Microcytic and hypochromic anaemia red cell indices?
MCV and MCH low
Microcytic and hypochromic anaemia common examples:
- Iron deficiency
- Thalassaemia
Normocytic and normochromic anaemias red cell indices?
MCV and MCH normal
Normocytic and normochormic anaemias common examples:
- Blood loss (acute)
- Haemolysis (occasionally macrocytic)
- Chronic disease (occasionally microcytic hypochromic)
- Marrow infiltration
Macrocytic anaemias red cell indices?
MCV raised
Macrocytic anaemias common examples:
Megaloblastic anaemias
4 causes of anaemia
- Loss of red cells due to bleeding
- Increased destruction of red cells (haemolytic anaemias)
- Failure of production of red cells by the bone marrow
- Dilution of red cells by increased plasma volume (e.g. hypersplenism)
3 causes that lead to failure of production of red cells by the bone marrow
- Nutritional deficiency (e.g. iron, vitamin B12, folate)
- Reduced bone marrow erythroid cells (e.g. aplastic anaemia, marrow infiltration by leukaemia or malignancy)
- Ineffective red cell formation (e.g. chronic inflammation, thalassaemia, renal disease)
Normal lifespan of RBC
120 days
To maintain its integrity in circulation for its lifespan, non-nucleated red cell needs:
- Longevity
- Flexibility
- Enzymes to maintain: shape, membrane integrity, metabolism, haemoglobin in reduced state
Anaemia will result unless the bone marrow can increase its?
Increase its output of red cells sufficiently to compensate for increased rate of destruction.
Haemolytic anaemia is due primarily to?
Accelerated red cell destruction when BM is unable to compensate.
Intravascular haemolysis occurs when?
Severe injury to red cells (eg. by trauma or complement) can result in red cell destruction in the intravascular space.
Haemolytic anaemia: less severely damaged red cells are? Which one is this?
Trapped and destroyed by macrophages in the spleen, and to a lesser extent in the liver.
Extravascular haemolysis
Intrinsic red cell defects may be caused by:
- Membrane defects (e.g. hereditary spherocytosis)
- Haemoglobin defects (e.g. thalassaemias, sickle cell anaemia)
- Red cell enzyme defects (e.g. G6PD)
- The acquired disorder Paroxysmal nocturnal haemoglobinuria (PNH)
Extrinsic factors causing haemolytic anaemia can include:
- Burns
- Oxidant drugs and chemicals
- Red cell auto-auto-antibodies
- Splenomegaly
- Infections such as malaria
- Mechanical damage to red cells.
In all cases, increased red cell breakdown leads to increased?
Increased lactate dehydrogenase (LDH) release and increased formation of bilirubin.
Most helpful lab findings of haemolysis are?
- Raised serum uncojugated bilirubin
- Raised serum LDH (lactate dehydrogenase)
- Raised urinary urobilinogen (not bilirubin)
When intravascular haemolysis occurs, what is released? This leads to?
Haemoglobin is released leads to absent serum haptoglobin.
Haptoglobin binds to?
Haemoglobin
Methaemalbumin is composed of?
Albumin bound to heme
Intravascular haemolysis occurs shows a positive ____ and ____ and later _____.
Shows a positive Schumm’s test for methaemalbumin, haemoglobinuria and later haemosiderinuria.
Haemoglobinuria is?
Excretion of free haemoglobin in urine
Haemosiderinuria is?
Iron in urinary sediment
Additional findings of haemolytic anaemias include evidence of?
- Compensatory red cell production by bone marrow
- Increased numbers of young red cell in the circulation (elevated reticulocyte count and polychromasia)
Morphological evidence of red cell damage include:
- Spherocytes (sphere shaped RBCs)
- Fragmented red cells
- Heinz bodies (denatured haemoglobin)
Red cell survival in haemolysis can be determined using?
Radio-isotope techniques.
Spherocytes are?
Sphere-shaped RBCs
Heinz bodies are?
