lecture 2 - blood: introduction to haemoglobin Flashcards
average amount of blood in human body
female adults – average of 5 litres
male adults – average of 5.5 litres
what is blood?
a connective tissue
blood functions
- gas transport & exchange
- distributing solutes
- immune functions
- maintains body temp
- regulates blood clotting
- maintaining pH
- maintaining BP
what solutes does plasma transport?
ions
nutrients
hormones
metabolic waste
blood constituents
consists of a complex liquid (plasma) in which the cells are suspended
• erythrocytes: RBCs
• leukocytes: WBCs
• thrombocytes: platelets
if blood is places in a test tube (with anticoagulant) how will the cells settle?
the heavier cells will settle to the bottom of the tube
top layer = plasma
55% and lightest layer
soluble materials - mostly water
middle layer = buffy coat
1%
WBCs and platelets
bottom layer = RBCs 44% the haematocrit (packed cell volume) represents the % of total blood volume occupied by RBCs
normal haematocrit for males & females
females = 42% males = 45%
functions of plasma
thermoregulation
transport
components of plasma
- water
- plasma proteins
- dissolved small molecules
how does water influence blood viscosity?
less water = thicker blood = sluggish flow
4 plasma proteins
- serum albumin
- globulins
- clotting proteins (fibrinogen)
- regulatory proteins
what % of plasma volume is taken up by plasma proteins?
around 8%
serum albumin
- 55% of plasma proteins
- maintains osmotic pressure of plasma
- assists in transport of lipids & steroid hormones
- large protein synthesised in the liver
globulins
- 38% of plasma proteins
- bind to and transport ions, hormones and lipids
- immune proteins: antibodies or gammaglobulins, made by leukocytes
clotting proteins (fibrinogen)
- 7% of plasma proteins
- essential for blood clotting
- synthesised in the liver
what is the remaining 1% of plasma proteins?
regulatory proteins such as enzymes, proenzymes and hormones
how can plasma proteins be identified?
by electrophoresis - separation by size and charge
can be a diagnostic tool - electrophoretic patterns of plasma proteins change in a number of clinical conditions
what is cirrhosis?
liver disease (cirrhosis) has many causes, including cancer, alcoholism, and viral hepatitis
results in progressive decrease in production of plasma proteins; leads to decreased colloidal osmotic pressure; results in fluid loss to extracellular spaces, producing severe edema in the abdomen; termed ascites
decline in clotting factor levels also causes easy bruising and delays clotting; may be fatal
structure and function of RBCs
indented, disc shaped cells
primary function is oxygen transport
enables efficient oxygen transport
what is the volume of a RBC?
80-96 femtolitres
referred to as mean cell volume (MCV)
what are microcytic RBCs?
small RBCs
found in iron deficiency anaemia
what are macrocytic RBCs?
large RBCs
found in folate (vitamin B9) deficiency anaemia
what is erythropoiesis?
RBC formation
what happens in erythropoiesis?
1) comes from hematopoietic stem cells
2) become an erythrocyte CFU - becomes committed to becoming a RBC
3) pro-erythroblast develops into an early erythroblast - iron needs to be present here
4) late erythroblast is where the nucleus starts to shrink and is ejected from the cells along with other organelles
5) reticulocytes then become erythrocytes
order of formation in erythropoiesis
- red bone marrow
- hematopoietic stem cells
- erythrocyte CFU
- proerythroblast
- early erythroblast
- late erythroblast
- reticulocyte
- erythrocyte
erythrocyte synthesis
- a feedback loop
- takes about 26 days
- starts in bone marrow
- finishes in blood vessels
- EPO in the kidneys is what stimulates red bone marrow to increase erythropoietin to increase the RBC count
erythrocytes: end of life
- squeezing through capillaries causes damage
- with age cells become fragile and easily rupture
- recognised by monocytes which engulf old RBCs and take them to liver and spleen
- haemoglobin is decomposed to heme and globin
how are the heme components of the blood recycled?
heme minus the iron is converted to biliverdin and then to bilirubin, which is secreted in bile from the liver - bile pigments eventually leave the body in faeces and urine
the iron is transported in the blood by the protein transferrin and stored by the protein ferritin in the liver
how are the erythrocyte membrane proteins and globin proteins of the blood recycled?
they are broken down into amino acids, some of which are used to make new erythrocytes
what is glucose-6-phosphate dehydrogenase (G6PD) deficiency?
