Thrombosis and Haemostasis, Table of Contents Thromb Haemost 1999; 82(02): 576-584DOI: 10.1055/s-0037-1615883 Research Article Schattauer GmbH Structure and Function of von Willebrand Factor Authors Author Affiliations Zaverio M. Ruggeri 1 Roon Research Center for Arteriosclerosis and Thrombosis, Division of Experimental Hemostasis and Thrombosis, Department of Molecular and Experimental Medicine, Department of Vascular Biology, The Scripps Research Institute, La Jolla, CA, USA Recommend Article Abstract Buy Article(opens in new window) Introduction The reader will find here a concise summary of established notions on the structure and function of von Willebrand factor (vWF), followed by a brief discussion of selected recent advances that illustrate how this molecule supports platelet function in hemostasis and thrombosis. A comprehensive review of the topic is beyond the scope of this chapter and may be found elsewhere.1-3 Full Text References References 1 Ruggeri ZM, Saldivar E. Platelets, hemostasis and thrombosis. Ruggeri ZM. ed. Von Willebrand Factor and the Mechanisms of Platelet Function. Berlin: Springer; 1998: 1-32. 2 Ruggeri ZM. Structure and biosynthesis of von Willebrand factor. In: Ruggeri ZM. ed. Von Willebrand Factor and the Mechanisms of Platelet Function. Berlin: Springer; 1998: 33-77. 3 Ruggeri ZM, Savage B. Biological functions of von Willebrand factor. In: Ruggeri ZM. ed. Von Willebrand Factor and the Mechanisms of Platelet Function. Berlin: Springer; 1998: 79-109. 4 Zimmerman TS, Ratnoff OD, Powell AE. Immunologic differentiation of classic hemophilia (Factor VIII deficiency) and von Willebrand’s disease. With observations on combined deficiencies of antihemophilic factor and proaccelerin (Factor V) and on an acquired circulating anticoagulant against antihemophilic factor. J Clin Invest 1971; 50: 244-254. 5 van Mourik JA, Bouma BN, La Bruyere WT, de Graaf S, Mochtar IA. Factor VIII, a series of homologous oligomers and a complex of two proteins. Thromb Res 1974; 4: 155-164. 6 Ruggeri ZM, Zimmerman TS. Variant von Willebrand’s disease: characterization of two subtypes by analysis of multimeric composition of factor VIII/von Willebrand factor in plasma and platelets. J Clin Invest 1980; 65: 1318-1325. 7 Hoyer LW, Shainoff JR. Factor VIII-related protein circulates in normal human plasma as high molecular weight multimers. Blood 1980; 55: 1056-1059. 8 Perret BA, Furlan M, Beck EA. Studies on factor VIII-related protein. II. Estimation of molecular size differences between factor VIII oligomers. Biochim Biophys Acta 1979; 578: 164-174. 9 Ruggeri ZM, Zimmerman TS. The complex multimeric composition of factor VIII/von Willebrand factor. Blood 1981; 57: 1140-1143. 10 Dent JA, Galbusera M, Ruggeri ZM. Heterogeneity of plasma von Willebrand factor multimers resulting from proteolysis of the constituent subunit. J Clin Invest 1991; 88: 774-782. 11 Titani K, Kumar S, Takio K, Ericsson LH, Wade RD, Ashida K, Walsh KA, Chopek MW, Sadler JE, Fujikawa K. Amino acid sequence of human von Willebrand factor. Biochemistry 1986; 25: 3171-3184. 12 Fowler WE, Fretto LJ, Hamilton KK, Erickson HP, McKee PA. Substructure of human von Willebrand factor. J Clin Invest 1985; 76: 1491-1500. 13 Fowler WE, Fretto LJ. Electron microscopy of von Willebrand factor. In: Zimmerman TS, Ruggeri ZM. eds. Coagulation and Bleeding Disorders. The Role of Factor VIII and von Willebrand Factor. New York: Marcel Dekker, Inc; 1989: 181-193. 