11.1: Anticoagulant Drugs: Low-Molecular-Weight Heparins
Hemostasis is a crucial process that prevents excessive blood loss from damaged blood vessels. It involves various mechanisms such as vasoconstriction, platelet adhesion and activation, and fibrin formation. The importance of each mechanism depends on the type of vessel injury. In contrast, thrombosis is the abnormal formation of a blood clot within the blood vessels, leading to potential complications if the clot obstructs blood flow. Thrombosis can be caused by increased coagulability of the blood, which may be inherited as thrombophilia.
Arterial and venous thrombi have distinct structures and characteristics. Arterial thrombi mainly consist of platelets within a fibrin mesh and are often associated with atherosclerosis. They can cause tissue ischemia or cell death. Venous thrombi have a small white head and a large jelly-like red tail. Thrombi can break off and circulate in the bloodstream as emboli, potentially causing severe complications when they lodge in vital organs such as the lungs or brain.
The coagulation process involves a complex enzyme cascade that converts liquid blood into a gel-like clot. This cascade is tightly regulated by inhibitors such as antithrombin III to prevent excessive clotting. The vascular endothelium also plays an active role in limiting thrombus extension. The intrinsic or 'contact' pathway and the tissue factor pathway contribute to fibrin formation during coagulation. Thrombin, a key enzyme, plays multiple roles in the process, including fibrinogen cleavage, platelet aggregation, and modulation of smooth muscle contraction.
The endothelium has a dual role in promoting and limiting thrombosis. It produces substances such as prostaglandin I2 and nitric oxide, which inhibit platelet function and promote vasodilation. The endothelium also synthesizes tissue plasminogen activator and expresses thrombomodulin, which activates protein C—an anticoagulant that inactivates factors Va and VIIa. Genetic mutations, such as the factor V Leiden mutation, can lead to inherited thrombophilia by causing resistance to activated protein C.
Thrombotic and thromboembolic diseases have significant consequences, including myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism. Antiplatelet and fibrinolytic drugs are commonly used to treat platelet-rich 'white' thrombi. At the same time, injectable anticoagulants (heparins and thrombin inhibitors) and oral anticoagulants (warfarin and related compounds) are utilized for 'red' thrombi. Heparin, both unfractionated and low-molecular-weight preparations, is a potent anticoagulant that inhibits coagulation by activating antithrombin III. Low-molecular-weight heparins (LMWHs) are often preferred due to their more predictable effects, longer half-life, and lower incidence of certain side effects.
