Exam 1 Flashcards
Fetus hematopoietic organs
liver & spleen
adult hematopoietic organs
bone marrow- pelvis, ribs, vertebrae, skull, epiphyses of the femur & humerus
Blood cells are produced in the:
bone marrow
bone marrow contains:
stem cells
stem cells produce three types of blood cells:
WBCs, RBCs, & plts
blood islands
clusters of stem cells in the human embryo
chief site of blood cell formation until shortly before birth
liver and spleen
_____ of development, hematopoeisis commences in the bone marrow
fourth month
up until age 18, all of the marrow throughout the skeletonis hematopoietically active. after that:
only the vertebrae, ribs, sternum, skull, pelvis & proximal areas of humerus & femur are active
in adults, only about ___ of marrow space is active in hematopoiesis
half
hematon:
separate microenvironments of developing progenitor cells. isolated by reticular cells
important hematopoietic components that provide growth factors, collagen & cell adhesion proteins
endothelial cells, firboblasts, macrophages, & adipocytes
pluripotent
stem cells- unique potential to ultimately become any of the mature hematopoietic cells
stem cells are characterized by:
high proliferative capacity
potential to differentiate along all lineage pathways
property of self renewal
important property of stem cells
property of self renewal- ability to generate additional stem cells through mitosis w/out differentiation
hematopoietic cytokines
protein molecules actively secreted by cells of bone marrow & influence proliferation & differentiation of stem cells into mature blood cells
Platelets & RBCs do not have
a nucleus
WBCs include:
granulocytes (eos, baso, neutro)
monocytes/macrophages
lymphocytes (B&T cells)
most common PMN
neutrophils
neutrophils have
multi-lobe nucleus
primary neutrophils contain
proteins (defensisns), proteolytic enzymes, lysozymes
secondary neutrophils contain
NADH oxidase components
Basophils
basic
involved in allergic rxns
Heparin & histamine
Eosinophils
acid
defense against paracites
high numbers in GIT & lungs
Monocytes circulate in the ___ and
marcophages are found in ____
blood stream; tissues (liver & lymphh nodes)
most common type of blood cell
RBCs
diameter of a typical RBC
6-8 microns
RBCs produce energy via
glycolysis
production of RBCs can be stimulate dby
erythropoietin
main sites of destruction of RBCs
liver & spleen
hemoglobin is eventually excreted as
bilirubin
platelets aka
thrombocytes
platelets are
fragmented pieces of megakaryocyte cytoplasm released from bone marrow into the blood stream
what is required for the differientiation of stem cells into platelets
thrombopoietin
CBC contains
RBC & WBC count, Hgb, Hct, RDW, reticulocyte count, platelet count & mean platelet count, MCV< MCH< MCHC
Hct
% volume of blood composed of RBCs
usually 3X Hgb
Anemia
reduction in the oxygen carrying capacity of blood
decrease RBC volume measured by Hct or Hgb
anemia classification based on:
appearance (size) of RBCs
degree of Hgb- color
underlying mechanism
< folate or B12 causes defective
DNA synthesis and therefor can’t make RBCs
< iron cause deficient
heme synthesis
hemolytic anemia
> RBCs destruction
shortened lifespan of RBCs
accumulation of hgb catabolism products
erythropoiesis
spherocytosis:
abnormal shape, can’t fit through vessels
disorder of RBC membrane cytoskeleton
thalassaemia syndromes
deficient globin synthesis
sickle cell anemia
structural abnormal globin synthesis
extravascular hemolysis
phagocytic destruction of senescent RBCs takes place within the phagocytic cells of the spleen
intravascular hemolysis
lyses of RBCs occur within the vascular compartment. occurs when RBCs are damaged by mechanical injury, complement(transfusion), exogenous toxic factors (malaria)
characteristics of intravascular hemolysis
hemoglobinemia, hemoglobinuria, jaundice, methemoglobinuria(oxidized Hgb), hemosiderinuria
haptoglobin levels go ____ in intravascular anemia
down
characteristics of extravascular hemolysis
do NOT have Hgb-emia or Hgb-uria
jaundice
mayhave decreased haptoglobin
may have hypertrophy of mononuclear phagocytes-> splenomegaly
hereditary spherocytosis
anemia due to RBC membrane protein disorder
autosomal dominant
RBC are spherical due to deficiency in RBC protein spectrin
can have chronic hemolytic anemia
splenomegaly
jaundice
spectrin
major component of RBC cytoskeleton
along with Band 3, are responsible fore maintenance of normal shape, strength & flexibility
G6PDH deficiency
leads to hemolytic anemia due to inability to neutralize oxidative stress
H2O2 accumulates in RBCS
how does accumulation of H2O2 cause RBC lysis?
