3.1 Haemopoeisis, Spleen And Bone Marrow Flashcards
1
Q
What is the difference between monocytes and macrophages?
A
Monocytes circulate in the blood, macrophages are located within tissues
2
Q
What is the reticuloendothelial system?
A
Part of the immune system. It is formed from monocytes in blood and a network of tissues which contain phagocytic cells.
3
Q
What are the main functions of the spleen?
A
Extramedullary haemopoesis
Blood pooling
Immunological function
Sequestration and phagocytosis
4
Q
What is haemopoeisis?
A
the process by which blood cells are formed
5
Q
Where does haemopoeisis occur after birth?
A
In bone marrow.
In children long bones such as femur
In adult main sites are pelvis, sternum, ribs and vertebrae.
6
Q
What is the common precursor cell to all blood cell lineages?
A
Haemopoietic stem cells.
7
Q
What are the five major lineage pathways arise from the haemopoietic stem cells in bone marrow?
A
Thrombopoiesis Granulopoiesis Monocytopoiesis Erythropoiesis Lymphopoiesis
8
Q
What is thrombopoiesis?
A
formation of platelets (also called thrombocytes) involved in clot formation.
9
Q
Describe the formation of platelets(thrombocytes) from a haemopoietic stem cell?
A
Multipotent haemopoietic stem cell (haemocytoblast) differentiates into the common myeloid progenitor.
Thrombopoietin stimulates the common myeloid progenitor o form a megakaryocyte. Small fragments that bud off of the megakaryocyte called platelets.
10
Q
Describe the structure of platelets
A
Platelets have no nuclei and are essentially membrane bound fragments of cytoplasm that bud off from megakaryocytes
11
Q
Describe the structure of a megakaryocyte
A
very large mononucleate cells with several copies of each pair of chromosomes (i.e. polyploid cells).
12
Q
What are the 3 different types of granulocyte?
A
Basophils
Neutrophils
Eosinophils
13
Q
How are granulocytes formed?
A
Granulocytes arise from myeloblast cells which in turn arise from common myeloid progenitor cells. Common myeloid progenitor cells are a differentiation of the haemopoietic stem cell.
14
Q
What is the function of neutrophils?
A
Mature neutrophils migrate to areas of inflammation by chemotaxis where they phagocytose invading microbes and destroy them by releasing reactive oxygen species.
15
Q
What is the function of eosinophils?
A
Possess the ability to phagocytose and are associated with the immune responses to multicellular parasites such as helminths
16
Q
What is inappropriate eosinophil activation associated with?
A
Asthma and allergy
17
Q
What is the function of basophils?
A
Immune cell that play a role in parasitic infections and allergy.
18
Q
What are monocytes?
A
Monocytes are phagocytic immune cells that circulate in the blood for ~1-3 days before moving into tissues where they differentiate into macrophages or dendritic cells.
19
Q
What is the function of macrophages?
A
To protect tissues from foreign substances by phagocytosis, antigen presentation and cytokine production.
20
Q
How are monocytes formed?
A
Similar lineage to granulocytes. Haemopoietic stem cell Common myeloid progenitor Myeloblast Monocyte
21
Q
How do B lymphocytes mature?
A
- The development of B lymphocytes commences in the fetal liver and bone marrow and during their development immunoglobulin genes rearrange to allow production of antibodies with a wide array of specificities.
- Final maturation of B-cells requires exposure to antigen in the lymph nodes and results in mature B- lymphocytes with the capacity to recognize non-self antigens and produce large quantities of specific antibodies.
22
Q
Describe the development of T lymphocytes
A
- T- lymphocytes progenitors on the other hand arise from fetal liver and migrate to the thymus early in gestation.
- Immature T cells undergo rearrangement of the T cell receptor genes resulting in the ability to produce a vast array of different T cell receptors which can recognise a wide range of antigens presented to them by antigen-presenting cells.
23
Q
What are antigen presenting cells?
A
dendritic cells
macrophages
Langerhans cells
B cells
24
Q
Describe how lymphocytes are formed
A
Multipotent haemopoietic stem cell
Common lymphoid progenitor
Small lymphocyte
B lymphocyte / T lymphocyte
25
What is erythropoiesis?
Erythropoiesis is the process by which red blood cells (erythrocytes) are produced in the bone marrow
26
Why is erythropoiesis a continual process?
since red blood cells have a finite lifespan of around 120 days in the bloodstream and lack the ability to divide
27
What molecules stimulate erthropoiesis?
1. Expression of the transcription factors GATA1, FOG1 and PU.1 commits progenitor cells in the marrow to the erythroid lineage.
2. Further expansion of the erythroid precursors is largely driven by the hormone erythropoietin
28
Where is erythropoietin released?
From the kidneys
29
What factors regulate the production of erythropoietin in the kidneys?
