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Semester 4 > Therapeutics & Investigations 2 (Part 1) > Flashcards

Therapeutics & Investigations 2 (Part 1) Flashcards

1
Q

What is (nutritional) anaemia

A
  • Condition when # of RBCs + therefore their o2 carrying capacity is insufficient to meet bodily needs
  • Fall in Hb concentration, seen with not enough RBCs
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2
Q

What is haemoglobin

A
  • Iron containing o2 transport, metalloprotein that is within RBCs
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3
Q

what happens when there is a fall in Hb

A
  • Reduction in Hb causes anaemia, a reduction in o2 carrying capacity
  • Changes how it gives oxygen to the different tissues
  • In the LAB measure = always done by haemoglobin concentration
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4
Q

components of blood?

A
  • Made of RBC, WBCs, platelets

- Bone marrow is in the long bones of an adult/ pelvic bones, femur and sternum etc

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5
Q

what is anaemia?

A
  • Condition where # RBCs and their o2 carrying capacity, is insufficient to meet body physiologic needs.
  • Anaemia is decrease in # RBCs / less than normal quantity of Hb in the blood
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6
Q

how would you clinically diagnose anaemia?

A
  • Measured in g/L (or decilitre)
  • Less than 6 months = high Hb, and then become a lower level for the first 6 months until about 5 year as you are growing and have more needs
  • Then goes higher in childhood
  • By adolescence = at normal range for an adult
  • Females = always losing blood
  • Normal range drops even further for pregnant ladies because there is a rise in ones physiological volume
  • Lower Hb = more severe anaemia
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7
Q

what are the 4 needs of RBC maturation?

A
  1. Vitamin B12 and folic acid 2. DNA synthesis 3. Iron synthesis 4. Hb synthesis (iron needed for Hb synthesis)
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8
Q

Describe normal erythropoesis

A
  • Maturation of RBCs has 4 needs: 1. Vitamin B12 and folic acid 2. DNA synthesis 3. Iron synthesis 4. Hb synthesis (iron needed for Hb synthesis)
  • Vitamins, cytokines (erythropoeitin)
  • Healthy environment for bone marrow (functional bone marrow )
  • Erythropoiesis = production of red blood cells
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9
Q

what are the mechanisms of action for anaemia

finding out why the persons iron is low

A

1 - Failure of production of RBCs
• = Hypoproliferation, Reticulocytopenic (early RBCs which can be measured)
2 - Ineffective erythropoiesis
• All of the right bits = enough iron, b12 etc but the bone marrow cannot do the right things with it
3 - Decreased survival :
• Blood loss, haemolysis (RBC destruction), reticulocytosis
• Either not producing it or losing / destroying it too much

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10
Q

describe - Failure of production of RBCs as a mechanism of action of anaemia

A

• = Hypoproliferation, Reticulocytopenic (early RBCs which can be measured)

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11
Q

describe - Ineffective erythropoiesis as a mechanism of action of anaemia

A

• All of the right bits = enough iron, b12 etc but the bone marrow cannot do the right things with it

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12
Q

describe - Decreased survival : as a mechanism of action of anaemia

A
  • Blood loss, haemolysis (RBC destruction), reticulocytosis

* Either not producing it or losing / destroying it too much

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13
Q

Anaemia = one of causes if low Hb levels
after getting full blood count, also get a marker of what size the RBC are
WHAT DO MICROCYTIC CELLS LOOK LIKE?

A
  • Iron deficiency, heme deficiency
  • Thalassamia - globin deficiency
  • Anaemia of chronic disease
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14
Q

Anaemia = one of causes if low Hb levels
after getting full blood count, also get a marker of what size the RBC are
WHAT DO NORMOCYTIC CELLS LOOK LIKE?

A
  • Anaemia chronic disease
  • Aplastic anaemia
  • Chronic renal failure
  • Bone marrow infiltration
  • Sickle cell disease
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15
Q

Anaemia = one of causes if low Hb levels
after getting full blood count, also get a marker of what size the RBC are
WHAT DO MACROCYTIC CELLS LOOK LIKE?

A
  • B12 deficiency, folate deficiency
  • Myelodysplasia
  • Alcohol induced
  • Drug induced
  • Liver disease
  • Myxoedema
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16
Q

what are nutritional anaemias

A
  • Lack of essential ingredients that the body gets from food sources
  • Iron, vitamin B12, folate deficiency
  • Patient with reduced concentration of Hb because they have not been able to get building blocks from their food
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17
Q

what are the characteristics of iron

A
  • Essential for oxygen transport, most abundant trace in the body. Daily need for iron for erythropoesis varies, depending on gender + physiological needs (e.g. pregnancy or normal )
  • Needs differ at various stages of development.
    • Meat, seafood (gives you haem which is more easy to absorb - good value for iron content),
    • Vegetables like spinach (non haem, so more is needed), wheat products, fruits and eggs etc have high iron levels.
  • No natural way for the body to excrete iron = unless you are bleeding or using the muscles - need slightly varied levels of iron
  • Milk based diet = do not absorb iron levels as much. In growing years / pregnancy = should keep up with daily losses.
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18
Q

What do fe3+ ions bind to when they circulate

A
  • Bind to plasma transferrin

- Accumulate in the cells in form of ferritin.

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19
Q

describe iron metabolism and the states that it exists in

A
  • There is more than 1 stable form of iron
    Exists in 2 states
    1. FERRIC state = 3+
    2. FERROUS state = 2+
  • Humans contain 4-5g iron, and most of the iron in the body is there as circulating Hb, at about 2.5g
  • Nearly all of the remainder is as storage proteins - ferritin, which is a storage protein, and haemosiderin. These are found in the liver cells, spleen and bone marrow.
  • Iron gets absorbed from the duodenum via the enterocytes into plasma, binds to transferrin
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20
Q

What are the iron containing proteins? - haem

A
  • Has porphyrin complex
  • Ferrous Fe2+
  • Exists in Hb, Myoglobin, catalases, peroxisases
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21
Q

What are the iron containing proteins? - non haem

A
  • Iron transport proteins like lactoferrin and lactoferrin
  • Iron storage proteins
  • Ferritin = short term
  • Haemosiderin = long term
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22
Q

describe Iron absorption

A
  • This is regulated by GI mucosal cells mechanism: maximal absorption in the duodenum and the proximal jejunum
  • The amount that is absorbed is the type that is ingested - heme, ferrous (red meat, used to contain Hb) > than non heme, ferric forms which is bound to other substances
  • Heme iron makes up 10-20% of dietary iron
  • Other foods, GI acidity, state of iron storage levels and bone marrow activity - these are all factors that affect absorption.
  • Taking vitamin C helps with absorption - things like milk and dairy/tea can stop absorption,
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23
Q

describe Iron transport and storage

A
  • From the duodenum into the mucosal cells, and then combine with Apoferritin –> ferritin. Or cross to the plasma where they bind to transferrin, so can enter cells via transferrin receptor (e.g. erythroid precursors).
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24
Q

what are the characteristics of Hepcidin - nearly 13 years old: iron regulatory mechanism process

A
  • Body also has this system of regulating how much we need
  • Iron regulatory hormone hepcidin and its receptor and iron channel ferroportin, control dietary absorption, storage, iron tissue distribution
  • Hepcidin goes up when we have got enough iron. Hepcidin = abundance
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25
Q

What controls dietary absorption of iron?

A
  • Hepcidin = iron regulatory hormone, and its receptor
  • Ferroportin = iron channel
  • There is transferrin receptor on the early RBCs
  • Transferrin is trying to get as much iron as possible into the red blood cells
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26
Q

What does hepcidin cause?

A
  • It causes ferroportin internalisation, and degradation (the iron channel). This will therefore decrease iron transfer into the blood plasma from the duodenum, from macrophages involved in recycling senescent erythrocytes + from iron storing hepatocytes.
  • Hepcidin = feedback that is regulated by iron concentrations in the plasma and the liver, and by erythropoietic demand for iron.
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27
Q

describe the gastrointestinal transport mechanisms (11 main steps)

A
  1. Dietary iron is either derived from haemoglobin/myoglobin (haem iron) or is bound to other substances (nonhaem iron). Haem iron makes up to 10-20% of the dietary iron and is found in animal foods that originally contained hemoglobin, such as red meats, fish, and poultry. It is well absorbed.
    1. Haem is digested enzymatically free of globin and enters the cell as an intact metalloporphyrin, presumably by a vesicular mechanism.
    2. It is degraded within the enterocyte by heme oxygenase with release of inorganic iron that traverses the basolateral cell membrane in competition with nonhaem iron to bind transferrin in the plasma.
    3. Non-haem iron makes up 80-90% of the iron in food. It is less well absorbed. This is the form of iron added to iron-enriched and iron-fortified foods.
    4. Both calcium and tannins (found in tea and coffee) reduce nonhaem iron absorption.
    5. Most dietary inorganic iron is ferric iron.
    6. Ferric iron can enter the enterocyte via the integrin-mobilferrin pathway (IMP)
    7. Some ferric iron is reduced in the intestinal lumen by membrane reductase duodenal cytochrome B (DTC1).
    8. Ferrous iron is transported across the plasma membrane by the divalent metal transporter DMT-1.
    9. Within cells, iron is stored as ferritin (to protect the cell from oxidative damage) or exported across the basolateral surface by the iron transporter ferroportin. Exported iron is converted to ferric iron by the membrane oxidase hephaestin and bound to transferrin for distribution to tissues.
    10. The enterocyte is informed of body requirements for iron by transporting iron from plasma into the cell using a holotransferrin receptor.
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28
Q

describe the interactions of hepcidin

A
  • Hepcidin interaction with ferroportin controls the main iron flows into plasma.
  • Iron flows and reservoirs are depicted in blue
  • Iron in hemoglobin in red, and hepcidin and its effect in orange.
  • RBC indicates red blood cell; and Fpn, ferroportin.
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29
Q

Iron deficiency - describe reasons

A
  • Can be because not enough is in, or losing too much
  • Not enough in: poor diet, malabsorption (eatinng what should be enough but body is not absorbing it properly), increased physiological needs
  • Losing too much: blood loss, menstruation, GI tract loss, paraistes
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30
Q

describe the Lab investigations for ion deficiency

A
  • 1st = FBC (checks for red blood cells) - Hb, MCV, MCH, reticulocytes + blood film
  • Iron studies : ferritin, transferring saturation, TIBC
  • Other studies = BMAT and iron stains
  • Always include a blood film when asked which measurements that you should do
    Take out some of the bone marrow from the back, look at the early red blood cells and stain with iron
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31
Q

describe the Iron studies laboratory tests - the blood tests that you can do.

(BLOOD TEST: FERRITIN)

A
  • Primary storage protein, and providing reserve, water soluble

Reliable for iron deficiency = if this is low then you know that you do not have enough stored iron

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32
Q

describe the Iron studies laboratory tests - the blood tests that you can do.

Urine test : Haemosiderin

A
  • Water insoluble, Fe - protein complex
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33
Q

describe the Iron studies laboratory tests - the blood tests that you can do.
Blood test : Transferrin saturation

A
  • Made by liver inversely proportional to Fe stores. This is vital for Fe transport.
  • Uptake of Fe from protein, needs transferring to be attached to the cell via the transferrin receptor.
  • Looking at the ratio of serum iron and total iron binding capacity, revealing the percentage of transferring binding sites that have been occupied by iron
  • Can test for saturation “seeing how many full seats on a bus there is “ - if you are iron deficient then this will be lower
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34
Q

describe the Iron studies laboratory tests - the blood tests that you can do.

Blood test: Iron binding capacity

A
  • Irons capacity to bind with transferring.

- Maximum amount of iron that it can carry - which indirectly reflects transferrin levels

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35
Q

describe the Iron studies laboratory tests - the blood tests that you can do.

Blood test: Transferrin saturations

A
  • How much transferrin is available to be able to bind iron - how much of the serum iron is actually bound
  • E.g. value of 10% means, that 10% iron binding sites of transferrin is getting occupied by iron at that point.
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36
Q

describe the Iron studies laboratory tests - the blood tests that you can do.
(Serum Fe)

A
  • Massively variable throughout the day - increases if you have just had a meal
  • Not that useful , but can put into context with the others
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37
Q

what are the characteristics of Transferrin / Transferrin receptors

A
  • Made by the liver, production inversely proportional to Fe stores.
  • Vital for Fe transport, uptake of Fe from the protein needs transferrin to be attached to the cell via the transferrin receptor
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38
Q

What is the total iron binding capacity?

