Cytokines, Endothelium, and Adhesive Molecules in Pathologic Thrombopoiesis

Clonal thrombocytosis (CT) associated with myeloproliferative disorders (MPD) is believed to be secondary to autonomous unregulated platelet production. Secondary or reactive thrombocytosis (RT) can be observed in a number of clinical circumstances and may be related to persistent production of some thrombopoietic factors acting on megakaryocytes (MK). The goal of this study is to assess the serum concentrations of these cytokines in control subjects and patients with MPD associated with thrombocythemia, RT, and autoimmune thrombocytopenic purpura (ATP). Eleven patients with MPD, five with chronic myeloid leukemia (CML), three with polycythemia vera (PCV), two with essential thrombocythemia (ET), one with myelofibrosis, 15 with RT, eight with ATP, and 12 healthy volunteers were enrolled in the study. Serum interleukin (IL)-1β, IL-6, tumor necrosis factor-alpha (TNF), fibronectin, intracellular adhesion molecule-1 (ICAM-1), and thrombomodulin (TM) were measured in these groups. Interleukin-1β, IL-6, and TNF levels were high in patients with RT and ATP, suggesting that these cytokines act on early uncommitted progenitors, promoting commitment along the MK lineage and leading to thrombocytosis or compensation for thrombocytopenia. TM was significantly increased in patients with MPD compared to all other groups, probably indicating the presence of subclinical endothelial damage. Fibronectin levels were high in MPD and RT patients. This finding can be secondary to high platelet turnover in these patients. We found that ICAM-1 levels were high in patients with clonal thrombocytosis. ICAM-1 can be one of the factors initiating the events ultimately leading to clonal thrombocytosis. Thrombocythemia associated with MPD is an autonomous phenomenon not regulated by cytokines.

[1]  A. Girolami,et al.  Soluble Plasma Thrombomodulin Levels in Patients with Chronic Myeloproliferative Disorder , 1999, Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis.

[2]  I. Haznedaroglu,et al.  Interleukin‐1 β and interleukin‐6 in clonal versus reactive thrombocytosis , 1995 .

[3]  I. Haznedaroglu,et al.  Megakaryocytopoietic cytokines in autoimmune thrombocytopenic purpura , 1995, American journal of hematology.

[4]  J. Nemunaitis,et al.  A phase I trial of recombinant human interleukin-6 in patients with myelodysplastic syndromes and thrombocytopenia. , 1995, Blood.

[5]  G. Ahmann,et al.  Plasma interleukin-6 and C-reactive protein levels in reactive versus clonal thrombocytosis. , 1994, The American journal of medicine.

[6]  T. Carlos,et al.  Leukocyte-endothelial adhesion molecules. , 1994, Blood.

[7]  R. Hoffman,et al.  Growth factors affecting human thrombocytopoiesis: potential agents for the treatment of thrombocytopenia. , 1992, Blood.

[8]  R. Hoffman,et al.  Human hematopoietic stem cell adherence to cytokines and matrix molecules. , 1992, The Journal of clinical investigation.

[9]  H. Asakura,et al.  Increased levels of plasma thrombomodulin in chronic myelogenous leukemia , 1992, American journal of hematology.

[10]  Tatsuya Hayashi,et al.  Plasma thrombomodulin as a marker of vascular disorders in thrombotic thrombocytopenic purpura and disseminated intravascular coagulation , 1992, American journal of hematology.

[11]  H. Asakura,et al.  Plasma levels of soluble thrombomodulin increase in cases of disseminated intravascular coagulation with organ failure , 1991, American journal of hematology.

[12]  H. Ishii,et al.  Soluble Thrombomodulin Antigen in Conditioned Medium Is Increased by Damage of Endothelial Cells , 1991, Thrombosis and Haemostasis.

[13]  Timothy A. Springer,et al.  Adhesion receptors of the immune system , 1990, Nature.

[14]  V. Dixit,et al.  Thrombospondin functions as a cytoadhesion molecule for human hematopoietic progenitor cells. , 1990, Blood.

[15]  T. Ishikawa,et al.  Establishment of Enzyme Immunoassay of Human Thrombomodulin in Plasma and Urine Using Monoclonal Antibodies , 1990, Thrombosis and Haemostasis.

[16]  William,et al.  Structure and function of thrombomodulin: a natural anticoagulant. , 1990, Blood.

[17]  R. Hoffman,et al.  Effect of interleukin 6 on in vitro human megakaryocytopoiesis: its interaction with other cytokines. , 1989, Experimental hematology.

[18]  S. Burstein,et al.  Human interleukin 6 is a direct promoter of maturation of megakaryocytes in vitro. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[19]  R. Rosenberg,et al.  Tumor necrosis factor suppresses transcription of the thrombomodulin gene in endothelial cells , 1988, Molecular and cellular biology.

[20]  D. Faller,et al.  Interleukin-1, tumor necrosis factor, and the production of colony-stimulating factors by cultured mesenchymal cells. , 1988, Blood.

[21]  C. Esmon.  The regulation of natural anticoagulant pathways , 1987, Science.

[22]  K. Zuckerman,et al.  Extracellular matrix production by the adherent cells of long-term murine bone marrow cultures , 1983 .

[23]  L. Lajtha,et al.  Conditions controlling the proliferation of haemopoietic stem cells in vitro , 1977, Journal of cellular physiology.

[24]  M. Long.  Population heterogeneity among cells of the megakaryocyte lineage , 1993, Stem cells.

[25]  H. Avraham.  Regulation of megakaryocytopoiesis , 1993, Stem cells.

[26]  L. Corash,et al.  Multiple in vivo effects of interleukin-3 and interleukin-6 on murine megakaryocytopoiesis. , 1991, Blood.

[27]  G. Riethmüller,et al.  De novo expression of intercellular-adhesion molecule 1 in melanoma correlates with increased risk of metastasis. , 1989, Proceedings of the National Academy of Sciences of the United States of America.