Physiology Flashcards
what is haemopoiesis?
the production of blood cells
- Derived from a relatively small pool of pluripotent stem cells capable of making all the different types of blood cells
where does haemopoiesis happen?
In adults mostly the bone marrow of axial skeleton
- Embryo – Yolk sac then liver then marrow, 3rd to 7th month – spleen
- At Birth – Mostly bone marrow, liver and spleen when needed
- Birth to maturity – number of actives sites in bone marrow decreases but retain ability for haematopoiesis
- Adult – not all bones contain bone marrow, haematopoiesis restricted to skull, ribs sternum, pelvis, proximal ends of femur (the axial skeleton)
what happens the more cells divide in haemopoiesis?
the more divisions the smaller the cells especially red cells
what is a megakaryocyte
Platelets make one megakaryocyte – a huge soup of many platelet nuclei and cytoplasms
properties of red cells
- Full of haemoglobin
- No nucleus
- Can’t divide or repair
- Limited lifespan
- No mitochondria
- High Surface area/volume ratio to allow for gas exchange – need to keep water out
- Flexible to squeeze through capillaries
- Specialized membrane required that can go wrong
how red cells keep water out
through maintaining specific ion concentration gradients with the sodium potassium pump
This pump allows the ion concentrations to be kept right and the systems in the cell to keep working
Keeps water out
Needs ATP (energy)
haemoglobin structure
deliver oxygen to the tissues, act as a buffer or H+, CO2 transport
o Tetrameric globular protein
o HbA(adults) – 2 alpha and 2 beta chains
o Haem group is Fe2+ in a flat porphyrin ring
o 1 haem per subgroup
o 1 O2 molecule binds to 1 Fe2+ (oxygen doesn’t bind to Fe3+)
end of a red cell lifespan
average lifespan 120 days occurs in spleen (& liver) aged RBC taken up by macrophages (out of circulation) RBC contents recycled globin chains - amino acids haem group - iron and bilirubin bilirubin taken to liver and conjugated bilirubin then excreted in bile (colours faeces and urine)
what regulates RBC production?
red cell production is regulated by erythropoietin
• Hypoxia sensed by kidney – erythropoietin produced – erythropoietin stimulates red cell production in bone marrow, erythropoietin levels drop – hypoxia sensed by kidney and so on
what is the metabolic pathway within RBC
glycolysis because no mitochondria
- this makes free radicals which inhibit oxygen transport
- GSH (glutathione) maintains redox balance
- The rate limiting enzyme in this process is glucose-6-phosphate dehydrogenase (G6PD)
- the hexose monophosphate shunt Generates NADPH that maintains GSH levels preventing oxidative damage limited by G6PD activity
carbon dioxide transport
o 10% dissolved in solution
o 30% is bound directly to Hb as carbamino-Hb
o Other 60% gets there as bicarbonate and red cell has an important role in generating that bicarbonate
what allosteric effectors affect O2 binding?
dissociation curve for haemoglobin is sigmoidal
1st O2 binds to haem in one subunit the Hb shape changes so it is easier for further O2 to bind
• A lot of oxygen is released in hypoxic environments so the haemoglobin system works
• Fetal Hb (a2g2) saturates more at the same pO2 so effectively takes O2 from the maternal circulation.
• In muscles the monomeric myoglobin (which otherwise is a similar structure to Hb) takes O2 from red cells and has different kinetics
things which affect O2 dissociation
o Curve is shifted right by molecules that interact with Hb (H+, CO2, 2,3 BPG).
o This results in more O2 delivered to tissues.
o When CO2 and H+ may be increased - good to have more O2 released in these conditions.
o 2,3 BPG (or sometimes called DPG) is increased in chronic anaemia
what is a reticulocyte
red cells which have just left the bone marrow
larger than average red cells
still have RNA remnants
stain purple/deeper red because of RNA
blood film appears ‘polychromatic’
up regulation of reticulocyte production by the bone marrow in response to anaemia takes a few days
iron metabolism
‘closed’ system - only able to absorb a small amount of iron
Tiny amount in circulation moving to/from storage site - principally marrow
Iron turnover in plasma pool is fast (4mg in pool and move 20mg/day)
Circulating iron is bound to transferrin.
