What are some of the characteristics of bone marrow tissue?
soft, spongy, very vascular, rich in blood supply RES endotheial cells provide stucture to marrow
What molecules are involved in controlling differentiation of hematopoiesis cells?
cytokines- chemical signals( are synergistic, lineage specific) growth factors- hormones- c-kit kigand causes further stem cell proliferation receptors- binding sites for chemical signals- cell surface(bind cytokines and growth factors)
What are some characteristics of stem cells?
morphology resembles a lymphocytes high nuclear:cytoplasm ratio light blue cytoplasm purple, open nucleus
Why cant we use heparin or Na citrate for specimen collection?
heparin- distorts morphology, clumps plasma Na citrate- causes dilutional error
how quickly should one perform a blood smear? when is it unacceptable?
within 2 hours of draw. unacceptable after 4 hours
What are the solutions involved in a Wright stain?
polychrom methylene blue eosin methanol(fixer) potassium and sodium phosphate buffers
What does the ideal pH on a wright stain look like?-generally
stains cellular detail with good resolution. cell borders are distinct. chromatin patterns are apparent.
What is the optimum cellular color?
RBC's- mauve or salmon. free from artifacts
too acidic ph looks like?
nuclear characteristics are pale blue cytoplsams looks gray instead of blue RBC's appear bright red/orange eosinophils granules are brilliant red-orange lact cellular contrast
causes of acidic pH?
stain time too short. extended buffer time. excess washing. old stain
too alkaline pH look like?
nuclear details appear deep dark purple blue with little ocntrast in chromatin patterns. neutorphil granules appear large and toxic. RBC are blue-green. eosinophils granules are blue-gray. lymphocytes cytoplasm is gray-lavender
causes of akaline pH?
smear too thick, extended staining time, insufficient washing, fresh stain, not aged
What is rouleax, agglutination?
roulaux- coin like stacking agglutination- clustering due to antigen interaction
tube length, tilt, temp, timing of test, surface vibrations, bubbles
three methods of ESR testing
westergren, wintrobe, mini- VES
what are the functions of hemoglobin
transfer o2, transfer co2, buffer blood. hct=3xHgb. 1/3 of RBC volume and 90% of weight=Hgb
what is hemoglobins stucture
Hb is a fluic protein that transports gases. tetramere with 4 globin units. two dimer protein pairs. oxygen attaches to a heme unit(2 alpha and 2 beta chains) must be in 2+ oxidation states
folding of globin units creates a hydrophobic pocket for the heme unit
What kind of Hb dimers are formed for a globin chain?
a2b2, a2g2, a2sigma2
What is the fetal hemoglobin? Where is it produced and what is its affinity for oxygen?
a2gamma2 predominant Hb in fetus. produced in lilver ad spleen. HbF has a higher affinity for o2 than HbA1
What is the adult hemoglobin?
HvA1(alpha2beta2)- predominant hgemoglobin of adults. beta chain synthesis does not exceed gamma chain synthesis until after birth. following birth, HbA will increae fo rthe next 12 months and HbF will be made in small amounts
What is the alternate hemoglobin?
HbA2 (alpha2 sigma 2) occurs late in fetal life. delta chain production begins 7.5-8 months gestation. 2.5% normally found post birth
What are the proportions of Hb at birth? In adulthood?
at birth- HbF-70% HbA1-30% adult: AbF-1%. HbA1-97%. HbA2-2.5%
What are some important steps in globin synthesis?
cells must have DNA. 65% of hemoglobinization is complete while thenucleus is intact 35% of Hb is assembed after nucleus is extruded assembly of chain occurs attached to ribosome.
What are some important steps in heme synthesis?
Heme is porphyrin ring + ferrous iron synthesis of heme occurs between the mitochondria nd cytoplasm of the red cell goes to cytoplasm when heme unit is complete and combines with globin chain
What are the steps of heme synthesis?
Delta-aminolevulinic aci is the rate limiting step
What is the molecule that causes O2 to be released more readily?
Factors that shift Hb curve right?
dec pH, dec pO2, inc temp, inc pCO2, in 2,3 DPG
Excess H+ is bound to what?
What is the Bohr effect and chloride shift
chloride shift accounts for 70% of CO2 transpotation to lungs. 25% of CO2 is directly bound to Hb and transported 5% is dissolved in the plasma
How is Hb measured? How is the test completed?
Whole blood is added to modified Drabkin's reagent. The red cells are lysed: Hb is released. All Hb is converted to the ferric state Fe+3 of metHb. MetHb is converted to cyanmethemoglobin by KCN. Absorbance measured at 540nm. RUN IN DUPLICATE
What is Drabkin's reagent chemical name?
potassium ferricyanid (K3Fe(CN)6
What is carboxyhemoglobin and what are some symptoms?
CO bound to heme. lips and nails have a cherry red color. CO: heme binding is 200% stronger than 2 acute carboxyhemoglobinemia=death smkers ahve increased CO level
What is extravascular degradation and what are the important steps?
Histiocyte reticular endothelial cells phagocytize red cells.
What is the clinical utility of MCV, MCH, MCHC?