A
  • Measurement of the capacity of transferrin, to bind iron
  • Amount of space that is still left for iron binding
  • Indirect measurement of transferrin - a transport protein that carries iron.
  • TIBC is technically easier to measure in the lab than transferrin levels directly,
  • In IDA, TIBC will be high
    • This is because there is more transferring produced, aiming to transport more iron to tissues that are in need.
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39
Q

what results would you get in iron deficiency anaemia?

A

reduced:
- Hb, MCV, MCH, serum iron, serum ferritin, TIBC (reflects transferrin), Transferrin saturation. Bone marrow iron studies

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40
Q

what are the stages of development of iron deficiency anaemia?

A
  • Before anaemia develops, iron deficiency occurs in several stages.
  • Serum ferritin is the most sensitive laboratory indicators of mild iron deficiency.
  • Stainable iron in tissue stores is equally sensitive, but is not performed in clinical practice.
  • % saturation of transferrin with iron and free erythrocyte protoporphyrin values do not become abnormal until tissue stores are depleted of iron.
  • Decrease in the [Hb] = when no iron available for haem synthesis.
  • MCV and MCH do not become abnormal for several months after tissue stores are depleted of iron.
  • Go from being normal, to full blown iron deficiency anaemia - serum ferritin starts to fall as you go towards the right
  • If you have no iron stores = deficient but not anaemic yet
  • Ferritin = answers easily if someone is iron deficient
    Low : iron, transferrin saturation
    High : TIBC
    Serum iron : low and normal
    Hepcidin = fat controller
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41
Q

23 year old female that is tired and lacks concentration
Full blood count measurement. - Reviewing the blood count of our patient, we can notice that she has a moderate anaemia, since her [Hb] is 9.7 g/dl.

A
  • Reviewing the blood count of our patient, we can notice that she has a moderate anaemia, since her [Hb] is 9.7 g/dl.
  • The anaemia is:
    • Microcytic (MCV 69.7 fl) and
    • Slightly hypochromic (MCHC 32.4 g/dl). - small red blood cells and a low Hb
  • The mean cell Hb is also low (22.6 pg).
  • The reticulocyte count is inappropriately normal, since we would expect the bone marrow to compensate the anaemia by producing more new red cells - not making new RBCs
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42
Q

Iron deficiency anaemia symptoms and signs

A

Symptoms
- Fatigue, Lethargy, Dizziness

Signs

  • Pallor of mucous membranes
  • Bounding pulse
  • Systolic flow murmurs
  • Smooth tongue, koilonychias
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43
Q

characteristics of B12 and folate deficiency

A
  • Both have similar lab findings + clinical symptoms. Can be found together, or separately.
  • Macrocytic anaemia - low Hb, and high MCV, with normal MCHC.
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44
Q

describe megaloblastic macrocytic anaemia?

A
  • Vitamin b12 folic acid deficiency
  • Drug realted
  • Interference with B13/FA metabolism
  • Seen in B12 and FA deficiency = peripheral smear by the macroovalocytes megaloblastic vs non megaloblastic slide
  • There are 7 lobes on this one when there should usually be 4.
  • Hypersegmented neutrophil
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45
Q

describe non megaloblastic macrocytic anaemia?

A
  • Alcoholism - impairs folate metabolism (direct toxicity with increased exposure of alcohol on the bone marrow)
  • Hypothyroidism
  • Liver disease
  • Myelodysplastic syndrome: pre cancerous cells, natur
  • Reticulocytosis
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46
Q

What are some causes of b12 deficiency - IMPAIRED ABSORPTION

A
  • pernicious anaemia, gastrectomy or ileal resection, zollinger ellison syndrome, parasites
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47
Q

What are some causes of b12 deficiency - DECREASED INTAKE

A
  • malnutrition, veganism
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48
Q

What are some causes of b12 deficiency - CONGENTIAL CAUSES

A
  • intrinsic factor receptor deficiency.

- cobalamin mutation (CG1 gene )

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49
Q

What are some causes of b12 deficiency - INCREASED REQUIREMENTS

A
  • haemolysis, HIV, pregnancy, growth spurts
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50
Q

What are some causes of b12 deficiency - MEDICATION

A
  • alcohol, NO, PPI (H2 antagonists), Metformin
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51
Q

What are the haematological consequences of vitamin B12 deficiency?

A

MCV = normal / raised
Hb = normal or low
Retic. count = low
LDH = raised
Blood film = Macrocytes, ovalocytes, hypersegmented neuts
BMAT = hypercellular, megaloblastic, giant metamyelocytes
MMA = increased

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52
Q

Clinical consequences of Iron deficiency - BRAIN

A
  • Cognition
  • Depression
  • Psychosis
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53
Q

Clinical consequences of Iron deficiency - Neurology

A
  • Myleopathy
  • Sensory changes
  • Ataxia

Spasticity (SACDC)

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54
Q

Clinical consequences of Iron deficiency - Tongue

A
  • Glossitis

- Taste impairment

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55
Q

Clinical consequences of Iron deficiency - Blood

A
  • Pancytopenia
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56
Q

what is pernicious anaemia?

A
  • Autoimmune disorder, that is a lack of IF, lack of B12 absorption, gastric parietal cell antibodies, IF antibodies.
  • Either making antibodies against the gastric parietal cells or against the intrinsic facto themselves
  • Treatment = vitamin B12 injections every 3 months = hyper segmented
  • Issues with the nervous system and the brain, cardiac disease, infertility.
  • Can affect WBC and platelet count as well
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57
Q

describe folate deficiency + characteristics of folate.

A
  • Present in most foods, similar presentations to B12 deficiency but no neurological consequences.
  • Necessary for DNA synthesis - adenosine, guanine, and thymidine synthesis.
  • because of increased demand, decreased intake/absorption
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58
Q

Iron deficiency treatments?

A
  • Diet, oral, parenteral iron supplementation

- Stopping the bleeding

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59
Q

Folic acid deficiency treatments?

A
  • Oral supplements
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60
Q

Vitamin B12 deficiency treatments

A
  • Oral vs intramuscular treatment
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61
Q

What are the causes of macrocytic anaemia? [MEGALOBLASTIC]

A
  • This is a low reticulocyte count

* Vitamin B12/ folic acid deficiency, drug related, interference with B12/FA metabolism

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62
Q

What are the causes of macrocytic anaemia? [NON - MEGALOBLASTIC]

A
  • Alcoholism, hypothyroidism, liver disease, myelodysplastic syndromes, reticulocytosis (haemolysis)
  • This gives you the fact that someone is anaemic and then size of their RBCs
  • LOW B12 and low folate = malabsorption
  • Folic acid is what you are given but folate is naturally in the body - can do a serum folate levels
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63
Q

What is normal haematopoiesis?

A
  • Blood cell production
  • Bone marrow, long bones
  • Maturation occurs in bone marrow. There are mature cells within peripheral blood
  • Progenitor cells mature and develop and once they get to a completed stage get kicked out into the circulating blood : testing what is circulating in the blood
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64
Q

what is the definition of the FBC (full blood count), what does it look for?

A
  • Each set of blood tests that are requested go to different tubes = purple tops contain EDTA to stop the blood clotting - if you let it stand for long enough then it will start to sediment out

Red blood cell results:
- Hb = [haemoglobin] in our blood = not commenting on the number of red blood cells; but g/L
- Hct = % of blood volume of RBC (percentage of the cell volume that are red blood cells = usually 50ish%.)
- MCV = average size of RBC
• Could have severe iron and b12 deeficiency anaemia and then have normal MCV as that is the norm
- MCH = average Hb content in each RBC (MCHC mean cell HB concentration)
- RDW = range of deviation around the RBC size
• Variation in sizes of the red blood cells
• Small RDW if they are really monomorphic and all similar sizes = someone with b12 and iron deficiency, even though you have a normal mean cell volume you will have a really high RDW.
- Reticulocyte count
- Blood film - useful to look at these for particular issues when numbers do not make sense

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65
Q

what, apart from the FBC could you look at?

A

White blood cells results
- Total WBC and differential
- Neutrophils, lymphocytes, monocytes, basophils, eosinophils
Platelet results
- Platelet count, and size of platelet
- Platelet count is low = look at blood fim, to see if the cells that we have look normal
Others = warning flags.
- Picks up abnormal cells that are not any of the ones that we know of - LUCs (large, unidentified cells)

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66
Q

what are some things that blood films show? [general]

A
  • Confirming numbers
  • Morphology = if the cells are normal
  • If there are cells present that there shouldn’t be
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67
Q

what are some things that blood films show? [red cells only]

A
  • Size: big or small, anisocytosis
  • Colour : Hb content
  • Shape: round, TDP, irregular, ellipocytes, poikylocytosis - variation in the shape, looks chaotic
  • Polychromasia
    • Early red cells coming though, looks a bit more purple
  • Inclusions: if there are other things sitting there that there shouldn’t be
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68
Q

what are some things that blood films show? [white cells only]

A
  • Numbers: too many or too few
  • Normal morphology - dysplastic features
  • Immature cells : myelocytes and precursors
  • Abnormal cells: blasts, atyprical lymphoid cells
  • Inclusions
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69
Q

Different blood tests use different tubes - describe what they are?

A 
Pink = EDTA, blood transfusion
Black = ESR, erythrocyte sedimentation rate 
Rust = biochem. Clots, can use the plasma 
Green = lithium
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70
Q

describe the iron deficiency anaemia

A
  • Small rims of Hb around the edge, platelets
  • Small RBCS and target cells have “bullseye” in the middle
  • Key = small and hypochromic
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71
Q

Describe macrocytic megaloblastic anaemia

Presence of big cells

A
  • this is when presence of big cells
  • really large - ovalocytes are present
  • Try to then find out if this was caused by folate or vitamin B12
    Could be deficient of both if you do not have stomach = no gastric parietal cells = less IF
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72
Q

describe acquired haemolytic anaemia - there is polychromasia and spherocytes

A
  • High reticulocyte count and his bone marrow is trying to keep up
  • Polychromasia = these large purpley cells, pick up stain in a different way
  • Lots of them are missing their area of central pallor
  • Could have devloped an antibody that recognises his own red blood cells as foreign = spleen picks them all up
  • Haemolysing (destroying) his own red blood cells
  • Spleen is working hard and taking in all of the abnormal blood cells which is why it is larger
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73
Q

describe Sickle cell anaemia

A
  • Have boat shaped cells

Should be able to diagnose because you can easily see these shapes

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74
Q

Tear drop Poikilocytosis - myelofibrosis or bone marrow infiltration with malignant disease

A
  • Pointy head
  • Suggests that there is something else like leukameia and fibrosis sitting inside the bone marrow
  • Would not be able to pick this up from the number
  • Slightly anaemic but might not have triggered the warning signs
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75
Q

Examples of full blood count results and their blood films : white blood cell abnormalities

A
  • Neutrophil leucocytosis
  • Nearly all of these will be neutrophils = someone who is unwell with something like sepsin so neutrophils have gone up and red cells are not working as well
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76
Q

Acute myeloblastic leukaemia - blast cells are present

A
  • Literally one platelet

- All of the cells are myeloblasts = leukamia cells. Only one neutrophil which is circled.

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77
Q

Chronic granulocytic leukaemia - all stages of cell maturation are represented

A
  • Left sided abdominal pain
  • Chronic leukaemia, there are some mature cells = chronic is at a later stage. Still needs treaetment - blasts, microcytes and monocytes.
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78
Q

Malarial parasitization of the red cells - rare : describe the characteristics

A
  • Can do a malarial antigen test
  • Febrile, confused, recently in Kenya
  • FALCIFERUM malaria = characteristic marks in each
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79
Q

Describe the haemostatic response to injury

A
  • Involves the vessel wall, platelets, coagulation, fibrinolysis
  • There are coagulation tests and they need interpretation
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80
Q

What is haemostasis

A
  • This is a protective process that we have evolved in order to maintain a stable physiology - explosive reaction that is designed to curtail blood loss, restore vascular integrity, and preserve life.
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81
Q

describe infections that can occur - Horseshoe crab, which lives in sandy banks

A
  • Limulus polyphemus, a primitive coagulation pathway that can be initiated by endotoxin
  • Has funny blood supply - no Hb, amebocyte is the main blood cell which has all of the coagulation proteins within it.

