Haemopoesis, spleen and bone marrow Flashcards
what is haemopoiesis
- process by which blood cells are formed
- involves specification of blood cell lineages and proliferation to maintain an adequate number of cells
where does haemopoiesis occur
- vasculature of yolk sac in early embryo
- embryonic liver by week 5-8 of gestation
- solely in bone marow after birth
main sites of haemopoiesis in adult bone marrow
- pelvis
- sternum
- skull
- ribs
- vertebrae
distribution of bone marrow
- extensive throughout skeleton in infant
- more limited distribution in adulthood - central areas and skull (axial)
sources of haemopoietic stem cells
- bone marrow aspiration
- GCSF mobilised peripheral blood stem cells - collected by leucopharesis
- umbilical cord stem cells
what is differentiation of haemopoetic stem cells determined by
- hormones
- transcription factors
- interactions with non-haemopoetic cells types e.g. endothelial cells
what are the five major lineage pathways of haemopoetic stem cells
- thrombopoesis - platelets
- erythropoesis - red blood cells
- granulopoesis - basophils, neutrophils, eosinophils
- monocytopoesis - monocytes
- lymphopoesis - B and T lymphocytes
haemopoietic stem cells (HPSCs)
- 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
what is extramedullary haematopoiesis
when HPSCs mobilise into circulating blood to colonise other tissues (e.g. spleen and liver) in pathological conditions like myelofibrosis or thalassaemia
thrombopoesis
HPSC
common myeloid progenitor
megakaryocyte
platelets (bud off from megakaryocytes)
thrombopoietin (TPO)
- produced by liver and kidney
- regulates production of platelets by increasing production of megakaryocytes
megakaryocytes
very large mononucleate cells with several copies of each pair of chromosomes (produce platelets)
platelets
- no nuclei
- membrane bound fragments of cytoplasm that bud off from megakaryocytes
- involved in clot formation
granulopoiesis
HPSC
common myeloid progenitor
myeloblast
granulocytes (basophil, neutrophil, eosinophil)
basophils
- 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
causes of basophilia
reactive
- immediate hypersensitivty reactions
- ulcerative collitis
- rheumatoid arthritis
myeloproliferative
- chronic myeloid leukemia
- myeloproliferative neoplasm: essential thrombocytaemia, polycythemia vera, myelofibrosis
- systemic mastocytosis
neutrophils
- 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
G-CSF hormone
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
what is neutrophilia
increase in the absolute number of circulating neutrophils
causes of neutrophilia
- infection
- myeloproliferative diseases
- acute inflammation
- smoking and drugs
- cancer
- cytokines
- metabolic and endocrine disorders
- acute haemmorhage
what is neutropenia
- neutrophil count <1.5 x 10^9/L
- severe if < 0.5 x 10^9/L
consequences of neutropenia
- severe life threatening bacterial infection
- severe life threatening fungal infection
- mucosal ulceration
- neutropenic sepsis - IV antibiotics given immediately
causes of neutropenia
reduced production
- B12/folate deficiency
- aplastic anaemia
- viral infection
- congenital
- infiltration
- radiation
- drugs
increased removal or use
- immune destruction - autoantibodes
- splenic pooling
- sepsis
eosinophils
- 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
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
monocytopoiesis
HPSC
common myeloid progenitor
myeloblast
monocyte
macrophage
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
causes of monocytosis
- bacterial infection e.g. tuberculosis
- inflammatory conditions e.g. rheumatoid arthritis, Crohn’s, ulcerative colitis
- carcinoma
- myeloproliferative disorders and leukamias
lymphopoiesis
HPSC
common lymphoid progenitor
small lymphocyte
B lymphocyte, T lymphocyte
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
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
lymphocytes
- originate in bone marrow
- B cells mature in bone marrow
- T cells mature in thymus
- natural killer cells (cell mediated cytotoxicity)
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
erythropoiesis
HPSC
common myeloid progenitor
erythrocyte
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
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
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
why are RBCs susceptible to oxidative damage
- lack nuclei so can’t replace damaged proteins by re-synthesis
- carry oxygen
- e.g. G6PDH deficiency
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
what is the normal Hb count
13.5 - 16.7 g/dl
what is the normal MCV (mean corpuscular volume)
80 - 100fl
function of erythrocytes
- deliver oxygen to tissues
- carry haemohglobin
- maintain haemoglobin in its reduced (ferrous) state
- maintain osmotic equilibrium
- generate energy
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
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
what does adult haemoblobin consist of
two alpha and two beta polypeptide subunits
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
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
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
2 configurations of haemoglobin
- oxyhaemoglobin - relaxed binding structure
- deoxyhaemoglobin - tight binding structure
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)
where is the spleen located
left upper quadrant of the abdomen
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
where does blood enter the spleen
- via the splenic artery
- white cells and plasma pass through white pulp
- red cells pass through red pulp
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
what is splenomegaly
enlarged spleen
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
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
hypersplenism
- overactive spleen
- low blood counts can occur due to pooling of blood in spleen
what is hyposplenism
lack of functioning splenic tissue
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
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
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
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
role of the RES
remove dead or damaged cells and identify and destroy foreign antigens in blood and tissues
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
patients with hyposplenism
- risk of sepsis from encapsulated bacteria (streptococcus pneumonia, haemophilus influenzae, meningococcus)
- immunised and given lifelong antibiotic prophylaxis
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)
what causes jaundice
excess unconjugated bilirubin in blood e.g. from haemolytic anaemias