indices help categorize enemias- abnormal morphology can be calssic for a disease state indicate iron storage levels. monitor transfusion therapy- MCV is patient specific
-Phlebotomy to remove RBCs and lower viscosity and make patient iron deficient to slow RBC production
note polycythemia rubivera is an inappropriate response cuz the oxygen tension is normal in one's body
Sx of polycythemia rubivera
The 4 Hs -Hypervolemia -Histaminemia -Hyperuricemia -Hyperviscosity
Hypervolemia: the plasma for some reason matches the rbc production for some reason Histaminemia: clx itchy, causes VD -> Headaches Hyperuricemia: Hematopoesis is up -> recycling of purines -> uric acid. This extra uric acid can bust the kidneys up and this is called Tumor lysis syndrome. Tx w/allopurinol
What are the levels of rbc mass, plasma volume, oxygen saturation, and erythropoetin like for poly rubivera and for high altitude/COPD
Poly Rubivera -RBC mass is up -Volume is up -Oxygen sat is normal -erythropoietin is down.....this hormone response to low oxygen tension
In high altitude or COPD -RBC mass is up -Volume is normal -Oxygen sat is down -Erythropoietin is up
-Normocytic anemia -always causes anemia -usually low platelets -usually high WBCs -metastases usually to lymph nodes and spleen -Blasts in blood -Acute vs chronic leukemia: do a blast count in the bone marrow if less than 30% are blast it's chronic
Type of leukemia age brackets
0-14: ALL 15-39: AML w/Auer Rods and acute myeloblasts 40-59: AML, CML pick one w/a blast count or philly chromosome in CML 60 or more: is CLL CLL is the most common regardless of age Most common cause of someone over 60 w/non-tender swollen lymph nodes is CLL-these are metastases to lymph nodes
The 2 tests for CML
1. Leukocyte Alkaline Phosphatase stain. Neoplastic CLL cells don't have this. CML has a low LAP score 2. Identification of the philly chromosome
What is extramedullary hematopoesis
Hematopoesis outside of the bone marrow
What is Agnogenic Myeloid Metaplasia
Occurs in myeloid proliferative disorders. -All hematopoetic cells move to the spleen and a couple stay behind. Megakaryocytes that stayed behind start laying down collagen -> fibrosis. Cells that remain have to get out of the cords that are not all thick and they get sheared -> tear drop cells
What kinds of Antibodies do you make in chronic lymphoblastic leukemia?
NONE These are undifferentiated blasts thus they can't get to plasma cells
What is the marker for Acute lymphoblastic leukemia
CD10 on B cells
How do you test for Hairy T Cell Leukemia
TRAP stain tartrate resistant acid phosphatase
Which cancer likes to invade gums
What are the 3 main features of acute progranulocytic leukemia
-Translocation of chromosome 15-17 -DIC -Retinoicacid is the treatment as it causes the undifferentiated cells to progress.
What are the highlights of CML
-Neutrophilia in PBS -Thrombocytosis in PBS -Philly Chromosome leads to a tyrosine kinase being on in pluripotent HSCs. -Shortened chromosome 22 -Bone Marrow Hyperplasia -Sx: fatigue, weightloss, early satiety, leukostasis, urticartia from too many basophils -Mild anemia*: even tho it's a myeloproliferative disease! ->pallor -Splenomegaly -Arthritus from uric acid deposits -In PBS you see all stages of cell differentiation -hypersegmented neutros -Completely environmental and there's no hereditary component -Age onset is 50s
What can too many neutrophils do in CML
-Sx of dyspnea, slurred speech, blurry vision, confusion. -Priapism, hemorrhage all due to sludging of leukocytes
neutrophils are sticky and cause these sx
In CML what is the leukocyte alkaline phosphatase like and B12 level
The leukocyte alkaline phosphatase is some stuff only in normal neutrophils and since these are malignant .... -B12 is increased but no one knows why
What is the blast crisis?
Its in CML where there's less differentiation all of the sudden and it starts looking like leukemia and sx get worse. -Possible extramedullary hematopoeisis.
What are the tx for CML
Interferon-no one knows how it works -BM transplant -Imatinib (gleevac): targets the tyrosine kinase of the Bcr-Abl protein
Describe Polycythemia Vera
-This is the erythrocytosis disorder -"Increased RBC mass, not count" -Vertigo, visual probs, fuzzy, early satiety all due to higher blood viscosity -Onsets 50-60s y/os -Pruritis regardless of hot or cold shower -Sx are similar to budd chiari of abd pain, ascites, and HSM -Dx it by elevated RBC and Hct w/o any secondary cause ie low oxygen tension or COPD. Ex if erythropoeitin is low and ur Hct is super high -Neutrophilia and thrombocytosis -Iron deficiency* but no anemia -Marrow is hypercellular w/inc megakaryos and no iron can be seen.
Labs for Polycythemia Vera
-Normal O2 sat -Hyperuricemia -Decreased erythro -Elevated B12
Fakers of the disease would be cardiopulmonary disease and kidneys make more erthryo, high altitude, CO poisoning.
