Hematopoiesis, Aplastic Anemia, HypOproliferative Disorders, WBC Flashcards
T/F
hematopoietic progenitor cells lack the ability to self-renew
T
myeloid growth facs
Erythropoietin (Epo)
Thrombopoietin (Tpo)
Granulocyte colony-stimulating factor (G-CSF)
Granulocyte-macrophage colony-stimulating factor (GM-CSF)
Macrophage colony-stimulating factor (M-CSF)
Interleukin-3 (IL-3)
Interleukin-6 (IL-6)
Stem cell factor/mast cell growth factor (SCF)
Epo MOA
Acts as a true hormone (produced at one site, circa in the blood and acts on a target organ)
Prod in kidney in response to local hypoxia –> acts on erythroid progenitors in the bone marrow to boost rbc prod
Tpo MOA
Prod in liver at constant rate
Binds to receptor on megakaryocyte and precursors in bone marrow –>Mk maturation/platelet prod
ALSO binds to same receptor on circulating platelets (if xs platelets –> free Tpo drops, platelet prod slows. If low platelets –> free Tpo rises, platelet prod incr.)
Pool of unbound Tpo is inversely related to
Pool of unbound Tpo is inversely related to NUMBER OF PLATELETS
myeloid growth facs act thru cell surface receptors to trigger _____ and _____
myeloid growth facs act thru cell surface receptors to trigger DIMERIZATION and ACTIVATION OF CELL KINASES
From the _____ stage on, cells are post-mitotic
From the METAMYELOCYTE stage on, cells are post-mitotic
mature blood cells circulate for how long
100-120 d
normal % of reticulocytes in blood
1%
clinical use of Epo
anemia of chronic kidney failure
chemo-induced anemia
clinical use of Tpo
chemo-induced thrombocytopenia
clinical use of G-CSF
chemo-induced neutropenia
aplastic anemia
clinical use of GM-CSF
chemo-induced neutropenia
site of active bone marrow hematopoiesis in adults
spine, pelvis, ribs, sternum, and skull
site of active bone marrow hematopoiesis in child
entire skeleton
usual site of BM biopsy
posterior superior iliac crest
bone marrow failure
cytopenia due to dec production
Aplastic anemia
bone marrow failure due to deficiency of hematopoietic stem cells –> in aplasia (lack of hematopoiesis) and pancytopenia (low rbc/wbc/platelet counts in the peripheral blood)
normal pyelogram contains ___ immature blast cells
normal pyelogram contains LESS THAN 5% immature blast cells
normal pyelogram
myeloid precursor:erythroid precursor
normally 2-4x as many myeloid precursors than erythroid precursors
fat makes up __% of the marrow normally
fat makes up 50-60% of the marrow normally
congenital aplastic anemia
fanconi anemia
Schwachmann-Diamond Syndrome \
Dyskeratosis congenita
Amegakaryocytic thrombocytopenia
Fanconi Anemia
congenital aplastic anemia
AR, Ashkenazi Jews
5-9 y/o (congenital malformations, abnormal thumbs, cytopenia)
damage due to defect in DNA repair pathway, 12 Dif gene mutations IDed
Schwachman-Diamond
congenital aplastic anemia
Rare, AR, homozygous mut SBDS (rRNA metabolism, mitotic spindle)
exocrine pancreatic deficiency, skeletal abnormalities, bone marrow failure
dyskeratosis congenita
congenital aplastic anemia
rare, XL or AD or AR
ectodermal dysplasia, BM failure, cancer predisposition
mut cause dysfunctional telomerase (pts have abnormally short telomeres, stem cell transplant is only cure)
Congenital amegakaryocytic thrombocytopenia
congenital aplastic anemia
rare, AD
infancy w/ isolated thrombocytopenia, absent megakaryocytes in BM
mut in MPL (gene for Tpo receptor)
acquired aplastic anemia
causes
Radiation, toxins/chemicals (benzene, organic solvents, cancer chemotherapy)
Drugs: methotrexate, chloramphenicol, gold, NSAID
Autoimmune disorders: lupus, mixed cyroglobulinemia, idiopathic
Lymphoid malignancy (thymoma/pure red cell aplasia)
Pregnancy
Virus (HIV, HBV, HCV, parvovirus B19)
Paroxysmal Nocturnal Hemoglobinuria
Unknown
Paroxysmal Nocturnal Hemoglobinuria (PNH)
acquired syndrome of hemolysis and BM failure
somatic mutation in PIG-A in HSC –> dec GPI-anchor needed for surface proteins on rbc