- favisim
- the 2nd most common enzyme defect
- X-linked, recessive genetic disorder
- predisposes to RBC breakdown when exposed to certain environmental triggers
why does glucose-6-phosphate dehydrogenase (G6PD) deficiency cause the breakdown of RBCs?
RBCs lack mitochondria so rely on the pentose phosphate pathway (PPP) to produce the energy needed to produce glutathione (G6PD is part of the PPP)
no G6PD = no glutathione = inability to resist oxidative stress
results in damage to RBC and breakdown in the spleen
can result in anaemia, newborn jaundice and kidney damage
what does haemoglobin do?
enables erythrocytes to transport oxygen
what does a haemoglobin molecule consist of?
the globin part - made up of 4 protein chains
4 iron containing haem groups - each iron atom can reversibly bind 1 molecule of oxygen
the haem (heme) group
- an iron containing pigment
- consists of a porphyrin ring containing 1 atom of iron
- appears relish when combined with oxygen and blueish when deoxygenated
what are the 4 types of globins?
alpha
beta
gamma
delta
how are globins normally distributed in humans?
97% of adults have 2 alphas and 2 betas (HbA)
2.5% of adults have 2 alphas and 2 deltas (HbA2)
foetuses have 2 alphas and 2 gammas (HbF)
Hb’s ability to bind oxygen is governed by..
- partial pressure of oxygen (pO2)
- number of free oxygen binding sites available in the molecules
- O2 binding is cooperative
what 2 forms does Hb exist in?
relaxed (r) form:
• has high O2 affinity
• exists at high pO2
• firmly binds oxygen
taut (t) form:
• low O2 affinity
• exists at low pO2
• releases oxygen
what else can Hb bind to apart from oxygen?
- carbon dioxide
- the acidic hydrogen ion portion (H+) of carbonic acid
- carbon monoxide
- regulatory molecules NO
what are the 2 major classes of inherited disorders for Hb production?
haemoglobinopathies
• abnormal globin chains are made
• sickle cell anaemia
the thalassaemias
• normal globin chains are made but in decreased amounts OR are absent due to defects at the level of gene expression
what is sickle cell anaemia?
- genetic disease
- caused by a mutation in the beta globin gene
- a glutamic acid residue is replaced by valine in the protein
- resultant haemoglobin polymerises at low pO2 forming long crystals of HbS - this causes RBCs to deform and become sickle shaped
how does sickle cell anaemia work?
- sticky patches give it the sickle shape and makes them rigid
- leads to damage and a reduction in the amount of RBCs
- they become trapped within small blood vessels and block them
- this deprived the downstream tissues of oxygen and causes ischemia (lack of oxygen) and infarction (cell death as a result of lack of oxygen)
what is ischemia?
lack of oxygen
what is infarction?
cell death as a result of lack of oxygen
sickle cell anaemia vs sickle cell trait
- homozygous = sickle cell anaemia
- heterozygous = sickle cell trait
- most common in afro-caribbean population
- sickle cell trait is 50% protective against mild malaria & 90% protective against sever malaria
what are the thalassemias?
group of diseases where synthesis of 1 or both of the alpha or beta globins is reduced
disease severity varies from minor, intermediate or major
either caused by:
• gross deletion of 1 or more globin genes
• gene mutation
what are the 2 classes of thalassemias?
alpha:
• production of alpha globin is deficient
• found predominantly in India and surrounding areas
beta:
• production of beta globin is defective
• predominantly in mediterranean region
alpha thalassemia
- production of alpha globins is reduced
- leads to excess of beta chains - unstable tetramers of four beta chains form (HbH)
- leads to abnormal O2 dissociation curves & RBC damage
- short lived RBCs - anaemia
- produced ‘golf ball’ cells after staining under a microscope
beta thalassemia
- relative excess of alpha chains
- do not form tetramers
- bind to and damage RBC membranes
- form toxic aggregates at high concs
- results in iron overload - organ damage
treatment: iron chelation therapy otherwise patients accumulate potentially fatal iron levels
alpha or beta thalassemia diagnosis by electrophoresis
alpha: reduced HbA and presence of HbH
beta: production of beta globins is reduced or absent, decreased HbA on
what is: • HbA • HbA2 • HbF • HbH
- HbA = 2 alpha and 2 beta
- HbA2 = 2 alpha and 2 delta
- HbF = 2 alpha and 2 gamma
- HbH = 4 beta
what are the 3 main functions of blood?
transport
protection
regualtion