14 Zimmerman TS, Dent JA, Ruggeri ZM, Nannini LH. Subunit composition of plasma von Willebrand factor. Cleavage is present in normal individuals, increased in IIA and IIB von Willebrand disease, but minimal in variants with aberrant structure of individual oligomers (Types IIC, IID and IIE). J Clin Invest 1986; 77: 947-951. 15 Dent JA, Berkowitz SD, Ware J, Kasper CK, Ruggeri ZM. Identification of a cleavage site directing the immunochemical detection of molecular abnormalities in type IIA von Willebrand factor. Proc Natl Acad Sci USA 1990; 87: 6306-6310. 16 Sporn LA, Marder VJ, Wagner DD. Inducible secretion of large, biologically potent von Willebrand factor multimers. Cell 1986; 46: 185-190. 17 Lopez-Fernandez MF, Ginsberg MH, Ruggeri ZM, Batlle J, Zimmerman TS. Multimeric structure of platelet factor VIII/von Willebrand factor. The presence of larger multimers and their reassociation with thrombin-stimulated platelets. Blood 1982; 60: 1132-1138. 18 Moake JL, Rudy CK, Troll JH, Weinstein MJ, Colannino NM, Azacar J, Seder RH, Hong SL, Deykin D. Unusually large plasma factor VIII: von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Engl J Med 1982; 307: 1432-1435. 19 Furlan M, Robles R, Lammle B. Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis. Blood 1996; 87: 4223-4234. 20 Tsai HM. Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion. Blood 1996; 87: 4235-4244. 21 Siediecki CA, Lestini BJ, Kottke-Marchant K, Eppell SJ, Wilson DL, Marchant RE. Shear-dependent changes in the three-dimensional structure of human von Willebrand factor. Blood 1996; 88: 2939-2950. 22 Mancuso DJ, Tuley EA, Westfield LA, Worrall NK, Shelton-Inloes BB, Sorace JM, Alevy YG, Sadler JE. Structure of the gene for human von Willebrand factor. J Biol Chem 1989; 264: 19514-19527. 23 Ginsburg D, Handin RI, Bonthron DT, Donlon TA, Bruns GAP, Latt SA, Orkin SH. Human von Willebrand factor (vWF): isolation of complementary DNA (cDNA) clones and chromosomal localization. Science 1985; 228: 1401-1406. 24 Mancuso DJ, Tuley EA, Westfield LA, Lester-Mancuso TL, Le Beau MM, Sorace JM, Sadler JE. Human von Willebrand factor gene and pseudogene: structural analysis and differentiation by polymerase chain reaction. Biochemistry 1991; 30: 253-269. 25 Jahroudi N, Lynch DC. Endothelial-cell-specific regulation of von Willebrand factor gene expression. Mol Cell Biol 1994; 14: 999-1008. 26 Ferreira V, Assouline Z, Schwachtgen JL, Bahnak BR, Meyer D, Kerbiriou-Nabias D. The role of the 5’-flanking region in the cell-specific transcription of the human von Willebrand factor gene. Biochem J 1993; 293: 641-648. 27 Aird WC, Jahroudi N, Weiler-Guettler H, Rayburn HB, Rosenberg RD. Human von Willebrand factor gene sequences target expression to a subpopulation of endothelial cells in transgenic mice. Proc Natl Acad Sci USA 1995; 92: 4567-4571. 28 Wu QY, Drout L, Carrier JL, Rothschild C, Berard M, Rouault C, Caen JP, Meyer D. Differential distribution of von Willebrand factor in endothelial cells. Comparison between normal pigs and pigs with von Willebrand disease. Arteriosclerosis 1987; 7: 47-54. 29 Bahnak BR, Wu Q-Y, Coulombel L, Assouline Z, Kerbiriou-Nabias D, Pietu G, Drouet L, Caen JP, Meyer D. Expression of von Willebrand factor in porcine vessels: heterogeneity at the level of von Willebrand factor mRNA. J Cell Physiol 1989; 138: 305-310. 