Skip to main content

Abstract

The heterogeneity of platelets is present at rest, upon stimulation by agonists, and within the hemostatic plug. Circulating platelets are heterogeneous in size, age, and responsiveness. Differences in platelet size, platelet age, and platelet genetics can result in variable reactivity and altered interactions of platelets both within and between individuals. Following stimulation by strong agonists, distinct activated platelet subpopulations of spread and aggregating platelets and procoagulant platelets can be identified. Procoagulant platelets differ in morphology and function from spread and aggregating platelets. Finally, morphologically and functionally distinct platelet subpopulations participate in the spatiotemporal regulation of hemostatic plug and thrombus formation.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 299.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 379.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 379.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • (1993) Recommendations of the International Council for Standardization in Haematology for Ethylenediaminetetraacetic Acid Anticoagulation of Blood for Blood Cell Counting and Sizing. International Council for Standardization in Haematology: Expert Panel on Cytometry. Am J Clin Pathol 100:371–372

    Google Scholar 

  • Abaeva AA, Canault M, Kotova YN, Obydennyy SI, Yakimenko AO, Podoplelova NA, Kolyadko VN, Chambost H, Mazurov AV, Ataullakhanov FI, Nurden AT, Alessi MC, Panteleev MA (2013) Procoagulant platelets form an α-granule protein-covered “cap” on their surface that promotes their attachment to aggregates. J Biol Chem 288:29621–29632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Agbani EO, van den Bosch MT, Brown E, Williams CM, Mattheij NJ, Cosemans JM, Collins PW, Heemskerk JW, Hers I, Poole AW (2015) Coordinated membrane ballooning and procoagulant spreading in human platelets. Circulation 132:1414–1424

    Article  CAS  PubMed  Google Scholar 

  • Alberio L, Safa O, Clemetson KJ, Esmon CT, Dale GL (2000) Surface expression and functional characterization of a-granule factor V in human platelets: effects of ionophore A23187, thrombin, collagen, and convulxin. Blood 95:1694–1702

    CAS  PubMed  Google Scholar 

  • Artemenko EO, Yakimenko AO, Pichugin AV, Ataullakhanov FI, Panteleev MA (2015) Calpain-controlled detachment of major glycoproteins from cytoskeleton regulates adhesive properties of phosphatidylserine-positive activated platelets. Biochem J 473:435–448

    Article  PubMed  CAS  Google Scholar 

  • Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton MA, Brunskill EW, Sayen MR, Gottlieb RA, Dorn GW, Robbins J, Molkentin JD (2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434:658–662

    Article  CAS  PubMed  Google Scholar 

  • Bergmeier W, Schulte V, Brockhoff G, Bier U, Zirngibl H, Nieswandt B (2002) Flow cytometric detection of activated mouse integrin αIIbβ3 with a novel monoclonal antibody. Cytometry 48:80–86

    Article  CAS  PubMed  Google Scholar 

  • Berny MA, Munnix IC, Auger JM, Schols SE, Cosemans JM, Panizzi P, Bock PE, Watson SP, Mccarty OJ, Heemskerk JW (2010) Spatial distribution of factor Xa, thrombin, and fibrin(ogen) on thrombi at venous shear. PLoS One 5:e10415

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bevers EM, Comfurius P, Zwaal RF (1983) Changes in membrane phospholipid distribution during platelet activation. Biochim Biophys Acta 736:57–66

    Article  CAS  PubMed  Google Scholar 

  • Boudreau LH, Duchez AC, Cloutier N, Soulet D, Martin N, Bollinger J, Paré A, Rousseau M, Naika GS, Lévesque T, Laflamme C, Marcoux G, Lambeau G, Farndale RW, Pouliot M, Hamzeh-cognasse H, Cognasse F, Garraud O, Nigrovic PA, Guderley H, Lacroix S, Thibault L, Semple JW, Gelb MH, Boilard E (2014) Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation. Blood 124:2173–2183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Braekkan SK, Mathiesen EB, Njølstad I, Wilsgaard T, Størmer J, Hansen JB (2010) Mean platelet volume is a risk factor for venous thromboembolism: the Tromsø Study, Tromsø, Norway. J Thromb Haemost 8:157–162

    Article  CAS  PubMed  Google Scholar 

  • Briedé JJ, Heemskerk JW, Hemker HC, Lindhout T (1999) Heterogeneity in microparticle formation and exposure of anionic phospholipids at the plasma membrane of single adherent platelets. Biochim Biophys Acta 1451:163–172

    Article  PubMed  Google Scholar 

  • Brooks MB, Catalfamo JL, Friese P, Dale GL (2007) Scott syndrome dogs have impaired coated-platelet formation and calcein-release but normal mitochondrial depolarization. J Thromb Haemost 5:1972–1974

