HAEMATOLOGY - ANAEMIA Flashcards
1
Q
What is anaemia?
A
A condition in which the number of RBC or Hb concentration within them is lower than normal, outside the reference range for that individual
Men - <13 g/dL Hb
Women <12g/dL Hb
‘A reduction in the quantity of haemoglobin in the blood’
2
Q
What are microcytic anaemias?
A
Iron deficiency (can manifest first as normocytic)
Sideroblastic
Thalassaemia
Anaemia of chronic disease (usually starts normocytic)
3
Q
What are macrocytic anaemia causes?
A
Megaloblastic - vitamin B12 and folate deficincies
Non-megaloblastic - alcoholism, hypothyroidism, drugs, reticulocytosis, liver disease, pregnancy, haemolytic anaemia
4
Q
What are normocytic anaemia causes?
A
Haemolytic causes:
- hereditary spherocytosis
Paroxysmal nocturnal haemoglobinuria
G6PD deficiency
Sickle cell anaemia
HbC disease
Micro and microangiopathic haemolytic anaemia
Autoimmune haemolytic anaemia
Non-haemolytic causes:
Iron deficiency (in early stages before becoming microcytic)
Anaemia of chronic disease (in early stages before becoming microcytic)
CKD
Aplastic anaemia
5
Q
What symptoms does anaemia present with?
A
Breathlessness
Fatigue + lethargy
Headaches
Palpitations
Faintness
Exacerbates cardio respiratory problems, especially in the elderly
Dysphagia
6
Q
What are signs of anaemia?
A
Pallor
Tachycardia
Systolic flow murmurcardiac failure
Koilonychia - spoon shaped nails
Glossitis
Postural hypotension
Jaundice
Bone deformities
Leg ulcers
Angular stomatitis
7
Q
In which anaemia would you find koilonychia?
A
Iron deficiency
8
Q
In which anaemia would you see jaundice?
A
Haemolytic
9
Q
In which anaemia would you see bone deformities?
A
Thalassaemia major
10
Q
In which anaemia would you find leg ulcers?
A
Sickle cell disease
11
Q
What MCV is microcytic anaemia?
A
<80fL
12
Q
What MCV is macrocytic anaemia?
A
> 100fL
13
Q
What MCV is normocytic anaemia?
A
80-100fL
14
Q
Using peripheral blood, what investigations should you do for anaemia?
A
Red cell indices
WCC
Platelet coun
Reticulocyte count
Blood film to see if abnormal red cell morphology is present
Ferritin levels
15
Q
What does a dimorphic blood film mean?
A
Two populations of RBCs are seen e.g. in a combined iron and folate deficiency in coeliac disease
16
Q
Using bone marrow, what investigations should you do for anaemia?
A
Aspiration to provide a film for microscopy of developing haemopoietic cells
The trephine provides an overall view of bone marrow architecture, cellulairty and abnormal infiltrates
17
Q
Whats the WHO criteria for anaemia in men and women?
A
Men Hb <13g/dL
Women Hb <12g/dL
18
Q
What ways is anaemia classified?
A
RBC size and morphology
Severity
Time coursE (acute or chronic)
Inheritance
Etiology (primary vs secondary)
RBC proliferation (hypo or hyper proliferative)
19
Q
Whats the mechanism behind microcytic anaemia?
A
Insufficient Hb production
20
Q
Whats the mechanism behind normoocytic anaemia?
A
Decreased blood volume and/or decreased erythropoeisis
21
Q
Whats the mechanism behind macrocytic anaemia?
A
Insufficient nucleus maturation relative to cytoplasm expansion due to…
- defective DNA synthesis
- defective DNA repair
22
Q
What is mild anaemia?
A
Hb level below normal range based on age and sex but >10-11g/dL
23
Q
What is moderate anaemia?
A
Hb level below normal range based on age and sex but 7-10g/dL
24
Q
What is severe anaemia?
