Haemopoesis, spleen and bone marrow Flashcards
(68 cards)
1
Q
what is haemopoiesis
A
- process by which blood cells are formed
- involves specification of blood cell lineages and proliferation to maintain an adequate number of cells
2
Q
where does haemopoiesis occur
A
- vasculature of yolk sac in early embryo
- embryonic liver by week 5-8 of gestation
- solely in bone marow after birth
3
Q
main sites of haemopoiesis in adult bone marrow
A
- pelvis
- sternum
- skull
- ribs
- vertebrae
4
Q
distribution of bone marrow
A
- extensive throughout skeleton in infant
- more limited distribution in adulthood - central areas and skull (axial)
5
Q
sources of haemopoietic stem cells
A
- bone marrow aspiration
- GCSF mobilised peripheral blood stem cells - collected by leucopharesis
- umbilical cord stem cells
6
Q
what is differentiation of haemopoetic stem cells determined by
A
- hormones
- transcription factors
- interactions with non-haemopoetic cells types e.g. endothelial cells
7
Q
what are the five major lineage pathways of haemopoetic stem cells
A
- thrombopoesis - platelets
- erythropoesis - red blood cells
- granulopoesis - basophils, neutrophils, eosinophils
- monocytopoesis - monocytes
- lymphopoesis - B and T lymphocytes
8
Q
haemopoietic stem cells (HPSCs)
A
- capable of self-renewal to maintain a certain number of stem cells throughout life
- can differentiate into variety of specialised cells
- HPSC transplantation now mainstream haematological procedure to treat blood cancers
9
Q
what is extramedullary haematopoiesis
A
when HPSCs mobilise into circulating blood to colonise other tissues (e.g. spleen and liver) in pathological conditions like myelofibrosis or thalassaemia
10
Q
thrombopoesis
A
HPSC
common myeloid progenitor
megakaryocyte
platelets (bud off from megakaryocytes)
11
Q
thrombopoietin (TPO)
A
- produced by liver and kidney
- regulates production of platelets by increasing production of megakaryocytes
12
Q
megakaryocytes
A
very large mononucleate cells with several copies of each pair of chromosomes (produce platelets)
13
Q
platelets
A
- no nuclei
- membrane bound fragments of cytoplasm that bud off from megakaryocytes
- involved in clot formation
14
Q
granulopoiesis
A
HPSC
common myeloid progenitor
myeloblast
granulocytes (basophil, neutrophil, eosinophil)
15
Q
basophils
A
- least common ( <1% of all leukocytes so rarely seen in differential WBC)
- large dense granules containing histamine, heparin, hyaluronic acid, serotonin
- granules stain deep blue to purple and mask nucleus
- active in allergic reactions and inflamatory conditions
16
Q
causes of basophilia
A
reactive
- immediate hypersensitivty reactions
- ulcerative collitis
- rheumatoid arthritis
myeloproliferative
- chronic myeloid leukemia
- myeloproliferative neoplasm: essential thrombocytaemia, polycythemia vera, myelofibrosis
- systemic mastocytosis
17
Q
neutrophils
A
- most common white cell
- mature neutrophils migrate to areas of inflammation by chemotaxis and phagocytose invading microbes and destroy them by releasing ROS
- live for 1-4 days
- contain fine granules
- multi-lobulated nucleus
18
Q
G-CSF hormone
A
glycoprotein growth factor and cytokine which:
- increases production of neutrophils
- speeds up release of mature cells of bone marrow
- enhances chemotaxis
- enhances phagocytosis and killing of pathogens
19
Q
what is neutrophilia
A
increase in the absolute number of circulating neutrophils
20
Q
causes of neutrophilia
A
- infection
- myeloproliferative diseases
- acute inflammation
- smoking and drugs
- cancer
- cytokines
- metabolic and endocrine disorders
- acute haemmorhage
21
Q
what is neutropenia
A
- neutrophil count <1.5 x 10^9/L
- severe if < 0.5 x 10^9/L
22
Q
consequences of neutropenia
A
- severe life threatening bacterial infection
- severe life threatening fungal infection
- mucosal ulceration
- neutropenic sepsis - IV antibiotics given immediately
23
Q
causes of neutropenia
A
reduced production
- B12/folate deficiency
- aplastic anaemia
- viral infection
- congenital
- infiltration
- radiation
- drugs
increased removal or use
- immune destruction - autoantibodes
- splenic pooling
- sepsis
24
Q
eosinophils
A
- in circulation for 3-8 hours
- lifespan 8-12 days
- immune response against multicellular parasites
- mediator of allergic responses
- granules contain cytotoxic proteins
- phagocytosis of antigen-antibody complexes
- inappropriate activation responsible for tissue damage and inflammation e.g. asthma
25
causes of eosinophilia
**common**
- allergic diseases
- parasitic infection
- drug hypersensitivity
- Churg-Strauss - autoimmune condition
- skin diseases
**rare**
- Hodgkin lymphoma
- myeloproliferative conditions
- acute lymphoblastic/myeloid leukemia
- eosinophilic leukaemia