30 Bonthron DT, Handin RI, Kaufman RJ, Wasley LC, Orr EC, Mitsock LM, Ewenstein B, Loscalzo J, Ginsburg D, Orkin SH. Structure of pre-pro-von Willebrand factor and its expression in heterologous cells. Nature 1986; 324: 270-273. 31 Verweij CL, Diergaarde PJ, Hart M, Pannekoek H. Full-length von Willebrand factor (vWF) cDNA encodes a highly repetitive protein considerably larger than the mature vWF subunit. EMBO J 1986; 5: 1839-1847. 32 Wagner DD, Fay PJ, Sporn LA, Sinha S, Lawrence SO, Marder VJ. Divergent fates of von Willebrand factor and its propolypeptide (von Willebrand antigen II) after secretion from endothelial cells. Proc Natl Acad Sci USA 1987; 84: 1955-1959. 33 Vischer UM, Wagner DD. von Willebrand factor proteolytic processing and multimerization precede the formation of Weibel–Palade bodies. Blood 1994; 83: 3536-3544. 34 Fay PJ, Kawai Y, Wagner DD, Ginsburg D, Bonthron D, Ohlsson-Wilhelm BM, Chavin SI, Abraham GN, Handin RI, Orkin SH, Montgomery RR, Marder VJ. Propolypeptide of von Willebrand factor circulates in blood and is identical to von Willebrand antigen II. Science 1986; 232: 995-998. 35 Montgomery RR, Zimmerman TS. von Willebrand’s disease antigen II: a new plasma and platelet antigen deficient in severe von Willebrand’s disease. J Clin Invest 1978; 61: 1498-1507. 36 Shelton-Inloes BB, Titani K, Sadler JE. cDNA sequences for human von Willebrand factor reveal five types of repeated domains and five possible protein sequence polymorphisms. Biochemistry 1986; 25: 3164-3171. 37 Colombatti A, Bonaldo P. The superfamily of proteins with von Willebrand factor type A-like domains: one theme common to components of extracellular matrix, hemostasis, cellular adhesion, and defense mechanisms. Blood 1991; 77: 2305-2315. 38 Hunt LT, Barker WC. von Willebrand Factor shares a distinctive cystein-rich domain with thrombospondin and procollagen. Biochem Biophys Res Commun 1987; 144: 876-882. 39 Ginsberg MH, Loftus JC, Plow EF. Cytoadhesins, integrins, and platelets. Thromb Haemost 1988; 59: 1-6. 40 Hynes RO. Integrins: versatility, modulation and signaling in cell adhesion. Cell 1992; 69: 11-25. 41 Wagner DD, Lawrence SO, Ohlsson-Wilhelm BM, Fay PJ, Marder VJ. Topology and order of formation of interchain disulfide bonds in von Willebrand factor. Blood 1987; 69: 27-32. 42 Voorberg J, Fontijn R, Calafat J, Janssen H, van Mourik JA, Pannekoek H. Assembly and routing of von Willebrand factor variants: the requirements for disulfide-linked dimerization reside within the carboxy-terminal 151 amino acids. J Cell Biol 1991; 113: 195-205. 43 Schneppenheim R, Brassard J, Krey S, Budde U, Kunicki TJ, Holmberg L, Ware J, Ruggeri ZM. Defective dimerization of von Willebrand factor subunits due to a Cys to Arg mutation in type IID von Willebrand disease. Proc Natl Acad Sci USA 1996; 93: 3581-3586. 44 Voorberg J, Fontijn R, van Mourik JA, Pannekoek H. Domains involved in multimer assembly of von Willebrand factor (vWF): multimerization is independent of dimerization. EMBO J 1990; 9: 797-803. 45 Mayadas TN, Wagner DD. Vicinal cysteines in the prosequence play a role in von Willebrand factor multimer assembly. Proc Natl Acad Sci USA 1992; 89: 3531-3535. 