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Blood and Circulation > Haematology (4-7) > Flashcards

Haematology (4-7) Flashcards

1
Q

What is haematology?

A

The study of blood
→ in particular the medical speciality concerned with disorders of the blood
→ large single organ system - blood and tissues in which it is formed

Patient care involves:
→ routine blood counts
→ blood transfusion
→ specialised management of patient with leukaemia or haemophilia

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2
Q

How much blood do we have?

A

About 4.7-5L

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3
Q

What 2 things make up the blood?

A

Cells
→ leukocytes - white blood cells
→ erythrocytes - red blood cells
→ platelets - fragments of cells

Plasma
→ water (mostly), electrolytes, dissolved gases, urea, proteins, lipids, glucose and lots of other things in trace quantities
→ some which shouldn’t be there i.e. alcohol, cotinine - metabolite of nicotine

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4
Q

How does blood look when centrifuged?

A

55% plasma → sits on top
<1 % buffy coat → WBC and platelets, sits in between
45% RBC → sits at the bottom of test tube

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5
Q

What are the concentration of the major cells types found in blood?

A

Erythrocytes (RBC) → 4-6 x 10^12 per L (40-50% vol)
Leukocytes (WBC) → 4-11 x 10^9 per L
Thrombocytes (platelets) → 1-4 x 10^11 per L

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6
Q

What are the blood cell lineages?

A

Blood stem cell → myeloid stem cell / lymphoid stem cell

Myeloid stem cell → RBC / platelets / myeloblast

Myeloblast → WBC granulocytes (eosinophil / basophil / neutrophil)

Lymphoid stem cell → lymphoblast → B lymphocyte / T lymphocyte / NKC

→ WBCs come from both myeloid and lymphoid lineages - all nucleated

(draw for revision)

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7
Q

Whats the difference between myeloid and lymphoid?

A

Myeloid → from bone marrow

Lymphoid → from lymph (the clear fluid from the thoracic lymph duct) - and by extension lymphoid tissue

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8
Q

What adaptation of erythrocytes (RBCs) allows them to squeeze through small vessels?

A

Despite being 7-8um in diameter, RBC can squeeze through 3mm capillaries

→ spectrin and actin link many of the proteins (ankyrin molecules) found on the membrane producing an underlying mesh
→ mesh provides flexibility to fold and bounce back - so can move through capillaries

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9
Q

What is the difference between anaemia and polycythaemia?

A

Anaemia → too few erythrocytes
→ pallor, breathlessness, fatigue - due to lack of O2 transport to tissues

Polycythaemia → too many erthyrcytes
→ raised blood viscosity causes strain on heart

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10
Q

What is erthyropoitin?

A

A glycoprotein hormone that stimulates red blood cell production (hematopoiesis)
→ synthetic drug misused in sports i.e. cycling - more RBC can transfer O2 more quickly
→ polycythaemia causes blood to become thick and viscous (60-70% RBC) - heart can’t pump it - can lead to death

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11
Q

What are leukocytes?

A

White blood cells
→ produced in primary lymphoid tissues - bone marrow, thymus
→ function in secondary lymphoid tissues - spleen, lymph nodes etc

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12
Q

What are the differences between different leukocytes (WBC)?

A

Lymphocytes → same size as RBC, consists of mostly nucleus, little cytoplasm
Neutrophils → slightly bigger than RBC, lobed nucleus, granules
Monocyte → 3x size of RBC, 1 big c shaped nucleus
Eosinophil → pink, blue nucleus
Basophil → granulated - dark blue all over

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13
Q

Are cells always circular?

A

No
→ cells in suspension circular - view things under a microscope in liquid so always see them round
→ in tissues can be a different shape

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14
Q

What stains do we use in haematology?

A

Most commonly haematoxylin and eosin

Eosin → pink acidic dye, binds proteins, stains cytoplasm, granules pink
Haematoxylin → blue-purple basic dye which binds nucleic acids

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15
Q

What is histochemistry?

A

Ability of specific enzymes within cell types to convert colourless substrate into coloured product
→ give enzyme substrate - product is brown - can detect where the cells are
→ non specific esterase’s important in defining moncytic lineage related to leukemias - brown neutrophils not good

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16
Q

What is the modern approach to detecting blood cells?

A

Using antigen markers → immunological detection, antibodies binding to extracellular/intracellular antigens

Immunocytochemistry → antibodies linked to fluorescent (advantage - sorting and counting by machine)
Immunohistochemistry → antibodies linked to enzymes o convert substrates

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17
Q

Why can antigen markers be used for leukocyte recognition?

