Interpreting the developmental dance of the megakaryocyte: a review of the cellular and molecular processes mediating platelet formation
Kellie R. Machlus
Hematology Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
Harvard Medical School, Boston, MA, USA
Search for more papers by this authorJonathan N. Thon
Hematology Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
Harvard Medical School, Boston, MA, USA
Search for more papers by this authorCorresponding Author
Joseph E. Italiano Jr
Hematology Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
Harvard Medical School, Boston, MA, USA
Department of Surgery, Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA
Correspondence: Joseph E. Italiano Jr., Hematology Division, Department of Medicine, Brigham and Women's Hospital, 1 Blackfan Circle, Karp 5, Boston, MA 02115, USA.
E-mail: [email protected]
Search for more papers by this authorKellie R. Machlus
Hematology Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
Harvard Medical School, Boston, MA, USA
Search for more papers by this authorJonathan N. Thon
Hematology Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
Harvard Medical School, Boston, MA, USA
Search for more papers by this authorCorresponding Author
Joseph E. Italiano Jr
Hematology Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
Harvard Medical School, Boston, MA, USA
Department of Surgery, Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA
Correspondence: Joseph E. Italiano Jr., Hematology Division, Department of Medicine, Brigham and Women's Hospital, 1 Blackfan Circle, Karp 5, Boston, MA 02115, USA.
E-mail: [email protected]
Search for more papers by this authorSummary
Platelets are essential for haemostasis, and thrombocytopenia (platelet counts <150 × 109/l) is a major clinical problem encountered across a number of conditions, including immune thrombocytopenic purpura, myelodysplastic syndromes, chemotherapy, aplastic anaemia, human immunodeficiency virus infection, complications during pregnancy and delivery, and surgery. Circulating blood platelets are specialized cells that function to prevent bleeding and minimize blood vessel injury. Platelets circulate in their quiescent form, and upon stimulation, activate to release their granule contents and spread on the affected tissue to create a physical barrier that prevents blood loss. The current model of platelet formation states that large progenitor cells in the bone marrow, called megakaryocytes, release platelets by extending long, branching processes, designated proplatelets, into sinusoidal blood vessels. This review will focus on different factors that impact megakaryocyte development, proplatelet formation and platelet release. It will highlight recent studies on thrombopoeitin-dependent megakaryocyte maturation, endomitosis and granule formation, cytoskeletal contributions to proplatelet formation, the role of apoptosis, and terminal platelet formation and release.
References
- Albers, C.A., Cvejic, A., Favier, R., Bouwmans, E.E., Alessi, M.C., Bertone, P., Jordan, G., Kettleborough, R.N., Kiddle, G., Kostadima, M., Read, R.J., Sipos, B., Sivapalaratnam, S., Smethurst, P.A., Stephens, J., Voss, K., Nurden, A., Rendon, A., Nurden, P. & Ouwehand, W.H. (2011) Exome sequencing identifies NBEAL2 as the causative gene for gray platelet syndrome. Nature Genetics, 43, 735–737.
- Bartley, T.D., Bogenberger, J., Hunt, P., Li, Y.S., Lu, H.S., Martin, F., Chang, M.S., Samal, B., Nichol, J.L., Swift, S., Johnson, M.J., Hsu, R-Y., Parker, V.P., Suggs, S., Skrine, J.D., Merewether, L.A., Clogston, C., Hsu, E., Hokom, M.M., Hornkohl, A., Choi, E., Pangelinan, M., Sun, Y., Mar, V., McNinch, J., Simonet, L., Jacobsen, F., Xie, C., Shutter, J., Chute, H., Basu, R., Selander, L., Trollinger, D., Sieu, L., Padilla, D., Trail, G., Elliott, G., Izumi, R., Covey, T., Crouse, J., Garcia, A., Xu, W., Del Castillo, J., Biron, J., Cole, S., Hu, M.C-T., Pacifici, R., Ponting, I., Saris, C., Wen, D., Yung, Y.P., Lin, H. & Rosselman, R.A. (1994) Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor Mpl. Cell, 77, 1117–1124.
- Battinelli, E.M., Markens, B.A. & Italiano, J.E. Jr (2011) Release of angiogenesis regulatory proteins from platelet alpha granules: modulation of physiologic and pathologic angiogenesis. Blood, 118, 1359–1369.
