Anaemia Flashcards
What is the definition of anaemia in men and women?
Men: <135 g/L
Women: <115 g/L
3 broad causes of anaemia based on mechanism and size
- decreased hB production
- Increased Hb consumption
- Dilutional anaemia
size: microcytic, macrocytic, normocytic
Causes of microcytic anaemia (FAST)
- F- Fe- iron deficiency anaemia
- A: anaemia of chornic disease
- S-siderbalstic anaemia
- T- thalassamiea (may not have anaemia if it is mild- eg thalassameia triat)
Causes of normocytic anaemia
All Hoes Fuck Prostitutes
A: anaemia of chronic disease
H: hypothyoridism
F: failure of bone marrow
P: pregnancy causing dilutional anaemia due to increase in plasma volume
Causes of macrocytic anaemia
FATRBC
Fetus (pregnancy)
Antifolates (eg phenytoin)
Thyroid (hypothyroidism)- thyroid hormone is required to produce EPO
Reticulocytosis -
B12 or folate deficiency
Cirrhosis (alcohol excess OR liver disease)
Other haem causes: Myelodysplastic syndromes, myeloproliferative disorders, multiple myeloma
Iron deficiency anaemia: iron studies, FBC, blood film, management
- microcytic anaemia
Iron studies
- low Fe
- low ferritin
- high transferrin
- high TIBC
Blood film
- pencil cells (aka cigar cells)
FBC
reactive thrombocytosis
Management
Ferrous sulphate and investigate underlying cause
Thalassaemia: key features
Blood film
basophillic stippling - aggregation of ribosomes
target cells
micocytic anaemia
iron studies
NORMAL
management
transfusions
iron chelation
Sideroblastic anaemia: key features
causes: congenital or acquired
**you have enough iron but body cannot incorporate it into haemoglobin so it builds up in diff places**
- iron accumulation within the bone marrow leading to ineffective erythropoiesis. you also get iron deposition in other parts leading to endocrine, liver and cardiac damage.
causes- myelodysplastic disorders, following chemotherapy, irradiation, alcohol excess, lead poisoning, anti-TB drugs or myeloprolfierative disease
blood film
basophilic stippling
bone marrow
ring sideroblasts
iron studies
- high iron
- high ferritin
- low transferrin
- low TIBC
management
treat underlying cause
PYRIDOXINE (vitamin B6) - aids with erythrpoiesis
anaemia of chronic disease
causes- infection, inflammation, malignancy
iron studies
- low iron
- raised ferrtin
- low transferrin- low TIBC
(same as sideroblastic anaemia)
+ RAISED CRP AND ESR
causes of megaloblastic anaemia and how to differentiate between them
causes of non-megaloblastic anaemia and how to differentiate between them
how to classify normocytic anaemia??
- Haemolytic
a) inherited - membrane, haemoglobin, metabolism
b) acquired
- autoimmune - warm vs cold
- alloimmune - rehsus or abo incomaptibility - Non-haemolytic
- anaemia of chronic disease
- failure of erythropoiesis
How to split up haemolytic anaemias?
**don’t forget that metallic heart valves can cause haemolytic anaemia**
**cancers can cause MAHA**
how to classify haemolysis (DIFF FROM CLASSIFICATION OF HAEMOLYTIC ANAEMIAS!!)
*with intravascular haemolysis the rbc get excreted through kidneys
classification of inherited haemolytic anaemias
types of red blood cell membrane disorders
- vertical interaction: hereditary spherocytosis
- horizontal interaction: hereditary elliptocytosis
**alphabetical order- he, vs**
guidelines for when to suspect rbc membrane disorders?
basc when you’ve ruled out everything else!!
when do you see retiuclocytes on blood film?
features of hereditary spherocytosis
inheritance- autosomal dominant
**in qs: often father has splenectomy**
blood film- spherocytes, polychromasia
test- positive osmotic fragility, positive eosin-5-maelimide test (MOST SENSITIVE)
treatment - folate supplementation, splenectomy (as you get extravascular haemolysis)
G6PD: inheritance
x linked recessive
**usually affects males**
g6pd: pathophysiology
G6PD generates NADPH via pentose phosphate pathway
Episodes of acute haemolysis following exposure to oxidative stress (e.g. fava beans, mothballs, drugs)
**NB: it’s generaly ACUTE haemolysis, very rarely chronic
Clinical consequences: common cause of neonatal jaundice
g6pd: blood film
bite cells (because macrophages take a BITE), heinz bodies, hemighost cells
*heinz bodies only seen when you stain with methyl-violet.*
(this is during an episode of acute haemolysis)
g6pd: treatment
avoidance of triggers
g6pd: type of haemolysis
intravascular haemolysis
low haptoglobins,increased unconjugated bilirubin, haemoglobinuria, high LDH
Which drugs can cause haemolysis in G6PD deficiency?