A

Antigen markers change as you move through leukocyte lineage
→ e.g. B cell - CD38+, CD138+
→ immunological detection allows you to define where lineage goes wrong

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18
Q

What are megakaryocytes?

A

Extend membrane processes into venules - give rise to platelets
→ should never be seen in circulation, only in the bone marrow

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19
Q

What is plasma?

A

Fluid component of blood
→ contains electrolytes
→ proteins ~70g/L albumin (main protein), globulins

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20
Q

What is the difference between serum and plasma?

A

Plamsa → fluid component of blood
Serum → fluid left after blood has clotted
→ contains all proteins of plasma i.e. antibodies, except those that are involved in clotting

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21
Q

Why is albumin an important plasma protein?

A

Its a carrier for many substances with low solubility in plasma
→ binds things weakly, important for transport
→ especially lipid hormones and fatty acids
→ binds Ca2+
→ helps maintain osmolarity of blood

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22
Q

What are some plasma proteins?

A

α-antitrypsin → inhibits trypsin (protease)
→ too much can cause liver problems due to amyloid plaques

Haptoglobulin → binds free haemoglobin, you have to recover iron - recycle into haemoglobin

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23
Q

What are the 2 pathways and 3 phases of the clotting cascade?

A

Phase 1 → 2 pathways: extrinsic - tissue trauma, intrinsic - blood trauma
→ factor x (mostly removed by blood flow) local feedback - activates prothrombinase

Phase 2 → common pathway
→ produces thrombin
→ vasoconstriction limits blood flow, platelets form sticky plug

Phase 3 → development of clot
→ produces insoluble fibrin
→ fibrin strands adhere to plug forming insoluble clot

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24
Q

What are the mechanisms to prevent excessive clotting?

A

Thrombomodulin → on endothelium binds thrombin - complex activates protein C which inactive factors Va and VIIa

Antithrombin → in plasma, inactivates thrombin

Protease ADAMTS13 → degrades vWF - von Willebrand factor - binds to platelets and collagen

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25
Q

How are blood clots removed?

A

Fibrinolytic mechanisms
→ depend on digestion of fibrin by the protease plasmin
→ present in plasma as an inactive precursor - plasminogen - activated by a rage of factors particularly tissue plasminogen activator tPA

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26
Q

What is haematopoiesis?

A

The formation of blood cellular components
→ highly organised differentiation process
→ ordered expression of different sets of genes
→ controlled by growth factors in the environment of the developing blood cell (the bone marrow in adults)
→ all blood cells are derived from haematopoietic stem cells

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27
Q

How many blood cells do we make daily?

A

5 x 10^11 blood cells daily

→ mature blood cells have short lifetimes so need to be constantly regenerated
→ accelerated when there is haematological stress e.g. infection - need more leukocytes, high altitude - need more RBC

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28
Q

When does haematopoiesis begin?

A

At a very early stage in embryonic development - about 3 weeks

At this time the embryo separates into 2 sets
→ one generating the embryo proper and all the tissues of the adult
→ one forming the yolk sac - mesoderm the site where blood cells and blood vessels are first formed

→ first genetic switch at ~8 weeks - liver starts to produce blood cells
→ as you start to make bones in a developing foetus you start to switch blood cell production to the bone marrow

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29
Q

What are haemangioblasts?

A

Mesoderm derived multipotent cells
→ differentiate to form (nucleated) red blood cells and endothelial cells - which generate a capillary system (plexus) within the yolk sac
→ at the same time the heart and aorta start to form - join up with the capillary plexus and the erythrocytes start to circulate

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30
Q

What is definitive erythropoiesis?

A

The later stage of embryogenetic haematopoiesis (before its ‘primitive erythropoiesis’ in the yolk sac)
→ occurs mainly in the liver and at birth switches to the bone marrow
→ produces entire range of blood cells you would find in an adult

31
Q

What are the range of cells found in the bone marrow highly specialised tissue?

A

Haematopoietic cells → form blood cells
Stromal cells → provide support functions for the haematopoietic cells, provide the specialised environment for haematopoiesis to occur
Osteoblasts → produce bone
Osteoclasts → break down bone

32
Q

What are the functions of bones?

A

Framework to hang muscles from
Where haematopoiesis occurs
Source of skeletal rigidity
Reservoir of Ca2+ and PO43-

33
Q

How does the bones that produce blood cells change throughout growth?

