Endogenous thrombopoietin levels during the clinical management ofacute myeloid leukaemia

CAN GONEN1, IBRAHIM C. HAZNEDAROGLU2, SALIH AKSU2, EBRU KOCA2,

HAKAN GOKER2, YAHYA BUYUKAS� _IIK2, NILGUN SAY_IINALP2, OSMAN OZCEBE2, &

SEMRA DUNDAR2

1Department of Internal Medicine, Hacettepe University School of Medicine, Sihhiye 06100, Ankara, Turkey, and2Department of Hematology, Hacettepe University School of Medicine, Sihhiye, 06100, Ankara, Turkey

AbstractThrombocytopenia represents a major problem in the management of acute myeloid leukaemia (AML). The data regardingthe alterations of endogenous thrombopoietin (TPO) regulation during the clinical course of AML are limited. The aimof this study was to investigate endogenous TPO dynamics in association with platelets during the clinical course of AML.We serially measured both TPO and platelets concurrently over the entire treatment period of newly diagnosed patientsreceiving both remission induction and consolidation chemotherapies. The median concentration of TPO in AML patients atthe initial diagnosis was 469.71pg/ml and increased significantly during the aplastic period due to remission inductionchemotherapy (median: 1085.33 pg/ml) but then decreased to a level (median: 45.26 pg/ml) encountered in the healthycontrol subjects (median: 56.90 pg/ml). In the cytopenic period due to consolidation treatment, TPO level again increasedsignificantly to a high level (median: 891.38 pg/ml) during the platelet nadir, but decreased toward normal (median:100.75 pg/ml) after the thrombocytopenic period had elapsed. In conclusion, endogenous TPO levels exhibit an inversefluctuation in relation to platelet counts during the clinical course of AML. Pharmacological stimulation of thrombopoiesisin AML with novel molecules, including the recombinant thrombopoietins and the small peptide agonists, should be basedon a critical administration strategy that must consider the endogenous levels of TPO. TPO levels in distinct AML diseasestates may explain the unsuccessful recombinant TPO trials and could help to design better strategies for ‘pharmacologicalstimulation of thrombopoiesis’ in AML.

Keywords: Acute myeloid leukaemia, endogenous, thrombopoietin, megakaryopoiesis

Introduction

Severe chemotherapy-induced thrombocytopenia is

a major cause of morbidity and mortality in patients

with acute myeloid leukaemia (AML) receiving

intensive chemotherapy [1]. Currently, prophylactic

platelet transfusions are the most effective manage-

ment for the prevention of severe haemorrhage

and thrombocytopenia in those patients. However,

this approach is far less than ideal because of the

refractoriness to platelet transfusions due to anti-

platelet antibody formation and increased risk for

transfusion complications [2]. Therefore, identifying

the mechanisms of megakaryothrombopoiesis and the

effects of endogenous or recombinant growth factors

stimulating this pathway needs further evaluation.

Thrombopoietin (TPO) is the primary regulator

of megakaryopoiesis and platelet production [3].

TPO is produced constitutively in the liver and

kidney, circulates in the bloodstream, and is delivered

to the bone marrow, where it stimulates all stages

of megakaryothrombopoiesis. After binding to its

receptor c-mpl, TPO initiates a complex series of

signalling events, resulting in proliferation and

differentiation of megakaryocytic progenitors [4].

Endogenous TPO concentrations are determined

mainly by the platelet/megakaryocyte mass through

c-mpl receptor-mediated uptake and catabolism [5].

The identification and cloning of TPO in 1994

have led to the development of recombinant forms of

the molecule [4,6]. Although the initial trials with

exogenous TPO administration in patients with solid

tumours were encouraging [7,8], three large trials in

acute myeloid leukaemia (AML) patients were

unsuccessful with regard to platelet transfusion

requirements and the duration of thrombocytopenia

after remission induction or consolidation che-

motherapies [9–12].

Correspondence: Can Gonen, Il|ca Mahallesi, Tur Sokak, Dokuz Eylul Sitesi, No: 8/13, Narlidere TR-35320, _IIzmir, Turkey. Tel: þ90-232-2387777.

