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Prepublished online as a Blood First Edition Paper on November 27, 2002; DOI 10.1182/blood-2002-07-1951. This Article Full Text (PDF) All Versions of this Article: 2002-07-1951v1 101/7/2628    most recent 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 Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Shi, J. Articles by Gilbert, G. E Search for Related Content PubMed PubMed Citation Articles by Shi, J. Articles by Gilbert, G. E Social Bookmarking                   What's this? Submitted July 1, 2002 Accepted November 6, 2002 Lactadherin inhibits enzyme complexes of blood coagulation by competing for phospholipid binding sites Jialan Shi and Gary E Gilbert* Medicine, Boston VA Healthcare System, Boston, MA, USA; Medicine, Brigham and Women's Hospital, Boston, MA, USA; Medicine, Harvard Medical School, Boston, MA, USA * Corresponding author; email: ggilbert{at}rics.bwh.harvard.edu. Lactadherin, a glycoprotein of the milk fat globule membrane, contains tandem C- domains with homology to discoidin-type lectins and to membrane-binding domains of blood-clotting factors V and VIII. We asked whether the structural homology confers the capacity to compete for the membrane-binding sites of factor VIII and factor V and to function as an anticoagulant. Our results indicate that lactadherin competes efficiently with factor VIII and factor V for binding sites on synthetic phosphatidylserine-containing membranes with half-maximal displacement at lactadherin concentrations of 1-4 nM. Binding competition correlated to functional inhibition of factor VIIIa-factor IXa (factor Xase) enzyme complex. In contrast to annexin V, lactadherin was an efficient inhibitor of the prothrombinase and the factor Xase complexes regardless of the degree of membrane curvature and the phosphatidylserine content. Lactadherin also inhibited the factor VIIa-tissue factor complex efficiently whereas annexin V was less effective. Because the inhibitory concentration of lactadherin was proportional to the phospholipid concentration, and because lactadherin was not an efficient inhibitor in the absence of phospholipid, the major inhibitor effect of lactadherin relates to blocking phospholipid sites rather than forming inhibitory protein-protein complexes. Lactadherin was also an effective inhibitor of a modified whole blood prothrombin time assay in which clotting was initiated by dilute tissue factor; 60 nM lactadherin prolonged the prothrombin time 150% vs. 20% for 60 nM annexin V. These results indicate that lactadherin can function as a potent phospholipid-blocking anticoagulant. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: L. N. Waehrens, C. W. Heegaard, G. E. Gilbert, and J. T. Rasmussen Bovine Lactadherin as a Calcium-independent Imaging Agent of Phosphatidylserine Expressed on the Surface of Apoptotic HeLa Cells J. Histochem. Cytochem., October 1, 2009; 57(10): 907 - 914. [Abstract] [Full Text] [PDF] A. S. Raymond and B. D. Shur A novel role for SED1 (MFG-E8) in maintaining the integrity of the epididymal epithelium J. Cell Sci., March 15, 2009; 122(6): 849 - 858. [Abstract] [Full Text] [PDF] S. K. Dasgupta, H. Abdel-Monem, P. Niravath, A. 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