Week 30- overview of bone marrow Flashcards
1
Q
What are the most common single gene disorders?
A
- Thalassaemias
2. Haemoglobin variants
2
Q
What are thalassaemias?
A
An imbalance of alpha and beta globin genes
3
Q
How do haemoglobin variants come about?
A
A point mutation in an alpha or beta globin gene
4
Q
How many haem molecules per rbc?
A
250mil
5
Q
Where is the alpha globin cluster located and what subunits are produced there?
A
Chromosome 11
Alpha and zeta subunits
6
Q
Where is the beta globin cluster located and what subunits are produced there?
A
Chromosome 16
Beta, gamma, delta and epsilon
7
Q
What are the major control points in gene expression?
A
Major control points:
- Modification of DNA
- Transcription
- RNA processing/transport
- Translation
- Post-translational modification
8
Q
What is an example of a genome level control for globin gene activity?
A
Activity inversely related to methylation of promoter region
9
Q
How does the alpha globin mRNA remain stable?
A
Alpha complex interactions within its 3’UTR protects its polyA tail and prevents degradation
10
Q
What is an example of a variant which affects alpha globin complex stability?
A
Part of the 3’UTR is translated:
Ribosome remains attached
Prevents alpha complex binding — shortening of polyA tail —leading to mRNA degradation
11
Q
What is the cause of the clinical symptoms of thalassemias?
A
Normally characterised by a decrease in production of the affected globin protein.
12
Q
What is the normal inheritance pattern of thalassemias?
A
Autosomal recessive
13
Q
What are the different haemoglobin stages in development?
A
- Embryonic haemoglobin
- Foetal haemoglobin
- Adult haemoglobin
14
Q
What can be said about the distribution for thalassemia variant distribution?
A
They can have geographic or ethnic clustering.
15
Q
What is alpha thalassemia?
A
A disease characterised by on or more deletions of alpha-globin alleles
16
Q
What is the normal make up of adult haemoglobin?
A
2 alpha and 2 beta globins (HbA)
17
Q
What is the normal make up of foetal haemoglobin?
A
2 alpha 2 gamma (HbF)
18
Q
How many alpha-globin alleles can someone have?
A
There is 4
19
Q
What is the 4 types of alpha thalassemias?
A
Between 1-4 deletions of the alpha-globin alleles:
1 deletion = silent carrier
2 deletions = alpha thalassemia trait
3 deletions = Haemoglobin H (HbH) disease
4 deletions = Hydrops fetalis
20
Q
What is the effects of a 1 deletion alpha thalassemia?
A
No effect —> silent carrier
Only very minimal decrease in alpha globin production
21
Q
What is the effect of a 2 deletion alpha thalassemia?
A
- Decreased aloha globin production-Normal beta globin production
- Reduced HbA formation (adult haemoglobin)
- No significant excess of Beta globin
- Occasional finding of HbH (excess Beta globin unstable binds to form this)
22
Q
What is the effect of a 3 deletion thalassemia?
A
- Larger decrease in alpha globin production - normal beta globin production
- Reduced alpha globin production reduces HbA formation and hence leaves lots of free beta globin.
- Beta globin unstable binds together to form unstable HbH (B4)
- HbH inclusion bodies obvious via microscopy
23
Q
What is the effect of a 4 deletion thalassemia?
A
- No alpha globin production
- Fetes relies on foetal haemoglobin to take maternal O2 (HbF)
- No alpha production but there is normal gamma globin production
- Gamma globin forms (Gamma 4) —> G4 has an extremely high oxygen affinity that it does not allow for O2 release at tissues
- Foetal death results from hypoxia and heart failure.
24
Q
What are some forms of Beta thalassemias?
A
- Beta0 —> absence of beta chain production
2. Beta+ —> reduction of beta chain production
25
How does Beta0 thalassemias normally arise?
```
Deletion mut
Initiation codon mut
Nonsense mut
Frameshift mut
Splicing mut
```
26
How do Beta+ thalassemias normally arise?
```
Promoter area
Polyadenylation signal’
5’ or 3’ UTR
Splicing abnormalities
May be severe mild or silent
```
27
What causes sickle cell anaemia?
Change in beta globin amino acid sequence
| Normally glutamic acid —> changed to valine
28
What is the effect of sickle cell anaemia?
Haemoglobin molecules crystallise when O2 concentrations are low —> causing RBC to sickle in shape and get stuck in small vessels
29
What is the distribution of sickle cell and malaria diseases?
