Peter Browlett Lectures Flashcards
L2, 6, 7, 11
what is haematopoesis
Process by which mature blood cells are generated
from stem cells in the bone marrow
Why do we need to study
haematopoiesis ?
blood tests are important part of management of patients
definition of haematopoetic tissue and 2 main examples
tissues generating non-lymphoid cells of the blood
- bone marrow (mainly sternum)
- spleen
what are the haematopoetic sites during development?
yolk sac, AGM endothelium and placenta –> fetal liver –> bone marrow
changes in bone marrow of distal bones with age
during childhood there is progressive fatty replacement of marrow thoughout the long bones, the fatty tissue can revert back to haematopoetic tissue
what is extramedullary haematopoiesis, when is this observed?
haematopoesis in the organs other than bone marrow, e.g. spleen or liver. Can be observed in diseased states
what is myelofibrosis
type of myeloproliferative neoplasm- abnormal clone of HPSC - resulting in fibrosis (or replacement wiht scar tissue)
what are the main constituents of bone marrow?
trabecular bone
fat cells (stromal cells)
HPSC
changes to the cellularity of bone marrow with age
decrease
decribe the hierachy of the haematopoesis
stem cells generate progenitor cells (lymphoid and myeloid)
what antigen is used to measure stem cells
CD34 antigen is expressed on the human HSC
3 sources of HSCs
Bone marrow
umbilical cord
peripheral blood
function of erythropoetin
stimulate RBC production
function of thrombopoetin
stimulates platelet production
function of granulocyte colony stimulating factor
stimulates neutrophil production
3 Assessment of Blood & Bone
Marrow
full blood count (automated, gives absollute nyumbers and cell types - impt to look at morphology)
bone marrow examination - HSC
stem cells - look for CD34 positive cells
what is acute myeloid leukemia
- symptoms
- diagnosis
- treatment
cancer of the myeloid line of blood cells - rapid growth of abnormal cells.
- tiredness, bruising and easy infections
- diagnosis by decrease RBC and platelets, bone marrow examination
- treatment by chemotherapy and supportive care, antibiotics to prevent infections.
the shape of a RBC allows for
flexibility
increased area for gas exchange
function of RBC
Hb carriage
O2 transport
what is hereditary spherocytosis
abnormality in the membrane of RB causing shortened lifespan of the RBC
the RBC keeps the Hb in a ___ ____ and maintains _______ ________
reduced state
osmotic equilibrium
what is G6PD deficiency?
inherited defects in enzyme that prevents free radical build up pathways causing haemolysis (shortened RBC survival)
basic structure of haemoglobin
2 alpha globulin chains and 2 beta globulin chains and haem group
how does iron deficiency cause anaemia?
reduced production of haem due to low iron
how do thalassaemias cause anaemia
impaired production of globin chains- results in low Hb
what are the 4 morhological stages of erythroid precursor cell differentiation?
progressice increase in Hb
chromatin clumping
extrude nucelus
loss of RNA
average lifespan of RBC
120 days
main regulator of erythropoesis
- where is this produced
- what triggers production?
erythropoetin
- produced in kidneys
- responds to low O2 tensions (increase EPO production)
what are 4 effects of EPO?
binds to the EPO receptor
- stimulates RBC progenitor cells
- increased Hb synthesis
- reduced RBC maturation time
- increased reticulocyte release
when is clinical use of recombinant EPO?
anaemia of renal failure
- also myelodysplastic syndromes
process of RBC destruction- what are the end products?
RBC breakdown in the liver by macrophages
- Hb is broken down into haem and globin chains
haem:
- iron –> bone marrow
- protoporphyrin - bilirubin (liver-bile)
definition of anaemia
low Hb than normal for the age and sex patient
cardiovascular responses to anaemia
increased cardiac output (right shift in Hb dissociation curve)
- makes O2 more readily available to tissues
difference between physiological and morphological classifications of anaemia?
physiological- impaired production or increased loss/reduced survival
morphological- based on the appearance and size of cells (microcytic/macrocytic)
2 categories of physiological anaemia?
ineffecitve production or decreased RBC survival
3 main causes of impaired RBC production
decifiencies (B12, folate, iron)
genetic defect in produciton (thalassaemia)
bone marrow failure (leukemia, irradiation or drugs)
2 cause so freduced RBC survival
blood loss (trauma or surgery)
haemolysis
what parameters are used to differentiate morphological anaemias?
