HEMATOPOIESIS

A lecture by: Maximo B. Axibal, Jr. MD FPSP

HEMATOPOIESIS

DEF: Process of ____ of cellular elements of the blood

Production, Differentiation, Maturation & Proliferation

Stages: Fetal or adult?

HEMATOPOIESIS Types of Maturation

Synchronous Asynchronous

Medullary Extramedullary

Introduction

BM largest tissue in the body Adult: 4 L; Child: 1. 6 L BM 1 site for blood cell formation
2.5 billion RBCs / kg / day 2.5 billion platelets / kg / day 1 billion granulocytes / kg / day

Introduction

# of circulating blood cells depends on:

Rate of production Rate of release Survival

Production & destruction occur simultaneously & constantly

INTERRELATIONSHIP OF BLOOD CELLS: Theories

Monopheletic (Downey, Ferat & Pappenheim) Polypheletic (Piney, Naegali, Schilling, Rosenthal, Osgood, Sabin, Cunningham & Doan) Naegali Modification of Schilling Sabin & her co-workers

HEMATOPOIESIS

HEMATOPOIESIS: Mesenchymal period

Start: 4th wk AOG End: 2nd mon AOG

Products: Nucleated megaloblastic RBC's (2 wks AOG) Minor production of MKs

HEMATOPOIESIS: Mesenchymal (Yolk Sac) period

Mesoblastic(19-20 d): Erythropoietic Islands PNRBCs

Mesodermal (8-12 w): Extraembryonic 3 Embryonic Hgbs Megakaryopoiesis

HEMATOPOIESIS: Hepatic period

Start: End of 11th wk AOG End: 6th mon AOG Products: Extravascular erythroblasts & anucleated macrocytic RBC's Megakaryocytes- 6th wk AOG Granulocytes6th wk AOG Lymphocytes4th mon AOG Monocytes5th mon AOG

HEMATOPOIESIS: Medullary period

Start: 10th wk AOG (6th mon AOG- predominant) End: Lifetime Products: RBC's- 10th wk AOG Thrombocytes Granulocytes/ monocytes Lymphocytes- w/ contributions from thymus, L.N. & spleen (Ag independent)

HEMATOPOIESIS: Medullary period

RBC - Alpha 1 & alpha2 beta2 3 wks postpartum BM (Medullary) 4th y - rate of BM production exceeds need for blood cells

MATURATION FEATURES: NUCLEUS (DNA)

DEC N:C CHROMATIN: HETEROGENOUS HOMOGENOUS (WBC) to CLUMPED (RBC) NUCLEOLI (RNA): PRESENT DISAPPEARS

INDENTATION APPEARS (GRANULOCYTES) LOBULATIONS APPEAR (GRANULOCYTES) SOMETIMES DISAPPEAR (RBC)

MATURATION FEATURES: CYTOPLASM (RNA)

DEC N:C DEEP BLUE LIGHT BLUE (WBC) sometimes PINK (RBC) GRANULES APPEAR CELL SIZE DECREASES IN SIZE

Bone Marrow Morphology (Erythropoiesis)

HEMATOPOIESIS

Hematopoietic Regulatory Factors

Cytokines: Regulate proliferation, differentiation, function Glycoproteins Multilineage or lineage specific Redundant & complex specificities Both positive & negative feedback mechanism

Colony Stimulating factors (CSF) Interleukins (IL) Stem Cell Factor (SCF) Tumor Necrosis Factor (TNF) Transforming growth factors (TGF) Interferon (IF)

GF (1o TARGET) CHR (SOURCE)

IL 1 (STEM CELLS, LYMPHOCYTES, ENDOTHELIAL CELL)

2 (MONOCYTE)

IL 3 (STEM CELLS, MYELOID, ERYTHROID, MK)

5 (T CELL)

GF (1o TARGET) CHR (SOURCE)

IL 4 (BASOPHIL, B/ T LYMPHOCYTE)

5 (T CELL)
5 (T CELL) 7 (WBC, FIBROBLAST)

IL 5 (EOSINOPHIL, B LYMPHOCYTE)

IL 6 (STEM CELLS, B/T LYMPHOCYTE)

GF (1o TARGET) CHR (SOURCE)

IL 7 (LYMPHOCYTE)

? (WBC)
? (WBC) ? (LYMPHOCYTE) 17 (MONO, EC, FIBROBLAST)

IL 8 (GRANULOCYTE)

IL 9 (GRANULOCYTE)

G- CSF (ERYTHROID CELLS, MK)

GF (1o TARGET) CHR (SOURCE)

M- CSF (MONOCYTE)

5 (MONO, EC)

GM- CSF (GRANULOCYTE, MONOCYTE, MK)

5 (T CELL, MONO, EC)

EPO (RBCs)

7 (KIDNEY, LIVER)

Hematopoietic Cell Release

Cellular migration:

Cords through endothelial cells circulation

Normally only mature cells released Immature cells released under abnormal circumstances: Immature RBCs- hypoxia, hemolytic anemias Immature granulocytes- severe infections, sepsis Marrow replacement- fibrosis, neoplasm

LYMPHOPOIESIS

LYMPHOBLAST PROLYMPHOCYTE MATURE LYMPHOCYTE

Lymphopoiesis

BM & lymphatic organs: T-cells

BM Thymus Mature T-cells PB

B cells

BM LN (educated) PB gut lymphoid tissue, spleen Plasma Cells

Lymphopoiesis (Lymphoblasts)

