Anticoagulants, Antithrombotics, and Hemostatics

Abstract

Maintenance of proper blood flow is a complex and highly regulated physiological process, with multiple complementary and opposing mechanisms of control. Imbalances in these mechanisms can lead to a variety of pathological consequences, such as hemorrhage or obstructive clot (thrombus) formation in veins or arteries, leading to stroke, pulmonary embolism, heart attack, and other serious conditions. One of the overriding challenges with current or future drug strategies for antithrombotic, thrombolytic (clot dissolving), and hemostatic therapy is the precise correction of the pathologic imbalance without overcompensating and thus creating safety issues. Unfractionated heparin is widely used as an anticoagulant, but is being replaced in many of its applications by currently available alternative parenteral agents such as the low molecular weight heparins and the direct thrombin inhibitors. These efficacious alternative agents offer advantages in terms of more predictable pharmacokinetics and improved safety, thereby reducing or eliminating the need for patient monitoring and reducing or eliminating the risk of heparin‐induced thrombocytopenia. Orally bioavailable direct thrombin and/or Factor Xa inhibitors now under development seem poised to become available over the next several years and will represent viable alternatives to both the parenteral anticoagulants and to warfarin, the only currently available oral anticoagulant. These agents promise the convenience of an oral drug without the need of intensive patient monitoring, as warfarin requires. Other therapeutic targets under current investigation for anticoagulation include Factor VIIa and Factor IXa. Antiplatelet agents such as aspirin, clopidogrel, and the parenteral GPIIb/IIIa antagonists are valuable and widely used drugs. New antiplatelet agents that act by already validated mechanisms (e.g., P2Y 12 receptor antagonism) or that act by mechanisms not targeted by current agents will also likely emerge in the not too distant future. Newer clot‐selective fibrinolytics have advantages over older agents such as streptokinase. Fibrinolytic agents still in development may offer further improvements in terms of safety and longer plasma half‐life.

Thrombin Receptor (Protease Activated Receptor-1) Antagonists as Potent Antithrombotic Agents with Strong Antiplatelet Effects

“…Antithrombotic agents are the mainstay of pharmacological therapy for acute coronary syndrome. , Mechanistically, the function of antithrombotic agents is either to prevent the formation of thrombi in the blood vessels or to dissolve the existing ones and restore blood flow. − Currently available antithrombotic agents can be classified into anticoagulants , antiplatelet agents , and fibrinolytic agents . The anticoagulants work either by modulating the endogenous levels of the key coagulation enzyme thrombin or by inactivating its enzymatic activity. − Antiplatelet agents inhibit platelet activation and aggregation, a key process of hemostasis and thrombus formation. , Fibrinolytic agents, which are intravenously administered under clinical emergency, work by lysis of existing clots and restore blood flow in occluded vessels. − …”