46 Kinoshita S, Harrison J, Lazerson J, Abildgaard CF. A new variant of dominant type II von Willebrand’s disease with aberrant multimeric pattern of factor VIII-related antigen (type IID). Blood 1984; 63: 1369-1371. 47 Loesberg C, Gonsalves MD, Zandbergen J, Willems C, Van Aken WG, Stel HV, van Mourik JA, DeGroot PG. The effect of calcium on the secretion of factor VIII-related antigen by cultured human endothelial cells. Biochim Biophys Acta 1983; 763: 160-168. 48 Wagner DD. Storage and secretion of von Willebrand factor. In: Zimmerman TS, Ruggeri ZM. eds. Coagulation and Bleeding Disorders. The Role of Factor VIII and von Willebrand Factor. New York: Marcel Dekker, Inc; 1989: 161-180. 49 Wagner DD. Cell biology of von Willebrand factor. Annu Rev Cell Biol 1990; 6: 217-246. 50 v.d. Kwast TH, Stel HV, Cristen E, Bertina RM, Veerman ECI. Localization of factor VIII-procoagulant antigen: an immunohistological survey of the human body using monoclonal antibodies. Blood 1986; 67: 222-227. 51 Takeuchi M, Nagura H, Kaneda T. DDAVP and epinephrine-induced changes in the localization of von Willebrand factor antigen in endothelial cells of human oral mucosa. Blood 1988; 72: 850-854. 52 Hop C, Fontijn R, VanMourik JA, Pannekoek H. Polarity of constitutive and regulated von Willebrand factor secretion by transfected MDCK-II cells. Exp Cell Res 1997; 230: 352-361. 53 Nachman RL, Levine R, Jaffe EA. Synthesis of factor VIII antigen by cultured guinea pig megakaryocytes. J Clin Invest 1977; 60: 914-921. 54 Sporn LA, Chavin SI, Marder VJ, Wagner DD. Biosynthesis of von Willebrand protein by human megakaryocytes. J Clin Invest 1985; 76: 1102-1106. 55 Bowie EJ, Solberg Jr LA, Fass DN, Johnson CM, Knutson GJ, Stewart ML, Zoecklein LJ. Transplantation of normal bone marrow into a pig with severe von Willebrand’s disease. J Clin Invest 1986; 78: 26-30. 56 Koutts J, Walsh PN, Plow EF, Fenton JW, Bouma BN, Zimmerman TS. Active release of human platelet Factor VIII-related antigen by adenosine diphosphate, collagen and thrombin. J Clin Invest 1978; 62: 1255-1263. 57 Roth GJ, Titani K, Hoyer LW, Hickey MJ. Localization of binding sites within human von Willebrand factor for monomeric type III collagen. Biochemistry 1986; 25: 8357-8361. 58 Pareti FI, Fujimura Y, Dent JA, Holland LZ, Zimmerman TS, Ruggeri ZM. Isolation and characterization of a collagen binding domain in human von Willebrand factor. J Biol Chem 1986; 261: 15310-15315. 59 Pareti FI, Niiya K, McPherson JM, Ruggeri ZM. Isolation and characterization of two domains of human von Willebrand factor that interact with fibrillar collagen types I and III. J Biol Chem 1987; 262: 13835-13841. 60 Mohri H, Yoshioka A, Zimmerman TS, Ruggeri ZM. Isolation of the von Willebrand factor domain interacting with platelet glyco-protein Ib heparin, and collagen, and characterization of its three distinct functional sites. J Biol Chem 1989; 264: 17361-17367. 61 Cruz MA, Yuan H, Lee JR, Wise RJ, Handin RI. Interaction of the von Willebrand factor (vWF) with collagen. J Biol Chem 1995; 270: 10822-10827. 62 Hoylaerts MF, Yamamoto H, Nuyts K, Vreys I, Deckmyn H, Vermylen J. von Willebrand factor binds to native collagen VI primarily via its A1 domain. Biochem J 1997; 324: 185-191. 63 Yamamoto H, Vermylen J, Hoylaerts MF. Exposure of von Willebrand factor to shear forces stimulates A1 domain mediated interaction with collagen. Thromb Haemost 1997; 78: 642-643. 