Releases immune cells that release coagulation factors

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82
Q

Haemolymphs contain amebocytes - what are amebocytes

A
  • These are proteins of the coagulation system, and proteins and peptides of the immune system
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83
Q

what is Disseminated intravascular coagulation (DIC)

A

Coagulation is activated by infection, and wards off bacteria from getting to more vital places in the body. Trying to ward off the bacteria from getting to more important parts of the body

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84
Q

Haemostasis continued (4 key components + definition)

A
  • Life preserving processes that are designed to maintain blood flow, respond to tissue injury, curtail blood loss, restore vascular integrity and promote healing and limit infection
  • There are 4 key components of haemostasis, Endothelium (blood vessel wall), Platelets, Coagulation, Fibrinolysis

Respond to tissue injury, stop blood loss, limit infection.

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85
Q

what are the factors that make up the blood clot?

A
  • Life preserving processes that are designed to maintain blood flow, respond to tissue injury, curtail blood loss, restore vascular integrity and promote healing and limit infection
  • There are 4 key components of haemostasis, Endothelium (blood vessel wall), Platelets, Coagulation, Fibrinolysis

Respond to tissue injury, stop blood loss, limit infection.

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86
Q

broad overview of the haemoastasis process?

A
  1. Vessel damage and blood loss
  2. Vascular spasm/vasoconstriction
  3. Platelet plug formation
  4. Coagulation
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87
Q

describe the 2nd step of haemostasis, vascular spasm / vasoconstriction?

A
  • With activation of the endothelial cells
  • Diameter of the blood vessel becomes smaller
  • Lots of smooth muscle around the blood vessel which undergoes vasoconstriction
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88
Q

describe the 3rd step of haemostasis, Platelet plug formation?

A
  • Act like putty, recognise the place that is damaged and stick to this area, but this is not very strong
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89
Q

describe the 4th step of haemostasis, coagulation?

A
  • Stronger. The fibrin comes and forms this mesh.
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90
Q

there are 3 phases to the haemostatic system - what are they?

A
  1. Primary haemostasis 2. Secondary haemostasis, 3. Fibrinolysis
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91
Q

what happens during Primary haemostasis

A
  • Vasoconstriction, immediate
  • Platelet adhesion within seconds, platelets changing shape and releasing lots of things to form this putty, which sticks on a short term basis.
  • Platelet aggregation and contraction, within minutes
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92
Q

what happens during secondary haemostasis

A
  • Activation of coagulation factors, within seconds
  • Formation of fibrin, within minutes
    • ( Phase 1 and 2 happen at the same time )
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93
Q

what happens during fibrinolysis

A
  • Activation of fibrinolysis, within minutes
  • Lysis of the plug, within hours
  • hoovering mechanism - this also happens almost straight away
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94
Q

Haemostasis at rest: triggers and cofactors separated

A
  • This is the lumen of the blood vessel, and has lots of components for haemostasis. Platelets, and von willebrand factor which is really important. People who do not have it, have von willebrands disease and will bleed excessively. This is the factor for platelets to adhere to the site of injury
  • Most of them circulate in a non activated form. One circulates in small amounts, which is factor 7a which is like the initiator of coagulation.
  • Endothelium is the barrier between all of these haemostatic components. Things in the sub endothelium are t he initiatiors when you injure yourself
  • Collagen = sticky protein
  • Tissue factor = vital for the development of clotting
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95
Q

describe Phase 1 of haemostatic system: Primary Haemostasis

A
  • Involves collagen. Will interact with VWF in blood which makes it unravel and act as the anchor for platelets to stick to this damaged area
  • When platelets do this they change shape themselves and produce suloperdia and increase their surface area and release components which make even more platelets and VWF to join on
  • This creates a phospholipid surface for the development of fibrin
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96
Q

Activity of v WF activity under shear stress

A
  • VWF is released from the endothelium when something is damaged

Gets unravelled, and platelets come and stick to it.

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97
Q

what is the benefit of platelet aggregation?

A
  • This prevents the excessive blood loss at the site of injury
    VWF= ligand / anchor to stick platelets to the damaged area fast.
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98
Q

in platelet activation, what changes do the platelets go through?

A
  1. resting platelet 2. activation 3. adhesion + spreading
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99
Q

What is the role of platelets in haemostasis

A
  • The plug of activated platelets is localised to the injury site. Provides phospholipid surface upon which secondary haemostasis occurs.
  • Tissue factor leads to thrombin and fibrin formation
  • Collagen causes platelets to adherer to them through VWF
  • More and more migration of platelet into the area that the platelet plug forms.
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100
Q

haemostatic plug formation overview?

A

vessel constriction –> formation of unstable platelet plug (+platelet adhesion and aggregation) –> stabilisation of the plug with fibrin blood coagulation –> dissolution of the clot + vessel repair fibrinolysis

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101
Q

what is dissolution

A

remodelling of the clot

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102
Q

Role of the fibrin mesh

A
  • It binds, and stabilises the platelet plug and other cells
  • Can see the red cells, platelets and fibrin mesh.
  • There are clotting factors that circulate in the plasma, most are made in the liver and most are q complex.
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103
Q

describe the Revised waterfall hypothesis

A
  • Coagulation is not what happens in the body = helps interpretation of clotting tests
  • Each reaction needs Ca2+, phospholipid, specific co factors
  • 7a binds a complex with tissue factor. Tissue factor is hidden in the sub endothelium. Can make a complex between the 2 and can drive forward coagulation.
  • Can activate factor 10 in the presence of factor 5 can turn pro thrombin into thrombin
  • Thrombin can convert fibrinogen into fibrin
  • X = extrinsic pathway, because tissue factor is extrinsic to blood
  • I = intrinsic pathway - clots because of foreign surface. Due to changes in ionic charge
  • Blood in a tube = if there is nothing there to stop it clotting then it will still clot when it comes into contact with a non physiological changes
  • 10 can cause thrombin to form and then eventually fibrin. Do not have clotting factors = bleeding. Some factors cause more bleeding that others when deficient
  • E.g. no factor 7 = 7 bleeding disorder because you do not have tissue factor 7 complex to drive forward coagulation
    • But losing factor 12 = no bleeding disorder
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104
Q

Revised cascade: initiation process

A
  • TF is outside the lumen, and there is formation of TF-FVIIa complex
  • Recruitment of FX, and formation of thrombin
  • Damage will lead to 7a coming into contact with the tissue factor and the complex is the initiator
  • Prothrombin becomes thrombin and this will then lead to fibrin
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105
Q

What is the cell based model of coagulation

SECONDARY HAEMOSTASIS

A
  • Forms a complex with factor 7, v important regulator. 7a cannot do this alone = have to activate lots of other factors, all on the surface or a platelet to allow this to happen. This will lead to the production of fibrin and fibrin mesh.
  • Process of forming a small amount of thrombin and then having to make more - development of more and more activated surfaces to make a huge amount of thrombin
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106
Q

What is fibrinolysis definition, + its main functions.

A
  • The process of clot dissolution. Limits where the clot forms = otherwise it could keep extending.
  • The main function is as a clot limiting mechanism and repair and healing mechanism.
  • Works via a series of tightly regulated enzymatic steps, feedback potentiation and inhibition.
  • The main key players are plasminogen, tissue plasminogen activation (t-PA) + urokinase (u-PA), plasminogen activator inhibitor -1 and -2, and alpha2 plasmin inhibitor (which are both negative regulators )
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107
Q

What are the main key players of fibrinolysis?

A
  • The main key players are plasminogen, tissue plasminogen activation (t-PA) + urokinase (u-PA), plasminogen activator inhibitor -1 and -2, and alpha2 plasmin inhibitor
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108
Q

what are the steps of fibrinolysis

A
  • plasminogen –> plasmin
    which is done by TPA (tissue plasminogen activator)
  • Plasmin is the active enzyme that will remove the clot, in doing so get some end products developed
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109
Q

When are fibrin degeneration products (FDP) made

A
  • When non cross linked fibrin, or fibrinogen gets broken down.
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110
Q

Haemostasis and thrombosis - is a balance: describe this!

A
  • Blood needs to be in a state of Eqm and not just clot all the time.
  • 4 factors = coag factors, platelets, fibrinolytic factors, anticoagulant proteins
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111
Q

what happens during thrombosis?

A
  • there is leaning towards coagulation factors, platelets
    and less towards fibrinolytic factors + anticoagulant proteins
    when there is too many platelets, there is too much clotting
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112
Q

Bleeding - what happens

A
  • There is a rise in fibrolytic factors (no clotting factors and not enough platelets ) and anticoagulant proteins
  • And a decrease in coagulation factors and platelets
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113
Q

Easy bruising - echymosis

A
  • Basically all bleeding disorders and often in mild situations, or heavy periods.
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114
Q

Objectives 2 - coagulation tests and their interpretation

A
  • Platelets are really small even on high power so you cannot tell what problem is
  • Patients platelets not working = specialised tests
  • VWF = not measured in most coagulation tests
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115
Q

What are the principles of clotting tests

A
  • Incubate plasma with reagents that are needed for coagulation - phospholipid, co factor. Trigger or activator. Calcium.
  • Then measure the time that is taken to form the fibrin clot.
  • Want to isolate the coagulation factors from the blood sample and administer triggering pathways, something like tissue factor
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116
Q

what is PT Prothrombin Time

A
  • This is sensitive to the extrinsic pathway, and to a lesser extent, the common pathway
  • It is TF driven.
  • PT time = one of the coagulation screening tests, tries to look at X path to see how long these reactions will take to occur, takes anything from 9-13 seconds, quite fast
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117
Q

What is APTT - activated partial thromboplastin time

A
  • Sensitive to intrinsic pathway, and to a lesser extent common pathway. Contact activated
  • Measures the intrinsic path and ability for blood to clot. Have to add something to activate 12, want to add a foreign substance (something like sand) which will rapidly cause the blood to clot.
    APTT is the slower way to make a clot = if it becomes a minute or longer = investigate what is missing in pathways.
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118
Q

What is TT - Thrombin time

A
  • Sensitive to defects in the conversion of fibrinogen to fibrin
  • Addition of thrombin = it will clot. Good to make sure that the end point is right
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119
Q

Overview of coagulation pathways

A
  • Ex = tissue factor added and making a clot

- Intrinsic = addition of clotting factors to make a clot

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120
Q

Give an overview of the total testing process

A
  1. Patient preparation and identification
  2. Specimen Collection
  3. Transportation and analysis
  4. Report
  5. Interpretation, clinical use of test result
  6. Proper order and test collection
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121
Q

Describe the process of blood sample collection for haemostasis testing

A
  • Accuracy of haemostasis lab tests depend on the quality of the specimen submitted, blood is anticoagulated with 3.2% (0.1009 M) sodium citrate
  • Most of the tubes contain 0.3mL anticoagulant, and need 2.7mLs of blood
  • Under filling the tube yields grossly inaccurate results :(
  • People are often difficult to bleed which is the issue.
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122
Q

Give examples of the pre analytical errors that can occur with haemostasis testing - Problems with blue top tube

A

Partial fill tubes, vaccuum leak and citrate evaporation

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123
Q

Give examples of the pre analytical errors that can occur with haemostasis testing - Problems with phlebotomy

A
  • Heparin contamination
  • Wrong labelling, slow fill, under fill, vigorous shaking
  • Different venepuncture
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124
Q

Give examples of the pre analytical errors that can occur with haemostasis testing - Biological effects

A
  • Hct > 55 or > 15 (too many RBC or cholesterol)

- Lipaemia, hyperbilirubinaemia, haemolysis

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125
Q

Give examples of the pre analytical errors that can occur with haemostasis testing - Laboratory errors

A
  • Delay in testing, prolonged incubation at 37 degrees celscius
  • Freeze/thaw deterioration
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126
Q

The components of the tube

A
  • Made up of 55% plasma, and 45% formed elements (cells)

- Plasma is made up of water, salt, plasma proteins, substances that are transported by the blood

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127
Q

What is the process of manual coagulation

A
  • Would tilt 3 times every 5 seconds + Once you have got the plasma then you can do manual APTT
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128
Q

Can also so automated coagulation

A

Uses computer systems, where the end point is much more easily measured

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129
Q

Can do mixing studies = factor deficiency

A
  • Clotting factor tests are abnormal and prolonged. Usually because there is a factor deficiency
  • Clotting factor NR 50-150 IU/dL
  • APTT normal (24-34s) if factor level within range
  • 50:50 mix 32s/28s
  • APTT of 95 - should be 30-40 seconds so this is taking too long. Can mix with control pattern. Lots of plasma in the lab which should give normal time - the normal time that we expect is APTT of 28
  • If normal, we can assume that clotting factors are also normal.
  • Mix test + control together, in theory you would be replacing all of the clotting factors = if all deficient in something and mix with normal then this should replace the deficiency
  • Might get 50% of all clotting factors = enough to make up the time and brings it back down to normal

If it DOES correct then this means that the test patient is deficient in something

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130
Q

Mixing studies: Inhibitors

A
  • The antibody is in excess, and inhibits added factor.
  • 50:50 mix, 75 seconds/30seconds
  • Situation where this will not correct = still too high. Starts off 2x normal volume, when mixed doesn’t come down because the patient has antibodies.
  • Still ab in the patient plasma, which interacts with the additional normal plasma that has been added, still get a normal APTT. Mixing studies do not work always.
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131
Q

describe Mixing studies?

