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416 Cards in this Set

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What does TPO do?
thrombopoietin - produces platelets

more platelets, more TPO bound, less to drive production
Structure of platelets
Alpha granules: contain fibrinogen,vWF, platelet factor 4

Dense bodies: ADP - activates nieghboring platelets
Mechanism of platelets?
(1)adhesion - reversible, requires vWF and collagen

(2)aggregation - irreverisble, requires fibrinogen
agonist, ADP, Calcium comes in, allows binding.

(3) secretion - irreversible, discharge of granules
Adhesion of platelets?
subendothelium exposes vWF. vWF binds to Gp1b and connects to collagen
Aggregation of platelets
calcium binds to Gp2b/3a and increases affinity for fibrinogen. Fibrinogen cross links neighboring platelets.
ITP?
immune mediated thrombocytopenia.

IgG against own platelets. (often Gp1/2/3 receptors)

Presents with petechiae or ecchymoses

Acute: children get after viral rash, spontaneous recovery

Chronic: need treatment

Pathogenesis: anti-platelet antibodies...Fc receptor engaged in spleen, macrophages consume platelet

Tx: steroids, splenectomy, immune globulin to overload Fc
DIC
disseminated intravascular coagulation- bone marrow suppresion or peripheral destruction and clearance

presents with mucocutaneous hemorrhage
IAP
infection associated purpura - direct vascular invasion by organism
TTP
presents with fever, anemia, thrombocytopenia, renal dysfunction, neurologic deficits

Blood: schistocytes + low platelets

pathogenesis: AdamsT13 on endothelial cell. normally cleaves vWF as it is secreted. without cleaving vWF very potent aggregating. (1)congential dysfunctional AdamsT13 or (2) acquired enzyme that blocks AdamsT13
Neonatal period ? and hemo findings
0-1mo

increased retic count
fetal erythrocytes have higher MCV
Early infancy period and hemo findings
2-6 months

physiologic anemia: baby swithces from HbF to HbA

Decreased in amount of Hb being produced, less retics
late infancy peroid and normal hemo findings
6-24 months

Rapid somatic growth - need more iron

adult type erythrocytes predominate
Prematurity and heme findings?
physiologic anemia occurs sooner and nadir deeper. Increased risk for Fe deficiency
Adolescence heme
need more iron. gender differences appear
Neonatal anemias?
Alloimmune

Spherocytosis

Elliptocytosis

Pyruvate Kinase deficiency

G6PD deficiency
Alloimmune anemia of neonate
IgG mediated...mom antibodies to father's and babies blood type
Sphereocytosis of neonate
auto dominant.
Increased MCHC. increased osmolarity fragility
Elliptocytosis anemia of neonate
auto dominant

protein spectrin defects most common
Pyruvate kinase deficiency anemia of neonate
auto recessive

neonatal jaundice
G6PD deficiency anemia of neonate
x linked. infection induced hemolysis. fava bean. or drug induced. have heinz body hemolytic anemia

heinz bodies on RBC
Early infancy anemias
Diamond blackfan anemia
Diamond blackfan anemia of infancy
congenital pure red cell aplasia

typical facies

thumb abnormalities

fetal red cells, very low retics, increased HbF
Late infancy anemias
(1)nutritional Fe deficit
(2) transient erythroblsatopenia of childhood (TEC) - normocytic, normochromic, low retics, very low hgb, spontaneous resolution
Fanconi's anemia
pancytopenia (all increased) with congenital abnormalities

bone marrow hypoplasia
radial/thumb abnorm

altered skin pigment

short stature
Anemais of adolescence
(1)Fe deficiency
(2) secondary to disease
(3) sports anemia
Alpha thalassemias
(1) silent carrier - 1 deletion
(2) minor - 2 deletions
(3) - H disease - 3 deletions
(4) fetal hydrops - 4 deletions fatal

alpha globin genes on c16
Beta thalassemias
(1)minor - microcytic, hypochromic, autosomal dominant, elevated HbA2

(2) major - transfusion dependent, autosomal recessive
Extravascular hemolysis
within macrophages outside of vascular stream

RBC broken into (1) globin -> iron binds to transferrin, excess stored as ferritin

(2)protoporphyrin -> bilirubin (as stones in gallbladder) -> bilirubin unconjugated -> liver -> excreted intenstive/urine
Intravascular hemolysis
major red cell lysis within circulation
Haptoglobin function
created by liver. secreted. acute phase reactant. binds free hemoglobin, and in return is internalized by the hepatocyte. Low or absent Hp is indicator of intravascular hemolysis
excess heme clearance
(1)free bound to hemopexin and albumin to be taken to liver for catabolism

(2) reabsorbed in proximal tubules (can accumulate in chronic hemolysis causing renal failure)
Direct Coombs (direct antiglobulin test{)
mix with antibodies against human Ig and compliment to see if antibodies are present to RBC
indirect coombs
test patients serum for antibodies...should only have antibodies to minor blood groups ABO. not Rh

ABO naturally occurring. Rh only through direct exposure
Warm agglutinin (AIHA)
IgG meidated lysis of RBC

extravascular clearance through spleen
Cold Agglutinin disease
IgM mediated intravascular lysis
Paroxysmal cold hemoglobinuria (PCH)
IgG mediated, acute illness often viral UTI

intravascular hemolytic anemia
HbA1
alpha beta

A1c - sugar added to beta
HbA2
alpha delta
HbF
alpha gamma
Bohr effect
shift right due to acidic pH
2,3 BPG on Po and Hgb
tenses Hb, shifts curve right
Megaloblastic anemia
inadequate conversion of deoxyuridylate to thymidylate.

(1) folate deficiency
(2) vit b12 deficiency

dyssynchrony of nucleus and cytoplasm
get macrocytic RBCs and hypersegmented nuetrophils

b12 converts homocyteine to methionine...folate reduces vit b12
Absorption of vit b12
intake through food, stomach frees, intrinsic factor binds, small intestine binds to intrinsic factor
vit b12 vs folate
methylmalonic acid elevated then just vit b12 deficits

homocysteine could be either
pernicious anemia
autoimmune loss of effchromatin cells that produce gastric intrinsic factor
CML
chronic myelogenous leukemia:

malignant cell is myeloblast but it matures.

presents: elevated WBC, but increased neutrophils, bands, metamylocytes, myelocytes, promyelos, and blasts...probably some eos and baso
dx of chronic myelogneous leukemia
philadelphia chromosome: translocation 9 to 22
chronic myelogenous leukemia phases
(1) chronic phase: <5% blasts in marrow
(2) accelerated phases: 5-20%

(3) blast criss >20%
Tx of Chronic myelogenous leukemia
(1) high interferon
(2) allogenic stem cell
(3) gleevec - tyrosine kinase inhibitor
Chronic lymphocytic leukemia
chronic lymphocytic leukemia

malignant cell = more differeniated

excess numbers of mature lymphocytes

CBC - high lymphs

present iwth anemia or thrombocytopenia

immune dysregulation
Dx Chronic lymphocytic leukemia
look for B cell with CD5 (t cell marker)