Tx for P vera is phlebotomy and allopurinol
Decribe Essential Thrombocytopenia
-target age is 50-70 -Erthromelalgia where BVs get blocked and inflamed -> seen as burning soles and palms -Thrombosis -Leukocytosis and marrow fibrosis -NO! splenomegaly Labs: increased Hct, RBC mass, plasma volume Microcytosis, neutrophilia, basophilia -Marrow hypercellular w/iron completely absent
Tx: anagrelide-prevents budding of platelets off megakaryocytes
Describe myelofibrosis which is another myeloproliferative disease
-Leukocytosis, thrombocytosis, and anemia -May go into a blast phase in 5-10 yrs -Death by an enlarged spleen
-ineffective blood cell production -May progress to leukemia -These are busted hematopoeisis disorders that have a tendency to go toward AML -Hypoproliferative macrocytic anemia is present -BM is hypercellular
Test: in CML what are the labs like for WBC, RBC, Plt, LAP score Spleen
WBC up RBC slight down Platelets up LAP down Spleen up
100% of people will go to blast crisis
Test: in CML what are the labs like for WBC, RBC, Plt, LAP score, Spleen
WBC up RBC up Plt up LAP score up Spleen is regular
Some go to blast crisis
Test: In essential thrombosis What is the WBC,RBC,Plt,LAP score, Spleen
WBC up RBC regular Plt Up LAP reg or slight up Spleen regular
Test: In MyeloFibrosis Whats the WBC,RBC, Plt, LAP score, spleen
WBC up RBCs down Plt up LAP normal Spleen up
Less than 20% go to blast crisis
In myelodysplastic syndromes Whats the WBC, RBC, Plt, LAP, and spleen like
WBC Down RBC Down Plt Down LAP Down Spleen Up
Sx of acute leukemia
Sx are due to failed hematopoeisis -fever, weakness, bleeding -pallow, petechiae, HSM
Types of Leukemia
1. ALL 2. Acute myelogenous leukemia
Difference between AML and CML
In AML all the symptoms and effects are quick -The BM is non-differentiated, it just blasts -Other cells are quickly pushed aside in the marrow causing a decrease in RBCs, platelets -You see oral lesions because there's no differentiated cells at all ie no neutrophils and thus mucus membranes ->oral lesions
AML sx -bleeding -Adenopathy -Splenomeg -Lekostasis
Sx of AML
Adenoids -Pancytopeia comes on quick cuz there's no differentiation Oral/rectal lesions -Lactose Dehydrogenase is increased -Associated w/Bloom and Fanconi syndrome which mess w/chromosomes -Hb down -bleeding from gums -Gums hypertropy -Ecchymoses -Congestive Heart failure -DIC -15:17 translocation -Kidney failure due to extra uric extra depositing in the kidney
AML bone marrow
BM is all blasts and no differentiation at all -Huge nuclei, little cytoplasm = blast -Not shown well in this pic but Auer rods are dx of AML
There are many different kinds of AML and they differ by the amount of granules in the cytoplasm of the blast cell. The pic shown here has no granules and makes it less curable cuz there's multiple chromosome abnormalities in these Types w/granules are usually due to a 15:17 translocation and are curable
Other possible chromosomal changes that might lead to AML
Missing a chromosome 5 or 7 Trisomy of 8 Missing chromo Y in a cell trisomy of 4
There's many different chromosomal abnormalities for the many types of AML. 2 are a translocation between chromosome 8 and 21 another type is translocation between 15:17
The translocation 8:21 and 15:17 are highly curable while ones like 9:22 are not favorable
Describe Acute Promyelocytic Leukemia
-sub type of AML -DIC-hemorrhaging is their main sx to come in to the doctor -Azurophilic granules-auer rods -t(15:17) or (11:17) -death form intracranial hemorrhage -This cancer type can be forced to differentiation by retinoic acid -This means that this subtype is highly curable -Also u can tx the sticky neutrophils with steriods which makes them unsticky. -This is the only cancer where u can do differentiation therapy....not prostate or breast cancer -APL translocated a retinoic acid receptor gene when it did the 15:17 and this makes it different from regular AML
Factors for poor survival and remission of AML
-Bad risks -elderly -prior radiation -transloc of 5 and 7 or mutations of those chromosomes -male gender -APL is usually in younger people -hx of preleukemia -higher white count
all lead to poor survival
Avg survival of AML
2 years and peeps die of pancytopenia and infection
-Cancer of immature B cell that can occur at the bone marrow stage or any stage in between becoming a plasma cell at a lymph node -If in BM it'll push aside everything else so no platelets or neutrophils -Usually a cancer of pre-B cell -CD 10 is the marker for this -Tdt + and CALLA+ which is common ALL antigen, CD10+ -A bunch of huge B lymphoblasts indicating that they're precursors
Subtypes of ALL
-Childhood type called L1 -Adult called L2 -Burkitt's lymphoma called L3 (transloc of 8:14)
The adult ALL can have a philly chromosome -ALL is PAS+ which is positive cytoplasmic granules (lymphenate) in blasts
Most B cell lymphomas occur during/after class switching
-CLL is before the lymph node -Hodgkins come from a broken germinal center -Multiple myeloma is a plasma cell -A memory B cell is burkitt's lymphoma and malt lymphomas
Describes Hodgekin Lymphoma
-Starts in a single node and moves contiguous orderly, node to node -Has RS cells
How to tell if a blast is from ALL or AML
AML stains w/peroxidase and Sudan Black B stain Sudan B will stain myeloblasts but not lymphoblasts Also no Auer rod in ALL, But AML doesn't ALWAYS have Auer rods -ALL is TDT+, CALLA+, and CD10 a pre-B cell marker. Tdt is used in B and T lymphocytes
Acute promyelocytic Leukemia
-Azurophilac granules -DIC -Translocation 15:17 or 11:17 -PML-RAR alpha -Tx retinoic acid -Distinct feature of APL is DIC caused by granules that activate thrombn and factor 10 and 2
Lymphoma vs myeloma
-Lymphoma tend to occur at immature B at a node or pre-B in BM -Myeloma occurs in a plasma cell
Describe Hodgekin's Lymphoma
-Starts in a single node and can spread to adjacent ones -Has a double incidence where its high in kids and elderly unlike NHDG where risk goes up w/age. -Slow progressive disease -Malignant cells are a small % of the tumor -First cancer curable w/chemo -Malignant cells called Reed-Sternberg cells which are large bi-nucleus cells w/prominent nucleoli -RS cells are transformed B cells
Describe RS Cells