E-mail: drcgnn@yahoo.com

Platelets, February 2005; 16(1): 31–37

ISSN 0953–7104 print/ISSN 1369–1635 � 2005 Taylor & Francis Ltd

DOI: 10.1080/09537100412331272578

Plat

elet

s D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Q

UT

Que

ensl

and

Uni

vers

ity o

f T

ech

on 1

0/31

/14

For

pers

onal

use

onl

y.

Although endogenous thrombopoietin levels have

been investigated in many different disease condi-

tions [13–15], the data regarding the endogenous

TPO level and its regulation in AML patients are

limited and largely depends on small sized case

series [16,17]. The aim of this study is to assess cir-

culating TPO concentrations during the clinical

management of AML. In order to develop optimal

schedules for exogenous TPO administration, it is

important to consider endogenous TPO response

characteristics in AML. TPO levels in distinct AML

disease states may explain the unsuccessful TPO trials

and could help to design better strategies for ‘‘phar-

macological thrombopoiesis stimulation’’ in AML.

Patients and methods

Patients and blood sampling

The study included 24 leukaemic patients (19

patients with AML, 2 patients with biphenotypic

leukaemia, 3 patients with chronic myeloid leukae-

mia in acute myelogenous transformation) and 27

healthy volunteers as the control group. The

characteristics of patients and healthy controls are

given in Table I. All leukaemia patients received

conventional remission induction chemotherapy

(idarubicin 12mg/m2, days 1–3 and arabinoside

100mg/m2, days 1–7) and, by the time remission

was achieved high dose arabinoside (3 g/m2 every

12 h on days 1, 3, 5) as a consolidation regimen.

Patients with renal failure (creatinine higher than

125 mmol/L) and hepatic injury (alanine aminotrans-

ferase 1.5 times the upper limit of normal) were

excluded from the study, because TPO is constitu-

tively produced by these organs. Peripheral blood

samples were collected sequentially from patients

during their initial diagnosis before remission induc-

tion chemotherapy, in the aplasic period due to

remission induction, before the consolidation ther-

apy while they were in remission, in the thrombocy-

topenic period due to consolidation chemotherapy

and after the cytopenic period while peripheral blood

counts began to return toward normal values.

Prophylactic platelet transfusions were given

when the morning platelet count was <20�109/l or

when clinically indicated (haemorrhage or before

an invasive intervention) irrespective of the platelet

count. Because platelet transfusions significantly

affect the endogenous levels of TPO, blood samples

were collected at least 12 h (but even more in most

of the thrombocytopenic subjects) elapsed since the

last platelet transfusion to exclude their possible effect

on TPO. The study protocol was approved by the

institutional review board of Hacettepe University

Medical School and all patients gave written

informed consent before the study.

Thrombopoietin assay

Plasma samples were collected in the morning after

8 h of fasting to avoid diurnal variations and stored

at �40�C until assayed. Plasma TPO concentrations

were measured with a commercial ELISA assay

(Quantikine, R&D Systems, Minneapolis, MN,

USA). Briefly, a murinemonoclonal antibody specific

for TPO was precoated on to a microplate. Assay

diluent composed of a buffered protein base with

preservative was added to each well. Standards and

samples were pipetted into wells and incubated for

3 h at 2–8�C. After aspiration and washing four times

with a buffer, monoclonal antibody against TPO

conjugated with horseradish peroxidase was added to

each well and incubated for 1 h at 2–8�C. Aspiration

and washing were repeated four times, and a mixture

of hydrogen peroxide and tetramethylbenzidine was

added to the wells and incubated for 30min at room

temperature. The reaction was stopped by the

addition of 2N sulphuric acid. The optical density

of each well was determined within 30min using a

microplate reader set at 450 nm. TPO concentrations

were extrapolated from a standard curve. The

minimal detectable level of TPO in this assay was

15 pg/mL.