It is transferred to the bone marrow macrophages that ‘feed it’ to red cell precursors
Iron is stored in ferritin mainly in the liver
transferrin structure and purpose
- Protein with two binding sites for iron atoms
- Transports iron from donor tissues (macrophages, intestinal cells and hepatocytes) to tissues expressing transferrin receptors (especially erythroid marrow)
-% saturation of transferrin with iron measures iron supply
o reduced in iron deficiency
o reduced in anaemia of chronic disease
o increased in genetic haemachromatosis
life span of neutrophils
7-8 hours
lifespan of platelets
7-10 days
what cell is the most abundant in the blood
red cells
what is a blast
a nucleated precursor cell
what are the 2 types of blasts
erythroblast
myeloblast
megakaryocyte
platelet precursor, polyploid
myelocyte
nucleated precursor between neutrophils and blasts
haemopoietic progenitor cell
precursor of the precursors
what are the developmental events in haemopoiesis
- Self-renewal: a property of stem cells, lost in descendants
- Proliferation: increase in numbers
- Differentiation: descendants commit to one or more lineages
- Maturation: descendants acquire functional properties and may stop proliferating
- Apoptosis: descendants undergo cell death
bone marrow
complex organ surrounded by a shell of bone with a neurovascular supply
• Red (haemopoietically active) versus yellow (fatty inactive) marrow: increase in yellow marrow with age – results in reduction in marrow cellularity in older individuals
blood supply to bone marrow
- Venous sinuses – nutrient artery and periosteal network
- Arterioles drain into ‘sinuses’ wide venous vessels which open into larger central sinuses. Sinuses are larger than capillaries and have a discontinuous basement membrane
myeloid:erythroid ratio
relationship of neutrophils and precursors to proportion of nucleated red cell precursors (ranges from 1.5:1 to 3.3:1) – can change (eg reversal in haemolysis as a compensatory response)
what are the regulators of haemopoiesis?
- Intrinsic properties of cells (e.g stem cells vs progenitor cells vs mature cells)
- Signals from immediate surroundings and the periphery (microenvironmental factors)
- Specific anatomical area (‘niche’) for optimal developmental signals
how is haemopoiesis assessed?
routine:
blood count,
cell indices (by non-specialists),
morphology (blood film-specialist) - morphological assessment normally sufficient for non-lymphoid
bone marrow examination (Less common (specialist))
lymphoid:
immunophenotyping (common assessment of lymphoid cells)
cytochemistry (rarely used)
what is immunophenotyping?
expression of antigens indicating lineage or stage of development often required for lymphoid cells but not other cells (usually)
- Identify patterns of protein (antigen) expression unique to a cell lineage
- Use antibodies (in combination) specific to different antigens
what is haemostasis
the arrest of bleeding and maintenance of vascular patency
what do platelets do?
- Endothelial (vessel wall) damage exposes collagen and releases Von Willebrand Factor (VWF), and other proteins to which platelets have receptors – platelet adhesion at the site of injury.
- There is then secretion of various chemicals from the platelets, which leads to aggregation of platelets at the site of injury
what is thrombocytopenia
reduced number of platelets
what factors can cause failure of platelet plug formation (primary homeostasis)
- Vascular
- Platelets - Reduced number (thrombocytopenia) or Reduced function
- Von Willebrand Factor
what happens when there is failure of platelet plug forming (primary homeostasis)?
Spontaneous Bruising and Purpura Mucosal Bleeding o Epistaxes o Gastrointestinal o Conjunctival o Menorrhagia Intracranial haemorrhage Retinal haemorrhages
what is secondary homeostasis
formation of fibrin clot
pathway of secondary homeostasis
TF/VIIa acts on V/Xa - initiation V/Xa converts prothrombin to thrombin thrombin activates VIII/IXa VIII/Xa act on V/Xa which in turn convert more prothrombin to thrombin (amplification) thrombin converts fibrinogen to fibrin
process of fibrinolysis
tissue plasminogen activator (tPA) converts plasminogen to plasmin
plasmin converts fibrin to FDPs (fibrin degradation products)
natural anticoagulants
- serine protease inhibitors - anti-thrombin (inhibits the factors TF/VIIa, V/Xa, VIII/Xa)
- Protein C and Protein S (inhibit factors V/Xa, VIII/Xa)
what are secondary lymphoid tissues
lymph nodes and spleen
- provide a location for cells of the immune system (lymphoid and accessory)
- filters for circulatory fluids (lymph - lymph nodes and blood - spleen)
what forms the lymphatic system
lymphatic vessels and lymph nodes located along their course form the lymphatic system
• Lymphatic channels are blind ended vessels that permit passive unidirectional flow (valves) of lymphatic fluid.
what does the lymphatic system do?
return fluid from extracellular connective tissues to the circulation
- prevent excessive accumulation of fluid in the tissues - oedema
- important function in fluid homeostasis
- allows lymph to pass through lymph nodes and allow interaction of cells and ‘molecules’ with cells of the immune system - protective function
properties of lymph nodes
groups of nodes drain particular territories
afferent channels drain lymph through the capsule into the peripheral sinus
lymph is filtered
o Fluid percolates through the node
o Immune reactions can be triggered
o Cells can enter the node (Immune cells and Cancer cells)
lymph nodes provide the ideal environment for immune responses to occur
what cells live in the lymph nodes
• Mononuclear phagocytes (macrophages), antigen presenting cells, and dendritic cells. • Endothelial cells Lymphocytes o B cells - Associated with follicles and germinal centres - Interfollicular - Plasma cells – mainly in the medulla o T cells - T helper cells - T cytotoxic cells o Natural killer cells
what is the sentinel lymph node
The first lymph node to which cancer cells are most likely to spread. (There may be more than one sentinel node.)