- Battinelli, E.M., Markens, B.A., Kulenthirarajan, R.A., Machlus, K.R., Flaumenhaft, R. & Italiano, J.E. Jr (2013) Anticoagulation inhibits tumor cell mediated release of platelet angiogenic proteins and diminishes platelet angiogenic response. Blood, 123, 101–112.
- Becker, R.P. & De Bruyn, P.P. (1976) The transmural passage of blood cells into myeloid sinusoids and the entry of platelets into the sinusoidal circulation; a scanning electron microscopic investigation. The American Journal of Anatomy, 145, 183–205.
- Behnke, O. (1965) Further studies on microtubules. A marginal bundle in human and rat thrombocytes. Journal of Ultrastructure Research, 13, 469–477.
- Behnke, O. (1968) An electron microscope study of the megacaryocyte of the rat bone marrow. I. The development of the demarcation membrane system and the platelet surface coat. Journal of Ultrastructure Research, 24, 412–433.
- Behnke, O. (1969) An electron microscope study of the rat megacaryocyte. II. Some aspects of platelet release and microtubules. Journal of Ultrastructure Research, 26, 111–129.
- Blair, P. & Flaumenhaft, R. (2009) Platelet alpha-granules: basic biology and clinical correlates. Blood Reviews, 23, 177–189.
- Bray, P.F. (2007) Platelet hyperreactivity: predictive and intrinsic properties. Hematology/Oncology Clinics of North America, 21, 633–645, v-vi.
- Breton-Gorius, J. & Reyes, F. (1976) Ultrastructure of human bone marrow cell maturation. International Review of Cytology, 46, 251–321.
- Chang, Y., Aurade, F., Larbret, F., Zhang, Y., Le Couedic, J.P., Momeux, L., Larghero, J., Bertoglio, J., Louache, F., Cramer, E., Vainchenker, W. & Debili, N. (2007) Proplatelet formation is regulated by the Rho/ROCK pathway. Blood, 109, 4229–4236.
- Chen, Y., Aardema, J., Kale, S., Whichard, Z.L., Awomolo, A., Blanchard, E., Chang, B., Myers, D.R., Ju, L., Tran, R., Reece, D., Christensen, H., Boukour, S., Debili, N., Strom, T.S., Rawlings, D., Vazquez, F.X., Voth, G.A., Zhu, C., Kahr, W.H., Lam, W.A. & Corey, S.J. (2013) Loss of the F-BAR protein CIP4 reduces platelet production by impairing membrane-cytoskeleton remodeling. Blood, 122, 1695–1706.
- Choi, E.S., Nichol, J.L., Hokom, M.M., Hornkohl, A.C. & Hunt, P. (1995) Platelets generated in vitro from proplatelet-displaying human megakaryocytes are functional. Blood, 85, 402–413.
- Clarke, M.C., Savill, J., Jones, D.B., Noble, B.S. & Brown, S.B. (2003) Compartmentalized megakaryocyte death generates functional platelets committed to caspase-independent death. Journal of Cell Biology, 160, 577–587.
- Cramer, E.M., Norol, F., Guichard, J., Breton-Gorius, J., Vainchenker, W., Masse, J.M. & Debili, N. (1997) Ultrastructure of platelet formation by human megakaryocytes cultured with the Mpl ligand. Blood, 89, 2336–2346.
- De Botton, S., Sabri, S., Daugas, E., Zermati, Y., Guidotti, J.E., Hermine, O., Kroemer, G., Vainchenker, W. & Debili, N. (2002) Platelet formation is the consequence of caspase activation within megakaryocytes. Blood, 100, 1310–1317.
- Department of Health and Human Services (2013) The 2011 National Blood Collection and Utilization Survey Report. DHHS, Washington, DC.
- Deppermann, C., Cherpokova, D., Nurden, P., Schulz, J.N., Thielmann, I., Kraft, P., Vogtle, T., Kleinschnitz, C., Dutting, S., Krohne, G., Eming, S.A., Nurden, A.T., Eckes, B., Stoll, G., Stegner, D. & Nieswandt, B. (2013) Gray platelet syndrome and defective thrombo-inflammation in Nbeal2-deficient mice. The Journal of Clinical Investigation, 123, 3331–3342.
