blood Flashcards
what are the sites of RBC degradation
spleen
liver
bone marrow
when are RBC’s degraded
when they display a specific oligosaccharide on their surface
list the adaptations of RBC’s
- biconcave disc shape, increases SA which increases gas exchange
- un-nucleated + no organelles, provides more space for Hb
- Hb concentrated at periphery of erythrocyte, facilitates gas exchange
what is the cytoskeleton of RBC’s made out of
spectrin
actin
adducin
explain why RBC’s are flexible + how they maintain their biconcave shape
cytoskeleton (spectrin/ actin/ adducin) is attached to ankyrin which is attached to a transmembrane protein
explain how ABO blood groups are determined
CHO chains attached to glycoproteins/lipids (glycocalyx) act as antigens to determine the blood group
where does prenatal hemopoiesis occur
liver
where does postnatal hemopoiesis occur
bone marrow (sinusoids/ stroma/ myeloid cells)
what do all blood cells arise from
pluripotent hematopoietic stem cells (PHSCs)
= 0.1% of nucleated cell population of bone marrow
what do PHSCs give rise to
more PHSCs
multipotent hematopoietic stem cells (MHSCs)
- CFU-Ly
- CFU-GEMM
what do MHSCs give rise to
unipotent/progenitor cells
what GFs/ cytokines control erythropoiesis + what is their function
IL-3 / IL-9
GM - CSF (granulocyte macrophage - CSF)
steel factor
erythropoietin hormone
function is to drive stem cells from G0 to G1 stage so they can synthesize the max amount of Hb
till what stage in erythropoiesis can erythroblasts divide by mitosis
polychromatophilic erythroblasts stage (where Hb synthesis starts)
what are the stages of erythropoiesis
1- progenitor cell is CFU-E
2- proerythroblast
3- basophilic erythroblasts (abundant ribosomes to synthesize Hb)
4- polychromatophilic (Hb synthesis occurs resulting in eosinophilia + basophilia due to present ribosomes)
5- orthochromatophilic (ribosomes decrease + nucleus becomes eccentric and is expelled)
6- reticulocyte (non-nucleated, w/ remnants of ribosomes, first to be released into circulation)
7- mature erythroblast
what does an abnormally high % of reticulocytes in blood indicate
normal % = 0.5-2.5%
abnormal increase indicates increased rate of erythropoiesis in conditions where the rate of RBC destruction exceeds rate of formation, such as hemorrhage/ anemia
Where is erythropoietin hormone formed
90% in kidney
10% in liver
What stimulates the formation of erythropoietin
Hypoxia
What are the general factors that affect erythropoiesis
Hormones (erythropoietin / thyroxin / androgen / growth hormone)
Vitamin C
Bone marrow
Liver
What are the maturation factors that affect erythropoiesis
vitamin B12 + folic acid
necessary for nuclear maturation and cell division
what are the factors necessary for Hb formation
protein
iron
copper (Fe absorption from GIT)
cobalt (utilization of Fe during Hb synthesis)
what are the derivatives of Hb
- oxyhemoglobin (ferrous/ Fe 2+)
- deoxyhemoglobin/ reduced Hb
- carbinohemoglobin (Hb + CO2)
- carboxyhemoglobin (Hb + CO)
- methemoglobin (blood is exposed to drugs/ oxidizing agents converting ferrous iron (Fe 2+) to ferric iron (Fe 3+) which is unable to carry oxygen)
what are the steps of heme synthesis
- glycine + succinylcholine CoA ( ALA synthase)
- ALA (ALA dehydratase)
- porphrobilinogen (deaminase)
- uroporphyrinogen (decarboxylase)
- coproporphyrinogin
- protoporhyrin IX + Fe 2+ (ferrochelatase)
- heme
what inhibits ALA synthase
vitamin B6 deficiency
hemin (Fe 3+)
what does lead inhibit in heme synthesis
ALA dehydratase
ferrochelatase
what does iron deficiency inhibit in heme synthesis
ferrochelatase
effect of lead poisoning on heme synthesis
inhibits ALA dehydratase + ferrochelatase resulting in an increase in ALA w/o an increase in porphobilinogen (protoporphyrin)
accumulation of ALA results in neurological symptoms such as learning disorders and decreased attention span in children
other presentations include microcytic anemia/ pallor + weakness caused by anemia/ abdominal pain/ lead lines in bone + teeth x-rays
