1. Under what circumstances would the plasma erythropoietin be raised?
Erythropoesis is upregulated by increased erythropoietin. Epo is produced in response to
signals in tissues which indicate that oxygen content is low ie in high altitudes or due to a
failure in the respiratory system to absorb the oxygen.
2. Why is extra folic acid prescribed in pregnancy?
Folic Acid (Folate) is, like Vitamin B12, a very important factor in the production of Red
Blood Cells. If these nutrients are lacking, there is a failure to produce RBCs in the bone
marrow and thus folic acid is given to a pregnant woman due to increased demand on her
RBC supply. Pregnancy means a higher blood volume and also a higher RBC count and
so folic acid requirements increase.
3. Explain the terms oxygenation and oxidation as applied to haemoglobin
Oxygenation is that normal process in the RBC where a molecular oxygen molecule
becomes attached to the Haem subunit of each haemoglobin chain in the Hb molecule
and is the transported to the tissues. Oxidation is where the iron part of the Hb molecule
in the RBC loses electrons and changes from its ferrous Fe2+ form to the ferric Fe3+ ion.
This may be caused by exposure to toxic chemicals.
4. What benefit do distance runners obtain by training at altitude?
At high altitudes, RBC counts are much higher in individuals because of lower levels of
oxygen. Athletes thus spend time at these altitudes so that their bodies become adjusted
to doing high levels of work with little oxygen supply and then perform better in races in
normal conditions of altitude due to the elevated RBC count.
5. What role do vitamin B12 and folic acid play in red cell production?
Both Vitamin B12 and Folic acid are required for the formation of thymidine
triphosphate, one of the essential building blocks of DNA. Deficiency of either thus
causes deformed and abnormal DNA which reduced nuclear maturation and cell division.
The end result is RBCs that can carry oxygen but have very flimsy membranes and thus
shorter life spans. Megaloblastic anemia is the resulting condition.
6. Where is the main site of red cell destruction?
Red Cell destruction takes places mainly in the bone marrow but can also occur in the
liver and spleen. Guyton- the RBC membrane becomes increasingly fragile with time and
the RBC eventually self destructs when moving through some tight spot in the
circulation. Many RBCs are destroyed when passing through the red pulp of the spleen.
7. Why in chronic haemolysis is folate deficiency more likely than B12 deficiency?
Hemolysis is when either physical distortion of the cells or attack by phagocytic white
blood cells destroys the membranes of the red blood cells, releasing hemoglobin into the
plasma. The body normally has a higher intake of Folate through vegetables etc though it
is easily destroyed by cooking. Much larger amounts are needed by the body but the
body’s store only holds enough supply for up to 4 months. A much larger supply of
Vitamin B12 is kept, this is not so easily destroyed and much less is needed on a daily
basis. Ie 3 or 4 years of defective absorption are required for a maturation failure anemia.
8. Discuss the factors that may contribute to reduced red cell formation.
Gastric damage or resection/Intestinal disorders/Dietary deficiencies lead to low levels of
Folate, Intrinsic factor and Vitamin B12.
Tumour growth/Infections/Therapy affect the functioning bone marrow; the main place
of RBC production and thus destruction of these areas means less stem cells.
Increased demand
Bleeding
Chronic disease
Marrow suppression/defects
Lack of EPO/Failure to respond to EPO. EPO is required to increase the number of stem
cells directed along the RBC producing pathway and to accelerate this process itself
increasing the number of reticulocytes in the blood.
9. What factors affect the affinity of haemoglobin for oxygen?
The pH of the blood affects the affinity, when pH increases (alkalosis) so does the
affinity
The partial pressure of CO2 when high causes a decreased affinity and when low
increases the affinity
Temperature when high decreases affinity and when low increases it.
Low levels of 2,3-DPG (diphospoglycerol) will increase affinity and high levels reduce it.
2,3-DPG promotes the release of Oxygen in peripheral tissues
The presence of Caroboxyhemoglobin and Methemoglobin increase the affinity of Hb for
O2 while abnormal Hb can cause a change in either direction depending on the
abnormality.
10. What effect does alteration of pH have on the glycolytic pathways within the red
cell?