A
  • The antibody is in excess, and inhibits added factor.
  • 50:50 mix, 75 secs/30secs
  • Situation where this will not correct = still too high. Starts off 2x normal volume, when mixed doesn’t come down because the patient has antibodies.
  • Still ab in the patient plasma, which interacts with the additional normal plasma that has been added, still get a normal APTT. Mixing studies do not work always.
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132
Q

describe what you would do during mixing studies?

A
  • Can mix patient plasma and normal plasma, in equal volumes (50:50 mix)
  • Repeat abnormal coagulation test
  • Test normalises, factor deficiencies
  • Test stays abnormal - inhibitor (usually antibody) - Does not correct back to normal = antibody usually responsible
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133
Q

Situation of Normal PT, abnormal APTT

Tests to see which of the factors is abnormal. [the test for inhibitor activity]

A
  • Specific inhibitors, 8,9,11

- Non specific (anti phospholipid Ab)

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134
Q

Situation of Normal PT, abnormal APTT

Tests to see which of the factors are abnormal + [the test for ifactor deficiency]

A
  • Isolated deficiency in instrinsic pathway - factors 8, 9, 11
  • Multiple factor deficiencies (rare)
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135
Q

Situation of Abnormal PT, Normal APTT : [Test for inhibitor activity]

A
  • Specific inhibitors, 7

- Non-specific (anti phospholipid)

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136
Q

Situation of Abnormal PT, Normal APTT : [Test for factor deficency]

A
  • Isolated deficiency of factor 7 (rare)
  • Multiple factor deficiencies (common)
    • Liver disease, vitamin K deficiency, warfarin, DIC
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137
Q

Situation of abnormal PT, abnormal APTT [Test for inhibitor activity]

A
  • Specific inhibitors, 5, 10, 2, 1 (rare)

- Non specific: anti phospholipid (common)

138
Q

Situation of Abnormal PT, Normal APTT : [Test for factor deficency]

A
  • Isolated deficiency of factor 5, 10 - prothrombin, fibrinogen
  • Multiple factor deficiencies (common)
    • Liver disease, vitamin K deficiency, warfarin, DIC
139
Q

Situation of normal PT and abnormal APTT - normal

A
  • Dysfibrinogenaemia
  • Abnormal fibrinolysis
    • e.g. anti plasmin deficiency
  • Elevated FDPs
140
Q

Situation of normal PT and abnormal APTT - abnormal

A
  • Von willebrands disease
  • Platelet disorder
  • FX111 deficiency

Non coagulation defect (e.g. vascular disorder)

141
Q

Laboratory evaluation - describe D Dimer testing

A
  • This is a measure of the D dimer. D dimer is a fibrin degradation product.
  • This is elevated in the situation of enhanced fibrinolysis, thrombosis, DIC
  • Not specific for thrombosis, also elevated as an acute phase reactant
  • A negative result is useful if clinical suspicion of VTE is low

D dimer = the breakdown products of fibrinolysis
Someone who clots a lot will have a lot of D dimer

D dimer test can be used as a negative diagnostic test for DVT

142
Q

Laboratory investigation of haemostasis test - FBC + smear

A

Platelet count
RBC and platelet morphology
Thrombocytopenia
TTP, DIC etc

143
Q

Laboratory investigation of haemostasis test - Coagulation

A 
Prothrombin time
Partial thromboplastin time 
Coagulation factor assays 
50:50 mix
Fibrinogen assay 
Thrombin time 
FDPs or D dimer 
Ex and intrinsic common pathways
Specific factor deficiencies 
Inhibitors, like antibodies 
Decreased fibrinogen
Qualitative and quantitative fibrinogen defects
fibrinolysis
144
Q

Laboratory investigation of haemostasis test - Platelet function

A

Von willebrand factor
Bleeding time
Platelet function analyser (PFA)
Vwd platelet disorders, in vivo test (non specific), qualitative platelet disorders

145
Q

describe the haemocytometer Neubauer Chamber

A
  • Old method of counting cells = put blood into this rectangle
  • Each of the squares contain 0.1ml of blood
  • This is an approximation and is older fashioned method.
  • Takes 5 minutes + to do single blood counts
146
Q

What would advia results look like

A
  • blood goes in, results come out
  • Drawing blood through fine capillary tube, applies electrical field across capillary and change electrical field which causes a characteristic change in current
  • MEASURING CHANGES IN CURRENT
  • Larger cells with more internal complexity will be on the sides - by applying certain standard settings the machines can separate the cells into different populations
  • If population of cells if abnormal then will flag this and look abnormal
  • Cells that do not fit criteria = machines will not get it right
  • Gives you directly measured parameters - reveals how much Hb is within them and dividing amount of Hb that are from each of the cells
  • Able to differentiate directly measured and derived variables
  • Directly measured
  • Derived variables = calculated from the directly observed numbers
  • Differential white cell count
  • Machine separates characteristics and determines whether they are normal or not.
  • The most common white blood cell is a neutrophil.
147
Q

What is the full haemoglobin blood count (FBC)

A

Normal male - 130 - 180g /L

Normal female - 120 - 160g /L

148
Q

White cell blood count - what is the FBC

A

Normal adult - 4.0 - 11.0 x 109 / L

- Slight variations in different labs (million per microlitre)

149
Q

what is the full platelet count?

A

Normal adult - 150 - 400 x 109 / L

Way more platelets in the blood, than white cells. Expect to see a lot more platelets

150
Q

Normal WBC differential?

A
  • The most common type are neutrophils, then lymphocytes, monocytes, eosinophils, and basophils respectively

These differences could be due to ethnic variations africans = fewer neutrophils

151
Q

Peripheral blood film

A
  • Take a drop of blood that is put at the head and take a slide and put in 30-40 degree angle so that the blood will spread along the edge of the slider, slide forward and spread the blood thin enough to look at individual cells
152
Q

What are the components of a Romanowsky stain

A
  • 2 stains are needed to separate the white cells well, staining with 2 different stains then you are staining different structures and blood cells.
    1. Azure B or methylene blue stain, basic dyes.
    2. Eosin Y, acidic dye
    • Buffer pH 6.8
  • Both are combined in the Romanowsky stain
153
Q

Morphology of normal neutrophils

A
  • Neutrophils recognised because they are segmented. Chain with rings around them, up to 5 is normal, and can easily recognise because they have segmented nucleus
154
Q

Lymphocytes characteristics + what are the 3 types? + what is their major role.

A
  • Major role of lymphocytes is in the adaptive Immune Response
  • Differentiation between self and non self
  • Viral attack - lymphocytes, produce antibodies to destroy that virus. Memory cells
  • 3 major types of lymphocytes are T cells, B cells, Natural killer NK cells
155
Q

characteristics of T cells

A
  • Cell mediated immunity
  • CD4+ T helper cells
  • CD8+ Cytotoxic T cells
  • Directly attack the infected cells and kill it
156
Q

characteristics of B cells

A
  • In humoral immunity, like antibody production
  • Make antibodies that bind to organisms and coat cells that are affected
  • When cell gets infected by the virus parts of the virus get expressed on the surface
157
Q

characteristics of NK cells

A
  • Innate immune system, attacks virally infected cells + tumour cells
158
Q

What is other name for NK cell

A

Large granular lymphocyte cell

159
Q

Characteristics of NK cells (large granular lymphocyte cells)

A
  • Blueness of cytoplasm comes from the antibodies, antibodies stay blue because they basophilic
  • Large granular lymphocytes, leukaemia = clonal expansion of these
160
Q

Characteristics of monocytes

Next most likely to see in the blood

A
  • Part of the innate immune system. Also phagosytosing cells, similar to neutrophils that are trying to engulf organisms
  • Monocytes try and do this too, do not have lots of visible granules
  • Usually only have 1 lobe, nucleus can look funny shaped. Recognise partly by shape and colour of nucleus and usually does not have any visible granules in sight, vacuoles present

Pale grey/blue granules - easily recognised

161
Q

What is seen in things like hives and allergic reactions like eczema and asthma

A

Degranulation of eosinophils

162
Q

what are the characteristics Basophils

A
  • Seeing too many means that you are worried person has a myeloproliferative disorder
  • Basophils are in the blood = eosinophils, have the power to go in and out of the blood stream
  • Blood is arguably the least important place for them to be - they go into the tissue and do their jobs, and then they die
  • Typical life span is 14 days of basophils
  • Red cells last for 120 days
  • Once made from the bone marrow = goes to the blood, then to the cell and then die. Same for the lymphocytes where you have a bank of memory cells - stay back as neurological memory and start multiplying again = do not get mumps /measles twice
163
Q

Describe the development of cells in the bone marrow

A
  • Pluripotent haemopoietic stem cells
  • THIS ALL HAPPENS IN THE BONE MARROW - need millions to keep up with the demand. Neutrophils only last for a few hours
  • Stem cells can be anything = they are asymmetrical
  • Production line that works via supply and demand, tightly regulated system - body signals the bone of what needs producing and will make it in response
  • Big demand for white cells = stem cells will go through a number of precursor stages through the bone marrow before getting to the finished article
  • Have 2 lines that are separating = lymphoids go on to produce the B lymphocyte, T lymphocyte and the rest of the cells
164
Q

Normal adult WBC count?

A

4.0- 11.0 x 109 / L

165
Q

What is leucocytosis

A

increase in white cells

166
Q

What is leucopenia

A

decrease in white cells

167
Q

Normal adult neutrophils count

A

Normal adult neutrophils

168
Q

What is neutropenia?

A

Decrease in neutrophils

Certain drugs, like ones that cause bone marrow failure can cause this.