Africa and some of asia
30
What is a benefit of having sickle cell disease?
Sickle Hb confers tolerance to plasmodium infections
31
What is the inheritance pattern of sickle cell?
Autosomal recessive
32
What is the most common genetic disorder in Australia?
Haemochromatosis (autosomal recessive pattern)
33
What is haemochromatosis?
A disorder of iron overload
| Affected people absorb too much iron from their diet
34
What is the formation of blood cells known as?
Haemopoiesis
35
What is the difference between haematopoiesis and haemopoiesis?
```
Haemato = process in which blood cells are produced
Haemo = formation of new cellular components of the blood in myeloid and lymphoid tissue
```
36
In adults where is all blood cells produced?
Red bone marrow
37
Where is red bone marrow located?
restricted to the bones of the axial skeleton-vertebrae, ribs, sternum, skull, sacrum, pelvis and proximal femora
38
What is the composition of bone marrow in the regions of red bone marrow?
50% fat —> 50% blood cells + precursors.
39
Can other bones in the body contribute to blood cell production (Haemopoiesis)?
Yes --> Fatty marrow in other bones can be used in times of increased demands of blood cells in some diseases
40
What is the origin of all blood cells?
A single pluripotent cell known as the haemocytoblast
41
Where is blood cells developed in foetal vs adult?
Foetal blood cells from yolk sac, liver, spleen
| Adult —> flat bone marrow
42
What are the two main branches of the haemocytoblast?
Common lymphoid progenitor (CLP)
| Common myeloid progenitor (CMP)
43
What does the CLP further branch into?
1. Pre B and pre T cells
2. B and T lymphoblasts
3. B and T lymphocytes
44
What does the CMP further branch into?
| Two main branches:
Granulocyte- monocytes progenitor and Megakaryocyte erythroid progenitor
45
What does the granulocyte monocytes progenitor branch and end at?
Basophil, neutrophil, eosinophils, monocytes
46
What does the Megakaryocyte erythroid progenitor branch and end?
Megakaryoblast —> Megakaryocyte —> platelets
| Pronormablast —> Normablast —> Erythrocytes
47
What are the main cell types in the peripheral blood and their corresponding precursor?
1. T-cells —> pre T cells
2. B-cells —> pre B cells
3. RBC —> Normablast
4. Megakaryocyte/Platelet —> Megakaryoblast
5. Granulocyte — granulocyte - monocyte progenitor
6. Monocytes —> granulocyte - monocyte progenitor
48
What is the protein responsible for blood type?
Agglutinogens
49
How many combinations of blood types are their?
3 alleles —> 2 parents —> 6 combinations
| A, B, O, AB, AO, BO
50
What is the Rhesus factor?
A blood protein that is either present or not. (Rh + vs Rh-)
| Can impact blood products received.
51
What blood groups can A type receive?
A and O can receive like blood and O
52
What blood groups can AB receive?
—> all
53
What is the size of an erythrocytes and how small is a capillary?
RBC --> 8uM
| Capillary is 3uM —> RBC bends to squeeze through
54
What type of iron is required for haem?
Fe2+ Not 3+
55
Define anaemia?
Reduction in the number of circulating erythrocytes and therefore haemoglobin, reducing the capacity of blood to carry oxygen.
56
What is the mechanisms leading to anaemia?
Loss of RBC production
Loss of blood volume
Increase in erythrocyte destruction
(OR COMBINATION OF THESE)
57
What are some common causes of Loss of RBC production anaemia?
1. Lack of nutrition —> iron, B12, folic acid
2. Increased requirements —> adolescence, pregnancy
3. Iron retention —> cancer, chronic infection, inflammation
4. Failure of bone marrow —> apoplastic anaemia, acute leukaemia
5. Reduced EPO —> eg kidney disease, thyroid?
58
What are some causes of increased red cell destruction anaemias?
1. Intrinsic red cell defect —> hereditary spherocytosis, enzyme deficiencies, thalassemias
2. Extrinsic factors —> AIHA, microcirculation abnormalities
59
What are some causes of increased red cell loss anaemias?
Haemorrhage, parasites
60
What are the prefixes for aneamia to classify based on cell size?
Micro —> small cells
Normo —> normal sized cells
Macro —> large cells
61
What are some suffixes that can be used to describe anaemia?
