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Guyton Hall Medical Physiology South Asia edition anticoagulants thromboembolic conditions heparin vitamin K
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Thromboembolic conditions and action of clinically used anticoagulants
Definition
A thromboembolic condition is a condition in which a blood clot (thrombus) forms within a blood vessel and may either obstruct blood flow at its site of formation or detach, travel in the circulation as an embolus, and lodge in a distant vessel. This may cause ischemia, infarction, or sudden obstruction of blood flow.
Common examples include:
- Deep-vein thrombosis of the lower limb
- Pulmonary embolism
- Thrombus formation in atrial fibrillation with systemic embolism
- Arterial thrombosis, such as coronary or cerebral thrombosis
- Thrombosis on prosthetic valves or in immobilized patients
In these conditions, anticoagulants are used mainly to prevent extension of an existing thrombus and formation of new thrombi. They do not directly dissolve a clot already formed. Physiological clot dissolution is carried out by the fibrinolytic system through plasmin.
Basis of anticoagulant action
Normally, coagulation culminates in formation of thrombin, which converts soluble fibrinogen into insoluble fibrin. Fibrin forms the meshwork of the blood clot. Anticoagulants delay coagulation by reducing thrombin activity or by decreasing the production of essential clotting factors.
According to Guyton and Hall, the main clinically useful anticoagulants are:
- Heparin
- Coumarins, chiefly warfarin
1. Heparin
Heparin is a potent, rapidly acting anticoagulant that is administered parenterally, classically intravenously for urgent anticoagulation.
Mechanism of action
Heparin is a highly negatively charged polysaccharide. By itself it has little anticoagulant action. Its main action is to bind to antithrombin III (also called antithrombin-heparin cofactor).
The heparin-antithrombin III complex:
- Increases the ability of antithrombin III to neutralize thrombin by about 100 to 1000 times
- Rapidly removes free thrombin from circulating blood
- Inactivates several activated clotting factors, especially factors IX, X, XI, and XII
Thus, heparin prevents thrombin from converting fibrinogen to fibrin and interrupts further propagation of the coagulation cascade.
Clinical effect
After intravenous injection, heparin acts almost immediately. Guyton and Hall notes that a small dose can increase clotting time from about 6 minutes to 30 minutes or more. Therefore, it immediately prevents or slows further development of a thromboembolic condition.
Its effect lasts approximately 1.5 to 4 hours, because it is degraded by heparinase.
Importance in thromboembolism
Heparin is particularly useful when rapid anticoagulation is required, for example in acute deep-vein thrombosis or pulmonary embolism. It does not remove the existing embolus, but prevents enlargement of the clot and formation of additional emboli while endogenous fibrinolysis acts.
2. Coumarins: Warfarin
Warfarin is an orally effective coumarin anticoagulant used when longer-term reduction of coagulation is required.
Mechanism of action
Several clotting factors are synthesized in the liver in a vitamin K-dependent active form. These include:
- Prothrombin or factor II
- Factor VII
- Factor IX
- Factor X
Warfarin inhibits vitamin K epoxide reductase complex 1 (VKORC1). This enzyme normally regenerates the active, reduced form of vitamin K.
When VKORC1 is inhibited:
- Active vitamin K becomes deficient.
- The liver cannot adequately carboxylate newly formed clotting factors.
- Prothrombin and factors VII, IX, and X are produced in biologically inactive form.
- The amount of functional clotting factors in blood progressively falls.
- Thrombin generation and fibrin formation are reduced.
Time course
Warfarin does not act immediately because active clotting factors already present in plasma must first be degraded.
- Coagulant activity falls to about 50% of normal after 12 hours.
- It falls to about 20% of normal after 24 hours.
- Following withdrawal, normal coagulation usually returns in 1 to 3 days.
Hence, warfarin is not ideal as the only drug in an acute emergency. Heparin may be used initially because of its immediate action, with warfarin used for continuing anticoagulation.
Comparison of heparin and warfarin
| Feature | Heparin | Warfarin |
|---|---|---|
| Route | Parenteral, commonly intravenous | Oral |
| Onset | Immediate | Delayed |
| Main mechanism | Potentiates antithrombin III and inactivates thrombin and activated factors | Inhibits vitamin K recycling and decreases synthesis of active factors II, VII, IX and X |
| Main role | Acute thromboembolic states | Long-term anticoagulation |
| Effect on an existing clot | Prevents enlargement, does not dissolve it | Prevents enlargement/new clot formation, does not dissolve it |
Conclusion
Thromboembolic conditions result from formation and possible migration of intravascular thrombi. Anticoagulants delay clotting and prevent propagation of thrombosis. Heparin acts immediately by greatly enhancing antithrombin III activity, thereby neutralizing thrombin and several activated coagulation factors. Warfarin acts more slowly by preventing vitamin K-dependent formation of active prothrombin and factors VII, IX, and X. Together, these agents help prevent extension and recurrence of thromboembolism.
Source: Guyton and Hall Textbook of Medical Physiology, “Anticoagulants for Clinical Use,” pp. 486-490 in the available textbook text.
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