Denatured haemoglobin
Haemolysis is defined as?
Survival time is less than 120 days in circulation
Rapid falls in haemoglobin concentration can only be the result of either?
Haemolysis or blood loss anaemia.
Clinical presence of _____ and _____ will help diagnose haemolysis
- Scleral jaundice
- Splenomegaly
Scleral jaundice is?
Staining of the sclera by bilirubin
Splenomegaly occurs when?
Red cell destruction occurs in the spleen
Laboratory parameters that help diagnose haemolysis:
- Increased reticulocytes
- Increased bilirubin (due to the breakdown of the haem component of haemoglobin)
- Elevated serum levels of lactate dehydrogenase (LDH). Contained within erythryocytes
- Absence of a serum protein known as haptoglobin
Function of haptoglobin
Binds haem and prevents its loss through the kidney.
Increased bilirubin occurs when?
Breakdown of the haem component of haemoglobin
______ in the urine detected by urinary sediment stained for iron deposited in epithelial cells - positive in situations of _______ haemolysis such as produced by _______.
Haemosiderin, intravascular, prosthetic heart valves.
Bone marrow examination is _____ to make the diagnosis of haemolytic anaemia
Rarely done
Bone marrow examination may show ______ in diagnosis of haemolytic anaemia.
- Erythryoid hyperplasia (increased number of red cell precursors)
- Detection of antibodies on the cell surface (immune mechanism of haemolysis is suspected)
Erythryoid hyperplasia definition:
Increased number of red cell precursors.
Detection of antibodies on the cell surface are done by?
Direct antiglobulin test or direct Coombs Test
Haemolysis occurs by a variety of mechanism:
- Abnormalities of the red cell membrane
- Abnormal cytoskeletal proteins
- Enzyme deficiencies in the red cell
- Abnormalities of the haemoglobin molecule structure or its synthesis
- Immune disorders
Describe mechanism of abnormalities of the red cell membrane leading to haemolysis:
Abnormalities of the red cell membrane and underlying cytoskeletal proteins which lead to loss of surface lipid and spherocyte formation (e.g. hereditary spherocytosis)
Most common enzyme deficiency in haemolysis
Glucose-6-phosphate dehydrogenase (G6PD) deficiency so that cell is unable to generate NADPH to counteract oxidant substances which are always present in our circulation. Excessive oxidant stress denatures haemomglobin, forming so-called Heinz bodies adherent to the red cell membrane and in turn leads to red cell destruction.
Typical examples of abnormalities of haemoglobin molecule structure or its synthesis (usually inherited)
Sickle cell anaemia and thalassemia.
How do immune disorders lead to red cell destruction?
Antibodies attach to the red cell membrane and leads to cell destruction during circulation of the cell through spleen and liver
Haematopoiesis or haemopoiesis is?
Formation of blood cellular components
In a healthy adult person, approximately, how many new blood cells are produced daily?
10^11 - 10^12 new blood cells are produced daily to maintain steady state levels in the peripheral circulation.
Haematopoietic stem cells are?
Self-renewing cells which reside in the bone marrow and have the unique ability to give rise to all of the different mature blood cell types
Haemopoiesis takes place in the bone marrow after?
After 7 months gestation
Fetal haemopoiesis occurs in?
Liver and spleen
In bone marrow, the microenvironment includes:
Includes stromal cells, extra-cellular matrix (ECM) and a microvascular network of thin walled venous sinusoids
Which stromal cells are supported in the ECM?
- Macrophages
- Fibroblasts
- Reticulum cells
- Fat cells
- Endothelial cells
Stromal cells are one important source of?
Haemopoietic growth factors and other cytokines
Stromal cells have an important role in?
Haemopoietic cell adhesion through cell adhesion molecules, and hence determine the localisation of haemopoiesis.