A
Hb level below normal range based on age and sex but <7g/dL
25
How can you remember the causes of microcytic anaemia?
TAILS
Thalassaemia
Anaemia of chronic disease
Iron deficiency
Lead poisoning
Sideroblastic
26
What are the subcategories in normocytic anaemia and give examples?
Haemolytic
- intrinsic - haemoglobinopathies, enzyme deficiencies, membrane defects
- extrinsic - haemolytic anaemias, infections, mechanical destruction
Non-haemolytic - blood loss, aplastic, (anaemia of chronic disease and iron deficiency in early stages)
27
What haemoglobinopathies cause haemolytic anaemia?
Sickle cell
HbC disease
Thalassaemia
28
What enzyme deficiencies cause haemolytic anaemia?
Pyruvate kinase deficiency
G6PD deficiency
29
What membrane defects can cause haemolytic anaemia?
Paroxysmal nocturnal haemoglobinuria
Hereditary spherocytosis
Hereditary elliptocytosis
30
What are the subcategories of macrocytic anaemia and give examples?
Megaloblastic - vitamin B12 and folate deficiencies, medications
Non-Megaloblastic anaemia - liver disease, alcohol use, diamond-blackfan anaemia, myelodysplastic syndrome, multiple myeloma, hypothyroidism
31
What medications can cause Megaloblastic macrocytic anaemia?
Phenytoin - inhibits folate
Sulfa drugs - inhibits folate
Trimethoprim - inhibits folate
MTX - inhibits folate
Hydroxyurea - inhibits DNA synthesis
6-mercaptopurine - interferes with DNA synthesis
32
How do you initially evaluate anaemia diagnostically?
For stable patients check FBC to confirm anaemia and assess severity
Classify anaemia by morphology and MCV to narrow down cause
Blood film, ferritin, iron studies, B12, folate, reticulocyte count, direct antigen test, haemoglobinopathy screen
In unstable patients treat acute blood loss anaemia immediately
33
How should you investigate microcytic anaemia?
Obtain iron panel to screen for IDA
34
How should you investigate macrocytic anaemia?
Check serum B12 and folate
Measure reticulocyte count
35
What does an increased reticulocyte count in macrocytic anaemia mean?
Haemolysis or blood loss
36
What does an decreased reticulocyte count in macrocytic anaemia mean?
Drug or alcohol toxicity, MYELODYSPLASTIC syndromes or pure red cell aphasia
37
How should you investigate normocytic anaemia?
Measure reticulocyte count
High - reassess for blood loss
Low - indicates hypoproliferative anaemia
38
What are some causes of iron deficiency anaemia?
Blood loss e.g. GI bleed, menorrhagia, hookworm,haemorrhagic gastritis
Poor diet/reduced intake (mostly children)
Malabsorption
Increased demand
39
What are some causes of anaemia of chronic disease?
Chronic infections e.g. TB or infective endocarditis
Chronic inflammation e.g. RA, SLE, crohns
Maliganncy
40
What are some causes of sideroblastic anaemia?
Inherited (most commonly x-linked but can be autosomal recessive or maternal)
Or acquired…
Examples include:
Excessive alcohol (mitochondrial damage)
lead poisoning (denatures enzymes important in haem synthesis)
vitamin B6 deficiency e.g. isoniazid treatment (affects mitochondria ability to form haem)
Myelodysplasia
41
What are the causes of vitamin B12 deficiency?
Impaired absorption e.g. pernicious anaemia, gastrectomy as no IF from terminal ileum, ideal disease, coeliac disease
Vegan diet
Tapeworm
?? PPI and contraceptive pill
42
Whats the cause of pernicious anaemia?
Autoimmune condition where antibodies form against the intrinsic factor or parietal cells. A lack of intrinsic factor prevents the absorption of vitamin B12 and the patient becomes B12 deficient
43
What are the causes of folate deficiency?