- Ebbe, S. (1976) Biology of megakaryocytes. Progress in Hemostatis and Thrombosis, 3, 211–229.
- Eckly, A., Heijnen, H., Pertuy, F., Geerts, W., Proamer, F., Rinckel, J.Y., Leon, C., Lanza, F. & Gachet, C. (2013) Biogenesis of the demarcation membrane system (DMS) in megakaryocytes. Blood, doi: 10.1182/blood-2013-03-492330.
10.1182/blood‐2013‐03‐492330 Google Scholar
- Fuentes, R., Wang, Y., Hirsch, J., Wang, C., Rauova, L., Worthen, G.S., Kowalska, M.A. & Poncz, M. (2010) Infusion of mature megakaryocytes into mice yields functional platelets. The Journal of Clinical Investigation, 120, 3917–3922.
- Gobbi, G., Mirandola, P., Sponzilli, I., Micheloni, C., Malinverno, C., Cocco, L. & Vitale, M. (2007) Timing and expression level of protein kinase C epsilon regulate the megakaryocytic differentiation of human CD34 cells. Stem Cells, 25, 2322–2329.
- Gobbi, G., Mirandola, P., Carubbi, C., Masselli, E., Sykes, S.M., Ferraro, F., Nouvenne, A., Thon, J.N., Italiano, J.E. Jr & Vitale, M. (2013) Proplatelet generation in the mouse requires PKCepsilon-dependent RhoA inhibition. Blood, 122, 1305–1311.
- Gunay-Aygun, M., Falik-Zaccai, T.C., Vilboux, T., Zivony-Elboum, Y., Gumruk, F., Cetin, M., Khayat, M., Boerkoel, C.F., Kfir, N., Huang, Y., Maynard, D., Dorward, H., Berger, K., Kleta, R., Anikster, Y., Arat, M., Freiberg, A.S., Kehrel, B.E., Jurk, K., Cruz, P., Mullikin, J.C., White, J.G., Huizing, M. & Gahl, W.A. (2011) NBEAL2 is mutated in gray platelet syndrome and is required for biogenesis of platelet alpha-granules. Nature Genetics, 43, 732–734.
- Gurney, A.L., Carver-Moore, K., de Sauvage, F.J. & Moore, M.W. (1994) Thrombocytopenia in c-mpl-deficient mice. Science, 265, 1445–1447.
- Haddad, E., Cramer, E., Riviere, C., Rameau, P., Louache, F., Guichard, J., Nelson, D.L., Fischer, A., Vainchenker, W. & Debili, N. (1999) The thrombocytopenia of Wiskott Aldrich syndrome is not related to a defect in proplatelet formation. Blood, 94, 509–518.
- Heijnen, H.F., Debili, N., Vainchencker, W., Breton-Gorius, J., Geuze, H.J. & Sixma, J.J. (1998) Multivesicular bodies are an intermediate stage in the formation of platelet alpha-granules. Blood, 91, 2313–2325.
- Italiano, J.E. Jr, Lecine, P., Shivdasani, R.A. & Hartwig, J.H. (1999) Blood platelets are assembled principally at the ends of proplatelet processes produced by differentiated megakaryocytes. Journal of Cell Biology, 147, 1299–1312.
- Ito, T., Ishida, Y., Kashiwagi, R. & Kuriya, S. (1996) Recombinant human c-Mpl ligand is not a direct stimulator of proplatelet formation in mature human megakaryocytes. British Journal of Haematology, 94, 387–390.
- Jiang, F., Jia, Y. & Cohen, I. (2002) Fibronectin- and protein kinase C-mediated activation of ERK/MAPK are essential for proplateletlike formation. Blood, 99, 3579–3584.
- Josefsson, E.C., James, C., Henley, K.J., Debrincat, M.A., Rogers, K.L., Dowling, M.R., White, M.J., Kruse, E.A., Lane, R.M., Ellis, S., Nurden, P., Mason, K.D., O'Reilly, L.A., Roberts, A.W., Metcalf, D., Huang, D.C. & Kile, B.T. (2011) Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets. Journal of Experimental Medicine, 208, 2017–2031.
