Blood Reviews
Volume 23, Issue 4 , Pages 177-189 , July 2009

Platelet α-granules: Basic biology and clinical correlates

  • Price Blair
  • ,
  • Robert Flaumenhaft

      Affiliations

    • Corresponding Author InformationCorresponding author. Address: Center for Life Science, Rm 939, Beth Israel Deaconess Medical Center, 3 Blackfan Circle, Boston, MA 02215, USA. Tel.: +1 617 735 4005; fax: +1 617 735 4000.

References 

  1. Frojmovic MM, Milton JG. Human platelet size, shape, and related functions in health and disease. Physiol Rev. 1982;62:185–261
  2. White JG, Clawson CC. The surface-connected canalicular system of blood platelets – a fenestrated membrane system. Am J Pathol. 1980;101:353–364
  3. Harrison P, Cramer EM. Platelet alpha-granules. Blood Rev. 1993;7:52–62
  4. Italiano JE, Richardson JL, Patel-Hett S, et al. Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood. 2008;111:1227–1233
  5. Sehgal S, Storrie B. Evidence that differential packaging of the major platelet granule proteins von Willebrand factor and fibrinogen can support their differential release. J Thromb Haemost. 2007;5:2009–2016
  6. Cramer EM, Harrison P, Savidge GF, et al. Uncoordinated expression of alpha-granule proteins in human megakaryocytes. Prog Clin Biol Res. 1990;356:131–142
  7. Hegyi E, Heilbrun LK, Nakeff A. Immunogold probing of platelet factor 4 in different ploidy classes of rat megakaryocytes sorted by flow cytometry. Exp Hematol. 1990;18:789–793
  8. Moebius J, Zahedi RP, Lewandrowski U, Berger C, Walter U, Sickmann A. The human platelet membrane proteome reveals several new potential membrane proteins. Mol Cell Proteom. 2005;4:1754–1761
  9. Li W, Rusiniak ME, Chintala S, Gautam R, Novak EK, Swank RT. Murine Hermansky-Pudlak syndrome genes: regulators of lysosome-related organelles. Bioessays. 2004;26:616–628
  10. King SM, Reed GL. Development of platelet secretory granules. Semin Cell Dev Biol. 2002;13:293–302
  11. Piper RC, Katzmann DJ. Biogenesis and function of multivesicular bodies. Annu Rev Cell Dev Biol. 2007;23:519–547
  12. Woodman PG, Futter CE. Multivesicular bodies: co-ordinated progression to maturity. Curr Opin Cell Biol. 2008;20:408–414
  13. Heijnen HF, Debili N, Vainchencker W, Breton-Gorius J, Geuze HJ, Sixma JJ. Multivesicular bodies are an intermediate stage in the formation of platelet alpha-granules. Blood. 1998;91:2313–2325
  14. Youssefian T, Cramer EM. Megakaryocyte dense granule components are sorted in multivesicular bodies. Blood. 2000;95:4004–4007
  15. Heijnen HF, Schiel AE, Fijnheer R, Geuze HJ, Sixma JJ. Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules. Blood. 1999;94:3791–3799
  16. Zucker-Franklin D. Endocytosis by human platelets: metabolic and freeze-fracture studies. J Cell Biol. 1981;91:706–715
  17. Behnke O. Coated pits and vesicles transfer plasma components to platelet granules. Thromb Haemost. 1989;62:718–722
  18. Behnke O. Degrading and non-degrading pathways in fluid-phase (non-adsorptive) endocytosis in human blood platelets. J Submicrosc Cytol Pathol. 1992;24:169–178
  19. Stenberg PE, Pestina TI, Barrie RJ, Jackson CW. The Src family kinases, Fgr, Fyn, Lck, and Lyn, colocalize with coated membranes in platelets. Blood. 1997;89:2384–2393
  20. Pestina TI, Stenberg PE, Druker BJ, et al. Identification of the Src family kinases, Lck and Fgr in platelets. Their tyrosine phosphorylation status and subcellular distribution compared with other Src family members. Arterioscler Thromb Vasc Biol. 1997;17:3278–3285
  21. Panigada M, Porcellini S, Barbier E, et al. Constitutive endocytosis and degradation of the pre-T cell receptor. J Exp Med. 2002;195:1585–1597
  22. Heilmann E, Hynes LA, Friese P, George IN, Burstein SA, Dale GL. Dog platelets accumulate intracellular fibrinogen as they age. J Cell Physiol. 1994;161:23–30
  23. Cramer EM, Debili N, Martin JF, et al. Uncoordinated expression of fibrinogen compared with thrombospondin and von Willebrand factor in maturing human megakaryocytes. Blood. 1989;73:1123–1129
  24. Koedam JA, Cramer EM, Briend E, Furie B, Furie BC, Wagner DD. P-Selectin, a granule membrane protein of platelets and endothelial cells, follows the regulated secretory pathway in AtT-20 cells. J Cell Biol. 1992;116:617–625
  25. Daugherty BL, Straley KS, Sanders JM, et al. AP-3 adaptor functions in targeting P-selectin to secretory granules in endothelial cells. Traffic. 2001;2:406–413
  26. Disdier M, Morrissey JH, Fugate RD, Bainton DF, McEver RP. Cytoplasmic domain of P-selectin (CD62) contains the signal for sorting into the regulated secretory pathway. Mol Biol Cell. 1992;3:309–321
  27. Green SA, Setiadi H, McEver RP, Kelly RB. The cytoplasmic domain of P-selectin contains a sorting determinant that mediates rapid degradation in lysosomes. J Cell Biol. 1994;124:435–448
  28. Hartwell DW, Mayadas TN, Berger G, et al. Role of P-selectin cytoplasmic domain in granular targeting in vivo and in early inflammatory responses. J Cell Biol. 1998;143:1129–1141