Poor intake
Malabsorption e.g. coeliac disease and tropical sprue
Excess utilisation e.g. pregnancy, chronic haemolytic anaemia, malignant and inflammatory diseases or dialysis
Drugs e.g. trimethoprim or methotrexate
44
What can cause aplastic anaemia?
Primary: inherited or idiopathic
Secondary: benzene, drugs (chemo, antibiotics, Carbimazole and azathioprine), insecticides, ionising radiation, infections, miscellaneous e.g pregnancy
45
What cause thalassaemia?
Multiple gene defects decrease the rate of production of globin chains. Defects in alpha-globin chains leads to alpha thalassaemia. Defects in the beta-globin chains leads to beta thalassaemia. This leads to cell damage or death of RBC precursors in bone marrow = haemolysis
46
Whats the cause of sickle cell anaemia?
caused by a mutation in the gene that encodes the beta-globin chain of the hemoglobin molecule = haemoglobin S which polymerizes in the deoxygenated state, resulting in physical deformation or sickling of erythrocytes. Sickle erythrocytes promote vaso-occlusion and hemolysis
47
Why do women have a lower Hb than men?
Because of the effect of menstrual blood loss on mean haemoglobin
48
What is RDW?
Red cell distribution width - measure of variety of shapes and sizes of RBCs in sample.
49
What do RBCs look like in iron deficiency anaemia on a blood film?
Hypochromic, microcytic RBCs
50
How do we investigate iron deficiency anaemia? And what’s the problem with this?
We measure ferritin and if its low then its iron deficiency
The problem is that ferritin is an acute phase protein so a normal level does not rule of IDA. Because of this, ferritin levels must be checked alongside a CRP to rule out an inflammatory response
51
Other than ferritin, what else can you look at for IDA diagnosis?
Iron - should be low
Transferrin - should be high
Transferrin saturation - should be low
52
What is hereditary haemochromatosis?
an inherited condition where a mutation in the HFE gene causes increased iron absorption
53
What would iron studies look like for haemochromatoiss?
High ferritin
High iron
Low transferrin
High transferrin saturation
54
What would iron studies look like in anaemia of chronic disease?
Ferritin - norm or high
Low iron
Low transferrin
Low transferrin saturation
55
What would iron studies look like in haemolytic anemia?
Ferritin high
Iron high
Normal/.low transferrin
High transferrin saturation
56
What would you see on a blood film of Megaloblastic anaemia?
Large RBCs oval shape (oval macrocytes)
Often see red cell precursors
Abnormal WBCs
Hypersegmented neutrophils
May be lecupenia and thrombocytopenia if severe
57
What would you see in the bone marrow in Megaloblastic anaemia?
giant metamyelocytes - twice the size of normal RBC and have twisted nuclei
Megaloblasts
58
What are the complications of vitamin B12 deficiency?
Neurological changes - vision, memory, paraesthesia, ataxia, peripheral neuropathy
Infertility
Stomach cancer
Neural tube defects in child
59
Why is LDH high in Megaloblastic anaemia?
an accelerated turnover of bone marrow cells implying the release of this enzyme from dividing and/or decaying cells
60
Whats the pathophysiology of B12 ans folate deficiency causing Megaloblastic anaemia?
Deficiency in folate reduces the supply of the coenzyme methylene tetrahydrofolate which is needed to methylate deoxyuridine monophosphgate, a step required to build DNA
Deficiency of vit B12 also reduces the supply by slowing the demethylation of methyl tetrahydrofolate
61
How is vitamin B12 transported and absorbed?
Vit B 12 is liberated from protein complexes in food by gastric enzymes and then binds to R binder derived from saliva. B12 is released from R binder by pancreatic enzymes and then becomes bound to intrinsic factor (secreted by gastric parietal cells). Intrinsic factor carries b12 to cubilin (a receptor on surface of mucousa of ileum) and it can enter ileal cells, leaving intrinsic factor in the lumen. Vit B12 is transported from enterocytes to other tissues by glycoprotein transcobalamin - this makes it active
62
What is pernicious anaemia?
an autoimmune disorder in which there is atrophic gastritis with loss of parietal cells in the gastric mucosa and consequent failure of intrinsic factor production and vitamin B12 malabsorption.
