Download PDF
Semin Thromb Hemost 2004; 30(4): 441-450
DOI: 10.1055/s-2004-833479
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Platelet Secretory Mechanisms

Guy L. Reed1
  • 1Associate Professor, Harvard University, School of Public Health and Associate Physician, Massachusetts General Hospital Boston, Massachusetts
Further Information

Publication History

Publication Date:
08 September 2004 (online)

    Permissions and Reprints

Platelet granule secretion or exocytosis is required for normal platelet function and plays an important role in the pathogenesis of cardiovascular diseases. Platelets secrete molecules that amplify thrombosis, induce vascular remodeling, recruit and activate cells. The platelet secretory process begins in megakaryocytes where molecules are targeted to developing granules through specific vesicle trafficking and transporter mechanisms. Secretory granules may continue to mature in the circulation after the platelet has been released from the megakaryocyte. The platelet secretory process culminates when ligands interact with specific platelet receptors to trigger exocytosis. A convergence of new insights from several different organisms has begun to illuminate the molecular mechanisms responsible for the platelet secretory process, from granule development through membrane fusion and exocytosis.

KEYWORDS

Granules - secretion - exocytosis - genetic disorders

REFERENCES

  • 1 Dale G L, Friese P, Batar P et al.. Stimulated platelets use serotonin to enhance their retention of procoagulant proteins on the cell surface.  Nature. 2002;  415 175-179
    CrossrefPubMedGoogle Scholar
  • 2 Reed G L. Platelet secretion. In: Michelson AD Platelets. San Diego; Elsevier Science 2002: 181-196
    Google Scholar
  • 3 Reed G L, Fitzgerald M L, Polgar J. Molecular mechanisms of platelet exocytosis: insights into the “secrete” life of thrombocytes.  Blood. 2000;  96 3334-3342
    PubMedGoogle Scholar
  • 4 Flaumenhaft R. Molecular Basis of Platelet Granule Secretion.  Arterioscler Thromb Vasc Biol. 2003;  23 1152-1160
    PubMedGoogle Scholar
  • 5 Fukami M H, Holmsen H, Kowalska M A, Niewiarowski S. Platelet secretion. In: Colman RW, Hirsch J, Marder VJ, Clowes AW, George JN Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 4th. ed. Philadelphia; Lippincott Williams & Wilkins 2001: 516-573
    Google Scholar
  • 6 Rendu F, Brohard-Bohn B. The platelet release reaction: granules' constituents, secretion and functions.  Platelets. 2001;  12 261-273
    CrossrefPubMedGoogle Scholar
  • 7 Stenberg P E, McEver R P, Shuman M A, Jacques Y V, Bainton D F. A platelet alpha-granule membrane protein (GMP-140) is expressed on the plasma membrane after activation.  J Cell Biol. 1985;  101 880-886
    CrossrefPubMedGoogle Scholar
  • 8 Berman C L, Yeo E L, Wencel-Drake J D, Furie B C, Ginsberg M H, Furie B. A platelet alpha granule membrane protein that is associated with the plasma membrane after activation. Characterization and subcellular localization of platelet activation-dependent granule-external membrane protein.  J Clin Invest. 1986;  78 130-137
    PubMedGoogle Scholar
  • 9 Suzuki H, Kaneko T, Sakamoto T et al.. Redistribution of alpha-granule membrane glycoprotein IIb/IIIa (integrin alpha IIb beta 3) to the surface membrane of human platelets during the release reaction.  J Electron Microsc (Tokyo). 1994;  43 282-289
    PubMedGoogle Scholar
  • 10 Weiss H J, Witte L D, Kaplan K L et al.. Heterogeneity in storage pool deficiency: studies on granule-bound substances in 18 patients including variants deficient in alpha-granules, platelet factor 4, beta-thromboglobulin, and platelet-derived growth factor.  Blood. 1979;  54 1296-1319