Statistical analysis

Regarding the undetectable measurements (under

the minimal detectable level of the assay) encoun-

tered in the study, nonparametric tests were

preferred for the statistical analysis. The Friedman

two-way ANOVA test was used for the repeated

TPO measurements. Statistically significant differ-

ences were tested further by the Wilcoxon signed

rank test for post-hoc pairwise comparisons between

the measurement periods. For comparison between

healthy controls and patients, the Mann–Whitney

U-test was used. P values below 0.05 were consid-

ered statistically significant. Results are expressed as

themedian and interquartile range (IQR).Correlation

between variables was tested by Spearman correla-

Table I. Essential characteristics of the study groups

Patient group Control group P

Age

Mean�SD 48.8� 15.9 44.2�18.4 NS

Minimum–Maximum 19–90 19–89

Gender

Male 12 17 NS

Female 12 10 NS

AML class (FAB)

M1 1

M2 14

M4 3

M5 1

CML Blastic Tx. 3

Biphenotypic 2

Abbreviations: AML, acute myeloid leukemia; CML Blastic Tx,chronic myeloid leukaemia in acute myelogenous transformation;FAB, French–American–British; NS, nonsignificant.

32 C. Gonen et al.

Plat

elet

s D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Q

UT

Que

ensl

and

Uni

vers

ity o

f T

ech

on 1

0/31

/14

For

pers

onal

use

onl

y.

tion analysis. The Statistical Package for Social

Sciences (SPSS), version 10.0 for Windows, was

used to analyse the data.

Results

There was no significant difference regarding the

age and gender distribution between the groups

(Table I).

Platelet counts

Platelet counts were significantly lower in the patient

group as compared to the normal control subjects

(median: 217.0; IQR: 46.5� 109/l), before (median:

39.0; IQR: 63.7� 109/l, P<0.05) and during remis-

sion induction chemotherapy (median: 14.0; IQR:

14.5� 109/l, P<0.05), but subsequently restored to

normal levels during complete remission (median:

244.0; IQR: 173.0� 109/l). Also platelet counts were

significantly lower during the consolidation therapy

(median: 17.0; IQR: 15.5� 109/l, P<0.05) as

compared to the healthy controls. After the con-

solidation therapy, thrombocyte level (median:

181.0; IQR: 127.5� 109/l, P>0.05) began to

increase, returning toward normal (Figure 1).

TPO levels

The median TPO level in the patient group during

diagnosis was 469.71 pg/ml (IQR: 586.16 pg/mL)

which increased significantly during remission

Figure 1. Changes in thrombopoietin levels and platelet counts during the clinical course of acute myeloid leukaemia. Dx, diagnosis; C/T,

consolidation therapy; RI, remission induction.

Endogenous thrombopoietin in Aml 33

Plat

elet

s D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Q

UT

Que

ensl

and

Uni

vers

ity o

f T

ech

on 1

0/31

/14

For

pers

onal

use

onl

y.

induction chemotherapy (1085.33 pg/mL, IQR:

1140.73 pg/mL, P<0.05) but then decreased to

normal levels obtained from healthy controls

(56.90 pg/mL, IQR: 20.50 pg/mL) during

complete remission (45.26 pg/mL, IQR: 94.05

pg/mL, P>0.05). In the cytopenic period due to

consolidation chemotherapy, TPO level again

increased significantly (891.38 pg/mL, IQR: 796.72

pg/mL, P<0.001) as compared to the pre-consolida-

tion remission period and subsequently decreased

(100.75 pg/mL, IQR: 129.87 pg/mL, P <0.05)

toward normal levels at end of the cytopenic period.

The median TPO level was significantly lower in

the remission period as compared to the values

obtained during remission induction chemotherapy

(P<0.001). Also TPO levels were significantly low

during the consolidation treatment as compared to

both pre- and post-consolidation periods (P<

0.001). The plasma TPO levels obtained during the

clinical management of AML and observed in the

control subjects are plotted in Figure 1.

Plasma levels of TPO in relation to the platelet counts

There was a negative correlation (r¼�0.731,

P<0.001) between the TPO levels and platelet

counts obtained from control subjects and from

AML patients during the consolidation therapy and

thereafter (Figure 2).

Endogenous TPO level and infectious complications

Patients with fever and proven infectious complica-

tions in the clinical course of AML are given in

Table II. All patients were receiving antimicrobial

treatment while blood sample collection. There was

no difference in endogenous TPO levels between

patients with or without fever and proven infectious

complications (P>0.05).

