Platelet functions and clinical effects in acute myelogenous leukemia

Summary

Platelets interact with normal peripheral blood cells via adhesion as well as soluble mediators, and platelet released mediators can affect hematopoietic stem and progenitor cells. Interactions may also be involved between platelets and circulating malignant cells, which is suggested by the effects platelets seem to have on metastasis and the various platelet abnormalities observed in various malignant disorders, including acute myelogenous leukemia (AML) and other leukemias. It is only recently that the interactions between platelets and AML cells have been characterized in detail, and studies show that; i) platelets and AML blasts can affect functional characteristic of each other, ii) chemotherapeutic drugs frequently used in AML therapy can alter several platelet functions, iii) the systemic levels of various cytokines are enhanced during AML chemotherapy, including cytokines known to affect both leukemic blasts and platelet activation, and iv) platelet secretion of growth factors are clearly detected in peripheral blood stem cells autografts. In this review we describe platelet interactions with normal leukocytes, normal hematopoietic and leukemic cells and the possible clinical relevance of these interactions in AML.

Keywords

Platelets - hematopoiesis - AML - chemotherapy - PBSCT

 

• References

• 1 Chaer RA, Graham JA, Mureebe L. Platelet Function and Pharmacologic Inhibition. Vasc Endovasc Surg 2006; 40: 261-267.
• 2 Jurk K, Kehrel B. Platelets: physiology and biochemistry. Semin Thromb Hemost 2005; 31: 381-392.
• 3 Bruserud Ø, Foss B, Hervig T. Effects of normal platelets on proliferation and constitutive cytokine secretion by human acute myelogenous leukaemia blasts. Platelets 1997; 8: 397-404.
• 4 Bruserud Ø, Foss B, Ulvestad E. et al. Effects of acute myelogenous leukemia blasts on platelet release of soluble P-selectin and platelet-derived growth factor. Platelets 1998; 9: 352-358.
• 5 Gupta GP, Massague J. Platelets and metastasis revisited: a novel fatty link. J Clin Invest 2004; 114: 1691-1693.
• 6 Foss B, Ulvestad E, Bruserud Ø. Platelet-derived growth factor (PDGF) in human acute myelogenous leukemia (AML): PDGF receptor expression, endogenous PDGF release and responsiveness to exogenous PDGF isoforms by in vitro cultured AML blasts. Eur J Haematology 2001; 67: 267-278.
• 7 Foss B, Mentzoni L, Bruserud Ø. Effects of vascular endothelial growth factor on acute myelogenous leukemia blasts. J Hematother Stem Cell Res 2001; 10: 81-94.
• 8 Foss B, Ulvestad E, Hervig T. et al. Effects of cytarabine and various anthracyclins on platelet activation: characterization of in vitro effects and their possible clinical relevance in acute myelogenous leukemia. Int J Cancer 2002; 97: 106-114.
• 9 Bruserud O, Foss B, Abrahamsen JF. et al. Autologous stem cell transplantation as post-remission therapy in adult acute myelogenous leukemia: does platelet contamination of peripheral blood mobilized stem cell grafts influence the risk of leukemia relapse?. J Hematother Stem Cell Res 2000; 9: 433-443.
• 10 Foss B, Abrahamsen JF, Bruserud Ø. Peripheral blood stem cell grafts contain high levels of platelet-secreted mediators. Transfusion 2001; 41: 1431-1437.
• 11 Nomura S, Inami N, Kanazawa S. et al. Elevation of Platelet Activation Markers and Chemokines during Peripheral Blood Stem Cell Harvest with G-CSF. Stem Cells 2004; 22: 696-703.
• 12 Li JJ, Huang YQ, Basch R. et al. Thrombin induces the release of angiopoietin-1 from platelets. Thromb Haemost 2001; 85: 204-206.
• 13 Biró E, Sturk-Maquelin KN, Vogel GM. et al. Human cell-derived microparticles promote thrombus formation in vivo in a tissue factor-dependent manner. J Thromb Haemost 2003; 1: 2561-2568.
• 14 Gutensohn K, Maerz M, Kuehnl P. Alteration of platelet-associated membrane glycoproteins during extracorporeal apheresis of peripheral blood progenitor cells. J Hematother 1997; 6: 315-321.
• 15 Saigo K, Kumagai S, Sugimoto T. et al. RANTES and p-Selectin in peripheral blood stem cell harvest. Ther Apher 2001; 5: 517-518.