    PubMedGoogle Scholar
  • 11 Hermansky F, Pudlak P. Albinism associated with hemorrhagic diathesis and unusual pigmented reticular cells in the bone marrow.  Blood. 1959;  14 162
    PubMedGoogle Scholar
  • 12 Novak E K, Hui S W, Swank R T. Platelet storage pool deficiency in mouse pigment mutations associated with seven distinct genetic loci.  Blood. 1984;  63 536-544
    PubMedGoogle Scholar
  • 13 Packham M A, Mustard J F. The role of platelets in the development and complications of atherosclerosis.  Semin Hematol. 1986;  23 8-26
    PubMedGoogle Scholar
  • 14 Ross R, Glomset J, Harker L. Response to injury and atherogenesis.  Am J Pathol. 1977;  86 675-684
    PubMedGoogle Scholar
  • 15 Huo Y, Schober A, Forlow S B et al.. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E.  Nat Med. 2003;  9 61-67
    CrossrefPubMedGoogle Scholar
  • 16 Blann A D, Lip G Y, Beevers D G, McCollum C N. Soluble P-selectin in atherosclerosis: a comparison with endothelial cell and platelet markers.  Thromb Haemost. 1997;  77 1077-1080
    PubMedGoogle Scholar
  • 17 Smith F B, Lowe G D, Fowkes F G et al.. Smoking, haemostatic factors and lipid peroxides in a population case control study of peripheral arterial disease.  Atherosclerosis. 1993;  102 155-162
    CrossrefPubMedGoogle Scholar
  • 18 Davi G, Romano M, Mezzetti A et al.. Increased levels of soluble P-selectin in hypercholesterolemic patients.  Circulation. 1998;  97 953-957
    PubMedGoogle Scholar
  • 19 Rak K, Beck P, Udvardy M, Pfliegler G, Misz M, Boda Z. Plasma levels of beta-thromboglobulin and factor VIII-related antigen in diabetic children and adults.  Thromb Res. 1983;  29 155-162
    CrossrefPubMedGoogle Scholar
  • 20 Yamanishi J, Sano H, Saito K, Furuta Y, Fukuzaki H. Plasma concentrations of platelet-specific proteins in different stages of essential hypertension: interactions between platelet aggregation, blood lipids and age.  Thromb Haemost. 1985;  54 539-543
    PubMedGoogle Scholar
  • 21 Ramsis N, El-Hawary A A, Ismail E. Relation between carotid intima-media thickness, platelet surface activation and endothelial cell markers.  Haemostasis. 1998;  28 268-275
    CrossrefPubMedGoogle Scholar
  • 22 Sixma J J, Slot J W, Geuze H J. Immunocytochemical localization of platelet granule proteins.  Methods Enzymol. 1989;  169 301-311
    PubMedGoogle Scholar
  • 23 Harrison P, Savidge G F, Cramer E M. The origin and physiological relevance of alpha-granule adhesive proteins.  Br J Haematol. 1990;  74 125-130
    PubMedGoogle Scholar
  • 24 Beckstead J H, Stenberg P E, McEver R P, Shuman M A, Bainton D F. Immunohistochemical localization of membrane and alpha-granule proteins in human megakaryocytes: application to plastic-embedded bone marrow biopsy specimens.  Blood. 1986;  67 285-293
    PubMedGoogle Scholar
  • 25 Niewiarowski S. Proteins secreted by the platelet.  Thromb Haemost. 1977;  38 924-938
    PubMedGoogle Scholar
  • 26 Schmaier A H. Platelet forms of plasma proteins: plasma cofactors/substrates and inhibitors contained within platelets.  Semin Hematol. 1985;  22 187-202
    PubMedGoogle Scholar
  • 27 Handagama P, Rappolee D A, Werb Z, Levin J, Bainton D F. Platelet alpha-granule fibrinogen, albumin, and immunoglobulin G are not synthesized by rat and mouse megakaryocytes.  J Clin Invest. 1990;  86 1364-1368
    PubMedGoogle Scholar