Chromic —> colour —> eg hypochromic (light), hyperchromic (dark)
Cytic —> just means cell —> eg macrocytic = large cells
62
Causes of microcytic anaemia?
1. Defect in haem synthesis —> iron deficiency, chronic disease
2. Defect in globulin synthesis —> alpha or Beta chain synthesis issues (thalassemias)
63
Causes of Normocytic anaemia?
1. Haemorrhage —> can be things like peptic ulcers, varices, etc
2. Chronic renal failure
3. Haemolytic anaemia
4. Red cell pooling in spleen
5. Rbc production failure
6. Early stages of iron deficiency anaemia or chronic disease
7. Bone marrow failure/suppression
8. Bone marrow infiltration
9. Hypersplenism (gets from portal cirrhosis
64
Causes of Macrocytic anaemia?
Normally from abnormal haemopoiesis —> RBC precursors continue to produce haem and cellular proteins but have issues dividing properly —> hence larger
1. Vit B12 deficiency
2. Pernicious anaemia
3. Leukemias
4. Liver disease and ethanol toxicity
5. Recent major blood loss with adequate iron stores (reticulocytes increased)
6. Haemolytic anaemia (reticulocytes increased)
65
What are reticulocytes?
Immature erythrocytes (RBCs)
66
What does pernicious anaemia mean?
Pernicious anaemia is where the body cannot absorb Vit B12 and hence RBC production is non functioning --> large immature RBC circulate the blood and are non functioning
67
What are some causes of haemolytic aneamia?
1. Intrinsic—> inherited factors that accelerate RBC degradation
2. Extrinsic —> microorganisms, drugs, chemicals
68
What are the two classifications of haemolytic?
1. Intravascular—> occurs if there is acute RBC damage
| 2. Extravascular —> occurs when defective RBC are removed by the spleen
69
What is polycythaemia?
Too many RBCS in circulation
70
What causes pseudo polycythaemia
Reduced blood volumes —> give signs of polycythemias but are classified as pseudo.
71
True causes of polycythaemias?
1. Too much blood—> over transfusing
2. Too much EPO —> increases RBC production
3. Abnormal bone marrow function
72
What results can polycythemia have?
Hyperviscosity
| Hypertension
73
What is leucocytosis?
Higher than normal white cells —> sign of inflammation, most commonly infection but can be due to parasites, bone tumours or leukaemia.
74
What is neutropenia?
Lack of neutrophils in the blood —> a type of white blood cell important for first line immune defence.
75
How is abnormal White cell count investigated?
* History and examination
* Haemoglobin and platelet count
* Automated differential
* Examine blood film
76
What too consider when assessing a white cell abnormality?
* Abnormality -White cells only, or all 3 lineages (red cells/platelets/white cells) ? •White cells 1 cell type only, or all lineages? (e.g. neuts/eos/monocytes/lymphocytes)
* Mature cells only or mature and immature cells?
77
Common causes for rise in neutrophils?
1. Infection
2. Tissue inflammation
3. Physical stress —> adrenaline, corticosteroids
4. Neoplasia
78
Common causes for rise in eosinophils?
Parasitic infection
| Allergic disease eg Asthma
79
Common causes for rise in lymphocytes?
Infection (bacterial, viral, other)
Cancer of the blood or lymphatic system
An autoimmune disorder causing ongoing (chronic) inflammation
80
What is a reactive lymphocyte?
Normal haematopoiesis —> polyclonal/ reactive
81
What is a malignant lymphocyte?
Abnormal/clonal —> eg leukaemia
82
How is haematopoiesis disturbed in cancers like leukemia, myeloma, lymphoma?
Mutation of single stem cell.
Neoplastic proliferation of lymphoid tissue (lymphoma)
B-cell neoplasticism growth (myeloma)
83
Cross- sectional study design?
Cross-sectional study design is a type of observational study design. In a cross-sectional study, the investigator measures the outcome and the exposures in the study participants at the same time.
84
Purpose of a cross sectional study?
Cross-sectional studies involve data collected at a defined time. They are often used to assess the prevalence of acute or chronic conditions, but cannot be used to answer questions about the causes of disease or the results of intervention.
85
Case control study design?
A case-control study is designed to help determine if an exposure is associated with an outcome
86
Purpose of a case control study?
The case–control study design is often used in the study of rare diseases or as a preliminary study where little is known about the association between the risk factor and disease of interest.
