Primordial (yolk sac): until week 3 of gestation

Liver, spleen, thymus: 5 weeks to 5 months

bone marrow: 5 months - life

Plasma proteins: liver makes most plasma proteins; B-lymphocytes make immunoglobulins; endothelial cells, megakaryocytes make VWF

Where does blood mainly develop in an adult?

Liver: produces granulocytes, platelets, and definitive erythroblasts (nucleated)

Spleen: produces mostly erythroctyes

Thymus: produces lymphocytes (T cells)

bone marrow: @ 2-3 mon, medullary tissue develops in clavicle. By 5 mon, all blood cell types are produced

Lymph nodes: produce lymphocytes and RBC from 5 months until birth

located in medullary cavity of long and flat bones

red marrow = hematopoiesis

yellow marrow= replaced by fat

Structure: stroma - connective tissue

hematopoietic cords- blood forming cells

sinusoids - point of entry into circulation

Site of Hematopoiesis

part of recticulo-endothelial system

- macrophages destroy old cells

- recycle cell components

Hemoglobin breakdown

- porphyrin - bilirubin - exreted in bile - stool

- iron: transported bound to transferritin; stored in ferritin, hemosiderin; recycled back into hemoglobin

When grown in culture, these cells give rise to colony of hemapoietic cells

aka colony-forming units

What are blasts?

Name the different types

Blasts are the earliest recoginzable lineage specific precursors. They are large, large nucleus (sometimes with prominent nucleolus), basophilic cytoblasm

Includes

Erythroid: erythroblasts

Myeloids: myeloblasts

lymphoids: lymphoblasts

platelets: megakaryoblasts

How do you correctly distinguish between the different bone marrow precusor cells in H&E stain?

You stain for antigens specific for the cell

Ex: megakaryocytes have VWF (clotting protein); Helper T-lymphocytes have CD4; mature neutrophils have LFA-1 (integrin)

Explain the Monophyletic theory

States that

•  bone cells are derived from a single pluripotent stem cell
• Stem cells are self-renewing and undifferentiated
• stem cells are stimulated and differentiated by growth factor

pluripotent cells (undifferentiated) become lineage specific cells (self-renewing), which become differentiated blood cells (incapable of self-renewing) 

What categories of cells are considered pluripotent?

Multipotent stem cells, including granulocytes, macrophages/monocytes, erythrocytes, megakaryocytes (platelets).

also includes Pre-B cells and Pre-T cells

Cytokines are growth factors (signaling proteins) that are used extensively in cell communication

Pluripotent cell:

stem cell factor and other early acting cytokine (interleukins 1, 3, 6, 11; Flt3 ligand

CFU-GM (Granulocyte-Macrophage):

Granulocyted/Macrophage colony stimulating factor and early acting cytokines

Granulocytes:

G-CSF (Granulocyte colony stimulating factor)

Monocytes:

M-CSF (monocyte colony stimulating factor)

Eosinophils:

Interleukin 5

Megakaryocytes (CFU-Meg):

Thrombopoietin, GM-CSF, and early acting cytokines

Blast-Forming units: Erythroids (BFU-E):

Erythropoietin, GM-CSF, IL-3, and SCF

Erythropoeitin is used to increase hematocrit levels in people with renal failure and HIV

G-CSF is used to increase neutrophils in people receiving chemotherapy

Thrombopoeitin is used to increase platelet count in people receiving chemotherapy

Early growth factors may be useful for treating aplastic anemia

GM-CSF alone is not effective enough

SCF is under study

early growth factors tend to have more effects on the vascular system causing capillary permeability and fluid leak

1. Proerythroblast
2. Basophilic erythroblast (smaller nucleus, blue cytoplasm)
3. Polychromatophilic erythroblast (smaller. darker nucleus, blue-gray cytoplasm)
4. Orthochromic Normoblast (very small, dark nucleus; gray-orange cytoplasm)
5. Recticulocyte (no nucleus, slightly gray-blue cytoplasm)
6. mature RBC