• 16 Arbuthnot C, Wilde JT. Haemostatic problems in acute promyelocytic leukaemia. Blood Reviews 2006; 20: 289-297.
• 17 Lopez-Pedrera C, Barbarroja N, Dorado G. et al. Tissue factor as an effector of angiogenesis and tumor progression in hematological malignancies. Leukemia 2006; 20: 1331-1340.
• 18 Arber DA. Realistic pathologic classification of acute myeloid leukemias. Am J Clin Pathol 2001; 115: 552-560.
• 19 Vyas P, Crispino JD. Molecular insights into Down syndrome-associated leukemia. Curr Opin Pediatr 2007; 19: 9-14.
• 20 Ross ME, Mahfouz R, Onciu M. et al. Gene expression profiling of pediatric acute myelogenous leukaemia. Blood 2004; 104: 3679-3687.
• 21 Bourquin J-P, Subramanian A, Langebrake C. et al. Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling. Proc Natl Acad Sci USA 2006; 103: 3339-3344.
• 22 Jungi TW, Spycher MO, Nydegger UE. et al. Platelet- leukocyte interaction: selective binding of thrombin- stimulated platelets to human monocytes, polymorphonuclear leukocytes, and related cell lines. Blood 1986; 67: 629-636.
• 23 Rinder HM, Bonan JL, Rinder CS. et al. Activated and unactivated platelet adhesion to monocytes and neutrophils. Blood 1991; 78: 1760-1769.
• 24 Moore KL, Stults NL, Diaz S. et al. Identification of a specific glycoprotein ligand for P-selectin (CD62) on myeloid cells. J Cell Biol 1992; 118: 445-456.
• 25 de Bruijne-Admiraal LG, Modderman PW, Von dem Borne AE. et al. P-selectin mediates Ca(2+)-dependent adhesion of activated platelets to many different types of leukocytes: detection by flow cytometry. Blood 1992; 80: 134-142.
• 26 Moore KL, Thompson LF. P-selectin (CD62) binds to subpopulations of human memory T lymphocytes and natural killer cells. Biochem Biophys Res Commun 1992; 186: 173-181.
• 27 Spangenberg P, Redlich H, Bergmann I. et al. The platelet glycoprotein IIb/IIIa complex is involved in the adhesion of activated platelets to leukocytes. Thromb Haemost 1993; 70: 514-521.
• 28 Long MW, Briddell R, Walter AW. et al. Human hematopoietic stem cell adherence to cytokines and matrix molecules. J Clin Invest 1992; 90: 251-255.
• 29 Tsai S, Patel V, Beaumont E. et al. Differential binding of erythroid and myeloid progenitors to fibroblasts and fibronectin. Blood 1987; 69: 1587-1594.
• 30 Del Maschio A, Evangelista V, Rajtar G. et al. Platelet activation by polymorphonuclear leukocytes exposed to chemotactic agents. Am J Physiol 1990; 258 (3 Pt 2): H870-879.
• 31 Tsuji T, Nagata K, Koike J. et al. Induction of superoxide anion production from monocytes an neutrophils by activated platelets through the P-selectin-sialyl Lewis X interaction. J Leukoc Biol 1994; 56: 583-587.
• 32 Piccardoni P, Evangelista V, Piccoli A. et al. Thrombin- activated human platelets release two NAP-2 variants that stimulate polymorphonuclear leukocytes. Thromb Haemost 1996; 76: 780-785.
• 33 Ruf A, Patscheke H. Platelet-induced neutrophil activation: platelet-expressed fibrinogen induces the oxidative burst in neutrophils by an interaction with CD11C/CD18. Br J Haematol 1995; 90: 791-796.
• 34 Elstad MR, La Pine TR, Cowley FS. et al. P-selectin regulates platelet-activating factor synthesis and phagocytosis by monocytes. J Immunol 1995; 155: 2109-2122.
• 35 Weyrich AS, Elstad MR, Mc Ever RP. et al. Activated platelets signal chemokine synthesis by human monocytes. J Clin Invest 1996; 97: 1525-1534.
• 36 Tzeng DY, Deuel TF, Huang JS. et al. Platelet-derived growth factor promotes polymorphonuclear leukocyte activation. Blood 1984; 64: 1123-1128.
• 37 Aziz KA, Cawley JC, Zuzel M. Platelets prime PMN via released PF4: mechanism of priming and synergy with GM-CSF. Br J Haematol 1995; 91: 846-853.