what differentiates porphyria’s from lead poisoning
both lead poisoning + porphyria’s are caused by accumulation of ALA which causes neurological symptoms
only porphyria’s have accumulations protoporphyrins (PBG) which causes photosensitivity
effect of iron deficiency on heme synthesis
inhibits ferrochelatase which introduces Fe 2+ into heme ring resulting in microcytic hypochromic anemia
effect of B6 deficiency on heme synthesis
inhibits ALA synthase
B6 deficiency is associated with ionized therapy for TB and may cause anemia
define porphyria
inherited defect in heme synthesis resulting in diseases of porphyrin metabolism
characterized by dermatologic/ neurological/ psychological manifestations
porphyria symptoms are caused by toxic accumulation of heme synthesis intermediates such as:
ALA accumulation causes neurological symptoms
porphyrin accumulation causes photosensitivity, symptoms are worsened by sunlight + cytochrome P450 inducing drugs which stimulate heme synthesis pathway to increase production (alcohol + barbiturates)
what are the types of porphyria
porphyria cutanea tarda
- deficiency in uroporphyrinogin decarboxylase
- late onset (4th/5th decade)
- autosomal dominant
- presentation: photosensitivity/ hyperpigmentation/ dark red pr brown urine
acute intermittent porphyria
- deficiency in porphobilinogen deaminase (increase in ALA + PBG)
- autosomal dominant
- late onset
- presentation: NO photosensitivity/ episodic psychological symptoms ( paranoia, anxiety, depression)/ abdominal pain/ dark red or brown urine
what are the steps of heme degradation
- reticuloedothelial system
- macrophages of spleen/ liver/ BM phagocytoses RBCs and lysosomal enzymes degrade Hb into heme + globin
- globin broken down into AA
- heme broken down by heme oxygenase into biliverdin + Fe 3+
- biliverden (green) gets reduced to bilirubin (yellow) by biliverdin reductase - blood
- bilirubin-albumin complex transported in blood to liver (water insoluble) - liver
- bilirubin dissociates from albumin and binds to glucuronic acid forming conjugated bilirubin (water soluble)
- conjugated bilirubin either gets excreted in urine / secreted in bile + small intestine - GIT
- bilirubin gets deconjugated by intestinal bacteria and metabolized into urobilinogen
- most urobilinogen gets oxidized to stercobilin + excreted in feces
- some urobilinogen is converted into urobilin + excreted in urine
- some urobilinogen gets reabsorbed into enterohepatic circulation back to liver
what proteins bind to Fe 3+ after it gets released by heme degradation
ferritin for storage
transferrin for transport in blood to tissues (to resynthesize heme)
clinical picture of erythroblastosis fetalis
- anemic newborn (first 1-2 months after birth)
- spleen/hepatomegaly (increased production of RBCs trying to compensate for hemolyzed RBCs)
- nucleated blastocyst forms of RBCs in circulation (due to rapid production of RBCs trying to compensate for hemolyzed RBCs)
- jaundice + kernicterus (due to increased conc. of bilirubin by hemolysis)
prevention of erythroblastosis fetalis
anti-D antibody administration to mother 72 hrs before delivery/ 28-30 weeks gestation
prevents sensitization of mother
treatment of neonates w/ erythroblastosis fetalis
removing Rh +ve blood and replacing it w/ Rh -ve blood for the first few weeks of life (to prevent kernicterus) until anti-Rh agglutinates from mother are destroyed
transfusion of whole blood is indicated in cases of:
acute blood loss
shock
transfusion of packed RBCs is indicated in cases of:
chronic/severe anemia
leukemia
transfusion of platelets concentrate is indicated in cases of:
thrombocytopenia
bleeding due to platelet dysfunction
define transfusion reaction
when antibodies in recipient plasma bind to antigen do RBCs of donor causing agglutination + hemolysis releasing Hb into plasma
what are the manifestations of transfusion reaction
allergic reaction (type II HS)
circulatory overload ?
febrile reaction ?