    Article  CAS  PubMed  Google Scholar 

  • Calderwood DA, Fujioka Y, de Pereda JM, Garcia-alvarez B, Nakamoto T, Margolis B, Mcglade CJ, Liddington RC, Ginsberg MH (2003) Integrin beta cytoplasmic domain interactions with phosphotyrosine-binding domains: a structural prototype for diversity in integrin signaling. Proc Natl Acad Sci U S A 100:2272–2277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cecchetti L, Tolley ND, Michetti N, Bury L, Weyrich AS, Gresele P (2011) Megakaryocytes differentially sort mRNAs for matrix metalloproteinases and their inhibitors into platelets: a mechanism for regulating synthetic events. Blood 118:1903–1911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cesari F, Marcucci R, Caporale R, Paniccia R, Romano E, Gensini GF, Abbate R, Gori AM (2008) Relationship between high platelet turnover and platelet function in high-risk patients with coronary artery disease on dual antiplatelet therapy. Thromb Haemost 99:930–935

    CAS  PubMed  Google Scholar 

  • Choo HJ, Saafir TB, Mkumba L, Wagner MB, Jobe SM (2012) Mitochondrial calcium and reactive oxygen species regulate agonist-initiated platelet phosphatidylserine exposure. Arterioscler Thromb Vasc Biol 32:2946–2955

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chu SG, Becker RC, Berger PB, Bhatt DL, Eikelboom JW, Konkle B, Mohler ER, Reilly MP, Berger JS (2010) Mean platelet volume as a predictor of cardiovascular risk: a systematic review and meta-analysis. J Thromb Haemost 8:148–156

    Article  CAS  PubMed  Google Scholar 

  • Colombo G, Gertow K, Marenzi G, Brambilla M, de Metrio M, Tremoli E, Camera M (2011) Gene expression profiling reveals multiple differences in platelets from patients with stable angina or non-ST elevation acute coronary syndrome. Thromb Res 128:161–168

    Article  CAS  PubMed  Google Scholar 

  • Dachary-prigent J, Freyssinet JM, Pasquet JM, Carron JC, Nurden AT (1993) Annexin V as a probe of aminophospholipid exposure and platelet membrane vesiculation: a flow cytometry study showing a role for free sulfhydryl groups. Blood 81:2554–2565

    CAS  PubMed  Google Scholar 

  • Dachary-prigent J, Pasquet JM, Freyssinet JM, Nurden AT (1995) Calcium involvement in aminophospholipid exposure and microparticle formation during platelet activation: a study using Ca2+-ATPase inhibitors. Biochemistry 34:11625–11634

    Article  CAS  PubMed  Google Scholar 

  • Dale GL (2005) Coated-platelets: an emerging component of the procoagulant response. J Thromb Haemost 3:2185–2192

    Article  CAS  PubMed  Google Scholar 

  • Dale GL, Friese P, Hynes LA, Burstein SA (1995) Demonstration that thiazole-orange-positive platelets in the dog are less than 24 hours old. Blood 85:1822–1825

    CAS  PubMed  Google Scholar 

  • Dale GL, Friese P, Batar P, Hamilton SF, Reed GL, Jackson KW, Clemetson KJ, Alberio L (2002) Stimulated platelets use serotonin to enhance their retention of procoagulant proteins on the cell surface. Nature 415:175–179

    Article  CAS  PubMed  Google Scholar 

  • Delaney MK, Liu J, Kim K, Shen B, Stojanovic-terpo A, Zheng Y, Cho J, Du X (2014) Agonist-induced platelet procoagulant activity requires shear and a Rac1-dependent signaling mechanism. Blood 124:1957–1967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Denis MM, Tolley ND, Bunting M, Schwertz H, Jiang H, Lindemann S, Yost CC, Rubner FJ, Albertine KH, Swoboda KJ, Fratto CM, Tolley E, Kraiss LW, Mcintyre TM, Zimmerman GA, Weyrich AS (2005) Escaping the nuclear confines: signal-dependent pre-mRNA splicing in anucleate platelets. Cell 122:379–391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Diacovo TG, Roth SJ, Buccola JM, Bainton DF, Springer TA (1996) Neutrophil rolling, arrest, and transmigration across activated, surface-adherent platelets via sequential action of P-selectin and the b2-integrin CD11b/CD18. Blood 88:146–157

    CAS  PubMed  Google Scholar 

  • Du X, Saido TC, Tsubuki S, Indig FE, Williams MJ, Ginsberg MH (1995) Calpain cleavage of the cytoplasmic domain of the integrin beta 3 subunit. J Biol Chem 270:26146–26151

    Article  CAS  PubMed  Google Scholar 

  • Fadok VA, Voelker DR, Campbell PA, Cohen JJ, Bratton DL, Henson PM (1992) Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol 148:2207–2216

