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31 Cards in this Set

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What 3 cytoskeleton proteins give RBC's their shape and flexibility?
1. Spectrin
2. Ankryn
3. Actin
What are 2 primary and 2 secondary causes of polycythemia?
Primary:
- Myeloproliferative disorder
- Mutation in EPO receptor gene (thinks EPO always there)

Secondary:
- Hypoxia (lung disease, env, defective hgb)
- Increased EPO production
What has:
- nucleus with 2-5 lobes
- granules in the cytoplasm
- 12-15um diameter?
What are of it's functions?
Granulocytes!
- phagocytosis and destruction of foreign material
- Cytotoxic (e.g. by having a respiratory burst)
- inflammation
(- generate radicals from iron bound to bacteria)
Granulocytopenia is caused by:
1. Decreased production (5 causes?)
2. Increased destruction (3 causes)
1. Decreased production:
- defective differentiation
- substrate deficiency (B12/folate)
- Marrow infiltration
- Toxicity to precursors (medication/infection)
- Congenital or benign increase in apoptosis
2. Increased destruction:
- hypersplenism
- autoimmune (e.g. lupus)
- alloimmune (HIV, medication, etc)
What are 3 causes of granulocytosis (DRS)?
1. Demargination - stress can cause them to go from endothelium to blood
2. Reactive - inc production d/y cancer, infection, inflamm. etc.
3. Primary - leukemia
What are 3 causes of monocytosis?
1. Chronic inflamations (IBS, rhematoid)
2. Chronic infections (TB, syphillis)
3. Malignancies (leukemia)
What are 3 functions of monocytes?
Phagocytosing debris and microbes
Antigen presentation
Acute inflammation
List some causes for each of the following:
- psedothrombocytopenia (2)
- thrombocytopenia (dec production=4; inc destruction=3)
- thrombocytosis (3)
Pseudo: Platelet clumping/satelitism (in vitro phenomena)
Thrombocytopenia:
- acquired or congenital defect in differentiation
-substrate deficiency (B12/folate)
-marrow infiltration; toxicity
Increased destruction: consumption (DIC, sepsis), Immune (viral, auto), Sequestration (hypersplenism)
Thrombocytosis:
- reactive (infection, bleeding, Fe deficiency)
- primary (myeloproliferative disorders)
- redistributive (post splenectomy)
How does bone marrow change with age?
- 3-6 months
- birth
- adolescents
Yolk sac--> paraortic region --> liver --> bone marrow
Liver major source from 3-6 months.
At birth bone marrow is in all bone cavities. Marrow replaced by adipocytes as you age.
By adolescents only in central bone cavities.
What is one thing that BM does NOT have?
lymphatic channels!
The BM is a 'microenvironment', what is the function of the following 3 components?
1. Stromal cells
2. Accessory cells
3. Extracellular matrix
1. Stromal cells
- produce cytokines and negative regulators
2. Accessory cells
- T cells: IL-3, TNF, IFN-y
- Mphages: eat dead RBC's & expelled nuclei; express VCAM for adhesion
3. Extracellular matrix (produced by stromal cells)
- homing and mobilization of stem cells (adhesion molecules bind specific precursor cells to certain sites in the BM)
Where does the following occur (in the BM)?
1. Erythropoiesis
2. Granulopoiesis
3. Megakaryopoiesis
1. Erythropoiesis: Erythroid islands surrounding a central Mphage
2. Granulopoiesis: Adjacent to bony trabeculae
3. Megakaryopoiesis: Adjacent to sinus endothelium
Trace the order of Granulopoiesis from stem cell to Neutrophil:
myeloblast --> _____--->_____ ---> metamyelocyte --> ______ --> ______
From what point are the cells no longer dividing and instead maturing?
* stem cell
* Myeloblast
* Promyelocyte
* Eosino/neutro/basophilic myelocyte
* Metamyelocyte
* Band cell (Stab cell)
* Granulocytes (Eosino/neutro/basophil)