transfusion transmitted infection
hemolytic reaction (may result in jaundice)
kidney/renal failure
what are the 3 causes of acute renal failure after transfusion reaction
- antigen-antibody reaction releases toxic substances from hemolyzing RBCs which causes powerful renal vasoconstriction
- loss of circulating RBCs + production of toxic substances from hemolysis and immune reaction cause circulatory shock where arterial BP falls and renal blood flow + urine output increase
- excess Hb released into circulating blood that cannot bind to haptoglobin leaks through glomerular membranes into kidney tubules + precipitates + blocks them
renal vasoconstriction + renal blockage together cause acute renal shutdown
list the normal types of Hb
HbA - 2a/ 2b, 90%
HbA1c - 2a/ 2b + glucose, 4-6%
HbA2 - 2a/ 2 delta, 2-3%
HbF - 2a/ 2 gamma, <2%
define hemoglobinopathies
a group of genetic disorders caused by the production of structurally abnormal Hb OR the synthesis of insufficient quantities of normal Hb OR (rarely) both
examples of hemoglobinopathies
sickle cell anemia
thalassemia
methemoglobinemia
what are the characteristics of sickle cell anemia
autosomal recessive disease
2 mutant B chains where glutamate at position 6 is replaced by valine forming a protrusion on B chain that fits into complementary site on B chain on another Hb molecule causing polymerization of Hb molecules at low oxygen tension causing RBC to become rigid + deformed
sickle cell RBCs are less flexible + have an increased tendency to adhere to vessel walls therefore cause micro vascular occlusions leading to localized hypoxia which results in pain + infarction/ ischemic death of tissue
clinical picture of sickle cell anemia
lifelong episodes of pain (crises)
chronic hemolytic anemia w/ associated hyperbilirubinemia
increased susceptibility to infections
acute chest syndrome
stroke
splenic/renal dysfunction
bone changes due to marrow hyperplasia
reduced life expectancy
what are the variables/factors that increase the severity of sickle cell anemia
factors which decrease Hb S affinity to oxygen such as:
increased pCO2
decreased pO2
decreased pH (acidosis)
increased 2,3-BPG
dehydration
how to diagnose sickle cell anemia
clinical picture
gel electrophoresis
DNA sequencing
treatment of sickle cell anemia
hydration
analgesics
aggressive antibiotic therapy if infection is present
transfusion if patient is at a high risk of fatal occlusion
intermittent blood transfusion w/ packed RBCs which decreases risk of stroke
hydroxyurea, an anti tumor drug which increases levels of circulating Hb F which decreases RBC sickling leading to a decreased risk of painful crises + decreased mortality
stem cell transplantation
what is the selective advantage of individuals w/ the sickle trait (heterozygotes)
less susceptible to severe malaria caused by the parasite plasmodium falciparum which spends an obligatory part of its life cycle in the RBC
RBC life cycle of sickle cell is less than 20 days compared to normal 120 days therefore it prevents the parasite from growing
what are the characteristics of methemoglobinemia
heme iron gets oxidized from Fe 2+ to Fe 3+ producing methemoglobin which cannot bind to oxygen
can be acquired or congenital
acquired via: oxidation by action of drugs
- nitrate sulfanilamide
- acetaminophen (paracetamol)
- sodium nitroprusside
- ROS (endogenous product)
congenital:
- substitution of histidine by tyrosine resulting in permanent oxidation of Fe forming Hb M (irreversible)
- deficiency of NADH cytochrome b5 reductase/ NADH-methemoglobin reductase which is responsible for conversion of methemoglobin (Fe 3+) to hemoglobin (Fe 2+) (reversible)
clinical picture of methemoglobinemia
characterized by chocolate cyanosis, blue coloration of skin/mucous membranes + brown colored blood as a result of dark colored methemoglobin
symptoms are related to the degree of tissue hypoxia including:
anxiety
headache
dyspnea
coma + death (rare)
treatment of methemoglobinemia
reversible - methylene blue, a reducing agent
irreversible repeated blood transfusion
what are the characteristics of thalassemia
hereditary hemolytic disease in which an imbalance in synthesis of globin chains occurs resulting in a decreased conc. of Hb
caused by genes deletion/ nucleotide substitution or deletion
either no globin chains are produced (a0/ b0)
or globin chains are synthesized at a reduced level (a+-/ b+-)
what are the types of thalassemia
B thalassemia major (2)/minor (1)
a thalassemia major (3)/minor (2)
describe B thalassemia
synthesis of B globin chain is decreased (B+-) or absent (B0)
result of point mutation which affects production of functional mRNA
a globin chains cannot form stable tetramers w/o B globin chains so they precipitate and cause premature death of RBCs
