blood Flashcards
final exam
what is contained in blood?
- 55% plasma: water, plasma proteins
- 45%: formed elements: RBCs (99.9%), platelets and WBCs
hematopoisesis
the formation of formed elements (RBCs, WBCs, platelets) through formation of myeloid or lymphoid progenitor cells
what are the plasma proteins? (with relative abundances)
- albumin (60%)
- globulins (35%)
- fibrinogen (4%)
- others (1%)
what is serum?
plasma- fibrinogen
where do cells come from in the first 8 weeks, 3-7 months, and as an adult?
- yolk sac
- liver, spleen
- bone marrow
hematotoxicology
the study of adverse effects of the exogenous chemicals on blood and blood-forming tissues (including drugs and non-therapeutic chemicals)
types of toxicity in hematotoxicity
primary, secondary
primary hematotoxicity
one or more blood component directly affected; common serious effects of xenobiotics
secondary hematotoxicity
toxicity because of other tissue injuries or systemic disturbances (sepsis, allergy, chronic inflammatory disease)
consequences of hematotoxicology (which cell does it target)
- hypoxia (erythrocytes)
- hemorrhage (platelets)
- infection (immune cells)
erythron
all stages of the erythrocyte, including precursors in the bone marrow and circulating mature RBCs
targets of xenobiotics that affect erythrocytes
- production
- function
- survival
what is a common effect of xenobiotics that effect erythrocytes?
anemia:
- reduction in proportion of RBCs
- A person’s level of hemoglobin within them is lower than a healthy person
anemia definition
a reduction in the oxygen carrying capacity of blood due to decreases in hemoglobin (Hb) concentration and red blood cell (RBC) volume.
symptoms of anemia
weakness, lethargy, dyspnea
which organs can be affected by anemia
all b/c interferes with oxygen delivery to peripheral tissue
3 groups of anemia
- caused by blood loss
- decreased or faulty RBC production/maturation
- increased destruction of RBCs
RBC production dependent on: ?
frequent cell division and high rate of Hb synthesis
Hb range in males and females
males: 14-18 g/dl
females: 12-16 g/dl
heme
a porphyrin ring surrounding a single ion of iron (can interact reversibly with oxygen molecule)
what does each Hb contain
2 α chains and 2 β chains (making up the Globin), each containing 1 heme
types of anemias
iron deficiency anemia, sideroblastic anemias, megaloblastic anemia
erythropoiesis process
- proerythroblast from erythroid progenitor
- Actively synthesize hemoglobin
- Hemoglobin appears (day 3)
- normoblast (Nuclei pyknotic)
- reticulocyte (Still contains some RNA – ejected nucleus)
- mature RBC (day 7-8)
steps to hemoglobin synthesis
in bone marrow:
- initial: in mitochondria, takes glycine and Succinyl-CoA and converts it – rate limiting step
- intermediate steps: in cytoplasm
- final steps: Incorporation of iron into the porphyrin ring (in mitochondria)
which step is altered in iron deficiency anemia?
final step where iron is incorporated into porphyrin ring to make heme
recommended intake of iron for male and female
male: 8 mg/day
female: 18 mg/day
what can cause iron deficiency anemia?
- Inadequate iron consumption
- Decreased iron absorption
- Iron loss secondary to blood loss
- drugs that contribute to bleeding (e.g. NSAIDs)
sideroblastic anemia definition
Abnormal utilization of iron
what characterized sideroblastic anemia
the presence of ring sideroblasts in the bone
marrow; Erythroblasts with iron-loaded mitochondria (caused by buildup of iron)
what are the causes of sideroblastic anemia
defections in the synthesis of the porphyrin ring by:
- hereditary causes
- Acquired due to exposure of toxic substance (more common)
effect of lead (Pb)
interferes with the first, second and last step of heme synthesis:
- first (rate-limiting): Aminolevulinic acid synthase
(ALAS)
- second: δ-aminolevulinic dehydratase
(ALAD)
last: incorporation of iron in porphyrin ring by Ferrochelatase
what does PLP do?
is a cofactor for ALAS activity
what is PLP?
pyridoxal-5-phosphate, an active form of vitamin B6
effect of Isoniazid
inhibits PLP, which inhibits ALAS activity
megaloblastic anemia
low RBC count, characterized by RBC precursors called megaloblasts (in the bone marrow) that are larger than normal
what causes megaloblastic anemia
Any defect that causes a slowing of DNA synthesis (inhibits nuclear division) such as folate or vitamin B12 deficiency or malabsorption (since needed for DNA synthesis)
where does vitamin b12 and folate come from
vit. B12: all foods of animal origin
folate: many foods of plant origin
path of dietary vitamin B12
- ingested
- combined with haptocorrin in stomach
- trsnsferred to intrinsic factor by gastric parietal cells
- goes down small intestine
- complex binds to receptor in terminal ileum
- then it enters circulation, where it can be utilized by cells or stored in the liver
path of dietary folate
- ingested
- undergoes hydrolysis in GI
- absorbed in duodenum and jejunum
- enters enterocytes, where enters folate cycle (makes N5-methyl THF)
- enters cell or stored in liver
what nucleotide is rate-limiting factor for DNA synthesis, why?
thymidylate since requires folate and vit. B12, so it is the one that is made the least
how does chronic alcohol consumption lead to megaloblastic anemia?
