Haemopoiesis and Bone marrow Flashcards
Haemopoiesis
production of blood cells that occurs in the bone marrow
where does haemopoiesis occur in embryos
yolk sac
where does haemopoiesis occur in foetus
spleen
near the end of pregnancy where does haemopoiesis occur in
bone marrow
tissue where haemopoiesis occurs most
pelvis sternum skull ribs vertebrae (Where a trephine biopsy is taken)
trephine biopsy
A bone marrow trephine biopsy is when a tiny core of the bone marrow tissue is removed.
where is bone marrow found
in the parietal region of the bone
Haemopoietic stem cells (HPSCs)
- Can self-renew (more than other adult tissue) - Can differentiate into variety of specialised cells
extramedullary haematopoiesis
Extramedullary hematopoiesis (EMH or sometimes EH) refers to hematopoiesis occurring outside of the medulla of the bone (bone marrow). It can be physiologic or pathologic. Physiologic EMH occurs during embryonic and fetal development mainly.
pathological causes of extramedullary haematopoiesis
e.g. myelofibrosis or thalassaemia can mobilize into circulating blood to colonise other tissues
uses of HPSCs
- Harvested and frozen, then given to pts undergoing chemotherapy and then re-inject and help regenerate blood cells
source of HPSCs
- Bone marrow aspiration (rarely done) - G-CSF mobilises peripheral blood stem cells - Umbilical cord stem cell
Haemopoeisis is controlled by
a variety of hormones and originates from one cell – the multipotent haematopoietic stem cell (HPSC), sometimes called a haemocytoblast.
what stimulates RBC production
Erythropoietin released by the kdineys
what stimulates platelet production
Thrombopoietin
what stimulates lymphocyte production
Interleukins and TNF-α
The HPSCs differentiate into either
common myeloid progenitor cells or common lymphoid progenitor cells, and from them all the other blood cells develop.
myeloid cells
o Erythrocytes o Myeloblast: basophiles, neutrophils, eosinophils, monocytes/ macrophages o Megakaryocyte–> platelets
platelets come from
megakaryoctes
lymphoid cells
B and T cells
Reticuloendothelial system (RES)
Part of the immune system made up of monocytes in the blood and network of tissues which contain phagocytic cells- removes damaged and dying cells from circulation
main organs of RES
Spleen (red pulp) and liver
-cytopenia
reduction in the number of blood cells
-cytosis or philia
increase in the number of blood cells
erythropoiesis
a continuous process which produces erythrocytes in the bone marrow.
function of erythrocytes
- carry Hb delivering oxygen to tissue - generate energy
characteristics of erythrocyte
- biconcave (flexible) - no nucleus or mitochondria (can carry lots of Hb)
Erythrocytes have a classical biconcave structure with a diameter of
8µm.
Erythrocytes small size and shape allow them to
deform and squeeze through the lumen of capillaries and therefore supply all areas of the body with oxygen.
Structure of Haemoglobin
Haemoglobin is a globular protein with a tetramer structure of two pairs of globin chains – in an α2β2 structure. Each chain has its own essential prosthetic haem group (a protoporphyrin ring and an iron atom).
how much oxygen can bind to Hb
One molecule of O2 binds to the haem group (x 4) and causes movement of the iron into the plane of the ring, and a conformational change in the structure. Each haemoglobin molecule can bind 4 O2 molecules.
There are two states in the hemoglobin
the T state and the R state
T state
the tense state- has less of an affinity for oxygen than the R state
R state
relaxed state- higher affinity
Cooperativity of Hb
When oxygen binds to haemoglobin, it converts from the T state to the R state, and it is much easier for oxygen to bind – this especially favours oxygen loading in the lungs where there is a very high pO2, and the release of oxygen at the tissues where there is a very low pO2
Erythrocyte membrane structure
Proteins of the erythrocyte membrane are essential for maintaining the biconcave shape of the cell. This is achieved by vertical interaction between the membrane, its associated membrane proteins and the cytoskeleton. The proteins of the erythrocyte membrane include: Band 3 – A Cl-/HCO3- exchanger (integral protein) which links to protein 4.2 and ankyrin. Ankyrin – Links integral membrane proteins to the underlying spectrin-actin cytoskeleton. Protein 4.2 – ATP-binding protein which may regulate the association of band 3 with ankyrin. Spectrin – Crosslinks with actin, forming a molecular scaffold that links the plasma membrane to the actin cytoskeleton.
changes in the components of the RBC membrane
can make the cell less flexible- will breakdown more easily and be removed by the spleen from circulation
Each red blood cell has a lifespan of 120 days and erythropoiesis is therefore required as they cannot undergo mitosis (due to a lack of a nucleus). The process is as follows:
1) Cells are formed from common myeloid progenitor cells and are committed to the path of erythropoiesis by transcription factors. 2) This causes them to differentiate from CMP cells to reticulocytes, by extruding the nucleus and the majority of their organelles – this requires the hormone erythropoietin (EPO). 3) Once reticulocytes are in the bloodstream, they mature over two days into erythrocytes by removing the rest of their organelles (to make more space inside for haemoglobin).