- idiopathic hypereosinophilic syndrome
26
monocytopoiesis
HPSC
common myeloid progenitor
myeloblast
monocyte
macrophage
27
monocytes
- **largest cells** in blood
- circulate in blood for **1-3 days**
- differentiate into **macrophages or dendritic cells**
- **phagocytose** micro-organisms and breakdown cellular debris
- **antigen presenting role** to lymphocytes
- important in defence against **chronic bacterial infections**
28
causes of monocytosis
- bacterial infection e.g. tuberculosis
- inflammatory conditions e.g. rheumatoid arthritis, Crohn's, ulcerative colitis
- carcinoma
- myeloproliferative disorders and leukamias
29
lymphopoiesis
HPSC
common lymphoid progenitor
small lymphocyte
B lymphocyte, T lymphocyte
30
B lymphocytes (humoral immunity)
- **antibody** (immunoglobulin) forming cells
- development commences in **fetal liver and bone marrow**
- **immunoglobulin** genes rearrange to allow production of variety of antibodies
- final maturation of B cells requires exposure to antigen in **lymph nodes**
- mature B cells have capacity to **recognise non-self antigens** and produce lots of **specific antibodies**
31
T lymphocytes (cellular immunity)
- **CD4+ helper cells, CD8+ cells**
- progenitors arise from **fetal liver**
- migrate to **thymus** early in gestation for maturation
- rearrangement of T cell receptor genes to produce variety of **T cell receptors**
- recognise wide range of antigens presented by **antigen-presenting cells**
32
lymphocytes
- originate in bone marrow
- B cells mature in bone marrow
- T cells mature in thymus
- natural killer cells (cell mediated cytotoxicity)
33
causes of lymphocytosis
**reactive**
- viral infections
- bacterial infections - whooping cough
- stress related: MI, cardiac arrest
- post splenectomy
- smoking
**lymphoproliferative**
- chronic lymphocytic leukaemia (B cells)
- T or NK cell leukaemia
- lymphoma
34
erythropoiesis
HPSC
common myeloid progenitor
erythrocyte
35
why does erythropoiesis need to be a continual process
- RBCs have finite lifespan of 120 days in the bloodstream
- RBCs lack the ability to divide
36
erythropoietin
- secreted by kidney
- stimulates RBC production
- increases in response to hypoxia (decrease in blood oxygen level)
- 165 aa glycoprotein hormone
- inhibits apoptosis of CFU-E progenitor cells
- nucleated erythroblasts extrude nucleus and most of their organelles forming reticulocytes
37
what are reticulocytes
- immature red blood cells
- in bloodstream they extrude remnants of organelles and take 1-2 days to mature into RBCs
- reticulocyte count gives good diagnostic estimate of amount of erythropoiesis occuring
38
why are RBCs susceptible to oxidative damage
- lack nuclei so can't replace damaged proteins by re-synthesis
- carry oxygen
- e.g. G6PDH deficiency
39
erythrocytes
- 40-50% of total blood volume
- 4.4-5.9 x 10^12 cells/L
- anucleate biconcave discs ~ 8 µm in diameter
- shape optimises laminar flow properties of blood and allow them to squeeze through small capillaries
40
what is the normal Hb count
13.5 - 16.7 g/dl
41
what is the normal MCV (mean corpuscular volume)
80 - 100fl
42
function of erythrocytes
- deliver oxygen to tissues
- carry haemohglobin
- maintain haemoglobin in its reduced (ferrous) state
- maintain osmotic equilibrium
- generate energy
43
proteins in lipid bilayer of erythrocytes
**spectrin**: links plasma membrane to actin cytoskeleton
**ankyrin**: links integral membrane proteins to underlying spectrin-actin cytoskeleton
**Band 3**: chloride and bicarbonate exchange and linkage of membrane to cytoskeleton
**protein 4.2**: ATP binding protein
- facilitate **vertical interactions** with the cytoskeleton of the cell which are essential for maintaining the red cell’s **biconcave shape and deformability**
- gene mutations result in **hereditary spherocytosis**
44
plasma membrane of erythrocytes
- **lipid bilayer**
- changes to plasma membrane cause cells to become **less deformable and more fragile**
- **RBCs break down** as they pass through capillaries
- **spleen** recognises cells as abnormal and **removes them** from circulation so patient loses cells at more rapid rate
- **haemolytic anaemia** results
45
what does adult haemoblobin consist of
two alpha and two beta polypeptide subunits
46
structure of haemoglobin
- **tetramer** of two pairs of globin chains
- each subunit associated with **haem group**
- haem group comprises of **porphyrin ring** with **ferrous iron** (Fe2+) at centre that binds oxygen
47
fetal vs adult haemoglobin
- switches at **3-6 months **of age
- fetal Hb = **alpha** and **gamma** chains
- fetal Hb has **higher binding affinity** for O2 to allow transfer of oxygen to fetal blood from mother
48
how does haemoglobin bind oxygen
