clot dissolution, or lysis.

OVERVIEW OF THROMBOSIS

Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets (thrombocytes) and fibrin to form a blood clot to prevent blood loss. Even when a blood vessel is not injured, blood clots may form in the body under certain conditions. A clot that breaks free and begins to travel around the body is known as an embolus.

When a thrombus occupies more than 75% of cross-sectional area of the lumen of an artery, blood flow to the tissue supplied is reduced enough to cause symptoms because of decreased oxygen (hypoxia) and accumulation of metabolic products like lactic acid. More than 90% obstruction can result in anoxia, the complete deprivation of oxygen, and infarction. Thromboembolism is the combination of thrombosis and its main complication, embolism.

In classical terms, thrombosis is caused by abnormalities in one or more of the following ( Virchow's triad):

-         The composition of the blood (hypercoagulability or thrombophilia)

-         Quality of the vessel wall (endothelial cell injury)

-         Disturbed blood flow (stasis, turbulence)

Hypercoagulability

Hypercoagulability is caused by, for example, genetic deficiencies or autoimmune disorders. Recent studies indicate that neutrophils play a pivotal role in deep venous thrombosis, mediating numerous pro-thrombotic actions.

Endothelial cell injury

Causes of injury to the vessel wall include trauma, surgery,infection or turbulent flow at bifurcations. The main mechanism is exposure of tissue factor to the blood coagulation system.

Disturbed blood flow

Causes of disturbed blood flow include stagnation of blood flow past the point of injury, or venous stasis which may occur in heart failure, or after long periods of sedentary behaviour, such as sitting on a long airplane flight. Also, atrial fibrillation, causes stagnant blood in the left atrium (LA), and can lead to a thromboembolism (e.g pulmonary embolism). Cancers or malignancies such as leukemia may cause increased risk of thrombosis by external compression on a blood vessel for example, or (more rarely) extension into the vasculature (for example, renal cell cancers extending into the renal veins).

Also, treatments for cancer (radiation, chemotherapy) often cause additional hypercoagulability.

Anticoagulants

Anticoagulant drugs inhibit the development and enlargement of clots by actions on the coagulation phase. They do not lyse clots or affect the fibrinolytic pathways.  Examples include heparin and its low molecular weight forms - enoxaparin, dalteparin , ardeparin , and tinzaparin.

Others include orally effective anticoagulants such as warfarin and coumarin

HEPARIN

Two types of heparin are used clinically. The first and older of the two, standard (unfractionated) heparin E. heparin sodium is animal extract e.g heparin sodium. The second and newer type, called low-molecular-weight heparin (LMWH), is derived from unfractionated heparin e.g as given above.

MOA

Heparin binds to antithrombin III, an inhibitor of the coagulation cascade. It specifically inhibits thrombin and therefore prevents the conversion of fibrinogen to fibrin. Heparin also blocks thromboplastin (tissue factor) generation. It also blocks several clotting factors VII, X, XI, and XII.

Heparin is not absorbed after oral administration and therefore must be given parenterally. Intravenous administration results in an almost immediate anticoagulant effect.

The low-molecular-weight heparins (LMWH) have a more predictable anticoagulant response due to greater tissue availability, a longer-lasting effect and lower incidence of side effects such as thrombocytopenia.

HEPARIN SODIUM

Review in emdex under the following topics – Therapeutic category, Indications, Mechanism of action (as above), Dosage, Side effects, Contra indications and nursing considerations.

ENOXAPARIN

Review in emdex under the following topics – Therapeutic category, Indications, Mechanism of action (as above), Dosage, Side effects, Contra indications and nursing considerations.

Heparin Antagonist: The specific heparin antagonist protamine can be employed to neutralize heparin in cases of serious hemorrhage. Protamines are basic low-molecular-weight, positively charged proteins that have a high affinity for the negatively charged heparin molecules. The binding of protamine to heparin is immediate and results in the formation of an inert complex. Protamine has weak anticoagulant activity.

ORALLY EFFECTIVE ANTICOAGULANTS

Unlike heparin, the oral anticoagulants induce hypocoagulability only in vivo. They are vitamin K antagonists. Vitamin K is required to catalyze the conversion of the precursors of vitamin K–dependent clotting factors II, VII, IX, and X. They are classified into

-         Coumarin derivative e.g warfarin, dicoumarol

-         Indandione derivatives e.g phenindione and diphenindione.

Warfarin is the oral anticoagulant of choice probably because indandione anticoagulants have greater toxicity than the coumarin drugs.

The antidote to warfarin is vitamin K. In haemorrhage secondary to adverse effects of warfarin, vit. K is administered intravenously. However, serious hemorrhage may be stopped by administration of fresh frozen plasma or plasma concentrates containing vitamin K–dependent factors.

WARFARIN

Review in emdex under the following topics – Therapeutic category, Indications, Mechanism of action (as above), Dosage, Side effects, Contra indications and nursing considerations.

Direct Thrombin Inhibitor Anticoagulants

Two drugs that are direct inhibitors of thrombin but that do not involve antithrombin III or vitamin K in their mechanism of action have been approved to provide intravenous anticoagulation in patients with heparin- induced thrombocytopenia. These drugs include Lepirudin and bivalirudin.

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