Hematopoiesis

1. 4 stimulators

2. Sites  - adult (2)

3. Sites - fetus

1. STIMULATORS:

-cytokines (interleukins)

-erythropoietin (from kidney, RBC formation)

-leukopoietin (WBC formation)

-thrombopoietin (platelet formation)

2. Adult Sites:

-Bones marrow (axial skel, long bones, skull)

-Lymph nodes

3. Fetal Sites:

-Yolk sac

-placenta

-Later bone marrow, spleen, liver, lymph

Adolescent RBCs

-% of all peripheral circulating RBCs?

-size

Senescent (Aged, damaged) RBCs

-where are the macrophages that eat them?

-what is recylced, via what?

-used in production of...

Reticulocytes

-1%

-larger than mature RBCs

Old RBCs

-liver, spleen, Bone Marrow macrophages

-iron & globin recycled via transferrin

-Bilirubin production

A variant form of hemoglobin found in people with sickle cell disease.

-what is the variation

HgB S

-variation in beta chain (substitution of valine for glutamic acid)

RBC Labs:state nl values

1. HgB

2. Hct

3. MCV

4. MCH

5. MCHC

1. HgB - Male 13-18, Female 12-15

2. Hct - Packed red cell volume, 3x# of Hgb (M 48%, F 38%)

3. MCV - 80-100, average size

4. MCH - 27-31, average mass

5. MCHC - 32-36, conc of Hgb

Anisocytosis

Poikilocytosis

Anisocytosis - unequal RBC sizes

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Poikilocytosis - unequal RBC shapes

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3 types of anemias based on MCV (size) and examples:

-MCV<70

-MCV normal

-MCV >100

-MCV<70

Microcytic, hypochromic

IDA

-MCV normal

Normocytic, normochromic

Hemolytic Anemia, Acute Bld loss

-MCV >100

Macrocytic, Normochromic

Megaloblastic Anemia

1. Anemias from Impaired Production

2. Anemias from Excessive bld loss/increased destruction

1. Anemias from Impaired Production

-IDA

-Megaloblastic (folate, B12 def)

-Pernicious (no intrinsic factor)

-Aplastic Anemia (marrow problem results in pancytopenia)

-Renal Failure (no erythropoietin)

-Chronic Dz

2. Anemias from Excessive bld loss/increased destruction

-Acute bld loss

-Sickle Cell

-Autoimmune Hemolytic

-Hereditary spherocytosis

-Thalassemia

-GDPD def

RBCs are vulnerable to oxidants,

  hemoglobin is oxidized to methemoglobin,

  and denatured to form Heinz bodies.

  alpha or beta Hgb chains

  the bone marrow with an absolute increase

  in total RBC mass with elevated white cell

  and platelet counts.

-what Hct qualifies as this disorder?

Polycythemia Vera

-Hct >54% in men, >51% in women

1.Myeloid cell line

2. lymphoid cell line

Both WBCs:

1. Myeloid cells: Granulocytes (neuto/eosino/basophils) & Agranulocyte (monocytes)

2. Lymphoid cells: Agranulocyte (lymphocyte)

Function and nl values of WBCs

1. Neutrophils - include lifespan

2. Eosinophils

3. Basophils

4. Monocytes- incl lifespan

5. Lymphocytes - incl lifespan

1. Neutrophils defense, life 4-5 d, 55-65%

2. Eosinophils allergic rxn detox, 1-3%

3. Basophils allergic rxns, 0.3-0.5%

4. Monocytes phagocytize, 1-3 d in circulation, months to years in tissue. 3-8%

5. Lymphocytes B cells->plasma cells to secrete antibodies (humoral immunity); T cells (cell mediated immunity).  Life is hours to yrs.  20-30%

Etiologies:

1. Neutropenia

2. Lymphocytosis

3. Lymphopenia: transient vs. progressive

4. Monocytosis

5. Eosinophilia

6. Basophilia

1. Neutropenia

drug induced, congenital

2. Lymphocytosis

physiologic in kids, pathologic

3. Lymphopenia

virus (transient), HIV (progressive)

4. Monocytosis

chronic infxn (TB, syphilis), leukemia

5. Eosinophilia

parasites, allergic rxn, hodgkins dz, leukemia

6. Basophilia

chronic myelogenous leukemia

referring to a group of disorders characterized by autonomous proliferation of one or more hematopoietic elements in the bone marrow. 