MCV, Hb concentration and blood film observations
what is the haematocrit
the ratio of colume of RBC to the total volume of blood
3 causes of microcytic hypochromic (reduced Hb) anaemia
iron deficiency
chronic illness (iron block)
genetic - thalassaemia
what are the 4 ways to diagnose iron deficiency?
measure serum iron, iron binding capacity (transferrin) and iron saturation, serum ferritin
what does serum iron measure?
measures the amount of iron in the liquid portion of the blood
what does transferrin measure?
directly measures the level of transferrin in the blood. Transferrin is the protein that transports iron around in the body. Under normal conditions, transferrin is typically one-third saturated with iron. This means that about two-thirds of its capacity is held in reserve
what does serum ferritin measure?
reflects the amount of stored iron int he body
what does TIBC measure?
(total iron-binding capacity)—measures the total amount of iron that can be bound by proteins in the blood. Since transferrin is the primary iron-binding protein, the TIBC test is a good indirect measurement of transferrin availability.
what does UIBC measure?
(unsaturated iron-binding capacity)—The UIBC test determines the reserve capacity of transferrin, i.e., the portion of transferrin that has not yet been saturated with iron. UIBC also reflects transferrin levels.
what does Transferrin saturation measure?
a calculation that reflects the percentage of transferrin that is saturated with iron (100 x serum iron/TIBC)
Iron is normally absorbed from food in the ____ ______ and transported throughout the body by binding to ________, a protein produced by the _____. In healthy people, most of the iron transported is incorporated into the production of ________. The remainder is stored in the tissues as ______.
Iron is normally absorbed from food in the small intestine and transported throughout the body by binding to transferrin, a protein produced by the liver. In healthy people, most of the iron transported is incorporated into the production of hemoglobin. The remainder is stored in the tissues as ferritin.
what is haemachromatosis?
rare genetic disease in which the body absorbs and builds up too much iron, even on a normal diet.
serum iron, UIBC and serum feritin levels in iron deficiency
increased UIBC and decreased SF
serum iron, saturation, TIBC and serum feritin levels in anaemia of chronic disease (inflammation)
ferritin is normal or high (ferritin is a acute phase protein)
normal or slightly decreased serum iron and TIBC
normal saturation
why is ferritin known as a acute phase protein? why does this increase with chronic disease
increases with inflammation
- liver damage can cause ferritin to leak out
- also in hodgkins lymphoma
4 causes of iron deficiency
diet (vegetarian)
malabsoprtion (proximal small bowel)
increased demands (pregnancy)
chronic blood loss (GI tract malignancy)
what are the 2 forms of iron replacement therapy? example for each?
oral= ferogradumet IV= ferric carboxymatlose
what is hepcidin, why is it high during inflammation and what are the downstream effects?
regulator of entry of iron into the bloodstream
- inflammation causes high hepcidin, serum iron falls due to iron trapping within the macrophages and liver cells + decreased gut iron absoprtion.
this causes iron deficiency and hence anaemia
RBC cellular characteristics of beta thalassaemia
fragmented or irregular shaped RBC
Small or microcytic RBC
diagnosis of thalassaemia
blood counts (Hb, MCV and RBC counts) - iron studies and phenotypic analysis
5 main causes of macrocytic anaemia
B12/folate def alcohol liver disease primary bone marrow disorders hypothyroidism
example of macrocytic megaloplastic anaemia cause- what is the mechanism?
B12/folate deificiency
- impaired DNA synthesis
causes of low B12/folate
diet - vegans (B12 is in milk, eggs and meat) malabsorption - gastrectomy - immune (pernicious anaemia) - terminal ileum disease
why do B12 deficiencies present late?
the body has stores of B12 for 3-4 years
causes of low folate
lack of veges
coeliac
increased demands (pregnancy)
2 types of haemolytic anaemia
intrinsic = inherited defect in the RBC membrane
extrinsic = autoimmune
clinical presentation of haemolytic anaemia
anaemia
jaundice, splenomegaly
raised reticulocyte count (due to increased production)
what are the 2 main types of leukocytes?
phagocytes
lymphocytes
sub-categories of phagocytes and examples
granulocytes (neutrophils-90%, eosino and basophils)
monocytes
describe teh kinetics of granulocyte production?