63
Which foods is folate found in?
Green vegetables and offal e.g. liver and kidney
Note: cooking these causes a loss of 60-90% of folate
64
Whats the main cause of
- vitamin B12 deficiency?
- folate deficiency?
B12 - pernicious anaemia
Folate - poor intake or malabsorption or antifolate drugs e.g. methotrexate
65
Whats a symptoms specific to B12 deficiency?
Neuropathy
66
How is vitamin B12 deficiency managed?
Hydroxycobalamin can be given IM for 2 weeks
67
How is folate deficiency managed?
Folic acid daily for 4 months
68
What are the complications of folate deficiency?
Infertility
Cardiovascular disease
Cancer
Premature childbirth or placental absorption
Neural tube defects in newborn
69
How do we diagnose anaemia of chronic disease?
It’s a diagnosis of exclusion
70
What characteristics on blood film would you see in haemolytic anaemia?
Macrocytic polychromatic
71
What would you see on a blood film of someone with hereditary spherocytosis?
Circular, densely stained red cells with no central pallor - because RBCs are spherical shape
72
What is alloimmune haemolytic anaemia?
occurs if your body makes antibodies against red blood cells that you get from a blood transfusion
This can occur in haemolytic disease of the newborn and transfusion reactions after transplantation
73
What is a microangiopathic haemolytic anaemia?
where the small blood vessels have structural abnormalities that cause haemolysis of the blood cells travelling through them. Imagine a mesh inside the small blood vessels shredding the red blood cells. This is usually secondary to an underlying condition:
Haemolytic Uraemic Syndrome (HUS)
Disseminated Intravascular Coagulation (DIC)
Thrombotic Thrombocytopenia Purpura (TTP)
Systemic Lupus Erythematosus (SLE)
Cancer
74
Where are thalassaemia most present?
Mediterranean countries and Asia, Africa and middle east
75
Where are G6PD deficiency most present?
Africa, Mediterranean and Asia
76
What do raised LDH and bilirubin suggest?
Increased haemoglobin breakdown
77
What does a reduction in haptoglobins mean?
When large amounts of free haemoglobin are released into circulation they bind to haptoglobin to prevent its toxic effects. In large amounts of free Hb, decreased haptoglovin is a marker of haemolysis
78
Where do we get dietary iron from?
Non-haem iron - fortified cereals, whole grains, leafy greens, dairy, eggs, nuts and seeds
Haem iron - meat, poultry, seafood
79
Whats the key molecules that regulates iron absorption?
Hepcidin - regulates the activity of ferroportin (an iron exporting protein)
High hepcidin (e.g. in inflammatory states) destroys ferroportin and limit iron absorption
80
What is iron bound to in the plasma?
Transferrin (a beta globulin synthesised in the liver)
81
What are the causes of iron deficiency anaemia?
Blood loss
Increased demands e.g. growth or pregnancy
Decreased absorption e.g. post-gastrectomy
Poor intake
82
How is IDA treated?
Oral iron usually ferrous sulphate 200mg 3 times a day with vitamin C continue until 3 months after Hb has returned to normal
If poor tolerance then consider parenteral iron or red cell transfusion
83
Whats the pathophysiology of anaemia of chronic disease?
decreased release of iron from the bone marrow to developing erythroblasts, an inadequate EPO response to the anaemia, and decreased red cell survival.
84
What are the characteristics of sideroblastic anaemia?
a refractory anaemia, a variable number of hypochromic cells in the peripheral blood, and excess iron and ring sideroblasts in the bone marrow. Accumulation of iron in mitochondria of erythroblasts
85
What defines aplastic anaemia?