CD19 and Cd23 + cd5
Richter's transformation in Chronic lymphocytic leukemia
development of diffuse larger B cell lymphoma from one CLL clone
confirm with PET scan
Hairy cell leukemia
very slow growing

B cell with Cd 103 (t cell marker)

Dx with TRAP stain

tx with cladribine
Acute lymphocytie leukemia
acute lymphocytic leukemia:

epidemology: males>females

present with problems with blood
Favorable prognosis for Acute lymphocytic leukemia
hyperdiploidy
12->21 trans
trisomy 4,10,17
T cell lymphoblastic leukemia/lymphoma
males>females
5-12 years
B cell acute lymphoblastic leukemia/lymphoma
1-10 years

treat for 5 months not 2.5-3 years
Tx of Acute lymphocytic leukemia
remission induction chemo: 4 weeks
intensification for 6 months
continuation for 2-3 years
Relapse Acute lymphocytic leukemia
testicles and CNS are sanctuaries
Acute myelogenous leukemia
acute myeloid leukemia

excess immature cells in the blood

myeloblast abnormal

presentation: progressive fatigue, WBC high but low ANC, rash, prolonged infection
Dx Acute myelogenous leukemia
>20% blasts in the bone marrow

see auer rods
Tx of Acute myelogenous leukemia
(1) induction chemo 7+3+3

cytarabine
deunorubicin
etoposide

check BM nadir at 2 weeks

(2)consolidation chemo - very high dose of cytarabine...2 doses every 12 hours on day 1, 3, and 5. Do once a month for three months
Prognosis with Acute myelogenous leukemia
genetic mutations largest predictor
Acute promyelocytic leukemia
acute promyelocytic leukemia

abnormal cell: promyelocyte
dx Acute promyelocytic leukemia nd tx
translocation 15 ->17

Tx: 7+4+ATRA

Atra - vitamin A. induce promyelocytes to differenate
Neutrophil development
myeloblast->promyeloblast-> myelocyte-> metamyelocyte ->band ->neutrophil
RBC development
proerythroblast -> basophilic eryth ->polychromatophilic erythro ->orthochromatophilic ->reticulocyte ->RBC
Microcytic anemias
decrease in hgb synthesis

Fe deficit
anemia
thalassemias
sideroblastic anemia
macrocytic anemia
defective DNA synthesis...asynchrony of nucleus and cytoplasm

Vit B12
folate (most common)
inherited megaloblastic
drug induced
CINV phases
Acute - 1-2 hrs peaks 4-10

Delayed 1-5 hours peaks 48-72

Anticipatory phase - conditioned response
5Ht3 antagonists
tx acute phase

ondansetron
granisetron
dolasetron
palonosetron - iv only
NK-1 antagonist
blocks sub P
delayed type CINV
Dopamine Antagonists
phenothaizine
butyrophenones
substituted benzamide
phenothaizine
prochlroperazine
promethazine

effective for delayed type
butyrophenones
droperidol
substituted benzamide
metoclopramide
Benzodiazepine
use for anxiety associated nausea
corticosteroids
increases appetite
cannabinoids
marinol
general CINV guidelines
acute: 5Ht3 + dexamethasone + aprepitant

delayed: metoclopramide/dronabinol/
phenothiazine
Filgrastim
supports proliferation of neutrophils

G-CSF

use: cancer patietns with myelosuppresive chemo

adverse: bone pain
pegylated filgrastim (neulasta)
give as outpatient

large flat dose 24-72 hours post chemo

G-CSF
sargramostim
increases neutrophils, macrophages, monocytes

Use: autologous BM transplant

M-CSF
EPO
enhances RB production

use: non-curable pts
Oprelvekin (neumega)
promotes megakaryocyte production

platelet transfusion is better
transfusion complicatoins of platelets
sepsis
transfusion complication of RBC
hemolytic anemia
transfusion complication of plasma
TRALI
Alkylating agents mechanism of action
causes mistmatch in DNA
(1)template replicated misread
(2)cross linking prevents unwinding
(3)makes strand fragile
Alkylating agents: names of drugs
(1)cyclophosphamide
(2) ifosfamide
(3)platinums
Cyclophosphamide
prodrug, must be converted by liver into intermediate that is then metabolized to phosphoramide mustard and acrolein

acrolein - causes hemorrhagic cystitis

toxicity: myelosuppression
Ifosfamide
prodrug converted to acrolein and isoforamic mustard

Toxicity: hemorrhagic cystitis
MESNA
uroprotectant that binds to acrolein...must be given in advance of treatment with cyclophosphamide/ifosfamide
Platinum drugs and toxicities
cisplatin
toxicity: vomiting and nephrotoxicity

carboplatin - myelosuppression

oxaliplatin - cold induced neuropathy
Amifostine
chemoprotectant agent for platinums
Anthracyclines: mechanism of action and drugs
(1)inhibit topo II
(2) intercalation between DNA bp blocking synthesis
(3) formation of free radicals that damage DNA

doxorubicin
daunorubicin
idarubicin
epirubicin
mitoxantrone

Toxicity: myelosuppression

doxo/daunorubicin - cardiotoxicity
Chemo protectant for anthracyclines
dexrazoxane: cardioprotectant
disrupts iron antracycline complex
prevents free radical formation

also liposomal doxorubicin: liposomal delivery - less cardiotoxicity
Mitoxantrone
second line anthracycline

side effects: blue green urine
Antifolates:
methotrexate
pemetrexed
methotrexate
anti folate

inhibits dihydrofolate reductase (cant make DNA bps)

use: Leucovorin to rescue good cells after treatment

tox: myelosuppression and mucositis
nephrotoxicity (avoid NSAIDs) - prevent with alkalinizing urine
pemetrexed
inhibits multiple enzymes invovled in folate metabolism

adverse: cutaneous rxns
Pyrimidine Antagonist
(1)cytarabine
(2)gemcitabine
(3)clofarabine
(4) nelarabine
(5) fluorouracil
cytarabine
arabinose analog of cytosine

action: blocks DNA polymerase

Tox: myelosuppression
Gemcitabine
effective against solid tumors

tox: myelosuppression
fluorouracil
fluorinated analog of uracil

metabolized to FdUMP which binds TS and prevents conversion of T to U

Tox: myelosupprression
bloody diarrhea, mucositis
Purine Analogs:
action: inhibit de novo purine synthesis
(1)mercaptopurine
(2) thioguanine
(3)fludarabine/cladribine
Mitotic inhibitors:
action: spindle poison

(1) vinca alkaloids
(2) taxanes
Vinca alkaloids
inhibit assembly of microtubules

(1)vincristine - neurotoxicity

(2)vinblastine - myelosuppression

(3) vinorelbine - myelosuppression
Taxanes
make microtubules too rigid

toxicity: myelosuppression, mucositis

(1)paclitaxel
(2) docetaxel
Epipodophylltoxins
inhibit topo II

tox: myelosuppression
camptothecins
inhibit topo I

Tox:
(1) topotecan - myelosuppression

(2) irinotexan - diarrhea
L-asparaginase
degrades asparagine

Tox: pancratitis, hypersensitivity
Bortezomib
selective reversible inhibitor of proteasome