87
Cohort study design?
A study design where one or more samples (called cohorts) are followed prospectively and subsequent status evaluations with respect to a disease or outcome are conducted to determine which initial participants exposure characteristics (risk factors) are associated with it.
88
Purpose of a cohort study?
Cohort studies are a type of medical research used to investigate the causes of disease and to establish links between risk factors and health outcomes.
89
What are the two types of cohort study?
Prospective --> monitoring a cohort going forward
| Retrospective --> monitoring a cohort is a historical cohort context
90
What is the design of interventional studies?
An interventional study is one in which the participants receive some kind of intervention, such as a new medicine, in order to evaluate it.
91
What is the purpose of interventional studies?
to test efficacy of specific treatments or combination treatments
92
What is the design of qualitative studies?
A qualitative research design is concerned with establishing answers to the whys and hows of the phenomenon in question (unlike quantitative). Due to this, qualitative research is often defined as being subjective (not objective), and findings are gathered in a written format as opposed to numerical.
93
What is the purpose of qualitative studies?
Qualitative research is aimed at gaining a deep understanding of a specific organization or event, rather a than surface description of a large sample of a population
94
What is the design of systematic reviews?
Systematic reviews are a type of literature review that uses systematic methods to collect secondary data, critically appraise research studies, and synthesize findings qualitatively or quantitatively.
95
What is the purpose of systematic reviews?
to deliver a meticulous summary of all the available primary research in response to a research question.
96
Where is iron absorbed in the body?
The duodenum
97
How is iron absorbed?
Gastric acid lowers the pH in the proximal duodenum, enhancing the solubility and uptake of ferric iron
98
How is iron transported?
Transferrin is the major iron transport protein (transports iron through blood). Fe3+ is the form of iron that binds to transferrin, so the Fe2+ transported through ferroportin must be oxidized to Fe3+. ... Once oxidized, Fe3+ binds to transferrin and is transported to a tissue cell that contains a transferrin receptor.
99
What is the effect of low iron on RBC production?
1. Limits the production of haem
2. Low haem limits production of RBC haemoglobin
3. Low haemoglobin reduces bloods capacity to carry oxygen
100
How does low folate and or B12 affect RBC production?
Deficiency of folate or vitamin B12 inhibits purine and thymidylate syntheses, impairs DNA synthesis, and causes erythroblast apoptosis, resulting in anaemia from ineffective erythropoiesis (RBC production)
101
What is the structure of haemoglobin?
Haemoglobin is a globular protein with a quaternary structure.
Consists of four polypeptide subunits --> 2 alpha chains and 2 beta chains.
102
What is the function of haemoglobin?
Oxygen transporting protein of RBCs
103
What is the three main hormones involved in the renin system for blood pressure regulation?
1. Renin
2. Angiotensin 2
3. Aldosterone
104
What impacts renin release from the kidneys?
1. Reduced NaCl delivery to the distal tubule of the macula densa
2. Reduced perfusion pressure in the kidney
3. Sympathetic stimulation of the Juxtaglomerular apparatus (JGA)
105
What is the general flow of mechanisms in the Angiotensin renin system?
1. Renin release
2. Renin cleaves Angiotensin to form Angiotensin 1
3. Angiotensin 1 is converted to angiotensin 2 by angiotensin converting enzymes (ACE)--> these are found mainly in the lungs and renal and capillary endothelium
4. Angiotensin 2 has numerous sites of action:
- Adrenal cortex --> stimulates the production of aldosterone (stimulates Na+ and subsequently water reabsorption)
- Cardiovascular --> acts on AT1 receptors in arterioles to drive vasoconstriction
- Neural --> hypothalamus action to stimulate thirst
106
How does the baroreflex (baroreceptor reflex) have effect?
1. Baroreceptors (stretch sensitive mechanoreceptors in the atria, vena cavae and most importantly the carotid sinuses and aortic arch
2. When stretch is detected --> signals trigger vagal nuclei
3. Sympathetic nervous system is inhibited and parasympathetic is activated
4. Decreased cardiac output via decrease in heart rate, resulting in a tendency to lower blood pressure.
5. NOTE --> the baroreflex can have the opposite action to increase BP via sympathetic activation
107
What does sympathetic activation do to the heart and vasculature?
Heart --> stimulate
| Vasculature --> constrict
108
What does parasympathetic activation do to the heart and vasculature?