basically all sulfa drugs can cause haemolysis
sulph- drugs: sulphonamides, sulphasalazine and sulfonylureas can trigger haemolysis
what antibodies present in warm aha
IgG
antibodies in cold aha
IgM
causes of cold vs warm aha
warm: associated with CLL, SLE, Methyldopa (basc non infectious)
cold: associated with mycoplasma, EBV, Hep C (basc infections)
_____________________
passmed:
Warm AIHA
Warm is the most common type of AIHA. In warm AIHA the antibody (usually IgG) causes haemolysis best at body temperature and haemolysis tends to occur in extravascular sites, for example the spleen.
Causes of warm AIHA
idiopathic
autoimmune disease: e.g. systemic lupus erythematosus*
neoplasia
lymphoma
chronic lymphocytic leukaemia
drugs: e.g. methyldopa
Management
treatment of any underlying disorder
steroids (+/- rituximab) are generally used first-line
Cold AIHA
The antibody in cold AIHA is usually IgM and causes haemolysis best at 4 deg C. Haemolysis is mediated by complement and is more commonly intravascular. Features may include symptoms of Raynaud’s and acrocynaosis. Patients respond less well to steroids
Causes of cold AIHA
neoplasia: e.g. lymphoma
infections: e.g. mycoplasma, EBV
*systemic lupus erythematosus can rarely be associated with a mixed-type autoimmune haemolytic anaemia
what type of haemolysis does cold vs warm aha cause
warm- extravascular
cold- intravascular
how to treat AHA?
same for cold and warm
treat underlying cause
steroids
rituximab (anti CD20)
pathophysiology of MAHA
non-immune mediated small vessel disease
endothelial damage–>platelet aggretation, fibrin aggregation. RBC get stuck within the small blood vessels and haemolysed.
blood film in MAHA
schistocytes, thrombocytopaenia
which disorders do you see maha in?
hus, ttp, dic
how to distinguish causes of maha using clotting tests?
TTP+HUS: normal PT, APTT and fibrinogen
DIC: prolonged PT and APTT, low fibrinogen
what causes HUS?
Escherichia coli O157:H7 – Shiga-like toxin
epideiology of HUS
More frequent but less severe in children
triad of symptoms in HUS + management
MAHA, thrombocytopaenia, acute renal failure. self limiting in children
often after an episode of diarrheoa
managemebt- supportive
TTP pentad
MAHA, thrombocytopaenia, acute renal failure, fever, neuroligical symptoms
what defect causes TTP
deficiency of ADAMSTS enzyme.
this causes overactiivty of vWF–> too much clotting
**this can be inherited or acquired*
why is it important to catch TTP?
because it has high mortality rate.
need to catch early to treat quickly with supportive care and plasma exchange (to remove the antibodies that are attacking ADAMSTs13 enzyme)
**the reason it affects the brain selectively to cause neuro symptoms is because the brian is particularly susceptible to ischameia*
summarise the physiology of haemoglobin
- 4 globin chains surround haem group
- globin chains coded for by alpha and beta genes
- we have 4 alpha genes and 2 beta genes
- types of haemoglobin:
a) HbA: 2 alpha, 2 beta (>95% of adult Hb)
b) HbA2: 2 alpha, 2 gamma (<3% of adult Hb)
c) HbF: 2 alpha, 2 delta (<1% if adult Hb, more common in babies)
Which part of Hb does alpha thalassaemia, beta thalassaemia, SCD and HbH disease affect?
Alpha thalassaemia and HbH disease affect the alpha globin gene.
Beta thalssaemia and SCD affect the beta globin gene
What is the embryonic form of haemoglobin?
Hb gower/ portland.