-transformed B cells in a lymphoma -Lack all B and T cell antigens -Variable expression of CD20+, but usu always express CD15 and 30+ -bi-loped nuclei and eosinophilac nucleoli call owl's eye
What are the 5 classical Hodgekin Lymphoma Subtypes
Describe Nodular Sclerosis HDG This one is the the most common
-Nodular w/fibrous bands separate the lymph follicle -Have lacunar variant cuz there's space around th RS nuclei -Loss cytoplasm
Describe Lymphocyte rich classical HDG Lymphoma
-RS cells w/bunch of lymphocytes -Rare or no eosinophils -Nodular pattern w/no fibrosis
Describe Mixed cellularity Hodgekins
-RS cells w/histiocytes -lots of eosinophils -lots of plasma cells
Describe Lymphocyte Depletion HDG lymphoma
-Fibrosis -Lack of inflammatory cells -RS cells
Describe Nodular lymphocyte predominant HDG
-Nodular -distinct type of RS cells w/L&H variants wpopcorn shaped nuke -CD20+ -This type of HDG doesn't req chemo
Pic of nodular HDG lymphoma
Dense collagen bands separting tumor nodules
Hodgekin Lymphoma Clx presentation
-Painless adenoid in neck or axilla -fever, night sweats, weight loss, pruritis -Mediastinal mass where it might be located causing chest pain, dry cough -Pruritis may occur at tumor site w/consuming alcohol -HSM -on ct or xray u see a widening of mediatrinum "Drink a beer and get itchy"
How to dx hodgekin
-Excisional biopsy ie not needle biopsy so you can see the fibrous bands. -Increased ESR, LDH are both elevated -Easy to pick up in PET scan -Only do a BM if super advanced cuz lymphomas don't start out in the bone marrow
Ann Arbor HDG and NHDG lymphoma staging
stage 1 one lymph node stage 2 two or more sites on same side of diaphragm stage 3 both sides of diaphragm stage 4 more than one organ outside lymphatics
Risk factors for HDG
-Male -Over 45 -Low Hb under 10 -Super high or low WBCs -Low albumin
For high risk cases add BEACOPP which includes prednisone
85% cure rate for HDG
Difference between NHDG and HDG
NHDG u die way more Most of the tumor cells in NHDG are malignant cells unlike HDG -HDG lymphomas are called that because they have an ordered spread from one lymph node to the next -HDG lymphomas have RS cells
Describe NHDG Lymphomas
-Lymphocytic lymphomas which are like the lymph node form of CLL -Burkitts lymphomas -follicular lymphomas -mantle lymphomas -diffuse large cell lymphomas
Describe Burkitt lymphoma
-IgH-Myc translocation -It is a diffuse large B cell type NHDG lymphoma -Produced by an 8:14 translocation -Gives a starry sky appearance in histo: macrophages in the lymph node eating up a bunch of dead cells
Even tho this is a cancer of lymphatics the bone marrow will show blasts with vacuolated cytoplasm and prominent nucleoli LDH will be very high
The types of NHDG lymphomas
-Follicular lymphomas-Most common adult lymphoma and hits B cells, t(14:18) -Diffuse large B cell: adults more than kids get it. It is mostly B cell. Usu presents w/extranodal mass. -Lymphoblastic lymphoma which is the most common child form. Usu presents w/ALL and a mediastinal mass. This is formed of immature T cells -Burkitt's lymphoma-hits adults and kids and made of B lymphocyte. -Small lymphocytic lymphoma-hits adults ad isof the B cell type. Can do richter's transformation into diffuse B cell lymphom
A diffuse large b cell lymphoma
A follicular B cell lymphoma
Follicular type is the only B cell lymphoma w/nodules
Aggressive NHDG vs Indolent
Aggressive : -diffuse large b cell lymphoma -quick growth, painful -extranodal sites like lung, kidneys -acute ilness -more common than indolent -CD20+ -Not tx w/surgery cuz grows so quick 60% of it stays in nodes and 40% goes elsewhere -The more mature the B cells in the lymphoma are the better the tx outcome -Tx is R-CHOP and stem cells
Indolent -follicular, small lymhphocytic -slow growth -just in lymph nodes -cytopenia from BM involvement is common -Tx w/rituximab to CD20
Another type of less common NHDG is Marginal zone lymphoma
-Includes MALT lymphoma -Indolent type slow grower -good prognosis -CD20+, CD5-,CD10-,CD23- -Very responsive to rituximab -Driven byH.Pylori
Another type of NHDG is Small lymphocytic lymphoma
-Sim to CLL (which is known for its smudge cells) but it's in a lymph node -CD20+, CD5+, CD23+ -Involves nodes, spleen, liver, BM -Can undergo "Richter's transformation" where the lyphmoma can change into a diffuse B cell lymphoma -Makes densely packed lymphocytes overcrowding the blood = smudge cells
Another type of NHDG is mantle cell lymphoma
-Involves GI tract -lyphoid polyposis -transloc 11:14
NHDG T cell lymphomas
-Super aggressive compared to B -Diffuse erythroderma -skin peeling -Sezary syndrome = diffuse erythroderma. Sezary cells : brain shaped nuclei in lymphocytes -Most are cutaneous T cell lymphomas -super itchy, dry skin
CHOP Cyclophosphamide Hydroxydaunomycin Oncovin Prednisone point is not to use overlapping toxicities
True statements about lymphomas
All hodgekin lymphoma and 90% of NHDG are derived fro mB cells Overall Hodgekin can be cured in 85% of cases The dx procedure for painless lymph node is excisional biopsy Rituximab is used only in NHDG
In AML you have leukostasis and low RBCs should you do a red cell transfusion?
no because the high number of leukos causes leukostasis or plugging of capillaries in brain, lungs -> dizziness and SOB and more RBCs->viscosity = fuel for the fire
Don't forget Auer rods distinguish between AML and ALL
Difference Between AML and CML
AML -px has too many immature granulocytes Auer Rods Lysing these white cells, these rods can -> gout -AML gets the fab classication of like M2 and M3. M2 has natural granulocyte maturation and M3 is very responsive to retinoic acid ie promyelocytic ones -M2 t(8:21) -M3 t(15:17) -M2 and M3 are both favorable
CML -px has too many differentiated granulocytes philly chromosome -Uses bcr-abl inhibitor imatinib
family history means nothing in both
Tx for AML
Induction chemo followed by consolidation chemo to get rid of residual tumor cells
How do you know if a leukemia is in the acute or chronic form
Acute u see nothing but blasts and chronic u see some differentiated cells acute can kill w/i 3 months cuz all u have are blasts
What is TdT like in lymphoma?
In lymph node cells are atleast immature B cells meaning they are not TdT positive so in lymphomas u see TdT-
Man gets a biopsy of a mediastinal mass and it looks like this
What is this?
