Term
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Definition
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Term
Primordial (Yolk sac): Week 3 of gestation
Liver, Spleen, Thymus: 5 weeks - 5 months
Bone marrow: 5 months - life
Plasma proteins
Liver makes most plasma proteins
B-lymphocytes make immunoglobulins
Endothelial cells, megakaryocytes make VWF |
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Definition
| Stages of Blood Development |
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Term
Germ Layer Derivation of Blood
Blood is a connective tissue, derived from extraembryonic mesoderm
Angioblasts within the yolk sac differentiate into blood islands and endothelium
Yolk sac: produces primitive erythroblasts (larger, nucleated, with embryonic hemoglobin) |
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Definition
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Term
Fetal Hematopoiesis
Liver: produces granulocytes, platelets, and definitive erythroblasts (nucleated red cells)
Spleen: produces mostly erythrocytes
Thymus: produces lymphocytes (T-cells)
Bone marrow: @ 2-3 months, medullary tissue first develops in the clavicle. By 5 months, all blood cell types are produced
Lymph nodes: produce lymphocytes and RBCs from 5 months until birth |
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Definition
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Term
What is Bone Marrow?
Bone marrow is in the medullary cavity of long and flat bones
Red marrow is active in hematopoiesis
Yellow marrow has been replaced by fat
Structure
Stroma: connective tissue
Hematopoietic cords: blood forming cells
Sinusoids: point of entry into circulation |
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Definition
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Term
Function of Bone Marrow
Site of hematopoiesis
Part of reticulo-endothelial system
-Macrophages destroy old cells
-Recycles cell components, e.g. proteins, iron
Hemoglobin breakdown
-Porphyrin --> Bilirubin --> excreted in bile --> stool
-Iron
Transported bound to transferrin
Stored in ferritin, hemosiderin
Recycled back into new hemoglobin |
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Definition
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Term
| When grown in culture, these cells will give rise to a colony (group) of hematopoietic cells |
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Definition
Colony-forming cells (CFCs)
a.k.a. colony-forming units (CFUs) |
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Term
| Made by endothelial cells and fibroblasts of the bone marrow stroma, T-lymphocytes, and macrophages |
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Definition
| Cytokines (Growth Factors) |
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Term
Earliest recognizable lineage-specific precursors
Large size
Large nucleus, sometimes with nucleoli
Blue cytoplasm (lots of protein synthesis) |
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Definition
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Term
Erythroid: erythroblasts
Myeloid (granulocytic): myeloblasts
Lymphoid: lymphoblasts
Platelets: ??? |
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Definition
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Term
Many bone marrow precursor cells look similar when stained with H&E.
In order to correctly identify cells, they can be stained for antigens specific to each cell type
Ex:
??? have VWF (clotting protein),
??? have CD4,
??? have LFA-1 (integrin) |
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Definition
Megakaryocytes
Helper T-lymphocytes
Mature neutrophils |
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Term
Blood cells are believed to be derived from a single pluripotent stem cell
Stem cells are self-renewing and undifferentiated
Stem cells are stimulated to replicate and differentiate by growth factors
What theory is this? |
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Definition
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Term
Pluripotent Stem Cells (undifferentiated, self-renewing) --> Committed lineage-specific precursors
(self-renewing) --> Differentiated blood cells
(incapable of replication)
are seen during? |
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Definition
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Term
Multipotent Stem Cell
Granulocytes
Macrophage/Monocytes
Erythrocytes
Megakaryocytes --> platelets
Pre-B Cell
Pre-T Cell |
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Definition
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Term
Growth Factor (Cytokines)
Pluripotent Stem Cell
Stem Cell Factor (SCF)
Other early acting cytokines
- Interleukins (IL) 1, 3, 6, 11; Flt3 ligand
CFU-GM (Granulocyte-Macrophage)
GM-CSF (Granulocyte/Macrophage Colony Stimulating Factor)
Early acting cytokines
Granulocytes
G-CSF (Granulocyte Colony Stimulating Factor)
Monocytes
M-CSF (Monocyte Colony Stimulating Factor)
Eosinophils
Interleukin-5
Megakaryocytes (CFU-Meg)
Thrombopoeitin
GM-CSF
Early acting cytokines
BFU-E (Blast forming units-Erythroid)
Erythropoietin
GM-CSF, IL-3, SCF |
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Definition
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Term
| Growth Factors in Clinical Medicine |
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Definition
Lineage specific growth factors have been purified, DNA cloned, and produced by recombinant technology
- Erythropoietin: used for increasing hematocrit in people with renal failure, HIV
- G-CSF: used to increase neutrophils in people receiving chemotherapy
- Thrombopoeitin: used to increase platelets in people receiving chemotherapy |