Adverse: peripheral neuropathy
thrombocytopenia
ATRA side effects
adverse: retinoic acid syndrome
Arsenic trioxide use and toxicity
adverse: QTC prolongation

give if retinoic acid syndrome
Thalidomide
thromboembolism
lenalidomide
myelosuppression
HDACs action and tox
block HDACs to allow cell to die from normal cell regulation

(1)vorinostat - tox: dehydration, anemia, thrombocytopenia, Gi problems
mTOR inhibitor
Temsirolimus - blocks translation of mRNA

Adverse: hypersensitivity, hyperglycemia, immunosuppression
Monoclonal ABs
(1) Rituximab: anti CD20 for B lymphocytes

(2)Gemtuzumab ozogamicin - bone marrow suppression

(3)alemtuzumab - immunosuppression
Tyrosine Kinase Inhibitors action
external - ligand or receptor (Abs)
internal - binding domain (small molecules)
Gleevec
tyrosine kinase inhibitor

cannot overcome T315I mutation
Trastuzumab
AB to tyrosine receptor/ligand

tox: congestive heart failure
cetuximab
causes acne form rash

EGFR blocker
panitumumab
derm toxicity
erlotinib
acne
dastinib
nausea/vomiting
Fibrin Clot formation
thrombin converts fibrinogen to fibrin
thrombin converts 13 to 13a

13a gamma cross links, then alpha cross links fibrin
Gamma vs alpha cross link
gamma is end to end (linear)

alpha 3d dimensional cross linking

gamma can be digested by plasmin
Thrombin formation:
TF binds to 7a

TF7a makes 9 to 9a

9a makes 10 to 10a

10a converts (2) prothrombin to thrombin
Thrombin feedbacks to its own production:
thrombin converts 5 to 5a

5a makes allows 10a to convert prothrombin to thrombin faster

Thrombin also makes 8 to 8a

8a is a cofactor that helps 9a convert 10 to 10a faster
Late event in Thrombin production regulation
TF7a can concert 10 to 10a, bypassing 9 to 9a

Results in the amplification of fibrin clot
Anticoagulation natural:
Antithrombin 3 (AT3) binds:

(1) thrombin to TAT

(2) 10a to 10At

(3) 9a to 9AT
Heparin:
accelerates 10a to 10AT
Protein C system:
Thrombin (2a) binds to thrombomodulin on endothelial cell surface

TM2a converts protein c to aPC (protein S)

aPC converts 5a to 5i (inactive) with protein S cofactor

aPC converts 8a to 8i (inactive) with protein S cofactor

leftover aPC binds to endothelial cell, makes tPA

tPA converts plasminogen to plasmin with a fibrin cofactor

plasmin converts fibrin to FDP
Virchow's Triad of thrombosis
(1) alteration in the vessel
(2)alteration in the blood
(3) stasis
DIC stage 1
hypercoagulable state

AT3 controls coagulation cascade, but too much thrombin produced for given stimulus

Increased risk of thrombosis

low dose of heparin shuts down AT3 effectiveness

use anti-platelet agents to block platelet aggregation
DIC Stage 2
thrombin escapes because AT3 is depleted

thrombin stimulates Protein C system and down regulates 5 and 8...reduced production of thrombin

tx: give platelets because they contain factor 5 and replace AT3...back to stage 1, give heparin
DIC Stage 3
late/severe DIC

left over Protein C is activated by fibrinolytic system

aPC inhibitor consumed, fibrinolysis activated, dissolves any fibrin clot, get free plasmin, dissolves plugs, and digests coag factors and fibrinogen

Tx: give: cryo, platelets, AT3, prothrombin

then give heparin to neutralize thrombin, then give AMICAR to inhibit plasma
Impact of aging on hematopoiesis
bone marrow decreases in cellularity with age. however stem cells can keep up (no decrease in peripheral blood numbers).

Difference is in reserve capacity...decreases with age
Implications of anemia in the elderly
incidence and prevalence increase with age.
iron deficiency, anemia of chronic diseases

associated with increased mortality
What is the relationship between age and risk of malignancy?
incidence of most malignancies increase with age
Why do elderly experience inferior outcomes from treatments?
1)treatment disparity - not a lot in clinical trails, also under treated (dose attenuated

2) tumor characteristics change - increased likelihood of MDR1 gene

3) host characteristics - physiologic changes, impairment in physical function, co-morbidities
Approach to the assessment and treatment of elderly patients
(1)characteristics of patient - life expectancy, reserve capacity

2) characteristics of tumor

3) characteristics of treatment
myelosuppresion, renal toxicity, mucositis, neurotoxicity, cardiac pretreatment
Autologous Stem Cell Transplant
from the same person

cells are not cure, but rescue from the cure.

if you need myelosuppressive therapy, use banked stem cells to rescue from this

Requirements: chemosensitive disease
healthy enough to harvest a graft

Risk of mortality: 5%

Negatives: more likely to relapse

Indications: Multiple myeloma
Allogenic BM transplant
From the same species.

Benefit: guarantee clean graft
has an immunologic benefit (new cells can recognize a tumor as bad)

Negatives: need to find an HLA match
GvHD
T cell mediated
Risks: increased age
prior exposure to blood groups
CMV status

Clinical: skin rash
liver disorder, dairrhea
HLA matching
1/4 of sibling being a match

6 genes A, B, D
Umbilical Cord Blood transplant
immediate access to stem cells

less allogenic (less likely to have GvHD)

less likely to be CMV positive

Problem: need more cord blood for an adult

cant get another collection for a new infusion
how does radiation treatment work?
Damages DNA of reproducing cells
Types of radiation therapy
betatron originally

now linear particle accelerators
Radiation use:
focal, local treatment for solid tumors

used often as multi-modal treatment plan
Radiation treatment plan
need multiple imaging studies to determine tumor location and size.

