PMID- 28548028
OWN - NLM
STAT- MEDLINE
DCOM- 20180912
LR  - 20190610
IS  - 1369-1635 (Electronic)
IS  - 0953-7104 (Print)
IS  - 0953-7104 (Linking)
VI  - 29
IP  - 4
DP  - 2018 Jun
TI  - Developmental differences between newborn and adult mice in response to 
      romiplostim.
PG  - 365-372
LID - 10.1080/09537104.2017.1316481 [doi]
AB  - Thrombocytopenia is frequent among sick neonates. While most cases are transient, 
      some neonates experience prolonged and severe thrombocytopenia. These infants 
      often pose diagnostic and therapeutic challenges, and may receive large numbers 
      of platelet transfusions. Romiplostim (ROM) is a thrombopoietin 
      (TPO)-receptor-agonist approved for treatment of adults with chronic immune 
      thrombocytopenia (ITP). The immature platelet fraction (IPF) is a novel measure 
      of newly produced platelets, which could aid with the diagnostic evaluation of 
      thrombocytopenic neonates. This study had the following two objectives: (1) 
      compare the response of newborn and adult mice to escalating doses of ROM in vivo 
      and (2) assess the correlation between IPF and megakaryocyte (MK) mass in newborn 
      and adult treated and untreated mice. In the first set of studies, newborn (day 
      1) and adult mice received a single subcutaneous (SC) dose of ROM ranging from 0 
      to 300 ng/g, and platelet counts were followed every other day for 14 days. Both 
      sets of mice responded with dose-dependent platelet and IPF increases, peaking on 
      days 5-7 post-treatment, but neonates had a blunted response (2.1-fold compared 
      to 4.2-fold maximal increase in platelet counts, respectively). On day 5 
      post-treatment with 300 ng/g ROM, MKs in the bone marrow (BM) and spleen of adult 
      mice were significantly increased in numbers and size (p < 0.0001 for both) 
      compared to controls. MKs in the spleen and BM (but not liver) of treated 
      neonates also increased in number, but not in size. The immature platelet count 
      (IPC, calculated as IPF x platelet count) was highly correlated with the MK 
      number and size in neonatal and adult BM and spleen, but not neonatal liver. The 
      lack of response of neonatal liver MKs was not due to a cell-intrinsic reduced 
      responsiveness to TPO, since neonatal liver progenitors were more sensitive to 
      murine TPO (mTPO) in vitro than adult BM progenitor. In vivo treatment of newborn 
      mice with high mTPO doses or with higher doses of ROM (900 ng/g) resulted in peak 
      platelet counts approaching 3-fold of controls. Taken together, our data indicate 
      that newborn mice are less responsive to ROM than adult mice in vivo, due to a 
      combination of likely pharmacokinetic differences and developmental differences 
      in the response of MKs to thrombopoietic stimulation, evidenced by neonatal MKs 
      increasing in numbers but not in size. PK/PD studies in human infants treated 
      with ROM are warranted.
FAU - Sparger, Katherine A
AU  - Sparger KA
AD  - a Division of Newborn Medicine , Boston Children's Hospital , Boston , MA , USA.
AD  - b Division of Neonatology , Massachusetts General Hospital for Children , Boston 
      , MA , USA.
FAU - Ramsey, Haley
AU  - Ramsey H
AD  - a Division of Newborn Medicine , Boston Children's Hospital , Boston , MA , USA.
FAU - Lorenz, Viola
AU  - Lorenz V
AD  - a Division of Newborn Medicine , Boston Children's Hospital , Boston , MA , USA.
FAU - Liu, Zhi-Jian
AU  - Liu ZJ
AD  - a Division of Newborn Medicine , Boston Children's Hospital , Boston , MA , USA.
FAU - Feldman, Henry A
AU  - Feldman HA
AD  - c Clinical Research Center , Boston Children's Hospital , Boston , MA , USA.
FAU - Li, Nan
AU  - Li N
AD  - a Division of Newborn Medicine , Boston Children's Hospital , Boston , MA , USA.
FAU - Laforest, Tahirih
AU  - Laforest T
AD  - a Division of Newborn Medicine , Boston Children's Hospital , Boston , MA , USA.
FAU - Sola-Visner, Martha C
AU  - Sola-Visner MC
AD  - a Division of Newborn Medicine , Boston Children's Hospital , Boston , MA , USA.
LA  - eng
GR  - P01 HL046925/HL/NHLBI NIH HHS/United States
GR  - R01 HL069990/HL/NHLBI NIH HHS/United States
PT  - Journal Article
DEP - 20170526
PL  - England
TA  - Platelets
JT  - Platelets
JID - 9208117
RN  - 0 (Receptors, Fc)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 9014-42-0 (Thrombopoietin)
RN  - GN5XU2DXKV (romiplostim)
SB  - IM
MH  - Adult
MH  - Animals
MH  - Humans
MH  - Infant, Newborn
MH  - Male
MH  - Mice
MH  - Receptors, Fc/*therapeutic use
MH  - Recombinant Fusion Proteins/pharmacology/*therapeutic use
MH  - Thrombocytopenia/*drug therapy
MH  - Thrombopoietin/pharmacology/*therapeutic use
PMC - PMC6192266
MID - NIHMS1504743
OTO - NOTNLM
OT  - Immature platelet fraction (IPF)
OT  - newborn
OT  - thrombocytopenia
OT  - thrombopoietin mimetic
EDAT- 2017/05/27 06:00
MHDA- 2018/09/13 06:00
PMCR- 2019/06/01
CRDT- 2017/05/27 06:00
PHST- 2017/05/27 06:00 [pubmed]
PHST- 2018/09/13 06:00 [medline]
PHST- 2017/05/27 06:00 [entrez]
PHST- 2019/06/01 00:00 [pmc-release]
AID - 10.1080/09537104.2017.1316481 [doi]
PST - ppublish
SO  - Platelets. 2018 Jun;29(4):365-372. doi: 10.1080/09537104.2017.1316481. Epub 2017 
      May 26.