Recombinant Coagulation Factors and Thrombolytic Agents
Coagulation and fibrinogenolysis exist in a mutually compensatory or balanced state. Endogenous regulatory mechanisms ensure that the processes of hemostasis and blood coagulation at a site of injury, and the subsequent fibrinolysis of the blood clot, are
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Recombinant Coagulation Factors and Thrombolytic Agents Nishit B. Modi
Introduction Coagulation and fibrinogenolysis exist in a mutually compensatory or balanced state. Endogenous regulatory mechanisms ensure that the processes of hemostasis and blood coagulation at a site of injury, and the subsequent fibrinolysis of the blood clot, are localized and well regulated. This ensures a rapid and efficient hemostatic response at a site of injury while avoiding thrombogenic events at sites distant from the site of injury or the hemostatic response from persisting beyond its physiologic need. This chapter will focus on recombinant products that are available to facilitate coagulation and for thrombolysis. Two models of blood hemostasis, a cascade model and a cell-based model, have been proposed. A schematic of the cascade and cell-based models of coagulation is presented in Fig. 15.1. The initial model of coagulation was proposed in the 1960s, encompassing a series of steps, or cascade, where enzymes cleaved a zymogen to generate the subsequent enzyme. In the cascade model, coagulation was divided into the intrinsic and extrinsic pathways. The extrinsic pathway was located outside the blood and consisted of tissue factor-dependent cofactors and enzymes and factor VIIa. The intrinsic system was localized within the blood and could be initiated through contact activation of factor XII, which leads to activation of subsequent components. The two pathways converged into the common pathway, leading to the generation of thrombin. While the cascade model was useful in explaining how the coagulation enzymatic steps occurred in vitro and in helping interpret
N.B. Modi, Ph.D. Departments of Nonclinical R&D and Clinical Pharmacology, Impax Pharmaceuticals, Hayward, CA, USA e-mail: [email protected]
laboratory tests, it did not adequately explain the hemostatic process as it occurs in vivo. More recently, a cell-based model of coagulation has been proposed (Hoffman 2003; Hoffman and Monroe 2005). This cell-based model emphasizes the interaction of clotting factors with cell surfaces and appears to explain some of the unresolved issues with the cascade model. The cell-based model of coagulation comprises four phases: initiation, amplification, propagation, and termination. The initiation phase is localized to cells expressing tissue factor (TF), which are generally localized outside the vasculature. Upon injury, blood is exposed to cells bearing TF, and factor VIIa rapidly binds to exposed TF. The TF-VIIa complex activates additional factor VII to factor VIIa which in turn activates small amounts of factor IX and factor X. Factor Xa binds factor Va to form the prothrombinase complex, which cleaves prothrombin to thrombin. During amplification, the small amount of thrombin generated diffuses away from the TF-bearing cells and activated platelets, exposing receptors and binding sites for activated clotting factors. Once platelets are activated, the release of granule contents leads to recruitment of additional platelets to the sit
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