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Thromb Haemost 2000; 83(06): 923-930
DOI: 10.1055/s-0037-1613944
Commentary
Schattauer GmbH

Platelets Release Thrombopoietin (Tpo) upon Activation: another Regulatory Loop in Thrombocytopoiesis?

Claudia C. Folman
1   From the Division of Internal Medicine and Dept. of Haematology, Academic Medical Centre, Amsterdam, the Netherlands
2   Dept. of Experimental Immunohaematology, CLB and the Laboratory of Experimental and Clinical Immunology, Academic Medical Centre, University of Amsterdam, Amsterdam
,
Gabor E. Linthorst
1   From the Division of Internal Medicine and Dept. of Haematology, Academic Medical Centre, Amsterdam, the Netherlands
,
Jan van Mourik
3   Dept. of Blood Coagulation, CLB and the Laboratory of Experimental and Clinical Immunology, Academic Medical Centre, University of Amsterdam, Amsterdam
,
Gijsbert van Willigen   #
4   Dept of Haematology, Thrombosis and Haemostasis Laboratory, University Medical Centre Utrecht, the Netherlands
,
Evert de Jonge
1   From the Division of Internal Medicine and Dept. of Haematology, Academic Medical Centre, Amsterdam, the Netherlands
,
Marcel Levi
1   From the Division of Internal Medicine and Dept. of Haematology, Academic Medical Centre, Amsterdam, the Netherlands
,
Masja de Haas
2   Dept. of Experimental Immunohaematology, CLB and the Laboratory of Experimental and Clinical Immunology, Academic Medical Centre, University of Amsterdam, Amsterdam
,
Albert EGKr von dem Borne
1   From the Division of Internal Medicine and Dept. of Haematology, Academic Medical Centre, Amsterdam, the Netherlands
2   Dept. of Experimental Immunohaematology, CLB and the Laboratory of Experimental and Clinical Immunology, Academic Medical Centre, University of Amsterdam, Amsterdam
› Author Affiliations
Further Information

Publication History

Received 21 October 1999

Accepted after resubmission 04 February 2000

Publication Date:
14 December 2017 (online)

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Summary

Thrombopoietin is produced at a constant rate by the liver and kidney and is removed from the circulation upon binding and subsequent uptake via the Tpo receptor, c-Mpl, expressed by platelets and megakaryocytes. Apart from uptake, this study shows that platelets can also function as a storage pool for Tpo.

Upon stimulation with various platelet agonists, full-length biologically active Tpo was released by platelets. Platelet fractionation experiments indicated that this Tpo most likely is contained in the granules. When platelets were preincubated with Tpo-peptide mimetic or truncated Tpo prior to maximal activation, a three- to fivefold increment in Tpo release was seen, whereas, the release of other granule proteins such as vWF-propeptide or serotonin remained unchanged. Therefore, the Mpl agonists might compete with Mpl-bound Tpo, thereby releasing Tpo into the platelet supernatant.

Intravascular release of Tpo by platelets might occur in patients with massive platelet activation, as occurs in patients with disseminated intravascular coagulation. The Tpo concentration in these patients is elevated (p <0.01) and correlates with markers for thrombin generation, TAT complexes and Fl+2 (rp =0.8 and 0.9; p <0.01). This suggests that the increment in Tpo concentration was attributed to Tpo release by activated platelets in vivo, which might be instrumental in subsequent stimulation of thrombocytopoiesis.

Keywords

Thrombopoietin - Tpo - platelets activation - c-Mpl

# G. v. Willigen is a research fellow of the Catharijne Foundation and supported by the Dirk-Zwager Assink Foundation.


 