- it damages the gastric mucosa and thus decreases production of intrinsic factor, which decreases vit. B12 absorption
- its affects intestinal mucosa to interfere with absorption of folic acid (jejunum) and Vitamin B12 (ileum)
what can cause drug-induced megaloblastic anemia?
- fluorouracil (suicide substrates): inhibits thymidylate synthase
- methotrexate: block metabolism of folate
aplastic anemia definition
inability of stem cells in bone marrow to generate mature blood cells (bone marrow hypoplasia)
forms of aplastic anemia
- pancytopenia
- reticulocytopenia
- pure red cell aplasia: rare
pancytopenia
deficiency in red cells, leukocytes and platelets
reticulocytopenia
reticulocyte (aka immature RBCs) count < 0.2%
Pure red cell aplasia
absent or infrequent erythroblasts
what causes aplastic anemia?
- genetic: mutations affects DNA repair
- damage to bone marrow: immune-mediated or direct toxicity
ways which you can acquire aplastic anemia (which specific chemicals)
- Iatrogenic (caused by treatment): radiation, drugs
- chemicals: pesticides, arsenic, benzene, mercury
most common rout of exposure of benzene
inhalation
where is benzene found/produced?
- widely used in industries (plastic, resin, fibers, rubber, …)
- in crude oil (gasoline)
- cigarette
- naturally by volcanoes and forest fires
IARC classification of benzene
class 1
how does benzene cause leukemia?
- converted to benzene oxide then to hydroquinone by CYP2E1 in liver
- it can go in bone marrow and become benzoquinone, which causes toxicity
normal lifespan of eryhthrocytes
120 days
hemolytic anemia definition
Increased destruction of erythrocytes
forms of hemolytic anemia
- immune
- non-immune (aka oxidative hemolytic anemia)
immune hemolytic anemia + cause(s)
- Interaction of antibodies (IgM or IgG) against antigens on the RBC – Initiates destruction of the RBC through complement or phagocytic cells
- rare complication of drugs – penicillin: Binds on RBC surface → immune response against drug-coated RBC
oxidative hemolytic anemia + cause(s)
- increase in ROS due to G6PD deficiency, which usually supplies NAPDH
- X chromosome-linked recessive mutation (males more affected): most asymptomatic until exposed to hemolytic trigger
- favism
favism
- is high in B-glucosides
- undergoes conversion to divicine and isouramil in digestive tract, which are highly reactive
- produces ROS
- Detoxified in a normal cell but not in G6PD deficient cell, causing RBC destruction due to oxidative damage
Methemoglobinemia definition
- a condition where the iron in hemoglobin is oxidized from the ferrous to the ferric state
- this is something that occurs normally, but the level of methemoglobin is kept very low (converted back by CYP450s)
effect of methemiglobinemia
- ferric hemoglobin not capable of binding and
transporting oxygen, which reduces oxygen-carrying capacity of the blood - leads to anemia, tissue hypoxia, cyanosis
what causes Methemoglobinemia?
- congenital: rare, Cytochrome b5 reductase deficiency
- acquired: food preservatives; sodium nitrate, nitrates in fertilizers (ground water/food)
why are infants more susceptible to methemoglobinemia?
- Have higher proportion of Fetal Hb (may be more rapidly oxidized to HetHb than adult Hb)
- Infants have lower levels of MetHb reductase than adults: more sensitive to nitrate/nitrite toxicity
what can be given to reverse methemoglobinemia? how does it work?
methylene blue
- acts as a substrate for NADPH MetHb reductase, so transfers its electrons to hemoglobin
what are platelets, what are they important for?
- small blood cells that form clots to stop bleeding
- important for blood clotting
where and by what are platelets produced?
in bone marrow by megakaryocytes
life of platelet
9-12 days
thrombocytopenia
abnormal depletion of platelets (too much destruction or inadequate production)
thrombocytosis
excessive number of platelets
effect of alcohol on platelets
causes destruction of megakaryocytes leading to thrombocytopenia
what can cause thrombocytopenia?
drugs such as penicillin, which can cause immune-mediated platelet destruction, by acting as a hapten on platelets
blood clot formation
need clotting factors that convert prothrombin to thrombin, which converts fibrinogen to fibrin, which acts as a net to form clots.
effect of warfarin
interferes with the vitamin K cycle, limiting the amount in its active form, which decreases clotting since vitamin K is a cofactor for clotting factors IX, VII, X, and II