  • 28 Browder T, Folkman J, Pirie-Shepherd S. The hemostatic system as a regulator of angiogenesis.  J Biol Chem. 2000;  275 1521-1524
    CrossrefPubMedGoogle Scholar
  • 29 Deuel T F. Protein granule factors. In: von Bruchhausen F, Walter U Platelets and Their Factors. Vol. 126. New York; Springer 1997: 247-296
    Google Scholar
  • 30 Gear A R, Camerini D. Platelet chemokines and chemokine receptors: linking hemostasis, inflammation, and host defense.  Microcirculation. 2003;  10 335-350
    CrossrefPubMedGoogle Scholar
  • 31 White J G. The dense bodies of human platelets: inherent electron opacity of the serotonin storage particles.  Blood. 1969;  33 598-606
    PubMedGoogle Scholar
  • 32 Holmsen H, Weiss H J. Secretable storage pools in platelets.  Annu Rev Med. 1979;  30 119-134
    CrossrefPubMedGoogle Scholar
  • 33 Nishibori M, Cham B, McNicol A, Shalev A, Jain N, Gerrard J M. The protein CD63 is in platelet dense granules, is deficient in a patient with Hermansky-Pudlak syndrome, and appears identical to granulophysin.  J Clin Invest. 1993;  91 1775-1782
    CrossrefPubMedGoogle Scholar
  • 34 Israels S J, McMillan E M, Robertson C, Singhory S, McNicol A. The lysosomal granule membrane protein, LAMP-2, is also present in platelet dense granule membranes.  Thromb Haemost. 1996;  75 623-629
    PubMedGoogle Scholar
  • 35 Febbraio M, Silverstein R L. Identification and characterization of LAMP-1 as an activation-dependent platelet surface glycoprotein.  J Biol Chem. 1990;  265 18531-18537
    PubMedGoogle Scholar
  • 36 Israels S J, Gerrard J M, Jacques Y V et al.. Platelet dense granule membranes contain both granulophysin and P-selectin (GMP-140).  Blood. 1992;  80 143-152
    PubMedGoogle Scholar
  • 37 Norcott J P, Solari R, Cutler D F. Targeting of P-selectin to two regulated secretory organelles in PC12 cells.  J Cell Biol. 1996;  134 1229-1240
    CrossrefPubMedGoogle Scholar
  • 38 Menard M, Meyers K M, Prieur D J. Demonstration of secondary lysosomes in bovine megakaryocytes and platelets using acid phosphatase cytochemistry with cerium as a trapping agent.  Thromb Haemost. 1990;  63 127-132
    PubMedGoogle Scholar
  • 39 Fukami M H, Salganicoff L. Human platelet storage organelles. A review.  Thromb Haemost. 1977;  38 963-970
    PubMedGoogle Scholar
  • 40 Ehrlich H P, Gordon J L. Proteinases in Platelets. Vol. 1. New York; Elsevier 1976
    Google Scholar
  • 41 Dangelmaier C A, Holmsen H. Determination of acid hydrolases in human platelets.  Anal Biochem. 1980;  104 182-191
    CrossrefPubMedGoogle Scholar
  • 42 Sollner T, Whiteheart S W, Brunner M et al.. SNAP receptors implicated in vesicle targeting and fusion.  Nature. 1993;  362 318-324
    CrossrefPubMedGoogle Scholar
  • 43 Weber T, Zemelman B V, McNew J A et al.. SNAREpins: minimal machinery for membrane fusion.  Cell. 1998;  92 759-772
    CrossrefPubMedGoogle Scholar
  • 44 Hanson P I, Heuser J E, Jahn R. Neurotransmitter release-four years of SNARE complexes.  Curr Opin Neurobiol. 1997;  7 310-315
    CrossrefPubMedGoogle Scholar
  • 45 Haas A. NSF-fusion and beyond.  Trends Cell Biol. 1998;  8 471-473
    CrossrefPubMedGoogle Scholar
  • 46 Morgan A, Burgoyne R D. A role for soluble NSF attachment proteins (SNAPs) in regulated exocytosis in adrenal chromaffin cells.  EMBO J. 1995;  14 232-239
    PubMedGoogle Scholar
  • 47 Zerial M, McBride H. Rab proteins as membrane organizers.  Nat Rev Mol Cell Biol. 2001;  2 107-117
    CrossrefPubMedGoogle Scholar
  • 48 Seabra M C, Mules E H, Hume A N. Rab GTPases, intracellular traffic and disease.  Trends Mol Med. 2002;  8 23-30