Total dose: determined by what NORMAL cells can tolerate.

give small dose over many days to weeks
Radiation therapy
Brachytherapy
short distance emitter for internalized treatment
steriotactic radiation therapy
use large doses for a shorter treatment interval
Myeloproliferative neoplasms (MPN)
effective and ordered hematopoiesis

cells in all stages of development
MPN clinical features
cytosis of blood - elevated counts of everything

organomegaly

multi-phase disease
Chronic myelogenous leukemia
clinical
CML - type of MPN

clinical: typically asymptomatic, large spleen, malaise, fatigue, weight loss, anemia

progressive: chronic, accelerated, ends in blast (acute ML)
Dx of Chronic myelogenous leukemia
philadelphia chromosome
t9.22
fusion of BCR and ABL genes

ABL has tyrosine activity

leukocytosis: neutrophils at all stages

anemia: little room for RBC development in BM

Thrombocytosis
BM of Chronic myelogenous leukemia patients
hypercellular

>20% blasts
Myelodysplastic syndrome (MDS)
cells do not mature effectively
clinical findings in Myelodysplastic syndrome
peripheral blood - cytopenias

no organomegaly

multiphase disease that ends in BM failure

older patients

Anemia: mild macrocytic

Thrombocytopenia

Neutropenia

Blasts<20%

dysplastic RBC - multi-lobed nuclei

Hypolobated granulocytes: pseudo pelger heut cells
Myelodysplastic vs myeloproliferative
BM involved in both...hypercellular

disordered cells in dysplasia

organs involved in only MPN

cytopenias in MDS

MPN usually translocation genetic alteration
ways to be immuno-compromised
(1) ANC<500: neutropenia

(2) decreased antibody production: hypogammaglobulinemia

(3)disrupted barriers

(4) decreased cell mediated immunity: CD4 <200
Preventative measures for transmission of endogenous organisms to ICH
suppressive measures on host
adminster prophylaxis, clean hands
preventative measures for transmission of exogenous organisms to ICH
strict hand washing most important
protective isolation
special air handling systems
special diets
Initial sign of infection in ICH
fever, but can be due to other malignancies
Likely infection if host deficit is phagocyte cells
extra cellular pathogens

fungi, candida
likely infection in ICH if cell mediated deficiency
intracellular pathogens

viruses, mycobacteria
likely infection if ICH is antibody deficient
encapsulated pathogens

strep pneumo

h. flu
Transplant recipients most likely infections
major defect is cell mediated immunity

1st month normal immune system

2month: immuno suppressed
get intracellular pathogens
Lymph node architecture:

Cortex:
primary and secondary follicles

b cells
lymph node arch

paracortex
t cells and dendritic cells
lymph node arch

medulla
plasma cells and medullary sinuses
lymph node arch

sinuses
macrophages
primary follicles in lymph node

and secondary
naive b cells

secondary b cells introduced to antigen, begin proliferative, b cells that don't match, pushed to periphral (germinal center where active proliferation occurring)
T cell development:
migrate from BM to thymus.

stop in thymic cortex. thymic epithelial cells act like Ag presenting cells. peripheral cortex has immature, rapidly proliferating cells

near medulla, mature and slow proliferation

5% make it to medullla
why do only 5% t cells make it to the medulla
(1) positive selection: thymic epithelial cells hsa MHC on surface and presents a peptide to T lymph. T lymph recognizes both and turns apoptosis off

(2) negative selection: central tolerance: any thymocyte that has high affinity for MHC is killed

Peripheral tolerance: many tissue specific antigens are not present in thymus, encountered in peripheral, once released
TCR determination of T cell location
alpha beta - stay in thymus

gamma/delta - migrate throughout body
non-hodgkin lymphomas
burkitt's lymphoma

pre b cell

pre t cell

CLL/SLL
Follicular Lymphoma
low grade nonhodgkins

increases with age

morphology: small cleaved cells

mature appearing
CD20, CD10

Grading: determined by percentage of centrocytes to centroblasts
more blasts - higher grade
Translocation in Follicular Lymphoma
t14-18
Tx of follicular lymphoma

prognosis:
not curable, reset clock

FLIPI scores determine prognosis

adverse: >60

stage iii/IV

hb<12

number of nodes >4

LDH > upper normal
Diffuse large B cell lymphoma
most common intermediate grade lymphoma

Cd19/Cd10

B cell lineage, larger than normal lymphocyte
abnormal architecture of lymph node

no standard cytogenetics

very responsive to chemo
Tx for diffuse large b cell lymphoma
R CHOP

rituximab

cyclophosphamide

hydroxyl-doxorubicin

oncovin

prednisone
Burkitt's Lymphoma
one of the fastest growing tumors

Types: african - jaw or face
american/sporadic - GI/abdomen
immunodeficient
African burkitts lymphoma
malaria infection causes excess B cell production

EBV infects tumor cell

Incidence 4-7 yo
male>female
american/sporadic burkitts lymphoma
involves abdomen, ovaries, kidneys, omentum,

only 15-30% EBV positive
immunodeficient burkitt's lymphoma
HIV+ or transplants

considered defining malignancy of AIDS
Dx of burkitt's lymphoma
Starry Sky pattern

cells are Cd20/CD10
Genetic abnormalities in burkitt's lymphoma
t8.14

t2.8

t8.22
tx of burkitt's lymphoma
8 months and complicated

must give CNS prophylaxis because burkitt's migrates there
B cell differentiation...early expression of which marks?
TdT
Normal T cell immature surface marker
TdT

then cd4/8
B Cell lymphoblastic leukemia

clinical
clinically: children and adults
predominantly leukemic

agressive

prognosis: cytogenetics
b Acute lymphocytic leukemia cell phenotype
TdT positive

negative for cd 20 and negative sIg
Favorable phenotype for B Acute lymphocytic leukemia
t12.21
hyperploidy
unfavorable phenotype for B Acute lymphocytic leukemia
t9.22
t4.11
t1.19
T Acute lymphocytic leukemia
clinical
adolescents

predominantly lymphomatous

mediastinal mass
pleural effusion
T Acute lymphocytic leukemia phenotype
TdT and Cd4/CD8+
Chronic lymphocytic leukemia/small lymphocytic leukemia clinical
90% both lymphocytic and leukemia

usually asymptomatic

older adults

lymphocytes are small and mature

Smudge cells on morphology

anemia and thrombocytopenia

BM shows nodular or mixed
Small lymphocytic leukemia morphology
invades small lymph nodes

pseudo follicular proliferation centers

SOCCER BALLL chromatin
Small lymphocytic leukemia phenotype
b cell lymphoma

Cd19 Cd20 but expresses CD5 (t cell marker)
Follicular lymphoma

clinical
clinical: adults often asymptomatic

waxing and waning growth

replace normal architecture

leukemic phase - cells have prominent cleaves
buckholt cells
Follicular lymphoma phentoype
b cell lymphoma

cd 10, BCL2, BCL6
follicular lymphoma genotype
t14.18

BCL2 onco gene
Diffuse large B cell lymphoma

clinical
adults and children

rapidly enlarging mass...nodal or extranodal

de novo or progression from other disease

morphology: large nucleolated cells, irregular contours of nuclues
Burkitt lymphoma

morphology

phenotype
starry sky

MIB 100%
Burkitt lymphoma genotype
t8.14

t2.8

t8.22

moving of transcription factor

associated with EBV
Anaplastic large cell lymphoma
T cell lymphoma

children and adults

nodal or extra
Anaplastic large cell lymphoma infiltrate
sinusoidal infiltrate

hallmark cells
Anaplastic large cell lymphoma phenotype
CD30

ALK 1protein
CD3,4,43
Anaplastic large cell lymphoma genotype
TCR gene rearrangement

T2.5
Hodgkin lymphoma

morphology
reed sternberg cells 1-10% of tumor cell population

inflammatory cell background
hodgkin lymphoma phenotype
reed sternberg cells are CD30 and CD15 positive