- Junt, T., Schulze, H., Chen, Z., Massberg, S., Goerge, T., Krueger, A., Wagner, D.D., Graf, T., Italiano, J.E. Jr, Shivdasani, R.A. & von Andrian, U.H. (2007) Dynamic visualization of thrombopoiesis within bone marrow. Science, 317, 1767–1770.
- Kahr, W.H., Hinckley, J., Li, L., Schwertz, H., Christensen, H., Rowley, J.W., Pluthero, F.G., Urban, D., Fabbro, S., Nixon, B., Gadzinski, R., Storck, M., Wang, K., Ryu, G.Y., Jobe, S.M., Schutte, B.C., Moseley, J., Loughran, N.B., Parkinson, J., Weyrich, A.S. & Di Paola, J. (2011) Mutations in NBEAL2, encoding a BEACH protein, cause gray platelet syndrome. Nature Genetics, 43, 738–740.
- Kahr, W.H., Lo, R.W., Li, L., Pluthero, F.G., Christensen, H., Ni, R., Vaezzadeh, N., Hawkins, C.E., Weyrich, A.S., Di Paola, J., Landolt-Marticorena, C. & Gross, P.L. (2013) Abnormal megakaryocyte development and platelet function in Nbeal2−/− mice. Blood, 122, 3349–3358.
- Kaplan, J., De Domenico, I. & Ward, D.M. (2008) Chediak-Higashi syndrome. Current Opinion in Hematology, 15, 22–29.
- Kaufman, R.M., Airo, R., Pollack, S. & Crosby, W.H. (1965) Circulating megakaryocytes and platelet release in the lung. Blood, 26, 720–731.
- Kaushansky, K. (1994) The mpl ligand: molecular and cellular biology of the critical regulator of megakaryocyte development. Stem Cells, 12 Suppl 1, 91–96; discussion 96-97.
- Kaushansky, K. (2005) The molecular mechanisms that control thrombopoiesis. The Journal of Clinical Investigation, 115, 3339–3347.
- Kaushansky, K. (2008) Historical review: megakaryopoiesis and thrombopoiesis. Blood, 111, 981–986.
- Kaushansky, K. (2009) Determinants of platelet number and regulation of thrombopoiesis. Hematology American Society of Hematology Education Program, 2009, 147–152.
10.1182/asheducation-2009.1.147 Google Scholar
- Kaushansky, K., Lok, S., Holly, R.D., Broudy, V.C., Lin, N., Bailey, M.C., Forstrom, J.W., Buddle, M.M., Oort, P.J., Hagen, F.S., Roth, G.J., Papayannopoulou, T. & Foster, D.C. (1994) Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin. Nature, 369, 568–571.
- Kraytman, M. (1973) Platelet size in thrombocytopenias and thrombocytosis of various origin. Blood, 41, 587–598.
- Kuter, D.J., Beeler, D.L. & Rosenberg, R.D. (1994) The purification of megapoietin: a physiological regulator of megakaryocyte growth and platelet production. Proceedings of the National Academy of Science of the United States of America, 91, 11104–11108.
- Lecine, P., Villeval, J.L., Vyas, P., Swencki, B., Xu, Y. & Shivdasani, R.A. (1998) Mice lacking transcription factor NF-E2 provide in vivo validation of the proplatelet model of thrombocytopoiesis and show a platelet production defect that is intrinsic to megakaryocytes. Blood, 92, 1608–1616.
- Li, W., Rusiniak, M.E., Chintala, S., Gautam, R., Novak, E.K. & Swank, R.T. (2004) Murine Hermansky-Pudlak syndrome genes: regulators of lysosome-related organelles. BioEssays, 26, 616–628.
- Lok, S., Kaushansky, K., Holly, R.D., Kuijper, J.L., Lofton-Day, C.E., Oort, P.J., Grant, F.J., Heipel, M.D., Burkhead, S.K., Kramer, J.M., Bell, L.A., Sprecher, C.A., Blumberg, H., Johnson, R., Prunkard, D., Ching, A.F.T., Mathewes, S.L., Bailey, M.C., Forstrom, J.W., Buddle, M.M., Osborn, S.G., Evans, S.J., Sheppard, P.O., Presnell, S.R., O'Hara, P.J., Hagen, F.S., Roth, G.J. & Foster, D.C. (1994) Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivo. Nature, 369, 565–568.