• 38 Dercksen MW, Weimar IS, Richel DJ. et al. The value of flow cytometric analysis of platelet glycoprotein expression of CD34+ cells measured under conditions that prevent P- selectin-mediated binding of platelets. Blood 1995; 86: 3771-3782.
• 39 Michalevicz R, Katz F, Stroobant P. et al. Plateletderived growth factor stimulates growth of highly enriched multipotent haemopoietic progenitors. Br J Haematol 1986; 63: 591-598.
• 40 Su RJ, Zhang XB, Li K. et al. Platelet-derived growth factor promotes ex vivo expansion of CD34+ cells from human cord blood and enhances long-term culture-initiating cells, non-obese diabetic/severe combined immunodeficient repopulating cells and formation of adherent cells. Br J Haematol 2002; 117: 735-746.
• 41 Trink B, Wang G, Shahar M. et al. Functional platelet- derived growth factor-beta (PDGF-beta) receptor expressed on early B-lineage precursor cells. Clin Exp Immunol 1995; 102: 417-424.
• 42 Ruscetti FW, Akel S, Bartelmez SH. Autocrine transforming growth factor-beta regulation of hematopoiesis: many outcomes that depend on the context. Oncogene 2005; 24: 5751-5763.
• 43 Pircher R, Jullien P, Lawrence DA. Beta-transforming growth factor is stored in human blood platelets as a latent high molecular weight complex. Biochem Biophys Res Commun 1986; 136: 30-37.
• 44 Yang M, Li K, Ng MH. et al. Thrombospondin-1 inhibits in vitro megakaryocytopoiesis via CD36. Thromb Res 2003; 109: 47-54.
• 45 Sagar BM, Rentala S, Gopal PN. et al. Fibronectin and laminin enhance engraftibility of cultured hematopoietic stem cells. Biochem Biophys Res Commun 2006; 350: 1000-1005.
• 46 Zhou YQ, Levesque JP, Hatzfeld A. et al. Fibrinogen potentiates the effect of interleukin-3 on early human hematopoietic progenitors. Blood 1993; 82: 800-806.
• 47 Gerber HP, Malik AK, Solar GP. et al. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature 2002; 417: 954-958.
• 48 Katoh O, Tauchi H, Kawaishi K. et al. Expression of the vascular endothelial growth factor (VEGF) receptor gene, KDR, in hematopoietic cells and inhibitory effect of VEGF on apoptotic cell death caused by ionizing radiation. Cancer Res 1995; 55: 5687-5692.
• 49 Broxmeyer HE, Cooper S, Li ZH. et al. Myeloid progenitor cell regulatory effects of vascular endothelial cell growth factor. Int J Hematol 1995; 62: 203-215.
• 50 Gewirtz AM, Calabretta B, Rucinski B. et al. Inhibition of human megakaryocytopoiesis in vitro by platelet factor 4 (PF4) and a synthetic COOH-terminal PF4 peptide. J Clin Invest 1989; 83: 1477-1486.
• 51 Han ZC, Bellucci S, Tenza D. et al. Negative regulation of human megakaryocytopoiesis by human platelet factor 4 and beta thromboglobulin: comparative analysis in bone marrow cultures from normal individuals and patients with essential thrombocythaemia and immune thrombocytopenic purpura. Br J Haematol 1990; 74: 395-401.
• 52 Yang M, Srikiatkhachorn A, Anthony M. et al. Serotonin stimulates megakaryocytopoiesis via the 5-HT2 receptor. Blood Coagul Fibrinolysis 1996; 7: 127-133.
• 53 Han ZC, Lu M, Li J. et al. Platelet factor 4 and other CXC chemokines support the survival of normal hematopoietic cells and reduce the chemosensitivity of cells to cytotoxic agents. Blood 1997; 89: 2328-2335.
• 54 Zhang J, Lu SH, Liu YJ. et al. Platelet factor 4 enhances the adhesion of normal and leukemic hematopoietic stem/progenitor cells to endothelial cells. Leuk Res 2004; 28: 631-638.
• 55 Majka M, Janowska-Wieczorek A, Ratajczak J. et al. Numerous growth factors, cytokines, and chemokines are secreted by human CD34(+) cells, myeloblasts, erythroblasts, and megakaryoblasts and regulate normal hematopoiesis in an autocrine/paracrine manner. Blood 2001; 97: 3075-3085.
• 56 Baj-Krzyworzeka M, Majka M, Pratico D. et al. Platelet-derived microparticles stimulate proliferation, survival, adhesion, and chemotaxis of hematopoietic cells. Exp Hematol 2002; 30: 450-459.