ζ2ε2
(2 zeta, 2 epsilon)
Levels of different haemoglobin genes over time
Summary:
- alpha stays high throughout
- beta was ow in foetal stage, increases ina dulthood
- gamma was high in foetal stage and then decreases in adulthood
- delta was nonexistent in foetal stage, increases in adulthoot but levels are always low
- zeta and episilon only present in foetal stage
Describe the pathophysology of sickle cell disease
- substitution mutation in codon 6 of the beta globin gene
- GAG–>GTG (glutamine–>valine)
- gives rise to HbS instead of HbA
–> in conditions of low oxygen tension, you get polymerisation of HbS and resultant sickling.
What are the 4 forms of sickle cell disease?
- SCA: Hb SS
- SCT: Hb AS
- Sickle beta thalassaemia: HbS/B. Inherit HbS from one parent and B thalassaemia trait from the other parent. severity similar to Sickle cell anaemia
- Sickle haemoglobin C disease: HbSC: one HbS from one parnet and HbC from the other parent
What age does sickle cell anaemia manifest?
3-6 months as before this HbF is still present
What are the two main features of sickle cell disease?
1) haemolysis:
2) vasoocclusion + (SICKLED)
What is the age of onset of the different types of consequences of sickle cell disease?
Childhood- stroke, splenomegaly + splenic crises, dactylitis
Teenage- impaired growth, priapism, gallstones, psych
Adults - hyposplenism, CKD, retinopathy, pulmonary hypertension
Diagnosis of sickle cell disease
Blood film: sickle cells, target cells
Sickle solubility test
Hb electrophoresis
Guthrie test at birth to administer pneumococcal prophylaxis
How to treat sickle cell disease?
Acute: opioid analgesia and exchange transfusions for severe crises (NOT TOP UP TRANSFUSIONS!)
Chronic:
- pneumovax, penicillin V, HIB vaccine
- folic acid and hydroxycarbamide (increases HbF %)
- regular exchange transfusions
- carotid doppler screening in childhood followed by prophylactic exchange transfusion
- new drugs - crizanulizimab
- allogeneic stem cell transplant - not funded in UK currently
-
Pathophysiology of thalassaemia
Unbalanced globin chain production
Leads to precipitation of the globin chains
Leads to haemolysis and ineffective erythropoiesis
Pathophysiology of beta thalassaemia
point mutations in beta globin gene
Leads to decreased beta chain production
So you get excess alpha chains
Increase in HbA2 and HbF (as a compensatory mechanism due to decrease in HbA)
What are the different phenotypes of beta thalssaemia?
Beta thalssaemia major: B0B0- absent beta globin chain production
- severe anaemia at 3-6 months
- failure to thrive
- hepatosplenomegaly (extramedullary haematopoiesis)
- bony defmority
- severe anaemia and heart failure
Beta thalassaemia intermedia: BB0 or BB+
- moderate anaemia
- splenomegaly
- bony deformity
- gallstones (due to bilirubin release from haemolysis)
Beta thalassaemia minor: B+B0 or B+B+
- asymoptomatic carrier
- mild anaemia
____________________
- bony deformity = frontal bossing, maxillary hypertrophy, hair on skull
- hepatosplenomegaly
Treatment of beta thalssaemia
Blood transfusions with iron chelation
depends on severity
Pathophsyiology of alpha thalassaemia
Treatment?
Deletions - reduced α-chain synthesis, excess β-chains • 4 α genes, severity depends on number deleted
o α- thalassaemia trait (1/2 deleted) → Asymptomatic, mild anaemia o HbH (Bart’s) disease (3 deleted) → Moderate anaemia, splenomegaly o Hydrops Foetalis (4 deleted) → Incompatible with life
Treatment: same as beta thalssaemia
List some causes of intravascular haemolysis
- G6PD deficiency
- malaria
- paroxysmal nocturnal haemoglobinuria
- cold autoimmune haemolytic anaemia
- MAHA- eg HUS and TTP
- drugs
- ABO incompatibility
List some causes of extravascular haemolysis
- autoimmune
- alloimmune
- hereditary spherocytosis
Clinical consequences of chronic haemolytic anaemia
- anaemia (may or may not have depending on whether the bone marrow is able to replace the cells that are being destroyed)
- folate deficiency - due to increased turnover
- parvovirus b19 infection (reduced red cell lifespan)
- gallstones (because RBC broken down–>bilirubin released)
- iron overload (because of RBC breakdown–>compensatory increase in iron absorption. or because of iron overload from transfusions)
- osteoporosis
**eg parvovirus B19 infection can cause haemolytic crisis even in disorders like hereditary spherocytosis
Clinical features of haemolytic anaemia
- Pallor- if patient’s anaemic
- Jaundice- increased bilirubin
- Splenomegaly
- particularly prominent in extra-vascular haemolysis or extra-medullary haemopoiesis
- Pigmenturia, dark urine
- useful for diagnosis, especially when there’s haemoglobinuria
- Family Hx- evidence of inherited phenotype
Clinical features that help to diagnose haemolytic anaemia
- Age of onset (e.g. neonatal is more likely to be inherited)
- Pattern of haemolysis - episode or chronic:
- Episodic haemolysis characterises G6PD deficiency and some drug-induced haemolysis
- Mode of inheritance
- Other somatic effects:
- e.g. some glycolytic disorders are associated with neuromuscular disease (such as triosephosphate isomerase and phosphofructokinase deficiencies
Hereditary spherocytosis vs elliptocytosis
Spherocytosis: defects in vertical interaction (Band 3 and ankyrin)
Elliptocytosis: defects in horizontal interaction ( alpha and beta spectrin)
What type of haemolytic anaemia is caused by g6pd deficiency vs pyruvate kinase deficiency?