-physical exam finding?

myeloproliferative disorder

-hepatosplenomegaly

plasma cell cancer of the osseous tissue; in the course of its dissemination, may also involve

  non-osseous sites; characterized by uncontrolled proliferation of an abnormal clone of plasma cells, which secrete primarily IgG or IgA.

  Unknown causes.

malignant neoplasms coming from the transformation of a single cell line originally derived from hematopoietic stem cells.

-causes?

-risk factors?

-classification

Leukemias

-idiopathic

-risks: radiation, benzene, anti-tumor drug exposures

-Classifation: lymphocitic or myelogenous (acute and chronic)

neoplasm of the immune system

-2 types

*which is more common

*define each

*origin and proliferation

*etiologies

Lymphoma:

1. Hodgkin’s disease – specialized form characterized by       Reed-Sternberg cells that begin as a malignancy in a single lymph node and then spread to contiguous lymph nodes. Idiopathic

  2. non-Hodgkin’s lymphoma – a group of heterogenous       lymphocytic cancers that are multi-centric in origin and spread to various tissues throughout the body, including the bone marrow; occurs 3x more frequently than Hodgkin’s disease; etiology of most is unknown; viral cause is suspected in some; can originate in either T cells or B cells.

1. vessel spasm is neural and humoral

2. platelet plug formation

3. Clot formation (insoluble fibrin)

4. clot retraction and fibrous tissue growth

5. clot dissolution - requires activation of plasminogen to lyse clots, prot c inactivates factors V and VIII

Platelets

-formed where by what?

-processed via...

-hours from production to entrance into peripheral blood

-lifespan

-nl counts

Platelets

-formed thrombopoietin in bone marrow

-processed via spleen

-8 hours from production to entrance into peripheral blood

-lifespan 7-9 days

-nl counts 150K-400K

Platelet Plug Formation

-adherence

-activation

-aggregation

Platelet Plug Formation

-adherence: injured vessel wall looses nl (-) charge; (-) charged platelet adheres

-activation: platelet binds to von Willebrand factors at injury site; surface becomes spiny and exposes receptors

-aggregation

vWF

-produced by

-function

-circulating form

vWF= von willebrand factor

-produced by endothelial blood vessel cells

-function: bridges and activates platelet to exposed collagen

-circulating form: attached to factor VIII

Procoagulants

-inactive form

-cofactor of VIII

-produced where?

-vit K dep factors

-inactive form

factors I-XIII circulating in blood (some names to know:

I fibrinogen, II prothrombin, III thromboplastin, XIII fibrin stabilizing factor)

-cofactor of VIII

vWF

-produced where?

liver, except VIII

-vit K dep factors

II, VII, IX, X

Anticoagulants (4)

-which is vit K dependent?

1. antithrombin III

2. Heparin - released by basophils and mast cells; supress fibrin formation

3. alpha 2 macroglobin

4. prot C (vit k dependent) deactivates factors V and VIII

3 stages of blood clot formation

*THIS IS ON TEST*

I: prothrombin (II) activator formed via instrinsic and extrinsic pathways

II: converted to thombin

III: fibrinogen to fibrin (factor XIII stabilizes)

PT

-reported in INR, pt:control (sec)

-extrinsic pathway

-warfarin therapy

PTT

-intrinsic pathway

-unfractionated heparin therapy

-not needed for newer fractionated heparin

Causes: vit K def or liver disease

Result: bleeding via coagulation defect

antigen-antibody reactions

some drugs and venoms

circulating cellular debris

retained placental fragments

...can all cause intravascular clotting

DIC (Disseminated Intravascular Coagulation)

Complications:

-exsanguination

-CV shock

-multiple organ failure

-death

-heparin interferes with what stage of clotting?

-heparin interferes with stage II to cut the sequence off.