• 57 Kim HK, Song KS, Park YS. et al. Elevated levels of circulating platelet microparticles, VEGF, IL-6 and RANTES in patients with gastric cancer: possible role of a metastasis predictor. Eur J Cancer 2003; 39: 184-191.
• 58 Villmow T, Kemkes-Matthes B, Matzdorff AC. Markers of platelet activation and platelet-leukocyte interaction in patients with myeloproliferative syndromes. Thromb Res 2002; 108: 139-145.
• 59 Yang ZF, Ho DW, Lau CK. et al. Platelet activation during tumor development, the potential role of BDNFTrkB autocrine loop. Biochem Biophys Res Commun 2006; 346: 981-985.
• 60 Ostman A. PDGF receptors-mediators of autocrine tumor growth and regulators of tumor vasculature and stroma. Cytokine Growth Factor Rev 2004; 15: 275-286.
• 61 Al-Mondhiry H. beta-Thromboglobulin and platelet- factor 4 in patients with cancer: correlation with the stage of disease and the effect of chemotherapy. Am J Hematol 1983; 14: 105-111.
• 62 Grignani G, Pacchiarini L, Ricetti MM. et al. Mechanisms of platelet activation by cultured human cancer cells and cells freshly isolated from tumor tissues. Invasion Metastasis 1989; 9: 298-309.
• 63 Avram S, Lupu A, Angelescu S. et al. Abnormalities of platelet aggregation in chronic myeloproliferative disorders. J Cell Mol Med 2001; 5: 79-87.
• 64 Jaime-Perez JC, Cantu-Rodriguez OG, Herrera-Garza JL. et al. Platelet aggregation in children with acute lymphoblastic leukemia during induction of remission therapy. Arch Med Res 2004; 35: 141-144.
• 65 Ibele GM, Kay NE, Johnson GJ. et al. Human platelets exert cytotoxic effects on tumor cells. Blood 1985; 65: 1252-1255.
• 66 Verheul HM, Pinedo HM. Tumor growth: A putative role for platelets?. Oncologist 1998; 3: ii.
• 67 Veikkola T, Alitalo K. VEGFs, receptors and angiogenesis. Semin Cancer Biol 1999; 9: 211-220.
• 68 Brown LF, Berse B, Jackman RW. et al. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in adenocarcinomas of the gastrointestinal tract. Cancer Res 1993; 53: 4727-4735.
• 69 Ho C-L, Hsu L-F, Phyliky RL. et al. Autocrine Expression of Platelet-Derived Growth Factor B in B Cell Chronic Lymphocytic Leukemia. Acta Haematol 2005; 114: 133-140.
• 70 Pietras K, Sjoblom T, Rubin K. et al. PDGF receptors as cancer drug targets. Cancer Cell 2003; 05 3 439-443.
• 71 Steinhilber D, Radmark O, Samuelsson B. Transforming growth factor beta upregulates 5-lipoxygenase activity during myeloid cell maturation. Proc Natl Acad Sci USA 1993; 90: 5984-5988.
• 72 Bikfalvi A, Gimenez-Gallego G. The Control of Angiogenesis and Tumor Invasion by Platelet Factor-4 and Platelet Factor-4-Derived Molecules. Semin Thromb Hemost 2004; 30: 137-144.
• 73 Silverstein RL, Asch AS, Nachman RL. Glycoprotein IV mediates thrombospondin-dependent plateletmonocyte and platelet-U937 cell adhesion. J Clin Invest 1989; 84: 546-552.
• 74 Tuszynski GP, Wang TN, Berger D. Adhesive proteins and the hematogenous spread of cancer. Acta Haematol 1997; 97: 29-39.
• 75 Cowan DH, Haut MJ. Platelet function in acute leukemia. J Lab Clin Med 1972; 79: 893-905.
• 76 Cowan DH. Platelet metabolism in acute leukemia. J Lab Clin Med 1973; 82: 54-66.
• 77 Ramos OF, Moron EC, Castro De, Arenas R. Platelet function abnormalities in acute leukaemia. Haematologia 1981; 14: 383-391.
• 78 Tiwari NN, Singh VP, Dube B. et al. Platelet function in leukaemias. J Assoc Physicians India 1984; 32: 805-807.
• 79 Woodcock BE, Cooper PC, Brown PR. et al. The platelet defect in acute myeloid leukaemia. J Clin Pathol 1984; 37: 1339-1342.