  • References

  • 1 de Gabriele G, Penington DG. Regulation of platelet production: Thrombopoietin. Br J Haematol 1967; 13: 210-5.
    CrossrefPubMedGoogle Scholar
  • 2 Kuter DJ, Rosenberg RD. The reciprocal relationship of thrombopoietin (c-mpl ligand) to changes in the platelet mass during busulfan-induced thrombocytopenia in the rabbit. Blood 1995; 85: 2720-30.
    PubMedGoogle Scholar
  • 3 Debili N, Wendling F, Cosman D, Titeux M, Florindo C, Dusanter-Fourt I, Schooley K, Methia N, Charon M, Nador R, Bettaieb A, Vainchenker W. The Mpl receptor is expressed in the megakaryocytc lineage from late progenitors to platelets. Blood 1995; 85: 391-401.
    PubMedGoogle Scholar
  • 4 Porcelijn L, Folman CC, Bossers B, Huiskes E, Overbeeke MAM, van der Schoot CE, de Haas M, von dem Borne AEGKr. The diagnostic value of thrombopoietin levels measurements in thrombocytopenia. Thromb Haemost 1998; 79: 1101-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Kosugi S, Kurata Y, Tomiyama Y, Tahara T, Kato T, Tadokoro S, Shiraga M, Honda S, Kanakura Y, Matsuzawa Y. Circulating thrombopoietin level in chronic immune thrombocytopenic purpura. Br J Haematol 1996; 93: 704-6.
    CrossrefPubMedGoogle Scholar
  • 6 Tahara T, Usuki K, Sato H, Ohashi H, Morita H, Tsumura H, Matsumoto A, Miyazaki H, Urabe A, Kato T. A sensitive ELISA for measuring thrombopoietin in human serum: serum thrombopoietin levels in healthy volunteers and in patients with haematopoietic disorders. Br J Haematol 1996; 93: 783-8.
    CrossrefPubMedGoogle Scholar
  • 7 Folman CC, von dem Borne AEGKr, Rensink IHJAM, Gerritsen W, van der Schoot CE, de Haas M, Aarden L. Sensitive measurements of thrombopoietin by a monoclonal antibody based sandwich enzyme-linked immunosorbent assay. Thromb Haemost 1997; 78: 1262-97.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Emmons RVB, Reid DM, Cohen RL, Meng G, Young NS, Dunbar CE, Shulman NR. Human thrombopoietin levels are high when thrombocytopenia is due to megakaryocyte deficiency and low when due to increased platelet destruction. Blood 1996; 87: 4068-71.
    PubMedGoogle Scholar
  • 9 Kunishima S, Tahara T, Kato T, Kobayashi S, Saito H, Naoe T. Serum thrombopoietin and plasma glycocalicin concentrations as useful diagnostic markers in thrombocytopenic disorders. Eur J Haematol 1996; 57: 68-71.
    PubMedGoogle Scholar
  • 10 Hou M, Andersson PO, Stockelberg D, Mellqvist UH, Ridell B, Wadenvik H. Plasma thrombopoietin levels in thrombocytopenic states: implication for a regulatory role of bone marrow megakaryocytes. Br J Haematol 1998; 101: 420-4.
    CrossrefPubMedGoogle Scholar
  • 11 Meng YG, Martin TG, Peterson ML, Shuman MA, Cohen RL, Wong WL. Circulating thrombopoietin concentrations in thrombocytopenic patients, including cancer patients following chemotherapy, with or without peripheral blood progenitor cell transplantation. Br J Haematol 1996; 95: 535-41.
    CrossrefPubMedGoogle Scholar
  • 12 Heits F, Katschinski DM, Wilmsen U, Wiedemann GJ, Jelkman W. Serum thrombopoietin and interleukin 6 concentrations in tumour patients and response to chemotherapy-induced thrombocytopenia. Eur J Haematol 1997; 59: 53-8.
    PubMedGoogle Scholar
  • 13 Shinjo K, Takeshita A, Nakamura S, Naitoh K, Yanagi M, Tobita T, Ohnishi K, Ohno R. Serum thrombopoietin levels in patients correlate inversely with platelet counts during chemotherapy-induced thrombocytopenia. Leukemia 1998; 12: 295-300.
    CrossrefPubMedGoogle Scholar
  • 14 Zent CS, Ratjczak J, Ratajczak MZ, Anastasi J, Hoffman PC, Gewirtz AM. Relationship between megakaryocyte mass and serum thrombopoietin levels as revealed by a case of cyclic amegakaryocytic thrombocytopenic purpura. Br J Haematol 1999; 105: 452-8.
    CrossrefPubMedGoogle Scholar