1) thrombocytosis >1 million

2) arterial thrombi (assoc with endoth cell damage and platelet activation)

3) venous thrombi (assoc with stasis)

Anticoagulant Drugs: warfarin and heparin

-function

-monitoring

-reversal

Blood Clotting Defects

1. Congenital

2. Acquired

1. congenital:

-hemophilia A (factor VIII def 1:10,000)

-christmas disease/hemophilia B (factor IX def)

2. acquired

-liver disease

-vit K deficiency

Thrombolytic drugs (3) for MI/DVT

t-PA

streptokinase

urokinase

1) DNA to mRNA in TRANSCRIPTION

2) mRNA TRANSLATES protein

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Adenine-Thymine

Cytosine-Guanine

Mitosis

1. occur in what cells

2. results in formation of

3. how many divisions

4. how many daughter cells/cycle

Mitosis

1. occur in somatic cells

2. results in formation of 23 pairs of chromosomes

3. 1 division

4. 2 daugher cells

Meiosis

1. occurs in

2. results in formation of

3. how many divisions

4. how many daughter cells/cycle

Meiosis

1. occurs in replicating germ cells

2. results in formation of gametes/reproductive cells, each having single set of 23 chromosomes

3. two divisions

4. four daughter cells

Sex chromosomes

1. men

2. women

Sex chromosomes

1. men XY

2. women XX

1. alt forms of gene, one from each parent

2. position genes occupy on chromosome

3. genes organized in structures

1. allele- alt forms of gene, one from each parent

2. locus- position genes occupy on chromosome

3. chromosomes- genes organized in structures

Accidental errors in duplication of DNA

1. term

2. three causes

3. why do they occur (3 factors)

Accidental errors in duplication of DNA

1. term - mutations

2. three causes -

a) substitution of 1 base pair for another

b) loss/addition of 1+ base pairs

c) rearrangement of base pairs

3. Environmental, chemical ,radiation

Arrangment of alleles:

1. person in whom the two alleles of a given pair are the same (AA or aa)

2. persons having different alleles (Aa) at a gene locus

Arrangment of alleles:

1. person in whom the two alleles of a given pair are the same (AA or aa)

homozygotes

2. persons having different alleles (Aa) at a gene locus

heterozygotes

Genetic trates

Disorders of Single-Gene Inheritance (Mendelian)

single gene diseases (autosomal dominant)

1. multiple or skipped generations

2. gender preferences

3. % of the couple's children affection

single gene diseases (autosomal dominant)

1. multiple generations

2. gender preferences equal

3. 50% of the couple's children affection

Autosomal Dominant Single Gene Diseases

1. atrophy and loss of striatal neurons in the caudate nucleus, putamen, and frontal cortex.  Assoc with triplet of CAG on short arm of chromosome 4.

2. mutation in the LDL receptor produces a deficit in receptor abundance, resulting in incr circulating LDL levels.

3. connective tissue disorder manifested by changes in the skeleton, eyes, and CV system due to mutation in gene that encodes in fibrillin, a key compenent of connective tissue

4. platelet adhesion defect

1. Huntington's Chorea: atrophy and loss of striatal neurons in the caudate nucleus, putamen, and frontal cortex.  Assoc with triplet of CAG on short arm of chromosome 4.

2. Familial Hypercholesterolemia: mutation in the LDL receptor produces a deficit in receptor abundance, resulting in incr circulating LDL levels.

3. Marfan's Syndrome: connective tissue disorder manifested by changes in the skeleton, eyes, and CV system due to mutation in gene that encodes in fibrillin, a key compenent of connective tissue

4. Von Willebrand's Disease: platelet adhesion defect

Cystic Fibrosis:   most common AR disease, mutation in gene result in absent or abnormal expression of the chloride channel as well as misregulation of a sodium channel.

Sickle Cell Disease: seen in 1/600 African American births. Caused by mutation in the ß-globin gene on chromosome 11, alters the hemoglobin molecule, erhthrocyts assume “sickle” shape under condition of low oxygen tension.

seen in 1/600 African American births. Caused by mutation in the ß-globin gene on chromosome 11, alters the hemoglobin molecule, erhthrocyts assume “sickle” shape under condition of low oxygen tension.

Autosomal Recessive Single Gene Disease

x-linked (x-chromosome) single gene diseases

1. gender affected

2. generations affected

3. % of sons with trait/disease

4. List 3 disease

x-linked (x-chromosome) single gene diseases

1. gender affected - Men

2. generations affected - skipping common

3. % of sons with trait/disease - 50%

4 . Hemophilia A, Duchenne muscular dystrophy, fragile X syndrome.