  29. Briquet-Laugier V, Lavenu-Bombled C, Schmitt A, et al. Probing platelet factor 4 alpha-granule targeting. J Thromb Haemost. 2004;2:2231–2240
  30. El Golli N, Issertial O, Rosa JP, Briquet-Laugier V. Evidence for a granule targeting sequence within platelet factor 4. J Biol Chem. 2005;280:30329–30335
  31. Woulfe DS, Lilliendahl JK, August S, et al. Serglycin proteoglycan deletion induces defects in platelet aggregation and thrombus formation in mice. Blood. 2008;111:3458–3467
  32. Tooze SA, Martens GJ, Huttner WB. Secretory granule biogenesis: rafting to the SNARE. Trends Cell Biol. 2001;11:116–122
  33. Hayward CP, Song Z, Zheng S, et al. Multimerin processing by cells with and without pathways for regulated protein secretion. Blood. 1999;94:1337–1347
  34. Cramer EM, Meyer D, le Menn R, Breton-Gorius J. Eccentric localization of von Willebrand factor in an internal structure of platelet alpha-granule resembling that of Weibel-Palade bodies. Blood. 1985;66:710–713
  35. Huang RH, Wang Y, Roth R, et al. Assembly of Weibel-Palade body-like tubules from N-terminal domains of von Willebrand factor. Proc Natl Acad Sci USA. 2008;105:482–487
  36. Blagoveshchenskaya AD, Hannah MJ, Allen S, Cutler DF. Selective and signal-dependent recruitment of membrane proteins to secretory granules formed by heterologously expressed von Willebrand factor. Mol Biol Cell. 2002;13:1582–1593
  37. Wagner DD, Saffaripour S, Bonfanti R, et al. Induction of specific storage organelles by von Willebrand factor propolypeptide. Cell. 1991;64:403–413
  38. Handagama P, Scarborough RM, Shuman MA, Bainton DF. Endocytosis of fibrinogen into megakaryocyte and platelet alpha-granules is mediated by alpha IIb beta 3 (glycoprotein IIb–IIIa). Blood. 1993;82:135–138
  39. Handagama P, Bainton DF, Jacques Y, Conn MT, Lazarus RA, Shuman MA. Kistrin, an integrin antagonist, blocks endocytosis of fibrinogen into guinea pig megakaryocyte and platelet alpha-granules. J Clin Invest. 1993;91:193–200
  40. Handagama PJ, Amrani DL, Shuman MA. Endocytosis of fibrinogen into hamster megakaryocyte alpha granules is dependent on a dimeric gamma A configuration. Blood. 1995;85:1790–1795
  41. Handagama PJ, Shuman MA, Bainton DF. Incorporation of intravenously injected albumin, immunoglobulin G, and fibrinogen in guinea pig megakaryocyte granules. J Clin Invest. 1989;84:73–82
  42. Handagama PJ, George JN, Shuman MA, McEver RP, Bainton DF. Incorporation of a circulating protein into megakaryocyte and platelet granules. Proc Natl Acad Sci USA. 1987;84:861–865
  43. George JN, Saucerman S. Platelet IgG, IgA, IgM, and albumin: correlation of platelet and plasma concentrations in normal subjects and in patients with ITP or dysproteinemia. Blood. 1988;72:362–365
  44. Bouchard BA, Meisler NT, Nesheim ME, Liu CX, Strickland DK, Tracy PB. A unique function for LRP-1: a component of a two-receptor system mediating specific endocytosis of plasma-derived factor V by megakaryocytes. J Thromb Haemost. 2008;6:638–644
  45. Bouchard BA, Williams JL, Meisler NT, Long MW, Tracy PB. Endocytosis of plasma-derived factor V by megakaryocytes occurs via a clathrin-dependent, specific membrane binding event. J Thromb Haemost. 2005;3:541–551
  46. Tavassoli M. Fusion–fission reorganization of membrane: a developing membrane model for thrombocytogenesis in megakaryocytes. Blood Cells. 1979;5:89–99
  47. Italiano JE, Lecine P, Shivdasani RA, Hartwig JH. Blood platelets are assembled principally at the ends of proplatelet processes produced by differentiated megakaryocytes. J Cell Biol. 1999;147:1299–1312
  48. Patel SR, Hartwig JH, Italiano JE. The biogenesis of platelets from megakaryocyte proplatelets. J Clin Invest. 2005;115:3348–3354
  49. Handagama P, Jain NC, Kono CS, Feldman BF. Scanning electron microscopic studies of megakaryocytes and platelet formation in the dog and rat. Am J Vet Res. 1986;47:2454–2460
  50. Junt T, Schulze H, Chen Z, et al. Dynamic visualization of thrombopoiesis within bone marrow. Science. 2007;317:1767–1770
  51. Richardson JL, Shivdasani RA, Boers C, Hartwig JH, Italiano JE. Mechanisms of organelle transport and capture along proplatelets during platelet production. Blood. 2005;106:4066–4075
  52. Nurden AT, Nurden P. The gray platelet syndrome: clinical spectrum of the disease. Blood Rev. 2007;21:21–36
  53. White JG. Medich giant platelet disorder: a unique alpha granule deficiency I. Structural abnormalities. Platelets. 2004;15:345–353
  54. White JG, Key NS, King RA, Vercellotti GM. The White platelet syndrome: a new autosomal dominant platelet disorder. Platelets. 2004;15:173–184
  55. Kimura Y, Hart A, Hirashima M, et al. Zinc finger protein, Hzf, is required for megakaryocyte development and hemostasis. J Exp Med. 2002;195:941–952
  56. Benit L, Cramer EM, Masse JM, Dusanter-Fourt I, Favier R. Molecular study of the hematopoietic zinc finger gene in three unrelated families with gray platelet syndrome. J Thromb Haemost. 2005;3:2077–2080
