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Blood, 15 July 2006, Vol. 108, No. 2, pp. 414-415. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Lozier, J. Search for Related Content PubMed Articles by Lozier, J. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS Comment on Jacquemin et al, page 515 Factor VIII biosynthesis: new inspirations? Jay Lozier FDA CENTER FOR BIOLOGICS EVALUATION AND RESEARCH Many years of study have been devoted to the seemingly simple question of where coagulation factor VIII is made, but the question has never been completely answered. There remains more to know about the origin of coagulation factor VIII in the circulation. Jacquemin and colleagues have shown in this issue of Blood that factor VIII is synthesized in the lung microvascular endothelium. Liver transplantation in human patients with hemophilia A restores normal factor VIII levels.1 Reciprocal organ transplantation studies between normal dogs and those with hemophilia A have shown that the liver is the primary (but not the only) source of factor VIII, however.2 It has been shown in mice that hepatocytes and sinusoidal endothelial cells are the cellular sites of synthesis in the liver.3 However, hepatocyte-specific toxins eliminate almost all factor VIII from the circulation in this species.4 Northern blot analysis of factor VIII expression is technically difficult (since the transcript is large and not very abundant) and has yielded inconclusive results. More sensitive methods to detect factor VIII transcripts (eg, reverse transcriptase–polymerase chain reaction [RT-PCR]) have shown factor VIII mRNA in liver, spleen, and peripheral lymphocytes in humans and other species.4-7 Furthermore, in humans it is known that factor VIII levels remain normal or even elevated in patients with liver disease, even when other coagulation factors are greatly diminished. All of these findings point to hepatic as well as extrahepatic synthesis of factor VIII. Jacquemin and colleagues have shown in this issue of Blood that factor VIII is synthesized in the lung microvascular endothelium. They did so by ventilating and perfusing human cadaveric lungs with a synthetic medium and measuring levels of factor VIII and other proteins during the course of perfusion. Significant amounts of factor VIII (and von Willebrand factor) appeared in the perfusate while factor V, fibrinogen, and immunoglobulin G (IgG) remained unchanged for the duration of the experiments. In vitro studies were performed on conditioned medium from cultivation of fibroblasts, epithelial cells, macrophages, smooth muscle cells, and microvascular endothelial cells. Factor VIII synthesis was observed only in the endothelial cells. The rate of factor VIII synthesis by these endothelial cells in vitro could be extrapolated to account for about 20% of the human factor VIII produced in vivo. Thus, the pulmonary endothelium makes a significant contribution to the factor VIII found in the circulation. This kind of study could be profitably applied to other organs, and it would not be surprising if factor VIII synthesis could be demonstrated in other nonhepatic sites. Perhaps more of this work will appear in the pages of Blood, where much of this story has already been told. Footnotes This work is the opinion of the author and does not constitute US government policy. References Bontempo FA, Lewis JH, Gorenc TJ, et al. Liver transplantation in hemophilia A. Blood. 1987;69: 1721-1724.[Abstract/Free Full Text] Webster WP, Zukoski CF, Hutchin P, et al. Plasma factor VIII synthesis and control as revealed by canine organ transplantation. Am J Physiol. 1971;220: 1147-1154.[Free Full Text] Do H, Healey JF, Waller EK, Lollar P. Expression of factor VIII by mouse liver sinusoidal endothelial cells. J Biol Chem. 1999;274: 19587-19592.[Abstract/Free Full Text] Doering CB, Josephson CD, Craddock HN, Lollar P. Factor VIII expression in azoxymethane-induced murine fulminant hepatic failure. Blood. 2002;100: 143-147.[Abstract/Free Full Text] Healey JF, Lubin IM, Lollar P. The cDNA and derived amino acid sequence of porcine factor VIII. Blood. 1996;88: 4209-4214.[Abstract/Free Full Text] Cameron C, Notley C, Hoyle S, et al. The canine factor VIII cDNA and 5' flanking sequence. Thromb Haemost. 1998;79: 317-322.[Medline] [Order article via Infotrieve] Naylor JA, Green PM, Rizza CR, Giannelli F. Factor VIII gene explains all cases of haemophilia A. Lancet. 1992;340: 1066-1067.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: FVIII production by human lung microvascular endothelial cells Marc Jacquemin, Arne Neyrinck, Maria Iris Hermanns, Renaud Lavend'homme, Filip Rega, Jean-Marie Saint-Remy, Kathelijne Peerlinck, Dirk Van Raemdonck, and Charles James Kirkpatrick Blood 2006 108: 515-517. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Lozier, J. Search for Related Content PubMed Articles by Lozier, J. 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