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Term
| Growth Factors in Clinical Medicine |
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Definition
Early growth factors may be useful for aplastic anemia
- GM-CSF alone is not good treatment for aplastic anemia
- SCF is under study
- Early growth factors tend to have more effects on the vascular system, potentially causing capillary permeability and fluid leak |
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Term
Proerythroblast
Large nucleus, very dark blue cytoplasm --> Nucleus gets smaller, cytoplasm changes from dark blue to gray --> Nucleus is extruded, cytoplasm becomes pink |
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Definition
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Term
| PROERYTHROBLAST --> BASOPHILIC ERYTHROBLAST: smaller nucleus, blue cytoplasm --> POLYCHROMATOPHILIC ERYTHROBLAST: smaller, darker nucleus, blue-gray cytoplasm --> ORTHOCHROMIC NORMOBLAST: very small, dark nucleus, gray-orange cytoplasm --> RETICULOCYTE: - NO nucleus, slightly gray-blue tinged cytoplasm --> MATURE ERYTHROCYTE: NO nucleus, pink bi-concave disk |
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Definition
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Term
Abnormal hemoglobin production
- Thalassemias (next slide, panel 1)
- Sideroblastic anemia: ringed sideroblasts (panel 2)
Abnormal nuclear development (panel 3)
- Megaloblastic anemia (B12 and folic acid deficiencies)
Absent erythropoeisis: red cell aplasia (panel 4)
- May be acquired or congenital |
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Definition
| Abnormalities of Erythropoeisis |
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Term
| MYELOBLAST Large nucleus, medium blue cytoplasm --> Nucleus gets smaller, Cytoplasm changes from blue to gray, Primary granules develop --> Nucleus becomes segmented, Cytoplasm becomes pink-salmon, Specific granules develop |
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Definition
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Term
MYELOBLAST: Large nucleus, medium blue cytoplasm --> PROMYELOCYTE: Larger cell size, cytoplasm may be lighter blue, Primary granules (small, red) overlie the nucleus --> MYELOCYTE: Nucleus becomes smaller, cytoplasm becomes pink-salmon, Specific granules develop --> METAMYELOCYTE: Nucleus becomes indented,
Cytoplasm is pink-salmon, specific granules present --> Band form: U-shaped nucleus, Cytoplasm is pink-salmon, specific granules present --> Mature granulocyte: Neutrophil, eosinophil, or basophil |
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Definition
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Term
Abnormalities of nuclei
- Megaloblastic anemia can also affect myeloid development:
-very large band forms
-hypersegmented neutrophils
- Absent myelopoiesis
-Acquired or congenital neutropenia
- Excess promyelocytes (leukemia) (panel 4) |
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Definition
| Abnormalities of Myelopoeisis |
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Term
Monocyte Development
MONOBLAST: indistinguishable visually from other myeloblasts --> PROMONOCYTE: larger than monocyte, may have folded nucleus --> MONOCYTE/MACROPHAGE (aka Histiocyte): may contain undigested storage material (organisms, iron, lipids, carbohydrate, etc.) |
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Definition
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Term
Keys to Macrophages
Normal bone marrow macrophage
Bone marrow macrophage ingesting histoplasmosis organisms |
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Definition
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Term
Storage diseases
Macrophages may be large and filled with undigested material due to lysosomal enzyme deficiencies
ex: Gaucher’s disease
Glucocerebrosidase deficiency
Causes enlargement of spleen, liver, and brain damage |
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Definition
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Term
Gaucher disease (“cotton candy”)
Cystinosis (crystals)
Niemann-Pick disease: lipid storage disorder
Iron overload (iron stain and Wright stain)
Hemophagocytosis (ingesting other blood cells) |
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Definition
| Keys to Macrophage Storage Diseases |
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Term
| LYMPHOBLASTS: large size, large nucleus, small amount of blue cytoplasm (High nuclear:cytoplasmic ratio) --> lYMPHOCYTES smaller, denser nucleus, sometimes more cytoplasm |
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Definition
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Term
Absent B- or T-lineage cells
- Causes immunodeficiency
- Congenital (B, T, or combined)
- Acquired
ex: Acquired Immunodeficiency Syndrome (AIDS) from HIV-1 infection
Abnormal or excess growth of lymphoid cells |
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Definition
| Abnormalities of Lymphopoiesis |
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Term
Multiple myeloma (excess plasma cells)
Abnormal plasma cell with stored cytoplasmic material
Normal lymphoid follicles (lymph node)
Loss of lymphoid follicle architecture in advanced HIV infection |
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Definition
| Key to Lymphoid Disorders |
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Term
| MEGAKARYOBLAST: looks like lymphoblast--> MEGAKARYOCYTE: very large cells with multi-segmented nucleus (16-64n)-->PLATELETS: cytoplasmic buds from megakaryocytes (Demarcation membrane subdivides cytoplasm |
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Definition