  57. Balduini CL, Pecci A, Loffredo G, et al. Effects of the R216Q mutation of GATA-1 on erythropoiesis and megakaryocytopoiesis. Thromb Haemost. 2004;91:129–140
  58. Tubman VN, Levine JE, Campagna DR, et al. X-Linked gray platelet syndrome due to a GATA1 Arg216Gln mutation. Blood. 2007;109:3297–3299
  59. Lo B, Li L, Gissen P, et al. Requirement of VPS33B, a member of the Sec1/Munc18 protein family, in megakaryocyte and platelet alpha-granule biogenesis. Blood. 2005;106:4159–4166
  60. Gissen P, Johnson CA, Morgan NV, et al. Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis–renal dysfunction–cholestasis (ARC) syndrome. Nat Genet. 2004;36:400–404
  61. Detter JC, Zhang Q, Mules EH, et al. Rab geranylgeranyl transferase alpha mutation in the gunmetal mouse reduces Rab prenylation and platelet synthesis. Proc Natl Acad Sci USA. 2000;97:4144–4149
  62. Swank RT, Jiang SY, Reddington M, et al. Inherited abnormalities in platelet organelles and platelet formation and associated altered expression of low molecular weight guanosine triphosphate-binding proteins in the mouse pigment mutant gunmetal. Blood. 1993;81:2626–2635
  63. Tiwari S, Italiano JE, Barral DC, et al. A role for Rab27b in NF-E2-dependent pathways of platelet formation. Blood. 2003;102:3970–3979
  64. TheBarral DC, Ramalho JS, Anders R, et al. Functional redundancy of Rab27 proteins and the pathogenesis of Griscelli syndrome. J Clin Invest. 2002;110:247–257
  65. Fukuda M. Versatile role of Rab27 in membrane trafficking: focus on the Rab27 effector families. J Biochem. 2005;137:9–16
  66. Karniguian A, Zahraoui A, Tavitian A. Identification of small GTP-binding rab proteins in human platelets: thrombin-induced phosphorylation of rab3B, rab6, and rab8 proteins. Proc Natl Acad Sci USA. 1993;90:7647–7651
  67. Kruit JK, Drayer AL, Bloks VW, et al. Plant sterols cause macrothrombocytopenia in a mouse model of sitosterolemia. J Biol Chem. 2008;283:6281–6287
  68. Rees DC, Iolascon A, Carella M, et al. Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia. Br J Haematol. 2005;130:297–309
  69. Flaumenhaft R. Molecular basis of platelet granule secretion. Arterioscler Thromb Vasc Biol. 2003;23:1152–1160
  70. Sudhof TC, Rothman JE. Membrane fusion: grappling with SNARE and SM proteins. Science. 2009;323:474–477
  71. Lemons PP, Chen D, Bernstein AM, Bennett MK, Whiteheart SW. Regulated secretion in platelets: identification of elements of the platelet exocytosis machinery. Blood. 1997;90:1490–1500
  72. Flaumenhaft R, Croce K, Chen E, Furie B, Furie BC. Proteins of the exocytotic core complex mediate platelet alpha-granule secretion. Roles of vesicle-associated membrane protein, SNAP-23, and syntaxin 4. J Biol Chem. 1999;274:2492–2501
  73. Bernstein AM, Whiteheart SW. Identification of a cellubrevin/vesicle associated membrane protein 3 homologue in human platelets. Blood. 1999;93:571–579
  74. Polgar J, Chung SH, Reed GL. Vesicle-associated membrane protein 3 (VAMP-3) and VAMP-8 are present in human platelets and are required for granule secretion. Blood. 2002;100:1081–1083
  75. Polgar J, Lane WS, Chung SH, Houng AK, Reed GL. Phosphorylation of SNAP-23 in activated human platelets. J Biol Chem. 2003;278:44369–44376
  76. Ren Q, Barber HK, Crawford GL, et al. Endobrevin/VAMP-8 is the primary v-SNARE for the platelet release reaction. Mol Biol Cell. 2007;18:24–33
  77. Chen D, Bernstein AM, Lemons PP, Whiteheart SW. Molecular mechanisms of platelet exocytosis: role of SNAP-23 and syntaxin 2 in dense core granule release. Blood. 2000;95(Feb 1):921–929
  78. Schraw TD, Rutledge TW, Crawford GL, et al. Granule stores from cellubrevin/VAMP-3 null mouse platelets exhibit normal stimulus-induced release. Blood. 2003;8:8
  79. Lemons PP, Chen D, Whiteheart SW. Molecular mechanisms of platelet exocytosis: requirements for alpha-granule release. Biochem Biophys Res Commun. 2000;267:875–880
  80. Lai KC, Flaumenhaft R. SNARE protein degradation upon platelet activation: calpain cleaves SNAP-23. J Cell Physiol. 2003;194:206–214
  81. Feng D, Crane K, Rozenvayn N, Dvorak AM, Flaumenhaft R. Subcellular distribution of 3 functional SNARE proteins: Human cellubrevin, SNAP-23, and Syntaxin 2. Blood. 2002;99:4006–4014
  82. Houng A, Polgar J, Reed GL. Munc18-syntaxin complexes and exocytosis in human platelets. J Biol Chem. 2003;278:19627–19633
  83. Shirakawa R, Higashi T, Tabuchi A, et al. Munc13-4 is a GTP-Rab27-binding protein regulating dense core granule secretion in platelets. J Biol Chem. 2004;279:10730–10737
  84. Dent J, Kato K, Peng XR, et al. A prototypic platelet septin and its participation in secretion. Proc Natl Acad Sci USA. 2002;99:3064–3069
  85. Whiteheart SW, Schraw T, Matveeva EA. N-Ethylmaleimide sensitive factor (NSF) structure and function. Int Rev Cytol. 2001;207:71–112
  86. Polgar J, Reed GL. A critical role for N-ethylmaleimide-sensitive fusion protein (NSF) in platelet granule secretion. Blood. 1999;94:1313–1318