Anaemia due to bone marrow failure
Pancytopenia with hypocellularity of the bone marrow
Virtual absence of reticulocyte
86
Whats the pathophysiology of aplastic anaemia?
a reduction in the number of pluripotent stem cells, together with a fault in those remaining or an immune reaction against them so that they are unable to re-populate the bone marrow. Failure of only one cell line may also occur, resulting in isolated deficiencies such as the absence of red cell precursors in pure red cell aplasia.
87
What can cause aplastic anaemia?
Inherited e.g. fanconi anaemia
Secondary to chemicals, drugs, insecticides, ionising radiation, infections, paroxysmal nocturnal haemoglobinuria
Miscellaneous e,g pregnancy
88
What is Fanconi anaemia?
autosomal recessive condition
A congenital cause of aplastic anaemia
It usually presents between the ages of 5 and 10years and is associated with an increased risk of malignancies.
Classic features include abnormal thumbs, absent radii, short stature, skin hyperpigmentation, including café au lait spots, abnormal facial features (triangular face, microcephaly), abnormal kidneys, and decreased fertility.
89
What are the clinical manifestation of bone marrow failure?
Anaemia
Bleeding - bruising, blood blisters, ecchymoses, epistaxis
Infections
90
Whats the main danger in aplastic anaemia?
Infection - can deplete WBC
91
Whats the treatment of choice for patients with severe aplastic anaemia under the age of 40?
Haemopoietic stem cell transplant
92
What is hereditary spherocytosis?
An autosomal dominant condition that causes defects in the red cell membrane - ankrin and spectrin (membrane skeletal proteins) deficiency or mutation which makes RBCs more rigid and less deformable than normal red cells = spherocytes. They are unable to pass through the splenic microcirculation so they have a shortened lifespan.
(This is why they get splenomegaly)
93
Outline the pathophysiology of sickle cell anaemia?
Deoxygenated HbS molecules polymerize to produce long chains which are insoluble. The flexibility of the cells is decreased, and they become rigid and take up their characteristic sickle appearance. This process is initially reversible but, with repeated sickling, the cells eventually lose their membrane flexibility and become irreversibly sickled. This shorter so red cell survival and impairs the passage of cells through the micro circulation causing tissue infarction.
94
What precipitates sickling in sickle cell anaemia?
Infection
Dehydration
Cold
Acidosis
Hypoxia
95
Why do those with sickle cell anaemia feel well despite being anaemia?
HbS releases its oxygen to the tissues more easily than normal haemoglobin
96
What is HbSS and HbS?
HbSS - homozygous sickle cell - most severe
HbS - sickle cell trait (heterozygous) - asymptomatic
97
What’s the molecular basis of sickle cell anaemia?
Substitution of a glutamine for a valine at position 6 = mutant beta globin = haemoglobin S
Valine is hydrophobic so promotes the stickiness of RBCs
98
What is haemoglobin S?
2 alpha chains and 2 abnormal beta chains
99
What type of hereditary pattern is sickle cell anaemia?
It’s autosomal recessive - abnormal gene on beta globin on chromosome 11.
100
How is sickle cell anaemia diagnosed?
FHx
Anaemia
Blood film will show sickled RBC
Electrophoresis to look for haemoglobin S (more modern techniques are HPAC and mass spectrometry)
Pregnant women at risk of being carriers are offered testing during pregnancy! It’s also tested for on newborn screening heel prick test at 5 days old
101
Whats the link between sickle cell anaemia and malaria?
Sickle cell anaemia is prevalent in areas where malaria is prevalent
This is because sickled haemoglobin makes RBC less suitable for parasites to parasitise.
Sickle cell-trait pt have a survival advantage
102
What are the differences between clinical features of sickle cell anaemia in children and adults?
Children - delayed growth, dactylitis (infarction of small bones of hands), acute splenic sequestration (infarction/enlargement in spleen), aplastic crisis (occurs when infection with parvovirus which is tropic for RBC precursors), cardio respiratory problems, renal impairment
Adults - same problems can occur but in addition acute resp failure, cardiac problems, liver failure, renal problems, a vascular necrosis of hip, chronic ulcers over medial malleolus, increased risk of stroke
103
Whats the leading cause of mortality for sickle cell anaemia and why?