Oxygen saturation of blood - Erythropoietin production by the kidneys increases in response to a decrease in the oxygen level in the bloodstream (hypoxia) thereby stimulating more red blood cell production
30
What is the function of erythropoietin?
main function is to inhibit apoptosis (programmed cell death) of CFU-E (colony-forming units of the erythroid cell line) progenitor cells. Activation of the erythropoietin receptor on these cells allows them to develop, proliferate and differentiate
31
Describe the cell lineage of an erythrocyte
```
Haemopoietic stem cell
Common myeloid progenitor
Erythroblast
Reticulocyte
Erythrocyte
```
32
What is an erythroblast?
An erythrocyte progenitor cell. Are nucleated and contain organelles.
33
What is an reticulocyte?
Immature erythrocytes. Formed after erythroblasts extrude their nucleus and most of their organelles. Reticulocytes are then released into the circulation. Once in the bloodstream reticulocytes extrude their remnants of organelles such as mitochondria and ribosomes and take ~1 to 2 days to mature into red blood cells.
34
Why is a reticulocyte count of a blood sample useful?
provides a good diagnostic estimate of the amount erythropoiesis occurring in a patient’s bone marrow.
35
Why are erythrocytes prone to oxidative damage?
Since mature red blood cells lack nuclei, they are unable to replace damaged proteins by re-synthesis making them particularly susceptible to oxidative damage in diseases such as glucose-6-phosphate dehydrogenase deficiency.
36
Why does pyruvate kinase deficiency result in haemolytic anaemia?
Pyruvate kinase catalysed the last step in glycolysis. This enzyme catalyses the final step in glycolysis, transferring the phosphate from phosphoenolpyruvate to ADP to form ATP. This is the second ATP producing “pay-back” step of the process. Since red blood cells lack mitochondria, pyruvate kinase deficiency inhibits their only metabolic pathway which can supply ATP for cellular processes. The sodium potassium ATPase pump activity is inhibited from insufficient ATP to provide energy and the red cells lose potassium to plasma. Water moves down its concentration gradient out of cells causing them to shrink resulting in cellular death and haemolytic anaemia.
37
What is haemolytic anaemia?
Haemolytic anaemia is a disorder in which red blood cells are destroyed faster than they can be made. The destruction of red blood cells is called haemolysis.
38
Describe the structure of erythrocytes
They are anucleate biconcave discs ~ 8 µm in diameter with a flattened depressed centre which gives them a dumbbell-shaped cross section.
39
Describe the structure of the erythrocyte membrane
The erythrocyte cell membrane is a lipid bilayer that contains proteins such as spectrin, Ankyrin, Band 3 and protein 4.2.
Band 3 is an integral protein, ankyrin and protein 4.2 are both peripheral proteins that attach the Spectrin cytoskeleton to the membrane via band 3.
40
What disease occurs as a result of gene mutations in the membrane associated proteins?
hereditary spherocytosis which causes the red cells to lose their biconcave shape.
41
What is the composition of adult Haemoglobin A?
Two alpha- and two beta- polypeptide subunits in a α2b2 tetramer.
42
What is the haem group?
The haem group is responsible for binding a molecule of O2 to each subunit of haemoglobin. It is comprised of a porphyrin ring with ferrous iron (Fe2+) at the centre responsible for binding oxygen.
43
When does haemoglobin undergo conformational change?
When shifting between the oxygen unbound and oxygen bound states. conformational change which enhances the binding affinity of subsequent oxygen molecules.
44
Why is the oxygen binding curve a sigmoidal shape?
Due to conformational change enhancing the affinity of subsequent oxygen molecules. This enables haemoglobin to load oxygen in in the lungs where there is a high oxygen tension and release it in the tissues where there is a low oxygen tension
45
What decreases haemoglobin affinity for oxygen?
decreased by 2,3- Bisphosphoglycerate (BPG) (an intermediate of glycolysis), a fall in pH or an increase in CO2 (the Bohr effect), all producing a rightward shift in the oxygen dissociation curve
46
What produces an increase in affinity of haemoglobin for oxygen?
a fall in CO2, a fall in BPG or an increase in pH would result in a leftward shift in the dissociation curve due to increased affinity of haemoglobin for oxygen.
47
Why does fetal haemoglobin have a higher than usual affinity for oxygen?
fetal haemoglobin has a higher binding affinity for O2 than adult haemoglobin which allows transfer of O2 to fetal blood from the mother.
48
Where is the spleen located?
left upper quadrant of the abdomen
49
How does blood enter the spleen?
Through the splenic artery
50
What blood components pass through the white pulp of the spleen?
The white cells and plasma
51
What blood components pass through the red pulp of the spleen?
Erythrocytes
52
What is the role of the spleen?
A blood filter
The red pulp removes old red cells and metabolises the haemoglobin whilst the white pulp synthesises antibodies and removes antibody-coated bacteria and blood cells.
serves a blood pooling function from which platelets and red cells can be rapidly mobilised during bleeding.
53
What is splenomegaly?
Enlargement of the spleen
54
What causes splenomegaly?