169
Q

Terminology related to neutrophilias:

Toxic granulation

A
  • Toxic granulation

- Granules increasing the toxic granules within them

170
Q

Terminology related to neutrophilias:

Shift to the LEFT

A

Myeloid maturation
In the development of the white cells within the bone marrow, to arrive at the mature segmented neutrophil
In the bone marrow drill out and see all of these stages in the bone marrow the blasts are the most immature parts and they gradually get more granules.
Segmentation eventually = then neutrophil is typically released
This is called Left shift, in acute severe infection you might see some precursors
Left shift =usually points towards infection

171
Q

Terminology related to neutrophilias:

Shift to the RIGHT

A
  • Hypersegmented neutrophil

- Right shift = look at vitamin B12 + folic acid levels

172
Q

Terminology related to neutrophilias:

Dohle bodies

A
  • Innate issues and errors of neutrophil function
  • Dohle bodies = large bluish forms of granules
  • Large bluish longitudinal shapes, infections and inflammations. 3 things = the dohle body, toxic granulation and thirdly non fully segmented neutrophil
173
Q

Neutrophilia

A
  • Neutrophils become much more numerous
  • Maybe a neutrophil count of 20-30
  • Increased number of neurophils, they are left shifted and there is toxic granulation.
    Other causes of neutrophilia :
  • Bacterial infection, inflammation, vasculitis, myocardial infarction, carcinoma, steroid treatment, myeloproliferative disorders, treatment with myeloid growth factors
  • Neutrophils try to go to the site of the blood vessels - go to the side of the blood flow so that they can leave

Bone marrow

174
Q

How would you do an investigation of neutrophilia

A
  1. FBC, and differential white cell count.
  2. Blood film examination.
  3. Bacterial culture screen for infection
  4. Bone marrow examination and chromosome analysis for chronic myeloid leukaemia
  5. Philedelphia chromosome: translocation between chromosomes 9 + 22
  6. Molecular analysis for BCR - ABL oncogene
    • Fusion gene product is what drives hematopoiesis
    • Clone that comes from this abnormality starts drawing out
    • Chromosomal abnormalities w microscope but can also look for product of this fusion gene
175
Q

what is Neutropenia

A
  • Viral infection, drug induced like sulphonamindes
  • Radiotherapy and chemotherapy, part of pancytopenia in bone marrow failure (aplastic anaemia) or infiltration e.g. leukaemia - reduces the progenitors in the marrow, altogether
  • Racial = benign ethnic neutropenia

Marrow infiltrated with what should not be there interferes with the production of RBCs

176
Q

how would you do Investigation of eosinophilia

A
  • FBC + differential white cell count
  • Blood film examination
  • Stool examination for the ova and parasites
177
Q

Investigation of monocytosis

A
  • FBC and differential white cell count
  • Blood film examination - for abnormal white blood cells, for malarial parasites
  • Bone marrow examination - leukaemia
    TB cultures
178
Q

Lymphocytosis - cells that are clear cut - Normal physiological status

A
  • Lymphocytosis of childhood (1-6 years)

- Normal = 5.5 -8.5 x 109 / L

179
Q

Infectious mononucleosis (glandular fever)

A
  • Hererophile antibodies - Abs that react against antigen which is totally unrelated to the antigen which originally stimulated it.
  • Like human antibodies reacting against sheep/horse/bovine cells
180
Q

describe Clearview infectious mononucleosis

A
  • Take serum from a patient that you think has the infection, run on little bit of acetate cgel and then there are antibodies against antibodies whne you detect this
  • Form a line a precipitate

Test is fast = wide looking cells in the blood have mono nucleosis, in the 1st few days of the disease this might not show up.

181
Q

how would you investigate lymphocytosis + what do findings suggest

A
  • Mature lymphocytes, could mean chronic lymphocytic leukaemia or lymphoma
  • Immunophenotying to determine if the lymphocytes are B cells or T cells
    • B cells = demonstrate clonality by light chain restriction
    • T cells = demonstrate clonality by T cell receptor gene rearrangement studies
182
Q

What would you look for in investigation of white cell disorders

A
  • FBC and differential white cell count, blood film examination
  • These are the 2 factors that you must look at when you are investigating a white cell disorder
183
Q

What is anaemia?

A
  • Reduced Hb level, for the age + gender of the person
184
Q

What is haemolytic anaemia?

A

Anaemia. Due to shortened RBC survival

185
Q

Describe the normal RBC cycle?

A

RBCs= made in the bone marrow. BM needs:
Ø Iron to make Hb
Ø B12 and folate for the DNA synthesis
Ø Make portophyrins that make haem
Ø Need erythropoietin, drives haemotopoieses (which is driven by the kidneys)
Ø Make globin chains
- RBCs leave bone marrow. Leave nucleus behind and get matured anucleated cells circulating
- Survive 120 days and get old and senescent and then removed by the liver

186
Q

Mature RBC metabolic pathways

A
  • Glycolytic pathway
  • Hexose - monophosphate shunt
    • These are important for the survival of the red cells
    • Generates glucose metabolism
187
Q

Mature RBC membrane characteristics

A
  • Membrane =biconcave disk,
    • High surface area so able to deform and pass through small surfaces and can also pass through the spleen
  • Haemoglobin is contained inside.
188
Q

what occurs in Haemolysis (general)

A
  • There is shortened red cell survival (30-80days).
  • If you have all of the correct building blocks: this makes the bone marrow compensate with increased RBC production. There are therefore more young cells in the circulation - reticulocytosis +/- nucleated RBC.
  • If you have brisk compensation you will get nucleated RBCs because of the bone marrow compensation
189
Q

What happens in compensated haemolysis (+ what happens to Hb)

A
  • RBC production is able to compensate for the decreased RBC life span
  • = normal Hb.
  • Able to produce enough RBCs to maintain Hb.
  • If you can’t compensate = end up with anaemia.
190
Q

What is incompletely compensated haemolysis (+ what happens to Hb)

A
  • RBC production is not able to keep up with decreased RBC life span

So there is decreased Hb

191
Q

What are the Clinical findings in haemolytic anaemia

A
  • Jaundice, Pallor and fatigue, splenomegaly, dark urine
  • Unconj. Bilirubin making breakdown product
  • More conjugated = more bilirubin

Red cell removal usually happens at spleen = if the spleen is enlarged this could be an issue.

192
Q

What happens in a haemolytic crises

A
  • Haemolytic crises = increased anaemia and jaundice with infections and preciptants. This is a complication. Start to haemolyse more due to infections or drugs.
193
Q

What happens in aplastic crises

• Long term haemolytic anaemias

A
  • Anaemia, reticulocytopenia, with parovirus infection (common in children)

If bone marrow is already going on overdrive and you are dependent on it to maintain you Hb then this could easily slightly fall.

194
Q

what are the clinical findings of haemolytic anaemia

A
  • Gallstones with pigment, leg ulcers, folate deficiency (increased use.) from the breakdown of RBCs.
  • Severe haemolysis = folate deficient because our body easily depletes our folate stores if we have rapid erythropoesis
  • Free Hb acts as NO scavenger.
  • Can get leg ulcers. This can also occur with other haemolytic anaemias
195
Q

The lab findings of haemolytic anaemia: total

A 
INCREASE IN: 
- Reticulocyte count 
• Making more red cells to compensated
- Unconjugated bilirubin
- LDH (lactate dehydrogenase)
• Released from the red cells 
- Urobilinogen
• If there is intravascular haemolysis. Reabsorption in the tubules and then you will later see haemosiderin in the urin after about a week
- Urinary haemosiderin
- Blood film is abnormal.
- Low serum haptoglobin, which is the protein that binds free haemoglobin.
196
Q

CLINICAL features of haemolytic anaemia

A

Jaundice
Pallor
Sphenomegaly
Pigment gallstones (chronic)
Inherited anaemia = gallstones by teenage yrs.
Risk of aplastic crisis from parvovirus B19

197
Q

LAB features of haemolytic anaemia

A
  • Normal / low Hb, reticulocytosis (+/- NRBC), raised LDH, raised unconjugated bilirubin,
  • decreased haptoglobin,
  • decreased haptoglobin,
  • increased urobilinogen (+/- haemoglobinuria). - urine dip stick
    • Normal does not rule out anything
  • Abnormal blood film
198
Q

Classifying haemolytic anaemias

A
  • Can look at the site of the red cell destruction. Some happening inside the vessels
  • TTP = intravascular
  • Extravascular = red cell removal outside the vessels
  • Looking at where the origin of the red cell damage is
199
Q

describe Acquired haemolytic anaemias

A

Immune, drugs, mechanical, microangiopathic, infections, burns, paroxysmal nocturnal haemoglobinuria.

200
Q

describe RBC Membrane disorders

A
  • Normal red cell membrane structure
    • Lipid bilayer, integral proteins, membrane skeleton + various proteins within it that hold it all together
    • Important for allowing the red cell to deform and then regain its normal shape
    • Can get defects in the sets of protein
    • Vertical issues = spherocytic changes. SPECTRIN
    ○ Hereditary sperocytosis
    • Horizontal issues = hereditary ellipocytosis. Blood films that look like ellipocytes
  • Defects in vertical interaction - (hereditary spherocytosis)
  • Spectrin, Band 3, Protein 4.2, Ankyrin
  • Defects in horizontal interaction (hereditary elliptocytosis)
    Protein 4.1, Glycophorin C, (spectrin - HPP)
201
Q

Describe Hereditary spherocytosis

A
  • Usually known that one parent has it because it is autosomal dominant. Spleen loses membrane as the red cell goes through = end up with a spherical cell rather than biconccave disk
  • Common hereditaray haemolytic anaemia, inherited in autosomal dominant fashion (75%), defects in proteins are involved in vertical interactiosn between the membrane skeleton + the lipid bilayer.
  • Decreased membrane deformability. Bone marrow makes biconcave RBC. But as the membrane is lost, the RBC becomes spherical.
202
Q

describe the appearance of Spherocytes

A
  • Lost central pallor and there are rounder
  • This is what you would get as you lose the membrane
  • Go from being a biconcave disk to a sphere
  • Normal Hb = abnormal blood film and increased reticulocyte count –> severe haemolysis that makes you transfusion dependent

Clinically can look like the following below: like the other haemolytic anaemias

203
Q

Clinical features Hereditary spherocytosis?

A
  • Asymptomatic to severe haemolysis, neonatal jaundice
  • Jaundice, splenomegaly, pigment gallstones
  • Reduction in eosin-5-maleimid (EMA) binding - binds to band 3 in the membrane. This is reduced in most people with spherocytosis
  • Positive family history - one may already have spherocytosis
  • Negative direct antibody test
    • Do not have antibodies binding to the red cell membrane, not an immune mediated process.
204
Q

Management of Hereditary spherocytosis?

A
  • Monitoring
    • Warn of risk of aplastic crises and gallstones
  • Folic acid (supplementary)
  • Transfusion, splenectomy
  • Spleen = main site of removal. Tranfusion dependent = look at taking the spleen out. Enough to make them not transfusion dependent
  • There are some spherocytic cells where haemolysis is much less
205
Q

describe Hereditary ellitocytosis

A
  • Slightly less common
  • Elliptoid cells
  • Mild haemolysis = not even anaemic often and its an incidental pick up from a blood film
  • If they have 2 mutations
    Slightly more severe haemolysis
206
Q

ENZYMOPATHIES:

RBC metabolic pathways

A
  • Glycolysis - energy - ATP.
  • Na/K pump, with 3Na+ OUT and 2K+ IN
  • ATP becomes ADP + Pi.
  • HMS = reducing power, NADPH /GSH
  • There are lots of metabolic pathways in the RBCs that do functions for red cell survival.
  • There are pathways that generate ATP and glutathione
  • The 2 most common mutations =
    ○ G6PD mutation
    § Hexose monophosphate shunt abnormality.
    § Hb is susceptible to oxidation by free radicals
    § Clumps together and aggregates and forms a heinz body
    § These both reduce red cell deformability.
    § X linked = common when seen with malaria. More severe in medeterranian
    § Lyeinasation = females can also be affected as well as males
    § Can be asymptomatic as well as having acute haemolytic crises.
    § Anaemia = usually driven by oxidative stress which can be caused by any bacterial or infections.
207
Q

What is the Rapoport Luebering shunt

A

When there is 2,3 Bi Phosphoglycerate (2,3 BPG) = that modulates the o2 binding to haemoglobin.