g6pd deficiency: acute episodic
pk: chronic haemolysis
Features of intravascular haemolysis
- increased LDH
- low haptoglobins
First line investiigations for haemolysis
- FBC:
- Anaemia (not always present)
- Increased reticulocytes (except in Parvovirus)
- Bilirubin:
- Hyperbilirubinaemia
- Blood film:Polychromasia :
- an appearance where cells take up both the eosinophilic and basophilic dye
- have a bluish appearance
- Due to the presence of reticulocytes
- Identify intravascular haemolysis:
- Increased LDH (enzyme in RBCs)
- Reduced or absent haptoglobins (protein binds to Hb)
- Haemoglobinuria can be assessed by visual inspection
- Urinary haemosiderin/ haemoglobin:
- requires a special stain for iron
- e.g. Perl’s stain or Prussian blue
- detects iron in urine excreted from tubular cells
- implies intravascular haemolysis
- Direct Antiglobulin Test:
- Detects presence of immunoglobulin on RBCs
- Check for autoimmune haemolysis
- Osmotic fragility:
- Suggests hereditary spherocytosis
- The dye binding test is being used more frequently now
- G6PD +/- PK activity:
- G6PD tends to be characterised by episodic haemolysis following exposure to oxidants
- PK deficiency causes chronic haemolytic anaemia
- Haemoglobin separation A and F%:
- to exclude Hb disorders- Hb separation via electrophoresis or more commonly HPLC, along with blood count
- Heinz body stain:
- Suggests oxidative haemolysis- G6PD deficiency
- Ham’s test/ Flow cytometry of GPI-linked proteins:
- Ham’s test looks at the sensitivity of red cells to lysis by acidified serum
- These are tests for paroxysmal nocturnal haemoglobinuria
- Thick and thin blood film: malaria
WHen is splenectomy indicated for haemolytic anaemia?
Causes of increased and decreased reticulocyte count
DDx for basophilic stippling
- sideroblastic anaemia
- lead poisoning
- thalassamiea
Thalassamiea minor vs major
major
- severe anaemia
- marked blood film reticulocytosis and anisopoikilocytosis.
- Paradoxically, HbA2 is often only mildly elevated or normal.
minor
- mild hypochromic, microcytic anaemia - microcytosis is characteristically disproportionate to the anaemia
- HbA2 raised (> 3.5%)
Folate deficiency
(B12 usually takes a longer time to develop)
eosin 5 maelimide test
G6PD deficiency
Raised conjugated bilirubin
TTP
In which condition do you see reactive thrombocytsois?
IRON DEFICIENCY ANAEMIA
mechanism is unclear
What are some clinical signs of iron deficiency anaemia?
Koilonychia, atrophic glossitis, angular cheilosis, post-cricoid webs (Plummer-Vinson syndrome), brittle hair and nails.
What are the causes of iron deficiency anaemia?
**bleeding until proven otherwise**
In which scenario can blood transfusions be better than oral iron supplements to treat irion defieincy anaemiaS?
severe infection or sepsis
What is the mechanism of anaemia of chronic disease?
Cytokine driven inhibition of rbc production
- Inflammatory markers like IFNs, TNF and IL1 reduce EPO receptor production (and thus EPO synthesis) by kidneys.