  87. Morrell CN, Matsushita K, Chiles K, et al. Regulation of platelet granule exocytosis by S-nitrosylation. Proc Natl Acad Sci USA. 2005;102:3782–3787
  88. Clary DO, Griff IC, Rothman JE. SNAPs, a family of NSF attachment proteins involved in intracellular membrane fusion in animals and yeast. Cell. 1990;61:709–721
  89. Fitzgerald ML, Reed GL. Rab6 is phosphorylated in thrombin-activated platelets by a protein kinase C-dependent mechanism: effects on GTP/GDP binding and cellular distribution. Biochem J. 1999;342:353–360
  90. Shirakawa R, Yoshioka A, Horiuchi H, Nishioka H, Tabuchi A, Kita T. Small GTPase rab4 regulates Ca2+-induced alpha-granule secretion in platelets. J Biol Chem. 2000;275:33844–33849
  91. Zerial M, McBride H. Rab proteins as membrane organizers. Nat Rev Mol Cell Biol. 2001;2:107–117
  92. Berger G, Masse JM, Cramer EM. Alpha-granule membrane mirrors the platelet plasma membrane and contains the glycoproteins Ib, IX, and V. Blood. 1996;87:1385–1395
  93. Maynard DM, Heijnen HF, Horne MK, White JG, Gahl WA. Proteomic analysis of platelet alpha-granules using mass spectrometry. J Thromb Haemost. 2007;5:1945–1955
  94. Niiya K, Hodson E, Bader R, et al. Increased surface expression of the membrane glycoprotein IIb/IIIa complex induced by platelet activation. Relationship to the binding of fibrinogen and platelet aggregation. Blood. 1987;70:475–483
  95. Berger G, Caen JP, Berndt MC, Cramer EM. Ultrastructural demonstration of CD36 in the alpha-granule membrane of human platelets and megakaryocytes. Blood. 1993;82:3034–3044
  96. Nurden P, Jandrot-Perrus M, Combrie R, et al. Severe deficiency of glycoprotein VI in a patient with gray platelet syndrome. Blood. 2004;104:107–114
  97. Suzuki H, Murasaki K, Kodama K, Takayama H. Intracellular localization of glycoprotein VI in human platelets and its surface expression upon activation. Br J Haematol. 2003;121:904–912
  98. Piersma SR, Broxterman HJ, Kapci M, et al. Proteomics of the TRAP-induced platelet releasate. J Proteom. 2008;
  99. Hernandez-Ruiz L, Valverde F, Jimenez-Nunez MD, et al. Organellar proteomics of human platelet dense granules reveals that 14–3-3zeta is a granule protein related to atherosclerosis. J Proteom Res. 2007;6:4449–4457
  100. Coppinger JA, Cagney G, Toomey S, et al. Characterization of the proteins released from activated platelets leads to localization of novel platelet proteins in human atherosclerotic lesions. Blood. 2004;103:2096–2104
  101. Coppinger JA, O’Connor R, Wynne K, et al. Moderation of the platelet releasate response by aspirin. Blood. 2007;109:4786–4792
  102. Cramer EM, Breton-Gorius J, Beesley JE, Martin JF. Ultrastructural demonstration of tubular inclusions coinciding with von Willebrand factor in pig megakaryocytes. Blood. 1988;71:1533–1538
  103. Gralnick HR, Williams SB, McKeown LP, Krizek DM, Shafer BC, Rick ME. Platelet von Willebrand factor: comparison with plasma von Willebrand factor. Thromb Res. 1985;38:623–633
  104. Bowie EJ, Solberg LA, Fass DN, et al. Transplantation of normal bone marrow into a pig with severe von Willebrand’s disease. J Clin Invest. 1986;78:26–30
  105. De Meyer SF, Vandeputte N, Pareyn I, et al. Restoration of plasma von Willebrand factor deficiency is sufficient to correct thrombus formation after gene therapy for severe von Willebrand disease. Arterioscler Thromb Vasc Biol. 2008;
  106. Rendu F, Brohard-Bohn B. The platelet release reaction: granules’ constituents, secretion and functions. Platelets. 2001;12:261–273
  107. Hayward CP, Furmaniak-Kazmierczak E, Cieutat AM, et al. Factor V is complexed with multimerin in resting platelet lysates and colocalizes with multimerin in platelet alpha-granules. J Biol Chem. 1995;270:19217–19224
  108. Jeimy SB, Fuller N, Tasneem S, et al. Multimerin 1 binds factor V and activated factor V with high affinity and inhibits thrombin generation. Thromb Haemost. 2008;100:1058–1067
  109. Kiesselbach TH, Wagner RH. Demonstration of factor XIII in human megakaryocytes by a fluorescent antibody technique. Ann NY Acad Sci. 1972;202:318–328
  110. Monkovic DD, Tracy PB. Functional characterization of human platelet-released factor V and its activation by factor Xa and thrombin. J Biol Chem. 1990;265:17132–17140
  111. Gould WR, Silveira JR, Tracy PB. Unique in vivo modifications of coagulation factor V produce a physically and functionally distinct platelet-derived cofactor: characterization of purified platelet-derived factor V/Va. J Biol Chem. 2004;279:2383–2393
  112. Hu CJ, Baglia FA, Mills DC, Konkle BA, Walsh PN. Tissue-specific expression of functional platelet factor XI is independent of plasma factor XI expression. Blood. 1998;91:3800–3807
  113. Veljkovic DK, Rivard GE, Diamandis M, Blavignac J, Cramer-Borde EM, Hayward CP. Increased expression of urokinase plasminogen activator in Quebec platelet disorder is linked to megakaryocyte differentiation. Blood. 2009;113:1535–1542