Some components of extracellular matrix (ECM) include:
- Fibronectin
- Laminin
- Collagen
- Proteoglycans
Haemopoietic stem cell is capable of:
- Self-renewal
- Differentiation to erythryoid, lymphoid or myeloid (granulocytic, monocytic, erythryoid or megakaryocyte) progenitors
Haemopoietic stem cells are described as:
- Multipotent or pluripotent
- No unique morphological characteristics
- Morphologically identical to a small to intermediate sized lymphocyte
Exposure to haemopoietic growth factors leads to a?
Leads to a stem cell committed in one direction of development i.e. differentiation.
Stem cell committed to any given lineage is?
Irreversible
Once committed to a given lineage, stem cell’s capacity for self-renewal is?
Renewal capacity is lost as maturation progresses.
Haemopoietic growth factors are produced by?
Produced by an array of haemopoietic and stromal cells which reside in the marrow.
Erythryoipoietin is produced mainly from?
Kidney
Growth factors are in general _____ although ____ factors also exist.
Generally stimulatory, although inhibitory factors also exist.
Growth factors act in synergy with each other especially in ___________.
Low concentrations
List haemopoietic growth factors that have established roles in clinical practice:
- EPO (erythropoietin)
- GCSF (Granulocyte - colony stimulating factor)
- GM-CSF (granulocyte/monocyte - colony stimulating factor)
Other factors (e.g. haemopoietic cytokines) that are required for normal haemopoiesis (especially erythryopoiesis) include:
- Metals (iron, manganese, cobalt)
- Vitamins (VitB12, folic acid, vitamin C, E, B6, thiamine, riboflavin and pantothenic acid)
- Amino acids
- Hormones
Most common nutritional deficiency states that lead to alterations in haemopoiesis are?
- Vitamin B12 deficiency
- Folate deficiency
- Mineral iron deficiency
Deficiency in any of the three nutritional elements (B12, folate, iron) results in?
Results in a reduction in production of RBC containing haemoglobin, commonly known as anaemia
Anaemia manifests clinically as non-specific symptoms including:
- Lethargy
- Tiredness
- Dyspnoea
- Headache
Diagnosis of anaemia relies on?
History, physical examination and lab tests, commencing with blood count and blood film examination
Most common cause of anaemia throughout world is by?
Iron deficiency
Iron deficiency is caused in underdeveloped countries due to?
Gastrointestinal blood loss from hookworm infection
In our modern developed society, most common cause of iron deficiency is?
Menstrual blood loss in fertile women. So common as to be considered almost ‘normal for age’
Diagnosis of iron deficiency in older men and women that isn’t explained by obvious blood loss may be caused by?
- Carcinoma of the gastrointestinal tract
- Peptic or drug-induced inflammation and ulceration of the stomach
Iron deficiency anaemia is also common in ___ and _____ due to poor iron intake.
Infants, young children
Laboratory hallmark of iron deficiency is?
Presence of microcytosis or small red blood cells
Microcytosis is best appreciated from?
Best appreciated from electronically derived mean corpuscular volume (MCV) which is provided on blood counts returned to requesting doctors
Normal MCV is?
80-100 femtolitres (fl)
Iron deficiency MCV?
Under 80 fl
Which specific studies test for iron deficiency?
- Serum iron level
- Serum transferrin
- Serum ferritin
Transferrin is?
Iron carrying protein in the blood
Serum Ferritin is?
Best measurement of overall iron stored in the body
Reductions in folic acid or vitamin B12 in body result in anaemia characterised by?
By an increase in red cell size (macrocytosis) and specific appearances within the bone marrow (megaloblastosis)
Folic acid/vitamin b12 deficiency anaemia MCV?
MCV > 100 fl
Blood film of folic acid/vitamin b12 deficiency shows?
Large red cells and variations are red cell size and shape.
May also be changes in neutrophils which can show marked nuclear hypersegmentation
T/F - All causes of macrocytosis induce megaloblastosis of the bone marrow
False, not all
Commonest cause of macrocytosis in our community not associated with megaloblastic anaemia
Excess alcohol consumption
Unlike iron deficiency, lack of folic acid or vitamin B12 is rather?
