Thrombopoietin

1
THROMBOPOIETIN
K.PAVITHRAN MD, DM Assistant Professor Department
of Hematology Medical College Hospital Trivandrum
-695011
2
Thrombocytopenia- important clinical problem in
hematology/oncolgy Platelet transfusion -
expensive, complications 30 Thrombopoietin -
term coined by Kelemen in 1958 Synonyms - c-Mpl
ligand, mpl ligand, megapoietin, megakaryocyte
growth and development factor (MDGF)
3
MEGAKARYOCYTOPOIESIS
MK
PLATELETS
IMMATURE CELL
PPSM
CPC
IL - 3
THROMBOPOETIN
KL
PIXY- 321
IL-6, IL-11,GM-CSF
4
Thrombopoietin cloned in 1994 Glycoprotein, 353
aminoacids, Mol wt 30KD Gene on chromosome
-3q27 Structure
-21 1
153/154
332
Signal peptide region
Erythropoietin like region
Carbohydrate rich region
Conserved cysteine residues
Glycosylation sites
5
Regulation of Thrombopoietin expression
Circulating level inversely proportional to the
platelet mass Platelets contain a TPO
receptor Normal or elevated levels of platelets
inhibit the action of TPO on target
cells Importance 1. Platelet transfusions may
blunt recovery of MK 2. Cytokines/ diseases may
modify the hepatic production 3. Molecules could
be developed to block clearance 4. Abnormal
platelets may alter TPO levels
6
Two forms available recombinant human
Thrombopoietin (rTPO) Pegylated recombinant
Human Megakaryocyte Growth and Development
Factor (Peg-rHuMGDF) Physiology
Synthesized in liver, kidney Thrombopoietin
receptor (c-MPL) homologue of oncogene -
v-mpl v-mpl transforming gene of murine
myeloproliferative leukemia virus human
TPO receptor cloned in 1992 activates signal
transduction pathway
7
Potential clinical uses 1. Chemotherapy of solid
tumors 2. Bone marrow transplantation 3. Acute
leukemia chemotherapy 4. Radiation therapy 5.
Aplastic anemia / bone marrow failure states 6.
ITP and thrombocytopenia of HIV 7. Harvesting
peripheral blood progenitor cells 8. Platelet
apheresis

8
Side effects of thrombopoietin 1.
Thrombocytosis 2. Thrombosis 3. Marrow
fibrosis 4. Veno-occlusive disease 5. Interaction
with other growth factors

9
Clinical trials of thrombopoietin 1. Solid tumor
chemotherapy TPO safe, stimulates platelet
production Platelet count returned to
baseline faster 2. Bone marrow transplantation
ABMT - platelet transfusion requirements
reduced by 48 Not effective in peripheral
blood SCT 3. Delayed recovery or engraftment
failure - TPO not effective
10
4. Acute leukemia TPO expression on
leukemic cells In vitro studies No
effect on median time to transfusion inde-
pendent platelet recovery. No stimulation of
leukemia. Blood 1999 943694-701 5.
Transfusion medicine single dose increases
the circulating platelet count and
yield by 2-3 fold compared to placebo
11
Recombinant human Thrombopoietin Phase I/II
study The need for platelet transfusion reduced
from 75 in first cycle to 25 in 2nd cycle in
carboplatin induced thrombocytopenia Vadhan-Raj
et al. Ann Int Med 2000132364-8 Randomised
controlled study No effect on the duration of
thrombocytopenia or platelet transfusion
requirement in AML Schiffer CA, et al. Blood
2000952530-5
12
Other thrombopoietitic substances Interleukin
1, 3, 6, 11, GM-CSF, Steel factor, PIXY-321,
promegapoietin (IL-3/TPO) Interleukin 11
(Oprelvekin)

13
Interleukin -11 Produced in Escherichia coli (E.
coli) by recombinant DNA methods Dose 50ug/kg
2-3 weks. Available as 5mg vials Side
effects Fluid retention, arrhythmias, visual
disturbance 1 develop antibodies Randomised
controlled trials Tepler I et al. Blood
1996873607-14 Issacs C, et al. JCO
1997153368-77 FDA approved for clinical use