How does recombinant Factor VIIa produce hemostasis?
  Recombinant Factor VIIa (recombinant activated Factor VII) induces hemostasis at the site of injury independent of the presence of Factor VIII or Factor IX by forming complexes with exposed tissue factor (TF), and this distinct mechanism of action explains its potential for effective hemophilia treatment. The key to the initiation of hemostasis is the formation of TF- Factor VIIa complex at the site of injury. TF is a membrane-bound lipoprotein expressed on cells in the sub-endothelium (TF-bearing cells). Tissue injury disrupts the endothelial cell barrier that normally separates TF-bearing cells from the circulating blood. Once exposed to the blood, TF serves as a high affinity receptor for Factor VIIa. Activated Factor VII (Factor VIIa) is found in the circulation at concentrations roughly corresponding to 1% of the total Factor VII protein mass. Factor VIIa alone shows very little proteolytic activity, only attaining full enzymatic potential when complexed to TF. The TF- Factor VIIa complex converts Factor X to Factor Xa leading to the generation of small amounts of thrombin on the TF-bearing cells. In normal individuals without hemophilia, this limited amount of thrombin subsequently activates the cofactors Factor V and Factor VIII, as well as platelets accumulated at the site of injury. The activated platelets expose phosphatidyl serine on their membrane and provide the template for further thrombin generation. Factor IXa, Factor VIIIa and Factor Va bind efficiently to the surface of the activated platelet and further activation of Factor X into Factor Xa occurs via the complex between Factor IXa and Factor VIIIa. The full thrombin burst is mediated by the Factor Xa in complex with Factor Va . A full thrombin burst is necessary for the formation of a fully stabilized and solid fibrin hemostatic plug. For this to occur, the presence of TF- Factor VIIa-complexes, Factor IXa, and Factor VIIIa are usually required). Patients with hemophilia patients lack normal Factor VIII (hemophilia A) or Factor IX (hemophilia B). For this reason they are not capable of inducing full thrombin generation and this leads to the formation of an unstable primary hemostatic plug. Substitution therapy with Factor VIII or Factor IX concentrate normalizes the hemostatic function of these patients. However, in those hemophilia patients who have developed inhibitors against Factor VIII or Factor IX, substitution therapy does not lead to a normalization of the hemostatic system. In such patients, high doses of Factor VIIa have been demonstrated to induce hemostasis.
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