Page 2062 - Williams Hematology ( PDFDrive )

2036 Part XII: Hemostasis and Thrombosis Chapter 119: Reactive Thrombocytosis 2037

EPO often induces functional iron deficiency. If so, because iron defi- 5. Yonemura Y, Kawakita M, Masuda T, et al: Synergistic effects of interleukin 3 and inter-
ciency leads to thrombocytosis, the excessive cardiovascular morbidity leukin 11 on murine megakaryopoiesis in serum-free culture. Exp Hematol 20:1011, 1992.
and mortality associated with the administration of EPO and ESAs to 6. Carrington PA, Hill RJ, Stenberg PE, et al: Multiple in vivo effects of interleukin 3 and
interleukin 6 on mouse megakaryocytopoiesis. Blood 77:34, 1991.
patients is hypothesized to be secondary to the thrombocytosis. Consis- 7. Schlerman FJ, Bree AG, Kaviani MD, et al: Thrombopoietic activity of recombinant
tent with this view is that even a high normal platelet count was found human interleukin 11 in normal and myelosuppressed nonhuman primates. Stem Cells
14:517, 1996.
associated with enhanced cardiovascular morbidity and mortality in 8. Debili N, Massé J-M, Katz A, et al: Effects of the recombinant hematopoietic growth
2
a longitudinal study of healthy Norwegian men. In support of this factors interleukin-3, interleukin-6, stem cell factor, and leukemia inhibitory factor on
hypothesis (that the excessive cardiovascular morbidity and mortality is the megakaryocytic differentiation of CD34+ cells. Blood 82:84, 1993.
secondary to the thrombocytosis) is the finding that patients with renal 9. Farese A, Myers LA, MacVittie TJ: Therapeutic efficacy of recombinant leukemia
insufficiency on high therapeutic doses of EPO (>20,000 U/week) and inhibitory factor in a primate model of radiation-induced marrow aplasia. Blood 84:
3675, 1994.
hemoglobin (Hgb) values in excess of 13 g/dL are more likely to develop 10. Avecilla ST, Hattori K, Heissig B, et al: Chemokine-mediated interaction of hematopoi-
functional iron deficiency and thrombocytosis, and that those individu- etic progenitors with the bone marrow vascular niche is required for thrombopoiesis.
Nat Med 10:64, 2004.
als in whom the platelet count exceeds 300,000/μL display a statistically 11. Hodohara K, Fujii N, Yamamoto N, Kaushansky K: Stromal cell derived factor 1 acts
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significantly higher 3-year mortality rate. An alternate explanation is synergistically with thrombopoietin to enhance the development of megakaryocytic
that EPO directly increases thrombopoiesis independently of iron defi- progenitor cells. Blood 95:769, 2000.
ciency and/or enhances the vascular reactivity of platelets. This hypoth- 12. Tsuji-Takayama K, Tahata H, Izumi N, et al: IFN-gamma in combination with IL-3 accel-
erates platelet recovery in mice with 5-fluorouracil-induced marrow aplasia. J Interferon
esis is based on the finding that megakaryocytes and platelets bear Cytokine Res 16:447, 1996.
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EPO receptors, and that TPO, which stimulates very similar signaling 13. Kaushansky K, O’Hara PJ, Berkner K, et al: Genomic cloning, characterization, and mul-
pathways as EPO in receptor-bearing cells (Chap. 17), primes platelets tilineage expression of human granulocyte-macrophage colony-stimulating factor. Proc
Natl Acad Sci U S A 83:3101, 1986.
to enhanced aggregation responses to classic platelet agonists. Still 14. Broudy VC, Lin NL, Kaushansky K: Thrombopoietin (c-mpl ligand) acts synergistically
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other researchers have hypothesized that an alternate form of the EPO with erythropoietin, stem cell factor, and IL-11 to enhance murine megakaryocyte col-
receptor, made up of the classic EPO receptor and the β subunit of the ony growth and increases megakaryocyte ploidy in vitro. Blood 85:1719, 1995.
GM-CSF, IL-3, and IL-5 receptors, is displayed on vascular endothelial 15. 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.
