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 Blood, 15 July 2008, Vol. 112, No. 2, pp. 240-249.
Prepublished online as a Blood First Edition Paper on May 9, 2008; DOI 10.1182/blood-2008-02-124941.

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REVIEW ARTICLE

Dynamics of factor VIII interactions determine its immunologic fate in hemophilia A

Sébastien Lacroix-Desmazes13, Ana-Maria Navarrete13, Sébastien André13, Jagadeesh Bayry13, Srinivas V. Kaveri13, and Suryasarathi Dasgupta13

1 Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris; 2 Université Paris Descartes, Paris; Inserm, Paris; and 3 Inserm, Paris, France

Procoagulant factor VIII (FVIII) is either produced endogenously under physiologic conditions, or administered exogenously as a therapeutic hemostatic drug in patients with hemophilia A. In the circulation, FVIII interacts with a multitude of glycoproteins, and may be used for coagulation at the sites of bleeding, eliminated by scavenger cells, or processed by the immune system, either as a self-constituent or as a foreign antigen. The fate of FVIII is dictated by the immune status of the individual, the location of FVIII in the body at a given time point, and the inflammatory microenvironment. It also depends on the local concentration of FVIII and of each interacting partner, and on the affinity of the respective interactions. FVIII, by virtue of its promiscuity, thus constitutes the core of a dynamic network that links the coagulation cascade, cells of the immune system, and, presumably, the inflammatory compartment. We describe the different interactions that FVIII is prone to establish during its life cycle, with a special focus on players of the innate and adaptive immune response. Lessons can be learned from understanding the dynamics of FVIII interactions—lessons that should pave the way to the conception of long-lasting hemostatic drugs devoid of iatrogenic immunogenicity.


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