Burkitts starry night many cells of one kind ie macrophages eat dead stuff and they are the white cells in the pic
Clinical case of a women w/a non-healing tongue ulcer who was dx w/leukemia earlier
she has a granulocytic sarcoma or chloroma -u tx this as leukemia cuz this is an example that leukemia can deposit into tissues -Subtype of AML most associated with chloromas is M5 which is a monocytic leukemia -AML M5 is infiltrative
Adjuvants-give when no longer can see disease or after surgery Neoadjuvants-give before a surgery Salvage-first therapy didn't work so try something else, like palliative therapy. Induction-given to reduce remission Consolidation-get residual tumor cells Maintenance-given a long time after remission
Name two diseases or tumors where chemo does nothing
adenocarcinoma and GI adenocarcinomas
Clinical trial stuff
stage 1-seek a tolerable dose 2. What's a max dose 3. how efficacious comared to other 4. in the markt
Drugs for cancer
Alkylating agents-make DNA breaks Antibiotics-blocks DNA unwinding Plant alkaloids-Inhib MTs Camptothecins-Inhib topo 1 Antimetabolites-trick immune system Hormonal Agents-may cause a cell to mature Novel Therapies- new stuff like giving retinoic acid
Alkylating agents for cancer
-Nitrogen mustard -Creates a Carbon+ like an electrophile which binds to nitrogen in DNA bases which causes DNA breaks -Toxic to ears and kidneys -They alkylate DNA -> repression -drug names: cyclophosphamide, mechlorethamine, ifosfamide, busulfan, dacarbazine, procarazine
Antibiotics for cancer
-Binds DNA between base pairs and prevents uncoiling of DNA, this is called inter-chelating -Also can inhibit topoisomerase 2 which is used in cell development -Side fx: cardiotoxic, alopecia, myelosuppression. -drug names: doxorubicin, duanorubicin, bleomycin, procarbozine, dactinomycin
Plant alkaloids for cancer
-Inhibit microtubules -Includes the drugs vinca alkaloids, taxanes, camptothecins, and epipodophyllotoxins -Vinca alkaloids are neurotoxic, and from the perrywinkle plant. Side effects are marrow suppression, and they eat up MTs in nerves. Drug names are vincristine and vinblastine
-Taxanes from the yew tree. causes way too many microtubules but has some complex way of stopping them. Drug names are paclitaxel, docetaxel. Adv effects are neuro and arthralgia
Camptothecins: inhib topoisomerase 1-> DNA breakage. Drugs names ironotecan, tpotecan. Side fx are myelosuppression and cholinergic reaction
-Epips inhibit topoisomerase 2. Drug names for Epis are etoposides, teniposides.
Antimetabolites for cancer
-Antimetabolites: like antifolates, substitute for metabolites that are normally put into key molecules. Drug types are methotrexate (inhibs dihydrofolate reductase -> inhibs purine and thymidylate synthesis. Side fx are pulmonary, liver, bone marrow suppression -Another antimetabolite is 5-FU which is an inhib of thymidylate synthase -Another antimetabolite is hydroxy urea which does marrow suppression
Note* a second drug class is -Hormonal agents: Tamoxifen is an anti-estrogen. -Novel therapies like retinoic acid for APL Imatinib for CML's Bcr-Abl Rituximab for non-hodgekin lymphoma. Trastuzumab
A primary polycythemia has a high or low erythropoeitin?
All of the sx of polycythemia vera are due to blood viscosity
This HA, weakness, sweating, gouty arthritus, fingers and toes turn red. -HSM due to extramedullary hematopoeisis. -iron deficient -> microcytosis -No stainable iron
How can polycythemia vera kill you
Thrombosis transformation to acute leukemia Myelofibrosis with myeloid metaplasia
Pvera bone marrow biopsy
hyper cellular w/high number of megakaryocytes no stainable iron either
also note that 95% of peeps w/p vera have a JAK2 mutation
Tx for pvera
ASA Hydroxyurea anagrelide phlebotomy
In CLL what cell markers are there
U have B cells w/CD19, 20, 5. Usually cd5 is on a T cell When u see these 3 CDs on a b cell it auto means CLL -This can lead to autoimmune hemolytic anemia
Sx and smear of hairy b cell leukemia
-TRAP stain-shows hairy cell -"doc i finally dropped this extra weight that i haven't been able to get rid of"
Slide of essental thrombocytopenia
jak2 mutation only occurs in like 50% of these so can't make a dx based on it
Where are the B cells located that have CD19/20,
If B cells have CD19 and 20 they are in the blood
B memory cell cancer is CLL Plasma cell cancer is Myeloma
-Myeloma makes multiple copies of one antibody -It looks hyperglobulinemia but actually it's hypo cuz u lose diversity of other antibodies due to suppression molecules and u can't fight encapsulated bacteria -People die by infxn of encap bacteria
Describe myeloma's pathogenesis
After it becomes crazy in the lymph node it infiltrates the bone marrow -Suppression of platelets, rbcs, other white blood cells ->pancytopenia -It activates osteoclast activity ->bone lesions -Causes hypercalcemia and these deposits can hit the kidney
Clinical presentation of myeloma px
-Focal bone pain -Comes in w/broken arm or leg -High levels of the particular antibody that is being made can be found in the blood. -The high serum Ig being made can make the blood viscous -> sx -Myeloma is monoclonal so like it's only idiotype of an IgG or IgM not all of one isotype being over produced
Diagnosis of myeloma
-Monoclonal plasma cells inbone marrow -The specific myeloma proten/Ig in the serum or urine -Myeloma related organ dysfxn *u need the last one cuz some elderly can get the first two normally -One may also see excess light chains in the urine or serum -Renal failure w/amyloidosis -It can be hyper Ig whatever ...most common is IgG