cause oxidation of sulfhydryl groups like globin chains in RBCs-> denaturation of Hgb & formation of Heinz bodies
Heinz bodies damage
RBC membrane and cause extravascular hemolysis
causes of oxidative stress
Drugs, infections, fava beans
Coombs’ test
distinguish between anemia caused by immune mediated response & other forms of anemia
Coombs- antihuman antibodies
Direct Coomb’s test
detect antibodies bound to RBCs
Indirect Coombs’ test
detects antibodies in the serum
3 key defects in erythropoiesis:
- defective DNA synthesis due to lack of B12 or folate- Macrocytic
- impaired heme synthesis due to lack of iron- Microcytic
- impaired erythropoiesis due to marrow stem cells failure- normocytic
major form of B12 deficiency anemia
pernicious macrocytic anemia- results from lack of intrinsic factor resulting in malabsorption of B12
B12 & folate are ______ in the DNA synthetic pathway
coenzymes
synthesis of RNA & protein are unaffected
to absorb B12 you need
intrinsic factor secreted by gastric parietal cells
vitamin B12 aka
Cobalamin- complex organometallic compound
_______ are the ultimate origin of cobalamin in the food chain
microorganisms
B12 is released from protein bound form by
pepsin in the stomach
free B12 binds to proteinsc called
cobalophilins or R-binders
________ delivers B12 to the liver & other cells in the body
transcobalamin II
Atrophic gastritis
loss of gastric mucosal folds & thinning of gastric mucosa with parietal cells-> no IF
antibodies detected in pernicious anemia
Type 1: blocks binding of B12 to IF
Type 2: block binding of IF or IF-B12 to its receptor on ileal cells
type 3: bind to the gastric proton pump on parietal cells
folate deficiency anemia is similar to B12 EXCEPT
NO neurological changes
important metabolic rxns that depend on THF
synthesis of purine, methionine, & deoxythymidylate monophosphate
form of folate in green veggies
folypolyglutamates
most common anemia world wide
iron deficiency
iron content in the body is distributed into:
functional(globin) & storage comparentments
ferritin is stored within
parenchymal cells in the liver
mononuclear phagocytic cells in spleen & bone marrow
can be found within all tissues
hemosiderosis
excess iron causes hemosiderin to accumulate within cells & tissues
in iron deficiency, plasma ferritin is always
below 12mg/L
in iron overload, plasma ferritin is at
high values approach 5000mg/L
iron is stored in
ferritin
iron is transported in plasma by
transferrin
iron absorption takes place mainly in
the duogenum
major function of plasma transferrin is to
deliver iron to cells
_____ cells have high affinity receptors for transferrin
immature RBCs
aplastic anemia common cause
exposure to chemicals/drugs-> suppression of multipotent myloid cells-> inadequate production of differentiated cell line
anemia of chronic disease
associated with < erythroid porliferation & impaired iron utilization & may mimic iron deficiency
common method to narrow possible cause of anemia
erythrocyte morphology- different anemias lead to different erythrocyte morphology
RBC indices asses:
size & Hgb content of RBCs
MCH (mean cell Hgb)
average amount of Hgb inside a RBCs
goals of treatment
alleviate signs & symptoms
correct underlying etiology
prevent complications & recurrence
oral iron best absorbed in the:
Fe2+ (ferrous) form
sickle cell syndrome:
a hereditary autosomal recessive genetic blood disorder affecting the hemoglobin beta chain
Sickle cell syndrome is characterized by
red blood cells that ssume an abnormal, rigid, sickle shape
Sickle cell syndrome results in
deformation, increased rigidity and destruction of RBCs
Sickle cell trait (SCT)
only one abnormal allele; usually symptomatic
sickle cell disease (SCD)
both alleles are mutated; develop SCA; multisystem disease associated with episodes of acute illness and progressive organ damage
SCD results in
impaired circulation, vasocclusive disorders, vessel damage and RB destruction; severe morbidity and early mortality
global distribution is indicative of two factors:
- survival advantage in malaria-endemic regions
2. subsequent migrations.