• Identified by dye or radioactive isotopes
• If negative – tumour is localised
• If positive – tumour has spread and further investigation and treatment need to be considered.
• Recall that metastatic cells will be identified first in the subcapsular sinus
properties of the spleen
secondary lymphoid organ
located high in the left upper quadrant of the abdomen (not palpable unless substantially enlarged)
very vascular organ - Supplied by splenic artery (branch of coeliac axis) and drained by splenic vein (with SMV forms portal vein)
Rupture is a surgical emergency, Trauma, A diseased spleen is more prone to rupture
An encapsulated organ.
Parenchyma includes red pulp and white pulp
what are the 2 key borders of the spleen
Diaphragmatic surface
Visceral surface - Left Kidney, gastric fundus, tail of pancreas, splenic flexure of colon.
red pulp of the spleen
Red pulp contains sinusoids and cords.
Sinusoids are
o fenestrated
o lined by endothelial cells
o supported by hoops of reticulin.
Cords contain macrophages and some fibroblasts and cells in transit (RBC, WBC, PC and some CD8+ T cells)
Fulfills the same function for blood as lymph nodes do for lymph fluid i.e. acts as a filter for the blood
o Detect, retain and eliminate unwanted, foreign or damaged material
o Facilitate immune responses to blood borne antigens
white pulp of the spleen
- White pulp comprises the peri-arteriolar lymphoid sheath (PALS). - CD4+ lymphoid cells
- This is expanded by lymphoid follicles - May show reactive changes as in lymph node
- Antigen reaches white pulp via the blood.
- APCs in the white pulp present antigen to immune reactive cells
- When stimulated by antigen, T and B cell responses may occur
how do monocytes and granulocytes (inclu. neutrophils mature)
arise from a common precursor – mature and proliferate in the marrow and circulate before entering tissues to function
what does the prescence of myelocytes in the blood indicate
Presence of less mature forms e.g. myelocytes indicates marrow stress or damage to the normal marrow architecture allowing them to exit the marrow prematurely and is often described as left shift in a blood film
what is neutrophil margination
- Not all neutrophils in the circulation are circulating, a proportion adhere to the vessel wall in a reversible attachment process using a number of adhesion molecules that may eventually result in them squeezing between the endothelial cells and entering the tissues
- Marginating pool not in the blood count
- Steroid treatment and some other situations can partly explain why a neutrophilia is seen as they reduce margination
what is neutrophilia
Increased number of circulating neutrophils, other than by the inhibition of margination it can be caused by a number of stimuli
what is eosinophilia and what causes it
increased numbers of circulating eosinophils causes o Allergic reactions to drugs o Severe skin conditions e.g. atopic dermatitis o Asthma, atopy o Parastitic infections o Hodgkin’s lymphoma, T cell lymphomas o Pulmonary syndromes
what is a basophil
an infrequent circulating granulocyte
characteristic appearance - nucleus often obscured by dense blue/black granules
granules are rich in histamine and heparin
IgE receptors on the cell surface allow specific antibody/antigen interactions to cause degranulation - type 1 hypersensitivity
role of basophils
Role in health not entirely clear
Analogous to the tissue mast cell with similar function
Like eosinophils have a role in allergy and parasitic infections
what are mast cells
Tissue equivalent of basophils but have a different ontogeny
Degranulation releases mast cell tryptase as well as histamine and heparin
Mast cell tryptase can be measured and is a marker of degranulation/ excessive mast cell numbers
Malignant proliferation of mast cells called systemic mastocytosis
what is the function of monocytes
- Circulate for 1-2 days before entering the tissues
- Under the influence of local factors differentiate into tissue macrophages
- Roles in fighting infection through phagocytosis and antigen processing
what is infective mononucleosis
Activated T cells responding to EBV infection in B cells take on a typical morphological appearance with abundant blue cytoplasm that wraps against neighbouring red cells in the blood film
• Typically caused by EBV infection but can be a result of HIV infection, CMV, viral hepatitis and toxoplasma
how is infective mononucleosis identified
Important to ensure correct pathogen identified
IgM specific antibodies confirm recent infection
IgG specific antibodies indicate past infection