Heart --> inhibition
| Vasculature --> dilation
109
What increases RBC formation in bone marrow?
EPO --> released in the kidneys in response to hypoxia
110
What stimulates white blood cell formation in the bone marrow?
Infection mediators
111
What increases platelet formation in the bone marrow?
Thrombopoietin is a glycoprotein hormone produced by the liver and kidney which regulates the production of platelets. It stimulates the production and differentiation of megakaryocytes, the bone marrow cells that bud off large numbers of platelets.
112
What is haemolysis?
The lysis of RBCs
113
What is the common causes of haemolysis?
```
Extrinsic:
1. Infection
2. Tumour
3. Autoimmune disorder
4. Medication
5. Leukemia
6. Lymphoma
Intrinsic:
1. Sickle cell anaemia
2. Thalassemia
```
114
What are the general symptoms of anaemia?
1. Fatigue, energy loss
2. SOB with exercise
3. Dizziness
4. Pale skin, nail beds, palms
5. Fast heart rate
6. Cramps
115
What are some symptoms of iron deficiency anaemia?
1. Koilonychias (upward curvature of the nails
2. Soreness of the mouth with cracks in the corners
3. Pica --> strange food cravings
116
What are some particular symptoms of B12 deficiency anaemia?
1. Tingling in hands or feet
2. Wobbly gait
3. --> neurological issues (touch, stiffness, dementia)
117
What are some symptoms of haemolytic anaemia?
1. Jaundice
2. Brown/red urine
3. Leg ulcers
4. Gallstone symptoms
5. Failure to thrive in infants
118
What is the typical clinical presentation of someone with sickle cell disease?
Usually at about 5months of age:
1. Anaemia related fatigue
2. Episodes of pain --> when sickle cells block blood vessels
3. Swelling of hands and feet --> from sickle cell blockages
4. Frequent infections --> as sickle cells damage the spleen
5. vision problems --> eye vessels get blocked by sickle cells
119
What are some symptoms of thalassaemia's?
Usually shows up later in childhood or adolescence
1. Dark urine
2. Delayed growth/development
3. Excessive fatigue
4. Yellow/pale skin
5. Bone deformities in the face
120
What does anaemia look like under the microscope?
1. Size of the cells can classify anaemia (Micro, normo, and macrocytic)
2. Colour can classify anaemia (hyper/hypo chromic)
121
How does flow cytometry work?
In this process, a sample containing cells or particles is suspended in a fluid and injected into the flow cytometer instrument. The sample is focused to ideally flow one cell at a time through a laser beam, where the light scattered is characteristic to the cells and their components.
122
What is RBC mean on a FBC?
The number of red blood cells
123
What is HGB on a FBC?
Haemoglobin levels
124
What is HCT on FBC?
Haematocrit --> ratio of red blood cells to total blood volume
125
What is MCV on FBC?
mean corpuscular volume (mean cell volume) --> determines the average size of the RBCs --> can show if micro, normo or macrocytic
126
What is MCH on FBC?
Mean cell haemoglobin --> average NUMBER of haemoglobin inside a RBC
--> these values can be seen to be higher in macrocytic cells as they have more volume and the opposite for microcytic
127
What is MCHC on FBC?
Mean cell haemoglobin concentration --> CONCENTRATION of haemoglobin in RBC
- -> can determine hyper or hypochromic cells
- -> will be lower in iron deficiency anaemias and thalassaemia's
128
What is RDW on FBC?
Red cell distribution width --> calculation of cell size variation of RBCs
--> RDW is commonly higher in some anaemias such as pernicious (B12) (more immature cells which are actually larger than mature cells
129
What does serum iron measure in iron studies?
Measures iron levels in liquid blood
130
What does ferritin measure in iron studies?
Measures amounts of stored iron in the body
131
What does transferrin (TIBC) measure in iron studies?
Total iron binding capacity --> shows how much spare capacity the circulation has to transport iron. It is equal to the amount of non-bonded transferrin (iron transport protein) + serum iron.
132
What does transferrin saturation measure in iron studies?
The saturation levels of transferrin --> represented as a percentage
133
What does soluble transferrin receptor measure in iron studies?
Levels of transferrin receptor (iron binding capacity in blood) --> is normally elevated in iron deficiency anaemia
134
What are the common deliver methods of iron to patients?
1. Dietary change
2. Supplements
3. Iron injection intramuscular
4. Infusion
5. Transfusion