• 80 Pogliani EM, Colombi M, Cofrancesco E. et al. Platelet dysfunction in acute megakaryoblastic leukemia. Acta Haematol 1989; 81: 1-4.
• 81 Leinoe EB, Hoffmann MH, Kjaersgaard E. et al. Multiple platelet defects identified by flow cytometry at diagnosis in acute myeloid leukaemia. Br J Haematol 2004; 127: 76-84.
• 82 Gerrard JM, Israels ED, Bishop AJ. et al. Inherited platelet-storage pool deficiency associated with a high incidence of acute myeloid leukaemia. Br J Haematol 1991; 79: 246-255.
• 83 Nouvel C, Caranobe C, Sie P. et al. Platelet volume, density and 5 HT organelles (mepacrine test) in acute leukaemia. Scand J Haematol 1978; 21: 421-426.
• 84 Gerrard JM, Mc Nicol A. Platelet storage pool deficiency, leukemia, and myelodysplastic syndromes. Leuk Lymphoma 1992; 8: 277-281.
• 85 Tallman MS, Hakimian D, Kwaan HC. et al. New insights into the pathogenesis of coagulation dysfunction in acute promyelocytic leukemia. Leuk Lymphoma 1993; 11: 27-36.
• 86 Higuchi T, Shimizu T, Mori H. et al. Coagulation patterns of disseminated intravascular coagulation in acute promyelocytic leukemia. Hematol Oncol 1997; 15: 209-217.
• 87 Naresh KN, Sivasankaran P, Veliath AJ. Platelet function in chronic leukemias. Indian J Cancer 1992; 29: 49-55.
• 88 Faldt R, Ankerst J, Zoucas E. Inhibition of platelet aggregation by myeloid leukaemic cells demonstrated in vitro. Br J Haematol 1987; 66: 529-534.
• 89 Katz FE, Michalevicz R, Lam G. et al. Effect of platelet- derived growth factor on enriched populations of haemopoietic progenitors from patients with chronic myeloid leukaemia. Leuk Res 1987; 11: 339-344.
• 90 Fiedler W, Graeven U, Ergun S. et al. Vascular endothelial growth factor, a possible paracrine growth factor in human acute myeloid leukemia. Blood 1997; 89: 1870-1875.
• 91 Gabrilovich D, Ishida T, Oyama T. et al. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differenti- ation of multiple hematopoietic lineages in vivo. Blood 1998; 92: 4150-4166.
• 92 Hussong JW, Rodgers GM, Shami PJ. Evidece of increased angiogenesis in patients with acute myeloid leukemia. Blood 2000; 95: 309-313.
• 93 Aguayo A, Estey E, Kantarjian H. et al. Cellular vascular endothelial growth factor is a predictor of outcome in patients with acute myeloid leukemia. Blood 1999; 94: 3717-3721.
• 94 Aguayo A, Kantarjian H, Manshouri T. et al. Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. Blood 2000; 96: 2240-2245.
• 95 Foa R, Bussolino F, Ferrando ML. et al. Release of platelet-activating factor in human leukemia. Cancer Res 1985; 45: 4483-4485.
• 96 Foss B, Nesthus I, Bergheim J. et al. Serum levels of thrombopoietin and stem cell factor in acute leukemia patients with chemotherapy-induced cytopenia and complicating infections. Platelets 1999; 10: 17-23.
• 97 Oda A, Miyakawa Y, Druker BJ. et al. Thrombopoietin primes human platelet aggregation induced by shear stress and by multiple agonists. Blood 1996; 87: 4664-4670.
• 98 Fontenay-Roupie M, Huret G, Loza JP. et al. Thrombopoietin activates human platelets and induces tyrosine phosphorylation of p80/85 cortactin. Thromb Haemost 1998; 79: 195-201.
• 99 Grabarek J, Groopman JE, Lyles YR. et al. Human kit ligand (stem cell factor) modulates platelet activation in vitro. J Biol Chem 1994; 269: 21718-21724.
• 100 Nomura S, Nakamura T, Cone J. et al. Cytometric analysis of high shear-induced platelet microparticles and effect of cytokines on microparticle generation. Cytometry 2000; 40: 173.-181.
• 101 Bruserud Ø, Akselen PE, Bergheim J. et al. Serum concentrations of E-selectin, P-selectin, ICAM-1 and interleukin 6 in acute leukaemia patients with chemotherapy- induced leucopenia and bacterial infections. Br J Haematol 1995; 91: 394-402.
• 102 Bruserud Ø, Halstensen A, Peen E. et al. Serum levels of adhesion molecules and cytokines in patients with acute leukaemia. Leuk Lymphoma 1996; 23: 423-430.