208
Q

Describe Glucose 6 phosphate deficiency - What is the role of the HMP shunt

A
  • Makes reduced glutathione, and protects the cell from oxidative stress
209
Q

Describe Glucose 6 phosphate deficiency - What are the effects of oxidative stress

A
  • Hb oxidation by oxidant radicals

This leads to denatured Hb aggregates + forms Heinz bodies which clump to the sides

210
Q

How are heinz bodies formed

A
  • When there is oxidation of Hb, by oxidant radicals

Which leads to denatured Hb aggregates. This will form Heinz bodies , which bind to the membrane. Oxidised membrane proteins = reduced RBC deformability

211
Q

What happens when there is G6PD deficiency

A
  • This is a hereditary, X linked disorder which is common in African, Asian, Mediterranean & Middle Eastern Populations
  • Mild in African (type A) and more severe in Mediterraneans (Type B)
  • Clinical features range from asymptomatic to acute episodes, to chronic haemolysis.
  • Get blister cells where the Hb is blistered away from the Hb
  • Reduced G6PD on enzyme assay - have more of all of the enzyme. High reticulocyte count = means that you can get false normal enzyme activity because there are more younger cells.
212
Q

Morphology of oxidative haemolysis

A
  • Bite cells = where macrophages have taken “bites” out of the red cells. They are also called helmet cells.
  • Pyruvate kinase = generates ATP which is essential for powering membrane cation pumps which is important for membrane deformability
  • Depending of the degree of deficiency, can be transfusion dependent anaemia or other type.
  • See compacted cells with spikes around them which are called Sputnick cells.
213
Q

What happens in a pyruvate kinase deficiency

A
  • Needed to make ATP. Essential for membrane cation pumps (deformability). Autosomal recessive. Chronic anaemia.
    ○ Mild to transfusion dependent
    Improves with splenectomy
214
Q

describe Haemoglobinopathies

A
  • Hb made from haem and globin chains
  • This is issue with the GLOBIN CHAINS
  • Normal Hb
215
Q

descrobe Normal haemoglobin

A
  • Adult - HbA which is 2x alpha chains from chromosome 16 and 2x beta from chromosome 11
  • Uterine life = make early Hb called portland and gower. Alpha chains are needed from early on in fetal life. Main fetal Hb = 2 alpha and 2 gamma chains
  • From the 3rd trimester they go quickly

HbA = percentage goes up from first year of life until there is adult Hb.

216
Q

What can go wrong: Quantitative - thalassaemias

A

• Production of increased / decreased amount of a globin chain - structurally normal
• Do not make enough alpha chains or beta chains
• What you produce is normal but there is just not enough
If there is XS they all bind together - but they will damage the cells

217
Q

What can go wrong: Qualitative - variant haemoglobins

A

• Production of a structurally abnormal globin chain

218
Q

descrobe Thalassaemias

A
  • Imbalanced alpha and beta chain production, alpha and beta chain production
  • There are excess unpaired globin chains, which are unstable
    • Precipitate and damaged RBC + their precursors
    • Ineffective erythropoiesis in bone marrow
    Haemolytic anaemia
219
Q

How would you diagnose for the thalassaemia trait

A
  • Asymptomatic. Microcytic hypochromic anaemia. Low Hb, MCV, MCH
  • Increased RBC. Often confused with a FE deficiency. HbA2 increased in Beta thalassaemias trait (daignostic)
  • A - thal trait is often by exclusion
  • Globin chain synthesis, rarely done now

DNA studies

220
Q

Beta thalassaemia major - characteristics

A
  • The transfusion is dependent in the 1st year of life - if there is NOT a transfusion then the following will happen:

Failure to thrive, progressive hepatosplenomegaly, bone marrow expansion + skeletal abnormalities, death in 1st 5 years of life from anaemia

221
Q

What are the side effects of transfusion to overcome beta thalassaemia’s major

A
  • Iron overload.
    • Endocrinopathies
    • Heart failure
    • Liver cirrhosis
222
Q

What are the clinically significant sickling syndromes:

A

• HbSS, HbSC,
• HbS- D punjab
• HbS- O Arab
• HbS- B thalassaemia
Common inherited disorder. Shape of cells = sickle shaped.
Presence of at least HbS mutation, which is a point mutation. In combination with another S mutation or another mutation
Commonest = SS and SC. All result in sickle cell disease
Polymerisation = gives them long sickled shape. Can get leucocytosis
Patients with sickle = higher white cell counts and get more problems. Haemolysis which acts as a NO scavenger that can lead to things like stroke, pulmonary occlusion

Vascular occlusion = leads to pain and is when the RBCs get stuck in the vessels.

223
Q

Pathophysiology of SCD

A

Abnormal vessel formation, progressive visual loss, pulmonary hypertension

224
Q

what are the Acute complications of SCD

A 
LIST 
	Ø  ischaemic stroke & haemorrhagic 
	Ø Cholecystisis 
	Ø Hepatic sequestration 
	Ø Dactylitis 
	Ø Bone pain + infarcts 
	Ø Osteomyelitis 
	Ø Retinal detachment 
	Ø Vitreous haemorrhage 
	Ø Chest syndrome 
	Ø Splenic seqeuestration 
	Ø Haematuria: papillary necrosis 
	Ø Priapism 
	Ø Aplastic crises 
	Ø Leg ulcers
225
Q

what are the chronic complications of SCD

A 
LIST 
	Ø Silent infarcts 
	Ø Pulmonary hypertension 
	Ø Chronic lung disease, bronchiestasis 
	Ø Erectile dysfuntion 
	Ø Azoospermia 
	Ø Chronic pain syndromes 
	Ø Delayed puberty 
	Ø Moya moya

Retinopathy, visual loss

226
Q

Clinical features of SCD?

A
  • Painful crises, aplastic crises
  • If child is born in UK diagnosis is made at birth to make sure they are started on penicillin by 3 months of age to reduce infant morality
  • People present with acute pain
  • Infections
  • Acute sickling
    • Chest syndrome
    • Splenic sequestration
    • Stroke
  • Chronic sickling effects (chronic organ damage)
    • Renal failure
    • Avascular necrosis bone
227
Q

Laboratory features of SCD?

A 
- Anaemia 
	• Hb often 65-85
- Reticulocytosis 
- Increased NRBC
- Raised bilirubin

Low creatinine

228
Q

How would you confirm the diagnosis of sickle cell anaemia: solubility

A
  • Confirm that there is Sickle Hb
  • Which will precipitate out and cause a cloudy solution.
  • Solubility test, expose the blood to reducing agent, HbS precipitated
  • Positive in trait + disease
229
Q

How would you confirm the diagnosis of sickle cell anaemia - electrophoresis

A
  • Electrophoresis

To differentiate between SCD and sickle trait

230
Q

HPLC drawbacks?

A
  • Not definitive. Need sickle solubility test.

- Can get other Hb variants that would elute out at the same time as sickle Hb.

231
Q

Acquired haemolytic anaemias:

Immune haemolysis [autoimmune]

A 
- Idiopathic - for no good reason
	• Usually warm, IgG, IgM
- Drug meditated 
- Cancer associated 
	• LPDs (proliferative disoder) + autoimmune syndromes like lupus
- See in diff circumstances

Make antibodies against self

232
Q

Acquired haemolytic anaemias:
Immune haemolysis - Alloimmune
- Either in the neonatal period or in the transfusion reagent

A
  • Transplacental transfer
    • Haemolytic disease of the newborn: D, c, L
    • ABO incompatability
  • Transfusion related
    • Acute haemolytic transfusion reaction, ABO
  • Delayed haemolytic transfusion reaction
    • Rh groups, duffy
233
Q

describe Non immune acquired haemolysis

A
  • Paroxysmal noctural haemoglobin
  • Fragmentation haemolysis
    • Mechanical, microangiopathic haemolysis
    ○ Platelet consumption + red cell consumption
    • Disseminated intravascular coagulation
    • Thrombotic thrombocytopenic purpura
  • Other: severe burns, some infections like malaria.
234
Q

features of haemolysis?

A
  • Reticulocytosis, unconjugated hyperbilirubinaemia
  • Raised LDH
  • If you have not already got antibodies then they will give you anti D during pregnancy to bind with any D positive cells that will come through from the baby
  • Most of ABO = IgM but you have some IgG and ABO.
235
Q

How can someone get haemolytic anaemia

A
  • Can be inherited or acquired.
  • Membrane /enzyme/haemoglobin
  • Extrinsic: immune vs non immune
  • Clinical features with morphology + specialised tests can help to determine cause.
236
Q

Blood group antigens + blood group antibodies: what are antigens

A
  • Antigens are part of the surface of cells.

- All blood cells have antigens. [+ therefore specific surfaces]

237
Q

What are antibodies?

A
  • Found on the surface of cells. They are protein molecules (immunoglobulins, Ig), which are usually of the Ig classes IgG and IgM.

Found in the plasma, and produced by the immune system when there is foreign antigen.

238
Q

When do reactions to blood usually occur?

A
  • When the antibody that is in the plasma, reacts with an antigen that is on the cells.
239
Q

Blood group antigens

A
  • There are 26 blood groups that we know of. ABO + Rh are the clinically most important.
  • Antigens that are in transfused blood can make patient produce an antibody, only if the patient themselves do not have this antigen.
  • Freq. of antibody production is low - but increases, the more transfusions that are given.
240
Q

How many blood groups exist? + which are the most important.

A
  1. ABO + Rh are the most important groups.
241
Q

Stimulation of antibody production: methods

A

Blood transfusion • Blood carrying antigens foreign to the patient
Pregnancy • Fetal antigen that enters the maternal circulation during pregnancy / at birth
Environmental Factors • Naturally acquired. e.g. Anti A and Anti - B

242
Q

Examples of antibody - antigen reactions In vivo antibody - antigen reactions examples

A
  • Leads to the direct destruction of the cell.
    • Directly: when the cell breaks up in the blood stream (intravascular)
    • Indirectly: when liver + spleen remove cells that are coated in antibodies (extravascular)
243
Q

Examples of antibody - antigen reactions In vitro antibody - antigen reactions

A

Reactions are normally seen as agglutination tests

244
Q

What is agglutination

A
  • Clumping together. Of red cells into visible agglutinates by antigen - antibody reactions. Results from antibody cross linking with the antigens.
245
Q

What can agglutination identify

A
  1. Presence of a red cells antigen (blood grouping)

2. Presence of an antibody in the plasma (antibody screening + identification.)

246
Q

What is the clinical significance of the ABO grouping system?

A
  • A + B antigens are really common. (55% in the UK). Anti-A, Anti-B, or Anti-A,B antibodies are really common, in 97% in UK.
  • There is a high risk of A/B cells being transfused into someone with the antibody in a random situation. ABO antibodies can activate complement, which causes intravascular haemolysis.
  • Almost all serious/fatal transfusion reactions b/c of technical/clerical error are due to ABO incompatibility
    ABO = Blood cells either have a antigen, or b antigen, or either. A antigen on their cell surface, or B antigen on their cell surface. If they have neither then they are group O.
    They happen converesely. Someone who is A will have naturally occurring anti B antibodies
    Someone who is group O will have anti a and anti b antibodies.
  • If you selected a unit randomly in the blood bank there is therefore a high chance that something will go wrong.
247
Q

What does activation of complement cause?

A

Intravascular haemolysis.

248
Q

What are the genetics of ABO?

last year there was a question about this.

A
  • A + B phenotype is inherited codominantly.
249
Q

What are the ABO groups

A

Different blood groups
Ø Antigens poke out of RBC surface.
Ø Antibodies = made via B cells, T cells help + plasma cells. Before this can happen, antigens are made via the immune system.
Ø The immune system recognises something as non self.
Ø When there is exposure to a non self antigen (e.g. cold virus) = body makes Abs, to neutralise the virus.
Ø Abs made when there is recognition of non self things, and can be passed through the placenta.
Ø There are “A” & “B” like antigens on the gut
Ø See B antigens as non self = Abs against it are produced.
Ø B antigen is on the surface of group B.

250
Q

Blood groupings: HOW YOU WOULD TEST: Test red cells with:

• Anti A , B, D

A
  • Agglutination? show that a certain antigen is on the red cells.
  • No agglutination? will show the antigen is absent
251
Q

Blood groupings: HOW YOU WOULD TEST: Test patient plasma w/

A cells , B cells

A
  • Agglutination? Shows that a particular antibody is in the plasma / serum
  • No agglutination? Shows that the antibody is absent
252
Q

agglutination reactions

A
  • There are cards with wells.
    Ø Gel = impregnated with anti A and anti B.
    Ø Put patients RBCs on top, and then spin.
    Ø If there is an antibody-antigen reaction there is agglutination.
  • When there is agglutination in gel cards = it will be thicker and therefore can’t pass through the cards.
253
Q

FORWARD GROUP

agglutination reactions

A

• Looking at the antigens on the patients red cells

  • Put the red cells in, there is ANTI X antibody.
  • This interaction = agglutination.
  • Agglutinate cannot pass through during centrifugation
  • Therefore if there is agglutination, does not move downwards. It will sit on the top.
254
Q

REVERSEGROUP

agglutination reactions

A

• Looking at the antibodies in the patients plasma

  • B Cells agglutination. Therefore there must be anti B present in the B cells.
  • If someone is blood group A B = have A antigens and B antigens so do not expect them to have any antibodies.
255
Q

ABO compatibility

A

O = used to be known as the universal donor because they do not have A antigens or B antigens so there will not be agglutination when there is antibody-antigen reactions –> agglutination –> haemolysis.