X-linked recessive single gene diseases

1. Deficiency of clotting factor VIII, a protein that is encoded by a gene on the long arm of the X chromosome.

2. mutation in gene that encodes dystrophin, vital muscle protein.

3. Associated with a fragile site on the X chromosome where the chromatin fails to condense during mitosis

Second most common cause of mental retardation after Downs Syndrome

Hemophilia A: Deficiency of clotting factor VIII, a protein that is encoded by a gene on the long arm of the X chromosome.

Duchenne muscular dystrophy: mutation in gene that encodes dystrophin, vital muscle protein.

Fragile X syndrome:

Associated with a fragile site on the X chromosome where the chromatin fails to condense during mitosis

Second most common cause of mental retardation after Downs Syndrome

Trisomy 21 - alterations in chromosome #.

Related to maternal age.

monosomy X (23)

1. syndrome and chromosome

2. % spontaneously aborted

3. absence of

4.most common genetic cause of

5. webbing of

6. lymphadema of

monosomy X (23)

1. turners syndrome (45, X)

2. 99% spontaneously aborted

3. absence of ovaries

4.most common genetic cause of amenorrhea

5. webbing of neck

6. lymphadema of hands and feet

Polysomy X: XXY or XXXY

1. syndrome and chromosome # affected

2. sex

3. characteristics

Polysomy X: XXY or XXXY

1. syndrome and chromosome # affected. klinefelter's syndrome (47, XXY)

2. sex males

3. characteristics tall, seminiferous tubule dysgensesis, gynecomastia

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Radiation

Chemicals/Drugs

Infectious Agents

rubor

tumor

calor

dolor

functio laesa - loss of function

Steps in Acute inflammation

1. initial vasoconstriction at injury site

2. vasodilation of capillaries - slow/incr blood flow to area

3. Leakage of plasma prot= edema

4. Incr blood flow causes incr warmth and redness, tumor, loss of function

1. neutophils and monocytes: phagocytes adhere and emigrate to and through BV walls

2. Chemotaxis - attracts leukocytes

3. phagocytosis

Inflammatory response activates 3 key plasma protein systems:

1. COMPLEMENT: Classical (antigen-antibody), lectin (bacterial carbs), alt (gm neg and fungal cell wall) pathways.

2. CLOTTING: fibrin

3. KININ: bradykinin causes vasodilation, induces pain (w/PGs), smooth muscle contraction

5 Chemical Inflamm mediators

¨CAN SHIP¨

1. Cytokines

2. Arachidonic Acid Metab (PGs, Leukotrines, thromoxane A2)

3. Nitric Oxide - sm muscle relaxation, phagocytosis

4. Serotonin/Histamine

5. Platelet activating factor

Cellular bags of granules located in loose connective tissue, close to blood vessels and areas exposed to environment

-locations (3)

-activated by...

Mast Cells:

-skin, GI, Resp

-Activated by physical inj, chemicals, immunologic, TLRs

Cytokines

1. produced by macrophages

2.  protect against viral infections

3. initiates inflam response, causes muscle wasting (cachexia), its antibodies used to treat RA/inflamm diseases

1. interleukins: produced by macrophages

2.  interferons: protect against viral infections

3. TNF alpha: secreted by macrophages. initiates inflam response, causes muscle wasting (cachexia), its antibodies used to treat RA/inflamm diseases

chronic inflammation

-after what time pd?

-infiltration of...

-what forms?

-what fuses? surrounded by...

-after 2 weeks

-infiltration by macrophages and lymphocytes

-granulomas form

-macrophages fuse to multinucleated giant cells.  surrounded by lymphocytes

Errors in reconstruction

1. a large raised scar extending beyond the margins of the original wound; improper collagen formation

2. raised but stays within boundaries of wound.