- Long, M.W., Williams, N. & Ebbe, S. (1982) Immature megakaryocytes in the mouse: physical characteristics, cell cycle status, and in vitro responsiveness to thrombopoietic stimulatory factor. Blood, 59, 569–575.
- Long, M.W., Smolen, J.E., Szczepanski, P. & Boxer, L.A. (1984) Role of phorbol diesters in in vitro murine megakaryocyte colony formation. The Journal of Clinical Investigation, 74, 1686–1692.
- Lopez, J.J., Palazzo, A., Chaabane, C., Albarran, L., Polidano, E., Lebozec, K., Dally, S., Nurden, P., Enouf, J., Debili, N. & Bobe, R. (2013) Crucial role for endoplasmic reticulum stress during megakaryocyte maturation. Arteriosclerosis, Thrombosis, and Vascular Biology, 33, 2750–2758.
- Machlus, K.R. & Italiano, J.E. Jr (2013) The incredible journey: from megakaryocyte development to platelet formation. Journal of Cell Biology, 201, 785–796.
- Mazharian, A., Mori, J., Wang, Y.J., Heising, S., Neel, B.G., Watson, S.P. & Senis, Y.A. (2013) Megakaryocyte-specific deletion of the protein-tyrosine phosphatases Shp1 and Shp2 causes abnormal megakaryocyte development, platelet production, and function. Blood, 121, 4205–4220.
- Morison, I.M., Cramer Borde, E.M., Cheesman, E.J., Cheong, P.L., Holyoake, A.J., Fichelson, S., Weeks, R.J., Lo, A., Davies, S.M., Wilbanks, S.M., Fagerlund, R.D., Ludgate, M.W., da Silva Tatley, F.M., Coker, M.S., Bockett, N.A., Hughes, G., Pippig, D.A., Smith, M.P., Capron, C. & Ledgerwood, E.C. (2008) A mutation of human cytochrome c enhances the intrinsic apoptotic pathway but causes only thrombocytopenia. Nature Genetics, 40, 387–389.
- Nakao, K. & Angrist, A.A. (1968) Membrane surface specialization of blood platelet and megakaryocyte. Nature, 217, 960–961.
- Ni, H., Papalia, J.M., Degen, J.L. & Wagner, D.D. (2003) Control of thrombus embolization and fibronectin internalization by integrin alpha IIb beta 3 engagement of the fibrinogen gamma chain. Blood, 102, 3609–3614.
- Nichol, J.L., Hokom, M.M., Hornkohl, A., Sheridan, W.P., Ohashi, H., Kato, T., Li, Y.S., Bartley, T.D., Choi, E. & Bogenberger, J. (1995) Megakaryocyte growth and development factor. Analyses of in vitro effects on human megakaryopoiesis and endogenous serum levels during chemotherapy-induced thrombocytopenia. The Journal of Clinical Investigation, 95, 2973–2978.
- Ogawa, M. (1993) Differentiation and proliferation of hematopoietic stem cells. Blood, 81, 2844–2853.
- Olson, T.S., Caselli, A., Otsuru, S., Hofmann, T.J., Williams, R., Paolucci, P., Dominici, M. & Horwitz, E.M. (2013) Megakaryocytes promote murine osteoblastic HSC niche expansion and stem cell engraftment after radioablative conditioning. Blood, 121, 5238–5249.
- Oshevski, S., Le Bousse-Kerdiles, M.C., Clay, D., Levashova, Z., Debili, N., Vitral, N., Jasmin, C. & Castagna, M. (1999) Differential expression of protein kinase C isoform transcripts in human hematopoietic progenitors undergoing differentiation. Biochemical and Biophysical Research Communications, 263, 603–609.
- Patel, S.R., Hartwig, J.H. & Italiano, J.E. Jr (2005a) The biogenesis of platelets from megakaryocyte proplatelets. The Journal of Clinical Investigation, 115, 3348–3354.