Discussion

In this study, plasma TPO concentrations were

significantly increased during the initial diagnosis of

AML (Figure 1). As endogenous TPO concentra-

tions are regulated mainly by TPO receptors,

through receptor-mediated uptake, internalization

and catabolism, located on the surface of platelets,

megakaryocytes and progenitor cells, all of those

cell populations must be interpreted for a decision.

Decrements in the megakaryocytic mass as occurring

in aplastic anemia, is associated with high TPO

Thrombopoietin Level (pg/mL)

300025002000150010005000

Pla

tele

t Cou

nt (

/µL)

400000

350000

300000

250000

200000

150000

100000

50000

0

Figure 2. Relation between platelet count (/mL) and endogenous thrombopoietin level (pg/mL).

Table II. Patients with fever and infection in the clinical course of AML*

Patients with fever

(group A)

Patient with proven

infection (group B)

Initial diagnosis 11 14

Cytopenic period due to remission induction chemotherapy 6 8

Remission/pre-consolidation period 0 1

Cytopenic period due to consolidation chemotherapy 5 10

Post-consolidation period 2 7

*All patients were receiving antimicrobial treatment. Patients with clinical findings and positive blood cultures involved in group B whetherthey have fever or not. In group A, antibiotic or antifungal treatment initiated empirically.

34 C. Gonen et al.

Plat

elet

s D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Q

UT

Que

ensl

and

Uni

vers

ity o

f T

ech

on 1

0/31

/14

For

pers

onal

use

onl

y.

concentrations. On the contrary, increments in the

megakaryocyte mass as in autoimmune thrombo-

cytopenic purpura, is usually with normal or slightly

increased TPO levels [18]. Strikingly elevated TPO

levels in our patients are likely due to decreased

platelet and megakaryocyte masses (resulting in

fewer TPO receptors) caused by the leukemic

infiltration of the bone marrow disrupting the

megakaryothrombocytopoiesis. Although several

studies demonstrated the presence of TPO receptors

in the blasts of AML patients [19–21] and a reduced

endogenous TPO level could be expected based on

those findings, our results suggest the opposite way.

In a recent study, TPO receptors were detected in

only 47% of 114 AML cases, with no proliferative

response to TPO in a considerable proportion (80%)

of TPO receptor-positive leukaemia cells [22].

Low levels of TPO receptor expression with struc-

tural and functional discordance could help to

explain the high TPO levels encountered in our study.

Likewise, TPO levels similar to our results were

reported by Hsu et al. [17] and high TPO concen-

tration can imply that blastic cells and TPO receptors

on these cells are not large enough to influence the

circulating level of TPO in AML patients.

Endogenous TPO level increased further in

response to thrombocytopenia during remission

induction chemotherapy in our study (Figure 1).

Myeloablative chemotherapy probably diminished

TPO receptor-positive cell population further by

decreasing both megakaryocytic lineage in the

marrow and the production of platelets from mega-

karyocytic progenitors. After the cytopenic period due

to remission induction chemotherapy has elapsed,

both platelet count and TPO levels returned to

normal levels in our AML patients. This figure

represents structure–function relationship of a

normal bone marrow (AML in remission) and a

healthy megakaryothrombopocytopoiesis (normal

platelet count, normal level of TPO). In another

study, Hsu et al. [17] postulated that circulating

TPO level remained persistently high after chemo-

therapy for a sufficient peripheral platelet population.

However, our results are in contrast to their findings

and represent physiologically functioning megakar-

yothrombocytopoiesis by the time remission is

achieved.

Whereas platelet count decreased with subsequent

consolidation chemotherapy, TPO response in-

creased concomitantly in our present study. This

inverse fluctuation in the TPO level in response to

the thrombocytopenic consolidation chemotherapy

was similar to the affects of haemotoxic drug

administration in lymphoma patients with no bone

marrow involvement [23]. After the consolidation

period, while platelet count began to return toward

normal, TPO level also began to decrease toward

normal in our patients. TPO levels remained high in

accordance with the platelet counts in the post-

consolidation period in our study. This may be due

to early blood sampling in the study population before

the patients’ thrombocyte counts reached to their

maximal levels after the cytopenic chemotherapy, and

the patients probably were still in the late thrombo-

cytopenic period.