A

When you’re born all of your bones produce blood cells
→ as you age haematopoiesis occurs in less bones
→ in adults ribs, pelvis, skull produce blood cells

Can go wrong → you can lose regulation of where you produce blood cells

34
Q

How are bones structured?

A

Bone is a specialised form of connective tissue with a rigid ECM
→ rigid outer layer of dense compact cortical bone - consists of closely pacts circular osteons around central Haversian canal - high levels of vascularisation (important fro transporting newly made cells)
→ inner core is less dense ‘spongy’ bone - has holes - find bone marrow
→ ends called epiphysis, central section is called diaphysis
→ has medullary cavity - find bone marrow here

35
Q

After radiation why does a bone marrow transfusion help, but a blood transfusion doesn’t?

A

Bone marrow transfusion contained haematopoietic stem cells (HSC)
→ HSC are capable of self-renewal
→ however it was found that they eventually stop working - have a limit called ‘Hayflick limit’ - due to telomeres
→ HSC are not infinite

36
Q

What experiments were done to show the multi potency of haematopoietic stem cells?

A

BM cells were radiated - not enough to kill cells but enough to cause minor chromosome alterations → causes distinct marker so you can track lineage

They found the markers to be present in all cells → i.e. one cells drives entire lineage
Also found restrictive lineage → i.e. another stem cell drives lineage further along

Allowing for the collusion that theres a single haematopoietic stem cell
→ and stem cells with restricted lineage also (common lymphoid and myeloid progenitor cells)

37
Q

What marker does the haematopoietic stem cell express?

A

CD34
→ other cells also express CD34 (e.g. endothelial cells) so not unique to HSCs

38
Q

Where are haematopoietic stem cells found?

A

In 2 locations (niches) in the bone marrow
→ CD34 line the endosteum (boundary between solid bone & marrow) associated with osteoblasts
→ the perivascular region around vascular sinusoids

Hence ‘endosteal’ and ‘vascular’ niches
→ endosteal - contains long-term slowly dividing HSCs which maintain the vascular niche HSCs
→ vascular - HSCs more actively dividing and progenitor cells are produced

39
Q

How are haematpoietic stem cells regulated?

A

Within its niche - regulated by many proteins (signalling molecules)
→ mediated through; direct contact, soluble factors and intermediate cells
→ as soon as it divides - sister cell in different environment - receives different signals (also asymmetric division loads cell differently)

40
Q

How do we know the growth factors involved in differentiation?

A

In vitro culture of bone marrow cells
→ add growth factors and cytokines - monitor proliferation
→ better ethically

41
Q

What is erythropoiesis?

A

The process of making red blood cells
→ RBCs go through many phases
MEP → pro-erythroblast → erythroblast → reticulocyte → erythrocyte

Reticulocyte → non dividing, nucleus condensed and inactive, its process is to remove nucleus

42
Q

What is thrombopoiesis?

A

The generation of platelets
→ stimulated by thrombopoietin (TPO) and other non-specific growth factors
→ TPO produced constitutively mostly by liver
→ inflammation can double product by liver via cytokine IL-6
→ in thrombocytopenia (reduced platelets) BM stroll cells also produce TPO - platelets have TPO receptors so remove TPO from circulation

43
Q

How was the first successful human to human blood transfusion done?

A

In 1818 Dr. James Blundell, a British obstetrician performed the first successful blood transfusion of human blood for treatment of a postpartum haemorrhage
→ used patient’s husband as donor - extracted 4 ounces from his arm
→ he performed 10 transfusions - 5 were successful
→ also developed instruments for transfusion

44
Q

What did Karl Landsteiner get his Nobel price for?

A

In 1900, he showed that serum from some individuals could agglutinate or hemolyze the red blood cells of certain, but not all, other individuals - other individuals’ red blood cells were unaffected
→ worked out the different groups that would hemolyse each other and named these 3 type A, B, and C (today A, B and O)

45
Q

What is the genetics behind ABO blood groups?

A

The ABO blood group antigens are encoded by one genetic locus on chromosome 9

Has 3 alternative alleles for 1 gene:
→ 6 genotypes - AO, AA, BB, BO, AB, OO
→ 4 phenotypes - A, B, AB, O

Isoagglutinogen → encodes enzyme - allele affects activity
I^A → encodes N-acetylgalactosamine transferase
I^B → encodes a modified enzyme - galactose transferase activity
i^O → encodes non functional enzyme

I^A gives type A (dominant)
I^B gives type B (dominant)
I^A I^B gives type AB (co-dominance)
ii gives type O

46
Q

For the ABO blood groups how are the isoagglutinogen enzymes attached to red blood cells?