THROMBOPOIESIS

MEGAKARYOBLAST PROMK MK PLATELET

Megakaryopoiesis

MONOPOEISIS

MONOBLAST PROMONOCYTE MONOCYTE

Monopoiesis
Monoblast

Promonocyte

Mature Monocytes

GRANULOPOIESIS

MYELOBLAST PROMYELOCYTE MYELOCYTE METAMYELOCYTE (JUVENILE) STAB (BAND; STAFF) MATURE NEUTROPHIL (PMN/ SEG); EOSINOPHIL; BASOPHIL

GRANULOPOIESIS

Granulopoiesis (Myeloblast)

Granulopoiesis (Promyelocyte)

Granulopoiesis (Myelocyte)

Granulopoiesis (Metamyelocyte)

Granulopoiesis (Band)

Granulopoiesis (Segmented Neutrophil)

Granulopoiesis (Kinetics)

Stage/s capable of mitosis?

MYELOBLAST PROMYELOCYTE MYELOCYTE METAMYELOCYTE (JUVENILE) STAB (BAND; STAFF) MATURE NEUTROPHIL (PMN/ SEG); EOSINOPHIL; BASOPHIL

Stage where azurophilic granule formation begin?

MYELOBLAST PROMYELOCYTE MYELOCYTE METAMYELOCYTE (JUVENILE) STAB (BAND; STAFF) MATURE NEUTROPHIL (PMN/ SEG); EOSINOPHIL; BASOPHIL

Stage where specific granule formation begin?

MYELOBLAST PROMYELOCYTE MYELOCYTE METAMYELOCYTE (JUVENILE) STAB (BAND; STAFF) MATURE NEUTROPHIL (PMN/ SEG); EOSINOPHIL; BASOPHIL

Stage where nuclear indentation begin?

MYELOBLAST PROMYELOCYTE MYELOCYTE METAMYELOCYTE (JUVENILE) STAB (BAND; STAFF) MATURE NEUTROPHIL (PMN/ SEG); EOSINOPHIL; BASOPHIL

1st stage where granulocytes can be classified as N E or B?

MYELOBLAST PROMYELOCYTE MYELOCYTE METAMYELOCYTE (JUVENILE) STAB (BAND; STAFF) MATURE NEUTROPHIL (PMN/ SEG); EOSINOPHIL; BASOPHIL

ERYTHROPOIESIS

PRONORMOBLAST BASOPHILIC NB POLY- CHROMAT NB ORTHO- CHROMAT NB POLYCHROMATOPH ILIC NORMOCYTE MATURE RBC; ERYTHROCYTE; DISCOCYTE

ERYTHROPOIESIS

RUBRIBLAST PRORUBRICYTE RUBRICYTE METARUBRICYTE RETICULOCYTE MATURE RBC; ERYTHROCYTE; DISCOCYTE

Erythrocytic Series

Rubriblast, Pronormoblast, Erythroblast, E1 Prorubricyte, Early NB, Basophilic NB, E2 Rubricyte, Intermediate NB, Polychromatic NB, E4 Metarubricyte, Late NB, Orthochromatic NB, E5 Reticulocyte, Polychromatic Normocyte Erythrocyte (Normocyte, Akaryocyte, Erythroplastid, Discocyte)

Stages capable of mitosis?

PRONORMOBLAST BASOPHILIC NB POLY- CHROMAT NB ORTHO- CHROMAT NB POLYCHROMATOPH ILIC NORMOCYTE MATURE RBC; ERYTHROCYTE; DISCOCYTE

Stages capable of hgb synthesis?

PRONORMOBLAST BASOPHILIC NB POLY- CHROMAT NB ORTHO- CHROMAT NB POLYCHROMATOPH ILIC NORMOCYTE MATURE RBC; ERYTHROCYTE; DISCOCYTE

Stage where chromatin is clumped?

PRONORMOBLAST BASOPHILIC NB POLY- CHROMAT NB ORTHO- CHROMAT NB POLYCHROMATOPH ILIC NORMOCYTE MATURE RBC; ERYTHROCYTE; DISCOCYTE

Stage where nucleus is extruded out of the RBC?

PRONORMOBLAST BASOPHILIC NB POLY- CHROMAT NB ORTHO- CHROMAT NB POLYCHROMATOPH ILIC NORMOCYTE MATURE RBC; ERYTHROCYTE; DISCOCYTE

Erythropoiesis (Pronormoblast)

Erythropoiesis (Basophilic Normoblast)

Erythropoiesis (Polychromatophilic Normoblast)

Erythropoiesis (Orthrochromic Normoblast)

Erythropoiesis (Polychromatophilic Erythrocyte/Reticulocyte)

Erythropoiesis (Mature Erythrocyte/RBC)

Erythropoiesis
Proerythroblast Basophilic erythroblast

Polychromatophilic erythroblast

Orthochromatophilic erythroblast

Reticulocyte

Mature RBC

Erythropoiesis (Kinetics)

Bone Marrow Differentiation

Myeloid Stem Cell
Pluripotent Stem Cell Lymphoid Stem Cell

Erythroblast

Megblast

Myeloblast

Monoblast

Tlympho blast

Blympho blast

T-cell RBC Platelet PMN Eos Baso Mono

B-cell Plasma cell