  114. Hayward CP, Cramer EM, Kane WH, et al. Studies of a second family with the Quebec platelet disorder: evidence that the degradation of the alpha-granule membrane and its soluble contents are not secondary to a defect in targeting proteins to alpha-granules. Blood. 1997;89:1243–1253
  115. Novotny WF, Girard TJ, Miletich JP, Broze GJ. Platelets secrete a coagulation inhibitor functionally and antigenically similar to the lipoprotein associated coagulation inhibitor. Blood. 1988;72:2020–2025
  116. Schwarz HP, Heeb MJ, Wencel-Drake JD, Griffin JH. Identification and quantitation of protein S in human platelets. Blood. 1985;66:1452–1455
  117. Van Nostrand WE, Schmaier AH, Farrow JS, Cunningham DD. Protease nexin-II (amyloid beta-protein precursor): a platelet alpha-granule protein. Science. 1990;248:745–748
  118. Xu F, Previti ML, Van Nostrand WE. Increased severity of hemorrhage in transgenic mice expressing cerebral protease nexin-2/amyloid beta-protein precursor. Stroke. 2007;38:2598–2601
  119. May AE, Seizer P, Gawaz M. Platelets: inflammatory firebugs of vascular walls. Arterioscler Thromb Vasc Biol. 2008;28:s5–s10
  120. Bombeli T, Schwartz BR, Harlan JM. Adhesion of activated platelets to endothelial cells: evidence for a GPIIbIIIa-dependent bridging mechanism and novel roles for endothelial intercellular adhesion molecule 1 (ICAM-1), alphavbeta3 integrin, and GPIbalpha. J Exp Med. 1998;187:329–339
  121. von Hundelshausen P, Weber C. Platelets as immune cells: bridging inflammation and cardiovascular disease. Circ Res. 2007;100:27–40
  122. Larsen E, Celi A, Gilbert GE, et al. PADGEM protein: a receptor that mediates the interaction of activated platelets with neutrophils and monocytes. Cell. 1989;59:305–312
  123. Diacovo TG, Puri KD, Warnock RA, Springer TA, von Andrian UH. Platelet-mediated lymphocyte delivery to high endothelial venules. Science. 1996;273:252–255
  124. Frenette PS, Johnson RC, Hynes RO, Wagner DD. Platelets roll on stimulated endothelium in vivo: an interaction mediated by endothelial P-selectin. Proc Natl Acad Sci USA. 1995;92:7450–7454
  125. Massberg S, Enders G, Leiderer R, et al. Platelet-endothelial cell interactions during ischemia/reperfusion: the role of P-selectin. Blood. 1998;92:507–515
  126. Romo GM, Dong JF, Schade AJ, et al. The glycoprotein Ib-IX-V complex is a platelet counterreceptor for P-selectin. J Exp Med. 1999;190:803–814
  127. Gawaz M, Langer H, May AE. Platelets in inflammation and atherogenesis. J Clin Invest. 2005;115:3378–3384
  128. Braun OO, Slotta JE, Menger MD, Erlinge D, Thorlacius H. Primary and secondary capture of platelets onto inflamed femoral artery endothelium is dependent on P-selectin and PSGL-1. Eur J Pharmacol. 2008;592:128–132
  129. Ott I, Neumann FJ, Gawaz M, Schmitt M, Schomig A. Increased neutrophil–platelet adhesion in patients with unstable angina. Circulation. 1996;94:1239–1246
  130. Diacovo TG, Roth SJ, Buccola JM, Bainton DF, Springer TA. Neutrophil rolling, arrest, and transmigration across activated, surface-adherent platelets via sequential action of P-selectin and the beta 2-integrin CD11b/CD18. Blood. 1996;88:146–157
  131. Tabuchi A, Kuebler WM. Endothelium–platelet interactions in inflammatory lung disease. Vasc Pharmacol. 2008;49:141–150
  132. Zarbock A, Singbartl K, Ley K. Complete reversal of acid-induced acute lung injury by blocking of platelet–neutrophil aggregation. J Clin Invest. 2006;116:3211–3219
  133. Gleissner CA, von Hundelshausen P, Ley K. Platelet chemokines in vascular disease. Arterioscler Thromb Vasc Biol. 2008;28:1920–1927
  134. Brandt E, Petersen F, Ludwig A, Ehlert JE, Bock L, Flad HD. The beta-thromboglobulins and platelet factor 4: blood platelet-derived CXC chemokines with divergent roles in early neutrophil regulation. J Leukocyte Biol. 2000;67:471–478
  135. Slungaard A. Platelet factor 4: a chemokine enigma. Int J Biochem Cell Biol. 2005;37:1162–1167
  136. Zucker MB, Katz IR. Platelet factor 4: production, structure, and physiologic and immunologic action. Proc Soc Exp Biol Med. 1991;198:693–702
  137. Kasper B, Brandt E, Bulfone-Paus S, Petersen F. Platelet factor 4 (PF-4)-induced neutrophil adhesion is controlled by src-kinases, whereas PF-4-mediated exocytosis requires the additional activation of p38 MAP kinase and phosphatidylinositol 3-kinase. Blood. 2004;103:1602–1610
  138. Kasper B, Brandt E, Brandau S, Petersen F. Platelet factor 4 (CXC chemokine ligand 4) differentially regulates respiratory burst, survival, and cytokine expression of human monocytes by using distinct signaling pathways. J Immunol. 2007;179:2584–2591
  139. Scheuerer B, Ernst M, Durrbaum-Landmann I, et al. The CXC-chemokine platelet factor 4 promotes monocyte survival and induces monocyte differentiation into macrophages. Blood. 2000;95:1158–1166
  140. von Hundelshausen P, Koenen RR, Sack M, et al. Heterophilic interactions of platelet factor 4 and RANTES promote monocyte arrest on endothelium. Blood. 2005;105:924–930
