Page 1850 - Williams Hematology ( PDFDrive )

1824 Part XII: Hemostasis and Thrombosis Chapter 111: Megakaryopoiesis and Thrombopoiesis 1825

situations. 209,210 In general, the hormone has been useful in patients who production of functional platelets that show no evidence of in vivo activation. Blood
were administered moderately aggressive chemotherapeutic regimens 88:3288, 1996.
that produce clinically important thrombocytopenia. However, the 5. Machlus KR, Italiano JE Jr: The incredible journey: From megakaryocyte development
to platelet formation. J Cell Biol 201:785, 2013.
hormone has not been helpful in the setting of high-dose, prolonged 6. Junt T, Schulze H, Chen Z, et al: Dynamic visualization of thrombopoiesis within bone
cytotoxic therapy, as in the treatment of acute myelogenous leukemia, marrow. Science 317:1767, 2007.
or in stem cell transplantation, unless, as in the animal studies, it is 7. Harker LA, Finch CA: Thrombokinetics in man. J Clin Invest 48:963, 1969.
8. Machlus KR, Italiano JE Jr. The incredible journey: From megakaryocyte development
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administered to the stem cell donor. Thrombopoietin also reportedly to platelet formation. J Cell Biol 201:785, 2013.
increases platelet levels in patients with immune-mediated thrombocy- 9. Tronik-Le Roux D, Roullot V, Schweitzer A, et al: Suppression of erythro-megakaryocy-
topenia. The timing of drug administration can significantly impact topoiesis and the induction of reversible thrombocytopenia in mice transgenic for the
212
both the total amount of drug required and its efficacy. For example, thymidine kinase gene targeted by the platelet glycoprotein alpha IIb promoter. J Exp
213
Med 181:2141, 1995.
administration of one dose of drug before and once following myelo- 10. Debili N, Robin C, Schiavon V, et al: Different expression of CD41 on human lymphoid
suppressive therapy was as effective as any other multidose regimen. and myeloid progenitors from adults and neonates. Blood 97:2023, 2001.
This regimen resulted in significant reductions in nadir platelet counts 11. Wu G, Essex DW, Meloni FJ, et al: Human endothelial cells in culture and in vivo
express on their surface all four components of the glycoprotein Ib/IX/V complex.
and the need for platelet transfusion during chemotherapy cycles sup- Blood 90:2660, 1997.
plemented with thrombopoietin. Nevertheless, use of a modified form 12. Hickey MJ, Hagen FS, Yagi M, Roth GJ: Human platelet glycoprotein V: Characteri-
of recombinant thrombopoietin is associated with antibody formation zation of the polypeptide and the related Ib-V-IX receptor system of adhesive, leuc-
ine-rich glycoproteins. Proc Natl Acad Sci U S A 90:8327, 1993.
to the drug, which cross-reacts with and neutralizes the native hor- 13. Kahn ML, Diacovo TG, Bainton DF, et al: Glycoprotein V-deficient platelets have undi-
214
mone, resulting in thrombocytopenia. Although this effect has not minished thrombin responsiveness and do not exhibit a Bernard-Soulier phenotype.
been reported with a nonmodified recombinant thrombopoietin, most Blood 94:4112, 1999.
efforts using thrombopoietin in patients with thrombocytopenia are 14. Lopez JA, Andrews RK, Afshar-Kharghan V, Berndt MC: Bernard-Soulier syndrome.
Blood 91:4397, 1998.
focusing on small peptide or organic mimics that bind to and activate 15. Ramakrishnan V, DeGuzman F, Bao M, et al: A thrombin receptor function for platelet
the thrombopoietin receptor (reviewed in Ref. 218). 215–217 Both types glycoprotein Ib-IX unmasked by cleavage of glycoprotein V. Proc Natl Acad Sci U S A
98:1823, 2001.
of thrombopoietin mimetic agents have been tested in clinical trials 16. Breton-Gorius J, Reyes F: Ultrastructure of human bone marrow cell maturation. Int
(Chap. 117). Two lead indications have been tested; primary immune Rev Cytol 46:251, 1976.
thrombocytopenia (ITP) and IFN-induced thrombocytopenia in 17. Italiano JE Jr, Shivdasani RA: Megakaryocytes and beyond: The birth of platelets. J
patients being treated for chronic hepatitis C infection. The results of Thromb Haemost 1:1174, 2003.
these trials have been very promising. For example, in a randomized 18. Ebbe S, Stohlman F Jr: Megakaryocytopoiesis in the rat. Blood 26:20, 1965.
19. Vitrat N, Cohen-Solal K, Pique C, et al: Endomitosis of human megakaryocytes are due
control phase III clinical trial of a peptibody bearing four copies of a to abortive mitosis. Blood 91:3711, 1998.
c-Mpl receptor-stimulating peptide on an immunoglobulin scaffold, 84 20. Odell TT Jr, Reiter RS: Generation cycle of rat megakaryocytes. Exp Cell Res 53:321,
1968.
percent of heavily pretreated patients with ITP responded to treatment, 21. Tijssen MR, Ghevaert C. Transcription factors in late megakaryopoiesis and related
with rates being slightly lower or higher depending on whether they had platelet disorders. J Thromb Haemost 11:593, 2013.