    CAS  PubMed  Google Scholar 

  • Flaumenhaft R, Dilks JR, Richardson J, Alden E, Patel-hett SR, Battinelli E, Klement GL, Sola-visner M, Italiano JE (2009) Megakaryocyte-derived microparticles: direct visualization and distinction from platelet-derived microparticles. Blood 113:1112–1121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fujii T, Sakata A, Nishimura S, Eto K, Nagata S (2015) TMEM16F is required for phosphatidylserine exposure and microparticle release in activated mouse platelets. Proc Natl Acad Sci U S A 112:12800–12805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ghasemzadeh M, Kaplan ZS, Alwis I, Schoenwaelder SM, Ashworth KJ, Westein E, Hosseini E, Salem HH, Slattery R, Mccoll SR, Hickey MJ, Ruggeri ZM, Yuan Y, Jackson SP (2013) The CXCR1/2 ligand NAP-2 promotes directed intravascular leukocyte migration through platelet thrombi. Blood 121:4555–4566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gilbert GE, Sims PJ, Wiedmer T, Furie B, Furie BC, Shattil SJ (1991) Platelet-derived microparticles express high affinity receptors for factor VIII. J Biol Chem 266:17261–17268

    CAS  PubMed  Google Scholar 

  • Giles H, Smith RE, Martin JF (1994) Platelet glycoprotein IIb-IIIa and size are increased in acute myocardial infarction. Eur J Clin Invest 24:69–72

    Article  CAS  PubMed  Google Scholar 

  • Gilio K, van Kruchten R, Braun A, Berna-erro A, Feijge MA, Stegner D, van der Meijden PE, Kuijpers MJ, Varga-szabo D, Heemskerk JW, Nieswandt B (2010) Roles of platelet STIM1 and Orai1 in glycoprotein VI- and thrombin-dependent procoagulant activity and thrombus formation. J Biol Chem 285:23629–23638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gunebakmaz O, Kaya MG, Kaya EG, Ardic I, Yarlioglues M, Dogdu O, Kalay N, Akpek M, Sarli B, Ozdogru I (2010) Mean platelet volume predicts embolic complications and prognosis in infective endocarditis. Int J Infect Dis 14:e982–e985

    Article  PubMed  Google Scholar 

  • Guthikonda S, Alviar CL, Vaduganathan M, Arikan M, Tellez A, Delao T, Granada JF, Dong JF, Kleiman NS, Lev EI (2008) Role of reticulated platelets and platelet size heterogeneity on platelet activity after dual antiplatelet therapy with aspirin and clopidogrel in patients with stable coronary artery disease. J Am Coll Cardiol 52:743–749

    Article  CAS  PubMed  Google Scholar 

  • Hagberg IA, Roald HE, Lyberg T (1998) Adhesion of leukocytes to growing arterial thrombi. Thromb Haemost 80:852–858

    CAS  PubMed  Google Scholar 

  • Halestrap AP, Richardson AP (2015) The mitochondrial permeability transition: a current perspective on its identity and role in ischaemia/reperfusion injury. J Mol Cell Cardiol 78:129–141

    Article  CAS  PubMed  Google Scholar 

  • Harper MT, Londoño JE, Quick K, Londoño JC, Flockerzi V, Philipp SE, Birnbaumer L, Freichel M, Poole AW (2013) Transient receptor potential channels function as a coincidence signal detector mediating phosphatidylserine exposure. Sci Signal 6:ra50

    Article  PubMed  CAS  Google Scholar 

  • Hartwig JH (2006) The platelet: form and function. Semin Hematol 43:S94–S100

    Article  CAS  PubMed  Google Scholar 

  • Healy AM, Pickard MD, Pradhan AD, Wang Y, Chen Z, Croce K, Sakuma M, Shi C, Zago AC, Garasic J, Damokosh AI, Dowie TL, Poisson L, Lillie J, Libby P, Ridker PM, Simon DI (2006) Platelet expression profiling and clinical validation of myeloid-related protein-14 as a novel determinant of cardiovascular events. Circulation 113:2278–2284

    Article  CAS  PubMed  Google Scholar 

  • Hechler B, Nonne C, Eckly A, Magnenat S, Rinckel JY, Denis CV, Freund M, Cazenave JP, Lanza F, Gachet C (2010) Arterial thrombosis: relevance of a model with two levels of severity assessed by histologic, ultrastructural and functional characterization. J Thromb Haemost 8:173–184

    Article  CAS  PubMed  Google Scholar 

  • Heemskerk JW, Vuist WM, Feijge MA, Reutelingsperger CP, Lindhout T (1997) Collagen but not fibrinogen surfaces induce bleb formation, exposure of phosphatidylserine, and procoagulant activity of adherent platelets: evidence for regulation by protein tyrosine kinase-dependent Ca2+ responses. Blood 90:2615–2625

    CAS  PubMed  Google Scholar 

  • Heemskerk JW, Bevers EM, Lindhout T (2002) Platelet activation and blood coagulation. Thromb Haemost 88:186–193

    CAS  PubMed  Google Scholar 

  • Heijnen HF, Schiel AE, Fijnheer R, Geuze HJ, Sixma JJ (1999) Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules. Blood 94:3791–3799

    CAS  PubMed  Google Scholar 

  • Hovig T, Rowsell HC, Dodds WJ, Jorgensen L, Mustard JF (1967) Experimental hemostasis in normal dogs and dogs with congenital disorders of blood coagulation. Blood 30:636–668