  141. Walz A, Dewald B, von Tscharner V, Baggiolini M. Effects of the neutrophil-activating peptide NAP-2, platelet basic protein, connective tissue-activating peptide III and platelet factor 4 on human neutrophils. J Exp Med. 1989;170:1745–1750
  142. Schenk BI, Petersen F, Flad HD, Brandt E. Platelet-derived chemokines CXC chemokine ligand (CXCL)7, connective tissue-activating peptide III, and CXCL4 differentially affect and cross-regulate neutrophil adhesion and transendothelial migration. J Immunol. 2002;169:2602–2610
  143. Libby P. Atherosclerosis: disease biology affecting the coronary vasculature. Am J Cardiol. 2006;98:3Q–9Q
  144. Croce K, Libby P. Intertwining of thrombosis and inflammation in atherosclerosis. Curr Opin Hematol. 2007;14:55–61
  145. Collins RG, Velji R, Guevara NV, Hicks MJ, Chan L, Beaudet AL. P-Selectin or intercellular adhesion molecule (ICAM)-1 deficiency substantially protects against atherosclerosis in apolipoprotein E-deficient mice. J Exp Med. 2000;191:189–194
  146. Dong ZM, Brown AA, Wagner DD. Prominent role of P-selectin in the development of advanced atherosclerosis in ApoE-deficient mice. Circulation. 2000;101:2290–2295
  147. Burger PC, Wagner DD. Platelet P-selectin facilitates atherosclerotic lesion development. Blood. 2003;101:2661–2666
  148. Wang K, Zhou X, Zhou Z, et al. Platelet, not endothelial, P-selectin is required for neointimal formation after vascular injury. Arterioscler Thromb Vasc Biol. 2005;25:1584–1589
  149. Huo Y, Schober A, Forlow SB, et al. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med. 2003;9:61–67
  150. Schober A, Manka D, von Hundelshausen P, et al. Deposition of platelet RANTES triggering monocyte recruitment requires P-selectin and is involved in neointima formation after arterial injury. Circulation. 2002;106:1523–1529
  151. Koenen RR, von Hundelshausen P, Nesmelova IV, et al. Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice. Nat Med. 2009;15:97–103
  152. Boring L, Gosling J, Cleary M, Charo IF. Decreased lesion formation in CCR2−/− mice reveals a role for chemokines in the initiation of atherosclerosis. Nature. 1998;394:894–897
  153. Hayes IM, Jordan NJ, Towers S, et al. Human vascular smooth muscle cells express receptors for CC chemokines. Arterioscler Thromb Vasc Biol. 1998;18:397–403
  154. Sachais BS, Turrentine T, Dawicki McKenna JM, Rux AH, Rader D, Kowalska MA. Elimination of platelet factor 4 (PF4) from platelets reduces atherosclerosis in C57Bl/6 and apoE−/− mice. Thromb Haemost. 2007;98:1108–1113
  155. Karshovska E, Zernecke A, Sevilmis G, et al. Expression of HIF-1alpha in injured arteries controls SDF-1alpha mediated neointima formation in apolipoprotein E deficient mice. Arterioscler Thromb Vasc Biol. 2007;27:2540–2547
  156. Tiedt R, Schomber T, Hao-Shen H, Skoda RC. Pf4-Cre transgenic mice allow the generation of lineage-restricted gene knockouts for studying megakaryocyte and platelet function in vivo. Blood. 2007;109:1503–1506
  157. Scheld WM, Valone JA, Sande MA. Bacterial adherence in the pathogenesis of endocarditis. Interaction of bacterial dextran, platelets, and fibrin. J Clin Invest. 1978;61:1394–1404
  158. Klinger MH, Jelkmann W. Role of blood platelets in infection and inflammation. J Interferon Cytokine Res. 2002;22:913–922
  159. Durack DT. Experimental bacterial endocarditis. IV. Structure and evolution of very early lesions. J Pathol. 1975;115:81–89
  160. Sullam PM, Drake TA, Sande MA. Pathogenesis of endocarditis. Am J Med. 1985;78:110–115
  161. Vinter DW, Burkel WE, Wakefield TW, et al. Radioisotope-labeled platelet studies and infection of vascular grafts. J Vasc Surg. 1984;1:921
  162. Zucker-Franklin D, Seremetis S, Zheng ZY. Internalization of human immunodeficiency virus type I and other retroviruses by megakaryocytes and platelets. Blood. 1990;75:1920–1923
  163. Bik T, Sarov I, Livne A. Interaction between vaccinia virus and human blood platelets. Blood. 1982;59:482–487
  164. Clawson CC, Rao GH, White JG. Platelet interaction with bacteria. IV. Stimulation of the release reaction. Am J Pathol. 1975;81:411–420
  165. Maisch PA, Calderone RA. Adherence of Candida albicans to a fibrin–platelet matrix formed in vitro. Infect Immun. 1980;27:650–656
  166. McMorran BJ, Marshall VM, de Graaf C, et al. Platelets kill intraerythrocytic malarial parasites and mediate survival to infection. Science. 2009;323:797–800
  167. Cole AM, Ganz T, Liese AM, Burdick MD, Liu L, Strieter RM. Cutting edge: IFN-inducible ELR-CXC chemokines display defensin-like antimicrobial activity. J Immunol. 2001;167:623–627
  168. Tang YQ, Yeaman MR, Selsted ME. Antimicrobial peptides from human platelets. Infect Immun. 2002;70:6524–6533
  169. Krijgsveld J, Zaat SA, Meeldijk J, et al. Thrombocidins, microbicidal proteins from human blood platelets, are C-terminal deletion products of CXC chemokines. J Biol Chem. 2000;275:20374–20381