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Term
Abnormalities of Megakaryopoeisis
Absent megakaryocytes
- Congenital
Increased production
- Platelets destruction, ex. immune-mediated thrombocytopenia
- Myeloproliferative disorder: essential thrombocytosis |
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Definition
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Term
Key to Abnormal Megakaryocyte
Large, multi-nucleated megakaryocyte with ingested neutrophil
Megakaryocyte with single nucleus
Megakaryoblasts with surface staining for GpIIIaIIb (platelet adhesion molecule)
Increased numbers (immune thrombocytopenic purpura) |
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Definition
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Term
Abnormalities of Hematopoiesis
Deficient : Bone marrow failure
Disordered: Myelodysplastic syndrome
Excessive
- Myeloproliferative disorders (“pre-leukemias”)
- Leukemias |
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Definition
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Term
Bone Marrow Failure
Absent or deficient hematopoiesis
Deficiency of only one cell type (cytopenia)
- Red cell aplasia
- Neutropenia
- Thrombocytopenia
Deficiency of all cell types = aplastic anemia
Can be congenital or acquired
-Acquired can be due to
- Misdirected antibody production (autoimmune)
- Toxic effects of chemicals, medications
- Viral infections |
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Definition
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Term
Keys to Bone Marrow Failure
Giant pronormoblast: Parvovirus B19 infection
Parvovirus B19 antigen staining
Vacuolated pronormoblast: chloramphenicol toxicity
“Empty bone marrow” = Absent hematopoietic cells (severe aplastic anemia) |
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Definition
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Term
Aplastic Anemia
Absent hematopoiesis involving all cell types
Inherent abnormality or toxic effect on stem cells
Immunologic 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 BMT |
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Definition
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Term
| Erythropoeisis --> results in anemia --> whose symptoms are tiredness and pallor --> and can be treated by RBC transfusion, erythropoeitin |
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Definition
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Term
| Myelopoiesis --> results in neutropenia --> whose symptoms are baterial and fungal infections --> and can be treated by antimicrobial treat, G-CSF |
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Definition
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Term
| Megakaryopoeisis --> results in thrombocytopenia --> whose symtoms are bleeding --> and can be treated with platelet infusions and thrombopoietin |
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Definition
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Term
Aplastic anemia
Predisposition to acute myeloid leukemia
Short stature
Limb abnormalities
- small thumbs
- radial hypoplasia
Genitourinary anomalies
Abnormalities of skin pigmentation |
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Definition
| Clinical features of Fanconi's anemia |
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Term
Leukemia
Excessive hematopoieis
- Any of the blood cells may be produced in abnormally large numbers, due to loss of growth regulation
- Dysregulation is often due to genetic mutations due to translocation of oncogenes
- Blood cell malignancies are called leukemias
- Single cell type, or mixed (stem cell abnormality)
Leukemias cause death by tissue infiltration and impairing the functions of normal organs
Malignant cells from other organs can also metastasize to the bone marrow |
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Definition
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Term
Cytogenetic Abnormality in Chronic Myelogenous Leukemia
“Philadelphia” Chromosome
t(9;22)
Translocation of ABL gene from chrom. 9 right next to BCR gene on chrom. 22
BCR-ABL fusion gene product
BCR encodes a GTPase activating protein
ABL encodes a tyrosine kinase
BCR-ABL fusion product causes
- increased cell proliferation
- decreased apoptosis
- defective stromal adhesion and signaling. |
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Definition
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Term
Key to Bone Marrow Malignancies
Lymphoid leukemia
Myeloid leukemia (granules and Auer rods)
Chronic myelogenous leukemia (increased numbers of all types of myeloid cells)
Metastatic prostate cancer |
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Definition
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Term
Hematopoietic stem cells differentiate into other tissues:
Blood
Neurons
Hepatocytes
Myocardium
Endothelium |
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Definition
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Term
Bone Marrow Smears
Objectives of reviewing bone marrow samples
- Determine whether a normal number of bone marrow cells are present
- Determine whether there is appropriate cellularity
- Identify whether abnormal cells are present
- Describe the appearance of the bone marrow in words
Look around at low power
- Adequate sample? Bone spiccules present?
- Are all cell varieties present? Megakaryocytes? -- Abnormal cells? (Storage cells are quite large)
Higher power
- Analyze each lineage individually
- Proper differentiation of each lineage?
- Abnormal cells? (e.g. leukemia) |
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Definition
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