HISTOLOGY & CELL BIOLOGY

BLOOD & HEMATOPOIESIS II

HEMATOPOIESIS

Blood Formation:

Prenatal

1. 2 weeks ‑ 8 weeks: yolk sac produces blood islands2. 6 weeks ‑ birth: liver production3. 2nd trimester ‑ birth: spleen production4. 3rd trimester ‑ adulthood: bone marrow

Postnatal

1. Exclusively in bone marrow2. In disease states, spleen and liver can produce blood cells

Bone Marrow

1. structure: reticular fibers, veins, arteries, sinusoids, islands of cells

2. red marrow: active hematopoiesis

3. yellow marrow: fat in reticular cells, inactive hematopoiesis

Production

1. greater than 109 (billion) cells produced daily

2. stem cells ‑ pleuripotent, low numbers, give rise to:

3. multipotential cells

a. colony forming units ‑ spleen (myeloid cell lines) b. colony forming units ‑ lymphocytes (lymphoid cell lines)

4. progenitor cells ‑ committed to a single cell line, limited self renewal

5. precursor cells ‑ morphologically distinct, no self renewal

a. generally referred to as a "_____blast" which differentiates to a "____cyte" b. as cells develop; decrease in size, nuclei condense

PHSC

CFU-GEMMMyeloid stem cell

CFU-NM

CFU-Ba

BFU-E

CFU-LyB

CFU-Ly

MHSC

CFU-E

CFU-Meg

CFU-Eo CFU-Eo

CFU-Ba

CFU-N

CFU-M

MKB MKC

CFU-LyT

Stem Cells%

Progenitor Cells%

Promonocyte

Myeloblast

Myeloblast

Myeloblast

Proerythroblast

Precursor Cells%

PrelymphocytesLym

phop

oiesis

Myelopoiesis

FAF

Regulation

1. hematopoietic growth factors (colony stimulating factors) ‑ glycoproteins

2. interleukins, granulocyte colony stimulating factor, erythropoietin, etc.

3. stem cell factor (steel factor) ‑ stromal cells of the bone marrow, stimulates division

4. hematopoietic cells will die unless exposed to growth factors

ERYTHROPOIESIS

Erythropoiesis (erythrocyte formation)

1. ~ 2 x 109 erythrocytes per day in the bone marrow• 2. controlled by cytokines and erythropoietin (kidney); takes about 3 ‑ 5 days to complete development

Rate is regulated by oxygen levels: hypoxia (lower than normal oxygen levels) is detected by cells in the kidneys kidney cells release the hormone erythropoietin into the blood erythropoietin stimulates erythropoiesis by the bone marrow

Erythropoiesis (erythrocyte formation)

1. proerythroblast: 14 ‑19 um, no hemoglobin, large nucleus, basophilic cytoplasm

2. basophilic (early) erythroblast: 12 ‑ 17 um, some hemoglobin, condensing nucleus

3. polychromatophilic erythroblast: 12 ‑ 15 um, "muddy" cytoplasm

4. orthochromatophilic (late) erythroblast (normoblast): 8 ‑ 12 um, increased hemoglobin

5. reticulocyte: 7 ‑ 8 um, loses nucleus, some ribosomes (blue with cresyl blue stain)

6. erythrocyte: 7.5 um, only hemoglobin, no ribosomes

Identify the cells:

Identify the cells:

GRANULOCYTOPOIESIS

Granulocytopoiesis (granulocyte formation)

1. ~ 800,000 neutrophils, 170,000 eosinophils, 60,000 basophils per day

2. controlled by cytokines; takes about 11 days

Granulocytopoiesis (granulocyte formation)

1. myeloblasts: common precursor, 12 ‑ 14 um, no granules, cytoplasmic blebs

2. promyelocyte: 16 ‑ 24 um, large nucleus, azurophilic granules (not specific)

Neutrophilic, Eosinophilic or Basophilic:

3. myelocyte: 10 ‑ 12 um, condensed rounded nucleus, specific granules

4. metamyelocyte: kidney‑shaped nucleus, specific granules

5. band (stab): C‑shaped nucleus, specific granules

6. mature form: neutrophil, eosinophil, basophil

Identify the cells:

Identify the cells:

THROMBOPOIESIS (platelet formation)

1. controlled by thrombopoietin

2. megakaryoblast: 25 ‑ 40 um, endomitosis, polyploid ( ~ 32N)

3. megakaryocyte: 40 ‑ 100 um, large multi‑lobed nucleus

4. platelets are formed from fragments of megakaryocyte cytoplasm (1000's per cell)

5. platelet demarcation channels

MONOCYTOPOIESIS (monocyte formation)

1. monoblasts: large, undifferentiated cells

2. promonocytes: 16 ‑ 18 um, kidney‑shaped nucleus, azurophilic granules

3. monocytes: "sky" blue cytoplasm, kidney-shaped nucleus3. H&E stain

4. enter the circulation, proceed to tissue spaces, differentiate into macrophages

LYMPHOPOIESIS (lymphocyte formation)

1. colony forming units (CFU) ‑ lymphocyte (B = bursa equivalent; T = thymus)

2. lymphoblasts: large, undifferentiated cells

3. prolymphocytes: medium‑sized cells, condensing chromatin, no cell surface antigens

4. some migrate from bone marrow to thymus, divide and differentiate to T‑cells

5. others remain in bone marrow, differentiate to B‑cells, migrate to lymph tissues

DEFINITION: Pancytopenia due to the failure of bone marrow to produce blood cells

CAUSES OF BONE MARROW FAILUREApproach:

Pancytopenia1.Consider causes of peripheral destruction: hypersplenism, sepsis, immune...

Typically, these will be associated with a hypercellular marrow2. Perform bone marrow investigation

a. Hypercellular marrow bone marrow infiltration

-hematologic maliganciesleukemiasmyelomalymphoma

-carcinoma-storage disorders

myelodysplastic syndromes B12 or folate deficiency

b. Hypocellular marrow aplastic anemia (not enough elements making blood)

- congenital- Fanconi’s anemia

- acquired- idiopathic- drugs/chemicals- radiation- viruses

Conceptual classification of pancytopenia

Pancytopenia

Increased destruction sequestration Decreased production

MyelodysplasiaMarrow infiltrateB12 deficiencyAplastic anemia

DrugsViruses

Radiation

HypersplenismImmune destruction sepsis

A practical approach to pancytopeniaPancytopenia

Review medsExamine spleen consider sepsisOrder: retics, B12, ANA, SPE & abd U/S

HypercellularPeripheral destructionHypersplenismMDSMarrow infiltrationHematologic malignancy Solid tumor Storage diseases OtherMegaloblastic anemiamyelofibrosis

HypocellularAplastic anemiaDrugs/chemicals

VirusesRadiation

Fanconi anemiaidiopathic

Bone marrowinvestigation

Other medical applications RBC

Anemia Hemorrhage, Deficient erythropoiesis Accelerated destruction of circulating RBCs Deficiencies of Fe+, vit B12, folic acid

Increase or decrease in number WBC

Inflammation, allergic reaction, hypersensitivity reactions, infections four main types of leukemia are:

Acute lymphoblastic leukemia, or ALL, most common leukemia in children. Adults can also get it.

Acute myelocytic leukemia, or AML., affects both children and adults. Chronic lymphocytic leukemia, or CLL, most common leukemia in

adults, mostly those who are older than 55. Children almost never get it.

Chronic myeloblastic leukemia, or CML, occurs mostly in adults. Platelets

Bleeding problems- Increase vs decrease in numbers

Acknowledgement

L.C. Junqueira and J. Carneiro, 2005, Basic Histology, 11th Edition, Lange Medical Books, New York.

Cormack DH, 2001, Essential Histology 2nd Edition, Lippincott Williams & Wilkins, Philadelphia.

MH Ross & W Pawlina, 2006, Histology: A text and Atlas with correlated cell and molecular biology, 5th Edition, Lippincott Williams & Wilkins, Philadelphia.