  • 15 Nagasawa T, Hasegawa Y, Shimizu S, Kawashima Y, Nishimura S, Suzu-kawa K, Mukai H, Hori M, Komeno T, Kojima H, Ninomiya H, Tahara T, Abe T. Serum thrombopoietin level is mainly regulated by megakaryocyte mass rather than platelet mass in human subjects. Br J Haematol 1998; 101: 242-4.
    CrossrefPubMedGoogle Scholar
  • 16 Fielder PJ, Gurney AL, Stefanich E, Marian M, Moore MW, Carver-Moore K, de Sauvage FJ. Regulation of thrombopoietin levels by c-Mpl-mediated binding to platelets. Blood 1996; 87: 2154-61.
    PubMedGoogle Scholar
  • 17 Fielder PJ, Hass P, Nagel M, Stefanich E, Widmer R, Bennett GL, Keller GA, de Sauvage FJ, Eaton D. Human platelets as a model for the binding and degradation of thrombopoietin. Blood 1997; 89: 2782-8.
    PubMedGoogle Scholar
  • 18 Chen J, Herceg-Harjacek L, Groopman JE, Grabarek J. Regulation of platelet activation in vitro by the c-Mpl ligand thrombopoietin. Blood 1995; 86: 4054-62.
    PubMedGoogle Scholar
  • 19 Montrucchio G, Brizzi MF, Calosso G, Marengo S, Pegoraro L, Camussi G. Effects of recombinant human megakaryocyte growth and developmental factor on platelet activation. Blood 1996; 87: 2762-8.
    PubMedGoogle Scholar
  • 20 Wun T, Paglieroni T, Hammond WP, Kaushansky K, Foster DC. Thrombopoietin is synergistic with other hematopoietic growth factors and physiologic platelet agonists for platelet activation in vitro. Am J Hematol 1997; 54: 225-32.
    CrossrefPubMedGoogle Scholar
  • 21 Fontenay-Roupie M, Huret G, Loza J, Adda R, Melle J, Maclouf J, Dreyfus F, Levy-Toledano S. Thrombopoietin activates human platelets and induces tyrosine phosphorylation of p80/85 cortactin. Thromb Haemost 1998; 79: 195-201.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Hiyoyama K, Wada H, Shimura M, Nakasaki T, Katayama N, Nishsikawa M, Shiku H, Tahara T, Kato T. Increased serum levels of thrombopoietin in patients with thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, or disseminated intravascular coagulation. Blood Coag Fibrin 1997; 08: 345-9.
    CrossrefPubMedGoogle Scholar
  • 23 Kawasugi K, Gotoh M, Gohchi K, Matuda J, Kinoshita T, Miyazaki H. Increased endogenous levels of thrombopoietin and interleukin-6 without elevation of interleukin 11 in patients with DIC. Blood. 1998 92. 32a (Abstract).
    PubMedGoogle Scholar
  • 24 Beer JH, Buchi L, Steiner B. Glycocalicin:a new assay-the normal plasma levels and its potential usefulness in selected diseases. Blood 1994; 83: 691-702.
    PubMedGoogle Scholar
  • 25 Steinberg MH, Kelton JG, Coller BS. Plasma glycocalicin. An aid in the classification of thrombopenic disorders. N Engl J Med 1987; 317: 1037-42.
    CrossrefPubMedGoogle Scholar
  • 26 Modderman PW, Admiraal LG, Sonnenberg A, von dem Borne AEGKr. Glycoproteins V and Ib-K form a noncovalent complex in the platelet membrane. J Biol Chem 1992; 276: 364-9.
    PubMedGoogle Scholar
  • 27 Modderman PW, Huisman HG, van Mourik JA, von dem Borne AEGKr. A monoclonal antibody to the human platelet glycoprotein Ilb/IIIa complex induces platelet activation. Thromb Haemost 1988; 60: 68-74.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Cwirla SE, Balasubramanian P, Duffin DJ, Wagstrom CR, Gates CM, Singer SC, Davis AM, Tansik RL, Mattheakis LC, Boytos CM, Schatz PJ, Baccanari DP, Wrighton NC, Barrett RW, Dower WJ. Peptide agonist of the thrombopoietin receptor as potent as the natural cytokine. Science 1997; 276: 1696-9.
    CrossrefPubMedGoogle Scholar
  • 29 Borchiellini A, Fijnvandraat K, ten Cate JW, Pajkrt D, van Deventer SJH, Pasterkamp G, Meijer-Huizinga F, Zwart-Huinink L, Voorberg J, van Mourik JA. Quantitative analysis of von Willebrand factor propeptide release in vivo: Effect of experimental endotoxemia and administration of 1-deamino-8-D-arginine vasopressin in humans. Blood 1996; 88: 2951-8.
    PubMedGoogle Scholar