BM biopsy of myeloma
Clinical findings are bone fractures pancytopenias infections renal failure-calcium and uric acid hyperviscosity
What is rouleaux (rolo's) sign
In a PBS the high levels of the Ig floating in the blood will null the negative charges in the RBCs and they will stick together...pretty diagnostic -The high levs will also stick to platelets and coag factors which may cause bleeding
Descbe myeloma cells at the level of the bone
They upreg the bone to spit out VGEF for blood They upreg the bone to put out IL6 and TNF alpha as growth factors fro myeloma
The bigger the myeloma mass the worse the survival is
Tx for myeloma
Biphosphonates-turn down myeloma cells interaction at the bone-stim osteoblasts i think Immunomod drugs-thalidomide and lenalidomide-works to block IL 6 and TNF alpha Proteosome inhibitors: all cells have these but myeloma cells are more susceptible
What is waldenstroms macroglobulinemia
Some weird lymphoid-plasmacytoid cell in marrow in blood make a specific IgM but it's not a plasma cell! -hyperviscosity, fatigue, malaise, SOB, bleeding
NO BONE LESIONS THO
What are B sx and who gets them
-Temp greater than 38 -Night sweats -unintentional weight last over 6 months
What is serum protein electrophoesis used to dx
It is used to dx multiple myeloma w/that high Ig specific protein
How to stage a lymphoma
Use Ann Arbor staging Stage 1-4 then A-no B symptoms B: the lymphoma includes the presence of the B symptoms
What is APLES
It is a prognostic index for NHDG lymphoma Age Performance status (of the bug) Lactate Deyhydrogenous up Extranodal involvement Ann Arbor Staging
What is the tx for B cell NHDG lymphoma
Chemo and rituximab
RS cells in a lymph node
RS cells in a lymph node they really stand out
if these looked more like popcorn it would be NLPHL Nodular-lymphocyte-predominant-hodgkins lymphoma
Diffuse Large B Cell Lymphoma
What kind of lyphoma is this and what is the treatment
Follicular lymphoma-outlines of follicules. -The progression is really slow and the disease is incurable so you watch and wait BU if the px has night sweats and loses weight then u do chemo *This is because the follicular lymphoma can turn into a diffuse one.
If you biopsy a lymph node and you see owl's eye's what kind of lymphoma is it
What is a syngeneic bone marrow transplant
A transplant from an identical twin.
Explain in bone marrow transplants why there is a 2 week window risk for infection
It is the time it takes to erradicate the old HSCs and for the new ones to start
When doing HLA matching, how many things do you have to match
3 HLA class 1 x 2 3 HLA class 2 x 2 Total of 12
Sources of stem cells
Bone marrow peripheral blood stem cells umbilical vein
Diseases that a stem cell transplant can cure: leukemias, myeloma,
Why are bone marrow stem cells better than peripheral blood stem cells
They are more immature and thus less likely to have graft versus host disease
What is the process of graft vs host disease
-Prechemo or radiation damages tissues that release TNF and IL1 -Transplant is performed and these cytokines supercharge the donor WBCs -> attack -The attack is a TH1 response
Fx of graft vs host
GVH sx present in the skin liver, GI mostly due to neutrophils Tx for GVH are steroids which make neutrophils less sticky
What is the classic side fx of mono and amoxicillin
What is the classic bug for a cough that leads to vomiting?
note* adults don't ge diphtheria
Name all the erythemas
Erythema migrans-lyme disease targetoid Erythema infectiosum-parvo virus Erythema multiforme from acute drug reaction
Name the two bugs that stupid Ixodes mosquito can carry
Babeosis and lyme disease
How do you test someone for a recent strep infection
serum for Anti-DNAase B
Describe the skin lesions for a fixed drug reaction
Perfect scattered silver dollar circles that are scattered all over
Describe viral meningitis
Normal glucose, high % of lymphocytes
What drug is better oseltamavir or rimantadine
Rimantadine has resistance so Oselt is better Rimantadine only hits Flu A and Oselt hits A and B
What is herceptin
transtuzumab used for HER2Neu breast cancer
4.7-6.1 x 10^6/ uL
4.2-5.4 x 10^6/ uL
4.8-10.8 x 10^3 / uL
150-400 x 10^3 / uL
14-18 g/ dL
12-16 g/ dL
HCT (hematocrit) Male
HCT (hematocrit) Female
MCV (mean cell volume)
MCH (mean cell Hb)
MCHC (mean cell Hb conc)
RDW (red cell distribution width)
1.4-6.5 x 10^3/ uL
1.2-3.4 x 10^3/ uL
.11-.59 x 10^3/ uL
0-.7 x 10^3/ uL
0-.5 x 10^3/ uL
0-.2 x 10^3/ uL
WBC unopette sample volume & diluent volume
25 uL, 0.475 mL
WBC unopette diluent type
TURKS 3% acetic acid
RBC unopette sample volume & diluent volume
10 uL, 1.99 mL
RBC unopette diluent type
WBC/PLT unopette sample volume & diluent volume
10 uL, 1.98 mL
WBC/PLT unopette diluent type
1% ammonium oxalate
Eosinophil unopette sample and diluent volume
25 uL, 0.775 mL
Eosinophil unopette dilution and diluent type
1:32, phloxine B
WBC unopette dilution
WBC/PLT unopette dilution
RBC unopette dilution
WBC x 100 / 100 + nrbc + dmeg
absolute counts =
diff % x cell count
manual retic counts must match by __ %
retic % =
retic count x 100/ 1000 rbc
Heinz body visible with __ stain
RBC x MCV / 10
HCT x 10 / RBC
Hb x 10 / RBC
Hb x 100 / HCT
Hb x 3 =
buffy coat smear used when
wbc < 1 x 10^9 /L
normal HCT for males
normal HCT for females/ children
Sickle cell screen detects which Hb?
