1. Childhood hematopoiesis and hematological features Yongmin Tang Dept. Hematology-oncology Chidlren’s Hospital Zhejiang University School of medicine

2. Questions: How much have you known about our hematopoietic system? What components does our blood system consist of ? What do you think the blood components are derived from? What functions does our hematopoietic system undertake? What is the main organ that the hematopoiesis occurs in elderly children and adults? Why? Is hematopoiesis in children different from that in adults?

3. Hematopoietic Stem Cells (HSC), CD34 is the marker of HSCs. 5 um All the daughter blood cells are derived from the HSCs.

4. Early development of the fertilized egg.

5. Development of hematopoietic stem cells

6. PLURIPOTENT STEM CELL CD34+CD38- HPP-CFU, LTC-IC,CFU-BL MYELOID STEM CELL CD34+CD38- CD33+CD13+ LYMPHOID STEM CELL TdT+CD34+ BFU-MK CD34+ CD61+/- BFU-E CD71+ CD36+/- CFU-GM CD34+CD33+ CFU-M CFU-G CD19+ T PROGENITOR CD7+ TOTIPOTENT STEM CELL T4 T8 CFU-E CD71+ CD36+ CFU-MK CD61+ SELF-RENEWAL B CELL B PROGENITOR HEMATOPOIESIS

7. The features of hematopoiesis in children HEMATOPOIESIS DURING FETAL DEVELOPMENT HEMATOPOIESIS AFTER BIRTH 3. Medullary hematopoiesis: 4th-5th months 2. Hepatic hematpoiesis: 2nd - 6th months 1. Mesoblastic hematopoiesis: 3rd – 6th wks

8. Hematopoisis during fetal development Islet of Yolk Sac In liver In BM Migration of HSCs liverBM HSC Mesoblastic Hepatic Madullary

9. (Wks ） Dynamic changes of hematopoiesis during fetal development

10. hepatosplenomegaly with circulating nucleated erythrocytes in the blood stream HEMAYOPOIESIS AFTER BIRTH 1. Medullary hematopoiesis: “ red marrow ” “ yellow marrow ” When needed: Yellow marrow  red marrow  hematopoiesis compensation 2. Extramedullary hematopoiesis:

11. Comparisons of hematopoietic locations between preschool children and adults

12. Blood pictures in children (1) Juxtaglomerular apparatus A. RBC -----> EPO ------> RBC Fetal stage: RBC 5 ~ 7 x 10 12 /L Hb 150 ~ 220g/L Afferent arteriole of glomerulus Efferent arteriole of glomerulus

13. Blood pictures in children (2) Physiological hemolysis: circulating nucleated RBC with elevated reticulocytes (stopping lysing within 1wk) Physiological anemia: infant 2-3 months RBC 3 x10 12 /L Hb 100 g/L (self-limited, recovers within 6 months)

14. Dynamic changes of RBC during infancy Age RBC counts ( x 10 12 /L)

15. Low limits of Hb in different age groups Newborns 145 g/L 1 ～ 4m 90 g/L 4 ～ 6m 100 g/L 6m ～ 6y 110 g/L 6y ～ 14y 120 g/L 4% of increase per 1000 meter above sea level.

16. 0 － 3d 4~7d4~6wkafter 5mon 4 ~ 6%0.5~1.5% 2~8%0.5~1.5% Reticulocytes ：

17. Molecular structure of hemoglobin

19. Types and proportions of hemoglobin during embryo, fetus and infancy stages

20. Different proportions of Hb during infancy and early young children

21. Blood pictures in children (2) fetal 6 M at birth 1yr 2 yradults HbF (  2  2) 90% 70% < 5% < 2% < 2% HbA (  2  2) 5~10% 30% 93% 95% 95% HbA2 (  2  2) < 1% 2~3%

22. Dynamic changes of WBC during childhood period (x 10 9 /L)at birth6~12hday7infant> 8yrs 15~2021~2812104~8 B. White blood cell count and differential count:

23. DC (%)at birth4~6dd7~ 4yrs 4 ~ 6 yrs 7 yrs N L N L N L N L N L 65 35 50 50 35 65 50 50 as adult (%) 80 60 50 40 20 0 Neutrophils Lymphocytes Age Blood pictures in children (3) 4 ~ 6yrs4 ~ 6 d

24. Blood picture in children (4) Platelets: normal 100 ~ 300 x10 9 /L Total blood volume: Newborn: 10% of body weight Childhood: 8 ~ 10% of BW Adults: 6 ~ 8% of BW

25. Important nutritional components for erythropoiesis Iron Vitamin 12 Folic acid

26. Features of iron metabolism in children Iron store: Factors affecting fetal iron store: Mechanism of iron supply in fetus: restricted premature, severe maternal iron deficiency, intra-uterus transfusion etc.

27. Anemic pale

28. RBCs of IDA Blood smear(2):

29. Metabolism of Vit B12 and Folic acid Folic acid: food: rich in green vegetible, lack in sheep milk ; Absorptive site: at upper portion of jejunum; Vitamin B12: Food: rich in animal derived food; Absorptive site: terminus of ileum; Absorption helping factor: internal factor.

30. Pathogenesis of nutritional megaloblastic anemia 5-Mythotetrahydroxyl Folic acid Vit B 12 + Vit C DNA synthesis Megaloblasts Fragile Invalid hematopoiesis Uridine dThymidine 4H-FA2H-FA

31. Lipid Metabolites: Methyl Malonic acid Succinic Acid Citric Cycle Vit B 12 Pathogenesis of Vit B12 induced nervous system manifestation Vit B12: associated with the formation of nerve sheath lipoprotein to maintain the integrated function of CNS and peripheral nerve fibers. Vit B12 deficiency ： degeneration of peripheral nerve, combined subacute degeneration of spinal cord and damage to the brain.

32. Hyperfragmented neutrophil

33. Clinical relevant cytokines or hormones associated with hematopoiesis EPO G-CSF GM-CSF IL-11 TPO

34. Clinical Application of CD34 + cells CD34 as marker of HSC or HPC for quantitation

35. Selection of the stem cell sources for transplantation (BM, PBSC, Cord blood) Positive selection of the CD34+ cells for tumor purging Gene therapy Clinical Application of CD34+ cells

36. Thank you for attention !