    CrossrefPubMedGoogle Scholar
  • 49 Lemons P P, Chen D, Bernstein A M, Bennett M K, Whiteheart S W. Regulated secretion in platelets: identification of elements of the platelet exocytosis machinery.  Blood. 1997;  90 1490-1500
    PubMedGoogle Scholar
  • 50 Reed G L, Houng A K, Fitzgerald M L. Human platelets contain SNARE proteins and a Sec1p homologue that interacts with syntaxin 4 and is phosphorylated after thrombin activation: implications for platelet secretion.  Blood. 1999;  93 2617-2626
    PubMedGoogle Scholar
  • 51 Polgar J, Reed G L. A critical role for N-ethylmaleimide-sensitive fusion protein (NSF) in platelet granule secretion.  Blood. 1999;  94 1313-1318
    PubMedGoogle Scholar
  • 52 Flaumenhaft R, Croce K, Chen E, Furie B, Furie B C. 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
    CrossrefPubMedGoogle Scholar
  • 53 Bernstein A M, Whiteheart S W. Identification of a cellubrevin/vesicle associated membrane protein 3 homologue in human platelets.  Blood. 1999;  93 571-579
    PubMedGoogle Scholar
  • 54 Chen D, Bernstein A M, Lemons P P, Whiteheart S W. Molecular mechanisms of platelet exocytosis: role of SNAP-23 and syntaxin 2 in dense core granule release.  Blood. 2000;  95 921-929
    PubMedGoogle Scholar
  • 55 Lemons P P, Chen D, Whiteheart S W. Molecular mechanisms of platelet exocytosis: requirements for alpha-granule release.  Biochem Biophys Res Commun. 2000;  267 875-880
    CrossrefPubMedGoogle Scholar
  • 56 Polgar J, Chung S H, Reed G L. 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
    CrossrefPubMedGoogle Scholar
  • 57 Feng D, Crane K, Rozenvayn N, Dvorak A M, Flaumenhaft R. Subcellular distribution of 3 functional platelet SNARE proteins: human cellubrevin, SNAP-23, and syntaxin 2.  Blood. 2002;  99 4006-4014
    CrossrefPubMedGoogle Scholar
  • 58 Polgar J, Lane W S, Chung S H, Houng A K, Reed G L. Phosphorylation of SNAP-23 in activated human platelets.  J Biol Chem. 2003;  278 44369-44376
    CrossrefPubMedGoogle Scholar
  • 59 Rizo J, Sudhof T C. Snares and Munc18 in synaptic vesicle fusion.  Nat Rev Neurosci. 2002;  3 641-653
    PubMedGoogle Scholar
  • 60 Houng A, Polgar J, Reed G L. Munc18-syntaxin complexes and exocytosis in human platelets.  J Biol Chem. 2003;  278 19627-19633
    CrossrefPubMedGoogle Scholar
  • 61 Schraw T D, Lemons P P, Dean W L, Whiteheart S W. A role for Sec1/Munc18 proteins in platelet exocytosis.  Biochem J. 2003;  374 207-217
    CrossrefPubMedGoogle Scholar
  • 62 Pfeffer S. Membrane domains in the secretory and endocytic pathways.  Cell. 2003;  112 507-517
    CrossrefPubMedGoogle Scholar
  • 63 Novak E K, Reddington M, Zhen L et al.. Inherited thrombocytopenia caused by reduced platelet production in mice with the gunmetal pigment gene mutation.  Blood. 1995;  85 1781-1789
    PubMedGoogle Scholar
  • 64 Stinchcombe J C, Barral D C, Mules E H et al.. Rab27a is required for regulated secretion in cytotoxic T lymphocytes.  J Cell Biol. 2001;  152 825-834
    CrossrefPubMedGoogle Scholar
  • 65 Swank R T, Jiang S Y, 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
    PubMedGoogle Scholar
  • 66 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
    CrossrefPubMedGoogle Scholar
  • 67 King S, Reed G. Development of platelet secretory granules.  Semin Cell Dev Biol. 2002;  13 293-302
    CrossrefPubMedGoogle Scholar
  • 68 Fitzgerald M L, Reed G L. 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
    CrossrefPubMedGoogle Scholar
  • 69 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
    PubMedGoogle Scholar