Uncommon
Lack of vitamin B12 is most commonly caused by?
Poor absorption from the bowel.
Poor absorption of B12 from bowel is often due to an autoimmune disease known as?
Pernicious anaemia, a disease of the elderly only(?)
Describe process of pernicious anaemia
Antibody produced autoimmunely destroys gastric cells which normally secrete intrinsic factor. Lack of intrinsic factor ceases B12 absorption because it binds to vitamin B12 in stomach for absorption in terminal ileum.
Folic acid absorption occurs in the?
Occurs in jejunum and does not require intrinsic factor
List factors that impairs absorption of folic acid
- Small bowel disease (e.g. coeliac disease)
- Surgical removal of large segments of small intestine can therefore impair its absorption
- Poor diets of elderly, severely depressed individuals and adolescents can also become deficient in folic acid
Erythropoietin is the hormone principally responsible for?
Stimulating production of red cells in the bone marrow
Erythropoietin is produced in the?
Kidneys
Inadequate amounts of iron leads to?
Immature red blood cells in bone marrow
Iron is an ubiquitous element in nature which is incorporated into numerous proteins:
- Haemoglobin
- Myoglobin
- Cytochrome systems
- Most of the enzymes and cofactors of the Krebs Cycle
In general, a 70kg man has approximately how much iron?
4.5g of iron
More than half of iron in a human is in the form of?
Haemoglobin
One third of iron in a human is in the form of?
Storage iron (ferritin and haemosiderin)
Remainder of iron in a human is in the form of?
Myoglobin and essential enzymes
Normal dietary intake of iron is about?
10-15 mg/day
How much normal dietary intake of iron is absorbed?
10% of 10-15 mg/day
Major site of iron absorption is in the?
Upper small bowel
Dietary iron, which is conjugated in food, is deconjugated by?
Deconjugated by peptic enzymes and hydrochloric acid in the stomach
Dietary iron, once deconjugated, is transported to?
Transported to early part of duodenum where soluble iron complexes are absorbed
How many iron pools are there?
Two pools: haem-iron pool and non-haem iron pool
Haem-iron pool comprises of?
Haemoglobin and myoglobin which is normally well absorbed
Non-haem iron pool is found in?
Vegetables, eggs etc. not as well absorbed
Non-haem iron absorption can be improved in the presence of?
Presence of reducing substances like ascorbic acid
Iron absorption is favoured by?
Organic iron, iron in ferrous form and by acid pH and vitamin C
Iron absorption is retarded by?
Retarded by iron in the inorganic form, by ferric iron and by an alkali stomach and small intestine
Dietary iron absorption requires that iron crosses both what?
Crosses both the apical and basolateral membranes of epithelial cells in the duodenum to enter the blood where it binds to transferrin.
_______ transports non-haem iron across the apical membrane
Divalent metal transporter 1 (DMT1)
Iron must be in the _____ form for absorption
Fe2+ form
Dietary non-haem iron is mostly in the _____ form and therefore must be _____ prior to absorption.
Fe3+ form, reduced
Dietary non-haem iron is reduced using?
Reduced using a reductase: duodenal cytochrome B (DcytB)
DcytB (duodenal cytochrome B) is located on the?
Located on the apical membrane of the enterocyte
Haem iron is absorbed how?
Absorbed directly and uses a transported yet to be identified
Once iron is inside the enterocyte, iron can be either?
Either stored as ferritin or exported into plasma by the basolateral iron exporter: ferroportin
Intestinal iron absorption depends on body requirements and seems to occur by modulating the expression of?
Expression of DMT1, DcytB and ferroportin by a variety of pathways.
Hypoxia leads to upregulation of ____ and ____ via hypoxia-inducible factor (HIF) and increases _____ absorption.