Endogenous TPO levels might be influenced by

the broad cytokine response during infections in

patients with chemotherapy-induced cytopenia [24].

However, we did not find a statistically significant

difference in regarding the endogenous TPO levels

between patients with or without infection and fever

(Table II). Although, the main aim of our present

research was not to test the interactions of TPO and

cytokine dynamics during infection, several probable

explanations can be drawn for that complicated

issue. First, the aforementioned relationship between

TPO level and the cytokine response can be not so

strong that a significant difference can be shown.

Second, maximally stimulated endogenous TPO in

response to aplastic chemotherapy can impair further

increase in TPO levels. Third, a properly instituted

antimicrobial therapy as in our patient cohort, can

suppress the acute phase response limiting the high

TPO response.

Two recombinant thrombopoietins, recombinant

human thrombopoietin (rhTPO) and pegylated

recombinant human megakaryocyte growth and

development factor (PEG-rHuMGDF) have been

developed and evaluated in patients with AML.

Unfortunately, exogenous TPO administration have

failed to shorten the duration of severe thrombocy-

topenia or to reduce the need for platelet support

in either the induction or consolidation setting of

AML therapy. Archimbaud et al. randomised

AML patients to receive either 2.5 or 5 mg/kg per

day of PEG-rHuMGDF or placebo administered

subcutaneously 1 day after the last dose of che-

motherapy [10]. This ‘after the chemotherapy

regimen’ had no effect on median time to transfu-

sion-independent platelet recovery at any dose

schedule. Schiffer et al. used a similar study design

to evaluate the exogenous TPO administration [11].

Patients were randomised to receive placebo or

PEG-rHuMGDF in doses of either 2.5 or 5 mg/kgper day for a maximum duration of 28 days or until

the platelet count reached 50 000/mL. Again,

no beneficial effect was observed with ‘after the

chemotherapy regimen’ in this study, as in the pre-

vious report. In a very recent multicenter, rando-

mised, placebo-controlled, double blind study,

Geisssler et al. used a different schedule; ‘prior and

concurrent PEG-rHuMGDF regimen’ [12]. In this

study, patients in first remission from de novo AML

were randomised to receive either PEG-rHuMGDF

30 mg/kg per day as a single dose 7 days before the

consolidation chemotherapy (day �6), placebo as a

single dose on day �6, PEG-rHuMGDF 30 mg/kgadministered on day �6 followed by 10 mg/kg per

Endogenous thrombopoietin in Aml 35

Plat

elet

s D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Q

UT

Que

ensl

and

Uni

vers

ity o

f T

ech

on 1

0/31

/14

For

pers

onal

use

onl

y.

day on days �5 to day 6 (through consolidation and

including the day after chemotherapy) or placebo

administered on day �6 to day 6. However, there

were no significant differences in the number of days

of platelet transfusions between either intervention

or placebo groups. On the contrary, in patients

receiving PEG-rHuMGDF there was a trend

towards delayed haematopoietic reconstitution.

Twoexplanationscanbedrawnaccordingtoourresults

and the aforementioned exogenous TPO trials. First,

the number of progenitors responsible to exogenous

TPO in the bone marrow decreased to low levels

after intensive chemotherapy in patients with AML.

This finding is in contrast to solid tumour patients

where less myelotoxic regimens allow TPO respon-

sive progenitor cells to survive. Survival of TPO

responsive cells after less myelotoxic regimens in

solid tumour patients could be an explanation for the

observation that exogenous TPO administration

were able to promote reconstitution of megakaryo-

thrombopoiesis in clinical trials [7–9]. Second, a

high TPO response observed after the myeloablative

chemotherapies behaves as a maximum, and further

increasing the TPO pool do not offer additional

advantage, and can even be harmful [12]. Recently,

a detailed mathematical model of thrombopoiesis

has been put forward and validated in animal models

[25]. By modulating the inter-dosing interval accord-

ing to the megakaryothrombocytic lineage cell

kinetics, this model allows to administer exogenous

TPO in a smaller total dose without losing efficacy.