    CAS  PubMed  Google Scholar 

  • Hovig T, Dodds WJ, Rowsell HC, Mustard JF (1968) The transformation of hemostatic platelet plugs in normal and Factor IX deficient dogs. Am J Pathol 53:355–373

    CAS  PubMed  PubMed Central  Google Scholar 

  • HUA VM, Abeynaike L, Glaros E, Campbell H, Pasalic L, Hogg PJ, Chen VM (2015) Necrotic platelets provide a procoagulant surface during thrombosis. Blood 126:2852–2862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ivanciu L, Stalker TJ (2015) Spatiotemporal regulation of coagulation and platelet activation during the hemostatic response in vivo. J Thromb Haemost 13:1949–1959

    Article  CAS  PubMed  Google Scholar 

  • Ivanciu L, Krishnaswamy S, Camire RM (2014) New insights into the spatiotemporal localization of prothrombinase in vivo. Blood 124:1705–1714

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jobe SM, Leo L, Eastvold JS, Dickneite G, Ratliff TL, Lentz SR, di Paola J (2005) Role of FcRg and factor XIIIA in coated platelet formation. Blood 106:4146–4151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jobe SM, Wilson KM, Leo L, Raimondi A, Molkentin JD, Lentz SR, DI Paola J (2008) Critical role for the mitochondrial permeability transition pore and cyclophilin D in platelet activation and thrombosis. Blood 111:1257–1265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jorgensen L, Rowsell HC, Hovig T, Mustard JF (1967) Resolution and organization of platelet-rich mural thrombi in carotid arteries of swine. Am J Pathol 51:681–719

    CAS  PubMed  PubMed Central  Google Scholar 

  • Junt T, Schulze H, Chen Z, Massberg S, Goerge T, Krueger A, Wagner DD, Graf T, Italiano JE, Shivdasani RA, von Andrian UH (2007) Dynamic visualization of thrombopoiesis within bone marrow. Science 317:1767–1770

    Article  CAS  PubMed  Google Scholar 

  • Karpatkin S (1978) Heterogeneity of human platelets. VI. Correlation of platelet function with platelet volume. Blood 51:307–316

    CAS  PubMed  Google Scholar 

  • Klovaite J, Benn M, Yazdanyar S, Nordestgaard BG (2011) High platelet volume and increased risk of myocardial infarction: 39,531 participants from the general population. J Thromb Haemost 9:49–56

    Article  CAS  PubMed  Google Scholar 

  • Kulkarni S, Jackson SP (2004) Platelet factor XIII and calpain negatively regulate integrin αIIbβ3 adhesive function and thrombus growth. J Biol Chem 279:30697–30706

    Article  CAS  PubMed  Google Scholar 

  • Kulkarni S, Woollard KJ, Thomas S, Oxley D, Jackson SP (2007) Conversion of platelets from a proaggregatory to a proinflammatory adhesive phenotype: role of PAF in spatially regulating neutrophil adhesion and spreading. Blood 110:1879–1886

    Article  CAS  PubMed  Google Scholar 

  • Kurt M, Onal IK, Sayilir AY, Beyazit Y, Oztas E, Kekilli M, Turhan N, Karaman K, Akdogan M (2012) The role of mean platelet volume in the diagnosis of hepatocellular carcinoma in patients with chronic liver disease. Hepatogastroenterology 59:1580–1582

    CAS  PubMed  Google Scholar 

  • Laffont B, Corduan A, Plé H, Duchez AC, Cloutier N, Boilard E, Provost P (2013) Activated platelets can deliver mRNA regulatory Ago2•microRNA complexes to endothelial cells via microparticles. Blood 122:253–261

    Article  CAS  PubMed  Google Scholar 

  • Laffont B, Corduan A, Rousseau M, Duchez AC, Lee CH, Boilard E, Provost P (2015) Platelet microparticles reprogram macrophage gene expression and function. Thromb Haemost 115:311–323

    Article  PubMed  Google Scholar 

  • Lancé MD, Sloep M, Henskens YM, Marcus MA (2012) Mean platelet volume as a diagnostic marker for cardiovascular disease: drawbacks of preanalytical conditions and measuring techniques. Clin Appl Thromb Hemost 18:561–568

    Article  PubMed  Google Scholar 

  • Lefer AM, Campbell B, Scalia R, Lefer DJ (1998) Synergism between platelets and neutrophils in provoking cardiac dysfunction after ischemia and reperfusion: role of selectins. Circulation 98:1322–1328

    Article  CAS  PubMed  Google Scholar 

  • Leytin V, Allen DJ, Mykhaylov S, Mis L, Lyubimov EV, Garvey B, Freedman J (2004) Pathologic high shear stress induces apoptosis events in human platelets. Biochem Biophys Res Commun 320:303–310

    Article  CAS  PubMed  Google Scholar 

  • Liu F, Gamez G, Myers DR, Clemmons W, Lam WA, Jobe SM (2013) Mitochondrially mediated integrin αIIbβ3 protein inactivation limits thrombus growth. J Biol Chem 288:30672–30681