DcytB, DMT1, iron
Iron regulatory proteins (IRPs) bind to _____ on DMT1 and ferroportin and control the expression of both depending on enterocyte iron levels.
Iron responsive elements (IREs)
What is the new hormone discovered that is critical in iron homeostasis?
Hepcidin
Hepcidin is a protein produced and released by the?
Liver
Hepcidin function
Hepcidin controls dietary iron absorption and release of iron from reticuloendothelial macrophages in response to changes
What changes and factors will affect hepcidin release
Changes in:
- iron stores
- Erythropoietic activity
- Haemoglobin
- Oxygen content
- Inflammation
As body iron stores increase, liver releases hepcidin which inhibits?
Inhibits the efflux of iron from intestinal enterocytes and macrophages by down-regulating ferroportin.
Therefore iron from diet is not released into portal blood and is trapped inside enterocytes. Sloughed over time into the bowel.
Abnormalities in hepcidin regulation play an important role in the anaemia of chronic disease as ________ also induces hepcidin expression and in ________.
Inflammation; hereditary haemochromatosis
Iron bound to ferritin is used for?
Used for haemoglobin synthesis and intermediary metabolism
Iron may be stored as?
Ferritin or haemosiderin
Iron loss does not appear to be ____ and under normal conditions iron is excreted through _____ and the sloughing of _____.
regulated; blood loss; epithelial cells
Macrocytosis refers to a blood condition in which RBCs are?
Larger than normal
Large circulating red cells are not always associated with a pathological process
True
RBCs of ___ and ____ tend to be larger than normal adult RBCs.
Newborns and infants
Macrocytic anaemia describes an anaemia state characterised by?
Presence of abnormally large RBCs in the peripheral blood
Two types of macrocytic anaemia?
Megaloblastic anaemia; non-megaloblastic macrocytic anaemia
Non-megaloblastic anaemia is caused by the ______ or change in membrane structure or water content of the RBCs.
Increased reticulocytes
Megaloblastic anaemia is caused by impaired DNA synthesis due to?
- Deficiency of vitamin B12 (cobalamin) and/or vitamin B9 (folate)
- Abnormalities of Vitamin B12/folate metabolism (nitrous oxide exposure, anti-folate drugs)
- Other defects of DNA synthesis (congenital enzyme deficiency, drugs)
List possibilities that impaired DNA synthesis can lead to?
- Macrocytic RBCs
- Abnormalities in leukocytes and platelets
- Epithelial changes particularly in the rapidly dividing epithelial cells of the mouth and gastrointestinal tract
Vitamin B12 is a water soluble vitamin only produced by?
produced only by gut bacteria in human
Where is vitamin B12 found?
Animal products and not affected by cooking.
Describe process of vitamin B12 absorption
- Intake
- Released from food carrier proteins (proteolysis in acidic environment of the stomach)
- B12 binds to haptocorrin in stomach
- Haptocorrin degrades
- pH change in duodenum favour B12 binding to gastric intrinsic factor
- Intrinsic factor-B12 complex binds to cubam receptor
- After lysosomal release, B12 exits via the basolateral membrane of the enterocyte (facilitated by multidrug resistance protein 1 [MDR1])
- B12 binds to transcobalamin
- B12 stored in liver
- Some B12 is excreted in bile and undergoes enterohepatic circulation
Function of haptocorrin
Binds to vitamin B12 to protect from acid degradation in stomach
Gastric intrinsic factor is produced by?
Gastric parietal cells
Function of cubam receptor?
This receptor mediates the uptake of the intrinsic factor-B12 complex in the enterocytes of the distal ileum via receptor-mediated endocytosis
MDR1 means?
Multidrug resistance protein 1
Transcobalamin function?
This is the blood carrier of B12 that is responsible for cellular delivery of B12
Dietary B12 intake per day?
5-10 ug per day
List causes of B12 deficiency
- Inadequate intake
- Digestion and absorption problems
- Transport abnormalities
What could cause transport abnormalities leading to B12 deficiency?