  • 70 Brass L F. Thrombin and platelet activation.  Chest. 2003;  124 18S-25S
    CrossrefPubMedGoogle Scholar
  • 71 Ware J A, Chang J D. Protein kinase C and its interactions with other serine-threonine kinases. In: von Bruchhausen F, Walter U Platelets and Their Factors. Vol. 126. New York; Springer 1997: 247-296
    Google Scholar
  • 72 Rink T J, Smith S W, Tsien R Y. Cytoplasmic free Ca2+ in human platelets: Ca2+ thresholds and Ca- independent activation for shape-change and secretion.  FEBS Lett. 1982;  148 21-26
    CrossrefPubMedGoogle Scholar
  • 73 Knight D E, Hallam T J, Scrutton M C. Agonist selectivity and second messenger concentration in Ca2+-mediated secretion.  Nature. 1982;  296 256-257
    CrossrefPubMedGoogle Scholar
  • 74 Authi K S, Evenden B J, Crawford N. Metabolic and functional consequences of introducing inositol 1,4,5-trisphosphate into saponin-permeabilized human platelets.  Biochem J. 1986;  233 707-718
    PubMedGoogle Scholar
  • 75 Watson S P, Ruggiero M, Abrahams S L, Lapetina E G. Inositol 1,4,5-trisphosphate induces aggregation and release of 5-hydroxytryptamine from saponin-permeabilized human platelets.  J Biol Chem. 1986;  261 5368-5372
    PubMedGoogle Scholar
  • 76 Walker T R, Watson S P. Synergy between Ca2+ and protein kinase C is the major factor in determining the level of secretion from human platelets.  Biochem J. 1993;  289 277-282
    PubMedGoogle Scholar
  • 77 Chung S H, Polgar J, Reed G L. Protein kinase C phosphorylation of syntaxin 4 in thrombin-activated human platelets.  J Biol Chem. 2000;  275 25286-25291
    CrossrefPubMedGoogle Scholar
  • 78 Geanacopoulos M, Turner J, Bowling K E, Vandenberg S R, Gear A R. The role of protein kinase C in the initial events of platelet activation by thrombin assessed with a selective inhibitor.  Thromb Res. 1993;  69 113-124
    CrossrefPubMedGoogle Scholar
  • 79 Rozenvayn N, Flaumenhaft R. Protein kinase C mediates translocation of type II phosphatidylinositol 5-phosphate 4-kinase required for platelet alpha-granule secretion.  J Biol Chem. 2003;  278 8126-8134
    CrossrefPubMedGoogle Scholar
  • 80 Gerrard J M, McNicol A, Saxena S P. Protein kinase C, membrane fusion and platelet granule secretion.  Biochem Soc Trans. 1993;  21 289-293
    PubMedGoogle Scholar
  • 81 Arbuzova A, Schmitz A A, Vergeres G. Cross-talk unfolded: MARCKS proteins.  Biochem J. 2002;  362 1-12
    CrossrefPubMedGoogle Scholar
  • 82 Flaumenhaft R. Molecular basis of platelet granule secretion.  Arterioscler Thromb Vasc Biol. 2003;  23 1152-1160
    PubMedGoogle Scholar
  • 83 Wang J, Arbuzova A, Hangyas-Mihalyne G, McLaughlin S. The effector domain of myristoylated alanine-rich C kinase substrate binds strongly to phosphatidylinositol 4,5-bisphosphate.  J Biol Chem. 2001;  276 5012-5019
    CrossrefPubMedGoogle Scholar
  • 84 Elzagallaai A, Rose S D, Trifaro J M. Platelet secretion induced by phorbol esters stimulation is mediated through phosphorylation of MARCKS: a MARCKS-derived peptide blocks MARCKS phosphorylation and serotonin release without affecting pleckstrin phosphorylation.  Blood. 2000;  95 894-902
    PubMedGoogle Scholar
  • 85 White J G. Electron microscopic studies of platelet secretion.  Prog Hemost Thromb. 1974;  2 49-98
    PubMedGoogle Scholar
  • 86 Morgenstern E, Neumann K, Patscheke H. The exocytosis of human blood platelets. A fast freezing and freeze-substitution analysis.  Eur J Cell Biol. 1987;  43 273-282
    PubMedGoogle Scholar
