Mechanism of Platelet Granule Release and its Role in Thrombus Formation: Lead Contributor to discoveries, Robert Flaumenhaft, MD, PhD, Division of Hemostasis and Thrombosis at BIDMC and Harvard Medical School
Reporter: Aviva Lev-Ari, PhD, RN
It is well known that platelets are crucial for stopping bleeding. Platelets prevent excessive posttraumatic blood loss at sites of vascular injury by forming a platelet plug. Upon exposure of the subendothelial extracellular matrix, platelets are recruited to the site of injury and become activated, resulting in firm adhesion and subsequent platelet aggregation. The molecular mechanisms underlying the formation of a hemostatic platelet plug are relatively well understood: upon exposure of the subendothelial matrix, platelets either interact directly with matrix proteins (eg, via glycoprotein VI [GPVI] and α2β1 to collagen) or bind to von Willebrand factor (VWF) that is deposited at the site of injury. Transient interactions between platelet GPIb and VWF support platelet tethering at sites of high shear stress. Firm adhesion and subsequent aggregation is mediated by activated integrin receptors such as αIIbβ3. G-protein–coupled receptors mediate activation signals after being triggered by soluble agonists such as thrombin, thromboxane A2, and adenosine 5′-diphosphate, which reinforce thrombus propagation.
SOURCE
http://www.bloodjournal.org/content/129/12/1573?sso-checked=true
To address the role of platelet granule content in maintaining vascular integrity in inflammation, Deppermann et al generated Unc13d−/−/Nbeal2−/− mice.1 Platelets from these mice are unable to secrete their α- or dense-granule content. The authors used these mice in models of lung inflammation, skin inflammation, and brain infarction. Similar to previous studies, intradermal hemorrhage was observed in platelet-depleted wild-type (WT) mice at the site of inflammation. Strikingly, no bleeding was observed in the inflamed skin of Unc13d−/−/Nbeal2−/− mice. Analogous results were observed in lung inflammation. These experiments show that release of α or dense granules is not necessary to maintain vascular integrity at sites of acute inflammation in skin and lung. Much different results were however obtained in the stroke model used by the authors. Indeed, when subjected to transient middle cerebral artery occlusion, Unc13d−/−/Nbeal2−/− mice were prone to intracranial bleeding in the infarcted areas. Cerebral hemorrhage in these mice resulted in a significantly increased mortality compared with WT animals. In an elegant approach using platelet transfusion experiments, the authors showed that the observed effects of combined Munc13-4 and Nbeal deficiency were related to the platelet-specific secretion effects and not to potential defects in other cells.
SOURCE
http://www.bloodjournal.org/content/129/12/1573?sso-checked=true
Abstract
Current understanding of how platelets localize coagulation to wound sites has come mainly from studies of a subpopulation of activated platelets. In this review, we summarize data from the last 4 decades that have described these platelets with a range of descriptive titles and attributes. We identify striking overlaps in the reported characteristics of these platelets, which imply a single subpopulation of versatile platelets and thus suggest that their commonality requires unification of their description. We therefore propose the term procoagulant platelet as the unifying terminology. We discuss the agonist requirements and molecular drivers for the dramatic morphological transformation platelets undergo when becoming procoagulant. Finally, we provide perspectives on the biomarker potential of procoagulant platelets for thrombotic events as well as on the possible clinical benefits of inhibitors of carbonic anhydrase enzymes and the water channel Aquaporin-1 for targeting this subpopulation of platelets as antiprocoagulant antithrombotics.
SOURCE
Robert Flaumenhaft, MD, PhD – A Biography
Blood Rev. 2009 Jul;23(4):177-89. doi: 10.1016/j.blre.2009.04.001. Epub 2009 May 17.Platelet alpha-granules: basic biology and clinical correlates.