previously undergone splenectomy. Likewise, the administration of a 22. Bastian LS, Kwiatkowski BA, Breininger J, et al: Regulation of the megakaryocytic gly-
219
small, orally available organic thrombopoietin mimetic to patients with coprotein IX promoter by the oncogenic Ets transcription factor Fli-1. Blood 93:2637,
1999.
ITP resulted in 81 percent of patients achieving a platelet count above 23. Ramachandran B, Surrey S, Schwartz E: Megakaryocyte-specific positive regulatory
50 × 10 /L. These studies have led to FDA approval of the two throm- sequence 5′ to the human PF4 gene. Exp Hematol 23:49, 1995.
9
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bopoietin agonists for use in patients with ITP. The same molecule was 24. Furihata K, Kunicki TJ: Characterization of human glycoprotein VI gene 5′ regulatory
and promoter regions. Arterioscler Thromb Vasc Biol 22:1733, 2002.
administered to patients with modest hepatic insufficiency undergoing 25. Sevinsky JR, Whalen AM, Ahn NG: Extracellular signal-regulated kinase induces
IFN/ribavirin therapy for hepatitis C; 75 percent of such patients were the megakaryocyte GPIIb/CD41 gene through MafB/Kreisler. Mol Cell Biol 24:4534,
able to complete 3 months of therapy without IFN dose reduction, com- 2004.
pared to 6 percent of patients given placebo. 221 26. Rojnuckarin P, Drachman JG, Kaushansky K: Thrombopoietin-induced activation of
the mitogen-activated protein kinase (MAPK) pathway in normal megakaryocytes:
Thrombopoietin mimics have also been tested in combination Role in endomitosis. Blood 94:1273, 1999.
with other agents for the treatment of chronic ITP. For example, the 27. Vyas P, Norris FA, Joseph R, et al: Inositol polyphosphate 4-phosphatase type I regu-
combination of recombinant human thrombopoietin plus rituximab lates cell growth downstream of transcription factor GATA-1. Proc Natl Acad Sci U S A
97:13696, 2000.
results in higher response rates and longer duration of response than 28. Pevny L, Simon MC, Robertson E, et al: Erythroid differentiation in chimaeric mice
rituximab alone. 222 blocked by a targeted mutation in the gene for transcription factor GATA-1. Nature
A number of studies have suggested that thrombopoietin mimics 349:257, 1991.
could lead to marrow fibrosis, particularly if used for long periods of 29. Shivdasani RA, Fujiwara Y, McDevitt MA, Orkin SH: A lineage-selective knockout
establishes the critical role of transcription factor GATA-1 in megakaryocyte growth
time. For example, in a series of patients treated with several different and platelet development. EMBO J 16:3965, 1997.
thrombopoietin mimics over 60 patients were shown to develop modest 30. Song WJ, Sullivan MG, Legare RD, et al: Haploinsufficiency of CBFA2 causes famil-
223
degrees of marrow fibrosis, that progressed with time. Careful study ial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat
Genet 23:166, 1999.
of these patients will be required to assess the true incidence and predic- 31. Ichikawa M, Asai T, Saito T, et al: AML-1 is required for megakaryocytic maturation
tors of such complications of therapy. and lymphocytic differentiation, but not for maintenance of hematopoietic stem cells in
adult hematopoiesis. Nat Med 10:299, 2004.
32. Elagib KE, Racke FK, Mogass M, et al: RUNX1 and GATA-1 coexpression and cooper-
REFERENCES ation in megakaryocytic differentiation. Blood 101:4333, 2003.
33. Ebbe S, Phalen E, Stohlman F Jr: Abnormalities of megakaryocytes in W-WV mice.
1. Hanson SR, Slichter SJ: Platelet kinetics in patients with bone marrow hypoplasia: Evi- Blood 42:857, 1973.
dence for a fixed platelet requirement. Blood 66:1105, 1985. 34. Broudy VC, Lin NL, Kaushansky K: Thrombopoietin (c-mpl ligand) acts synergistically
2. Dettke M, Hlousek M, Kurz M, et al: Increase in endogenous thrombopoietin in healthy with erythropoietin, stem cell factor, and interleukin-11 to enhance murine megakary-
donors after automated plateletpheresis. Transfusion 38:449, 1998. ocyte colony growth and increases megakaryocyte ploidy in vitro. Blood 85:1719, 1995.
3. Harker LA, Marzec UM, Hunt P, et al: Dose-response effects of pegylated human 35. Gainsford T, Roberts AW, Kimura S, et al: Cytokine production and function in cmpl–
megakaryocyte growth and development factor on platelet production and function in deficient mice: No physiologic role for interleukin-3 in residual megakaryocyte and
nonhuman primates. Blood 88:511, 1996. platelet production. Blood 91:2745, 1998.
4. O’Malley CJ, Rasko JE, Basser RL, et al: Administration of pegylated recombinant 36. Kaushansky K, Broudy VC, Lin N, et al: Thrombopoietin, the Mp1 ligand, is essential
human megakaryocyte growth and development factor to humans stimulates the for full megakaryocyte development. Proc Natl Acad Sci U S A 92:3234, 1995.

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