Although human validation of the mathematical

thrombopoiesis model has not been validated,

animal studies were encouraging in this area.

In conclusion, endogenous TPO levels show an

inverse fluctuation in relation to platelet counts

during the clinical management of AML. Both

the disease, itself, at the initial diagnosis and

myeloablative chemotherapy during the clinical

management disrupt bone marrow megakaryo-

thrombocytopoiesis and reduce circulating platelets.

Decrements in the megakaryocyte/platelet pool

leads to fewer TPO receptors for TPO binding.

This condition reduces TPO clearance. Therefore,

circulating TPO levels remain high. Inadequate

TPO responsive megakaryopoietic progenitor popu-

lation in the bone marrow further complicates the

growth response to TPO. Thus, a ‘high plasma

TPO-low TPO responsive cell state’ takes place.

Most of the clinical TPO researches [10,11]

‘improperly’ tried to administer (extra) exogenous

TPO at that unfavourable state. The results of those

trials were discouraging from the clinical point of

view. Newly developing efficient mathematical

models of thrombopoiesis [25] may be useful to

overcome the restrictions of clinical TPO use in

the future. Recombinant thrombopoietins and

small peptide agonists mimicking TPO could

be successful only when based on a well understood

and structured critical administration strategy that

considers endogenous levels of TPO during the

course and treatment of AML.

Acknowledgements

This work was supported by Hacettepe University

Scientific Research Foundation (No: 0202101024).

References

[1] Tornebohm E, Lockner D, Paul C. A retrospective analysis

of bleeding complications in 438 patients with acute

leukemia during the years 1972–1991. Eur J Haematol

1993;50:160–7.

[2] Schiffer CA. Diagnosis and management of refractoriness to

platelet transfusion. Blood Rev 2001;15:175–80.

[3] Kaushansky K. Thrombopoietin. New Engl J Med 1998;

339:746–54.

[4] Haznedaroglu _II C, Goker H, Turgut M, Buyukas� |k Y,

Benekli M. Thrombopoietin as a drug: biologic expectations,

clinical realities, and future directions. Clin Appl Thromb

Hemost 2002;8:193–212.

[5] 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. Blood 1995;85:2720–30.

[6] Linker C. Thrombopoietin in the treatment of acute myeloid

leukemia and in stem-cell transplantation. Semin Hematol

2000;37(Suppl. 4):35–40.

[7] Vadhan-Raj S, Murray LJ, Bueso-Ramos C, Patel S, Reddy

SP, Hoots WK, et al. Stimulation of megakaryocyte and

platelet production by a single dose of recombinant human

thrombopoietin in patients with cancer. Ann Intern Med

1997;126:673–81.

[8] Fanucchi M, Glaspy J, Crawford J, Garst J, Figlin R,

Sheridan W, et al. Effects of polyethylene glycol-conjugated

recombinant human megakaryocyte growth and develop-

ment factor on platelet counts after chemotherapy for lung

cancer. New Engl J Med 1997;336:404–9.

[9] Vadhan-Raj S, Verschraegen CF, Bueso-Ramos C,

Broxmeyer HE, Kudelka AP, Freedman RS et al.

Recombinant human thrombopoietin attenuates carboplatin

induced severe thrombocytopenia and the need for platelet

transfusions in patients with gynecologic cancer. Ann Intern

Med 2000;132:364–8.

[10] ArchimbaudE,OttmannOG,Yin JA,LechnerK,DombretH,

Sanz MA et al. A randomized, double-blind, placebo-

controlled study with pegylated recombinant human

megakaryocyte growth and development factor (PEG-

rHuMGDF) as an adjunct to chemotherapy for adults

with de novo acute myeloid leukemia. Blood 1999;94:

3694–701.

[11] Schiffer CA, Miller K, Larson RA, Amrein PC, Antin JH,

Zani VJ, et al. A double-blind, placebo-controlled trial of

pegylated recombinant human megakaryocyte growth and

development factor as an adjunct to induction and con-

solidation therapy for patients with acute myeloid leukemia.

Blood 2000;95:2530–5.