Abstract
alpha-Granules are essential to normal platelet activity. These unusual secretory granules derive their cargo from both regulated secretory and endocytotic pathways in megakaryocytes. Rare, inheritable defects of alpha-granule formation in mice and man have enabled identification of proteins that mediate cargo trafficking and alpha-granule formation. In platelets, alpha-granules fuse with the plasma membrane upon activation, releasing their cargo and increasing platelet surface area. The mechanisms that control alpha-granule membrane fusion have begun to be elucidated at the molecular level. SNAREs and SNARE accessory proteins that control alpha-granule secretion have been identified. Proteomic studies demonstrate that hundreds of bioactive proteins are released from alpha-granules. This breadth of proteins implies a versatile functionality. While initially known primarily for their participation in thrombosis and hemostasis, the role of alpha-granules in inflammation, atherosclerosis, antimicrobial host defense, wound healing, angiogenesis, and malignancy has become increasingly appreciated as the function of platelets in the pathophysiology of these processes has been defined. This review will consider the formation, release, and physiologic roles of alpha-granules with special emphasis on work performed over the last decade.
- PMID:
- 19450911
- PMCID:
- PMC2720568
- DOI:
- 10.1016/j.blre.2009.04.001
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Nachtigall MJ, Jessel RH, Flaumenhaft R, Nachtigall R, Yoles I, Naftolin F, Nachtigall LE. The selective estrogen receptor modulator DT56a (Femarelle) does not affect platelet reactivity in normal or thrombophilic postmenopausal women. Menopause. 2011 Mar; 18(3):285-8. PMID: 21037489.
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Dowal L, Sim DS, Dilks JR, Blair P, Beaudry S, Denker BM, Koukos G, Kuliopulos A, Flaumenhaft R. Identification of an antithrombotic allosteric modulator that acts through helix 8 of PAR1. Proc Natl Acad Sci U S A. 2011 Feb 15; 108(7):2951-6.PMID: 21282664.
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Flaumenhaft R. Filling a void in Gray Platelets. Blood. 2010 Dec 02; 116(23):4738-40. PMID: 21127182.
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Blair P, Flaumenhaft R. Platelet alpha-granules: basic biology and clinical correlates. Blood Rev. 2009 Jul; 23(4):177-89. PMID: 19450911.
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Graham GJ, Ren Q, Dilks JR, Blair P, Whiteheart SW, Flaumenhaft R. Endobrevin/VAMP-8-dependent dense granule release mediates thrombus formation in vivo. Blood. 2009 Jul 30; 114(5):1083-90. PMID: 19395672.
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Flaumenhaft R, Dilks JR, Richardson J, Alden E, Patel-Hett SR, Battinelli E, Klement GL, Sola-Visner M, Italiano JE. Megakaryocyte-derived microparticles: direct visualization and distinction from platelet-derived microparticles. Blood. 2009 Jan 29; 113(5):1112-21. PMID: 18802008.
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Flaumenhaft R, Dilks JR. Discovery-based strategies for studying platelet function. Mini Rev Med Chem. 2008 Apr; 8(4):350-7.PMID: 18473926.
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Flaumenhaft R, Rozenvayn N, Feng D, Dvorak AM. SNAP-23 and syntaxin-2 localize to the extracellular surface of the platelet plasma membrane. Blood. 2007 Sep 01; 110(5):1492-501. PMID: 17485553.
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Sim DS, Dilks JR, Flaumenhaft R. Platelets possess and require an active protein palmitoylation pathway for agonist-mediated activation and in vivo thrombus formation. Arterioscler Thromb Vasc Biol. 2007 Jun; 27(6):1478-85. PMID: 17303775.
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Flaumenhaft R, Tanaka E, Graham GJ, De Grand AM, Laurence RG, Hoshino K, Hajjar RJ, Frangioni JV. Localization and quantification of platelet-rich thrombi in large blood vessels with near-infrared fluorescence imaging. Circulation. 2007 Jan 02; 115(1):84-93. PMID: 17179017.
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Flaumenhaft R, Dilks JR, Rozenvayn N, Monahan-Earley RA, Feng D, Dvorak AM. The actin cytoskeleton differentially regulates platelet alpha-granule and dense-granule secretion. Blood. 2005 May 15; 105(10):3879-87. PMID: 15671445.
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Falati S, Gross PL, Merrill-Skoloff G, Sim D, Flaumenhaft R, Celi A, Furie BC, Furie B. In vivo models of platelet function and thrombosis: study of real-time thrombus formation. Methods Mol Biol. 2004; 272:187-97. PMID: 15226545.