S, C harlem, C z
rule of 3: Hb to HCT has to be within ___ % or less than or equal to __ from measured hCT
+ or - 3% or 3
Normoblasts (Nucleated RBC)
Reticulocyt (Supra-Vital Stains
Increased ESR On Peripheral Blood Smear ("Rouleaux Formation"
Aniocytosis (Variation In Size Of RBC) --> Single Arrow: Small RBC --> Large Arrow: Large RBC
Normochromic RBC's --> Normal Hb. Conc
Hypochromic RBC's --> Decr. In Hb --> Incr. in Central Pallor
Hyperchromic RBC's --> Incr. in Hb --> Loss And/Or Decr. In Central Pallor
Polychromasia --> RBC's with >1 Color
Spherocyte -->Hyperchromic Circular RBC's -->No Central Pallor -->Associated with Hereditary Spherocytosis
Macrocytes and Macro-ovalocytes --> Typical In Megaloblastic Anemia --> Low Platetlets -->High MCV -->Hypersegmented Neutrophil
Hgb A1: 5-20% Hgb A2: 2-3% Hgb F: 65-100%
-Homozy= Cooley's anemia -Thal's: Defect in globin chain production -Alpha chains or the beta chains -Mediterranean origin -Evident at 2-3 months of age (when adult hemoglobin production increases) -Severe hemolytic anemia -Death usually occurs in childhood or adolescence
WBCs are classified by their: -Defensive function -Nuclear morphology -Site of origin -Presence or absence of specific cytoplasmic granules > special staining technique required to visualize the cells
WBCs -Wright Stain
Appear BLUE: -NUCLEUS & some cytoplasmic granules -b/c cell structures with acidic groups bind the basic dye & appear blue.
Appear PINK: -CYTOPLASM & some cytoplasmic granules -b/c cell structures with basic groups bind the acidic dye & appear various shades of pink or red-orange.
WBCs -Classification by granule presence & color
Granulocytes -Classified according to staining characteristics of granules. 1. Neutrophils - Lavender 2. Eosinophils - Orange/red 3. Basophils - Blue/black Agranulocytes - lack granules 1. Lymphocytes 2. Monocytes
Differential WBC Count -Procedure
-Place one drop of blood S onto glass slide, spread the drop & air dry.
-Wright's Stain: A mixture of Methylene Blue basic dye and Eosin red-orange acidic dye. -Phosphate buffer applied directly on top of stain, rinse, dry & examine. -Oil immersion [100x] lens: count 100 WBCs -This gives the RELATIVE # of each type of WBC, expressed as a PERCENTAGE of the 100 cells counted.
Differential WBC Count -Calculating the Absolute # of each cell type
-"Absolute" (ABS) Number of cell type: Important for determining if patient has a sufficient # cells of a specific type.
ABS # = (Ttl. WBC) X Relative # of each cell type on the Diff. WBC count.
NOTE: Convert relative percentage to a decimal prior to performing calculation.
WBC Count: -Absolute vs. Relative
Example: -Adult with total WBC = 15,000 -WBC Diff.: * 30% neutrophils * 70% lymphocytes Is this patient REALLY neutropenic? -Abs # neutrophils = 15,000 X 0.30 = 4500 -Patient has a normal absolute neutrophil count and only has a relative neutropenia, NOT V absolute neutropenia.
PluriPotent Stem Cell -> 1. Lymphoid Stem Cell -> A. Thymus > T cell B. NK Cell C. B cell -> Plasma Cell 2. Myeloid Stem Cell -> A. Erythrocyte B. Megakaryocyte -> Platelets (blood clotting) C. Monocyte -> Macrophage D. Granulocytes
WBC -General Maturation Scheme
General Maturation Scheme in direction of less mature to -> more mature
-Cytoplasm: More basophilia -> less basophilia -Large nucleus -> smaller nucleus -Large nucleoli -> Small nucleoli -> then absent -Large cell size -> smaller cell size
Granulocytes -6 general stages of maturation following commitment of stem cell in bone marrow:
1. Myeloblast: Non-granular cytoplasm and red round nucleus
2. Promyelocyte: blast becomes pro when it develops distinct granules
3. Myelocyte [cell division possible through this stage]: pro becomes cyte when granules differentiate enough to be identified n/e/b
4. Metamyelocyte: has a slightly indented nucleus
5. Band: INDENTATION MORE THAN ½ Width hypothetical round nucleus.isthmus with sides wide enough to reveal two distinct margins with nuclear chromatin visible btw them
6. Segmented cell
Picture of Myeloblast
Picture of Promyelocyte, Myelocyte, & Metamyelocyte
Picture of Band & Segmented Granulocytes
band on left, segmented on right
Granulocytes -Classified by staining characteristics
Granulocytes 3 types of cells which have different immune functions. Morphologically similar until myelocyte stage.
1. Neutrophil: fine Pinkish/Lavender granules 2. Eosinophil: bright Orange/red granules 3. Basophil: dark Blue/black granules
WBCs -Granulocytes 1. Neutrophils/PMNs
-All PMNs capable of phagocytosis -Neutrophils are the most common PMN (polymorphonuclear leukocytes) -are primary defense against microbial invasion -Acute bacterial infection, inflammation, & trauma stimulate neutrophil production -> ^'d total WBC count -Granules contain leukocyte alkaline phosphatase (LAP) -Cytoplasm may show vacuoles during active phagocytosis -Toxic granulation: * Dark purple granules in cytoplasm * mb dt severe infections, burn pts. -Shift to the left: * Increased Band neutrophils in peripheral circulation + response to bacterial infection -Nucleus becomes hypersegmented with vitamin B12 or folic acid deficiency
Picture shows: toxic granulation in the small inserted photo and nucleus hypersegmentation in the other 3 PMNs.
Lymphocytes - three types 1. T cells: Mature in thymus. Involved in cellular mediated immunity: -T-suppressor cells (CD8) -T-helper cells (CD4) 2. B cells (CD19, CD20): Mature in bone marrow. Participate in humoral immunity, produce antiBodies.