[12] Geissler K, Yin JA, Ganser A, Sanz MA, Szer J,

Raghavachar A, et al. Prior and concurrent administration

of recombinant human megakaryocyte growth and develop-

ment factor in patients receiving consolidation chemotherapy

for de novo acute myeloid leukaemia – a randomized,

placebo-controlled, double-blind safety and efficacy study.

Ann Hematol 2003;82:677–83.

[13] Kos� ar A, Haznedaroglu _IIC, Buyukas� |k Y, Ozcebe O,

Kirazl| S, Dundar S. Circulating thrombopoietin and

36 C. Gonen et al.

Plat

elet

s D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Q

UT

Que

ensl

and

Uni

vers

ity o

f T

ech

on 1

0/31

/14

For

pers

onal

use

onl

y.

interleukin-6 in newly diagnosed autoimmune versus aplastic

thrombocytopenia. Haematologica 1998;83:1055–6.

[14] Ertenli _II, Kiraz S, Erturk H, Haznedaroglu _II C, Celik _II,

Calguneri M, Kirazl| S. Circulating thrombopoietin in

systemic sclerosis. J Rheumatol 1999;26:1939–41.

[15] Haznedaroglu _II C, Atalar E, Ozturk MA, Ozer N, Ovunc K,

Aksoyek S, Kes S, Kirazl| S, Ozmen F. Thrombopoietin

inside the pulmonary vessels in patients with and without

pulmonary hypertension. Platelets 2002;13:395–9.

[16] Shinjo K, Takeshita A, Nakamura S, Naitoh K,

Yanagi M, Tobita T, et al. Serum thrombopoietin levels in

patients correlate inversely with platelet counts during

chemotherapy-induced thrombocytopenia. Leukemia 1998;

12:295–300.

[17] Hsu HC, Lee YM, Tsai WH, Jiang ML, Ho CH, Ho CK,

et al. Circulating levels of thrombopoietic and inflammatory

cytokines in patients with acute myeloblastic leukemia and

myelodysplastic syndrome. Oncology 2002;63:64–9.

[18] Espanol I, Hernandez A, Muniz-Diaz E, Ayats R,

Pujol-Moix N. Usefulness of thrombopoietin in the diagnosis

of peripheral thrombocytopenias. Haematologica 1999;84:

608–13.

[19] Wetzler M, Baer MR, Bernstein SH, Blumenson L,

Stewart C, Barcos M, et al. Expression of c-mpl mRNA,

the receptor for thrombopoietin, in acute myeloid

leukemia blasts identifies a group of patients with poor

response to intensive chemotherapy. J Clin Oncol 1997;15:

2262–8.

[20] Bouscary D, Preudhomme C, Ribrag V, Melle J, Viguie F,

Picard F, et al. Prognostic value of c-mpl expression in

myelodysplastic syndromes. Leukemia 1995;9:783–8.

[21] Bouscary D, Prudhomme C, Quesnel B, Melle J, Picard F,

Dreyfus F. c-mpl expression in hematologic disorders.

Leuk Lymphoma 1995;17:19–26.

[22] Takeshita A, Shinjo K, Izumi M, Ling P, Nakamura S, Naito

K, et al. Quantitative expression of thrombopoietin receptor

on leukaemia cells from patients with acute myeloid

leukaemia and acute lymphoblastic leukaemia. Br J

Haematol 1998;100:283–90.

[23] Engel C, Loeffler M, Franke H, Schmitz S. Endogenous

thrombopoietin serum levels during multicycle chemother-

apy. Br J Haematol 1999;105:832–8.

[24] Bruserud O, Foss B. Serum thrombopoietin levels in acute

leukemia patients with chemotherapy-induced cytopenia –

inverse correlation between serum levels and platelet counts.

Leukemia 1998;12:1653–4.

[25] Skomorovski K, Harpak H, Ianovski A, Vardi M, Visser TP,

Hartong SC, et al. New TPO treatment schedules of

increased safety and efficacy: pre-clinical validation of a

thrombopoiesis simulation model. Br J Haematol. 2003;123:

683–91.

Endogenous thrombopoietin in Aml 37

Plat

elet

s D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Q

UT

Que

ensl

and

Uni

vers

ity o

f T

ech

on 1

0/31

/14

For

pers

onal

use

onl

y.