• 103 Schonbohn H, Schuler M, Kolbe K. et al. Plasma levels of IL-1, TNF alpha, IL-6, IL-8, G-CSF, and IL1-RA during febrile neutropenia: results of a prospective study in patients undergoing chemotherapy for acute myelogenous leukemia. Ann Hematol 1995; 71: 161-168.
• 104 Reisbach G, Kamp T, Welzl G. et al. Regulated plasma levels of colony-stimulating factors, interleukin- 6 and interleukin-10 in patients with acute leukaemia and non-hodgkin's lymphoma undergoing cytoreductive chemotherapy. Br J Haematol 1996; 92: 907-912.
• 105 Cimino G, Amadori S, Cava MC. et al. Serum interleukin-2 (IL-2), soluble IL-2 receptors and tumor necrosis factor-alfa levels are significantly increased in acute myeloid leukemia patients. Leukemia 1991; 5: 32-35.
• 106 Aydogdu I, Ilhan O, Beksac M. et al. Serum erythropoietin levels in patients with leukemia on cytostatic treatment. Haematologica 1998; 29: 133-137.
• 107 Panella TJ, Peters W, White JG. et al. Platelets acquire a secretion defect after high-dose chemotherapy. Cancer 1990; 65: 1711-1716.
• 108 Hicsonmez G. The effect of cancer chemotherapy drugs on platelet aggregation. Turk J Pediatr 1974; 16: 1-7.
• 109 Kubisz P, Suranova J. Influence of cytostatics on some platelet functions in vitro II. Cytosine-arabinoside. Neoplasma 1974; 21: 711-716.
• 110 Matera C, Falzarano C, Vacca C. et al. Effects of some antineoplastic drugs (vincristine, doxorubicin and epirubicin) on human platelet aggregation. J Med 1994; 25: 2-16.
• 111 Lanzi C, Banfi P, Ravagnani F. et al. Diversity of effects of two antitumor anthracycline analogs on the pathway of activation of PKC in intact human platelets. Biochem Pharmacol 1988; 37: 3497-3504.
• 112 Pogliani EM, Fantasia R, Lambertenghi-Deliliers G. et al. Daunorubicin and platelet function. Thromb Haemost 1981; 45: 38-42.
• 113 Whaun JM, Clarke HD. The effect of daunomycin on platelets in vitro. Arch Int Pharmacodyn Ther 1989; 300: 292-304.
• 114 Shattil SJ, Hoxie JA, Cunningham M. et al. Changes in the platelet membrane glycoprotein IIb. IIIa complex during platelet activation. J Biol Chem 1985; 260: 11107-11114.
• 115 Janes SL, Wilson DJ, Chronos N. et al. Evaluation of whole blood flow cytometric detection of platelet bound fibrinogen on normal subjects and patients with activated platelets. Thromb Haemost 1993; 70: 659-666.
• 116 Ruf A, Patscheke H. Flow cytometric detection of activated platelets: comparison of determining shape change, fibrinogen binding, and P-selectin expression. Semin Thromb Hemost 1995; 21: 146-151.
• 117 Michelson AD, Barnard MR, Hechtman HB. et al. In vivo tracking of platelets: circulating degranulated platelets rapidly lose surface P-selectin but continue to circulate and function. Proc Natl Acad Sci U S A 1996; 93: 11877-11882.
• 118 Kumar A, Kumar R, Sandilium A. et al. 5-Fluorouracil induces defects in platelet function. Platelets 1999; 10: 137-140.
• 119 Nomura S, Ishii K, Kanazawa S. et al. Role of platelet- derived chemokines (RANTES and ENA-78) after stem cell transplantation. Transplant Immunology 2006; 15: 247-253.
• 120 Singh RK, Ino K, Varney ML. et al. Immunoregulatory cytokines in bone marrow and peripheral blood stem cell products. Bone Marrow Transplant 1999; 23: 53-62.
• 121 Ageitos AG, Varney ML, Bierman PJ. et al. Comparison of monocyte-dependent T cell inhibitory activity in GM-CSF vs G-CSF mobilized PSC products. Bone Marrow Transplant 1999; 23: 63-69.
• 122 Stroncek DF, Clay ME, Smith J. et al. Composition of peripheral blood progenitor cell components collected from healthy donors. Transfusion 1997; 37: 411-417.