- Iron metabolism is dysregulated. IL6 and LPS stimulate the liver to make hepcidin, which decreases iron absorption from gut (by inhibiting transferrin) and also causes iron accumulation in macrophages.
What are some causes of ACD?
Chronic infection (e.g. TB, osteomyelitis)
• Vasculitis
• Rheumatoid arthritis
• Malignancy etc.
In whcih cells does iron accumulate in in ACD?
in macrophages - almost like a protectvie mechanism to stop bacteria from having iron
Whaty are the two broad mechanisms of macrocytic anaemia?
Megaloblastic: folate or vitamin B12 deficiency
*To differentiate between them- folate deficiency onset much quicker; neurological sx with vitamin B12 deficiency (subacute combined degeneration of spinal cord), ELEVATED SERUM METHYLMALONIC ACID in Vit B12 deficiency, Schilling test positive in pernicious anaemia,
Non-megaloblastic: all the other causes
*differentiate between the causes via history and examination findings*
Summary of plasma iron studies
Clinical sx of vitamin B12 and folate deficiency
WHich protein is defective in hereditary spherocytsosis?
spectrin
Hereditary elliptocystosis
Where is G6PD deficiency prevalent?
Prevalent in areas with high malaria endemecity eg africa and medetirranean
How do you diagnose G6PD deficiency?
Need to do an enzyme 2-3 months after
*during an acute peisode the levels may be normal to reflect increased RBC production*
WHat is the mode of inheritance of PK deficiency?
What type of haemolysis do you get?
Autosomal recessive
results in a chornic haemolytic anaemia (as oppoed to G6PD where you get an acute haemolytic anaemia)
What tests are done in people with warm AIHA?
Tend to do CT-CAP because it tends to be in cancers like CLL
What is paroxysmal cold haemoglobinuria?
Heamoglobin in the urine usually caused by a viral infection eg: measles, syphilis, VZV
Donath-Landsteiner antibodies → stick to RBCs in cold → complement-mediated
haemolysis on rewarming (self-limiting as IgG so dissociate at higher temp than IgM).
**this is also a form of autoimmune haemolytic anaemia so would. be DAT positive**
What is a key infection that causes acquired haemolytic anaemia?
Malaria
*non-immune
WHat is paroxysmal NOCTURNAL haemoglobuuria?
(Dat negative)
Acquired loss of protective surface GPI markers on RBCs (platelets + neutrophils) →
complement-mediated lysis → chronic intravascular haemolysis especially at night.
• Morning haemoglobinuria, thrombosis (+Budd- Chiari syndrome – hepatic v thromb). • Diagnosis: immunophenotype shows altered GPI or Ham’s test (in vitro acid-induced
lysis).
• Treatment: iron/folate supplements, prophylactic vaccines/antibiotics. Expensive
monoclonal antibodies (eculizumab) that prevents complement from binding RBCs
What happens in DIC?
**rmb amniotic fluid embolism can cause this**
Ham’s test positive
paroxysmal nocturnla haemoglubinuria
**ppl go HAM at night**
Which proteins are deficient in PNH?
GPI proteins
these are ofund on the cell membrane
when lacking this makes them suspcetible to breakdown
Which of these is true about alpha thalssaemia?
4
hair on end appearance?
beta thalssaemia
what test is used to diagnose beta thalassaemia?
high performance liquid chromatography
how many genees
What infections are sickle cell disease patients susceptible to?
1) parvovirus B19–> can cause aplastic crisis
2) pneumoccocus- pneumonia and SEPSIS
3) salmonella- osteomyelitis
What coagulation abnormality do you see in anti phospholipid syndrome?
Prolonged APTT
What underlying disorders could MAHA be due to?
underlying cancers
if somoene has vitamin B12 and folate deficiency what do you treat first?
must treat vitamin B12 deficiency first as if you treat folic acid deficiency first this will precipitate subacute combined degeneration of the spinal cord
A 52-year-old woman attends clinic for investigation of abdominal pain and constipation. On examination you note blue lines on the gum margin. She mentions that her legs have become weak in the past few days. What is the most likely diagnosis?
LEAD POISONING
2 main ddx for abdo pain and neuro symptoms
- acute intermittent porphyria
- lead poisoning
What abnormlaity of the spleen is associated with coeliac disease?
hyposplenism–>can lead to howell jolly bodies in the bloodfilm