Abnormal hemoglobin production: Thalessemias and Sideroblastic anemia: ringed sideroblasts

Abnormal nuclear development: Megaloblastic anemia (B12 and folic acid deficiencies)

Absent erthropoeisis: red cell aplasia: can be acquired or congenital

1. Myeloblast: large nucleus, medium-blue cytoplasm
2. Promyelocyte: larger cell, blue cytoplasm, primary granules (red) overlap nucleus
3. Myelocyte: smaller nucleus; pink-salmon cytoplasm; production of specific granules
4. Metamyelocyte: nucleus is indented, pink-salmon cytoplasm, specific granules
5. Band form
6.  Mature granulocyte: neutrophil, basophil, eosinophil

Abnormal Nuclei: Megaloblastic anemia (Too large band forms or hypersegmented neutrophil nucleus)

Absent Myelopoeisis: can be acquired or congenital

Excess Promyelocytes: leukemia

Monoblast: indistinguishable visually from other myeoblast

Promonocyte: larger than monocyte, nucleus may be indented

Monocyte/Macrophage/Histiocyte: may contain undigested storage material (organisms, iron, lipids, carbs...)

Storage disease: Macrophages may be large and filled with undigested material due to lysosomal enzyme deficiencies

Gaucher's Disease: Glucocerebrosidase dificiency; causes enlargement of spleen, liver, and brain damage.

Some storage disorders include: Cystinosis, Niemann-Pick disease, Hemophagocytosis

Lymphoblast: large, large nucleus, small amt of blue cytoplasm; higher nuclear: cytoplasmic ratio

Lymphocyte: smaller, denser nucleus, sometimes more cytoplasm

Absent B or T lineage cells: results in immunodeficiency; can be acquired as in AIDS

Abnormal or excess growth of lymphoid cells

Megakaryoblast

 Megakaryocyte (formed by endomitosis)

 Platelets

Absent megakaryocytes: congenital

Increased Production: platelet destruction (ex. immune-mediated thrombocytosis)

Myeloproliferative disorder: essential thrombocytosis

Bone marrow failure - deficiency

Myelodyplastic Syndrome - disordered

excessive: Myeloproliferative disorders (pre-leukemias) and leukemias

Absent of defiecient hematopoiesis

Deficiency of only one cell type (cytopenia): neutropenia, thrombocytopenia, red cell aplasia

Deficiency of all cell types: aplastic anemia

Can be congenital or acquireda: misdirected antibody production (autoimmune), toxic effect of chemicals, viral infection

Absent hematopoeisis involving all cell types: inherant abnormality or toxic effect on stem cells, immunological destruction of stem cells, abnormal bone marrow microenvironment

May be treated by immunosuppression, growth factors, or bone marrow transplantation

High rate of mortality w/o bone marrow transplantation

Results in: anemia

Symptoms: tiredness, pallor

RBC transfusion, erythropoietin

Abnormal Myelopoiesis

Results in: Neutropenia

symptoms: bacterial, fungal infections

Treatment: Antimicrobial treatment, G-CSF

Results in : Thrombocytopenia

Symptoms: Bleeding

Treatment: Platelet transfusion

Aplastic anemia

Predispostion to acute myeloid leukemia

Short stature

Limb abnormalites: small thumbs, radial hypoplasia

Genitourinary anomalies

abnormalities of skin pigmentation

Excessive Hematopoeisis (any blood cell can be produced in large amt, due to loss of growth regulation); diregulation often due to genetic mutations due to translocation of oncogenes; blood cell malignancies = leukemias; single cell type or mixed

cause death by tissue infiltration and impairing function

malignant cells from other organs can metastasize to bone marrow

"philidelphia chromosome"

- t(9:22)

-translocation of ABL gene from chromosome 9 next to BCR gene on chromosome 22

-BCR-ABL gene fusion product

BCR encodes a GTPase activating protein

ABL activates a tyrosine kinase

Fusion product causes inc'd cell proliferation, decreased apoptosis, defective stromal adhesion and signaling