  • 87 Morimoto T, Ogihara S, Takisawa H. Anchorage of secretion-competent dense granules on the plasma membrane of bovine platelets in the absence of secretory stimulation.  J Cell Biol. 1990;  111 79-86
    CrossrefPubMedGoogle Scholar
  • 88 Barkalow K L, Italiano Jr J E, Chou D E, Matsuoka Y, Bennett V, Hartwig J H. Alpha-adducin dissociates from F-actin and spectrin during platelet activation.  J Cell Biol. 2003;  161 557-570
    CrossrefPubMedGoogle Scholar
  • 89 Otterdal K, Pedersen T M, Solum N O. Platelet shape change induced by the peptide YFLLRNP.  Thromb Res. 2001;  103 411-420
    CrossrefPubMedGoogle Scholar
  • 90 Kometani M, Sato T, Fujii T. Platelet cytoskeletal components involved in shape change and secretion.  Thromb Res. 1986;  41 801-809
    CrossrefPubMedGoogle Scholar
  • 91 Sasakawa N, Ohara-Imaizumi M, Okubo S, Hosaka S, Hayashi M, Kumakura K. Roles of actin filaments and the actin-myosin interaction in the regulation of exocytosis in chromaffin cells.  Ann N Y Acad Sci. 2002;  971 273-274
    PubMedGoogle Scholar
  • 92 Valentijn K, Valentijn J A, Jamieson J D. Role of actin in regulated exocytosis and compensatory membrane retrieval: insights from an old acquaintance.  Biochem Biophys Res Commun. 1999;  266 652-661
    CrossrefPubMedGoogle Scholar
  • 93 Menche D, Israel A, Karpatkin S. Platelets and microtubules. Effect of colchicine and D2O on platelet aggregation and release induced by calcium ionophore A23187.  J Clin Invest. 1980;  66 284-291
    PubMedGoogle Scholar
  • 94 Verhoeven A J, Mommersteeg M E, Akkerman J W. Kinetics of energy consumption in human platelets with blocked ATP regeneration.  Int J Biochem. 1986;  18 985-990
    CrossrefPubMedGoogle Scholar
  • 95 Berry S, Dawicki D D, Agarwal K C, Steiner M. The role of microtubules in platelet secretory release.  Biochim Biophys Acta. 1989;  1012 46-56
    PubMedGoogle Scholar
  • 96 Burgoyne R D, Cheek T R. Reorganisation of peripheral actin filaments as a prelude to exocytosis.  Biosci Rep. 1987;  7 281-288
    CrossrefPubMedGoogle Scholar
  • 97 Vitale M L, Seward E P, Trifaro J M. Chromaffin cell cortical actin network dynamics control the size of the release-ready vesicle pool and the initial rate of exocytosis.  Neuron. 1995;  14 353-363
    CrossrefPubMedGoogle Scholar
  • 98 Marcu M G, Zhang L, Nau-Staudt K, Trifaro J M. Recombinant scinderin, an F-actin severing protein, increases calcium-induced release of serotonin from permeabilized platelets, an effect blocked by two scinderin-derived actin-binding peptides and phosphatidylinositol 4,5-bisphosphate.  Blood. 1996;  87 20-24
    PubMedGoogle Scholar
  • 99 Heijnen H F, Debili N, Vainchencker W, Breton-Gorius J, Geuze H J, Sixma J J. Multivesicular bodies are an intermediate stage in the formation of platelet alpha-granules.  Blood. 1998;  91 2313-2325
    PubMedGoogle Scholar
  • 100 Youssefian T, Cramer E M. Megakaryocyte dense granule components are sorted in multivesicular bodies.  Blood. 2000;  95 4004-4007
    PubMedGoogle Scholar
  • 101 Cramer E M, Norol F, Guichard J et al.. Ultrastructure of platelet formation by human megakaryocytes cultured with the Mpl ligand.  Blood. 1997;  89 2336-2346
    PubMedGoogle Scholar
  • 102 Hartwig J, Italiano Jr J. The birth of the platelet.  J Thromb Haemost. 2003;  1 1580-1586
    CrossrefPubMedGoogle Scholar
  • 103 Youssefian T, Masse J M, Rendu F, Guichard J, Cramer E M. Platelet and megakaryocyte dense granules contain glycoproteins Ib and IIb-IIIa.  Blood. 1997;  89 4047-4057
    PubMedGoogle Scholar
  • 104 Cramer E M, Harrison P, Savidge G F et al.. Uncoordinated expression of alpha-granule proteins in human megakaryocytes.  Prog Clin Biol Res. 1990;  356 131-142