- maturation time
- circulating time
7-10 day maturation
6-10 hours circulation before entering tissues for phagocytosis
main regulators of granulopoiesis
haematopoetic growth factors
IL3, stem cell factor, G-CSF
what is G-CSF, (brand name) and effects- who is it used for?
granulocyte colony stimulating factor (filgastrim)
- used in patients with neutropenia (bone marrow failure, chemotherapy)
3 functions of neutrophils
chemotaxis
phagocytosis
killing bacteria
- (non)/oxidative
what is Neutrophil leucocytosis
increased number of neutrophils usually due to inflammation or infection
what is neutropenia, what are the risks (what is this called?)
patients with a low neutrophil count
- have an increased risk of infection
- -> febrile neutropenia
which of the phagocytes are granulocytes?
neutrophils
eosinophils
basophils
process of monocyte development
circulate for 1-3 days
- enter tissues (transform into macrophages)
what are the main phagocytic functions of monocytes?
chemotaxis
opsonisation
phagocytosis (and ingestion)
what are the 3 main roles of the monocytes?
phagocytosis
synthetic functions (complement, interferon)
antigen presentation
what is monocytosis? what are the 2 types? examples?
monocytosis- increased
- reactive= chronic infections (TB)
- malignant- acute/chronic myeloid leukemia (monoblastic type)
what is Eosinophilia and when is this observed?
increase in eosinophils- allergy/hypersensitivity reactions
also parasite infections
effects and function of basophils
close relationship to mast cells
- allergic symtpoms
granules contain histamine (vasoldilation)
what is the normal make up of citculating lymphocytes? (%)
75% ish T cells
10% B cells
NK cells
what are primary lymphoid organs and examples for B cells and T cell?
where lymphocytes are formed and mature
B= Bone marrow
T= Thymus
what are Secondary Lymphoid Organs
and examples?
where lymphocytes are activated
- lymph nodes
spleen
bone marrow
what are the 2 potential classifications of causes of lymph node enlargement?
reactive - viral/bacterial infection
malignancy- lymphomas or metastatic spread
causes of Lymphocytosis
reactive - viral (infectious mononucelosis)
malignant - chronic lymphocytic leukemia
Lymphopenia causes?
HIV infections (CD4 T cell deficit) - steroid therapy, bone marrow failure
define Polycythaemia
state of disease where haematocrit is increased
4 mains types of blood and bone marrow cancers
leukemia
myeloproloferative neoplasms
lymphomas
myeloma
what is the pathological process of leukemia
proliferation of immature bone marrow cells (lose abiloity to differentiate beyond “blast” cells)
- expand tha replace normal cells
- abnormal leukemic cells spill into the blood.
4 pathogenesis causes of leukemia?
congenital/inherited
viral infections
radiation
chemical/DNA changing drugs
2 subtypes of acute leukemia?
acute myeloid leukemia (AML)
Acute lymphoblastic leukemia (ALL)
2 types of leukemia?
acute, chronic
what are the 3 main clinical symptoms of Acute leukemia?
what are some less common symptoms?
loss on normal cells (RBC, platelets and neutrophils)
- fatigue (anaemia), bleeding (thrombocytopenia) and infections (neutropenia)
liver and spleen enlargement bone pain (marrow infiltration)
what ages are acute leukemia likely to present?
occur over all ages
- ALL - mainly childhood
AML - mainly adults
how is leukemia diagnosed?
full blood count
bone marrow biopsy
blood count results of leukemia
full blood count
- anaemia
- WBC increase
- usually severe thrombocytopenia
bone marrow biopsy indications of leukemia
over 20% blasts (myeloid or lymphoid)
treatment for acute leukemia
general/supportive care:
- infusion (RBC and platelets)
managing infections (antibiotics)
chemotherapy
HSC transplant
what are the 3 steps of acute leukemia chemotherapy?
Induction therapy- lower the number of plasma cells in bone marrow (induce remission)
consolidation- to mop up residual leukaemia
cells
maintainance therapy (only ALL)- keep patients in remission
what is autologous and allogenic HSC transplant?
autologous- own stem cells are taken in remission
allogenic- matched sibling or unrelated donor