- Patel, S.R., Richardson, J.L., Schulze, H., Kahle, E., Galjart, N., Drabek, K., Shivdasani, R.A., Hartwig, J.H. & Italiano, J.E. Jr (2005b) Differential roles of microtubule assembly and sliding in proplatelet formation by megakaryocytes. Blood, 106, 4076–4085.
- Patel-Hett, S., Richardson, J.L., Schulze, H., Drabek, K., Isaac, N.A., Hoffmeister, K., Shivdasani, R.A., Bulinski, J.C., Galjart, N., Hartwig, J.H. & Italiano, J.E. Jr (2008) Visualization of microtubule growth in living platelets reveals a dynamic marginal band with multiple microtubules. Blood, 111, 4605–4616.
- Patel-Hett, S., Wang, H., Begonja, A.J., Thon, J.N., Alden, E.C., Wandersee, N.J., An, X., Mohandas, N., Hartwig, J.H. & Italiano, J.E. Jr (2011) The spectrin-based membrane skeleton stabilizes mouse megakaryocyte membrane systems and is essential for proplatelet and platelet formation. Blood, 118, 1641–1652.
- Pleines, I., Hagedorn, I., Gupta, S., May, F., Chakarova, L., van Hengel, J., Offermanns, S., Krohne, G., Kleinschnitz, C., Brakebusch, C. & Nieswandt, B. (2012) Megakaryocyte-specific RhoA deficiency causes macrothrombocytopenia and defective platelet activation in hemostasis and thrombosis. Blood, 119, 1054–1063.
- Pleines, I., Dutting, S., Cherpokova, D., Eckly, A., Meyer, I., Morowski, M., Krohne, G., Schulze, H., Gachet, C., Debili, N., Brakebusch, C. & Nieswandt, B. (2013) Defective tubulin organization and proplatelet formation in murine megakaryocytes lacking Rac1 and Cdc42. Blood, 122, 3178–3187.
- Radley, J.M. & Haller, C.J. (1982) The demarcation membrane system of the megakaryocyte: a misnomer? Blood, 60, 213–219.
- Richardson, J.L., Shivdasani, R.A., Boers, C., Hartwig, J.H. & Italiano, J.E. Jr (2005) Mechanisms of organelle transport and capture along proplatelets during platelet production. Blood, 106, 4066–4075.
- Rojnuckarin, P. & Kaushansky, K. (2001) Actin reorganization and proplatelet formation in murine megakaryocytes: the role of protein kinase calpha. Blood, 97, 154–161.
- Sabri, S., Foudi, A., Boukour, S., Franc, B., Charrier, S., Jandrot-Perrus, M., Farndale, R.W., Jalil, A., Blundell, M.P., Cramer, E.M., Louache, F., Debili, N., Thrasher, A.J. & Vainchenker, W. (2006) Deficiency in the Wiskott-Aldrich protein induces premature proplatelet formation and platelet production in the bone marrow compartment. Blood, 108, 134–140.
- de Sauvage, F.J., Hass, P.E., Spencer, S.D., Malloy, B.E., Gurney, A.L., Spencer, S.A., Darbonne, W.C., Henzel, W.J., Wong, S.C., Kuang, W.J.K.J., Oles Hultgren, B., Solberg, L.A. Jr, Goeddel, D.V. & Eaton, D.L. (1994) Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand. Nature, 369, 533–538.
- Schulze, H., Korpal, M., Hurov, J., Kim, S.W., Zhang, J., Cantley, L.C., Graf, T. & Shivdasani, R.A. (2006) Characterization of the megakaryocyte demarcation membrane system and its role in thrombopoiesis. Blood, 107, 3868–3875.
- Sohma, Y., Akahori, H., Seki, N., Hori, T., Ogami, K., Kato, T., Shimada, Y., Kawamura, K. & Miyazaki, H. (1994) Molecular cloning and chromosomal localization of the human thrombopoietin gene. FEBS Letters, 353, 57–61.
- Solar, G.P., Kerr, W.G., Zeigler, F.C., Hess, D., Donahue, C., de Sauvage, F.J. & Eaton, D.L. (1998) Role of c-mpl in early hematopoiesis. Blood, 92, 4–10.