A

The enzymes ‘decorate’ carbohydrates attached to lipids on the outside of red blood cells
→ H-antigen attached to sphingosine to form a glycolipid - group O
→ group A has Gal-NAc attached to H-antigen
→ group B has galactose attached to H-antigen

47
Q

What are glycosphingolipids?

A

A subclass of glycolipids found in cell membranes

Cerebroside → ceramide with a single sugar residue
→ major lipids in ectoplasmic leaflet go myelin

Ganglioside → ceramide with a chain of sugar residues
→ many of the sugar residues are -ve charged
→ particularly abundant in nerve cells
→ also found on epithelial cells in GI tract

48
Q

How are ABO phenotypes determined?

A

By their expression on the red blood cell surface and the antibodies in the plasma

Group A → anti-B antibodies
Group B → anti-A antibodies
Group AB → no antibodies
Group O → anti-A and anti-B antibodies

49
Q

How do the different blood types react with different plasma antibodies (anti-A and anti-B)?

A

Group O → agglutinates with neither blood antibody
Group A → agglutinates with Anti-A
Group B → agglutinates with Anti-B
Group AB → agglutinates with both

→ blood transfusion will work if a person who is going to receive blood has a blood group that doesn’t have antibodies against the donor blood’s antigens

50
Q

What are agglutination assays?

A

Indicate the presence of antibodies against red blood cells
→ used in paternity testing

51
Q

Why can’t you always predict parentage from blood types?

A

Other genes are at play (e.g. A and AB parents having O child)
→ H is epistatic to I - expression of one gene modifies by the expression of another
→ individuals homozygous for h don’t have FUT1 a fructose transferase - the products of ABO cannot be formed - if you’re missing H then the ABO genotype doesn’t matter (Bombay phenotype)

52
Q

What is secretor status?

A

The present or absence of water soluble;e A and B (ABO blood group) antigens present in body secretions
→ people who secrete them into bodily fluids are known as secretors

Secretor → Se/Se or Se/se
Non-secretor → se/se
→ independent of blood type
→ encoded by gene FUT2

Non- secretors have increased risk of → oral disease, asthma, diabetes, alcoholism, infections, autoimmune diseases

53
Q

What blood group can receive blood from anyone?

A

AB+
→ has no ABO antibodies

(group O can donate to anyone)

54
Q

What is Rhesus blood group?

A

Rhesus (Rh) antigens are transmembrane proteins expressed on erythrocyte cell surface
→ encoded by RHD (D antigen) and RHCE (Cc and Ee antigens) genes
→ Rh + = both RHD and RHCE
→ Rh - = deleted RHD Ce
→ Rh antigens are highly immunogenic

85% European ethnict are Rh+ → Rh/Rh or Rh/rh

55
Q

What is Rh incompatibility in pregnancy?

A

Occurs if the mother is RhD- and 1st foetus is RhD+, their subsequent pregnancy can be affected
→ RBC from RhD+ foetus leak into the maternal circulation during birth
→ leads to production of anti-RhD IgG postpartum
→ in subsequent pregnancy IgG crosses placenta into foetal circulation - RhD+ foetus affected

56
Q

How is Rh incompatibility treated?

A

Mother receives anti-Rh antibody to prevent immunisation

Child receives blood transfusion with compatible blood

57
Q

What is ABO incompatibility?

A

When the mothers blood type is O and the baby’s is A or B
→ mothers immune system may react and make antibodies to the foetus red blood cells
→ anti-A and anti-B are IgMs and seem to be important in early pregnancy
→ can reduce or abolish the Rh incompatibility

58
Q

What are some major innovations in the 20th century around blood transfusions?

A

Compatibility testing
Anticoagulant solutions (lining glass with sodium citrate)
Preservative solutions (CPD-A1 - citrate, phosphate, dextrose, adenine)
Refrigeration
Blood banks
Venous access
Plastic blood bags
Component administration
Infectious disease testing (NAT - nucleic acid and ELISAs)
High-risk donor screening

59
Q

What is angiogenesis?

A

Formation of blood vessels as a consequence of trauma, embolism, cancer, diabetes
or regeneration of endometrium after menstruation
or just growth
→ endothelial cells grow in an ordered manner to generate new vessels (often have CD34 marker)
→ 2 types: sprouting or intussusceptive

60
Q

What is sprouting angiogenesis?

A

When a ‘sprout’ of solid endothelium grows out from a single capillary
→ lumen follows creating two capillaries

61
Q

What is intussusceptive angiogenesis?