63a Mazzucato M, Spessotto P, Masotti A, De Appollonia L, Cozzi MR, Yoshioka A, Perris R, Colombatti A, De Marco L. Identification of domains responsible for von Willebrand factor type VI collagen interaction mediating platelet adhesion under high flow. J Biol Chem 1999; 274: 3033-3041. 64 Fujimura Y, Titani K, Holland LZ, Roberts JR, Kostel P, Ruggeri ZM, Zimmerman TS. A heparin-binding domain of human von Willebrand factor. Characterization and localization to a tryptic fragment extending from amino acid residue Val-449 to Lys-728. J Biol Chem 1987; 262: 1734-1739. 65 Sobel M, Soler DF, Kermode JC, Harris RB. Localization and characterization of a heparin binding domain peptide of human von Willebrand factor. J Biol Chem 1992; 267: 8857-8862. 66 Fretto LJ, Fowler WE, McCaslin DR, Erickson HP, McKee PA. Substructure of human von Willebrand factor. Proteolysis by V8 and characterization of two functional domains. J Biol Chem 1986; 261: 15679-15689. 67 Fujimura Y, Titani K, Holland LZ, Russell SR, Roberts JR, Elder JH, Ruggeri ZM, Zimmerman TS. von Willebrand factor. A reduced and alkylated 52/48 kDa fragment beginning at amino acid residue 449 contains the domain interacting with platelet glycoprotein Ib. J Biol Chem 1986; 261: 381-385. 68 Mohri H, Fujimura Y, Shima M, Yoshioka A, Houghten RA, Ruggeri ZM, Zimmerman TS. Structure of the von Willebrand factor domain interacting with glycoprotein Ib. J Biol Chem 1988; 263: 17901-17904. 69 Scott JP, Montgomery RR, Retzinger GS. Dimeric ristocetin flocculates proteins, binds to platelets, and mediates von Willebrand factor-dependent agglutination of platelets. J Biol Chem 1991; 266: 8149-8155. 70 Berndt MC, Ward CM, Booth WJ, Castaldi PA, Mazurov AV, Andrews RK. Identification of aspartic acid 514 through glutamic acid 542 as a glycoprotein Ib-IX complex receptor recognition sequence in von Willebrand factor. Mechanisms of modulation of von Willebrand factor by ristocetin and botrocetin. Biochemistry 1992; 31: 11144-11151. 71 Knott HM, Berndt MC, Kralicek AV, O’Donoghue SI, King GF. Determination of the solution structure of a platelet-adhesion peptide of von Willebrand factor. Biochemistry 1992; 31: 11152-11158. 72 Matsushita T, Sadler JE. Identification of amino acid residues essential for von Willebrand factor binding to platelet glycoprotein Ib. J Biol Chem 1995; 270: 13406-13414. 73 Celikel R, Varughese KI, Madhusudan A, Yoshioka A, Ware J, Ruggeri ZM. Crystal structure of von Willebrand factor A1 domain in complex with the function blocking NMC-4 Fab. Nat Struct Biol 1998; 5: 189-194. 74 Emsley J, Cruz M, Handin R, Liddington R. Crystal structure of the von Willebrand factor A1 domain and implications for the binding of platelet glycoprotein Ib. J Biol Chem 1998; 273: 10396-10401. 75 Huizinga EG, van der Plas RM, Kroon J, Sixma JJ, Gros P. Crystal structure of the A3 domain of human von Willebrand factor: implications for collagen binding. Structure 1997; 5: 1147-1156. 76 Bienkowska J, Cruz MA, Handin RI, Liddington RC. The von Willebrand factor A3 domain does not contain a metal ion-dependent adhesion site motif. J Biol Chem 1997; 272: 25162-25167. 77 Lee J-O, Rieu P, Arnaout MA, Liddington R. Crystal structure of the A domain from the α subunit of integrin CR3 (CD11b/CD18). Cell 1995; 80: 631-638. 78 Qu A, Leahy DJ. Crystal structure of the I-domain from the CD11a/CD18 (LFA-1, αLβ2) integrin. Proc Natl Acad Sci USA 1995; 92: 10277-10281. 