  170. Kupferwasser LI, Yeaman MR, Shapiro SM, Nast CC, Bayer AS. In vitro susceptibility to thrombin-induced platelet microbicidal protein is associated with reduced disease progression and complication rates in experimental Staphylococcus aureus endocarditis: microbiological, histopathologic, and echocardiographic analyses. Circulation. 2002;105:746–752
  171. Sullam PM, Bayer AS, Foss WM, Cheung AL. Diminished platelet binding in vitro by Staphylococcus aureus is associated with reduced virulence in a rabbit model of infective endocarditis. Infect Immun. 1996;64:4915–4921
  172. Dhawan VK, Yeaman MR, Cheung AL, Kim E, Sullam PM, Bayer AS. Phenotypic resistance to thrombin-induced platelet microbicidal protein in vitro is correlated with enhanced virulence in experimental endocarditis due to Staphylococcus aureus. Infect Immun. 1997;65:3293–3299
  173. Mercier RC, Rybak MJ, Bayer AS, Yeaman MR. Influence of platelets and platelet microbicidal protein susceptibility on the fate of Staphylococcus aureus in an in vitro model of infective endocarditis. Infect Immun. 2000;68:4699–4705
  174. Del Conde I, Cruz MA, Zhang H, Lopez JA, Afshar-Kharghan V. Platelet activation leads to activation and propagation of the complement system. J Exp Med. 2005;201:871–879
  175. Schmaier AH, Smith PM, Colman RW. Platelet C1-inhibitor. A secreted alpha-granule protein. J Clin Invest. 1985;75:242–250
  176. Devine DV, Rosse WF. Regulation of the activity of platelet-bound C3 convertase of the alternative pathway of complement by platelet factor H. Proc Natl Acad Sci USA. 1987;84:5873–5877
  177. Knighton DR, Hunt TK, Thakral KK, Goodson WH. Role of platelets and fibrin in the healing sequence. an in vivo study of angiogenesis and collagen synthesis. Ann Surg. 1982;196:379–388
  178. Pipili-Synetos E, Papadimitriou E, Maragoudakis ME. Evidence that platelets promote tube formation by endothelial cells on matrigel. Br J Pharmacol. 1998;125:1252–1257
  179. Kisucka J, Butterfield CE, Duda DG, et al. Platelets and platelet adhesion support angiogenesis while preventing excessive hemorrhage. Proc Natl Acad Sci USA. 2006;103:855–860
  180. Nurden AT, Nurden P, Sanchez M, Andia I, Anitua E. Platelets and wound healing. Front Biosci. 2008;13:3532–3548
  181. Weltermann A, Wolzt M, Petersmann K, et al. Large amounts of vascular endothelial growth factor at the site of hemostatic plug formation in vivo. Arterioscler Thromb Vasc Biol. 1999;19:1757–1760
  182. Arisato T, Hashiguchi T, Sarker KP, et al. Highly accumulated platelet vascular endothelial growth factor in coagulant thrombotic region. J Thromb Haemost. 2003;1:2589–2593
  183. Pintucci G, Froum S, Pinnell J, Mignatti P, Rafii S, Green D. Trophic effects of platelets on cultured endothelial cells are mediated by platelet-associated fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor (VEGF). Thromb Haemost. 2002;88:834–842
  184. Brill A, Elinav H, Varon D. Differential role of platelet granular mediators in angiogenesis. Cardiovasc Res. 2004;63:226–235
  185. Massberg S, Konrad I, Schurzinger K, et al. Platelets secrete stromal cell-derived factor 1alpha and recruit bone marrow-derived progenitor cells to arterial thrombi in vivo. J Exp Med. 2006;203:1221–1233
  186. Jimenez B, Volpert OV, Crawford SE, Febbraio M, Silverstein RL, Bouck N. Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nat Med. 2000;6:41–48
  187. Bikfalvi A. Recent developments in the inhibition of angiogenesis: examples from studies on platelet factor-4 and the VEGF/VEGFR system. Biochem Pharmacol. 2004;68:1017–1021
  188. Perollet C, Han ZC, Savona C, Caen JP, Bikfalvi A. Platelet factor 4 modulates fibroblast growth factor 2 (FGF-2) activity and inhibits FGF-2 dimerization. Blood. 1998;91:3289–3299
  189. Ma L, Perini R, McKnight W, et al. Proteinase-activated receptors 1 and 4 counter-regulate endostatin and VEGF release from human platelets. Proc Natl Acad Sci USA. 2005;102:216–220
  190. Kark LR, Karp JM, Davies JE. Platelet releasate increases the proliferation and migration of bone marrow-derived cells cultured under osteogenic conditions. Clin Oral Implant Res. 2006;17:321–327
  191. Anitua E, Andia I, Sanchez M, et al. Autologous preparations rich in growth factors promote proliferation and induce VEGF and HGF production by human tendon cells in culture. J Orthop Res. 2005;23:281–286
  192. Nagai M, Sato S, Kamoi H, Kamoi K. Effects of application of platelet releasate in periodontal regeneration therapy. Int J Periodont Restorat Dent. 2005;25:571–583
  193. Moulin V, Lawny F, Barritault D, Caruelle JP. Platelet releasate treatment improves skin healing in diabetic rats through endogenous growth factor secretion. Cell Mol Biol (Noisy-le-grand). 1998;44:961–971
  194. Knighton DR, Ciresi KF, Fiegel VD, Austin LL, Butler EL. Classification and treatment of chronic nonhealing wounds. Successful treatment with autologous platelet-derived wound healing factors (PDWHF). Ann Surg. 1986;204:322–330