More erythrocytes can also be formed, driven by increased levels of EPO, in response to a shortage of oxygen in the blood.
Interstitial peritubular cells in the kidney detect hypoxia (reduced ability of blood to carry O2). This can be due to: decreased RBC count; decreased amount of haemoglobin; decreased availability of O2. Increased production of EPO in the kidney (and liver to smaller extent). EPO stimulates maturation and release of red cells from bone marrow, by preventing apoptosis of the common myeloid progenitor cells. Number of red cells and haemoglobin increases – so more O2 can be delivered to tissues.
lifespan of RBC
120 days
degradation of haemoglobin
1) scenescent red blood cells engulfed by macrophages in RES
2) Fe2+ of Haem recycles and converted to bilirubin (unconjugated)
3) Bilirubin is transported to the liver where it is conjugated with glucuronic acid forming bilirubin diglucoronide
4) bilirubin diglucoronide is secreted as Bile into duodenum 5) gluronic acid is removed by bacteria converting the bilirubin to urobilinogen
6) Urobillinogen is oxidised to stercobilin which is excreted in the faeces
7) some urobillinogen is absorbed into blood and transported to the kidneys, oxidised to urobilin and excreted in the urine
stercobilin
makes faeces brown
urobilin
makes wee yellow
low erythrocyte
anaemia
high erythrocyte
polycythameia or erythrocytosis
neutrophils are
- First-responder phagocyte - Most common white cell - Essential part of innate immune system - Circulate in bloodstream & invade tissues – live for 1-4 days
maturation of neutrophils controlled by
G-CSF, a glycoprotein growth factor & cytokine which: • Increases production of neutrophils • Speeds up release of mature cells from BM • Enhances chemotaxis • Enhances phagocytosis and killing of pathogens
recombinant G-CSF is routinely administered in causes when
more neutrophils are needed e.g. a patient with severe neutropenia and sepsis after chemotherapy
Neutrophilia
increase in absolutes no. of circulating neutrophils
only cells in circulation are
actually measured in a blood count (not in tissue).
causes of neutrophilia
actually measured in a blood count (not in tissue).
neutropenia
Neutrophil count <1.5 x 109/L (severe if < 0.5 x 109/L)
consequence of neutropenia
- Medical emergency o Bacterial and fungal infections o Mucosal ulceration e.g. painful mouth ulcers - Intravenous antibiotics must be given immediately
causes of neutropenia
1) reduced production 2) increased removal or use
reduced production of neutrophil
B12/folate deficiency malignancy or fibrosis radiation drugs (chemotherapy) viral infection aplastic anaemia congenital
increased removal or use of neutrophils
autoimmune destruction sepsis- rapid migration into tissue- BM unable to synthesis neutrophils ar a fast enough rate to maintain circulatory numbers splenic pooling
monocytes
- Typically largest cell in blood - Circulate for 1-3 days before migrating into tissues where they differentiate in macrophages or dendritic cells
role of monocytes
- Phagocytose microorganisms and breakdown/remove cellular debris - Antigen presenting role to lymphocytes - Important in defence against chronic bacterial infections e.g. TB and fungal infections)
monocytosis
increase in monocytes
when does monocytosis occur
• Bacterial infection e.g. tuberculosis • Inflammatory conditions e.g. rheumatoid arthritis, Crohn’s Ulcerative colitis • Carcinoma • Myeloproliferative disorders and Leukaemias
eosinophils
- In circulation for 3-8 hours before migrating into tissues - Lifespan 8-12 days
role of eosinophils
- Responsible for immune response against multicellular parasites e.g. Helminths - Mediator of allergic responses - Granules contain array of cytotoxic proteins e.g. eosinophil cationic proteins and elastase - Phagocytosis of antigen-antibody complexes
inappropriate inactivation of eosinophils
- Responsible for tissue damage and inflammation e.g. in asthma
causes of eosinophilia: common
allergic disease e.g. asthma drug hypersensitivity e.g. penicillin parasitic nfection Churg strauss
charge strauss
very rate autoimmune disease resulting in inflammation of small blood vessels
causes of eosinophilia: rare
- Hodgkins lymphoma (there are others)
basophils
- Least common and large
- Rarely seen in differential WBC as represent <1% of all leukocytes
- Large dense granules containing histamine, heparin, hyaluronic acid, serotonin
- Granules stain deep blue to purple and often so numerus they mask nucleus
role of basophils
- Active in allergic reactions and inflammatory conditions
reactive basophilia
- Immediate hypersensitivity reactions - UC - Rheumatoid arthritis
myeloproliferative basophilia
- CML - Systemic mastocytosis
lymphocytes originate in the
bone marrow
B cells have role in
humeral immunity- antibodies
T cells
cellular immunity (CD4+ helper cells + CD8+ cytotoxic)
NK cells
cell mediated cytotoxicity (innate)
reactive lymphocytosis
- Viral infections - Bacterial infections- esp whooping cough - Stress related: MI - Post splenectomy - Smoking
lymphoproliferative lymphocytosis i.e. malignant
- Chronic lymphocytic leukaemia - T or NK cell leukaemia - Lymphoma