Cells are maturing only from the myelocyte onwards!
How long do neutrophils last in the blood?
- a few hours then they regress into the tissues. When a chemokine binds their CXCR1,2 receptors they move out of the blood
- GM-CSF prolongs neutrophils in circulation
How does an eoisinophil develop? What chemokines stimulate it?
What causes it to leave circulation?
All the same as a neutrophil only ending in a eosinophil under the direction of IL3 & 5.
Eotaxin made in allergic infiltrates or asthmatic lungs, draws eoisinophils out.
What 2 chemokines stimulate the development of a basophil?
What do their granules contain? (H H L P) What don't they contain?
IL-3 and KIT ligand.
Granules have: Heparin, histamine, lipid, proteoglycan, but NO hydrolytic enzymes.
What is the order of cells in the development of monocytes?
CFU-GM --> monoblast --> _____ -->_____
What chemokines stimulate them?
Monocytes circulate in the blood for ___ days then do what (2)?
CFU-GM --> monoblast--> promonocytes --> monocytes
- Chemokines: M-CSF and IL-3
- circulate in blood for 3 days then become tissue macrophages or dendritic cells (APC)
** they also produce cytokines! (accessory cells of BM)**
What do dendritic cells do (2)? What don't they do (1)?
What precursors can they arise from (3)?
Dendritic cells:
- Antigen presentation
- stimulate primary T cell response
They DO NOT phagocytose!
Can arise from:
-lymphoid, meyloid or monocyte precursors
What is the origin and function of an osteoclast?
Differentiate from CFU-GM
They sit on the trabeculae and are responsible for the resorption of bone.
What is the order of cells in erythropoiesis?
Proerythroblast --> ______ --> _____ --> normoblast --> _______ --> *erythrocyte*
EPO is acting from what cell onwards?
Proerythroblast --> Basophillic erythroblas --> Polychromatic Eblast --> normoblast --> polychromatophilic Ecyte --> -->*erythrocyte*
From proerythroblast onwards, development is EPO dependent alone!
For erythropoietin, what
- stimulates its release
- effect on tissue
- negative feedback
- EPO release is stimulated in response to hypoxia in renal cells
- EPO binds surface cell receptors and is essential proliferation, differentiation and survival of cells
- Heme and TNF inhibit EPO
** EPO receptors are absent from mature RBC
What do megakaryocytes develop from? Order of 2 precursor cells?
How Mkcytes develop?
Develop from: BFU-MK and CFU-MK
Mblast --> ProMcyte --> M
** stimulated by TPO **
Grow by having ongoing DNA synthesis w/o mitosis = increasing DNA content such that nucleus folds and lobulates w/o separating.
What 2 things happen as a megakaryocye matures (ie before platelets start budding off?)
- acquires surface glycoproteins (VmF, GP1b/2a)
- develops granules (alpha, delta, gamma, peroxisomes).
What is the life span of the following cells:
- RBC
- WBC
- Platelet
- RBC = 120 days
- WBC = 3-4hrs
- Platelet = 10days
Natural Killer Cells
- function (2)
- appearance
- origin
Function:
- non-restricted cytotoxicity
- produce cytokines that influence hematopoiesis and immunity

Appearance: large cells with cytoplasmic granules

Origin: common lymphoid progenitor
What is the definition of:
-totipotent
-pleuripotent
-multipotent
-totipotent: can generate any type of cell including extra-embryonic membranes
-pleuripotent: same as above except can make extra-emb membranes
-multipotent: able to generate multiple cell types but only of a particular tissue type
What are the 3 attributes of hematopoietic stem cells?

What are the 3 choices that every HSC has open to it?
1. Capacity for self-renewal
2. Able to differentiate into any of the mature blood lineages
3. Able to regenerate the hematopoietic system post-radiation

1. Self-renew
2. Differentiate
3. Apoptosis
In addition to Stem Cell Factor and Flt3, what are some other cytokines that guide stem cell decisions?
1. T
2. H
3. B
4. N
+ delta
+ jagged
1. TPO - enhances megakaryocytic prolif and diff.
2. HedgeHog Protein: up-regulated BMP's and induces primitive hematop.
3. BMP - induce primitive hematop., and bone/cart formation
4. NOTCH - transmembrane receptor:
+ delta = increased generation of HSC and inc ability to diff
+ jagged = decreased proliferation
What factors w/in HSC will affect what the stem cell does?
1. Genes - A, M, G, I and H (what does this one do if up and down regulated?)
2. How is transcription regulated?
1. Genes: AML1, MYB, GATA2 and IKAROS,
Homeobox: up regulated = leukemia
down regulated = poor granulation

Transcription regulation is acheived by modifying histones to increase or decrease differentiation of HSC
What triggers apoptosis in HSC?
Overexpression of the gene BCL-2
-Lymphoma cells do not express BCL-2 at all and thus continue to grow and accumulate unchecked.
What are 3 ways of identifying stem cells?

What are 3 sources of HSC?
1. Cell surface antigens - do a phenotypic analysis (HSC won't have markers of specific mature lineages)

2. Efflux of dyes - HSC will pump out Rhodamine 123 and Hoechst - 33342

3. Cultures -- if placed on stromal cells of BM will differentiate into different lineages depending on what the environment favors

Sources of HSC: Peripheral blood (easiest to harvest), cord blood (only get a small amount) and bone marrow (most painful/invasive).