Deficiency of transcobalamin
What could cause inadequate intake of vitamin B12?
Diet of Vegans, pregnant vegetarians
What could cause inadequate release of B12 from food?
Gastroectomy, chronic atrophic gastritis, drugs
What could cause inadequate production of functional intrinsic factor
Prenicious anaemia, gastroectomy
What could cause terminal ileal disease leading to B12 deficiency?
Coeliac disease, ileal resection, Crohn’s disease
What could cause competition for intestinal B12 leading to B12 deficiency?
Fish tapeworm infection
Where can folate (water soluble vitamin) be found?
- Found in most foods with the highest in liver and yeast.
- Also high in green leafy vegetables and nuts
- Easily destroyed by cooking
Where is folate absorbed?
Small intestine
Common causes of folate deficiency include:
- Inadequate intake
- Malabsorption
- Increased requirements (pregnancy)
- Defective utilisation
- Hereditary defects
What pathologies can cause malabsorption of folate?
- Coeliac disease
- Alcohol abuse
- Drugs
B12 and folate are required for which reaction?
Methionine synthase reaction
List the steps in methionine synthase reaction
1) METHIONINE SYNTHASE transfers METHYL GROUP from METHYLTETRAHYDROFOLATE to HOMOCYSTEINE
2) METHYL-B12 is a co-enzyme used for forming METHIONINE
3) Resulting H4-FOLATE is returned to folate pool and made available for generation of METHYLENE-H4-FOLATE.
Methylene-H4-folate is the form required for ?
De novo synthesis of thymidine, which is essential for DNA replication and repair
Thymidine is essential for?
DNA replication and repair
Deficiency of folate or B12 results in the same biochemical perturbation in ?
Thymidine synthesis and DNA replication
In the case of B12 deficiency, folate is trapped in which form?
Trapped in unusable methyl-form.
B12 is involved in the conversion of _______ to _____ by the enzyme methylmalonyl-CoA mutase with _____ as a cofactor.
Methylmalonyl-CoA to succinyl-Coa; adenosyl-B12
Succinyl-CoA is a major intermediary of the _____ cycle
TCA cycle (tricarboxylic acid cycle)
In B12 deficiency, substrates of both B12-dependent reactions accumulate, which leads to increased levels of ____ and _______ in the plasma.
Methylmalonic acid; homocysteine
A combination of low levels of B12 and increased levels of folate was associated with?
Associated with higher concentrations of methylmalonic acid and total plasma homocysteine.
Describe clinical progression of megaloblastic anaemia and clinical symptoms
Progresses slowly, and symptoms include typical anaemic symptoms and neurologic abnormalities.
Orally, patient may present glossitis, angular cheilitis, recurrent oral ulcer, candidiasis, diffuse erythematous microsites and pale mucosa which offer the dentists an opportunity to participate in diagnosis of this condition.
In peripheral and central nervous systems, vitamin B12 appears to be involved in the synthesis of?
Glial cells synthesise lipoprotein myelin which surrounds axons and may also be required for the synthesis of some neuronal proteins.
When vitamin is deficient, even in absence of anaemia, _______ accumulate patchily in the myelin and coalesce, the largest fibres often being most affected.
Fatty deposits
Major consequence of damage to the myelin includes?
- Slowed conduction of action potentials
- High frequency information cannot be sustained
- Transmission ultimately becomes completely blocked.
- Cytoplasm of axons may also be affected directly or secondarily to myelin loss
- Peripheral nerves, the spinal cord or the brain may be involved, separately or together.
B12 deficiency: in peripheral nerves, a neuropathy may be evident, involving the axons of both ______ and ______.
Motoneurones; sensory neurones
In B12 deficiency, patients describe _____ in their hands and feet, often symmetrically (_________).
Tingling (pins and needles or paraesthesias); (glove and stocking distribution)
In B12 deficiency, abnormal sensations are probably related to the ____ and ____ of action potentials in sensory neurones.
