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MEH > Haemopoesis, spleen and bone marrow > Flashcards

Haemopoesis, spleen and bone marrow Flashcards

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
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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
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3
Q

main sites of haemopoiesis in adult bone marrow

A
  • pelvis
  • sternum
  • skull
  • ribs
  • vertebrae
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4
Q

distribution of bone marrow

A
  • extensive throughout skeleton in infant
  • more limited distribution in adulthood - central areas and skull (axial)
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5
Q

sources of haemopoietic stem cells

A
  • bone marrow aspiration
  • GCSF mobilised peripheral blood stem cells - collected by leucopharesis
  • umbilical cord stem cells
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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
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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
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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
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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

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10
Q

thrombopoesis

A

HPSC
common myeloid progenitor
megakaryocyte
platelets (bud off from megakaryocytes)

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11
Q

thrombopoietin (TPO)

A
  • produced by liver and kidney
  • regulates production of platelets by increasing production of megakaryocytes
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12
Q

megakaryocytes

A

very large mononucleate cells with several copies of each pair of chromosomes (produce platelets)

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13
Q

platelets

A
  • no nuclei
  • membrane bound fragments of cytoplasm that bud off from megakaryocytes
  • involved in clot formation
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14
Q

granulopoiesis

A

HPSC
common myeloid progenitor
myeloblast
granulocytes (basophil, neutrophil, eosinophil)

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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
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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

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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
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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

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19
Q

what is neutrophilia

A

increase in the absolute number of circulating neutrophils

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20
Q

causes of neutrophilia

A
  • infection
  • myeloproliferative diseases
  • acute inflammation
  • smoking and drugs
  • cancer
  • cytokines
  • metabolic and endocrine disorders
  • acute haemmorhage
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21
Q

what is neutropenia

A
  • neutrophil count <1.5 x 10^9/L
  • severe if < 0.5 x 10^9/L
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22
Q

consequences of neutropenia

A
  • severe life threatening bacterial infection
  • severe life threatening fungal infection
  • mucosal ulceration
  • neutropenic sepsis - IV antibiotics given immediately
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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

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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
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25
Q

causes of eosinophilia

A

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

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26
Q

monocytopoiesis

A

HPSC
common myeloid progenitor
myeloblast
monocyte
macrophage

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27
Q

monocytes

A
  • 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
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28
Q

causes of monocytosis

A
  • bacterial infection e.g. tuberculosis
  • inflammatory conditions e.g. rheumatoid arthritis, Crohn’s, ulcerative colitis
  • carcinoma
  • myeloproliferative disorders and leukamias
29
Q

lymphopoiesis

A

HPSC
common lymphoid progenitor
small lymphocyte
B lymphocyte, T lymphocyte

30
Q

B lymphocytes (humoral immunity)

A
  • 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
Q

T lymphocytes (cellular immunity)

A
  • 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
Q

lymphocytes

A
  • originate in bone marrow
  • B cells mature in bone marrow
  • T cells mature in thymus
  • natural killer cells (cell mediated cytotoxicity)
33
Q

causes of lymphocytosis

A

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
Q

erythropoiesis

A

HPSC
common myeloid progenitor
erythrocyte

35
Q

why does erythropoiesis need to be a continual process

A
  • RBCs have finite lifespan of 120 days in the bloodstream
  • RBCs lack the ability to divide
36
Q

erythropoietin

A
  • 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
Q

what are reticulocytes

A
  • 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
Q

why are RBCs susceptible to oxidative damage

A
  • lack nuclei so can’t replace damaged proteins by re-synthesis
  • carry oxygen
  • e.g. G6PDH deficiency
39
Q

erythrocytes

A
  • 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
Q

what is the normal Hb count

A

13.5 - 16.7 g/dl

41
Q

what is the normal MCV (mean corpuscular volume)

A

80 - 100fl

42
Q

function of erythrocytes

A
  • deliver oxygen to tissues
  • carry haemohglobin
  • maintain haemoglobin in its reduced (ferrous) state
  • maintain osmotic equilibrium
  • generate energy
43
Q

proteins in lipid bilayer of erythrocytes

A

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
Q

plasma membrane of erythrocytes

A
  • 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
Q

what does adult haemoblobin consist of

A

two alpha and two beta polypeptide subunits

46
Q

structure of haemoglobin

A
  • 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
Q

fetal vs adult haemoglobin

A
  • 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
Q

how does haemoglobin bind oxygen

A
  • 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
Q

2 configurations of haemoglobin

A
  • oxyhaemoglobin - relaxed binding structure
  • deoxyhaemoglobin - tight binding structure
50
Q

affinity of Hb for oxygen

A

decreased by: (rightward shift in oxygen dissociation curve)
- 2,3-bisphosphoglycerate (BPG)
- fall in pH
- increase in CO2 (Bohr effect)

51
Q

where is the spleen located

A

left upper quadrant of the abdomen

52
Q

what does the spleen consist of

A

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
Q

where does blood enter the spleen

A
  • via the splenic artery
  • white cells and plasma pass through white pulp
  • red cells pass through red pulp
54
Q

functions of the spleen

A
  • 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
Q

what is splenomegaly

A

enlarged spleen

56
Q

causes of splenomegaly

A
  • 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
Q

clinical significance of splenomegaly

A
  • 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
Q

hypersplenism

A
  • overactive spleen
  • low blood counts can occur due to pooling of blood in spleen
59
Q

what is hyposplenism

A

lack of functioning splenic tissue

60
Q

causes of hyposplenism

A
  • 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
Q

Howell Jolly bodies

A
  • 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
Q

examination of spleen

A
  • 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
Q

what is the reticuloendothelial system (RES)

A
  • 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
Q

role of the RES

A

remove dead or damaged cells and identify and destroy foreign antigens in blood and tissues

65
Q

types of macrophages

A
  • 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
Q

patients with hyposplenism

A
  • risk of sepsis from encapsulated bacteria (streptococcus pneumonia, haemophilus influenzae, meningococcus)
  • immunised and given lifelong antibiotic prophylaxis
67
Q

degradation of haem

A
  • 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
Q

what causes jaundice

A

excess unconjugated bilirubin in blood e.g. from haemolytic anaemias

MEH (26 decks)

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