EBV associated
hodgkin lymphoma genotype
Ig gene rearragement

B cell lymphoma
EPO and hypoxia
vHL does nto target HIF1 alpha for degradation. HIF1alpha binds HIF1beta which bind EPO. EPO-R signaling stimulates RBC production
Polycythemia Vera

mechanism
clonal disorder

RBC production independent of EPO

EPO low

problem: mutuation in JAK2...first signallying molecule in EPO pathway. Always on
Polycythemia Vera lab values
elevated hemoglobin and hematocrit

elevated RBC mass

BM cellularity is increased
Polycythemia Vera clinical findings/complaints
HA, visual changes dizziness, paresthesias, facial plethora

bleeding, bruising

thrombosis

painful red hands (erythromelaglia)
Polycythemia Vera dx
increased RBC mass

platelet>400

WCC>12k

low epo

BM biopsy
Polycythemia vera tx.
phlebotomy

hydroxyurea

aspirin
Essential thrombocythemia

mechanism
too many platelets

clonal disoder independent of TPO

often have JAK2 mutation
Essential thrombocythemia dx
sustained platelet count >450

hyperplasia of megakaryocytes on bone biopsy

absence of t9.22 (Test for cml)
essential thrombocythemia

natural hx
bleedign due to abnormal platelet function

thrombosis

splenomegaly

erythromelalgia
essential thrombocythemia

tx
hydroxyurea

aspirin
chronic idiopathic myelofibrosis

BM results
scarring

reticulin and or collagen fibrosis

decreased cellularity

dry taps
Chronic idiopathic myelofibrosis

clinical findings
marked splenomegaly

extramedullary hematopoiesis
chronic idiopathic myelofibrosis

blood results
pseudo-pelger-huet cells - neutrophils have two lobes

giant platelets

anemic
JAK2 mutations
Chronic idiopathic myelofibrosis

Tx
palliative
Myelodysplastic syndromes

dx
(1)bone marrow biopsy shows too many blasts

5-19% is MDS

or

(2)see dysplastic cells
Myelodysplastic syndrome prognosis
(1)Age

(2) IPSS scores
Myelodysplastic 5q syndrome
part of 5 q missing

have more benign disease
Plasma cell dyscarsias

types
plasma cells grow more than they should

(1)monoclonal gammopathy of undetermined significance (MGUS)

(2) multiple myeloma

(3) plasma cell leukemia
plasma cell dyscrasias dx
(1)measure number of place cells in BM

(2) measure amount of protein
Lab tests - comprehensive panel for plasma cell dyscrasias
get albumin and protein values...protein should be too high
lab test for plasma cell dyscrasias quantitative immunoglobulin
give values of each Ig
lab test for plasma cell dyscrasias

SPEP
albumin peak, alpha 1 peak, alpha 2 peak, beta peak

Gamma peak - most immunoglobulin
lab test for plasma cell dyscrasias

IEP
immunoglobulin electrophoresis

confirms clonality of Ig
lab test for plasma cell dyscrasias

serum free light chains
amount of light chains in the serum
Multiple myeloma - cell
plasma cell constantly producing Abs

nucleus off to side and flattened

cytoplasm bi-phasic colors
Multiple Myeloma clinical features
m>f

adults

lytic bone lesions
Multiple Myeloma lab findings
bence jones proteins in the urine

monoclonal serum gammopathy
Multiple myeloma pathology

phenotype

genotype
morphology: marrow plasmacytosis >30%

cd38, cd18

genotype: Ig clonally rearranged
Burkitt's Lymphoma genotype
IgH/c-myc rearrangement

t8.14
t2.8
t8.22

EBV implicated

MIB 100%
Hairy cell leukemia

clinically
older adults

pancytopenia

enlarged spleen
Hairy cell Leukemia clinical
older adults

pancytopenia

enlarged spleen
hairy cell leukemia morphology
characteristic cytoplasmic projections

fried egg appearance

dry bone tap from reticulin fibrosis

express cd103,cd25,cd11c

stain with TRAP
Mycosis Fungoides morphology
pautrier microabscesses - lymphocytes invading dermis

lutzner cells

sezary cells

Tcells CD4 only (no CD7)
Classic Hodgkin lymphoma dx
reed sternberg cells cd30/cd15
classic hodgkin lymphoma subtypes
(1)nodular sclerosis - fibrous bands divide into nodules, capsular fibrosis

mediastinal involvment

(2)mixed cellularity - mixed inflammatory background, diffuse growth

(3) lymphocyte depleted - background is small, reactive, lymphocytes

(4) lymphocyte rich - sheets of RS cells, tumor necrosis
Staging of hodgkin lymphoma
(1)involvement of a single node

(2) 2 or more lymph nodes on the same side of the daiphragm

(3) lymph nodes on both sides of the diaphragm

(4)multiple disseminated foci of involvement
leukocytosis definition
absolute increase in number of leukocytes in peripheral blood

adults: greater than 10.000
Leukemoid reaction definition
excessive white blood cell response (50,000 or more)
Corticosteroids affect on WBC
decrease emigration of neutrophils from blood into tissues

increase release of mature neutrophils from the bone marrow

decrease margination of neutrophils inside vasculature
Neutrophilia definition
absolute neutrophil count of 8000 or higher
mechanisms of neutrophilia
(1)increased production by bone marrow

(2)increased mobilization from sotarge pool

(3) failure to exit the circulation
Leukocyte adhesion deficiency (hereditary mutation)
number of circulating neutrophils is increased

delayed detachment or prolonged healing of umbilical stump

cant get leukocytes out of blood
lymphocytosis definition
normally 20-40% of circulating WBC


(1)relative lymphocytosis results when there is a neutrophilic leukocytosis

(2) absolte lymphocytosis
(a) >9000 in infant
(b) 7200 older children
(c)>4000 in adults
absolute vs relative lymphocytosis
absolute - acute infection, chronic infections

relative - normla in young, during viral infections, splenomegaly
benign reactive lymphocytosis
pronounced in pertusis, acute infectious lymphocytosis, infectious mono
eosinophilia definition
usually less than 5%

storage in pools 5 times larger

play role in phagocytizing antigen-antibody
causes of eosinophilia
allergic, parasitic infections
causes of basophilia
viral infections, chronic sinusitis
neutropenia definition
decrease in absolute neutrophil count (ANC)

age related limits:

term newborn <3000

infant <1100

child, adolescent, adult <900

altitude lower ANC
neutropenia risk of infection
1000-1500 none

1000-500 minimal

200-500 moderate to severe

<200
psuedo-neutropenia
low normal neutrophil count

treat with exercise or epinepherine
infection induced neutropenia
common during viral infections (increased use)
drug induced neutropenia
immune mediated or direct
immune neutropenia
antibodies directed to neutrophils or their precursors

chronic benign neutropenia: occur in children and adults. infections are infrequent despite low ANC
congenital neutropenia
cyclic neutropenia

autosomal disorder

kostmann syndrome: severe congenital neutropenia
lymphopenia
absolute lymphocyte count of <1000

decreased production

increased destruction

increased loss
presentation of Acute myeloid leukemia
progressive fatigue, dyspnea,