Sepsis
SSA can cause infarction of the spleen -> hyposplenic -> increases risk of infection mainly with encapsulated bacteria
(This is why children under 5 should receive pneumococcal vaccination and prophylactic penicillin)
104
What are the complications of sickle cell anaemia?
Vaso-occlusive crisis - acute pain in hands and feet mostly. Bones are a common site for this and it can lead to chronic infarcts
Increased risk of stroke!
Acute chest syndrome - caused by chlamydia, mycoplasma and S. pneumonia.
Pulmonary hypertension
Chronic anaemia due to chronic haemolysis
Splenomegaly - splenic pooling of RBC
Leg ulcers
Priapism
Cardiomegaly, cardia arrhythmias and iron overload cardiomyopathy, MI
Neurological complications - TIA, fits, cerebral infarction, cerebral haemorrhage, coma
Cholelithiasis
Hepatomegaly and liver dysfunction
renal, eye complications
Priapism - unwanted painful errection
Increased risk of infection
Growth and development delays - reach height by adulthood but remain below normal weight and sexual maturation is delayed
105
How do you manage acute chest syndrome in sickle cell anaemia?
Pain control
Treat sepsis if present
If hypoxaemic then a red cell exchange is performed - this suppresses production of HbS (aim to reduce HbS to <30%)
106
Where are leg ulcers common in sickle cell anaemia and why?
Over lateral and medial malleolus as poor blood supply - relates to vasoocculasion of small vessels
107
Why can sickle cell anaemia cause stroke?
Stenosis of ICA due to intimal hyperplasia (cell population increases within tunica intima).
108
What is an anaemic crisis?
Anaemia suddenly worsened in someone with sickle cell anaemia. E.g. infection with parvovirus causing aplastic crisis
Or splenic sequestration.
109
When is hydroxycarbamide offered to patients with sickle cell disease?
When you have 3 or more hospital admissions in the past year for a sickle cell crisis or have regular crises at home affecting normal life or have had 2 or more chest crises
110
How does hydroxycarbamide work in treating sickle cell disease?
Increases the number of RBC containing HbF
Helps keep RBC well hydrated and reduce their stickiness which may prevent a crises
Reduces the number of WBC which stops inflammation and crises
111
How do you manage thalassemia?
Lifelong treatment of regular blood transfusions to treat anaemia (if transfusion dependant i.e. homozygous or compound heterozygous) - particularly during times of infection of pregnancy
Chelation therapy to remove excess iron caused by regular blood transfusions
Stem cell or bone marrow transplants - cure but not done very often as significant risks
Long term folic acids
112
Whats the difference between homozygous and compound heterozygous beta thalassemia
Homozygous - identical mutations on both alleles
Compound heterozygous - different damaging mutations on both alleles
113
Outline the pathophysiology of carriers of beta thalassaemia?
the excess α chains combine with δ and result in modestly increased quantities of HbA2
114
Whats the difference in genetics of alpha and beta thalassemia?
Alpha - gene deletions
Beta - point mutations
115
What is iron needed for in RBCs?
To produce heme from protoporphyrin for haemoglobin
116
What is the pathophysiology of Glucose 6-phosphate dehydrogenase deficiency anaemia?
An X-linked recessive condition
G6PD deficiency means low levels of NADPH which means low levels of reduced glutathione
Glutathione usually neutralises free radicals so it leaves RBCs very susceptible
When these free radicals build up, it causes haemolysis
Damaged Hb in the RBCs can be directly damaged by free radicals and are known as Heinz bodies. Spleen macrophages attempt to remove Heinz bodies, leaving RBCs as ‘bite cells’.
When free radical production increases too much we get oxidative stress - this can be caused by infections, metabolic acidosis, foods and drinks, certain medications
117
Whats the Hb threshold for giving a blood transfusion?