A

When a single capillary forms a set of endothelial cells down the middle
→ ultimatelt forming 2 lumens

62
Q

What is the signal/stimulus for angiogenesis?

A

Usually ischaemia (lack of blood supply) which results in hypoxia (reduced O2) and lack of glucose
→ ischaemia occurs in growing tissues which out-strip the blood supply - or where the blood supply is compromised

Hypoxia stimulates the expression of genes for pro-angiogenic factors (when O2 is plentiful the genes are shut off)
→ hypoxia also stimulates EPO synthesis in kidney - proximal tubules have low O2 sensors - EPO release to bone marrow increases RBC

63
Q

What is HIF in angiogenesis?

A

Hypoxia-inducible factor (α and β)
→ activates transcription of genes for pro-angiogenic factors (main one VEGF)
→ HIF is destroyed by the presence of O2 - hypoxia induces angiogenesis

64
Q

What is VEGF in angiogenesis?

A

Vascular endothelial growth factor - main pro-angiogenic factor
→ binds to its receptor tyrosine kinase expressed only by endothelial cells and drives proliferation

In presence of O2 VHLp binds HIF-α and drags to proteasome → VEGF switched off

In hypoxia VHLp doesn’t bind HIF-α allowing it to dimerise with HIF-β → change in structure reveals nuclear localisation sequence → binds DNA just infant of VEGF promoter → VEGF transcription induced → growth of endothelial cells

65
Q

What is arteriogenesis?

A

Formation of arteries due to stress sensing
→ most common reason is that blood flow is obstructed in an artery - through a lump (e.g. embolism) blocking or narrowing (atherosclerosis)

New arteries develop from pre-existing anastomosing arterioles (small channel joining two larger channels)
→ due to the obstruction blood flow transfers from the main arteries to the anastomosing arteries - in response they enlarge

66
Q

What is the stimulus for arteriogenesis?

A

Mechanical (not ischaemia) acting on the endothelium lining of the arterioles
→ particularly through increased shear stress because of the increased blood flow in the anastomosing arteries (due to blockage in main arteries)
→ shear stress detected through stretching of plasma membrane - transmitted into cell interior via cytoskeleton
→ this indirectly activates a bundle of genes (40+) VEGF not involved - encoding growth factors and adhesion molecules - driving proliferation of endothelial cells and other cells in th tunica media

Exercise stimulates blood flow and so arteriogenesis

67
Q

What are cytopenias?

A

Blood disorders where there are fewer than normal pf specific cell types
→ e.g. lack of erythrocytes is an anaemia

68
Q

What are the principal types of anaemia?

A

Anaemia = a reduction in numbers or functionality of erythrocytes
→ leads to a reduction in the amount of O2 carried by the blood
→ characterised by paleness and fatigue
→ can be caused by bleeding, genetic disorders, leukaemia

Aplastic anaemia → too few cells
Iron deficiency anaemia → haemoglobin defect
Pericious anaemia → vit B12 deficiency

69
Q

What is thalassaemia?

A

A group of inherited conditions that affect haemoglobin - produce little to none
→ treatment: difficult server - blood transfusion or stem cell transplant
(anaemia not sorted with nutrition)

70
Q

How does anaemia arise from leukaemias?

A

Failure of erythropoiesis
→ the malignant cells displace the erythroid recourses from their bone marrow niches disrupting the lineage

71
Q

What are leukopenias?

A

Conditions where the white blood cell types may be reduced in number

e.g. neutropenia → neutrophils reduced - leads to susceptibility of infection
thrombocytopenia → reduction in platelets - leads to bleeding

72
Q

What is haematological neoplasia?

A

Neoplasia (uncontrolled growth) in blood and blood-forming tissue
→ leukaemia - bone marrow
→ lymphoma - lymph node
→ myeloma - bone marrow

73
Q

What occurs with leukaemia?

A

Abnormal cells arise in the bone marrow
→ stem cell niches in the BM become occupied with abnormal stem cells - normal cell production squeezed out
→ proliferating abnormal cells spill over into the circulation where they don’t divide - need the niche for proliferation

74
Q

What are lymphomas?

A

Abnormal cells arise in the lymph nodes and proliferate there - can spread to other lymph nodes destroying their functions (and other tissues including bone marrow)

Non-hodgkin lymphomas → B-cell neoplasia (precursor or mature), T-cell and NK-cell neoplasms (precursor or mature)
and Hodgkin lymphomas → two nuclei - loss of apoptosis, leads to inflammatory response

Blood and Circulation (5 decks)

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