256
Q

Rh grouping system - describe

A

There are 50+ antigens
- The most important antigen is called D. People with D antigen are RhD positive. (85% of UK).

People who do not make D antigen, are RhD negative (15%)

257
Q

What are the other main 4 Rh antigens that are known?

A

What are the other main 4 Rh antigens that are known?

  • C, c, E, e
258
Q

Rh (D) typing

A
  • Most important after ABO. Has to be tested in duplicate (or tested each time + compared to a historical result). Patient / donor classified as RhD positive, or RhD negative.
259
Q

What is the clinical significant of Rh

A

Transfusion

  • D antigen = very immunogenic and Anti D is easily stimulated. Prevention!
  • All Rh antibodies are capable of causing severe transfusion reaction - antibody detection
    Pregnancy
  • Rh antibodies are usually IgG. Can cause haemolytic disease of the newborn.
  • Anti-D is still most common cause of severe HDN.
260
Q

Describe the characteristics of Haemolytic Disease of the Newborn. (HDN) (What actually happens)

A
  1. Rh+ father.
    1. Rh- mum, carrying her 1st Rh+ fetus, there are Rh antigens from the developing fetus that can enter the mothers blood during delivery.
    2. In response to the fetuses Rh antigens, the mother makes anti RH antibodies.
    3. If woman gets pregnant with another Rh+ fetus, her anti-Rh antibodies will cross over the placenta + damage the fetal red blood cells.
      - At delivery some of the fetal cells will escape into the mothers circulation
261
Q

HDN - laboratory testing

A
  • Blood group + antibody screen @ antenatal booking. Identify pregnancies @ risk of HDN.
  • There could be RhD negative women, who may need anti D prophylaxis.

Blood group + antibody screen @ 28 weeks.

262
Q

What is RAADP

A
  • Injection. Of Anti D
    Ø Binds to + removes any fetal RhD positive RBCs in circulation.
  • 1500iu of anti D is given @ 28 weeks + a smaller dose
  • Usually 500 iu after delivery if baby RhD+
  • Can also give 2X smaller (500 iu) doses @ 28 + 34 weeks rather than 1 larger dose.
  • Anti D is also given, after anything that could cause a feto-maternal haemorrhage (bleed between the mum and the fetus) - like abdo trauma, intrauterine death, spontaneous or therapeutic abortion.
263
Q

Antibody screening - why?

A
  • Screen for clinically significant antibodies, that can cause haemolytic transfusion reaction.
  • if detected, antigen negative blood can be given = avoids immune reaction.
264
Q

Antibody screen: what happens if we detect an antibody

A
  • If an antibody is detected then we have to
    1. Identify the antibody
    2. 2. Assess its clinical significance.
    3. For transfusion + in pregnancy.
    There is an antibody in the patient plasma therefore there is agglutination
265
Q

How to identify an antibody

A

You would compare pattern of reactions with each reagent cell of ID panel - with the pattern of antigens on the reagent cells. Matching pattern will identify the antibody.

266
Q

Describe the ID panel profile

A
  • 10 cells, indirect antiglobulin test (IAT), anti D, panels get automated and then BMS will interpret.
267
Q

describe Zeta potential?

A

Ø IgM antibodies can span the gap that is between 2x red blood cells.
Ø IgG antibodies cannot span this cap, because they are too small to be able to overcome the ZETA potential (positive charge)
○ LISS = Low Ionic Strength Saline = negatively charged. Will neutralise + charge
- = IgG can now span the gap.
- Agglutination detected if Ab can connect RBCs.
- Have to get rid of the + charge ionic cloud = using LISS to neutralise ionic cloud.

268
Q

Why does LISS allow IgG to span the gap between 2 RBCs

A
  • Usually IgG antibodies are too small to span the gap, as they cannot overcome ZETA (positive) potential charge. LISS, which is low ionic strength saline is negatively charged & neutralises this positive ZETA potential.
269
Q

What is the indirect anti globulin test (IAT) used for

A
  • Used to detect IgG antibodies. LISS counteracts ZETA potential. Results in agglutination = they are able to stick together.
  • Used for: 1. Screening for antibodies, 2. Identifying antibodies 3. Cross matching donor blood with recipient plasma, where there are known Abs/ previous antibody history.
270
Q

What are the 3 uses of the indirect anti globulin test (IAT)

A
  1. Screening for antibodies,
  2. Identifying antibodies
  3. Cross matching donor blood with recipient plasma, where there are known antibodies or a previous history of antibodies.
271
Q

Describe the process of cross matching. - immediate spin cross match

A
  • Antibody screen, is negative
  • Checking donor red cells against patient plasma
    • ABO check, incubate for 2 to 5 minutes, room temp, spin + read#
  • ISX is basically checking the ABO group - therefore IgM antibodies, therefore no problem with ZETA potential - therefore there is no need to IAT.
272
Q

Describe the process of cross matching. Full indirect Antiglobulin Test (IAT) cross match

A
  • Antibody screen, positive or patient has known antibody history
  • Select antigen negative donor red cells, and incubate with patient serum for 15 minutes @ 37 degrees celsius.
273
Q

Describe the process of donor blood testing

A
  • Blood establishment - MHRA manufacturer of blood and products
  • Collection procedure arm cleansing / diversion pouch
  • Comprehensive testing of all products: viral
    • HIV 1 + 2, Hep B, Hep C, Syphilis, HTLV
  • Platelets, bacteria.

We do not test variant CDG = economic argument.

274
Q

Red cells characteristics

A
  • []RBCs. Packed cells in suspension of SAGM. These RBCs have o2 carrying capacity
  • Symptomatic anaemia.
  • If there is significant bleeding anticipated, can activate the major haemorrhage protocol.
275
Q

describe Fresh frozen plasma

A
  • FFP contains all clotting factors - given for coagulopathy with associated bleeding. Needs clotting screens to monitor. Only has 24hr life after thawing.
276
Q

Platelet characteristics

A
  • []RBCs. Packed cells in suspension of SAGM. These RBCs have o2 carrying capacity
  • Symptomatic anaemia.

If there is significant bleeding anticipated, can activate the major haemorrhage protocol.

277
Q

Cryoprecipitate components

A
  • Contains factor 8, VWF and fibrinogen

- 2 units are usually given @ one time, monitor fibrinogen levels by clotting screens

278
Q

How are blood glucose levels maintained from several sources?
(where we get glucose from)

A
  • Dietary carbohydrates
  • Glycogenolysis - breakdown of glycogen to glucose

Gluconeogenesis -making of glucose from not glucose sources

279
Q

What is the livers role in glucose metabolism

A
  • After meals = store glucose as glycogen
    Ø If there is XS glucose in the plasma, is stored as glycogen in the liver
    Ø When fasting the liver breaks glycogen down –> glucose available for the body
    Ø (Can also use amino acids, glycerol etc. maintains certain level of glucose in the plasma)
  • During fasting - this will make glucose available through glycogenolysis + gluconeogenesis
280
Q

Why should glucose levels be regulated

A
  • Brain + erythrocytes need a continuous supply and avoid deficiency - cannot make glucose on their own.
  • High glucose + metabolites cause pathological tissues :
    • micro/macro vascular diseases, including (diabetic) neuropathy - avoid excess + retinopathy
281
Q

What are the characteristics of insulin + where is it synthesised

A
  • There is a C chain in between which is removed and then a disulfide bond is formed. This produces insulin as well as the C peptide in circulation.
  • Insulin is the main regulator of glucose
  • Peptide hormone, 51 amino acids
  • Made in the B cells of the pancreas, as pro-insulin, which have amino terminal B chain and carboxyl terminal A chain.
  • In the endoplasmic reticulum there are peptidases - cleave to form C peptide on its own + insulin
    • Cleaved, to insulin and C peptide
  • Secretion is stimulated by a rise in blood glucose levels
282
Q

Describe the metabolic effects of insulin? in Increased: amino acid uptake, glycogen synthesis, fatty acid synthesis

A
  • Fall in ketogenesis
  • Gluconeogenesis
  • Glycogenolysis
283
Q

Describe the metabolic effects of insulin? in Increased: glucose uptake

A
  • In general tissues
284
Q

Describe the metabolic effects of insulin? in Increased: lipogenesis

A
  • Fall in lipolysis
285
Q

Describe the metabolic effects of insulin? In ncreased: amino acid uptake, glycogen synthesis

A

Fall in protein breakdown - reduce the uptake of proteases in muscle tissues therefore reduces the breakdown of proteins

286
Q

What are the 4 glucose counter regulatory hormones? + their actions

A
  • Glucagon, adrenaline, growth hormone, cortisol

Counteract the actions of insulin - storage of glucose in the form of glycogen. In fasting state, then the glycogen is broken down by glucagon

287
Q

Characteristics of GLUCAGON - (gcrh)

A
  • Secreted by the a cells of the pancreas. In response to hypoglycaemia.
  • Stimulates glycogenolysis + gluconeogenesis
288
Q

Characteristics of ADRENALINE - (gcrh)

A
  • Increased glycogenolysis + lipolysis
289
Q

Characteristics of GROWTH HORMONE - (gcrh)

A
  • Increased glycogenolysis + lipolysis
290
Q

Describe diabetes mellitus

A
  • Metabolic disorder
    • Chronic hyperglycaemia
    • Glycosuria
    • Associated abnormalities of lipid + protein metabolism. Should also include polydipsia (more glucose in circulation and peeing and drinking a lot) - abnormalities in metabolism of lipids and proteins
  • There is hyperglycaemia because of increased hepatic glucose production + fall in cellular glucose uptake
  • Blood glucose = BEYOND > 10mmol/L = exceeds renal threshold (There is excess in the kidney and it can only take a certain amount)- glycosuria
  • If there is lots of glucose in renal tubules, will produce osmotic effect - taking water from body = thirst + will make you drink more.
  • Long term complication = micro/macrovascular diseases.
291
Q

How would you diagnose Diabetes Mellitus: IN presence of symptoms like polyuria, polydipsia, weight loss - Random plasma glucose

A

> 11.1 mmol/L (200mg/dl)

- Check blood for presence of glucose at any given time 
- If you have symptoms and you are above the above levels then you have DM
292
Q

How would you diagnose Diabetes Mellitus: IN presence of symptoms like polyuria, polydipsia, weight loss - Fasting plasma glucose

A

> 7.0 mmol/L (120 mg/dl) Fasting = defined as no caloric intake for at least 8hrs
- Equal or more than 7millimol = have DM.
Or
2h plasma glucose > 11.1mmol/L (200mg/dl); 2hrs after 75g oral glucose tolerance test (OGTT)

293
Q

How would you diagnose Diabetes Mellitus: IN presence of symptoms like polyuria, polydipsia, weight loss - Oral Glucose Tolerance Test

A

> 11.1mmol/l

294
Q

How would you diagnose Diabetes Mellitus: WITHOUT presence of symptoms

A
  • w/o Weight loss, polyuria, polydipsia

Test the blood samples, on 2 separate days

295
Q

describe Impaired Glucose Tolerance (IGT)

Pre diabetic state

A
  • Fasting plasma glucose (6.1-6.9 mmol/L)

- OTTG value of

296
Q

Impaired Fasting Glycaemia (IFG)

A
  • Fasting plasma glucose
297
Q

The Oral Glucose Tolerance Test: who should OGTT be carried out on

A
  • In patients with Impaired Fasting Glycaemia
  • Unexplained glycosuria
  • In clinical features of diabetes with normal plasma glucose values
  • For the diagnosis of acromegaly, which is increased GH
    • When you give them 5-7g glucose in normal person, GH falls.
    • Will stay high in those who have acromegaly.
298
Q