79 Emsley J, King SL, Bergelson JM, Liddington TC. Crystal structure of the I domain from integrin α 2β1. J Biol Chem 1997; 272: 28512-28517. 80 Kamata T, Puzon W, Takada Y. Identification of putative ligand binding sites within I domain of integrin alpha 2 beta 1 (VLA-2, CD49b/CD29). J Biol Chem 1994; 269: 9659-9663. 81 Pierschbacher MD, Ruoslahti E. Cell attachment activity of fibronectin can be duplicated by small synthetic fragments of the molecule. Nature 1984; 309: 30-33. 82 Ruoslahti E, Pierschbacher MD. New perspectives in cell adhesion: RGD and integrins. Science 1987; 238: 491-497. 83 Hynes RO. Integrins: a family of cell surface receptors. Cell 1987; 48: 549-554. 84 Plow EF, Srouji AH, Meyer D, Marguerie G, Ginsberg MH. Evidence that three adhesive proteins interact with a common recognition site on activated platelets. J Biol Chem 1984; 259: 5385-5391. 85 Berliner S, Niiya K, Roberts JR, Houghten RA, Ruggeri ZM. Generation and characterization of peptide-specific antibodies that inhibit von Willebrand factor binding to GP IIb-IIIa without interacting with other adhesive molecules: selectivity is conferred by Pro 1743 and other amino acid residues adjacent to the sequence Arg1744-Gly1745-Asp1746. J Biol Chem 1988; 263: 7500-7505. 86 Beacham DA, Wise RJ, Turci SM, Handin RI. Selective inactivation of the Arg-Gly-Asp-Ser (RGDS) binding site in von Willebrand factor by site-directed Mutagenesis. J Biol Chem 1992; 267: 3409-3415. 87 Dejana E, Lampugnani MG, Giorgi M, Gaboli M, Federici AB, Ruggeri ZM. von Willebrand factor promotes endothelial cell adhesion via an Arg-Gly-Asp-dependent mechanism. J Cell Biol 1989; 109: 367-375. 88 Foster PA, Fulcher CA, Marti T, Titani K, Zimmerman TS. A major factor VIII binding domain resides within the amino-terminal 272 amino acid residues of von Willebrand factor. J Biol Chem 1987; 262: 8443-8446. 89 Bahou WF, Ginsburg D, Sikkink R, Litwiller R, Fass DN. A monoclonal antibody to von Willebrand factor (vWF) inhibits factor VIII binding. Localization of its antigenic determinant to a non-adecapeptide at the amino terminus of the mature vWF polypeptide. J Clin Invest 1989; 84: 56-61. 90 Ginsburg D, Bockenstedt PL, Allen EA, Fox DA, Foster PA, Ruggeri ZM, Zimmerman TS, Montgomery RR, Bahou WF, Johnson TA, Yang AY. Fine mapping of monoclonal antibody epitopes on human von Willebrand factor using a recombinant peptide library. Thromb Haemost 1992; 67: 166-171. 91 Tuley EA, Gaucher C, Jorieux S, Worrall NK, Sadler JE, Mazurier C. Expression of von Willebrand factor “Normandy:” an autosomal mutation that mimics hemophilia A. Proc Natl Acad Sci USA 1991; 88: 6377-6381. 92 Gaucher C, Mercier B, Jorieux S, Oufkir D, Mazurier C. Identification of two point mutations in the von Willebrand factor gene of three families with the “Normandy” variant of von Willebrand disease. Br J Haematol 1991; 78: 506-514. 93 Cacheris PM, Nichols WC, Ginsburg D. Molecular characterization of a unique von Willebrand disease variant. J Biol Chem 1991; 266: 13499-13502. 94 Kroner PA, Friedman KD, Fahst SA, Scott JP, Montgomery RR. Abnormal binding of factor VIII is linked with the substitution of glutamine for arginine 91 in von Willebrand factor in a variant form of von Willebrand disease. J Biol Chem 1991; 266: 19146-19149. 