the red blood cell and what can go wrong Flashcards
what 5 things do RBCs need to function
- efficient production (synthesis)
- to be pliable (get through small vessels)
- haemoglobin to carry oxygen
- enzymes for metabolism
- removal of defective cells
what is erythropoiesis
synthesis of red cells
where does erythropoiesis happen
in the bone marrow - alongside production of other blood cell lines
what is the progenitor cell for RBCs
myeloid stem cell
erythropoiesis pathway
stem cell ->immature RBC -> erythroblast -> nucleated RBC -> reticulocyte (nucleus lost) -> erythrocyte
requirements for erythropoiesis (5)
normal stem cell; normal maturation; healthy bone marrow microenvironment; growth factors (erythropoietin, GM-CSF); essential components (iron, vit B12, folate, amino acids)
what gives RBCs their pliability
their structure - biconcave shape that arises due to Band-3 proteins and Spectrin in the membrane
fucntions of band-3 and spectrin
band-3 : provides a verticle scaffold for the cell membrane;
spectrin: comprises the main component of the cytoskeleton (provides a horizontal scaffold)
what is HbA comprised of
2 alpha and 2 beta globulin chains + 4 haem groups
where are the genes for the alpha globulin chains (chromosome)
chromosome 16
where are the genes for the beta-like globulin chains
chromosome 11
why are there twice as many alpha genes as beta genes
alpha chains are more important - they are present on all forms of haemoglobin from foetal stage onwards
what are the beta-like globulin chains and what Hb are they associated with
β - HbA (adult)
γ - HbF (foetal)
δ - HbA2 (low levels)
when is the switch from γ to β chain synthesis complete
3-6 months after birth; remains the same in adult life
why is it important to note the delay in switch from HbF to HbA (occurs at 3-6mo)
conditions with a β chain gene mutation will not present at birth as HbF (gamma chains) is still predominant
examples of β-chain mutations that may manifest 3-6mo after birth
sickle cell haemoglobin; β-thalassaemia
why is haemoglobin different in the foetus
HbF has a higher oxygen affinity and so O2 therefore flows from the maternal circulation to foetal and more readily across the placenta
why are enzymes essential to the function of RBCs
RBCs have no nucleus or mitochondria and so rely on enzymes to maintain the integrity of the cell membrane
primary functions of enzymes in RBCs + examples (2)
- protection against oxidative stress: G6PD -> involved in the pentose phosphate pathway -> generates NADPH which stabilises the RBC;
- ATP production: pyruvate kinase is involved in glycolysis (first step of ATP production)
what is the lifespan of a normal RBC and what are they removed by
120 days; removed by macrophages
what is anemia
a haemoglobin concentration below the reference range (specific to age and biological sex of the pt)
what 3 things does anaemia occur as a result of
- too few RBC;
- reduced Hb levels (on a normal/raised number of RBCs);
- abnormally low haematocrit;
what is a haematocrit
the term used for the percentage/ratio of blood made up of RBCs - packed cell volume
what can reduce the haematocrit
reduction of RBCs or increase in plasma volume
what do the symptoms of anaemia depend on and why
the speed of onset - acute will have more marked symptoms while chronic will have less severe as the body has had time to compensate for Hb reduction
what ar the 3 types of anaemia (according to MCV)
microcytic; normocytic; macrocytic
5 causes of microcytic anaemia
iron deficiency; thalassaemia; anaemia of chronic disease; lead poisoning; sideroblastic anaemia
5 causes of normocytic anaemia
anaemia of chronic disease; acute blood loss; chronic renal failure; mixed B12/folate and iron deficency; bone marrow disorders
7 causes of macrocytic anaemia
B12/folate deficency; liver disease; drugs/alcohol; reticulocytosis (haemolyis); hypothyroidism; myelodysplasia; pregnancy
how else can anaemia be classified (not MCV)
reduced RBC production; increases destruction (haemolysis) or loss
what may cause an RBC stem cell to be defective
inherited condition; acquired (drugs, infections, immune)
what may cause defect maturation of an RBC
lack of nutrients important for DNA synthesis; blood disorder causing impaired maturation e.g. myelodysplasia
what may cause an unhealthy microenvironment for RBCs to be produced
damage (radiation, infections etc.); lack of space (fibrosis, primary haem malignancy, secondary malignancy)
what is the effect of chronic renal impairment on RBC production
reduced erythropoietin levels resulting in decreased stimulation of RBCs
what kind of anaemia usually occurs due to decreased RBC production (not due to iron/B12 deficiency)
normocytic, normochromic
what does a low reticulocyte count indicate (and low RBCs)
bone marrow failure -> numbers should be higher is bone marrow is responding to a drop in RBC
what is aplastic anaemia
bone marrow cannot make enough new blood cells for your body to work normally
what is myelodysplastic syndrome
a group of cancers in which immature blood cells in the bone marrow do not mature or become healthy blood cells
what is anaemia of chronic disease
ineffective iron utiisation due to raised hepcidin -> result of a chronic inflammatory disease
what does raised hepcidin cause
functional iron deficiency - in ability to use iron effectively in the production of red blood cells
anaemia of chronic disease ferratin + transferrin saturation levels
ferratin - high
transferrin saturation - low
what is haemolytic anaemia
anaemia due to RBC destruction > production
what is haemolysis
the breakdown of RBCs before their normal lifespan (120 days)
what happens to RBC production when haemolysis occurs and what cell will be increased in circulation due to this
production is increase, the bone marrow can increase production by 6-8x the normal rate; leads to increased number of reticulocytes circulating in the blood
why are reticulocytes purple in colour (on a blood film)
it still contains some RNA within it
3 signs of haemolysis
jaundice - when Hb breaks down, bilirubin is formed -> build up of it in the body causes jaundice;
dark urine - bilirubin -> urobilinogen which causes dark urine;
gallstones - when haemolysis is chronic
(possibly also haemoglobinuria and anaemia signs - fatigue etc.)
