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• W3121052902 abstract "Hypertensive disorders of pregnancy (HDP) is a disease in which the production of antiangiogenic factors causes endothelial dysfunction in placental blood vessels.1, 2 Endothelial dysfunction in placental blood vessels causes chronic hypoxic ischaemia in the fetus resulting in small-for-gestational-age (SGA) infants.3 SGA infants are defined as having a birth weight of less than the 10th percentile of the population-specific birth weight for a given gestational age.4 There have been some reports that SGA infants often have transient thrombocytopenia within the first three days of life5-7 due to low concentrations of serum thrombopoietin (Tpo).8, 9 However, the detailed mechanism of thrombocytopenia in SGA infants remains unclear. We investigated the causes of thrombocytopenia and a therapeutic strategy for treating SGA rats with thrombocytopenia. An Alzet osmotic pump (Muromachi Kikai Co., Tokyo, Japan) filled with L-NAME (Dojindo Laboratory, Kumamoto, Japan) was subcutaneously inserted into Wistar/ST rats on the eighth gestational day.10 The dose of L-NAME was 50 mg/kg/day. On gestational day 15, the osmotic pump was removed. Newborn rats from HDP model rats were used as SGA model rats. Blood cell counting (FUJIFILM VET Systems Co., Tokyo, Japan), analysis of gene expression by quantitative reverse transcription polymerase chain reaction using a Thermal Cycler Dice Real-Time System (Takara Bio Inc., Otsu, Japan), measurement of Tpo concentration in serum by enzyme-linked immunosorbent assay using a thrombopoietin (RAT) ELISA kit (BioVision, Milpitas, CA, USA) and liver histologic analysis by haematoxylin and eosin (HE) staining were performed. The primer pairs used for amplification are shown in Table S1. Finally, we examined the platelet-increasing effect of romiplostim (Kyowa Kirin Co. Ltd., Tokyo, Japan), a Tpo receptor agonist. Romiplostim solution (20 μg/kg) was intraperitoneally administered to SGA rats on postnatal day 1 (P1) and platelet measurements were performed. All statistical analyses were performed using SPSS (IMB, Chicago, IL, USA). Data are reported as the mean ± SEM. Statistical significance was set at P < 0·05. The body weight (Figure S1) and the number of platelets (Fig 1A) of the SGA rats were significantly lower than those of the control rats on P1, P3 and P7. White blood cells (WBC), red blood cells (RBC), haemoglobin (Hb) and haematocrit (Hct) were not significantly different between the control rats and SGA rats (Table S2). The Tpo gene was mostly expressed in the liver on P1, P3, P7 and P14 and became more specifically expressed in the liver with development in both the control rats and SGA rats (Figure S2). Tpo gene expression peaked on P3 in both the control rats and SGA rats, but significantly lower expression of Tpo was observed in the liver of SGA rats compared with the control rats on P1 and P3 (Fig 1B). The Tpo protein concentration in serum increased with development in both the control rats and SGA rats, but significantly lower expression of Tpo was observed in SGA rats than control rats on P3 (Fig 1C). Expression of the cMpl gene was significant higher in SGA rats than control rats on P3 at the peak of Tpo gene expression (Fig 1D). The liver to body weight ratio was lower in SGA rats than control rats on P1 (Fig 2A). Analysis of expression of the albumin gene in control and SGA rats confirmed an increase in expression with development in both groups, but the expression level was significantly lower in SGA rats than in control rats on P1 (Fig 2B). In both groups, the liver tissues were already mature by P1; that is, the hepatocytes were dense and hepatic lobules with distinct sinusoids had been formed. In SGA rats, vacuoles were observed in the hepatocytes on P1 and the hepatocyte clusters were sparser (Fig 2C). Thrombus formation in the central vein was not observed in either group. Finally, administration of romiplostim improved thrombocytopenia in SGA rats by P7 (Fig 2D). No significant abnormal behaviours were observed after administration of romiplostim. The results of our study suggest that thrombocytopenia in SGA rats is due to insufficient Tpo production relative to liver dysmaturation. In addition, romiplostim improved thrombocytopenia in SGA rats. Our findings should help elucidate the mechanism of thrombocytopenia and aid in the development of a therapeutic strategy for treating thrombocytopenia in SGA infants. In the present study, we prepared HDP model rats by continuous subcutaneous administration of L-NAME, an NO synthesis inhibitor.10 This causes chronic ischaemic hypoxia in the uterus, which disrupts fetal development. The liver to body weight ratio of SGA rats was lower than that of control rats in our study and histologic examination revealed that the liver of SGA rats was structurally dysmature. Expression of the albumin gene was reduced in SGA rats early after birth, which suggests there is reduced capacity for protein synthesis in SGA infants. These quantitative and qualitative characteristics of SGA rat liver, which have not been reported before, are presumed to be caused by chronic hypoxia in the uterus. The higher expression of cMpl might be due to compensation for the suppression of Tpo expression. Furthermore, recovery of the platelet count by early administration of romiplostim was observed. As the treatment with a Tpo receptor agonist is limiting, romiplostim cannot be expected to rapidly restore platelets to prevent severe bleeding because the effects of romiplostim appear slowly. In order to promptly recover platelets to avoid serious complications, platelet transfusion must be performed as a standard procedure. However, given the side effect and availability issues of blood transfusions, administration of a Tpo receptor agonist appears to be a potentially valuable treatment for human SGA infants, including preventive administration against thrombocytopenia. The present study is the first to demonstrate a decrease in Tpo production due to hepatic dysmaturation in SGA rats. Our data also demonstrate that administration of the Tpo receptor agonist romiplostim might be effective for treating thrombocytopenia in SGA infants. We acknowledge the assistance of the Research Equipment Sharing Center at Nagoya City University. This work was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science, KAKEN grant numbers 16K10101, 17K10197 and 18K07832. The authors declare no conflict of interest. ST designed the study, preformed all experiments, analyzed and interpreted the data and wrote the manuscript. HK collected and assembled the data, performed data analysis and interpretation and wrote the manuscript. KT, HA, HU and YY collected and assembled the data and performed data analysis and interpretation. MA designed the study, analyzed and interpreted the data and wrote the manuscript. All authors read and approved the final manuscript. Table SI. Primer pairs used for polymerase chain reaction amplification. Table SII. Blood cell counts of control and SGA rats. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article." @default.
• W3121052902 created "2021-01-18" @default.
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• W3121052902 date "2021-01-06" @default.
• W3121052902 modified "2023-09-26" @default.
• W3121052902 title "Insufficient thrombopoietin due to hepatic dysmature results in thrombocytopenia in small‐for‐gestational‐age rats" @default.
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• W3121052902 doi "https://doi.org/10.1111/bjh.17294" @default.
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