A side reaction in the glycolytic pathway leads to synthesis of 2,3-biphosphoglycerate.
This combines with Hb to reduce its affinity for oxygen. Conditions causing hypoxia
result in increased 2,3-BPG synthesis. When oxygen levels are low, carbon dioxide
partial pressure is normally high and may have associated acidosis with it, thus a low pH
may lead to more 2,3-BPG being produced while high pHs do not.
11. Describe the hazards associated with inheritance of the gene for sickle cell
haemoglobin.
In sickle cell anemia, which is present in 0.3 to 1.0 per cent of West African and
American blacks, the cells have an abnormal type of hemoglobin called hemoglobin S,
containing faulty beta chains in the hemoglobin molecule. When this hemoglobin is
exposed to low concentrations of oxygen, it precipitates into long crystals inside the red
blood cell. These crystals elongate the cell and give it the appearance of a sickle rather
than a biconcave disc. The precipitated hemoglobin also damages the cell membrane, so
that the cells become highly fragile, leading to serious anemia. Such patients frequently
experience a vicious circle of events called a sickle cell disease "crisis," in which low
oxygen tension in the tissues causes sickling, which leads to ruptured red cells, which
causes a further decrease in oxygen tension and still more sickling and red cell
destruction. Once the process starts, it progresses rapidly, eventuating in a serious
decrease in red blood cells within a few hours and, often, death.
12. Describe the mechanism of formation of haemoglobin. PAST EXAM Q
First, succinyl-CoA, formed in the Krebs metabolic cycle, binds with glycine to form a
pyrrole molecule. In turn, four pyrroles combine to form protoporphyrin IX, which then
combines with iron to form the heme molecule. Finally, each heme molecule combines
with a long polypeptide chain, a globin synthesized by ribosomes, forming a subunit of
hemoglobin called a hemoglobin chain. Each chain has a molecular weight of about
16,000; four of these in turn bind together loosely to form the whole hemoglobin
molecule.
13. Discuss the factors that influence haematological cell line differentiation.
The various cells are developed from the pluripotential stem cells in the bone marrow
under cytokine control. Each is upregulated according to need. The pluripotential cell
gives rise to a progenitor cell for each different cells line. The particular progenitor cell
and the subsequent products are all differentiated by cytokines for example interleukin
factors and Erythropoeitin. The need for a particular cell type triggers synthesis of the
particular cytokine and this in turn causes differentiation of the stem cell towards that cell
type.
14. What is the likely consequence of a total white cell count of 1 x 109/l ?
Normal WBC count is 4-11x109 /l thus the count of 1x109/l represents a very low count
(leucopenia). Hence a person would not be able to mount a defense against infection
whether bacteria or virus and the body would quickly be overcome by far spreading
viruses.
15. Describe and account for the difference in differential white cell count between
a 4 year old healthy child and a 20 year old adult.
A four year old would have a WBC count of between 6-15x109/l. The WBC count falls as
an individual grows older and develops natural resistance and a strong immune system to
the various viruses and infections which attack the body. The younger human requires
more WBCs to fight these new threats and give the adaptive immune system chance to
improve its response.
16. Which complement factors are responsible for a) chemotaxis and b)opsonisation?
Chemotaxis- is a process of attraction, target recognition, ingestion, killing, and
degradation of the end products Complement factor-C5a
Opsonisation-Is the process whereby particles, micro-organisms, or immune
complexes are coated with molecules which allow them to bind to receptors
or phagocytes, thereby enhancing their uptake. C3b
17. What is the first line of defence against bacterial infection?
Tissue macrophages ie. those already present in the tissue are the first line of defense.
The first effect is rapid enlargement of each of these cells. Next, many of the previously
sessile macrophages break loose from their attachments and become mobile, forming the
first line of defense against infection during the first hour or so. The numbers of these
early mobilized macrophages often are not great, but they are lifesaving.
18. What is the role of complement in the immune response?
19. What is meant by the term auto-immunity?
Auto-immunity refers to the system whereby the body’s defense system fails to recognize
its own tissues and attacks these instead of just foreign particles and bacteria. In Grave’s
disease for example, the immune system reacts against the thyroid stimulating hormone
receptor of the thyroid gland and in myasthenia gravis, it attacks the ACh receptors in
skeletal muscle.
