Tissue Factor, Lipid Rafts, and Microparticles Pavel Davizon, M.D., 1 Adam D. Munday, Ph.D., 1 and Jose ´ A. Lo ´ pez, M.D. 1,2 ABSTRACT Evidence is emerging that tissue-factor–bearing microparticles and other micro- particles arise from regions of the parent cell’s plasma membrane that are rich in lipid rafts. In this brief review, we summarize the evidence for the raft origins of microparticles and the implications of these origins for the biological and medical consequences of micro- particle production and for therapeutic strategies to diminish their production and potential to do harm. KEYWORDS: Tissue factor, lipid rafts, microparticles, thrombosis, cancer TISSUE FACTOR: BRIEF HISTORY, STRUCTURE, AND BIOLOGY Tissue factor (TF) is the primary initiator of blood coagulation under both physiological and pathological situations. Recent discoveries have highlighted its rele- vance not only in clotting but also in inflammation, 1 tumor growth, 2,3 and angiogenesis, 4,5 processes that are quite often interdependent. TF was first recognized in the late 1800s as a mysterious factor in brain emulsions that, when injected intravenously into rabbits, caused disseminated intra- vascular coagulation and death. 6 This factor was given a series of names, first in 1906 by Morawitz 7 who called it ‘‘thrombokinase,’’ followed by Nolf who in 1908 called it ‘‘tissue thromboplastin,’’ and finally by Howell who in 1935 introduced the term tissue factor. 8,9 It was not until 1985 that human TF was purified, 10 which led to the subsequent cloning of its cDNA and gene. 11–14 TF is encoded by a 12.5-kb gene located on human chromosome 1 (p21-p22). 15–17 The primary structure of mature tissue factor predicts a 263–amino acid type I transmembrane protein with a molecular mass of 45 kDa. TF possesses two extracellular disulfide bonds, one of them (Cys 186 –Cys 209 ) regulating TF procoagulant activity. 18 The TF cytoplasmic domain contains a single cysteine residue (Cys 245 ) that is prone to palmitoylation, discussed in detail later. 19,20 Early on, it was suggested that TF provides a ‘‘hemostatic envelope’’ 21 by virtue of being constitutively expressed in tissues immediately surrounding the blood, 22 in particular the adventitia of venules and arteries, where it is poised to arrest bleeding. 23 TF is also highly expressed in the lungs (bronchial mucosal and alveolar epithelium), brain, and kidneys. 21 TF ini- tiates the extrinsic coagulation pathway, so called be- cause it was believed physiological blood clotting only occurred when the blood contacted extravascular TF. However, in recent years it has become more widely appreciated that TF can also initiate coagulation within blood vessels through a circulating TF pool unassociated with cells. 24 Most of this circulating TF is carried on cell-derived microparticles, 25 although a soluble, alter- natively spliced form without significant coagulant ac- tivity has also been described. 26 Further, monocytes and endothelial cells can also express TF as a physiological response to stimuli such as bacterial lipopolysaccharide (LPS) and inflammatory cytokines. 27–29 Evidence has been presented that TF is expressed by platelets 30 and neutrophils, 31 but whether TF is synthesized in these cells in vivo is still disputed. 1 Research Division, Puget Sound Blood Center, and 2 Departments of Medicine and Biochemistry, University of Washington, Seattle, Washington. Address for correspondence and reprint requests: Jose ´ A. Lo ´pez, M.D., Research Division, Puget Sound Blood Center, 921 Terry Avenue, Seattle, WA 98104 (e-mail: josel@psbcresearch.org). Microparticles in Thrombosis and Hemostasis; Guest Editors, Nigel S. Key, M.D., and Hau C. Kwaan, M.D., Ph.D. Semin Thromb Hemost 2010;36:857–864. Copyright # 2010 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. DOI: http://dx.doi.org/10.1055/s-0030-1267039. ISSN 0094-6176. 857 Downloaded by: University of Washington at Seattle. Copyrighted material.