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lood C, Amisten S, Gullstrand B, Jönsen A, Allhorn M, Truedsson L, Sturfelt G, Erlinge D, Bengtsson AA (2010) Platelet transcriptional profile and protein expression in patients with systemic lupus erythematosus: up-regulation of the type I interferon system is strongly associated with vascular disease. Blood 116:1951–1957

    Article  CAS  PubMed  Google Scholar 

  • López-cuenca AA, Tello-montoliu A, Roldán V, Pérez-berbel P, Valdés M, Marín F (2012) Prognostic value of mean platelet volume in patients with non-ST-elevation acute coronary syndrome. Angiology 63:241–244

    Article  PubMed  Google Scholar 

  • Maroney SA, Haberichter SL, Friese P, Collins ML, Ferrel JP, Dale GL, Mast AE (2007) Active tissue factor pathway inhibitor is expressed on the surface of coated-platelets. Blood 109:1931–1937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martin JF, Kristensen SD, Mathur A, Grove EL, Choudry FA (2012) The causal role of megakaryocyte–platelet hyperactivity in acute coronary syndromes. Nat Rev Cardiol 9:658–670

    Article  CAS  PubMed  Google Scholar 

  • Mason KD, Carpinelli MR, Fletcher JI, Collinge JE, Hilton AA, Ellis S, Kelly PN, Ekert PG, Metcalf D, Roberts AW, Huang DC, Kile BT (2007) Programmed a nuclear cell death delimits platelet life span. Cell 128:1173–1186

    Article  CAS  PubMed  Google Scholar 

  • Mattheij NJ, Gilio K, van Kruchten R, Jobe SM, Wieschhaus AJ, Chishti AH, Collins P, Heemskerk JW, Cosemans JM (2013) Dual mechanism of integrin alphaIIbbeta3 closure in procoagulant platelets. J Biol Chem 288:13325–13336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mattheij NJ, Swieringa F, Mastenbroek TG, Berny-lang MA, May F, Baaten CC, van der Meijden PE, Henskens YM, Beckers EA, Suylen DP, Nolte MW, Hackeng TM, Mccarty OJ, Heemskerk JW, Cosemans JM (2015) Coated platelets function in platelet-dependent fibrin formation via integrin αIIbβ3 and transglutaminase factor XIII. Haematologica 101:427–436

    Article  PubMed  CAS  Google Scholar 

  • May AE, Seizer P, Gawaz M (2008) Platelets: inflammatory firebugs of vascular walls. Arterioscler Thromb Vasc Biol 28:s5–s10

    Article  CAS  PubMed  Google Scholar 

  • Moore KL, Patel KD, Bruehl RE, Li F, Johnson DA, Lichenstein HS, Cummings RD, Bainton DF, Mcever RP (1995) P-selectin glycoprotein ligand-1 mediates rolling of human neutrophils on P-selectin. J Cell Biol 128:661–671

    Article  CAS  PubMed  Google Scholar 

  • Moser M, Nieswandt B, Ussar S, Pozgajova M, Fässler R (2008) Kindlin-3 is essential for integrin activation and platelet aggregation. Nat Med 14:325–330

    Article  CAS  PubMed  Google Scholar 

  • Munnix IC, Kuijpers MJ, Auger J, Thomassen CM, Panizzi P, van Zandvoort MA, Rosing J, Bock PE, Watson SP, Heemskerk JW (2007) Segregation of platelet aggregatory and procoagulant microdomains in thrombus formation: regulation by transient integrin activation. Arterioscler Thromb Vasc Biol 27:2484–2490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murphy AJ, Bijl N, Yvan-charvet L, Welch CB, Bhagwat N, Reheman A, Wang Y, Shaw JA, Levine RL, Ni H, Tall AR, WANG N (2013) Cholesterol efflux in megakaryocyte progenitors suppresses platelet production and thrombocytosis. Nat Med 19:586–594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murphy AJ, Sarrazy V, Wang N, Bijl N, Abramowicz S, Westerterp M, Welch CB, Schuetz JD, Yvan-charvet L (2014) Deficiency of ATP-binding cassette transporter B6 in megakaryocyte progenitors accelerates atherosclerosis in mice. Arterioscler Thromb Vasc Biol 34:751–758

    Article  CAS  PubMed  Google Scholar 

  • Nesbitt WS, Westein E, Tovar-lopez FJ, Tolouei E, Mitchell A, Fu J, CARBERRY J, Fouras A, Jackson SP (2009) A shear gradient-dependent platelet aggregation mechanism drives thrombus formation. Nat Med 15:665–673

    Article  CAS  PubMed  Google Scholar 

  • Nilsson RJ, Balaj L, Hulleman E, van Rijn S, Pegtel DM, Walraven M, Widmark A, Gerritsen WR, Verheul HM, Vandertop WP, Noske DP, Skog J, Würdinger T (2011) Blood platelets contain tumor-derived RNA biomarkers. Blood 118:3680–3683