- when shifting between oxygen unbound and bound states haemoglobin undergoes a **conformational change** which **enhances binding affinity** of subsequent oxygen molecules
- 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
- gives the oxygen binding curve a **sigmoidal shape**
49
2 configurations of haemoglobin
- **oxyhaemoglobin** - relaxed binding structure
- **deoxyhaemoglobin** - tight binding structure
50
affinity of Hb for oxygen
**decreased by:** (rightward shift in oxygen dissociation curve)
- 2,3-bisphosphoglycerate (BPG)
- fall in pH
- increase in CO2 (Bohr effect)
51
where is the spleen located
left upper quadrant of the abdomen
52
what does the spleen consist of
**red pulp**
- sinuses lined by endothelial macrophages
- removes old red cells and metabolises the haemoglobin
**white pulp**
- similar structure to lymphoid follicles
- synthesises antibodies and removes antibody coated bacteria and blood cells
53
where does blood enter the spleen
- via the **splenic artery**
- white cells and plasma pass through white pulp
- red cells pass through red pulp
54
functions of the spleen
- **sequestration and phagocytosis**: old/abnormal red cells removed by macrophages
- **blood pooling**: platelets and red cells rapidly mobilised diring bleeding
- **extramedullary haemopoiesis**: pluripotent stem cells proliferate during haematological stress or if bone marrow fails
- **immunological function**: 25% of B cells and 15% of T cells in spleen
55
what is splenomegaly
enlarged spleen
56
causes of splenomegaly
- **portal hypertension** - back pressure from liver disease
- **increased workload of red or white pulp** - in RBC disorders increased number of defective red cells are removed from circulation
- **extramedullary haemopoiesis**
- **infiltration by leukaemias and lymphomas**
- **infiltration of other materials** - sarcoidosis, Gaucher's
- **infectious diseases** - malaria, schistosomiasis, HIV, glandular fever
57
clinical significance of splenomegaly
- **risk of splenic rupture** as spleen is no longer protected by rib cage
- **massive**: CML, myelofibrosis, malari, schistosomiasis
- **moderate**: lymphoma, leukaemias, myeloproliferative disorders, liver cirrhosis with portal hypertension, infections
- **mild**: infectious hepatitis, endocarditis, infiltrative disorders, autoimmune disorders
58
hypersplenism
- overactive spleen
- low blood counts can occur due to pooling of blood in spleen
59
what is hyposplenism
lack of functioning splenic tissue
60
causes of hyposplenism
- **splenectomy** - due to splenic rupture or cancer
- **sickle cell disease** - sickle cells block capillaries in red pulp and tissues becomes necrotic
- **gastrointestinal diseases** - Coeliac, Crohn's, ulcerative colitis
- **autoimmune disorders** - systemic lupus, rheumatoid arthritis, Hashimoto's disease
61
Howell Jolly bodies
- basophilic nuclear remnants (DNA) in circulating erythrocytes
- spleen would usually remove these cells
- presence in blood film is good indicator of reduced splenic function
62
examination of spleen
- never normal for spleen to be palpable **below costal margin** - protected by ribs
- start to palpate in **right iliac fossa (RIF)**
- 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
63
what is the reticuloendothelial system (RES)
- network of cells that are part of the larger **immune system**
- made up of **phagocytic cells**, **monocytes** in the blood and different types of **macrophages**
- main organs are **spleen** and **liver**
64
role of the RES
remove dead or damaged cells and identify and destroy foreign antigens in blood and tissues
65
types of macrophages
- **Kupffer cell** - liver
- **tissue histiocyte** - connective tissues
- **microglia** - central nervous system
- **peritoneal macrophage** - peritoneal cavity
- **red pulp macrophage** - spleen
- **Langerhans cell** - skin and mucosa
66
patients with hyposplenism
- **risk of sepsis from encapsulated bacteria** (streptococcus pneumonia, haemophilus influenzae, meningococcus)
- **immunised** and given **lifelong antibiotic prophylaxis**
67
degradation of haem
- **senescent red cells** engulfed by macrophages in RES
- Fe2+ is recycled
- haem metabolised to **bilirubin** which is transported in blood bound to **albumin**
- bilirubin taken up by liver and conjugated with **glucaronic acid** forming **bilirubin diglucoronide**
- secreted into **bile**
- bacteria in the intestines deconjugate and metabolise bilirubin into **colourless urobilinogen **
- oxidised to form **stercobilin** (responsible for the brown colour of faeces
- smaller amount of the urobilinogen is **reabsorbed** into blood and processed by the **kidneys** where it is oxidised to **urobilin** (gives urine its yellow colour)
68
what causes jaundice
excess unconjugated bilirubin in blood e.g. from haemolytic anaemias
