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

TABLE 119–1. Major Causes of Thrombocytosis complex (MHC) class I and class II molecules enhancing antigen rec-
ognition responses, and inhibition of proliferative responses in stem
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A. Reactive (secondary) thrombocytosis cells and erythroid progenitors. 39,40 These latter effects accounts for the
1. Transient reactive processes association of IFN-γ and aplastic anemia are discussed more fully in
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2. Acute blood loss Chap. 35. However, in stark contrast to the inhibitory effects of IFN-γ
3. Recovery (“rebound”) from thrombocytopenia on erythropoiesis, the cytokine stimulates megakaryocyte growth and
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4. Acute infection, inflammation differentiation. This is likely related to its stimulation of signal trans-
ducer and activator of transcription (STAT)-1 in megakaryocytes, as
5. Response to exercise transgenic expression of the transcription factor mimics the effect of the
B. Sustained processes cytokine, and corrects the thrombocytopenia seen in a genetic model
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1. Iron deficiency system. These findings argue that IFN-γ also contributes to the throm-
2. Postsplenectomy, asplenic states bocytosis seen in inflammatory states in humans.
Notwithstanding the above two mechanisms, patients with inflam-
3. Malignancies matory conditions and thrombocytosis might have an additional cause
4. Chronic inflammatory and infectious diseases (inflam- of the elevated platelet count. The evaluation of iron deficiency is often
matory bowel disease, rheumatoid arteritis, tuberculosis, difficult in patients with inflammation, as the most reliable indicator of
chronic pneumonitis) tissue iron stores, serum ferritin, is an acute-phase reactant, possibly
5. Response to drugs (vincristine, epinephrine, all-trans-retinoic obscuring a diagnosis of iron deficiency in patients with an inflamma-
acid, some antibiotics, cytokines, and growth factors) tory condition. In a recent study of patients with inflammatory bowel
6. Hemolytic anemia disease, thrombocytosis was eliminated in half of the subjects by the
administration or iron. 44

IL-6 production is dependent on the presence of IL-1 and tumor THROMBOCYTOSIS CAUSED BY
necrosis factor (TNF)-α, cytokines produced by lymphocytes and IRON DEFICIENCY
monocytes in response to phagocytosis of microorganisms, the bind-
ing of immune complexes, and several other innate immune stimuli. Although most patients with inflammation-related thrombocytosis dis-
IL-6 production is regulated primarily by transcriptional enhancement; play increased production of the hormone, TPO levels in patients with
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regulatory elements responsible for IL-6 promoter activation include iron deficiency and thrombocytosis are not elevated. In contrast, ery-
nuclear factor-κB (NFκB), adapter protein (AP)-1, CCAAT/enhancer thropoietin (EPO) levels are elevated in patients with iron-deficiency
binding protein (C/EBP) α and C/EBPβ. anemia, and are thought by some to be the responsible for the throm-
Although not critical for steady-state thrombopoiesis, as the com- bocytosis seen in iron deficiency, at least in part. Consistent with this
bined genetic elimination of c-mpl and the signaling component of the hypothesis, administration of EPO to animals and humans leads to a
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IL-6 receptor (gp130) produces no more severe thrombocytopenia modest increase in the platelet count. Although some have suggested
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than elimination of c-mpl alone, IL-6 contributes to inflammatory that this is a result of cross-reactivity of EPO on the TPO receptor,
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thrombopoiesis, primarily by stimulating the hepatic production of direct EPO- and TPO-receptor binding studies refute this hypothesis.
TPO. Most studies report that patients with inflammation display an Rather, megakaryocytic progenitors display EPO receptors, and their
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increased level of TPO, 31,32 but TPO is not the only cytokine responsi- binding of the hormone leads to many of the same intracellular bio-
ble for this effect, especially when corrected for the thrombocytosis, chemical signals as induced by TPO (Chap. 17).
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which would normally act to reduce levels of the hormone. Stimulation However, several lines of evidence indicate that pathophysiologic
of hepatocytes with IL-6 results in enhanced production of TPO mRNA mechanisms other than anemia must be responsible, at least in part, for
and protein. 34,35 the thrombocytosis seen in patients with iron deficiency. For example,
many patients with iron-deficiency anemia do not have thrombocytosis.
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Moreover, EPO levels are elevated in nearly all types of anemia, but iron
INTERFERON-γ deficiency is the only type of anemia that is regularly associated with
A second inflammatory cytokine that contributes to inflammatory thrombocytosis, other than the anemia of chronic inflammation, in which
thrombopoiesis is IFN-γ. The interferons are proteins first defined by the inflammatory state that causes the anemia by modulation of hepcidin
their ability to induce an antiviral state in mammalian cells. Biochem- levels (Chap. 37) also causes thrombocytosis (as discussed in “Thrombo-
ical fractionation revealed three classes of interferons: IFN-α, a family cytosis in Inflammatory Conditions” above). Thus, although several lines
of 17 distinct but highly homologous molecules; IFN-β, a single mole- of evidence suggest that enhanced levels of EPO as a consequence of the
cule more distantly related to the various isoforms of IFN-α; and IFN-γ, anemia associated with iron deficiency contribute to this form of reactive
a unique molecule that shares functional properties but not structure thrombocytosis, elevated EPO levels cannot completely account for it.
with the others. IFN-γ exerts the most profound hematologic effects
of the three classes of protein, including direct suppression of ery- THERAPEUTIC ERYTHROPOIETIN AND
throid colony-forming cell growth and the activation of macrophages
to secrete a number of inflammatory cytokines; several comprehensive ENHANCED CARDIOVASCULAR MORTALITY
reviews on IFN-γ have been published. 36,37 Several reports have linked the use of large doses of EPO or other
IFN-γ is produced by activated T lymphocytes and natural killer erythropoiesis-stimulating agents (ESAs) to enhanced cardiovascular
(NK) cells in response to T-cell antigen crosslinking and in response to mortality, and in patients with renal insufficiency, to progression to
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stimulation by the inflammatory mediators TNF-α, IL-12, and IL-15. dialysis in patients with renal insufficiency, although not all studies
Prominent hematologic effects include activation of macrophages to concur with these landmark results. Although also discussed in Chap.
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assume an inflammatory phenotype (e.g., secretion of TNF-α and 18, this finding is presented here because evidence is accumulating that
enhanced tumor cell killing), upregulation of major histocompatibility the rapid expansion of erythropoiesis caused by pharmacologic levels of

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