    Article  PubMed  Google Scholar 

  • Nishimura S, Nagasaki M, Kunishima S, Sawaguchi A, Sakata A, Sakaguchi H, Ohmori T, Manabe I, Italiano JE, Ryu T, Takayama N, Komuro I, Kadowaki T, Eto K, Nagai R (2015) IL-1α induces thrombopoiesis through megakaryocyte rupture in response to acute platelet needs. J Cell Biol 209:453–466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ostrovsky L, King AJ, Bond S, Mitchell D, Lorant DE, Zimmerman GA, Larsen R, Niu XF, Kubes P (1998) A juxtacrine mechanism for neutrophil adhesion on platelets involves platelet-activating factor and a selectin-dependent activation process. Blood 91:3028–3036

    CAS  PubMed  Google Scholar 

  • Otunctemur A, Bozkurt M, Besiroglu H, Polat EC, Ozcan L, Ozbek E (2015) Erectile dysfunction is positively correlated with mean platelet volume and platelet count, but not with eosinophil count in peripheral blood. Urol J 12:2347–2352

    PubMed  Google Scholar 

  • Paulus JM (1975) Platelet size in man. Blood 46:321–336

    CAS  PubMed  Google Scholar 

  • Pitchford SC, Yano H, Lever R, Riffo-vasquez Y, Ciferri S, Rose MJ, Giannini S, Momi S, Spina D, O’connor B, Gresele P, Page CP (2003) Platelets are essential for leukocyte recruitment in allergic inflammation. J Allergy Clin Immunol 112:109–118

    Article  CAS  PubMed  Google Scholar 

  • Plow EF, Meller J, Byzova TV (2014) Integrin function in vascular biology: a view from 2013. Curr Opin Hematol 21:241–247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rand ML, Wang H, Bang KW, Packham MA, Freedman J (2006) Rapid clearance of procoagulant platelet-derived microparticles from the circulation of rabbits. J Thromb Haemost 4:1621–1623

    Article  CAS  PubMed  Google Scholar 

  • Ray DM, Spinelli SL, Pollock SJ, Murant TI, O’brien JJ, Blumberg N, Francis CW, Taubman MB, Phipps RP (2008) Peroxisome proliferator-activated receptor gamma and retinoid X receptor transcription factors are released from activated human platelets and shed in microparticles. Thromb Haemost 99:86–95

    CAS  PubMed  PubMed Central  Google Scholar 

  • Remenyi G, Szasz R, Friese P, Dale GL (2005) Role of mitochondrial permeability transition pore in coated-platelet formation. Arterioscler Thromb Vasc Biol 25:467–471

    Article  CAS  PubMed  Google Scholar 

  • Ren Q, Ye S, Whiteheart SW (2008) The platelet release reaction: just when you thought platelet secretion was simple. Curr Opin Hematol 15:537–541

    Article  PubMed  PubMed Central  Google Scholar 

  • Risitano A, Beaulieu LM, Vitseva O, Freedman JE (2012) Platelets and platelet-like particles mediate intercellular RNA transfer. Blood 119:6288–6295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rosing J, Bevers EM, Comfurius P, Hemker HC, van Dieijen G, Weiss HJ, Zwaal RF (1985a) Impaired factor X and prothrombin activation associated with decreased phospholipid exposure in platelets from a patient with a bleeding disorder. Blood 65:1557–1561

    CAS  PubMed  Google Scholar 

  • Rosing J, van Rijn JL, Bevers EM, van Dieijen G, Comfurius P, Zwaal RF (1985b) The role of activated human platelets in prothrombin and factor X activation. Blood 65:319–332

    CAS  PubMed  Google Scholar 

  • Sakurai Y, Fitch-tewfik JL, Qiu Y, Ahn B, Myers DR, Tran R, Fay ME, Ding L, Spearman PW, Michelson AD, Flaumenhaft R, Lam WA (2015) Platelet geometry sensing spatially regulates α-granule secretion to enable matrix self-deposition. Blood 126:531–538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schoenwaelder SM, Yuan Y, Cooray P, Salem HH, Jackson SP (1997) Calpain cleavage of focal adhesion proteins regulates the cytoskeletal attachment of integrin alphaIIbbeta3 (platelet glycoprotein IIb/IIIa) and the cellular retraction of fibrin clots. J Biol Chem 272:1694–1702

    Article  CAS  PubMed  Google Scholar 

  • Schoenwaelder SM, Yuan Y, Josefsson EC, White MJ, Yao Y, Mason KD, o’reilly LA, Henley KJ, Ono A, Hsiao S, Willcox A, Roberts AW, Huang DC, Salem HH, Kile BT, Jackson SP (2009) Two distinct pathways regulate platelet phosphatidylserine exposure and procoagulant function. Blood 114:663–666

    Article  CAS  PubMed  Google Scholar 

  • Schulz C, Engelmann B, MASSBERG S (2013) Crossroads of coagulation and innate immunity: the case of deep vein thrombosis. J Thromb Haemost 11(Suppl 1):233–241