some of these surface proteins (CD55, CD59) limit complement action, so PNH cells susceptible to complement lysis –> hemolysis
high freq thrombosis
2 principle causes of severe aplastic anemia
- immune mediated stem cell suppression
2. stem cell damage/loss
2 main tx approaches for severe aplastic anemia
- immune suppression
2. stem cell replacement by transplantation
hypOproliferative anemias
Fe deficiency
B12 and folate deficiency
Anemia of chronic disease
anemia
physiologic definition
Erythropoiesis in bone marrow does not match demand for oxygen-carrying capacity (rbc) in peripheral blood circulation
inadequate delivery of O2 to tissues
anemia
operational definition
dec in Hb protein in red cells by >2 SD below normal mean
dec in Hct % (mL of RBC’s per 100 mL of blood)
Mean corpuscular volume (MCV)
size of rbc
calc via Hgb/RBC
Mean corpuscular hemoglobin (MCH)
Hb in single rbc
pg/cell
(Hb/rbc)
MCHC
Hb in given vol of rbc
g/dl
(Hgb/Hct)
RDW
rbc size distribution
%
if uniform size, low RDW
anemia signs/sx
fatigue pallor SOB tachycardia, palpitations orthostatic HTN
reticulocyte
youngest normal RBC entering circulation from BM
contains RNA remnants, ribosomal machinery
visualized w/ supravital stains
reticulocyte count
(% of rbc that have RNA remnants) * total rbc #
reticulocyte index
adjusts reticulocyte count in anemic state
reticulocyte count (%) * pt’s Hct / 40
(should be >2 in anemic pt if BM is inc reticulocytes appropriately)
hypOproliferative anemia
criteria
anemia with RI <2 and/or absolute reticulocyte count less than nil
hypERproliferative anemia
RI elevated and/or absolute reticulocyte inc in pt w/ anemia
hypOproliferative anemias
iron deficiency B12 deificency folate deficiency Epo deficiency hypOthyroidism lead/other toxins (EtOH) Infection (Parvo B19) BM failure (Fanconi's anemia) Myelodysplastic syndromes Anemia of chronic disease
low MCV (microcytic hypo proliferative anemias)
iron deficiency*
Pb tox
ACD
normal MCV (microcytic hypo proliferative anemias)
ACD *
kidney disease
red cell aplasia
high MCV (microcytic hypo proliferative anemias)
B12 deficiency*
Folate deficiency*
Myelodysplastic syndrome
Alcoholism
Fe deficiency causes
prematurity, rapid growth (infants) diet (toddlers) adolescents (menstruation, diet) pregnancy (depletion of stores) adults (overt or occult blood loss, Malabsorption, genetic)
Fe deficiency signs/sx
fatigue, pallor, dyspnea hair loss PICA restless legs spoon shaped nails (koilonychia) angular cheilitis swollen/sore tongue
hephaestin
ferrioxidase that reoxidases iron for release from enterocyte to plasma transferrin
ferroportin
key transport protein in exchange of Fe from enterocyte to transferrin
transferrin
secreted by hepatocytes
major transport protein in blood
delivers Fe to cells possessing appropriate cell-surface transferrin receptors
intestinal Fe absorption varies inversely w/ expression of ____ in ____
intestinal Fe absorption varies inversely w/ expression of HEPCIDIN in LIVER
primary Fe regulatory hormone
hepcidin
prod in liver
synthesized in response to inflammation/inc Fe stores
hepcidin prod is inhibited by
hepcidin prod is inhibited by INC Epo (DEMAND FOR Fe)
______ downregulates Ferroportin
HEPCIDIN downregulates Ferroportin
–> dec Fe absorption by enterocyte, dec Ferroportin-mediated Fe export from enterocyte to blood, dec Fe release from macrophage of RES
Ferritin
usable form of Fe
H2O soluble protein-iron complex w/ outer shell (apoferritin)
serum ferritin reflects Fe stores
serum _____ reflects Fe stores
serum FERRITIN reflects Fe stores
Fe deficiency CBC
anemia microcytosis (low MCV) Hypochromia (low MCH) dec rbc low reticulocyte count
rbc should be roughly the size of ____ nucleus
lymphocyte nucleus
Fe deficiency
serum Fe studies
serum Fe:
TIBC:
Ferritin:
Transferrin Sat:
serum Fe: low
TIBC: high
Ferritin: low
Transferrin Sat: low
tx of Fe deficiency
