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CHAPTER 119 ligand for the megakaryocytic growth factor receptor c-Mpl, is the
major humoral regulator of megakaryocyte survival, growth, and
REACTIVE development, although, curiously, it does not stimulate the final step
in thrombopoiesis: platelet release from megakaryocyte proplatelet pro-
THROMBOCYTOSIS cesses. Although TPO supports the entire continuum of megakaryocyte
development from stem cell to mature megakaryocyte, other cytokines
3
5,6
including interleukin (IL)-6, IL-3, IL-11, leukemia inhibitory factor
7
4
10
8,9
(LIF), fibroblast growth factor (FGF)-4, stromal cell-derived factor
12
Kenneth Kaushansky (SDF)-1, 10,11 interferon (IFN)-γ, and granulocyte-macrophage colony-
13
stimulating factor (GM-CSF) also affect thrombopoiesis, both in vitro
and in vivo. Many of these cytokines act in synergy with other cytok-
ines, including TPO. 11,12,14
SUMMARY The regulation of thrombopoiesis occurs primarily by humoral
mechanisms, with the levels of TPO inversely related to platelet
The three major pathophysiologic causes of thrombocytosis are (1) clonal, counts. 15,16 In contrast, other cytokines shown to affect megakaryopoie-
17
including essential (or primary) thrombocythemia and other myeloprolifera- sis in vitro do not vary with platelet levels. Despite these important
tive neoplasms; (2) familial, including rare cases of nonclonal myeloprolifera- insights, the regulation of TPO blood levels is complex, and incom-
tion resulting from thrombopoietin and thrombopoietin receptor mutations; pletely understood. The liver produces approximately half of all the
and (3) reactive, in which thrombocytosis occurs secondary to a variety of hormone that circulates, based on platelet production in liver specific
18
acute and chronic clinical conditions. This chapter deals with the latter causes knockout mice. However, platelet levels do not affect hepatic TPO
production; instead, platelets themselves have an important role in reg-
of thrombocytosis.
ulating plasma levels, as their receptors for TPO (c-mpl) remove it from
plasma. Thus, as the platelet count drops, increased free plasma TPO
19
levels stimulate megakaryopoiesis; conversely, as the platelet count rises,
depletion of free plasma TPO decreases platelet production. This modu-
The upper limit of the normal platelet count in most clinical labora- latory mechanism results in the steady-state level of platelet production.
tories is between 350,000/μL (350 × 10 /L) and 450,000/μL (450 × However, marrow stromal cells also produce TPO, and are responsive
9
20
10 /L). In a sample of 10,000 healthy individuals 18 to 65 years of age, to platelet products which serve to down-modulate expression of the
9
1 percent had platelet counts greater than 400,000/μL. Only in eight hormone. A third mechanism by which platelets regulate TPO levels
21
of these 99 individuals was thrombocytosis confirmed 6 months to 1 occurs through the Ashwell-Morell hepatocyte receptor, whereby their
year later. Nevertheless, it is clear that thrombocytosis is a feature of binding of senescent platelets leads to stimulation of hepatocyte signal-
1
several important disorders, including cancer, and that even a high ing pathways and subsequent expression of TPO. 22
normal platelet count is associated with morbidity and mortality. In a
longitudinal study of healthy Norwegian men, a platelet count in the
top quartile of the normal range (from 275 × 10 /L to 350 × 10 /L) was
9
9
associated with a twofold increase in cardiovascular mortality over a ENHANCED THROMBOPOIESIS
12-year followup. Whether the platelet count per se, or an underlying IN PATHOLOGIC STATES
2
inflammatory condition resulting in both thrombocytosis and acceler-
ated atherogenesis is responsible for these observations is not certain. THROMBOCYTOSIS IN INFLAMMATORY
The causes of thrombocytosis in which the platelet count exceeds the CONDITIONS
upper limit can be broadly categorized as (1) clonal, including essential
thrombocythemia and other myeloproliferative neoplasms, (2) familial, Inflammation is the most common cause of secondary thrombocytosis.
and (3) reactive, or secondary (see Chap. 85, Table 85–1). This chapter In one survey, thrombocytosis was believed secondary to one or more
focuses on the causes and molecular mechanisms that underlie reactive, inflammatory conditions in nearly 80 percent of all patients with an ele-
or secondary, thrombocytosis; clonal and familial thrombocytosis are vated platelet count. Table 119–1 lists the clinical conditions associated
discussed in detail in Chap. 85. with reactive thrombocytosis. The most common diagnoses in such
patients are inflammatory bowel disease and rheumatoid arthritis,
23
although most conditions in which the erythrocyte sedimentation rate
NORMAL THROMBOPOIESIS or C-reactive protein is elevated have been reported to cause secondary
thrombocytosis. Although several cytokines and lymphokines are ele-
The regulation of platelet production is discussed extensively in Chap. 111,
but a brief discussion here provides the appropriate background for vated in the blood of such patients, the most compelling evidence sug-
discussion of reactive thrombocytosis. Thrombopoietin (TPO), the gests that IL-6 and IFN-γ are responsible for the thrombocytosis seen in
patients with inflammation.
Interleukin-6
IL-6 was cloned by several groups of investigators using a number of
Acronyms and Abbreviations: EPO, erythropoietin; ESA, erythropoiesis- distinct assays, including antiviral activity, myeloma cell growth, hepa-
stimulating agent; FGF, fibroblast growth factor; GM-CSF, granulocyte- tocyte growth, and immunoglobulin secretion. The recombinant pro-
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macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; JAK, tein was later found to affect megakaryocyte growth and differentiation,
Janus kinase; LIF, leukemia inhibitory factor; MHC, major histocompati bility both in vitro and in vivo. 4,25,26 The IL-6 gene is present on the short arm
complex; NF, nuclear factor; SDF, stromal cell-derived factor; STAT, signal of human chromosome 7, and encodes a 26-kDa polypeptide produced
transducer and activator of transcription; TPO, thrombopoietin. in almost all tissues from T cells, fibroblasts, macrophages, and stromal
cells, and is a key regulator of the inflammatory response. 27

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