1. Increased workload, for example in haemolytic anaemia.
2. Congestion due to portal hypertension (increases back pressure)
3. Leukaemias and lymphomas
4. Expansion due to accumulation of waste products of metabolism (e.g. in Gaucher’s disease)
5. Some infectious diseases are also characterised by splenomegaly, most notably malaria, schistosomiasis, HIV and glandular fever caused by Epstein Barr virus.
55
What is hyposplenism?
reduced splenic function
56
What is hyposplenism associated with?
increased risk of overwhelming sepsis
57
What are the underlying causes of hyposplenism?
1. diseases which destroy spleen tissue such as sickle- cell disease and coeliac disease
2. splenectomy which may be required due to splenic rupture from trauma or because of cancer.
58
What may be present on the blood film of a patient with hyposplenism?
Howell-Jolly bodies which are basophilic nuclear remnants (clusters of DNA) in circulating erythrocytes.
During erythropoiesis erythroblasts normally expel their nuclei but in some cases a small portion of DNA remains. Normally such cells would be removed by the spleen so the presence of Howell-Jolly bodies is a good indicator of reduced splenic function.
59
What is the reticuloendothelial system?
The reticuloendothelial system is a network of cells located throughout the body and is part of the larger immune system.
60
What is the role of the reticuloendothelial system?
remove dead or damaged cells and to identify and destroy foreign antigens in blood and tissues. Critical to innate and adaptive immunity.
61
What cells are part of the reticuloendothelial system?
```
Monocytes
Macrophages
Kupffer cells
Tissue histiocytes
Microoglia
Langerhans cell.
```
62
How is bilirubin formed in the spleen?
haemoglobin removed from senescent erythrocytes is recycled by the spleen with the globin portion being degraded to its constitutive amino acids and the haem portion metabolised to bilirubin.
63
How is bilirubin removed?
Bilirubin travels from the spleen to the liver. In the liver it is conjugated with glucuronic acid and secreted in bile
64
What is stercobilin?
Bilirubin that has been deconjugated from glucuronic acid and then metabolised to colourless urobilinogen which is subsequently oxidized to form stercobilin (responsible for the brown colour of faeces). This is done by bacteria in the intestines.
65
What gives urine a yellow colour?
urobilinogen (product of metabolised bilirubin) that is reabsorbed into blood and processed by the kidneys where it is oxidised to urobilin (gives urine its yellow colour).
66
What risk occurs to patients after having spleen removed?
increased risk of sepsis and patients are usually given various vaccinations to compensate for inadequate opsonisation of bacteria.
67
What does a trephine biopsy allow us to view?
The architecture of bone marrow
68
Where is a kupffer cell found?
In the liver
69
Apart from bone marrow, where else can haemopoeisis occur?
Extramedullary haemopoiesis can occur in the spleen.
pluripotential stem cells of the Spleen proliferate during haematological stress or if marrow fails (e.g. in myelofibrosis)
70
How can you palpate splenomegaly?
It is never normal for the spleen to be palpable below the costal margin (must be enlarged)
Start to palpate in Right Iliac Fossa (RIF) or may miss massive splenomegaly
Feel for spleen edge moving towards
your hand on inspiration
Feel for the splenic notch
Measure in cm from costal margin in mid-
clavicular line
71
What may cause hyposplenism?
Splenectomy
Sickle cell disease (multiple infarcts and fibrosis)
Gastrointestinal disease (coeliac and Crohn’s disease)
Autoimmune disorders (rheumatoid arthritis)
72
What are patients with hyposplenism at risk of?
risk of sepsis from encapsulated bacteria.
73
What is spectrin?
Erythrocyte membrane protein. Actin crosslinking and molecular scaffold protein that links the plasma membrane to the actin cytoskeleton.
74
What is ankyrin?
Erythrocyte membrane protein. Links integral membrane proteins to the underlying spectrin-actin cytoskeleton.
75
What is band 3?
Erythrocyte integral membrane protein. Facilitates chloride and bicarbonate exchange across membrane and also involved in physical linkage of membrane to cytoskeleton (binds with ankyrin and protein 4.2).
76
What is protein 4.2?
ATP-binding protein which may regulate the association of band 3 with ankyrin.
77
What causes patients skin to become yellow in jaundice?
Senescent red blood cells engulfed by macrophages and bilirubin is released into the blood. This unconjugated bilirubin travels to the liver bound to albumin. If the uncongugated bilirubin levels are high in blood, this results in jaundice.
78
What s usually the first responder phagocyte?
Neutrophils
79
What hormone controls neutrophil development?
```
G-CSF.
Increases production of neutrophils
Speeds up release of mature cells from BM
Enhances chemotaxis
Enhances phagocytosis and killing of
pathogens
```
80
What could cause neutrophilia?
Infection • Tissue damage • Smoking • Drugs (e.g. steroids) • Myeloproliferative diseases • Acute inflammation • Cancer • Cytokines (G-CSF) • Metabolic disorders • Endocrine disorders • Acute Haemorrhage
81
What are the consequences of neutropenia?
Severe life threatening bacterial
infection • Severe life threatening fungal
infection • Mucosal ulceration e.g. painful
mouth ulcers