    PubMedGoogle Scholar
  • 105 Hegyi E, Heilbrun L K, 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
    PubMedGoogle Scholar
  • 106 Handagama P J, George J N, Shuman M A, McEver R P, Bainton D F. Incorporation of a circulating protein into megakaryocyte and platelet granules.  Proc Natl Acad Sci USA. 1987;  84 861-865
    PubMedGoogle Scholar
  • 107 Handagama P J, Shuman M A, Bainton D F. Incorporation of intravenously injected albumin, immunoglobulin G, and fibrinogen in guinea pig megakaryocyte granules.  J Clin Invest. 1989;  84 73-82
    CrossrefPubMedGoogle Scholar
  • 108 Harrison P, Wilbourn B, Debili N et al.. Uptake of plasma fibrinogen into the alpha granules of human megakaryocytes and platelets.  J Clin Invest. 1989;  84 1320-1324
    CrossrefPubMedGoogle Scholar
  • 109 George J N. Platelet immunoglobulin G: its significance for the evaluation of thrombocytopenia and for understanding the origin of alpha-granule proteins.  Blood. 1990;  76 859-870
    PubMedGoogle Scholar
  • 110 Handagama P, Bainton D F, Jacques Y, Conn M T, Lazarus R A, Shuman M A. Kistrin, an integrin antagonist, blocks endocytosis of fibrinogen into guinea pig megakaryocyte and platelet alpha-granules.  J Clin Invest. 1993;  91 193-200
    PubMedGoogle Scholar
  • 111 Morgenstern E. Coated membranes in blood platelets.  Eur J Cell Biol. 1982;  26 315-318
    PubMedGoogle Scholar
  • 112 Behnke O. Coated pits and vesicles transfer plasma components to platelet granules.  Thromb Haemost. 1989;  62 718-722
    PubMedGoogle Scholar
  • 113 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
    PubMedGoogle Scholar
  • 114 Klinger M H, Kluter H. Immunocytochemical colocalization of adhesive proteins with clathrin in human blood platelets: further evidence for coated vesicle-mediated transport of von Willebrand factor, fibrinogen and fibronectin.  Cell Tissue Res. 1995;  279 453-457
    PubMedGoogle Scholar
  • 115 Stenberg P E, Pestina T I, Barrie R J, Jackson C W. The Src family kinases, Fgr, Fyn, Lck, and Lyn, colocalize with coated membranes in platelets.  Blood. 1997;  89 2384-2393
    PubMedGoogle Scholar
  • 116 Stenberg P E. Ultrastructural organization of maturing megakaryocytes. In: Levine RF, Williams N, Levin J, Evatt BL Progress in Clinical and Biological Research. Vol. 215. New York; Alan R Liss 1986: 373-386
    Google Scholar
  • 117 Wojenski C M, Schick P K. Development of storage granules during megakaryocyte maturation: accumulation of adenine nucleotides and the capacity for serotonin sequestration.  J Lab Clin Med. 1993;  121 479-485
    PubMedGoogle Scholar
  • 118 Cramer E M. Platelet and megakaryocytes: anatomy and structural organization. In: Colman RW, Hirsch J, Marder VJ, Clowes AW, George JN Hemostasis and Thrombosis: Basic Principles and Clinical Practice, 4th ed. Philadelphia; Lippincott Williams & Wilkins 2001: 411-428
    Google Scholar
  • 119 Rao A K, Jalagadugula G, Sun L. Inherited defects in platelet signaling mechanisms.  Semin Thromb Hemost. 2004;  30 , (in press)
    PubMedGoogle Scholar
  • 120 Rosa J P, George J N, Bainton D F, Nurden A T, Caen J P, McEver R P. Gray platelet syndrome. Demonstration of alpha granule membranes that can fuse with the cell surface.  J Clin Invest. 1987;  80 1138-1146
    CrossrefPubMedGoogle Scholar
  • 121 Raccuglia G. Gray platelet syndrome. A variety of qualitative platelet disorder.  Am J Med. 1971;  51 818-828
    CrossrefPubMedGoogle Scholar