CBC: WBC high normal, ANC - low nuetrophil

hb low

plts low
acute myeloid dx
>20% blasts in marrow
potential side effect of Acute myeloid leukemia tx
Tumor lysis syndrome

rapid lysis of cells psills uric acide, into blood..causes kidney damage...phosphorous levels increase cardiac dysrythmia, calcium too low...causes nephropathy
consolidation therapy for Acute myeloid leukemia
give high does of Ara-C for 12 hours at 1,3,5 days over 4 months

toxicity changes: neuropathy
discharge drugs for Acute myeloid leukemia
acyclovir, fluconasol, moxyflocacil
good prognosis for acute myeloid leukemia
16.16 inversion

8-12 translocation
bad prognosis for acute myeloid leukemia
deletion of 5 or 7

111q23

MDR
Acute promyelocyte leukemia tx side effects
increased risk of DIC because primary granules formed in promyelocyte stage

(1)ATRA syndrome - fever, pulmonary tension

(2)hyperleukocytosis
Acute lymphocytic leukemia presentation
fatigue, leukopenia or leukocytosis, pallor, bruising, fever, hepatosplenomegaly

pancytopenia

lymphadenopathy

sepsis

bleeding

tumor lysis syndrome
Tumor lysis syndrome released molecules
LDH

uric acid

potassium

phosphorous

creatinine
Components of ALL treatment
induction

consolidation

CNS therapy - IV methotrexate
do CNS therapy throughout all phases of treatment

long term continuation
good prognosis for Acute lymphocytic leukemia
<50k WBC

young age

no CNS

hyperdiploidy

translocation 12.21
unfavorable prognosis for Acute lymphocytic leukemia
hypodiploidy
4.11 translocation
9.22 translocation (different protein product)
presentation of chronic myelogenous leukemia
high WBC

increased neutrophils, bands, metamyelocytes, myelocytes, promyelocytes, and blasts

high platelets
presentation of chronic lymphocytic leukemia
symptoms of anemia or thrombocytopenia

immune dysregulation - prolonged infections

hypogammaglobulinemia (low IgG)
chronic myelogenous leukemia tx
gleevec - TKI binds to c-kit on GISTs

and PDGFR alpha
why does gleevec work?
translocation of ABL (9.22) is always on


gleevec binds to site and prevents it from being on
Immune symptoms of Chronic lymphocytic leukemia
anemia

immune dysregulation

hypogammaglobulinemia

over active destruction of self cells - RBCs and platelets (seen in later stages)
treatment of chronic lymphocytic leukemia cos/benefit
early stages may just have high WBC, but not worth treatment until immune system dysregulation because of treatment costs
stages of chronic lymphocytic leukemia
0 - elevated lymphocyte count
1- elevated with lymphadenopathy
2 - elevated with splenomegaly
3 - elevated with anemia
4 - elevated with low platelets
karyorrhexis
stage of cellular necrosis in which the fragments of the nucleus fragments and its chromatin are distributed irregularly throughout the cytoplasm.

associated with cobalamin/folate deficiency
where is TPO produced?
liver
platelet function
(1) formation of mechanical plubs

(2) local release of vasoconstrictors

(3) catalysis of reactions of the soluble coagulation cascade leading to fibrin clot formation

(4) initiation of the tissue repair process

(5) regulation of local inflammation
heparin induced thrombocytopenia
IgG antibodies directed against the heparin-platelet factor 4 complex

suspect if platelet count falls to <100k

venous, arterial, and microvascular thrombosis threatens life and limb
pathogenesis heparin-induced thrombocytopenia
heparin binds to platelet factor 4

antibodies then bind to complex

Fc receptor on platelets is stimulated by this antibody...platelets get rapidly consumed

and a total decrease in available platelets
Thrombocytopenia
<150k

Causes (1) decreased platelet production

(2)decreased platelet survival

(3) sequestration

(4) dilutional
Thrombocytosis
>500k

complications: (1)thrombotic episodes
(2) bleeding

Causes: (1) primary - essential thrombocytosis

(2)secondary/reactive - infection, inflammation ,etc.
Immune Thrombocytopenic Purpura
may be secondary or primary

(1)antiplatelet antibodies to GpIIb/IIIA or GpI

dx: peripheral blood: thrombocytopenia

bm: normal or increased mega's
Coag Studies

Platelet Enumeration
normal

150-350l
Coag Studies

Bleeding time
BT

normal 2-9 mins
Coag studies

Aggregation studies
addition of platelet aggregators - ADP

dx: platelet function tests
coag studies

activated partial thromboplastin time (aPTT)
normal is 21-25 second

dx: increased aPTT - sensitive to intrinsic pathway abnormalities
XII, XI, IX, VIII, X, V

heparin
coag studies

prothrombin time (PT)
normal 10-14 seconds

Dx: increased PT - sensitive to extrinsic pathway
abnormalities: VII, X, V, II, fibrinogen

useful in vitamin K deficiency (2,7,9,10)
coag studies

Fibrinogen Degradation products (FDPs or D-dimers)
measures presence of fibrin or fibrinogen degradation products

useful for: DIC - very elevated

DVT - slightly elevated

Problem: cannot distinguish between plasmin action on fibrinogen vs fibrin. Therefore can be elevated when there is no clot present.

Usually: thrombin makes fibrin..fibrin makes 13, 13 cross links.
only see D dimers when fibrin cross linked
PT elevated

aPTT normal

Platelets normal
dx

7, 10, 5 deficiency, vit k deficiency
PT normal

aPTT high

Platelets norm
8,9,11 def, VWD, heparin
PT high

aPTT high

Platelets normal
vit k def

liver disease
PT high

aPTT high

Platelets low
DIC
PT norm

aPTT norm

Platelets low
hypersplenism, platelet destruction, platelet production problems, TTP, HUS
PT norm

aPTT norm

Platelets high
reactive vs MPD
PT norm

aPTT norm

Platelets norm
mild VWD
RBC fragmentation syndromes
(1) mechanical/vascular hemolysis

(2)microangiopathic hemolytic anemias (MAHA)
DIC
TTP
Hemolytic uremic syndrome
DIC - definition
a secondary condition in which microthrombi develop throughout the bloodstream, blocking small blood vessels and depleting platelts and clotting factors needed to control bleeding
broad terms DIC
simultaneous activation of
(1) coagulation system - widespread expression of TF
a. intravascular thrombuc formation compromising blood supply to organs
b. exhuastion of platelets and coagulation factors resulting in hemorrhage

(2) fibrinolytic system - plasmin degrades fibrinogen and fibrin, producing D-dimers, exacerbating bleeding
clinical pentad of TTP
(1)MAHA
(2)Neurologic abnormalities
(3)renal insufficiency
(4)fever
(5) thrombocytopenia
Laboratory Dx of TTP
(1)deficiency of vWF metalloproteinase ADAMTS13