20. Describe the process of phagocytosis.
On approaching a particle to be phagocytized, the neutrophil or macrophage first attaches
itself to the particle and then projects pseudopodia in all directions around the particle.
The pseudopodia meet one another on the opposite side and fuse. This creates an
enclosed chamber that contains the phagocytized particle. Then the chamber invaginates
to the inside of the cytoplasmic cavity and breaks away from the outer cell membrane to
form a free-floating phagocytic vesicle (also called a phagosome) inside the cytoplasm. A
single neutrophil can usually phagocytize 3 to 20 bacteria before the neutrophil itself
becomes inactivated and dies. A macrophage is a much more powerful digesting
phagocyte which can digest up to 100 bacteria and much larger particles. Once
phagocytized, most particles are digested by intracellular enzymes such as lysosomes and
other cytoplasmic granules which dump digestive enzymes and bactericidal agents into
the vesicle. Thus, the phagocytic vesicle now becomes a digestive vesicle, and digestion
of the phagocytized particle begins immediately.
21. What is meant by the terms primary and secondary immune responses?
The primary response is that which the innate system offers to a bacteria or infection the
first time it is encountered. The response is not very strong or effective in many cases.
The secondary response, by contrast, begins rapidly after exposure to the antigen (often
within hours), is far more potent, and forms antibodies for many months rather than for
only a few weeks. The difference is accounted for by the presence of memory cells,
lymphoblasts that developed into lymphocytes instead of plasma cells the first time the
antigen was encountered. This is the basis of the adaptive immune system.
22. What is the role of the T helper cell in the adaptive (secondary) immune
response? PAST EXAM Q
The helper T cells are by far the most numerous of the T cells, usually constituting more
than three quarters of all of them. They serve as the major regulator of virtually all
immune functions. T helper cells are the first lymphocytes to interact with the antigen
displayed on macrophages and dendritic cells. They can be divided into the type that aid
in the development of cell mediated responses effective against intracellular organisms
and the type that assist in the production of antibody which destroys extracellular
parasites. They do this by forming a series of protein mediators, called cytokines or
lymphokines that act on other cells of the immune system as well as on bone marrow
cells. The direct actions of antigen to cause B-cell growth, proliferation, formation of
plasma cells, and secretion of antibodies are slight without the "help" of the helper T
cells. Most antigens activate both T lymphocytes and B lymphocytes at the same time.
Lymphokines from helper T cells activate the specific B lymphocytes. It is the B
lymphocytes that are destined to form antibodies as part of the secondary response to an
infection.
23. Which class of immunoglobulin is likely to be involved in case of Rhesus
haemolytic disease of the newborn?
Erythroblastosis Fetalis ("Hemolytic Disease of the Newborn") is a disease of the fetus
and newborn child characterized by agglutination and phagocytosis of the fetus's red
blood cells. In most instances of erythroblastosis fetalis, the mother is Rh negative and
the father Rh positive. The baby has inherited the Rh-positive antigen from the father,
and the mother develops anti-Rh agglutinins from exposure to the fetus's Rh antigen. In
turn, the mother's agglutinins diffuse through the placenta into the fetus and cause red
blood cell agglutination. Anti-D immunoglobulin is involved here.
24. Describe the role of the antigen presenting cell in the immune response.
Before the immune system will recognize and respond to a new antigen, it must be
displayed on an antigen presenting cell. These compromise dendritic cells which are
particularly effective in starting a new response to a new antigen and macrophages. Both
pick up an antigen entering the body and transport it to local lymph nodes. Those
lymphocytes in the LN with receptors specific to the antigen will react with it and will
proliferate. Effector T lymphocytes can then invade the infected area and help remove the
antigen. Aside from the lymphocytes in lymphoid tissue, literally millions of
macrophages are also present in the same tissue. These line the sinusoids of the lymph
nodes, spleen, and other lymphoid tissue, and they lie in apposition to many of the lymph
node lymphocytes. Most invading organisms are first phagocytized and partially digested
by the macrophages, and the antigenic products are liberated into the macrophage
cytosol. The macrophages then pass these antigens by cell-to-cell contact directly to the
lymphocytes, thus leading to activation of the specified lymphocytic clones. The
macrophages, in addition, secrete a special activating substance that promotes still further
growth and reproduction of the specific lymphocytes. This substance is called
interleukin-1.