oral Fe (6 mg/kg daily, acidic cond)
IV Fe (2 mg/kg IV over 1hr, Fe sucrose)
transfusion (0.5mg Fe in each ml whole blood, only severe sx, AE: infection, rxns, Ab form)
Pb toxicity
Pb inhibits final steps in heme synthesis
Inhibits RNA breakdown
RNA aggregates in RBC (basophilic stippling)
anemia w/ low MCV
multiple non-hematologic comorbidities
Pb tox signs/sx
exposure to lead paint, exhaust fumes, contaminated H2O
sx: abd pain, anemia, neuro, fatigue, malaise, irritability
dx: serum Pb
anemia of chronic illness
normocytic anemia (MCV usually not less than 70)
assoc w/ inflammatory disorders
dysregulation of Fe transport, utilization and storage via induction of hepcidin expression by inflammatory cytokines
Fe released from enterocytes/macrophages is inhibited (down regulated ferroportin)
dec plasma Fe, normal BM Fe stores
folic acid
water-soluble vitamin
green leafy veggies, fortified grains, some fruits
easy absorption in duodenum/upper jejunum (polyglutamate conjugation and methylation)
folate deficiency causes
diet (old age, poverty, goats milk)
malabsorption (Chron’s, celiac sprue, GI surgery)
inc demands (pregnancy, hemolysis, rapid growth)
drugs (folate antagonists like methotrexate)
liver disease, EtOH
B12
animal (liver, red meat, some dairy)
complex absorption mech (R-binder proteins, intrinsic factor (parietal cells), receptors on terminal ileum, transcobalamin I/II)
daily req 1-2mg
bod stores 2-3mg
causes of B12 deficiency
malabsorption (gastrectomy, lack of intrinsic factor, pernicious anemia)
GI (ideal resection, stricture, celiac, tapeworm)
Transcobalamin II deficiency
NO toxicity
Meds (PPIs, metformin)
pernicious anemia
Ab-mediated destruction of parietal cells
reduced IF prod
dx via finding anti-IF Abs
macro-ovalocytic rbc
giant hyperhsegmented neutrophils
B12 neuropathy
progressive, affects peripheral sensory nerves and postero-lateral SC columns
tingling, balance/walking issues
impaired methylmalonyl CoA mutase
symmetrical, lower>upper limbs
impaired methylmalonyl CoA mutase
accumulation of S-adenosyl homocysteine and odd-chain FA
folate and B12 predispose to ____ defects
neural tube defects (anencephaly, spina bifida)
impaired methylation of myelin and lipids
B12 deficiency labs
serum B12:
RBC folate:
Serum folate:
serum B12: low
RBC folate: normal/low
Serum folate: normal/high
folate deficiency labs
serum B12:
RBC folate:
Serum folate:
serum B12: normal
RBC folate: low
Serum folate: low
in addition to checking serum B12 levels, evaluation of B12 deficiency can also include
checking for inc homocysteine and methylmalonic acid in blood (more sensitive than B12 in borderline cases)
endoscopy to evaluate for atrophic gastritis
blood for parietal Abs (in PA)
tx for B12/folate deficiency
administer vitamin
(may need to give both vitamins to correct hematology and neuropathy)
if absorption a problem –> replace parenterally (IV or IM)
indicators of response to B12/folate deficiency tx
inc appetite in 24-48 hr
inc reticulocyte count (3d)
Hb inc (2-3g/dl q2wk)
normal platelets and WBC (7-10d)
peripheral neuropathy may improve
spinal cord damage=IRREVERSIBLE
Fe overload
inc Fe absorption (hereditary hemochromatosis, chronic liver disease, ineffective red cell production)
inc Fe intake (African siderosis)
transfusional (Fe chelation needs in chronic transfusion states)
Hereditary hemochromatosis
- mutation in HFE chromosome 6
- AR
- xs absorb of Fe from GI tract
- inc transferrin sat and ferritin
- iron deposition in liver/heart/organs
- skin pigmentation/arthropathy
- inc transferrin saturation/high ferritin
- HFE mutation testing
- tx: phlebotomy
wbc
leukocytes
2 groups:
phagocytes (neutrophils, eos, basophil)
immunocytes (lymphocytes and plasma cells)
neutrophils
usu >50% circulating WBCs in adult
exit vasculature –> tissues to kill invaders
1st to arrive in inflammatory response
bands (WBC)
one step prior to mature eos
