Understanding the therapeutic action of recombinant factor VIIa in platelet disorders.
Recombinant factor VIIa (rFVIIa) is a pro-haemostatic agent that is effective in the treatment of bleeding in haemophilia complicated by inhibitors and some other haemorrhagic disorders. The rFVIIa product promotes haemostasis in these settings by enabling the rapid generation of thrombin on the surface of activated platelets which increases fibrin deposition. rFVIIa also has therapeutic activity in bleeding in platelet function disorders such as Glanzmann's thrombasthenia and thrombocytopenia. This suggests that rFVIIa also has a pro-haemostatic effect on platelets and this may contribute to the overall therapeutic action of this agent. The effects of high-concentration FVIIa on platelets have been studied in detail in experiments using ex vivo model systems of haemostasis under static and flow conditions. These experiments show that FVIIa potentiates multiple functional markers of platelet activation and this effect requires direct binding of FVIIa to the activated platelet membrane and the generation of thrombin. The mechanism of this potentiating effect of FVIIa on platelet activation is complex and is likely to require multiple platelet activation receptors and signalling pathways. These include the GPIb-IX-V glycoprotein complex and the thrombin protease activated receptors. The proposed mechanism of action of high-concentration FVIIa has important implications for the therapeutic activity of rFVIIa in vivo. This review summarizes the clinical and experimental evidence supporting a potentiating effect of FVIIa on platelet activation and discusses the likely mechanism of action.
Hers
Ingeborg
I
Department of Biochemistry, School of Medical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, UK.
Mumford
Andrew
A
D001791:Blood Platelet Disorders / Q000188:drug therapy; D015942:Factor VIIa / Q000494:pharmacology* / Q000627:therapeutic use; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D015539:Platelet Activation / Q000187:drug effects*; D019038:Platelet Glycoprotein GPIb-IX Complex; D044463:Receptor, PAR-1; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction; D013917:Thrombin / Q000096:biosynthesis
D019038:Platelet Glycoprotein GPIb-IX Complex; D044463:Receptor, PAR-1; D011994:Recombinant Proteins; C032193:glycoprotein receptor GPIb-IX; C103587:recombinant FVIIa; D015942:Factor VIIa; D013917:Thrombin