25. What are the possible consequences for a patient when they are given
immunosuppressant drugs?
Immunosuppressants dampen the response of the immune system to foreign invading
substances often necessary for certain treatments etc but this also has the effect of
weakening the bodies protection and exposes it to dangerous viruses and infections.
Viruses which might normally have little effects on a healthy individual could prove
hugely harmful and even lethal should the immune system be completely suppressed.
26. What are the hazards for a Rhesus negative woman with a rhesus positive
partner?
In most instances of erythroblastosis fetalis, the mother is Rh negative and the father Rh
positive. The baby has inherited the Rh-positive antigen from the father, and the mother
develops anti-Rh agglutinins from exposure to the fetus's Rh antigen. In turn, the mother's
agglutinins diffuse through the placenta into the fetus and cause red blood cell
agglutination. The agglutinated red blood cells subsequently hemolyze, releasing
hemoglobin into the blood. The fetus's macrophages then convert the hemoglobin into
bilirubin, which causes the baby's skin to become yellow (jaundiced). The antibodies can
also attack and damage other cells of the body. The jaundiced, erythroblastotic newborn
baby is usually anemic at birth, and the anti-Rh agglutinins from the mother usually
circulate in the infant's blood for another 1 to 2 months after birth, destroying more and
more red blood cells. The hematopoietic tissues of the infant attempt to replace the
hemolyzed red blood cells. The liver and spleen become greatly enlarged and produce red
blood cells in the same manner that they normally do during the middle of gestation.
Because of the rapid production of red cells, many early forms of red blood cells,
including many nucleated blastic forms, are passed from the baby's bone marrow into the
circulatory system, and it is because of the presence of these nucleated blastic red blood
cells that the disease is called erythroblastosis fetalis. The first baby is normally fine but
the risk of serious problems rises with each successive pregnancy.
27. A woman of blood group O has given birth to a group O baby - which of the
following men could be the father - a) a group O man b) a group A man
c) a group AB man d) a group B man
When neither A nor B agglutinogen is present, the blood is type O. If the baby is O type
then the parents both were of O-type blood as well. A group O man. Type A or B??? see
Diagram which only excludes AB.
28. Describe the roles of IgM and IgG in the primary and secondary responses to
antigenic challenge
IgM is the first antibody to be produced in the primary response of a tissue. When it
combines with an antigen it activates the complement system and leads to the production
of different factors with different effects.
IgG, which is a bivalent antibody, constitutes about 75 per cent of the antibodies of the
normal person. It is found in the extravascular tissues and can cross the placenta. It is the
main body synthesized in the secondary response and is of major importance in the
defence against micro-organisms and their toxins. Some IgG classes also activate the
complement system and act as immune antibodies.
29. What is meant by the term MALT? Which immunoglobulin class is associated
with this type of tissue?
MALT= Mucosa Associated Lymphoid Tissue. The mass of lymphoid tissue in the GI,
respiratory and genitourinary tracts is considered to be an organ of its own and is known
collectively as MALT. In large aggregations, it functions like lymph nodes, sampling
antigenic material and mounting both antibody-mediated and cytotoxic immune
responses where appropriate. Immunoglobulin A is the most dominant antibody
produced.
30. What is the sequence of reactions involved in platelet plug formation?
Platelet repair of vascular openings is based on several important functions of the platelet
itself. When platelets come in contact with a damaged vascular surface, especially with
collagen fibers in the vascular wall, the platelets themselves immediately change their
own characteristics drastically. They begin to swell; they assume irregular forms with
numerous irradiating pseudopods protruding from their surfaces; their contractile proteins
contract forcefully and cause the release of granules that contain multiple active factors;
they become sticky so that they adhere to collagen in the tissues and to a protein called
von Willebrand factor that leaks into the traumatized tissue from the plasma; they secrete
large quantities of ADP; and their enzymes form thromboxane A2. The ADP and
thromboxane in turn act on nearby platelets to activate them as well, and the stickiness of
these additional platelets causes them to adhere to the original activated platelets.