results in an increase of Hb A2 (a2/ delta 2) + Hb F (a2/ y2)
there are 2 copies of the B globin gene, one on each chromosome 11
if one copy is defective = B thalassemia minor
if both copies are defective = B thalassemia major / cooley’s anemia
clinical picture of B thalassemia
physical manifestations of B thalassemia appear several months after birth because B globin gene is not expressed until late in prenatal development (Hb F > Hb A)
seemingly heathy at birth but become severely anemic during 1st-2nd year of life
skeletal changes as a result of extra medullary hematopoiesis (formation + activation of blood cells outside BM as a result of hematopoietic stress)
treatment of B thalassemia
regular blood transfusions
hematopoietic stem cell transplantations (curative option)
describe a thalassemia
synthesis of a globin chain is decreased (a+-) or absent (a0)
result of deletional mutation
there are 4 copies of the a globin gene, two on each chromosome 16
if 1/4 a globin genes is defective = silent carrier, no physical manifestations of disease
2/4 defective genes = a-thalassemia trait
3/4 defective genes = Hb H, results in hemolytic anemia
4/4 defective genes = Hb bart, hydrops fetalis (fluid build up causing edema) + fetal death because a globin chains are required for the synthesis sis of Hb F (+ all Hb)
which diseases are accompanied by a resistance to malaria
heterozygote sickle cell anemia
heterozygote a/B thalassemia
G6PD deficiency (favism)
what are the functions of iron in the body
oxygen transport - component of Hb + myoglobin
cellular respiration - component of e- transport chain proteins
antioxidant - catalase, a heme enzyme, converts H2O2 —> H2O + O2 / Fe is a cofactor for catalase
*Fe 2+ reacts w/ H2O2 to form hydroxyl + hydroxide radicals which are dangerous and toxic to cells, catalase eliminates H2O2 which prevents the fenton reaction
where is Fe absorbed and what aids its absorption
Fe 2+ (ferrous) is absorbed in the proximal duodenum
aided by
low pH of HCL secreted into gastric lumen
reducing agents such as vitamin C
(keep Fe in soluble ferrous form)
what agents inhibit Fe absorption
tannins (tea)
phyates (grains, oats)
phosphates
*bind to Fe in intestinal lumen which prevents is absorption
+lowered gastric acidity/ increased pH
what is the process of Fe absorption
- Fe 3+ is reduced to Fe 2+ in intestinal lumen
- DMT1 on enterocytes transports Fe into cell
- inside enterocyte Fe 2+ gets oxidized to Fe 3+ and is stored by binding to ferritin OR Fe 2+ is transported through basolateral membrane and into circulation while bound to ferroportin
what is hepcidin + its function
hormone secreted by liver
controls Fe absorption into enterocytes and delivery to blood
acts by binding to + inactivating ferroportin
stimulated by increased plasma Fe conc.
what are the proteins of Fe transport + storage
ferritin - oxidizes Fe 2+ to Fe 3+ and binds to it for storage inside tissues
hemosiderin - denatured form of ferritin, binds to excess Fe 3+ preventing its escape into blood
ferroxidase / ceruloplasmin - oxidizes Fe 2+ to Fe 3+ for transport
transferrin - carries Fe 3+ in blood (transport) and delivers it to tissues for heme synthesis
ferroportin - binds to Fe 2+ in enterocyte + transports it to blood
difference between ferroportin / transferrin
ferroportin - from enterocyte/tissue to blood (transport)
transferrin - from blood to tissues (transport)
causes of Fe deficiency anemia
- increased iron loss
secondary to excessive bleeding (GIT/ menstrual sources/ hookworm infestation) - decreased iron uptake
diet low in Fe
malabsorption due to disease associated w/ flattening of duodenal mucosal villi
causes of iron overload
- hemochromatosis
genetic disorder, hepcidin deficiency
characterized by excessive intestinal absorption of dietary Fe resulting deposition of Fe in liver/ pancreas/ heart
causes tissue damage
primary hemochromatosis (inherited) referred to as bronze diabetes due to darkening of skin - hemosiderosis
deposition of hemosiderin in reticuloendothelial system (cells of spleen/ liver/ BM)
caused by multiple blood transfusions/ hemorrhage
when reticuloendothelial are saturated deposition occurs in other body parts leading to secondary hemochromatosis (acquired)
treatment of iron overload (hemochromatosis/ hemosiderosis)
iron chelation therapy using deferoxamine
laboratory determination of Fe status
serum iron
serum ferritin (cytoplasmic Fe storage protein gets secreted into serum, high serum ferritin = high iron level)
total iron binding capacity (reflects amount of transferrin in blood available to attach to Fe, in iron deficiency where iron level is low = TIBC is high / in iron overload where iron is high = TIBC is low)