• 123 Stroncek DF, Clay ME, Jaszcz W. et al. Collection of two peripheral blood stem cell concentrates from healthy donors. Transfus Med 1999; 9: 37-50.
• 124 Lemoli RM, Curti A, Tura S. Negative selection of autologous peripheral blood stem cells. Baillieres Best Pract Res Clin Haematol 1999; 12: 57-69.
• 125 Nagafuji K, Harada M, Takamatsu Y. et al. Evaluation of leukaemic contamination in peripheral blood stem cell harvests by reverse transcriptase polymerase chain reaction. Br J Haematol 1993; 85: 578-583.
• 126 Miyamoto T, Nagafuji K, Harada M. et al. Significance of quantitative analysis of AML1/ETO transcripts in peripheral blood stem cells from t(8;21) acute myelogenous leukemia. Leuk Lymphoma 1997; 25: 69-75.
• 127 Testoni N, Lemoli RM, Martinelli G. et al. Autologous peripheral blood stem cell transplantation in acute myeloblastic leukaemia and myelodysplastic syndrome patients: evaluation of tumour cell contamination of leukaphereses by cytogenetic and molecular methods. Bone Marrow Transplant 1998; 22: 1065-1070.
• 128 Lie AK, To LB. Peripheral Blood Stem Cells: Transplantation and Beyond. Oncologist 1997; 2: 40-49.
• 129 Deisseroth AB, Zu Z, Claxton D. et al. Genetic marking shows that Ph+ cells present in autologous transplants of chronic myelogenous leukemia (CML) contribute to relapse after autologous bone marrow in CML. Blood 1994; 83: 3068-3076.
• 130 Rill DR, Santana VM, Roberts WM. et al. Direct demonstration that autologous bone marrow transplantation for solid tumors can return a multiplicity of tumorigenic cells. Blood 1994; 84: 380-383.
• 131 Bruserud Ø, Foss B, Petersen H. Hematopoietic growth factors in patients receiving intensive chemotherapy for malignant disorders: studies of granulocyte- colony stimulating factor (G-CSF), granulocytemacrophage colony stimulating factor (GM-CSF), interleukin- 3 (IL-3) and Flt-3 ligand (Flt3L). Eur Cytokine Netw 2001; 12: 231-238.
• 132 Voss R, Scarlat T, Matzdorff A. et al. Flow cytometric detection of platelet activation in patients undergoing diagnostic and interventional coronary angiography. Platelets 1996; 7: 237-241.
• 133 Saigo K, Hashimmoto M, Kumagai S. et al. Platelet and RANTES contamination in peripheral blood stem cell products: comparison of three different instruments for PBSC harvesting. Vox Sanguinis 2003; 84: 241-242.
• 134 Wandt H, Ehninger G, Gallmeier WM. New Strategies for Prophylactic Platelet Transfusion in Patients with Hematologic Diseases. Oncologist 2001; 6: 446-450.
• 135 Stroncek DF, Rebulla P. Platelet transfusions. Lancet 2007; 370: 427-438.
• 136 Perez-Pujol S, Aras O, Lozano M. et al. Stored platelets contain residual amounts of tissue factor: evidence from studies on platelet concentrates stored for prolonged periods. Transfusion 2005; 45: 572-579.
• 137 De Stefano V, Sora F, Rossi E. et al. The risk of thrombosis in patients with acute leukemia: occurrence of thrombosis at diagnosis and during treatment. J Thromb Hemost 2005; 3: 1985-1992.
• 138 Kwaan HC, Vicuna B. Incidence and pathogenesis of thrombosis in hematologic malignancies. Semin Thromb Hemost 2007; 33: 303-312.
• 139 Hron G, Kollars M, Weber H. et al. Tissue factorpositive microparticles: cellular origin and association with coagulation activation in patients with colorectal cancer. Thromb Haemost 2007; 97: 119-123.
• 140 Kyrle PA, Hron G, Eichinger S. et al. Circulating P-selectin and the risk of recurrent venous thromboembolism. Thromb Haemost 2007; 97: 880-883.
• 141 Langer F, Amirkhosravi A, Loges S. et al. An in vitro study on the mechanisms of coagulation activation in acute myelogenous leukemia (AML): role of tissue factor regulation by cytotoxic drugs and GMCSF. Thromb Haemost 2004; 92: 1136-1146.
• 142 Ruud E, Holmstrøm H, Natvig S. et al. Prevalence of thrombophilia and central venous catheter-associated neck vein thrombosis in 41 children with cancer - a prospective study. Med Pediatr Oncol 2002; 38: 405-410.