Therefore, at the site of any opening in a blood vessel wall, the damaged vascular wall
activates successively increasing numbers of platelets that themselves attract more and
more additional platelets, thus forming a platelet plug. This is at first a loose plug, but it
is usually successful in blocking blood loss if the vascular opening is small. Then, during
the subsequent process of blood coagulation, fibrin threads form. These attach tightly to
the platelets, thus constructing an unyielding plug.
31. What is the role in haemostasis of the von Willebrand factor?
VWF and coagulation factor VIII circulate in the plasma as a non-covalently
bound complex. Formation of this complex is essential for survival of VIII
in plasma – it prevents its oxidation and degradation. VMF acts as a carrier protein for
factor VIII. Factor VIII has two active components, a large component with a molecular
weight in the millions and a smaller component with a molecular weight of about
230,000. The smaller component is most important in the intrinsic pathway for clotting,
and it is deficiency of this part of Factor VIII that causes classic hemophilia. Another
bleeding disease with somewhat different characteristics, called von Willebrand's disease,
results from loss of the large component. Factor VIII causes platelets to become activated
and adhere to the exposed endothelial surfaces. Activation causes the platelets to change
shape, aggregate, liberate and oxidate arachidonic acid, release the granule contents,
reorganize the membrane phospholipids and cause centripetal contraction of the platelet
skeleton.
32. Describe the coagulation cascade
.
33. How may aspirin inhibit haemostasis?
Aspirin is an anti-coagulant- it interferes with the cyclo-oxygenase activity in the platelet.
Thus it does not allow the blood to coagulate and thus prevent excessive bleeding.
34. Discuss the role of an anticoagulant you know and account for its method of
function
Commercial heparin is extracted from several different animal tissues and prepared in
almost pure form. Injection of relatively small quantities, about 0.5 to 1 mg/kg of body
weight, causes the blood-clotting time to increase from a normal of about 6 minutes to 30
or more minutes. Furthermore, this change in clotting time occurs instantaneously,
thereby immediately preventing or slowing further development of a thromboembolic
condition. The action of heparin lasts about 1.5 to 4 hours. By itself, it has little or no
anticoagulant properties, but when it combines with antithrombin III, the effectiveness of
antithrombin III for removing thrombin increases by a hundredfold to a thousandfold, and
thus it acts as an anticoagulant. Therefore, in the presence of excess heparin, removal of
free thrombin from the circulating blood by antithrombin III is almost instantaneous. The
injected heparin is destroyed by an enzyme in the blood known as heparinase.
35. What locally produced factors prevent extension of the coagulation process?
i) Plasma inhibitors –
Antithrombin lll (a plasma protein – single chain glycoprotein) – inhibits IXa,
Xa, XIa and XIIa. Synthesised in liver and endothelium (removes thrombin from the
blood along with fibrin)
Heparin and heparin cofactor II (complexes with thrombin: activity x100 in
presence of heparin)
a2 macroglobulins, a2 antiplasmin, and a2 antitrypsin
ii) Blood flow
iii) Plasmin and split products (Plasmin digests fibrin fibers and some other protein
coagulants such as fibrinogen, Factor V, Factor VIII, prothrombin, and Factor XII.
Therefore, whenever plasmin is formed, it can cause lysis of a clot by destroying many of
the clotting factors, thereby sometimes even causing hypocoagulability of the blood)
iv) Normal intact endothelium (smooth, has glycolayx and binds thrombin)
36. What is the function of the fibrinolytic system?
Thrombin acts on fibrinogen to remove four low-molecular-weight peptides from each
molecule of fibrinogen, forming one molecule of fibrin monomer that has the automatic
capability to polymerize with other fibrin monomer molecules to form fibrin fibers.
Therefore, many fibrin monomer molecules polymerize within seconds into long fibrin
fibers that constitute the reticulum of the blood clot. Clots are composed of a meshwork
of fibrin fibers running in all directions and entrapping blood cells, platelets, and plasma.
The fibrin fibers also adhere to damaged surfaces of blood vessels; therefore, the blood
clot becomes adherent to any vascular opening and thereby prevents further blood loss.