  • 30 Flachaire E, Beney C, Berthier A, Salandre J, Quincy C, Renaud B. Determination of reference values for serotonin concentration in platelets of healthy newborns, children, adults, and elderly subjects by HPLC with electrochemical detection. Clin Chem 1990; 36: 2117-20.
    PubMedGoogle Scholar
  • 31 Traiffort E, Hubert P, Tayeb N. Rapid determination of 5-hydroxytrypta-mine in whole blood by liquid chromatography with fluorimetric detection. J Chromatogr 1991; 571: 231-4.
    CrossrefPubMedGoogle Scholar
  • 32 Broekman MJ. Homogenization by nitrogen cavitation technique applied to platelet subcellular fractionation. MethEnzymol 1992; 215: 21-32.
    PubMedGoogle Scholar
  • 33 Giesberts AN, van Ginneken M, Gorter G, Lapetina EG, Akkerman J-WN, van Willigen G. Subcellular localization of α-subunits of trimeric G-proteins in human platelets. Biochem Biophys Commun 1997; 234: 439-44.
    CrossrefPubMedGoogle Scholar
  • 34 Scott JP, Montgomery RR. Platelet von Willebrand’s antigen II: active release by aggregating agents and a marker of platelet release reaction in vivo. Blood 1981; 58: 1075-9.
    PubMedGoogle Scholar
  • 35 Fay PJ, Kawai Y, Wagner DD, Ginsburg D, Bonthron B, Ohlsson-Wilhelm B, Chavin SI, Abraham GN, Handin RI, Orkin SH, Montgomery RR, Marder VJ. Propolypeptide of von Willebrand Factor circulates in blood and is identical to von Willebrand Antigen II. Science 1986; 232: 995-8.
    CrossrefPubMedGoogle Scholar
  • 36 McCarty JM, Sprugel KH, Fox NE, Sabath DE, Kaushansky K. Murine thrombopoietin mRNA levels are modulated by platelet count. Blood 1995; 86: 3668-75.
    PubMedGoogle Scholar
  • 37 Nagahisa H, Nagata Y, Ohnuki T, Osada M, Nagasawa T, Abe T, Todokoro K. Bone marrow stromal cells produce thrombopoietin and stimulate megakaryocyte growth and maturation but suppress proplatelet formation. Blood 1996; 87: 1309-16.
    PubMedGoogle Scholar
  • 38 Sungaran R, Markovic B, Chong BH. Localization and regulation of thrombopoietin mRNA expression in human kidney, liver, bone marrow, and spleen using in situ hybridization. Blood 1997; 89: 101-7.
    PubMedGoogle Scholar
  • 39 Guerriero A, Worford L, Holland HK, Guo GR, Sheehan K, Waller EK. Thrombopoietin is synthesized by bone marrow stromal cells. Blood 1997; 90: 3444-55.
    PubMedGoogle Scholar
  • 40 Hirayama Y, Sakamaki S, Matsunaga T, Kuga T, Kuroda H, Kusakabe T, Sasaki K, Fujikawa K, Kato J, Kogawa K, Koyama R, Niitsu Y. Concentrations of thrombopoietin in bone marrow in normal subjects and in patients with idiopathic thrombocytopenic purpura, aplastic anemia, and essential thrombocythemia correlate with its mRNA expression of bone marrow stromal cells. Blood 1998; 92: 46-52.
    PubMedGoogle Scholar
  • 41 Matsumoto A, Tahara T, Morita H, Usuki K, Ohashi H, Kokubo-Watarai A, Takahashi K, Shimizu E, Tsunakawa H, Ogami K, Miyazaki H, Urabe A, Kato T. Characterization of native human thrombopoietin in the blood of normal individuals and of patients with haematologic disorders. Thromb Haemost 1999; 82: 24-9.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 42 Kato T, Oda A, Inagaki Y, Ohashi H, Matsumoto A, Ozaki K, Miyakawa Y, Watarai H, Fuju K, Kokubo A, Kadoya T, Ikeda Y, Miyazaki H. Thrombin cleaves recombinant human thrombopoietin: one of the proteolytic events that generates truncated forms of thrombopoietin. Proc Natl Acad Sci USA 1997; 94: 4669-74.
    CrossrefPubMedGoogle Scholar
  • 43 Cohen-Solal K, Vitrat N, Titeux M, Vainchenker W, Wendling F. High-level expression of Mpl in platelets and megakaryocytes is independent of thrombopoietin. Blood 1999; 93: 2859-66.
    PubMedGoogle Scholar
  • 44 Stohlawetz P, Folman CC, von dem Borne AEGK, Pernerstorfer T, Eichler HG, Panzer S, Jilma B. Effects of endotoxemia on thrombopoiesis in men. Thromb Haemost 1999; 81: 613-7.
    Article in Thieme ConnectPubMedGoogle Scholar