95 Gu J, Jorieux S, Lavergne JM, Ruan C, Mazurier C, Meyer D. A patient with type 2N von Willebrand disease is heterozygous for a new mutation: Gly22Glu. Demonstration of a defective expression of the second allele by the use of monoclonal antibodies. Blood 1997; 89: 3263-3269. 96 Roberts DD, Williams SB, Gralnick HR, Ginsburg V. von Willebrand factor binds specifically to sulfated glycolipids. J Biol Chem 1986; 261: 3306-3309. 97 Christophe O, Obert B, Meyer D, Girma J-P. The binding domain of von Willebrand factor to sulfatides is distinct from those interacting with glycoprotein Ib heparin, and collagen and resides between amino acid residues Leu 512 and Lys 673. Blood 1991; 78: 2310-2317. 98 Ribes JA, Francis CW. Multimer size dependence of von Willebrand factor binding to crosslinked or noncrosslinked fibrin. Blood 1990; 75: 1460-1465. 99 Hada M, Kaminski M, Bockenstedt P, McDonagh J. Covalent crosslinking of von Willebrand Factor to fibrin. Blood 1986; 68: 95-101. 100 Tangelder GJ, Slaaf DW, Arts T, Reneman RS. Wall shear rate in arterioles in vivo: least estimates from platelet velocity profiles. Am J Physiol 1988; 254: H1059-H1064 101 Savage B, Saldivar E, Ruggeri ZM. Initiation of platelet adhesion by arrest onto fibrinogen or translocation on von Willebrand factor. Cell 1996; 84: 289-297. 102 Savage B, Almus-Jacobs F, Ruggeri ZM. Specific synergy of multiple substrate-receptor interactions in platelet thrombus formation under flow. Cell 1998; 94: 657-666. 103 Back CH, Radbill JR, Crawford DW. Analysis of pulsatile viscous blood flow through diseased coronary arteries of man. J Biomech (Tokyo) 1977; 10: 339-353. 104 Ikeda Y, Handa M, Kawano K, Kamata T, Murata M, Araki Y, Anbo H, Kawai Y, Watanabe K, Itagaki I, Sakai K, Ruggeri ZM. The role of von Willebrand factor and fibrinogen in platelet aggregation under varying shear stress. J Clin Invest 1991; 87: 1234-1240. 105 Phillips DR, Charo IF, Scarborough RM. GPIIb-IIIa: the responsive integrin. Cell 1991; 65: 359-362. 106 Polanowska-Grabowska R, Geanacopoulos M, Gear ARL. Platelet adhesion to collagen via the α2β1 integrin under flow conditions causes rapid tyrosine phosphorylation of pp125FAK . Biochem J 1993; 296: 543-547. 107 Keely PJ, Parise LV. The α2β1 integrin is a necessary co-receptor for collagen-induced activation of Syk and subsequent phosphorylation of phospholipase Cy2 in platelets. J Biol Chem 1996; 271: 26668-26676. 108 Nieuwenhuis HK, Akkerman JWN, Houdijk WPM, Sixma JJ. Human blood platelets showing no response to collagen fail to express surface glycoprotein Ia. Nature 1985; 318: 470-472. 109 Goto S, Ikeda Y, Saldivar E, Ruggeri ZM. Distinct mechanisms of platelet aggregation as a consequence of different shearing flow conditions. J Clin Invest 1998; 101: 479-486. 110 Weiss HJ. Platelet physiology and abnormalities of platelet function (first of two parts). N Engl J Med 1975; 293: 531-541. 111 Weiss HJ. Platelet physiology and abnormalities of platelet function (second of two parts). N Engl J Med 1975; 293: 580-588. 112 Sixma JJ, Wester J. The hemostatic plug. Semin Hematol 1977; 14: 265-299. 113 Kroll MH, Hellums JD, McIntire LV, Schafer AI, Moake JL. Platelets and shear stress. Blood 1996; 88: 1525-1541. 114 Ruggeri ZM, Dent JA, Saldivar E. Contribution of distinct adhesive interactions to platelet aggregation in flowing blood. Blood. In press.
