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Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003.

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Holland-Frei Cancer Medicine. 6th edition.

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, MD.

The humoral basis of megakaryocyte and platelet production has been more enigmatic than that of other lineages. Factors which have now been implicated in at least some aspects of thrombocyte development include IL-3, IL-6, IL-9, IL-11, G-CSF, GM-CSF, SCF, leukemia inhibiting factor, and TPO. The latter molecule is believed to be of paramount importance in the physiologic regulation of platelet production. Unfortunately, however, compared with the striking effects of the granulopoietic factors in neutropenic patients, use of the thrombopoietic molecules in the clinic setting has met with less success. Of interest, a random-peptide-screening approach has recently permitted the identification of a 29-amino acid peptide that promotes megakaryocyte growth and platelet formation by stimulating the TPO receptor (Table 58-8).39

Table 58-8. Thrombopoietin.

Table 58-8


TPO structure

Human TPO is a polypeptide of 353 amino acids, including a 21-amino acid secretory leader sequence.40 The protein consists of two domains. The amino-terminal 155 residues have 21% sequence identity and 46% overall sequence similarity with human EPO. It is this domain that binds to the TPO receptor-c-mpl. In contrast, the carboxyl-terminal 177 residues have no homology to any known proteins. Although deletion of the latter region does not affect the activity of the protein in vitro, it substantially reduces its bioavailability after parenteral administration.41

TPO production

The liver, kidneys, smooth muscle, and marrow are the most prominent among the sites expressing TPO (see Table 58-8).41,42 Plasma concentrations of TPO vary inversely with the platelet count consonant with current evidence which indicates that platelets themselves regulate TPO concentrations in plasma. Mature platelets remove TPO from solution and, in thrombocytopenic animals, plasma TPO concentrations fall soon after platelet transfusion and rise only after the platelet count drops again.

Biologic properties of TPO

That TPO participates in hematopoiesis in general, in addition to thrombopoiesis, is supported by experiments demonstrating that genetic elimination of TPO or its receptor causes a 65% to 95% reduction in the numbers of transplantable stem cells. The survival of TPO in the circulation is longer than that of other hematopoietic growth factors (half-life = 30 hours). Consequently, when TPO is administered to animals or humans, the platelet count begins to increase after 3 to 5 days, depending on the dose and the species. In animals treated with nonablative doses of chemotherapeutic agents, radiation, or both, TPO results in higher nadir platelet counts and accelerates platelet recovery by 7 to 14 days It also has favorable effects on the recovery of erythrocytes and granulocytes.41

TPO and human disease

High serum levels of TPO have been found in patients with autosomal dominant hereditary thrombocythemia.43 Overproduction has been attributed to a splice donor mutation in the gene for TPO, which leads to a shortened 5′-untranslated region that is more efficiently translated than its normal counterpart.43 Because platelets themselves regulate the level of circulating TPO, high levels of TPO are also found in patients with bone marrow failure states. Homozygous elimination of c-mpl (TPO receptor) results in congenital amegakaryocytic thrombocytopenia.

TPO in the clinic

Two forms of TPO have entered clinical trials.41,42 These forms are termed (1) TPO (the full-length polypeptide) and (2) polyethylene glycol- (PEG-) conjugated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) (a truncated protein containing only the receptor-binding region chemically modified by the addition of PEG).

Because its biologic action is prolonged (as a result of its action on both primitive and mature hematopoietic cells and its slow clearance from plasma), parenteral administration of TPO for 7 to 10 days results in increased platelet production 6 to 16 days later.44 Results of clinical trials of PEG-rHuMGDF or recombinant human TPO in patients with cancer who were receiving chemotherapy, albeit with regimens that produce only moderate thrombocytopenia, suggest that platelet counts return to baseline significantly faster and the nadir platelet counts are higher.45,46 However, the effectiveness of these molecules in accelerating platelet recovery after myeloablative therapy has not been impressive.47 Furthermore, in patients with delayed platelet recovery after peripheral-blood stem-cell or bone marrow transplantation, recombinant human TPO did not significantly raise platelet counts in most patients.48 This study was, however, compromised by the limited number of doses given to each patient (one to five injections per month). Because of the finding that platelets can remove TPO from the circulation, an issue that should be considered in future trials is the possibility that platelet transfusions may dampen the recovery of megakaryocytes after myelosuppressive therapy and may blunt response to exogenously administered TPO. Therefore, early treatment with this molecule may be more beneficial than treatment later during hematopoietic recovery.41 Finally, TPO can result in multilineage mobilization of peripheral blood progenitor cells. The kinetics of progenitor release differs from that after G-CSF. Following G-CSF peripheral blood progenitors increase almost immediately, peak at day 5 to 6, and decrease with G-CSF cessation. In contrast, Peg-MGDF resulted in a late and sustained increase in progenitors, with levels first detected on day 8, and climbing on day 12, despite cytokine discontinuation.50

PEG-rHuMGDF has also been given to normal subjects in a single dose of 3 mg per kilogram of body weight. Administration of this molecule increased the yield of platelets by a factor of nearly 4 and was associated with a quadrupling of platelet counts in the recipients of the apheresed platelets.49 Even so, because of the development of neutralizing antibodies and subsequent thrombocytopenia in some patients, clinical studies with the PEGylated molecule have been terminated.

In conclusion, the issue of whether clinically relevant thrombocytopenia can be ameliorated after chemotherapy of solid tumors may be moot, since severe thrombocytopenia is not commonly encountered in this setting. In leukemias and after transplantation, future studies will need to address dose-timing issues. Finally, since thrombocytopenia is a major cause of morbidity and mortality in bone marrow failure states (myelodysplasia, aplastic anemia, graft failure), investigations of TPO in these illnesses are urgently needed.

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Copyright © 2003, BC Decker Inc.
Bookshelf ID: NBK12518


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