Mode of action of Recombinant Factor VII

Recombinant activated factor VII (Novoseven) induces haemostasis at the site of injury independent of the presence of factor VIII (FVIII) or factor IX (FIX) by forming complexes with exposed tissue factor (TF), and this distinct mechanism of action explains its potential for effective haemophilia treatment.

The key to the initiation of haemostasis is the formation of TF-FVIIa complex at the site of injury (Figure 1). 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 FVIIa. Activated FVII is found in the circulation at concentrations roughly corresponding to 1% of the total FVII protein mass. FVIIa alone shows very little proteolytic activity, only realising full enzymatic potential when complexed to TF.

Figure 1: Initiation of coagulation (Step I)

The TF-FVIIa complex converts FX to FXa, leading to the generation of small amounts of thrombin on the TF-bearing cells (Figure 2). In normal individuals without haemophilia, this limited amount of thrombin subsequently activates the cofactors FV and FVIII, 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. FIXa, FVIIIa and FVa bind efficiently to the surface of the activated platelet and further activation of FX into FXa occurs via the complex between FIXa and FVIIIa. The full thrombin burst is mediated by the FXa in complex with FVa (Figure 3).

A full thrombin burst is necessary for the formation of a fully stabilised and solid fibrin haemostatic plug. For this to occur, the presence of TF-FVIIa complexes, FIXa, and FVIIIa are usually required (Figure 3). Haemophilia patients lack normal FVIII (haemophilia A) or FIX (haemophilia B). For this reason, they are not capable of inducing full thrombin generation and this leads to the formation of an unstable primary haemostatic plug.
Substitution therapy with FVIII or FIX concentrate normalises the haemostatic function of these patients. However, in those haemophilia patients who have developed inhibitors against FVIII or FIX, substitution therapy does not lead to a normalisation of the haemostatic system. In such patients, high doses of FVIIa have been demonstrated to induce haemostasis.
 


Figure 2: Initiation of coagulation (Step II)



Figure 3: Amplification of coagulation (Step III)

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Factor VII deficiency

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