3. pulling apart at the edges, greatest 5-12 days after suturing, often with wound sepsis/excessive strain/obesity  may see serous drainage from wound; needs surgical repair

4. deformity at the site of the wound; functio laesa (decreased ROM) burns, cirrhosis, duodenal strictures from ulcers healing

Errors in reconstruction

1. Keloid: a large raised scar extending beyond the margins of the original wound; improper collagen formation

2. Hypertrophic Scar: raised but stays within boundaries of wound.

3. Wound Dehiscence: pulling apart at the edges, greatest 5-12 days after suturing, often with wound sepsis/excessive strain/obesity  may see serous drainage from wound; needs surgical repair

4. Contracture: deformity at the site of the wound; functio laesa (decreased ROM) burns, cirrhosis, duodenal strictures from ulcers healing

1. cell growth not regulated by external signals

2. cells can invade other tissues

invasion: direct penetration of CA into neighboring tissues

metastasis: CA penetrates into lymph and blood to get to distal tissues

80% of cancerous mutations occur in what cells?

-dominant or recessive?

-due to what genetic action?

germline mutations tend to affect what genes?

somatic cells

-dominant (expressed)

-translocation

germline mutation affect tumor suppressor genes

Cancer Gene Classes

1. Protooncogenes: promote nl cell growth but are converted to oncogenes with mutation or incr expression

2. oncogenes: assist in turning nl cells to tumor cells

3. tumor suppressor genes: with malfunction, result in unregulated cell growth

Protein subfamily of small GTPases which function as on/off switches to cell growth, differentiation, and survival.  Inappropriate activation = CA.

-what % of adult Cancer has to do with this pathway?

RAS- family of 3 subproteins

50% of adult CA

This gene incodes for transcription factor and when mutated, causes cancer. 

-Regulates expression of what % of all genes?

-involved in the developement of what specific CA?

Myc

-15% of all gene expression

-Burkitt's Lymphoma

Hereditary nonpolyposis colon cancer (HNPCC) due to DNA repair system mutations.

-colon cancer in 3+ individuals of 2+ generations

1. loss of p53 (tumor suppressor gene)

2. gain of oncogene Bcl-2 (apoptosis inhibitor)

what family of protooncogenes are implicated in proangiogenic factors.

What pharmacologic drug fights this protooncogene family, used in the tx of many solid tumors.

VEGF family.

Bevacizumab (monoclonal antibody) vs. VEGF

molecular/tissue based assay which predicts future behavior of cancer

1. breast cancer (2)

2. colorectal cancer

3. pancreatic cancer

Biomarkers: molecular/tissue based assay which predicts future behavior of cancer

1. breast cancer: HER2, estrog/prog receptors

2. colorectal cancer: CEA

3. pancreatic cancer: CA 19-9

1. Tumor Lysis Syndrome: spontaneus/treatment related cell death releases K, Phos, uric acid, overwhelming kidneys.

-prophylaxis (hydration, allopurinol, phos binders)

-acute hemodialysis

2. SVC syndrome: obstructed blood flow from small cell R lung cancer, lymphoma, mediastinal CA, breast cancers.  DYSPNEA, facial/arm swelling, cough, chest pain, dysphagia

-CT

-XRT/chemo

-stenting

3. Spinal Cord Compression: 5-10% of CA pts have mets from breast, prostate, lung, lymphoma.  Motor and sensory complaints, saddle paresthesias, overflow incont.

-MRI entire spine

-corticosteroids ASAP, even before dx

-radiation

-surgical decompression

1. hypercalcemia (bones, groans, and psychiatric moans)

-hydration, biphosphonate, plicamycin, calcitonin

2. pain: somatic, visceral & neuropathic

-opiods

-ASA, aceta, COX II inhib, NSAIDS

-analgesics: anti-dep, anti-conv, corticoster, benzos

3. CNS symptoms, consider brain met.  H/A, focal weakness, alt ment stat, seizure, ataxia.

-MRI

-prophylactic anti-seizure meds

-radiotherapy, stereotactic, surgery

Fusion of BCR and ABL1 genes leads to ...

what CA is this seen in?

abnormal chromosome 22 (philadelphia chromosome) and dysregulated tyrosine kinase activity

...BIOLOGY OF CHRONIC MYELOID LEUKEMIA...

ductal carcinoma

(upper outer quandrant)

-partial mastectomy (lumpectomy) with local radiation vs.

-radical mastecotomy

-MRI to r/o other involvement

-sentinal lymph node biopsy

-BRCA testing

-5 years hormonal therapy (Tamoxifen)