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Blood, 15 November 2003, Vol. 102, No. 10, pp. 3466. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Levi, M. Search for Related Content PubMed Articles by Levi, M. Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Superactive analogs of factor VIIa: superglue for bleeding patients? Recombinant factor VIIa was introduced in clinical medicine 20 years ago and has been shown to be a highly effective prohemostatic agent. Primarily, recombinant factor VIIa was used in patients with congenital or acquired hemophilia and inhibiting antibodies toward factor VIII or IX, for which it has been licensed in most countries. In recent years, the potential of recombinant factor VIIa to act as a prohemostatic agent in other categories of patients with severe coagulation defects, or in patients with a pre-existing normal coagulation system but who experience excessive or life-threatening bleeding, has been explored. Although this application of recombinant factor VIIa is still in its initial phase and most of the experience is based on uncontrolled series of observations, this agent is indeed a promising candidate for (adjunctive) treatment for serious bleeding in many types of patients. In this issue of Blood, Tranholm and colleagues (page 3615) describe the properties of a series of analogs of factor VIIa, developed by genetic engineering using native factor VIIa as a template. These mutant compounds have a much higher enzymatic activity toward factor X, but similar binding affinity to tissue factor, compared with native factor VIIa. When tested in a tail-bleeding model in mice with acquired (antibody-induced) hemophilia A, the authors show that the factor VIIa analogs have a dose-dependent and potent ability to shorten the bleeding time and to reduce blood loss. The potency of the factor VIIa analogs was estimated to be 3- to 4-fold higher than that of native recombinant factor VIIa. These interesting results can be helpful in understanding the mechanism of action of recombinant factor VIIa in bleeding patients. Recombinant factor VIIa is thought to act locally at the site of tissue injury and vascular wall disruption, by binding to exposed tissue factor (or replacing zymogen factor VII from tissue factor) and generating small amounts of thrombin, sufficient to activate platelets. The activated platelet surface can then form a template on which recombinant factor VIIa can bind and directly or indirectly mediate further activation of coagulation, resulting in the generation of much more thrombin. The relative contribution of factor VIIa binding to tissue factor or to platelets is unclear. The present study underlines the importance of the tissue factor-independent effect of factor VIIa and demonstrates that the tissue factor-binding properties of factor VIIa may be less important in further improving the prohemostatic effect. It is tempting to speculate whether these superactive analogs of factor VIIa could result in more potent prohemostatic drugs. Although recombinant factor VIIa is effective in preventing or arresting bleeding in most patients with complex hemostatic disorders, there is a substantial 10% to 20% of cases with unsatisfactory hemostasis. The factor VIIa analogs might provide a more potent treatment option for these patients. Also, patients with excessive and life-threatening bleeding, for example in trauma or upon major surgery, could benefit from highly potent prohemostatic agents. Obviously, the superior efficacy of superactive factor VIIa analogs in these situations needs to be tested in clinical trials before any such claim can be substantiated. Also, the safety of these compounds may be a concern. In view of its potent prohemostatic effect, recombinant factor VIIa is surprisingly safe with an estimated incidence of thrombotic complications in 1% to 2% of patients, including complications that may not be related to the administration of the agent. In the current study by Tranholm et al, there was no sign of fibrin deposition after administration of the factor VIIa analogs at histologic analysis of the kidneys (although a more complete pathologic analysis, involving other organs, would have strengthened this observation). Nevertheless, a precise safety profile of analogs of recombinant factor VIIa will be required as well to assess their potential place in clinical medicine. Awaiting further evidence, superactive analogs of factor VIIa seem to be promising agents for prevention and treatment of excessive bleeding in the future. Marcel Levi University of Amsterdam Academic Medical Center CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Levi, M. Search for Related Content PubMed Articles by Levi, M. Social Bookmarking                   What's this?

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