patients with SCD experience
delayed growth (height & weight)
Life expectancy in SCD
males-42
females-48
life expectancy in SCT
males-60
females-68
it is the mutation of __ chain that accounts for the disease
beta
HgbS
Glutamic acid->valine(hydrophobic) at 6th AA
alters conformational structure of hgb
HgbC
substitution of glutamic acid with lysine
val6 of beta 2 chain in one HGS forms hydrophobic bonds with
Phe85 and Leu88 of second HbS beta-1 chain
solubility od deoxygenated HgS is ____ than HbA
Substantially lower
life span of sickled RBC
10-20 days
3 main problems are primarily responsible for the clinical manifestation of the disease:
- impaired circulation
- destruction of RBCs
- stasis of blood flow
factors promoting HbS polymerization
low pO2/hypoxia (high altitudes) increased CO2, low pH (physical inactivity) increased 2-3BPG in RBC high [HgS] low [HgF]
HgF
has gamma chains instead of beta, so no sickling
gamma globin chains bind HgS & inhibit HgS polymerization
hallmarks of SCD
microvascular vasoocclusion, inflammation, system disease
acute complications (sickle cell crisis)
vasoocclusive, splenic sequestration, aplastic, hemolytic
vasoocclusive pain crisis
hand & food syndrome (dactylitis- sausage digit)- infancy
joint and extremities
abdomen
hepatic- older pts
splenic sequestration crisis
splenic sinusoidal vaso-occlusion-> splenic sequestration -> acute splenomegaly & decreased circulating blood volume-> hypotension & shock/death
aplastic crisis
destruction of erythroid precursors in marrow-> anemia
low reticulocyte count
associated with paravirus B19, strep pneumo, salmonella, & H. influenzae
hemolytic crisis
particulary common in pts w/ G6PDH deficiency too
acute accelerated decrease in hemoglobin level & RBCs
transfusions are necessary
second most common complication of SCD & most common cause of death in adult patients
acute chest syndrome
SCD treatment
lifelong multidisciplinary pain control infection prophylaxis chronic transfusion therapy preventative therapies (HgF inducers) curative treatment (allogeneic stem cell transplantation) investigative therapies (gene therapy)
hydroyurea
HgF inducer
inhibits production of deoxynucleotides via the inhibition of ribonucleotide reductase
can prevent painful crisis
induces proliferation of early erythroid progenitors & increase NO levels
antioxidant properties
hydroxyurea decreases
frequency of acute chest syndrome, hospitalization, need for transfusion, morbidity & mortality
hydroxyurea is a possible alternative to:
chronic transfusion to decrease recurrent stroke
hydroxyurea side effects
significant bone marrow toxicity- leukopenia & thrombocytopenia
drowsiness, N/V/D, constipation, alopecia, abnormal liver enzymes, creatinine & BUN
sodium butyrate
naturally occurring short-chain fatty acids
inhibits histone deacetylation
shown to heal leg ulcers
decitabine
inhibits DNA methylation (prevents gamma->beta chain)
only therapy offering curative potential for SCD
allogenic hematopoietic stem cell transplanation
gene therapy in SCD
transfer of anti-sickling beta-globin genes
HIV lentiviral- mediated gene transfer can potentially correct hematological defects & organ damage