How would you to the OGTT (Oral Glucose Tolerance Test

A
  • 75g glucose, Test after 2 hours. Blood samples collected at 0 and 120 minutes after glucose.
  • Subjects tested fasting, after 3 days of normal diet that contains at least 250g carbohydrate
299
Q

What are the characteristics of the classifications of diabetes

A

Type 1, Type 2, Gestational, Secondary

300
Q

What are the characteristics of Type 1 DM

A
  • Insulin secretion deficiency. Because of autoimmune destruction of the B cells in the pancreas, by T cells
  • Autoimmune destruction of B cells. Environment + genetic factors interact
  • There is a strong link with the HLA genes within the MHC region on chromosome 6
  • Predominantly in children + young adults [NICK JONAS] & Sudden onset = days/weeks
  • Appearance of symptoms might come after pre-diabetic period of several months
301
Q

What happens in Type 1 DM

A

Autoimmune B cell destruction. HLA genes in the MHC region on chromosome 6 involved. + (environment & genetic involvement)

302
Q

Describe, in detail the pathogenesis of Type 1 DM

A
  • HLA class 2 cell surface. Normal will present as FOREIGN + SELF ANTIGENS to the T lymphocytes
  • This will initiate an autoimmune response
  • Circulating autoantibodies to various cell antigens, for instance:
    • Glutamic acid decarboxylase
    • Islet auto-antigen
    • Tyrosine-phosphatase-like molecule
303
Q

action of Glutamic acid decarboxylase in pathogenesis of Type 1 DM

A

○ Found in the pancreas - if there are auto antibodies to this there is desctruction to the beta cells / pancreas

304
Q

action of islet auto antigen in pathogenesis of Type 1 DM

A

○ Auto immunity = can be T cell mediated, or antibody mediated.
is the most commonly detect antibody associated with Type 1 DM

305
Q

What are the circulating autoantibodies that are involved in the pathogenesis of Type 1 DM

A
  • Glutamic acid decarboxylase
  • Islet auto-antigen
  • Tyrosine-phosphatase-like molecule
    • (most commonly detected antibody associated with T1 DM = islet cell antibody)
  • More than 90% of newly diagnosed people with T1 DM have 1+ of these antibodies. (Glutamic acid autoantibody, islet autoantibody)

Destruction of the B cells will therefore cause hyperglycaemia - as they cannot make insulin

306
Q

What happens when there is destruction of the pancreatic B cells (Type 1 DM)

A
  • Hyperglycaemia. Because of absolute deficiency of both: INSULIN + AMYLIN
  • Amylin = glucose regulatory peptide hormone
307
Q

What is Amylin + how does it lower blood glucose?

A
  • Glucoregulatory peptide hormone. That is co secreted with insulin
  • Lowers blood glucose, by:
    1. Slowing gastric emptying
      Ø Do not feel hungry that much, do not eat a lot, so glucose level does not get too high
    2. Suppressing glucagon output from the pancreatic cells
308
Q

What are the metabolic complications of Type 1 DM

A

Ø Become volume depleted - taking water from the body due to osmotic effect in the kidneys = makes you dehydrated
Ketoacidosis = More ketone bodies are produced = diabetic coma
Ø Hyperglycaemia = if too much glucose goes through the kidney and it gets overwhelmed = cannot reabsorb all of the glucose from the renal tubule
Ø High level of glucose in the kidney = osmotic effect and dras water in the tubule, which increases amount of urine that you pass

309
Q

What are the characteristics of Type 2 DM

A
  • HyperOsmolar, Non Ketotic state (HONK)
  • Ketone bodies are NOT produced. They are only produced because you do not have insulin
  • Absence of insulin there is increased lipid breakdown
  • Development of severe hyperglycaemia - extreme dehydration and the pathophysiology is the same as T1 DM. There are no ketone bodies.
310
Q

What are the metabolic complications of Type 2 DM

A
  • HyperOsmolar, Non Ketotic state (HONK)
    • Development of severe hyperglycaemia, extreme dehydration, increased plasma osmolality
    • No ketosis, minimal acidosis
    • Impaired consciousness: death if untreated.
311
Q

What are the aims of monitoring Type 2 DM

A
  • Avoid hypoglycaemia.

Glycated Hb (HbA1c) - aim at

312
Q

How can you self-monitor Type 2 DM

A
  1. Capillary blood measurement
  2. Urine analysis: glucose in the urine, gives indications of blood glucose
  3. Concentration above renal threshold
313
Q

describe Stepwise treatment of Type 2 diabetes

A
  1. Diet + exercise
  2. Oral monotherapy (metformin)
  3. Oral combination (sulphonylureas, Gliptins, GLP 1 analouges)
    Ø If all of these drugs do not work then you would give insulin injections

Insulin + oral agents

314
Q

What are the long term complications of Type 1 and 2 diabetes

A
  • Microvascular diseases
    • Retinopathy, nephropathy, neuropathy
    • Increased levels of insulin can lead to glycation of the proteins = damage to the small blood vessels cause damage to the kidneys
  • Macrovascular disease
    • Related to atherosclerosis heart attack + stroke
    • Changes in compliance which can lead to these long term complications
315
Q

How do you reduce the cardiovascular risk in DM

A
  • Get normal weight + waist circumference, eat low fat and salt, exercise, stop smoking
  • Maintain HbA1c
316
Q

What is hypoglycaemia + what does it result in

A
  • Plasma glucose than is less than (
317
Q

What are the causes of hypoglycaemia - insulinoma

A
  • When the body / pancreas makes XS insulin, lowers the blood glucose levels
318
Q

What are the causes of hypoglycaemia - drugs

A
  • Sulphonylureas, insulin, alcohol abuse
  • Can all also cause hypoglycaemia - alcohol can affect liver, which is important in gluconeogeneis
  • Liver is not able to make the glucose from non-glucose substances (like lactate & amino acids)
319
Q

What are the causes of hypoglycaemia - Inherited metabolic disorders

A
  • Glycogen storage diseases
  • Galactosaemia
  • Hereditary fructose intolerance
320
Q

What are the causes of hypoglycaemia - Endocrine diseases

A
  • Like cortisol disorder

+ severe liver disease, non-pancreatic tumours, post gastrectomy

321
Q

What are the adaptations to falling glucose levels in fasting

A
  • Insulin levels fall. This limits glucose entry into non cerebral tissues
    Ø Hepatic gluconeogenesis will be stimulated
    Ø Glycogen breakdown will be activated
    Ø Fatty acid oxidation will be activated
    Ø There will be released of counter regulatory hormone, raising glucose
    Glucagon
322
Q

What are the symptoms of hypoglycaemia (list the 2)

A

Neurogenic [autonomic] 2. Neuroglycopaenia

323
Q

What are the NEUROGENIC (autonomic) symptoms of hypoglycaemia and what is it triggered by?

A
  • Triggered by falling glucose levels. Activated by ANS + mediated by:
    • Sympathoadrenal release, of catecholamines + Ach
  • Shakiness, anxiety, nervousness, palpitations, sweating, dry mouth, pallor + pupil dilation
324
Q

What is insulinoma + what are the symptoms of it?

A
  • Tumour, in the insulin secreting B cells of the pancreas. Keep secreting insulin and insulin conc will go up to that low level of glucose.
  • Insulin is usually made as proinsulin, more proinsulin = more c peptide available in the blood as well as more insulin.
  • Symptoms = fasting hypoglycaemia, patients might present with behavioural changes, inappropriate high insulin concentration at a time when plasma glucose is low, and LESS Than 2.5 mmol/L
  • C peptide should be measured
325
Q

What are the NEUROGLYCOPAENIA symptoms of hypoglycaemia and what is it triggered by?

A
  • Because of neuronal glucose deprivation

Sign + symptoms include confusion, difficulty speaking, ataxia, paresthesisa, seizures, coma + death

326
Q

Inherited metabolic diseases : list

A
  1. Glycogen storage disease type 1 (Von Gierkes dieease)
  2. Galactosaemia
  3. Hereditary fructose intolerance
327
Q

Describe the inherited metabolic disease, GLYCOGEN STORAGE DISEASE TYPE 1 (Von Gierkes)

A
  • Deficiency of G6Phosphatase
  • There is impaired glucose release from glycogen
  • Glucose synthesis is blocked in this disease = blockage of the synthesis of glyocgen and also gluconeogenesis by the liver
  • Made in early infancy
  • Buildup of lactate which can also lead to acidosis.
    • Uncooked cornstarch, or slow releasing glycogen solution.
328
Q

Describe the inherited metabolic disease, GALACTOSAEMIA

A
  • There is a deficiency of Galactose 1 Phosphate, Uridyl Transferase:
  • Which means that there is liver damage
329
Q

Describe the inherited metabolic disease, HEREDITARY FRUCTOSE INTOLERANCE

A
  • Deficiency of fructose 1 phosphatase adolase B

Accumulation of fructose 1 phosphate in the liver

330
Q

Glycogen storage disease Type 1a

A
  • Autosomal rec. disorder.
  • Glucose synthesis from glycogen, or gluconeogenesis is blocked
  • Presents in:
    • Early infancy
    • Severe fasting hypoglycaemia
    • As the only source of glucose is dietary carbohydrate
331
Q

What does accumulation of glycogen cause

A
  • Hepatomegaly
  • Inability to produce glucose from lactate, causes acidosis
  • TX = uncooked cornstarch: which is a slow releasing glucose prep.
332
Q

Describe hepatic glycogen metabolism

A
  • If G6P is deficent then there is a limit to how much glucose that you can make

Build up of glycogen = hepato megaly

333
Q

What is galactosaemia? - another metabolic disorder

A
  • Defects in 3 enzymes can cause galacatosaemia.
  • Most common defect = galactose 1 phosphate uridyl transferase deficiency
  • Autosomal recessive disorder. Deficiency of Galactose 1 Phosphate Uridyl Transferase (G-1-PUT) impairs the conversion of :
    • Galactose 1 phosphate, to G1P
  • GaI1 phosphate accumulates in the liver = toxicity to the liver
  • Hypoglycaemia + vomiting / diarrhoea after starting milk feeds when these infant are fed / have diarrhoea.
  • Galactose excreted in the urine
  • Tx = exclude galactose from the diet
334
Q

What is the most common enzyme defect involved in galactosaemia?

A
  • Galactose 1 phosphate uridyl transferase deficiency

• Impairs the conversion of Galactose 1 phosphate to G1P.

335
Q

What is hereditary fructose intolerance

A

any deficiency of F1P will - Autosomal reccessive disorder that affects children
- Deficiency of fructose 1 phosphate aldolase B when ingested fructose accumulates.
Ø This inhibits glycogenolysis @ phosphorylase step
- Severe hypoglycaemia + vomiting after eating fruit and sweetened food
- Fructose is detected in urine, where it is detected.
- So avoid ingestion of fructose and sucrose
- Benign fructose intolerance - because of absence of fructokinase

336
Q

Describe the metabolism of fructose

A

any deficiency of F1P will inhibit this whole pathway = kidney cannot reabsorb and fructose will be found in the urine

337
Q

Adaptations to falling glucose levels in fasting

A
  • Fall in insulin levels = limits glucosek entry into non cerebral tissues
  • Hepatic gluconeogenesis is stimulated
  • Glycogen breakdown is activated
  • Fatty acid oxidation is activated
  • There is release of counter regulatory hormone raising glucose
    • Glucagon (
338
Q

neurogenic symptoms of hypoglycaemia

A
  • Triggered by falling glucose levels
  • Activated by ANS
    Ø Mediated by sympathoadrenal release of catecholamines and Ach

Shakes, anxiety, nervousness, palpitations, sweating, dry mouth, pallor, pupil dilation

339
Q

NEUROGLYCOPAENIA symptoms of hypoglycaemia

A
  • Because of neuronal glucose deprivation

Confusion, hard to speak, ataxia, paresethesia, seizures, coma, death

340
Q

What are the characteristics of Gestational Diabetes

A
  • Occurs for the 1st time in pregnancy

- Glucose levels get higher during pregnancy but then falls again once the mother has given birth.

341
Q

What are the characteristics of Secondary Diabetes

A
  • Chronic pancreatitis
  • Pancreatic surgery

Secretion of antagonists

Semester 4 (10 decks)

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