Blood Constituents and Safety Pharmacology: In Vitro and In Vivo Thrombosis and Hemostasis Assays

Thrombosis and related disorders represent the number one cause of mortality. The understanding of the mechanisms behind the pathogenesis of venous thromboembolism, acute coronary syndromes, cerebral vascular ischemic and thrombotic events, and diseases associated with thrombotic disorders has provided additional insights toward the development of various therapeutic approaches to control these pathogenic events. The roles of plasmatic proteins, blood cells, vascular endothelium, and target organs in both thrombogenesis and its control have been gradually clarified. Identification of endogenous inhibitors of thrombogenesis such as antithrombin III, tissue factor pathway inhibitor (TFPI), protein C, prostacyclin, nitric oxide, and physiologic activators of fibrinolysis has led to the development of both direct and indirect modalities to treat thrombosis. On the other hand, the knowledge of the proteases involved in thrombogenesis, including tissue factor, coagulation factors, adhesion molecules, and fibrinolytic inhibitors, has provided insights into the mechanisms by which thrombogenesis can be pharmacologically controlled. Pharmaceutical industry has played a key role not only in the development of new drugs but also in providing sizable resources to academic institutions to foster the development and clinical validation of the use of newer drugs. Such drugs as low-molecular-weight heparins, antithrombin agents such as hirudin, and antiplatelet drugs such as the GPIlb/Illa inhibitors and ADP receptor antagonists have emerged as improved therapeutic strategies over conventional drugs. The development of these drugs required a major undertaking by industry, requiring the allocation of sizable resources. Beside fiscal considerations, an objective assessment of the newer drugs at both preclinical and clinical levels was mandatory for optimal applications. The novel developments in antithrombotic drugs include mono-therapeutic approaches such as the anti-proteases (factors IIa, Xa, and VIIa), tissue factor targeting, platelet receptor targeting, and antithrombin III modulation. During the past decade, a remarkable progress has been made in the development of newer drugs to treat thromboembolic disorders. Over this last 10 years, concentrated efforts were carried out in introducing newer drugs (novel oral anticoagulant, oral antiplatelets) and novel usage of traditional antithrombotic drugs such as aspirin, heparin, oral anticoagulants, and combinations of two antiplatelets, antiplatelet with anticoagulant, antiplatelet with thrombolytic, and anticoagulant. This chapter provides update on various in vitro and in vivo strategies in evaluating antithrombotic efficacy/safety, experimental models, and latest advances in anticoagulant/antiplatelets.