    Article  PubMed  Google Scholar 

  • Schwertz H, Köster S, Kahr WH, Michetti N, Kraemer BF, Weitz DA, Blaylock RC, Kraiss LW, Greinacher A, Zimmerman GA, Weyrich AS (2010) Anucleate platelets generate progeny. Blood 115:3801–3809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sims PJ, Faioni EM, Wiedmer T, Shattil SJ (1988) Complement proteins C5b-9 cause release of membrane vesicles from the platelet surface that are enriched in the membrane receptor for coagulation factor Va and express prothrombinase activity. J Biol Chem 263:18205–18212

    CAS  PubMed  Google Scholar 

  • Sims PJ, Wiedmer T, Esmon CT, Weiss HJ, Shattil SJ (1989) Assembly of the platelet prothrombinase complex is linked to vesiculation of the platelet plasma membrane. Studies in Scott syndrome: an isolated defect in platelet procoagulant activity. J Biol Chem 264:17049–17057

    CAS  PubMed  Google Scholar 

  • Singer G, Urakami H, Specian RD, Stokes KY, Granger DN (2006) Platelet recruitment in the murine hepatic microvasculature during experimental sepsis: role of neutrophils. Microcirculation 13:89–97

    Article  CAS  PubMed  Google Scholar 

  • Smeets EF, Heemskerk JW, Comfurius P, Bevers EM, Zwaal RF (1993) Thapsigargin amplifies the platelet procoagulant response caused by thrombin. Thromb Haemost 70:1024–1029

    CAS  PubMed  Google Scholar 

  • Sökücü SN, Ozdemir C, Dalar L, Karasulu L, Aydin S, Altin S (2014) Complete blood count alterations after six months of continuous positive airway pressure treatment in patients with severe obstructive sleep apnea. J Clin Sleep Med 10:873–878

    PubMed  PubMed Central  Google Scholar 

  • Stalker TJ, Traxler EA, Wu J, Wannemacher KM, Cermignano SL, Voronov R, Diamond SL, Brass LF (2013) Hierarchical organization in the hemostatic response and its relationship to the platelet-signaling network. Blood 121:1875–1885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Suzuki J, Umeda M, Sims PJ, Nagata S (2010) Calcium-dependent phospholipid scrambling by TMEM16F. Nature 468:834–838

    Article  CAS  PubMed  Google Scholar 

  • Szasz R, Dale GL (2002) Thrombospondin and fibrinogen bind serotonin-derivatized proteins on COAT-platelets. Blood 100:2827–2831

    Article  CAS  PubMed  Google Scholar 

  • Tadokoro S, Shattil SJ, Eto K, Tai V, Liddington RC, De Pereda JM, Ginsberg MH, Calderwood DA (2003) Talin binding to integrin beta tails: a final common step in integrin activation. Science 302:103–106

    Article  CAS  PubMed  Google Scholar 

  • Tersteeg C, Heijnen HF, Eckly A, Pasterkamp G, Urbanus RT, Maas C, Hoefer IE, Nieuwland R, Farndale RW, Gachet C, de Groot PG, Roest M (2014) FLow-induced PRotrusions (FLIPRs): a platelet-derived platform for the retrieval of microparticles by monocytes and neutrophils. Circ Res 114:780–791

    Article  CAS  PubMed  Google Scholar 

  • Thiagarajan P, Tait JF (1990) Binding of annexin V/placental anticoagulant protein I to platelets. Evidence for phosphatidylserine exposure in the procoagulant response of activated platelets. J Biol Chem 265:17420–17423

    CAS  PubMed  Google Scholar 

  • Thiagarajan P, Tait JF (1991) Collagen-induced exposure of anionic phospholipid in platelets and platelet-derived microparticles. J Biol Chem 266:24302–24307

    CAS  PubMed  Google Scholar 

  • Thompson CB, Jakubowski JA (1988) The pathophysiology and clinical relevance of platelet heterogeneity. Blood 72:1–8

    CAS  PubMed  Google Scholar 

  • Thompson CB, Eaton KA, Princiotta SM, Rushin CA, Valeri CR (1982) Size dependent platelet subpopulations: relationship of platelet volume to ultrastructure, enzymatic activity, and function. Br J Haematol 50:509–519

    Article  CAS  PubMed  Google Scholar 

  • Thompson CB, Love DG, Quinn PG, Valeri CR (1983) Platelet size does not correlate with platelet age. Blood 62:487–494

    CAS  PubMed  Google Scholar 

  • Thompson CB, Jakubowski JA, Quinn PG, Deykin D, Valeri CR (1984) Platelet size and age determine platelet function independently. Blood 63:1372–1375

    CAS  PubMed  Google Scholar 

  • Thon JN, Montalvo A, Patel-hett S, Devine MT, Richardson JL, Ehrlicher A, Larson MK, Hoffmeister K, Hartwig JH, Italiano JE (2010) Cytoskeletal mechanics of proplatelet maturation and platelet release. J Cell Biol 191:861–874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Trowbridge EA, Slater DN, Kishk YT, Woodcock BW, Martin JF (1984) Platelet production in myocardial infarction and sudden cardiac death. Thromb Haemost 52:167–171

