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340 Part IV Disorders of Hematopoietic Cell Development

Liver (hepatocytes)
Kidney ? Bloodstream
Binding to platelets

Platelet flow
TPO flow Spleen
TPO protein
Platelet
c-MPL
production
Multipotential
progenitors

Megakaryocytopoiesis
Bone marrow
Fig. 28.7 REGULATION OF PLATELET COUNT BY THROMBOPOIETIN: THE “SPONGE”
MODEL. TPO is secreted at a constitutive rate primarily from liver, and perhaps other sources such as the
kidney, into the circulation. There it binds with high affinity to TPO receptors (c-Mpl) present on the surface
of platelets. The TPO is then internalized by the platelets and degraded. Free TPO (i.e., TPO not bound to
platelets) enters the bone marrow and stimulates megakaryocytopoiesis. Thus in the presence of high platelet
counts, little free TPO is available to stimulate megakaryocytopoiesis. Conversely, low platelet numbers lead
to increased free TPO and active megakaryocytopoiesis. The net result is preservation of total platelet mass.

efficiency, and decreased with mutations leading to constitutive TPO radiolabeled TPO and degrade it. Fourth, TPO levels are low to
receptor activation. In 2013, somatic mutations involving exon 9 of intermediate in normal individuals and in those with idiopathic
the calreticulin (CALR) gene were identified in a large number of thrombocytopenic purpura (where the bound TPO is destroyed along
non-JAK2 mutated myeloproliferative neoplasms (67−88% of cases), with the platelets). However, following chemotherapy, or in individu-
17
particularly ET and primary myelofibrosis. Theses mutations result als with aplastic anemia, levels are markedly elevated.
in the generation of an altered protein containing a novel carboxyl Although the model described above likely explains the predomi-
terminal domain. Recently, three groups have shown that the mutant nant basal regulation of platelet number by the TPO-TPO receptor
CALR leads to myeloproliferative neoplasms by activating C-Mpl and signaling system, overlying inducible mechanisms also probably exist.
its downstream pathways (Chapters 69 and 70). It has been shown that the TPO gene is transcriptionally activated in
BM stroma and spleen during times of thrombocytopenia, although
the degree to which this may contribute to total TPO levels is
Regulation of Platelet Mass by Thrombopoietin uncertain. In addition, IL-6 mediates upregulation of hepatic TPO
mRNA transcripts in inflammation-related thrombocytosis. Recent
Platelet counts are typically held at a relatively fixed level in humans, work shows that binding of desialylated platelets to the hepatic
3
ranging from 150,000 to 400,000/mm . The maintenance of platelet Ashwell-Morell receptor triggers TPO gene transcription and protein
number by the TPO-TPO receptor system involves an unusual production via a JAK 2/STAT3 pathway, linking platelet turnover
homeostatic mechanism among hematopoietic cytokine-mediated directly to TPO production. 18
regulation. This is sometimes referred to as the “sponge” model (Fig.
28.7). Unlike other cytokines, TPO is secreted predominantly in a
constitutive manner, mostly from the liver and kidney. High affinity Additional Cytokines Involved in Megakaryocytopoiesis
TPO receptors present on the platelet surface bind free TPO and
internalize it, where it is degraded. Therefore, when platelet counts Although TPO is the major cytokine regulating megakaryocytopoi-
are low, less TPO is removed, and more is available to stimulate esis, other cytokines have been shown to be active in vitro, particularly
megakaryocytopoiesis in the BM. Conversely, when platelet counts during earlier stages of megakaryocyte development. These include
rise above a given set point, they act as a “sink” for TPO, binding SCF, IL-3, IL-6, IL-11, LIF, G-CSF, and EPO. None of these factors
and destroying it before it can stimulate megakaryocytopoiesis in the are megakaryocyte-specific, but act as synergistic coregulators with
BM. Thus total platelet mass is preserved, rather than absolute TPO. Only SCF and TPO have been shown to affect megakaryocyte
platelet number. This may explain the mild to moderate thrombocy- development and platelet production in vivo using genetic ablation
topenia seen in certain disorders associated with large platelets, such experiments in mice. No effects were seen with knockout of IL-3,
as Bernard-Soulier syndrome. IL-6, IL-11 receptor, or LIF.
Several pieces of evidence support this model. First, it has been
known for over 40 years that the peripheral blood platelet count
varies inversely with plasma TPO activity. Second, TPO receptor Therapeutic Cytokine Stimulation of
−/−
deficient mice (c-Mpl ) have elevated levels of circulating TPO, and Megakaryocytopoiesis
this is reduced when the mice are transfused with washed platelets
from normal mice. Third, in contrast to platelets from TPO Since the identification of TPO as a major activator of mega-
receptor–deficient mice, platelets from normal mice bind purified karyocyte growth and maturation, there has been considerable