3. NK -Natural killer cells (CD56, CD57)
WBCs -Agranulocytes 1. Lymphocytes * Development
-Arise from the fixed tissue reticulum cell in the bone marrow -B lymph. mature in BM -T lymph. mature in the thymus -Plasma cells = B lymphocytes that are committed to active production of antibodies
-Atypical lymphocytes: are seen in some viral infections, e.g. infectious mononucleosis
-Arise in bone marrow from a common progenitor cell with the granulocytes -Can be produced rapidly as needed, spend longer time in circulation -Function as phagocytes, much the same as neutrophils do, engulf bacteria -Remove necrotic debris from blood
-Increase production from myelocyte stage in bone marrow via cell division
-Immature forms are released from bone marrow
-Band cells are most common = left shift
-Severe infections may see occasional metamyelocyte
1. Bone Marrow Pool: BMP -holds a 4-10 day supply of immature forms. -These can be released as needed as they mature. -Immature forms seen in circulation indicate dysregulation of release mechanism
2. Circulating Granulocyte Pool: CGP -is within the vascular tree, reflected by the WBC count
3. Marginal Granulocyte Pool: MGP -is formed by movement of WBC to vascular walls by being attracted to trophic substances. -Once they are attached to the vessel wall they can move through the wall via diapadesis, and travel to locations where they are needed
WBC: Early Infection
-Circulating granulocyte pool (CGP) "marginates" along endothelial lining of blood vessels near infected tissues
-Extravasation of CGP "diapedesis" to Site of infection
-Rapid migration rate to tissues, in excess of marrow release rate, can result in decreased WBC count in early stages of infection
-Bone marrow responds to demand for ^ WBCs With ^'ing bone marrow output
-the total body granulocyte pool (TBGP) ^'s, but due to continued margination, WBC count may still appear normal or decreased, aka "masked neutrophilia"
Bone marrow > CGP >>< MGP
WBC: Later Infection
-CGP and MGP finally equilibrate due to increased marrow output -WBC count increases & left shift appears -Indication that body is responding effectively
Bone marrow >> CGP > < MGP
WBC: Recovery from Infection
-Marrow output drops -WBC count decreases & left shift disappears -WBC count goes to normal
Bone marrow > CGP > < MGP
WBCs: -Leukemoid Reaction
Leukemoid reaction: -A nonleukemic WBC count greater than 50,000/mm3, or a differential count with NO more than 5% metamyelocytes or earlier cells.
Associated with: -Severe bacterial infections -severe toxic states (burns, necrotic tissue) -marrow replacement by tumor -severe hemolytic anemia -severe acute blood loss -juvenile rheumatoid arthritis
WBCs: -Differentiating Leukemoid Reaction and Chronic Myelocytic Leukemia (CMP)
Neutrophil granules contain leukocyte alkaline phosphatase (LAP), an enzyme marker used to differentiate CML from leukemoid rxn.
-In CML: LAP is low
-In Leukemoid reactions: LAP is high
Requires special LAP stain
Picture caption: -Left: Leukemoid Rxn w/ HIGH LAP -Right: CML w/ LOW LAP
WBCs: -Leukoerythroblastic Reaction
Leukoerythroblastic reaction: -Defined by the presence of both immature WBCs and nucleated RBCs in the peripheral blood
Causes: -Metastatic tumor in marrow - 25-30% -Leukemia - 20% -Myeloid metaplasia or polycythemia - 10% -Severe infection, megaloblastic anemia, severe acute hemorrhage - about 5% each
-progressive DZ of the BM where NEOPLASTIC BM STEM CELLS lodge and grow in multiple sites OUTSIDE the BM. -Typically, there is SPLEENIC ENLARGEMENT and a gradual replacement of the BM elements by FIBROSIS, -progressive ANEMIA and VARIABLE changes in WBC and PLT
In Myeloid Metaplasia, there's such high demand for blood cells that you get production outside the bone marrow (in spleen & liver)
WBC: -NRBC effect on WBC count
-Automated cell counters tally Nucleated RBCs as WBCs * NRBC are not hemolyzed by reagents * Need to correct total WBC count * Correction for NRBC always lowers total WBC count
-Formed in the bone marrow -Parent cell is the megakaryocyte -platelets are cytoplasmic fragments -Small, round anucleate cells -Platelets form aggregates when injury occurs to vascular endothelium to help maintain vascular integrity -Most platelets are found in the circulating blood where they survive for 7-10 days -25% -30% found in the spleen & liver (reservoir)
-Platelet Count * Normal Range
Normal findings: -Adult/elderly/child: 140,000-400,000/mm3 -Infant: 200,000-475,000 -Newborn: 150,000-300,000
Critical values (Do NOT change b/t labs): <50,000 or >1,000,000/mm3
platelet count < 150,000
The danger: -spontaneous hemorrhage. -Counts above 40,000 rarely exhibit spontaneous hemorrage, but prolonged bleeding with surgery is common. -At counts of <20,000 risk of spontaneous hemorrhage is severe. Petechiae (non-blanching) and ecchymosis common at this level
platelet count > 400,000
The danger: -As the platelet count increases, the probability of abnormal platelet function also increases, danger from thrombosis rises
platelet count > 1,000,000
The danger: -Not uncommon for patient to experience spontaneous bleeding & thrombosis. -Aggregation usually abnormal
Platelet Count: -Interfering Factors
-High altitude increases count
-Platelets have a natural tendency to clump
-Strenuous exercise may increase levels
-Decreased levels may occur prior to menses
-Estrogens increase levels
-Many drugs can increase or decrease platelets: Fischbach, p.1225-1227
-EDTA can cause platelets to form "satellites" around WBCs which Falsely decreases Platelet Count.
-Investigation of decreased Plt count should ALWAYS start with the above - ask lab to review a peripheral blood smear to check for these phenomena.
Pictures show: -platelet satellitism due to EDTA in small pic at upper right -platelet clumps due to microclots
Increased levels - Thrombocytosis
Causes: -MALIGNANT DISORDERS, ESP. CML (malignancy is found in 50% of those with unexpected increased platelet counts) -Polycythemia vera PCV -Acute infections, sepsis -POST-SPLENECTOMY syndrome = no reservoir -Rheumatoid arthritis and other inflammatory dz -Iron deficiency anemia -Primary (Essential) thrombocytosis