    CAS  PubMed  Google Scholar 

  • van Kruchten R, Mattheij NJ, Saunders C, Feijge MA, Swieringa F, Wolfs JL, Collins PW, Heemskerk JW, Bevers EM (2013) Both TMEM16F-dependent and TMEM16F-independent pathways contribute to phosphatidylserine exposure in platelet apoptosis and platelet activation. Blood 121:1850–1857

    Article  PubMed  CAS  Google Scholar 

  • Vogler M, Hamali HA, Sun XM, Bampton ET, Dinsdale D, Snowden RT, Dyer MJ, Goodall AH, Cohen GM (2011) BCL2/BCL-X(L) inhibition induces apoptosis, disrupts cellular calcium homeostasis, and prevents platelet activation. Blood 117:7145–7154

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Fang C, Gao H, Bilodeau ML, Zhang Z, Croce K, Liu S, Morooka T, Sakuma M, Nakajima K, Yoneda S, Shi C, Zidar D, Andre P, Stephens G, Silverstein RL, Hogg N, Schmaier AH, Simon DI (2014) Platelet-derived S100 family member myeloid-related protein-14 regulates thrombosis. J Clin Invest 124:2160–2171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Welsh JD, Colace TV, Muthard RW, Stalker TJ, Brass LF, Diamond SL (2012) Platelet-targeting sensor reveals thrombin gradients within blood clots forming in microfluidic assays and in mouse. J Thromb Haemost 10:2344–2353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Welsh JD, Stalker TJ, Voronov R, Muthard RW, Tomaiuolo M, Diamond SL, Brass LF (2014) A systems approach to hemostasis: 1. The interdependence of thrombus architecture and agonist movements in the gaps between platelets. Blood 124:1808–1815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Westein E, van der Meer AD, Kuijpers MJ, Frimat JP, van den Berg A, Heemskerk JW (2013) Atherosclerotic geometries exacerbate pathological thrombus formation poststenosis in a von Willebrand factor-dependent manner. Proc Natl Acad Sci U S A 110:1357–1362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wester J, Sixma JJ, Geuze JJ, van der Veen J (1978) Morphology of the early hemostasis in human skin wounds: influence of acetylsalicylic acid. Lab Invest 39:298–311

    CAS  PubMed  Google Scholar 

  • Wester J, Sixma JJ, Geuze JJ, Heijnen HF (1979) Morphology of the hemostatic plug in human skin wounds: transformation of the plug. Lab Invest 41:182–192

    CAS  PubMed  Google Scholar 

  • Weyrich AS, Dixon DA, Pabla R, Elstad MR, Mcintyre TM, Prescott SM, Zimmerman GA (1998) Signal-dependent translation of a regulatory protein, Bcl-3, in activated human platelets. Proc Natl Acad Sci U S A 95:5556–5561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang H, Kim A, David T, Palmer D, Jin T, Tien J, Huang F, Cheng T, Coughlin SR, Jan YN, Jan LY (2012) TMEM16F forms a Ca2 + -activated cation channel required for lipid scrambling in platelets during blood coagulation. Cell 151:111–122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zampieri FG, Ranzani OT, Sabatoski V, de Souza HP, Barbeiro H, da Neto LM, Park M, Pinheiro Da Silva F (2014) An increase in mean platelet volume after admission is associated with higher mortality in critically ill patients. Ann Intensive Care 4:20

    Article  PubMed  PubMed Central  Google Scholar 

  • Zarbock A, Singbartl K, Ley K (2006) Complete reversal of acid-induced acute lung injury by blocking of platelet-neutrophil aggregation. J Clin Invest 116:3211–3219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang H, Nimmer PM, Tahir SK, Chen J, Fryer RM, Hahn KR, Iciek LA, Morgan SJ, Nasarre MC, Nelson R, Preusser LC, Reinhart GA, Smith ML, Rosenberg SH, Elmore SW, Tse C (2007) Bcl-2 family proteins are essential for platelet survival. Cell Death Differ 14:943–951

    Article  CAS  PubMed  Google Scholar 

  • Zong WX, Thompson CB (2006) Necrotic death as a cell fate. Genes Dev 20:1–15

    Article  CAS  PubMed  Google Scholar 

  • Zucker-franklin D, Philipp CS (2000) Platelet production in the pulmonary capillary bed: new ultrastructural evidence for an old concept. Am J Pathol 157:69–74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Shawn Jobe M.D., Ph.D. .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Jobe, S. (2017). Platelet Heterogeneity. In: Gresele, P., Kleiman, N., Lopez, J., Page, C. (eds) Platelets in Thrombotic and Non-Thrombotic Disorders. Springer, Cham. https://doi.org/10.1007/978-3-319-47462-5_5

Download citation

Publish with us

Policies and ethics