  • 122 Gerrard J M, Phillips D R, Rao G H et al.. Biochemical studies of two patients with the gray platelet syndrome Selective deficiency of platelet alpha granules.  J Clin Invest. 1980;  66 102-109
    CrossrefPubMedGoogle Scholar
  • 123 Breton-Gorius J, Vainchenker W, Nurden A, Levy-Toledano S, Caen J. Defective alpha-granule production in megakaryocytes from gray platelet syndrome: ultrastructural studies of bone marrow cells and megakaryocytes growing in culture from blood precursors.  Am J Pathol. 1981;  102 10-19
    PubMedGoogle Scholar
  • 124 Cramer E M, Vainchenker W, Vinci G, Guichard J, Breton-Gorius J. Gray platelet syndrome: immunoelectron microscopic localization of fibrinogen and von Willebrand factor in platelets and megakaryocytes.  Blood. 1985;  66 1309-1316
    PubMedGoogle Scholar
  • 125 Levy-Toledano S, Caen J P, Breton-Gorius J et al.. Gray platelet syndrome: alpha-granule deficiency. Its influence on platelet function.  J Lab Clin Med. 1981;  98 831-848
    PubMedGoogle Scholar
  • 126 Nurden A T, Kunicki T J, Dupuis D, Soria C, Caen J P. Specific protein and glycoprotein deficiencies in platelets isolated from two patients with the gray platelet syndrome.  Blood. 1982;  59 709-718
    PubMedGoogle Scholar
  • 127 Gebrane-Younes J, Cramer E M, Orcel L, Caen J P. Gray platelet syndrome. Dissociation between abnormal sorting in megakaryocyte alpha-granules and normal sorting in Weibel-Palade bodies of endothelial cells.  J Clin Invest. 1993;  92 3023-3028
    PubMedGoogle Scholar
  • 128 Hannah M J, Williams R, Kaur J, Hewlett L J, Cutler D F. Biogenesis of Weibel-Palade bodies.  Semin Cell Dev Biol. 2002;  13 313-324
    CrossrefPubMedGoogle Scholar
  • 129 White J G. Ultrastructural studies of the gray platelet syndrome.  Am J Pathol. 1979;  95 445-462
    PubMedGoogle Scholar
  • 130 Falik-Zaccai T C, Anikster Y, Rivera C E et al.. A new genetic isolate of gray platelet syndrome (GPS): clinical, cellular, and hematologic characteristics.  Mol Genet Metab. 2001;  74 303-313
    CrossrefPubMedGoogle Scholar
  • 131 Jantunen E, Hanninen A, Naukkarinen A, Vornanen M, Lahtinen R. Gray platelet syndrome with splenomegaly and signs of extramedullary hematopoiesis: a case report with review of the literature.  Am J Hematol. 1994;  46 218-224
    PubMedGoogle Scholar
  • 132 Weiss H J, Lages B, Vicic W, Tsung L Y, White J G. Heterogeneous abnormalities of platelet dense granule ultrastructure in 20 patients with congenital storage pool deficiency.  Br J Haematol. 1993;  83 282-295
    CrossrefPubMedGoogle Scholar
  • 133 Huizing M, Helip-Wooley A, Dorward H, Claassen D, Hess R, Gahl W A. Hermansky-Pudlak syndrome: a model for abnormal vesicle formation and trafficking.  Pigment Cell Res. 2003;  16 584
    PubMedGoogle Scholar
  • 134 Swank R T, Novak E K, McGarry M P et al.. Abnormal vesicular trafficking in mouse models of Hermansky-Pudlak syndrome.  Pigment Cell Res. 2000;  13(suppl 8) 59-67
    CrossrefPubMedGoogle Scholar
  • 135 Gunay-Aygun M, Huizing M, Gahl W A. Molecular defects that affect platelet dense granules.  Semin Thromb Hemost. 2004;  30 , (in press)
    PubMedGoogle Scholar
  • 136 Fukami M H. Isolation of dense granules from human platelets.  Methods Enzymol. 1992;  215 36-42
    PubMedGoogle Scholar
  • 137 Fukami M H. Dense granule factors. In: von Bruchhausen F, Walter U Platelets and Their Factors. Vol. 126. New York; Springer 1997: 419-432
    Google Scholar

Guy L ReedM.D.  Assoc. Prof.

Harvard, School of Public Health, Cardiovascular Biology

677 Huntington Ave.

Boston, MA 02115

Email: reed@cvlab.harvard.edu