• 143 Ryningen A, Apelseth T, Hausken T. et al. Reticulated platelets are increased in chronic myeloproliferative disorders, pure erythrocytosis, reactive thrombocytosis and prior to hematopoietic reconstitution after intensive chemotherapy. Platelets 2006; 17: 296-302.
• 144 Chaoui D, Chakroun T, Robert F. et al. Reticulated platelets: a reliable measure to reduce prophylactic platelet transfusions after intensive chemotherapy. Transfusion 2005; 45: 766-772.
• 145 Cripe LD, Hromas R. Malignant disorders of megakaryocytes. Semin Hematol 1998; 35: 200-209.
• 146 Testoni N, Borsaru G, Martinelli G. et al. 3q21 and 3q26 cytogenetic abnormalities in acute myeloblastic leukemia: biological and clinical features. Haematologica 1999; 84: 690-694.
• 147 Shukla J, Rai S, Singh VP. Acute megakaryoblastic leukaemia: a clinico-haematological profile of five cases. Indian J Pathol Microbiol 2004; 47: 266-268.
• 148 Reilly JT. Idiopathic myelofibrosis: pathogenesis to treatment. Hematol Oncol 2006; 24: 56-63.
• 149 Shibata K, Nakano S, Watanabe M. et al. Acute megakaryocytic leukaemia (AML-M7) with myelofibrosis terminating in AML-MO with concurrent liver fibrosis. Eur J Haematol 1998; 60: 310-312.
• 150 Zheng LM, Zychlinsky A, Liu CC. et al. Extracellular ATP as a trigger for apoptosis or programmed cell death. J Cell Biol 1991; 112: 279-288.
• 151 Murgia M, Pizzo P, Steinberg TH. et al. Characterization of the cytotoxic effect of extracellular ATP in J774 mouse macrophages. Biochem J 1992; 288 (03) 897-901.
• 152 Khan NA, Ferriere F, Deschaux P. Serotonin-induced calcium signaling via 5-HT1A receptors in human leukemia (K 562) cells. Cell Immunol 1995; 165: 148-152.
• 153 Clifford EE, Parker K, Humphreys BD. et al. The P2X1 receptor, an adenosine triphosphate-gated cation channel, is expressed in human platelets but not in human blood leukocytes. Blood 1998; 91: 3172-3181.
• 154 Suchanek B, Struppeck H, Fahrig T. The 5-HT1A receptor agonist BAY x 3702 prevents staurosporineinduced apoptosis. Eur J Pharmacol 1998; 355: 95-101.
• 155 Meeson AP, Argilla M, Ko K. et al. VEGF deprivation- induced apoptosis is a component of programmed capillary regression. Development 1999; 126: 1407-1415.
• 156 Kim HR, Upadhyay S, Li G. et al. Platelet-derived growth factor induces apoptosis in growth-arrested murine fibroblasts. Proc Natl Acad Sci USA 1995; 92: 9500-9504.
• 157 Kisucka J, Butterfield CE, Duda DG. et al. Platelets and platelet adhesion support angiogenesis while preventing excessive hemorrhage. Proc Natl Acad Sci USA 2006; 103: 855-860.
• 158 Kottaridis PD, Gale RE, Langabeer SE. et al. Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors. Blood 2002; 100: 2393-2398.
• 159 Coffer PJ, Koenderman L, de Groot RP. The role of STATs in myeloid differentiation and leukemia. Oncogene 2000; 19: 2511-25122.
• 160 Hirai T, Masaki T, Kuratsune M. et al. PDGF receptor tyrosine kinase inhibitor suppresses mesangial cell proliferation involving STAT3 activation. Clin Exp Immunol 2006; 144: 353-361.
• 161 Hatfield KJ, Hovland R, Øyan AM. et al. Release of angiopoietin-1 by primary human acute myelogenous leukemia cells is associated with mutations of nucleo- phosmin, increased by bone marrow stromal cells and possibly antagonized by high system angiopoietin-2 levels. Leukemia. 2007 October 18 [Epub ahead of print].
• 162 Penserga ETP, Skorski T. Fusion tyrosine kinases: a result and cause of genomic instability. Oncogene 2007; 26: 11-20.
• 163 Shih LY, Huang CF, Wang PN. et al. Acquisition of FLT3 or N-ras mutations is frequently associated with progression of myelodysplastic syndrome to acute myeloid leukemia. Leukemia 2004; 18: 466-475.
• 164 Levi M. Platelets. Crit Care Med 2005; 33: S523-525.