blood results in haemolysis
MCV - normal or high (normocytic or macrocytic anaemia);
reticulocytes - raised;
unconjugated bilirubin - raised;
LDH - raised;
heptoglobin - low;
what is LDH and when does it become raised
an intracellular enzyme that catalyzes the conversion of lactate to pyruvate and back, as it converts NAD⁺ to NADH and back; it becomes raised when cell turnover is increased
intrinsic causes of haemolysis (3)
- membranopathy
- metabolism (enzymopathy)
- haemoglobinopathies
3 inherited RBC membrane abnormalities and their consequence
- hereditary spherocytosis
- hereditary elliptocytosis
- herediatry stomatocytosis
leads to RBCs that cannot maintain their biconcave shape -> leads them to being more eaily damages and thus removed by macrophages earlier in their lifecycle
what type of inheritance are RBC membrane defects usually
autosomal dominant
4 conditions that may be caused by inherited RBC defects
- mild anaemia presenting at any age;
- jaundice fluctuations (usually worse during infections);
- gallstones;
- aplastic crises precipitated by parvo virus (B19) - temporary failure in RBC production
what is an aplastic crisis
when the bone bone marrow suddenly stops making red blood cells so you develop severe and potentially life-threatening anemia
what is the Coomb’s test
a test used to detect antibodies that act against the surface of your red blood cells - antibodies directed against human antibody is added to a sample of the pt’s RBCs and if they are coated in antigen they will agglutinate by cross linking with the antibody
investigations for suspected inherited RBC membrane defect
FH, blood film, haemolysis screen, special tests (e.g. EMA binding, genetic testing)
treatment for inherited RBC membrane defect
folic acid; splenectomy (severe cases)
what is the most common enzymopathy associated with haemolysis
G6PD deficency
why is G6PD essential to the RBC
allows the RBC to protect itself from oxidative stress -> produces NADPH via pentose phosphate pathway which is needed for glutathioe regenration (this detoxified H2O2);
without this RBC breakdown when exposed to oxidative stress
what inheritance pattern is G6DP deficiency and how does this affect the epidemiology
X-linked recessive -> affects males more than females
examples of oxidative stressors that may cause acute haemolysis episodes
drugs; infections; moth balls; fava beans
what would a positive Coomb’s test indicate
autoimmune cause
where in the world are haemoglobin abnormalities more common
areas with malaria -> shorter RBC life span would offer protections against some forms of malaria thus giving them an evolutionary advantage
what is a cause of thalassaemia
reduced globin chain synthesis: α thalassaemia occurs due to reduce α chain synthesis and β due to reduce β chain synthesis
what kind of people is thalassaemia most common in
people of asain, african or mediterranean
consequences of thalassaemia pathway (4)
- chain imbalance
- excess α/β chains precipitate
- precipitated chains damage RBC membrane
- damaged cells destroyed prematurely by macrophages
thalassaemia major vs trait
major - NO α/β chains produced;
trait - reduced α/β chains produced (person is largely unaffected);
what is HbH disease
people who have 1/4 alpha genes functioning and produce Hb with four β chains instead -> variable phenotype, some require lifelong transfusion while others are mildly affected
β thalassaemia train Hb composition in the body
greater proportion of Hb is made up by HbA2 (2α + 2 δ)
what is important to know about with 2 gene deletion α thalassaemia trait (genetics) and why
whether the deletions are from the same chromosome (α-0-thalassaemia trait) or not (α-plus-thalassaemia trait) -> risk of conceiving a foetus with no α genes at all (if partner is also α-0-thalassaemic)
what kind of anaemia is seen in pts w thalassaemia/thalassaemia trait and what must be excluded in diagnosis
hypochromic, microcytic anaemia - must rule out iron deficiency
how can the relative quantities of each haemoglobin type be established
haemoglobin electrophoresis/ high performance liquid chromatography - separated the different haemoglobins according to their charge
why is HbA2 higher in beta thalassaemia trait
some excess α chains pair with δ chains leading to raised HbA2 levels
why does haemoglobin analysis not pick up alpha-thalassaemia trait?