  195. Steed DL, Goslen JB, Holloway GA, Malone JM, Bunt TJ, Webster MW. Randomized prospective double-blind trial in healing chronic diabetic foot ulcers. CT-102 activated platelet supernatant, topical versus placebo. Diabet Care. 1992;15:1598–1604
  196. Margolis DJ, Kantor J, Santanna J, Strom BL, Berlin JA. Effectiveness of platelet releasate for the treatment of diabetic neuropathic foot ulcers. Diabet Care. 2001;24:483–488
  197. Josifova D, Gatt G, Aquilina A, Serafimov V, Vella A, Felice A. Treatment of leg ulcers with platelet-derived wound healing factor (PDWHFS) in a patient with beta thalassaemia intermedia. Br J Haematol. 2001;112:527–529
  198. Herouy Y, Mellios P, Bandemir E, et al. Autologous platelet-derived wound healing factor promotes angiogenesis via alphavbeta3-integrin expression in chronic wounds. Int J Mol Med. 2000;6:515–519
  199. Senet P, Bon FX, Benbunan M, et al. Randomized trial and local biological effect of autologous platelets used as adjuvant therapy for chronic venous leg ulcers. J Vasc Surg. 2003;38:1342–1348
  200. Ho-Tin-Noe B, Goerge T, Cifuni SM, Duerschmied D, Wagner DD. Platelet granule secretion continuously prevents intratumor hemorrhage. Cancer Res. 2008;68:6851–6858
  201. Klement GL, Yip TT, Cassiola F, et al. Platelets actively sequester angiogenesis regulators. Blood. 2008;
  202. Patruno R, Arpaia N, Gadaleta CD, et al. VEGF concentration from plasma activated platelets rich correlates with microvascular density and grading in canine mast cell tumour spontaneous model. J Cell Mol Med. 2008;
  203. Caine GJ, Ryan P, Lip GY, Blann AD. Significant decrease in angiopoietin-1 and angiopoietin-2 after radical prostatectomy in prostate cancer patients. Cancer Lett. 2007;251:296–301
  204. George DJ, Regan MM, Oh WK, et al. Radical prostatectomy lowers plasma vascular endothelial growth factor levels in patients with prostate cancer. Urology. 2004;63:327–332
  205. Salgado R, Vermeulen PB, Van Marck E, Benoy I, Dirix L. Correspondence re: George ML et al. Correlation of plasma and serum vascular endothelial growth factor levels with platelet count in colorectal cancer: clinical evidence of platelet scavenging? Clin Cancer Res, 6: 3147–52, 2000. Clin Cancer Res. 2001;7:1481–1483
  206. Adams J, Carder PJ, Downey S, et al. Vascular endothelial growth factor (VEGF) in breast cancer: comparison of plasma, serum, and tissue VEGF and microvessel density and effects of tamoxifen. Cancer Res. 2000;60:2898–2905
  207. Caine GJ, Lip GY, Blann AD. Platelet-derived VEGF, Flt-1, angiopoietin-1 and P-selectin in breast and prostate cancer: further evidence for a role of platelets in tumour angiogenesis. Ann Med. 2004;36:273–277
  208. Salven P, Orpana A, Joensuu H. Leukocytes and platelets of patients with cancer contain high levels of vascular endothelial growth factor. Clin Cancer Res. 1999;5:487–491
  209. Gunsilius E, Petzer A, Stockhammer G, et al. Thrombocytes are the major source for soluble vascular endothelial growth factor in peripheral blood. Oncology. 2000;58:169–174
  210. Gasic GJ, Gasic TB, Stewart CC. Antimetastatic effects associated with platelet reduction. Proc Natl Acad Sci USA. 1968;61:46–52
  211. Pearlstein E, Ambrogio C, Karpatkin S. Effect of antiplatelet antibody on the development of pulmonary metastases following injection of CT26 colon adenocarcinoma, Lewis lung carcinoma, and B16 amelanotic melanoma tumor cells into mice. Cancer Res. 1984;44:3884–3887
  212. Skolnik G, Ericson LE, Bagge U. The effect of thrombocytopenia and antiserotonin treatment on the lodgement of circulating tumor cells. A vital fluorescence microscopic, electron microscopic and isotope study in the rat. J Cancer Res Clin Oncol. 1983;105:30–37
  213. Jain S, Zuka M, Liu J, et al. Platelet glycoprotein Ib alpha supports experimental lung metastasis. Proc Natl Acad Sci USA. 2007;104:9024–9028
  214. Karpatkin S, Pearlstein E. Role of platelets in tumor cell metastases. Ann Int Med. 1981;95:636–641
  215. Nash GF, Turner LF, Scully MF, Kakkar AK. Platelets and cancer. Lancet Oncol. 2002;3:425–430
  216. Borsig L, Wong R, Feramisco J, Nadeau DR, Varki NM, Varki A. Heparin and cancer revisited: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis. Proc Natl Acad Sci USA. 2001;98:3352–3357
  217. Kim YJ, Borsig L, Varki NM, Varki A. P-Selectin deficiency attenuates tumor growth and metastasis. Proc Natl Acad Sci USA. 1998;95:9325–9330
  218. Lawler K, Meade G, O’Sullivan G, Kenny D. Shear stress modulates the interaction of platelet-secreted matrix proteins with tumor cells through the integrin alphavbeta3. Am J Physiol Cell Physiol. 2004;287:C1320–C1327
  219. Belloc C, Lu H, Soria C, Fridman R, Legrand Y, Menashi S. The effect of platelets on invasiveness and protease production of human mammary tumor cells. Int J Cancer. 1995;60:413–417

PII: S0268-960X(09)00029-0

doi: 10.1016/j.blre.2009.04.001

Blood Reviews
Volume 23, Issue 4 , Pages 177-189 , July 2009