Slowing; asynchrony.
____ or ______ is associated with B12 deficiency in peripheral nerves, demonstrated by neurological testing
Numbness; loss of some sensation
________ is evident and in the long term, wasting of peripheral muscles may occur in B12 deficiency.
Motor weakness
In B12 deficiency, _____ reflexes are diminished in the affected regions.
Stretch reflexes
Vitamin B12 deficiency often affects two major pathways in the _________ of the spinal cord, a “combined degeneration”.
White matter
One major pathway (white matter affected by B12 deficiency) carries ________ sensory information from the body surface, joints and muscles to the brain (the _____ or _____ columns). Cell bodies of these bipolar neurones lie in the _______.
discriminative sensory information; dorsal or posterior; dorsal root ganglia
Second major pathway (___________) affected by B12 deficiency, transmits voluntary signals from the motor cortex to motorneurones projecting directly to muscles from the spinal cord.
Lateral corticospinal tract
Name sensory difficulties that an individual affected by major pathways affected by B12 deficiency
- Loss of proprioception (particularly in the dark)
- Loss of sense of vibration
Name motor disturbances that an individual affected by major pathways affected by B12 deficiency
- Unsteadiness when walking, due both to the damage to the descending motor pathway and loss of ascending sensory feedback
In absence of significant peripheral neuropathy, the _____ are exaggerated, motor tone is _______ and the ______ sign is present, all signs of damage to motor pathways from the brain to the motor neurones.
Stretch reflexes; increased; Babinski
Some demyelination is sometimes also seen in pathways in the brain, leading to:
Confusion, depression, moodiness, memory losses and even overt psychosis.
The cerebral manifestations, resembling ______, usually yield rapidly to appropriate treatment with vitamin B12.
Dementia
Recovery from demyelination and associated axonal damage is usually _____, particularly when lesions are longstanding.
Slow
Production of red cells by the bone marrow can be accelerated up to?
7 folds
Increased production of red cells by the marrow is achieved both by?
Expansion of the volume of red marrow and by shortening of the transit time for red cell maturation (skipped divisions).
Mechanism by which red cells of normal subjects are destroyed after their 120 day life span is still obscure, but may involve:
Continual loss of membrane components, the accumulation of products of oxidative damage and/or decreased deformability of the aged red cell leaving it unable to squeeze through the minute (1-2 m) fenestrations in the splenic microvasculature.
Effected red cells are finally phagocytosed by macrophages of the reticuloendothelial system, mainly in the?
Mainly in the spleen but also in the liver and bone marrow. Phagocytosis of red cells becomes more prominent when red cell survival is shortened (haemolysis).
Anaemia secondary to blood loss may be acute (following ____ or _____) or chronic (________).
Trauma or surgery; intermittent or slow bleeding from e.g. peptic ulcer or heavy menstrual loss - menorrhagia).
Clinical features of shock are?
- Very low blood pressure
- Rapid pulse
- Cold and discoloured extremities
- Sweating
- Dilated pupils
‘Reactive’ thormbocytosis
Raised platelet count
Leucocytosis
Reactive increase in white blood cells
Chronic blood loss results in ____ deficiency
Iron deficiency
Proper assessment of a person with blood loss anaemia require two critical processes:
- Careful history (abnormal bleeding, menstrual history in women, symptoms of peptic ulcer, altered bowel habit etc.)
- Physical examination - signs of acute bleeding, iron deficiency, abdominal masses etc.
Haemoglobin is a sophisticated oxygen carrier with ____ affinity for oxygen in the ____ and ____ affinity in respiring peripheral tissues.
High affinity for oxygen in lungs, low affinity in peripheral tissues
Transition in affinity for oxygen is achieved by haemoglobin through?