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Sim DS, Merrill-Skoloff G, Furie BC, Furie B, Flaumenhaft R. Initial accumulation of platelets during arterial thrombus formation in vivo is inhibited by elevation of basal cAMP levels. Blood. 2004 Mar 15; 103(6):2127-34. PMID: 14645013.
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Flaumenhaft R. Molecular basis of platelet granule secretion. Arterioscler Thromb Vasc Biol. 2003 Jul 01; 23(7):1152-60. PMID: 12738684.
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Celi A, Merrill-Skoloff G, Gross P, Falati S, Sim DS, Flaumenhaft R, Furie BC, Furie B. Thrombus formation: direct real-time observation and digital analysis of thrombus assembly in a living mouse by confocal and widefield intravital microscopy. J Thromb Haemost. 2003 Jan; 1(1):60-8. PMID: 12871540.
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Furie B, Furie BC, Flaumenhaft R. A journey with platelet P-selectin: the molecular basis of granule secretion, signalling and cell adhesion. Thromb Haemost. 2001 Jul; 86(1):214-21. PMID: 11487009.
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Rozenvayn N, Flaumenhaft R. Phosphatidylinositol 4,5-bisphosphate mediates Ca2+-induced platelet alpha-granule secretion: evidence for type II phosphatidylinositol 5-phosphate 4-kinase function. J Biol Chem. 2001 Jun 22; 276(25):22410-9. PMID: 11304526.
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Feng D, Flaumenhaft R, Bandeira-Melo C, Weller P, Dvorak A. Ultrastructural localization of vesicle-associated membrane protein(s) to specialized membrane structures in human pericytes, vascular smooth muscle cells, endothelial cells, neutrophils, and eosinophils. J Histochem Cytochem. 2001 Mar; 49(3):293-304. PMID: 11181732.
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Yang J, Hirata T, Croce K, Merrill-Skoloff G, Tchernychev B, Williams E, Flaumenhaft R, Furie BC, Furie B. Targeted gene disruption demonstrates that P-selectin glycoprotein ligand 1 (PSGL-1) is required for P-selectin-mediated but not E-selectin-mediated neutrophil rolling and migration. J Exp Med. 1999 Dec 20; 190(12):1769-82. PMID: 10601352.
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Croce K, Flaumenhaft R, Rivers M, Furie B, Furie BC, Herman IM, Potter DA. Inhibition of calpain blocks platelet secretion, aggregation, and spreading. J Biol Chem. 1999 Dec 17; 274(51):36321-7. PMID: 10593923.
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Flaumenhaft R, Furie B, Furie BC. Alpha-granule secretion from alpha-toxin permeabilized, MgATP-exposed platelets is induced independently by H+ and Ca2+. J Cell Physiol. 1999 Apr; 179(1):1-10. PMID: 10082126.
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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 Jan 22; 274(4):2492-501. PMID: 9891020.
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Flaumenhaft R, Abe M, Sato Y, Miyazono K, Harpel J, Heldin CH, Rifkin DB. Role of the latent TGF-beta binding protein in the activation of latent TGF-beta by co-cultures of endothelial and smooth muscle cells. J Cell Biol. 1993 Feb; 120(4):995-1002.PMID: 8432736.
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Flaumenhaft R, Kojima S, Abe M, Rifkin DB. Activation of latent transforming growth factor beta. Adv Pharmacol. 1993; 24:51-76. PMID: 8504067.
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Flaumenhaft R, Rifkin DB. The extracellular regulation of growth factor action. Mol Biol Cell. 1992 Oct; 3(10):1057-65. PMID: 1421565.
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Flaumenhaft R, Abe M, Mignatti P, Rifkin DB. Basic fibroblast growth factor-induced activation of latent transforming growth factor beta in endothelial cells: regulation of plasminogen activator activity. J Cell Biol. 1992 Aug; 118(4):901-9. PMID: 1380001.
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Flaumenhaft R, Rifkin DB. Cell density dependent effects of TGF-beta demonstrated by a plasminogen activator-based assay for TGF-beta. J Cell Physiol. 1992 Jul; 152(1):48-55. PMID: 1618922.
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