there is a global reduction in Hb rather than just one specific type reduced
what kind of anaemia is sickle cell disease
chronic haemolytic anaemia
alongside HbS, what else might be seen in a blood test of a sickle cell anaemic
leucocytosis; thrombocytosis - common in pts with poor splenic function
what is a compound heterozygote and what does it mean in terms of sickle cell anaemia
a type of germline variant that occurs when each parent donates one alternate allele and these alleles are located at different loci within the same gene - i.e. one parent donates a sickle cell allele and the other an absent β gene (β-thalassaemia trait) -> without this no β chains can be made so HbA cannot be produced, only HbS and HbA2
what is paroxysmal nocturnal haemoglobinuria
a rare disease in which RBCs lyse prematurely (haemolysis) - due to inability of the RBCs to protect themselves from being attacked by compliment proteins
4 extrinsic causes of haemolysis
antibody attack (against rbc memebrane); mechanical trauma to the rbc; infections; chemical + physical agents
what is autoimmune haemolytic anaemia
haemolytic anaemia caused by the person’s own antibodies attacking the rbc -> leads to their premature removal by the spleen
what test is used to detect autoimmune haemolytic anaemia
Coomb’s test
warm vs cold antibodies (AIHA)
warm - antibodies that bind to RBCs at body temperature, usually IgG;
cold - antibodies that bind below body temperature, usually IgM
4 causes of warm autoimmune haemolytic anaemia
- idiopathic (usually);
- autoimmune conditions e.g. SLE (secondary to);
- disordered immune system (low grade lymphoma, CLL etc.);
- drugs - antibodies agaisnt drug-RBC membrane complex (penicillin) or antibodies against the rbc membrane (methyldopa);
where does rbc breakdown happen in warm autoimmune haemolytic anaemia
the reticuloendothelial system (live + spleen)
4 causes of cold autoimmune haemolytic anaemia
IgM antibodies can activate complement and cause intravascular haemolysis;
1. idiopathic;
2. lymphoma (usually);
3. infections (EBV etc.);
4. paroxysmal cold haemoglobinura (rare, associated w siphylis);
paroxysmal cold haemolgobinuria pathophys
IgG antibody is formed which is capable to binding to RBCs in the cold but only capable of causing haemolysis in the warm where it can activate complement
AIHA lab findings
anaemia; reticulocytosis; raised LDH; raised unconjugated bilirubin; positive Coombs
warm autoimmune haemolytic anaemia blood film
spherocytes (red cells with no central pallor)
cold autoimmune haemolytic anaemia blood film
red cell agglutination
autoimmune haemolytic anaemia management
- treat any underlying cause;
- keep pt warm if cold AIHA and consider warming any blood for transfusion;
- folic acid supplements (otherwise anaemia would be worsened);
- tranfusion;
- immune suppression (coticosteroids for warm, rituximab (anti- CD20) for both);
- splenectomy if resistant
what can mechanical trauma cause to the rbc
intravascular haemolysis
3 examples of mechanical trauma causes
- microangiopathic haemolytic anaemia;
- fault mechanical heart valves;
- march harmoglobinuria (repeated mechanical force on capillaries in feet e.g. during marching or marathon running);
4.
Coomb’s and urine test results for mechanical rbc trauma haemolysis
Coomb’s -ve; urine +ve for Hb (as haemolysis occurs in BVs)
blood film of mechanical trauma haemolysis
schistocytes - fragmented red blood cells
what infections can cause haemolysis
malaria;
what chemical/physical agents can cause haemolysis (5)
drugs (dapsone); copper; lead; burns; snake/spider bites etc.
what condition is an acquired cause of instrinsic haemolysis
paroxysmal nocturnal haemoglobinuria
where is there a defect in PNH
bone marrow stem cells -> defect in the anchoage of surface proteins because of the absence of glycoslyphoshatidylinositol (GPI)
why do rbcs lyse in PNH
the lack of GPI means that the red cell is not protected form lysis by compliment
findings in a PNH pt (bloods, urine)
blood - high levels of free Hb;
urine - dark
what are PNH pts at an increased risk of
clot formation esp at unusal sites e.g. hepatic veins