(2) consumptive thrombocytopenia

(3) schistocytes in blood smears
Hemolytic Uremic Syndrome (HUS)

clinical features
(1)Microangiopathic hemolytic anemia (MAHA)
(2)Thrombocytopenia
(3)Renal insufficiency
(4)bloody diarrhea
Hemolytic Uremic Syndrome (HUS)

lab dx
(1)E. coli infectious gastroenteritis
0157:H7 produces Shiga-like toxin

(2)consumptive thrombocytopenia

(3) schistocytes in blood smear
von Willebrand's Factor

functions
(1)carrier protein for VIII - increases serum half life

(2)binds to GpIb receptor on platelet adhesion to damaged endothelium
von willebrand's disease
bleeding disorder - mucocutaneous bleeding disorders

auto dominant or recessive

(1)mild form (type 1 and 2) - patients asymptomatic

(2)severe forms (type 3) usually have factor 8 problems as well
vWD dx
(1)hematologic eval of peripheral blood

(2)screening for hemostasis

(3)vWD panel - multimeric analysis of vWF
(a) Type 1 - generalized decrease
(b) Type 2 - loss of HMW
(c) Multimer absence
Factor 8 deficiency
Factor 8 synthesized in liver, circulates bound to vWF, activated by IIa and enhances activation of 10 by 9a. Inactivated by Protein C
Hemophilia A
sex-linked recessive - Xq28
Factor 8 deficiency

spectrum of bleeding manifestations

suspect if: (1) family hx
(2) appearance of bleeding in neonatal period
(3) pattern of bleeding (joint, muscle) easy bruising
Hemophilia B
factor 9 deficiency

vitamin K dependent
activated by 11a and 7a

X linked recessive
or can be acquired with liver disease, vitamin K deficiency

spectrum of bleeding disorders
Acquired coagulopathies
(1)liver disease - major producer of all factors but vWF

(2)vitamin k deficiency - 2, 7, 9, 10, protein c/s

(3) disseminated intravascular coagulopathy DIC
Factor 5 leiden
most common inherited thrombotic disorder
auto dominant

mutation in factor 5 renders the cofactor resistant to proteolysis by activated protein c

recurrent venous thromboembolism

Dx. DNA mutation analysis

Tx. prophylaxis
Anticoagulants/Fibrinolysis
(1)antithrombin III
downregulates 12a, 11a, 10a, 9a

(2)proteins C and S
downregulates 5a and 8a

(3) Plasmin
degrades fibrin making d-dimers
Thrombosis
(1)endothelial injury

(2) abnormal blood flow

(3) hypercoagulability
Hypercoagulability
(1)primary - genetic thrombi

(2) secondary - arterial and venous
Antiphospholipid Antibody Syndrome
prothrombotic disorder
(1) autoantibodies directed against a number of antigens complexed to phospholipids

(2)recurrent venous and arterial thromboembolism, fetal loss, thrombocytopenia, neurologic manifestations

(3) most often diagnoses because of incidental paradoxical elevated aPTT
Hemophilia A genetics
Factor 8

X chromosome - long arm

missense, frameshit, deletions or inversions

inversion of intron 22 common, but most are point mutations
Hemophilia A/B inheritance
sex linked recessive

30% spontaneous
Clinical manifestations of Hemophilia A/B
joint bleeds - target joint where blood repeatedly leaks into

deep muscle bleeds

hematomas

dental extraction
severity of hemophilia A/B
severe - present early childhood

moderate - after minor trauma or surgery

mild - often unaware until trauma
Complications of hemophilia
(1) hemophilic arthropathy - repeated bleeds cause synovitis, ultimately destroying synovial membrane and muscles

(2)synovitis and increased blood flow to the joint may lead to epiphyseal overgrowth and limb length discrepancy

(3) intramuscular/soft tissue bleeding can cause compaction and ultimately extremity compartment syndrome
Hemophilia B genetics
factor 9 deficiency

X linked mutation
Lab findings for Hemophilia A
PFA normal

Platelet Count normal

Prothrombin time normal (extrinsic pathway)

activated partial thromboplastin time (aPTT) long (intrinsic pathway)
Tx of hemophilia
prophylaxis

give missing factor if possible or

FFP

or plasma derivatives

AMICAR - stabilizes fibrin clot
Complications of hemophilia treatment
(1) development of inhibitors to factors

(2) infections
Acquired hemophilia
development of neutralizing and clearing anti-factor 8 antibodies

more common in elderly or post partum
von willebran disease genetics
auto dominant

bleeding due to reduced level or abnormal vWF
vWF function
(1)promotes platelet adhesion to damaged endothelium

(2) carrier molecule for factor 8, increasing half life
Clinical manifestations of VWD
mucous membranes - menses extremely common

skin cuts

post trauma

post op
lab findings in VWD
PFA prolonged

platelet count normal

PT normal

aPTT normal/prolonged
Tx of vWD
(1)DDAVP - stimulates release of factor 8 and vWF fro endothelial cells but only works for about 3 days

(2) Humate P - concentrated factor 8 and vWF
Therapy based on levels of pain
mild pain - acetaminophen, NSAIDs, or mild opioids (darvocet)

moderate pain - small doses of oxycodone alone

severe/debilitating pain - morphine
Non-narcotic analgesics
Acetaminophen

Salicylates

NSAIDs

nonacetylated salicylates
Acetaminophen use/benefits/metabolism
analgesic and antipyretic effects

metabolized in liver

use with mild pain

inhibits synthesis of prostaglandins in CNS and peripherally blocks brain impulse generation
NSAIDs
analgesic, antipyretic, and anti-inflammatory effects

inhibits COX

Dose response curve plateus

particularly helpful in bone pain

limitations - gastrophy, anti-platelet effect, renal toxicity,
COX2 inhibitors
patients where an NSAID is indicated

history of GI ulcers

elderly

low platelet count

receiving anti coagulation

receiving corticosteroids

(Celebrex)
Celebrex
used for acute or chronic pain

use for FAP

interacts with warfarin
Tramadol
complex MOA

get benefit of opioids without addiction
morphine
well tolerated

adverse: sedation, urinary retention, decreased respirations, constipation

become tolerant to everything but constipation (must give with laxative)
oxycodone
slightly more potent than morphine

milder side effect profile
hydromorphone (dilaudid)
approximately 6 times more potent than morphine

less nausea/vomiting

useful in liver/renal failure patients
oxymorphone
very potent

only used by pain specialists
fentanyl
available IV, PO, transdermal patch, transmucosal sucker

100x more potent than morphine

heat increases absorption (fever and heat pads)
meperidine
not recommended for use because of high toxicity
methadone
cheap form of pain management

dosing is complex

opioid agonist and NMDA antagonist

high drug interaction
adjuvant therapy for pain
tricyclic antidepressants

anticonvulsants - neurotin

corticosteroids - pain from infiltration
Heparin MOA
MOA: complexes with AT3 to accelerate its ability to inactivate factors 2a, 9a, 10a
Unfractionated heparin tx
monitor aPTT when given as treatment

binds to AT3 to accelerate inactivation of factor 10a. it can also bind and inactivate thrombin.