- Suzuki, A., Shin, J.W., Wang, Y., Min, S.H., Poncz, M., Choi, J.K., Discher, D.E., Carpenter, C.L., Lian, L., Zhao, L., Wang, Y. & Abrams, C.S. (2013) RhoA is essential for maintaining normal megakaryocyte ploidy and platelet generation. PLoS One, 8, e69315.
- Tablin, F., Castro, M. & Leven, R.M. (1990) Blood platelet formation in vitro. The role of the cytoskeleton in megakaryocyte fragmentation. Journal of Cell Science, 97 (Pt 1), 59–70.
- Thon, J.N., Montalvo, A., Patel-Hett, S., Devine, M.T., Richardson, J.L., Ehrlicher, A., Larson, M.K., Hoffmeister, K., Hartwig, J.H. & Italiano, J.E. Jr (2010) Cytoskeletal mechanics of proplatelet maturation and platelet release. Journal of Cell Biology, 191, 861–874.
- Thon, J.N., Peters, C.G., Machlus, K.R., Aslam, R., Rowley, J., Macleod, H., Devine, M.T., Fuchs, T.A., Weyrich, A.S., Semple, J.W., Flaumenhaft, R. & Italiano, J.E. Jr (2012a) T granules in human platelets function in TLR9 organization and signaling. Journal of Cell Biology, 198, 561–574.
- Thon, J.N., Devine, M.T., Jurak Begonja, A., Tibbitts, J. & Italiano, J.E. Jr (2012b) High-content live cell imaging assay used to establish mechanism of trastuzumab emtansine (T-DM1)-mediated inhibition of platelet production. Blood, 120, 1975–1984.
- Thon, J.N., Macleod, H., Begonja, A.J., Zhu, J., Lee, K.C., Mogilner, A., Hartwig, J.H. & Italiano, J.E. Jr (2012c) Microtubule and cortical forces determine platelet size during vascular platelet production. Nature Communications, 3, 852.
- Villeval, J.L., Cohen-Solal, K., Tulliez, M., Giraudier, S., Guichard, J., Burstein, S.A., Cramer, E.M., Vainchenker, W. & Wendling, F. (1997) High thrombopoietin production by hematopoietic cells induces a fatal myeloproliferative syndrome in mice. Blood, 90, 4369–4383.
- Wei, M.L. (2006) Hermansky-Pudlak syndrome: a disease of protein trafficking and organelle function. Pigment Cell Research, 19, 19–42.
- Wendling, F., Maraskovsky, E., Debili, N., Florindo, C., Teepe, M., Titeux, M., Methia, N., Breton-Gorius, J., Cosman, D. & Vainchenker, W. (1994) cMpl ligand is a humoral regulator of megakaryocytopoiesis. Nature, 369, 571–574.
- White, J.G. & Krivit, W. (1967) An ultrastructural basis for the shape changes induced in platelets by chilling. Blood, 30, 625–635.
- Yan, X.Q., Lacey, D., Hill, D., Chen, Y., Fletcher, F., Hawley, R.G. & McNiece, I.K. (1996) A model of myelofibrosis and osteosclerosis in mice induced by overexpressing thrombopoietin (mpl ligand): reversal of disease by bone marrow transplantation. Blood, 88, 402–409.
- Yang, H., Lang, S., Zhai, Z., Li, L., Kahr, W.H., Chen, P., Brkic, J., Spring, C.M., Flick, M.J., Degen, J.L., Freedman, J. & Ni, H. (2009) Fibrinogen is required for maintenance of platelet intracellular and cell-surface P-selectin expression. Blood, 114, 425–436.
- Youssefian, T. & Cramer, E.M. (2000) Megakaryocyte dense granule components are sorted in multivesicular bodies. Blood, 95, 4004–4007.
- Zimmet, J. & Ravid, K. (2000) Polyploidy: occurrence in nature, mechanisms, and significance for the megakaryocyte-platelet system. Experimental Hematology, 28, 3–16.
- Zucker-Franklin, D. & Philipp, C.S. (2000) Platelet production in the pulmonary capillary bed: new ultrastructural evidence for an old concept. American Journal of Pathology, 157, 69–74.