higher # w/ acute bacterial infection
eosinophils
sim to neutrophils - phagocytosis but less responsive
worms/wheezes/weird diseases…
ellergies, parasites, TB, sarcoidosis, Addison’s disease, Hodgkin’s disease
basophils
uncommon in peripheral blood
histamine release –> inflammation
histolog: blue, coarse granules, can barely see nucleus underneath
if >5-10%, consider CML
monocytes
function:
- phagocytosis
- present antigen to T-cell lymphocytes
- secrete cytokines
lifespan:
- marrow–>brief
- circ–> 20-40 hr
- tissue–> months/yrs (differ to macrophage)
inc monocyte count
chronic infection (TB) chronic inflammation (sarcoid) chronic neutropenia recovery from neutropenia preleukemia myeloproliferative syndrome
dec monocyte count
bone marrow failure
corticosteroids
myelosuppressive drugs
dohle bodies
cytoplasmic inclusions, ribosome rich ER seen in sepsis, G-CSF use
Plger-Huet anomaly
majority of granulocytes have bilobed nucleus, rather than typical 3-5 lobes
benign hereditary disorder
myelodysplastic syndrome
granulopoiesis growth facs
IL-1, IL-3, IL-5 (eos), IL-6, IL-11
GM-CSF, G-CSF, M-CSF
released from stromal cells and T lymphocytes (stim by endotoxin, IL1, TNF)
chemoattractants
- complement cleavage fragments
- products released by bacteria/host cells
- neutrophils –> C5a
- GCPR
leukocyte adhesion molecules
glycoprotein molecules (B2 integral and selectin ligand –> bind B2 ligand and selectin on endothelial cells)
opsonization
antigens are bound by Ab or complement (C3b) –> enhanced phagocytosis
neutralization (oxygen-independent)
- phagosome-lysosome fusion and acidification
- hydrolytic and proteolytic enzymes
neutralization (oxygen-dependent)
respiratory burst
NADPH oxidase reduces O2 to H2O2 (hydrogen peroxide), which then works w/ myeloperoxidase to kill bacteria.
left shift in wbc
more immature granulocytic forms seen (band cells)
inherited causes of leukocytosis
Down syndrome
WBC dysfunctional disorders
acquired causes of leukocytosis
inflammation stress infection meds malignancy asplenia
neutropenia causes (decreased production, congenital)
kostmann’s syndorme
benign (ethnic/familial)
cyclic
bone marrow failure (rare)
neutropenia causes (decreased production, acquired)
drug
infectious
malignanct
toxicity
neutropenia causes (increased destruction)
infection
immune (neonatal alloimmune, AI, SLE)
splenomegaly
drug
inherited phagocytic functional disorders
- myeloperoxidase deficiency
- leukocyte adhesion defect
- chediak-hegashi syndrome
- specific granule deficiency
- hyperimmunoglobin E, recurrent infection syndrome (Job’s)
- chronic granulomatous disease (CGD)
chronic granuomatous disease (CGD)
XLR (gene codes for NADPH oxidase enzyme)
- DEFECT IN RESPIRATORY BURST ENZYME COMPLEX
- severely diminished H2O2 prod (can’t destroy organisms)
- problem w/ catalase + microbes (breakdown H2O2)
- severe skin/sinopulmonary infec/granulomas/abcesses/sepsis
- lymphadenopathy, hepatosplenomegaly
- nitroblue-tetrazolium (NBT) NEGATIVE
Which disease has trouble killing catalase + organisms?
Name some catalase + organisms
chronic granuomatous disease (CGD)
Staphylococci, E coli, Klebsiella species, Pseudomonas, fungi aspergillus, nocardia
myeloperoxidase deficiency
- usually partial defect
- respiratory burst affected but can still produce H2O2
leukocyte adhesion defect
- extremely rare AR disorder
- beta integrin and selection ligand can’t adhere to endothelial surfaces
- unable to phagocytose bacteria coated w/ C3
- DELAYED UMBILICAL CORD LOSS, poor wound healing, bacterial infections
- leukocytosis
Chediak-Higashi Syndrome
AR
- failure of phagolysosome formation, neutropenia
- partial albinism, giant lysosomes, neuropathy, lymphoma
- recurrent skin/systemic infections, Staph aureus
Job’s Syndrome
hyperimmunoglobin E (recurrent infection syndrome)
- rare AD, STAT3 mut
- inc IgE, eczema, recurrent skin/sinopulmonary infections
- defect in chemotaxis