Measures of the intrinsic pathway...follow by aPTT
Unfractionated heparin prophylaxis
do not need to monitor

binds to antithrombin to accerlate inactivation of factor 10a...can also bind and inactivate thrombin
LMW heparin
do not monitor for tx or prophylaxis
Types of LMW heparin
enoxaparin - lovenox

dalteparin - fragmin

fondaparinux - arixtra
enoxaparin (lovenox)
indicated in the tx and prophylaxis of VTE
Dalteparin (Fragmin)
prevention of VTE and treatment of VTE
Fondaparinux
inhibits factor 10a

good option for herparin-induced thrombocytopenia (HIT

VTE treatment and prophylaxis

can cause renal insufficiency
warfarin MOA
inhibits the production of vitamin k dependent factors: 2,7,9,10

protein C, protein S
warfarin
monitor INR - varies by indication

most slowly adjust rates because warfarin can readily vary by interactions

(1) highly protein bound so affected by other drugs

(2) vitamin k levels vary by diet - leafy green veggies

monitor PT (prothombin time) extrinsic pathway
Aspirin
MOA: inhibits cyclooxygenase which blocks the formation of (1) thromboxane-TXA2---inhibits platelet aggregation and activation

(2) prostacyclin
Ticlopidine
MOA: inhibits platelet activation and aggregation

interacts with CYP3A4
Clopidogrel
MOA: blocks ADP receptors---inhibits platelet activation and aggregation

prevents activation of GP2b/3a
heparin induced thrombocytopenia (HIT)
heparin binds to platelet factor 4

an IgG antibody binds to the heparin/PF4 complex. This complex binds to an activated platelet surface. Results in platelet clearance (thrombocytopenia)
Heparin-induced thrombocytoepnic thrombosis (HITT)
heparin binds to platelet factor 4. This complex binds to an activated platelet surface. An IgG antibody binds to the heparin/PF4 complex. Results in platelet clearance - get thrombocytopenia.

Fc portion of IgG further activates platelets, resulting in thrombosis.
eosinophil
basophillic erythroblasts
basophillic on the left

polychromatic center and right
orthochromatophillic erythroblast
promyelocyte
myelocyte
metamyelocyte with indenting nucleus
neutrophil
eosinophilic myelocyte
eosinophilic myelocyte
eosinophillic metamyelocyte
Reed Sternberg
pseudo pelger huet cell

associated with MDS
Burkitt's Lymphoma
burkitt's lymphoma
Reed Sternberg

Classical hodgkins
Pautrier microabscesses associated with mycosis fungoides
Parvovirus B19 clinical syndromes
(1) hydrops fetalis

(2) erythema infectiosum (fifth diease)

(3) aplastic crises in hemolytic subjects

(4) seronegative RA syndrome - Arthropathy

(5) chronic anemia in immunocompromised hosts
Parvovirus B19 pathogenesis
infects EPC

acute infection causes mild illness in most immunocompetent children
rash about time of seroconversion
fever, myalgias, HA precede rash by a few days
EBV pathogenesis
tropism for monocytes
Phase I engraftement
pre-engraftment - neutropenic

most likely to get G-, staphylococcus, GI strepp
Phase II post-engraftment
impaired cell mediated immunity

get viruses

CMV, EBV,
Phase III engraftment
impaired cellular and humoral immunity as B cells maturation takes a few years

more likely to get encapsulated organism infections (Pneumo)
Risk factors of CMV in BMT recipients
seropositive status

older age

conditioning regimens with agents other than cyclophosphamide

GvHD
Therapy for CMV
IV Gamcyclovir+ Ig either CMV or IVIg

Gamcyclovir is myelosuppressive - target prophylaxis recommended
Strategies to reduce risk of CMV disease
(1) prophylaxis

(2) preemptive therapy for targeted patients
Herpes Zoster incidence with age
with increasing age, increasing incidence
Vaccine for Herpes Zoster
helps reduce risk in older adults in healthy adults

but no vaccine approved for immunocompromised
At what stage of granulocyte development are the specific granules that differentiate the cell types first apparent?
Specific granules first appear at the myelocyte stage.
– In many cases clusters of developing blood cells comprise predominantly white cells or red cells, rather than highly-intermixed groups of both. What accounts for this relative segregation?
Because of the progressive restriction of the potentiality of blood precursor cells, many colonies form which will produce only one type of blood cell (e.g., erythrocytes, granulocytes or monocytes). Remember also that growth factors, which may act over some distance, influence the developmental pathways. Finally, the developing cells continue to divide through the earlier stages, so that also contributes to the clustering of cells in the same lineage.
What accounts for the basophilia of the cytoplasm in early stages in erythrocyte development and the eosinophilia in later stages?
In the early stages of red cell development the large number of polyribosomes required for the production of hemoglobin result in basophilic staining in the cytoplasm (because of the basophilia of the RNA associated with the polyribosomes). As hemoglobin accumulates, eosinophilia in the cytoplasm increases and basophilia decreases as the number of polyribosomes declines.
– In hereditary spherocytosis the normal binding between the proteins ankyrin and spectrin is absent. What type(s) of blood cells would be affected in this disorder? In what way(s) might their structure and/or function be compromised and why?
Normally, the internal surface of the cell membrane of erythrocytes is braced by cytoskeletal proteins through interactions of the proteins ankyrin and spectrin. When the normal binding of those proteins is compromised, the red cell membrane is not braced and the cell is easily deformed and does not form its normal, biconcave shape. The cells are more fragile and do not resist changes in osmotic pressure. The cells are more vulnerable to sequestration and destruction by macrophages.
What obvious cytological feature of RBCs accounts, in large part, for their limited life span? In what organ(s) are worn-out or damaged RBCs destroyed?
Mature erythrocytes do not have a nucleus or other organelles necessary for protein synthesis and thus no ability to replace worn-out or damaged structural proteins and enzymes. Worn out erythrocytes are removed primarily by macrophages in the spleen and bone marrow (also in the liver, I believe).
What type(s) of cytoplasmic granules are common to all granulocytes? What type(s) differ among the granulocytes? How does this relate to the cells’ functions?
All granulocytes contain azurophilic granules (aka primary granules), which are essentially lysosomes (even the agranulocytes, lymphocytes and monocytes, may show some azurophilic granules). These granules contain acid hydrolases, as well as antibacterial and digestive substances. The specific, or secondary granules, differ among the three types of granulocytes. The specific granules in each type of granulocyte contain a variety of substances, some of which are easily related to the specific functions of each cell type. For example, lysozyme in the neutrophilic granules is involved in digesting phagocytosed bacteria, the major basic protein in eosinophilic granules appears to function in the killing of parasites, and basophilic granules contain heparin and histamine, which play a role in the early inflammatory response and allergic reactions.