Conformational change induced by allosteric effectors (small molecules which bind at other sites on this protein)
Describe the functional haemoglobin
- Tetramer
- Consists of two types of polypeptide chains (alpha2-gamma2 - foetal) or (alpha2beta2 - adult)
- Haem bound as a prosthetic group to each subunit
Describe adult tetramer properties
- Molecular weight of approximately 64,500 Da
- each chain contains 8 alpha-helices (similar to monomeric myoglobin)
Monomeric myoglobin function
Stores oxygen in peripheral tissues such as skeletal muscle.
OxyHb is in the ______ conformation and deoxyHb is in the _____ conformation.
R (relaxed), T (tense)
Binding of a molecule of ____ to one haem site is communicated to remote sites in the tetrameric molecule.
Oxygen
Contact regions between the alpha and beta-subunits act as _______ between the R- and T- forms of haemoglobin
Switches
Concentration of haemoglobin in erythrocytes is approximately _____, equivalent to ___ subunits.
334 mg/ml, 20 mM
Solubility of oxygen in blood plasma is approximately _____ mM.
0.1 mM
Whole blood containing erythrocytes and haemoglobin can carry oxygen at concentrations of up to?
10 mM.
Exercising skeletal muscle has a ____ pH to anaerobic glycolysis and the ____ produced binds to haemoglobin and reduces its affinity for bound oxygen, facilitating oxygen supply.
lower; H+
Lowering pH in exercising skeletal muscle reducing affinity for bound oxygen is known as the _____ which results in the release of Oxygen in peripheral tissue; converse is true in the lungs.
Bohr effect.
Carbon dioxide is carried by haemoglobin as a ____ bound to the ____ of the protein.
Carbamate; N-terminus
The high carbon dioxide concentrations found in capillaries induce haemoglobin to release ?
Release bound oxygen
___________ also decreases the affinity of haemoglobin for oxygen by binding the central cavity of deoxyHb.
2,3-Biphosphoglycerate (2,3-BPG)
There is an interplay between the binding sites for __, __, __ and ____ mediated by induced conformational changes in the protein of haemoglobin.
oxygen, hydrogen ion, carbon dioxide, 2,3-BPG
Foetal Hb has a ____ oxygen affinity than maternal Hb which facilitates the transfer of oxygen from the maternal circulation.
higher oxygen affinity
The thalassaemias are the commonest _____ diseases in man with a broad distribution throughout the Mediterranean region, Middle East, Indian sub-continent and South-east Asia.
monogenic
The alpha+ thalassaemias are caused by deletion of _______ and affected erythrocytes may have a shorter life-time in the circulation.
deletion of one of the two alpha-globin genes
Sickle cell anaemia is caused by the homozygous haemoglobin mutation, _______ which aggregates as rigid 14-strand fibres.
Glu6 Beta- >Val
The haemoglobin ___, causes sickle cell anaemia with a characteristic change in erythrocytes from biconcave discs to a sickle shape at ____ oxygen concentrations.
haemoglobin S, low oxygen concentrations
Sickle cell disease, like thalassaemia, confers resistance to _____.
Malaria
Sickle cell anaemia haemoglobin mutation ____ the life-time of the erythrocyte in the circulation and may affect the ability of certain strains of the parasite to infect erythrocytes.
shorten
Malarial parasites growing inside erythrocytes digest up to 80% of the host cell’s haemoglobin within an _______.
acidic digestive vacuole
The amino acids derived from _____ of haemoglobin are used for energy production and to synthesize ____ proteins.
Proteolysis; parasites
Potentially toxic haem which is released during proteolysis is polymerized in a chemical process, not requiring an enzyme, into an insoluble pigment called _____.
Haemozoin.
Quinoline antimalarial drugs such as _____, ______ and ______, inhibit the chemical polymerization of haem which accumulates in the parasite and kills it.
quinine, chloroquine, and mefloquine.
______ accumulates by approximately 1000-fold in the acidic vacuole of the parasite.
Chloroquine
Drug resistance, found often with ____, may be due to reduced accumulation of the drug in the vacuole.
Malaria