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cells, and in that site could mediate enhanced vascular events. Thus, Blood 85:2720, 1995.
given the widespread use of ESAs in patients with anemia caused by 16. Kuter DJ: The physiology of platelet production. Stem Cells 14(Suppl 1):88, 1996.
cancer, kidney failure, myelodysplastic syndromes, and many other con- 17. Cockrell EM, Gorman J, Hord JD, et al: Endogenous interleukin-11 (IL-11) levels in
ditions, verifying these hypotheses or disproving them and establishing newly diagnosed children with acquired severe aplastic anemia (SAA). Cytokine 28:55,
2004.
new ones appears to be important and a field ripe for new discovery. 18. Qian S, Fu F, Li W, et al: Primary role of the liver in thrombopoietin production shown
by tissue-specific knockout. Blood 92:2189, 1998.
19. Fielder PJ, Hass P, Nagel M, et al: Human platelets as a model for the binding and degra-
CLINICAL FEATURES OF REACTIVE 20. Sungaran R, Markovic B, Chong BH: Localization and regulation of thrombopoietin
dation of thrombopoietin. Blood 89:2782, 1997.
THROMBOCYTOSIS mRNA expression in human kidney, liver, bone marrow and spleen using in situ hybrid-
ization. Blood 89:101, 1997.
21. McIntosh B, Kaushansky K: Marrow stromal production of thrombopoietin is regulated by
The clinical features of secondary thrombocytosis are almost always transcriptional mechanisms in response to platelet products. Exp Hematol 36:799, 2008.
a result of the underlying disorder provoking the reaction, usually an 22. Grozovsky R, Begonja AJ, Liu K, et al: The Ashwell-Morell receptor regulates hepatic
inflammatory condition or iron-deficiency anemia. It is also highly thrombopoietin production via JAK2-STAT3 signaling. Nat Med 21:47, 2015.
unusual for the thrombocytosis per se to provoke any untoward symp- 23. Griesshammer M, Bangerter M, Sauer T, et al: Aetiology and clinical significance of
toms. Although pathologic thrombosis is a major feature of primary thrombocytosis: Analysis of 732 patients with an elevated platelet count. J Intern Med
245:295, 1999.
thrombocythemia (Chap. 85), it is virtually absent in reactive thrombo- 24. Kishimoto T: The biology of interleukin-6. Blood 74:1, 1989.
cytosis, unless provoked by other features of the underlying condition 25. Asano S, Okano A, Ozawa K, et al: In vivo effects of recombinant human interleukin 6 in
primates: Stimulated production of platelets. Blood 75:1602, 1990.
(e.g., vasculitis) or completely unrelated conditions in the patient (e.g., 26. Ishibashi T, Kimura H, Shikama Y, et al: Interleukin-6 is a potent thrombopoietic factor
atherosclerotic disease). Whether this is because patients with reac- in vivo in mice. Blood 74:1241, 1989.
tive thrombocytosis do not have as high platelet counts, on average, as 27. Naka T, Nishimoto N, Kishimoto T: The paradigm of IL-6: From basic science to medi-
cine. Arthritis Res 4(Suppl 3):S233, 2002.
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patients with primary thrombocythemia ; or because they have smaller 28. Sehgal PB: Regulation of IL6 gene expression. Res Immunol 143:724, 1992.
mean platelet volumes ; or are a result of the activated signaling char- 29. Gainsford T, Nandurkar H, Metcalf D, et al: The residual megakaryocyte and platelet
56
acteristic of the platelets or other blood cells in patients with myelopro- production in c-Mpl-deficient mice is not dependent on the actions of interleukin-6,
liferative diseases; or because of the presence of a mutant Janus kinase interleukin-11, or leukemia inhibitory factor. Blood 95: 528, 2000.
(JAK) 2, or a constitutively active TPO receptor, is uncertain at this 30. Wolber EM, Fandrey J, Frackowski U, Jelkmann W: Hepatic thrombopoietin mRNA is
57
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increased in acute inflammation. Thromb Haemost 86:1421, 2001.
time. Nevertheless, because vascular complications of reactive throm- 31. Heits F, Stahl M, Ludwig D, et al: Elevated serum thrombopoietin and interleukin-6 con-
bocytosis are so unlikely to be a consequence of the elevated platelet centrations in thrombocytosis associated with inflammatory bowel disease. J Interferon
Cytokine Res 19:757, 1999.
count, treatment of the thrombocytosis per se is not recommended in 32. Ishiguro A, Suzuki Y, Mito M, et al: Elevation of serum thrombopoietin precedes throm-
reactive thrombocytosis except in very unusual circumstances. bocytosis in acute infections. Br J Haematol 116:612, 2002.
33. Ceresa IF, Noris P, Ambaglio C, et al: Thrombopoietin is not uniquely responsible for
thrombocytosis in inflammatory disorders. Platelets 18:579, 2007.
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