The fibrinolytic system breaks fibrin back down into its soluble fragments. This is done
by a serine protease called plasmin which is activated from plasminogen by plasminogen
activators. Thus the fibrin in haemostatic plugs can eventually be broken down.
37. Define the terms thrombosis and embolism.
Thrombosis: Refers to clot formation within a blood vessel.
Embolism: Describes the process when a thrombus (clot) formed in one part of the
circulation breaks off and passes to another part.
Both processes may occur on venous or arterial sides of the blood circulation.
38. Describe the overall response to blood vessel injury resulting in bleeding.
Following platelet plug formation, there are three essential steps: (1) In response to
rupture of the vessel or damage to the blood itself, a complex cascade of chemical
reactions occurs in the blood involving more than a dozen blood coagulation factors. The
net result is formation of a complex of activated substances collectively called
prothrombin activator. (2) The prothrombin activator catalyzes conversion of
prothrombin into thrombin (3) The thrombin acts as an enzyme to convert fibrinogen into
fibrin fibers that enmesh platelets, blood cells, and plasma to form the clot. Within a few
minutes after a clot is formed, it begins to contract and usually expresses most of the fluid
(serum) from the clot within 20 to 60 minutes. As the clot retracts, the edges of the
broken blood vessel are pulled together, thus contributing still further to the ultimate state
of hemostasis. The injured tissues and vascular endothelium very slowly release a
powerful activator called tissue plasminogen activator (t-PA) that a few days later, after
the clot has stopped the bleeding, eventually converts plasminogen to plasmin, which in
turn removes the remaining unnecessary blood clot.
39. What are the major factors which threaten to disturb blood pH?
?????????????????????
40. What are the major buffer systems of the body?
Buffer systems
a) Hemoglobin
b) Proteins
c) Phosphate buffer
d) Bicarbonate
41. By what mechanisms does the body excrete H+ ions?
Hydrogen ions are excreted in the urinary system.
42. How does the respiratory system contribute to pH regulation?
pCO2 is the respiratory component of the acid-base balance. Dissolved carbon dioxide
corresponds to the acidic part of the pH of plasma and so when it is depleted, the
ventilation rate is decreased and it is hence retained for longer in the blood. Increased
carbon dioxide levels cause an increase in ventilation to reduce this and so the respiratory
system regulates pH in the blood via CO2 concentrations.
43. What is the relationship between plasma K+ and arterial pH?
Efflux of potassium from cells leads to an increase in plasma K+ and therefore acidemiaa low pH. Entry of potassium into cells is often associated with a low hydrogen ion
concentration on plasma and therefore a high pH- alkalemia.
44. What are the functions of the kidney in the role of pH regulation?
The kidneys control plasma bicarbonate concentration (the basic component of pH) by
regulating its reabsorption and synthesis as the renal tubular cells are sources of it.
45. What is the relationship between plasma bicarbonate and CO2 levels?
Plasma CO2 levels are normally around 1.2mmol/l and plasma bicarbonate levels are
about 0.0017mmol/l. Theoretically however all carbon dioxide is converted to
bicarbonate in a slow equilibrating reaction where carbon dioxide combines with water to
form carbonic acid which then dissociates into hydrogen ions and bicarbonate. Plasma
pH is determined by the ratio between the concentrations of both.
46. What is the basis for the 'chloride shift'?
As bicarbonate is formed primarily in the RBC rather than in the plasma, the bicarbonate
will diffuse out of the cell down its concentration gradient into the plasma (hence more
bicarbonate is carried in the plasma, the proportional amount determined by the volume
of plasma relative to RBCs). To preserve electroneutrality, the anion chloride moves from
the plasma into the RBC.
47. pH compatible with life
= 7.36 - 7.46
What is the normal adult total white cell count and differential white cell count?
4-11x109/l WBCs
Neutrophils- 2.5-7.5x109/l
Eosinophils- 0.04-0.4x109/l
Basophils- 0.01-0.1x109/l
Lymphocytes- 1.5-3.5x109/l
Monocytes-0.2-0.8x109/l
<<<<Remaining Unanswered questions>>>>
27,39,41
What is the normal adult total white cell count and differential white cell
count?
How is haemoglobin formed?