<70g/L
118
What is HbSC?
Some patients inherit one HbS and another abnormal haemoglobin (HbC) resulting in a milder form of sickle cell disease (HbSC)
119
How is the definitive diagnosis of sickle cell disease made?
is by haemoglobin electrophoresis
120
What are the 2 types of autoimmune haemolytic anaemias?
Warm and cold
According to what temperature the antibodies best cause haemolysis
121
What test is done for autoimmune haemolytic anaemia?
Positive direct anti globulin test (Coombs test)
122
What is warm autoimmune haemolytic anaemia?
The most common type of autoimmune haemolytic anaemia
the antibody (usually IgG) causes haemolysis best at body temperature and haemolysis tends to occur in extravascular sites, for example the spleen.
Strongly positive direct Coombs test
123
What can cause warm AIHA?
Idiopathic
Autoimmune disease e.g. SLE
Neoplasia - lymphoma or chronic lymphocytic leukaemia
Drugs e.g. methyldopa
124
What is 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. At lower temperatures antibodies attach to RBC and cause agglutination which the immune system can then destroy in the spleen.
Typically secondary to other conditions such as lymphoma, leukaemia, SLE, EBV, CMV or HIV.
Features may include symptoms of Raynaud's and acrocynaosis. Patients respond less well to steroids
Positive in direct Coombs test
125
What can cause cold AIHA?
Neoplasia e,.g. Lymphoma
Infections e.g. mycoplasma or EBV
126
What are the symptoms of pernicious anaemia?
Anaemia features - lethargy, pallor, dyspnoea
Neurological features - Peripheral neuropathy with numbness or paraesthesia (pins and needles). Loss of vibration sense or proprioception. Visual changes. Mood or cognitive changes
Mild jaundice
Glossitis
127
What is subacute combined degeneration of the spinal cord?
progressive weakness, ataxia and paresthesias that may progress to spasticity and paraplegia
128
Why can phenytoin cause macrocytic anaemia?
Because its an antifolate drug so can cause a folate deficiency
129
Why does pregnancy cause anaemia?
an increase in plasma volume disproportionate to the increase in haemoglobin, causing an overall decrease in haemoglobin concentration.
130
Whats the FBC, peripheral blood smear for iron deficiency anaemia?
FBC - low Hb, low MCV
Peripheral blood smear - microcytic hypochromic anisocytosis and poikilocytosis
131
What iron studies do we do for iron deficiency anaemia?
low ferritin, decreased serum iron and increased total iron binding capacity. (Note ferritin will be increase in any acute phase reaction)
132
What’s the most common caus of anaemia globally?
IDA
133
Where is iron stored in the body?
In RBC
In liver as ferritin and hemosiderin
134
What would you find on FBC, peripheral blood smear for anaemia of chronic diseaseS?
FBC - low Hb and low/normal MCV
Peripheral blood smear - initially nromochromic normocytic but turns into hypochromic microcytic
135
Why would ferritin be raised in anaemia of chronic diseases?
Because its an acute phase reactant
136
Whats the pathology behind anaemia of chronic diseases?
These conditions all produce elevation of IL-6 which stimulates hepcidin production and release from the liver, which in turn shuts down ferroportin, reducing circulating iron levels.
137
How do you treat anaemia of chronic diseases?
Treat underlying disorder
Recombinant EPO therapy can be used in anaemia of renal disease
(No point transfusing as they would fall back to where they were)
138
Whats the genetic background of inherited sideroblastic anaemia?
X-linked disease or autosomal recessive
X-linked is caused by a mutation in ALAS2 (so mostly in boys)
139
Whats the pathophysiology of sideroblastic anaemia?
Defective protoporphyrin synthesis which results in impaired incorporation of iron to form haem, whose biosynthesis takes place partly in the mitochondrion. This leads to deposits of iron in the mitochondria that form a ring around the nucleus called a ring sideroblast. It may be congenital or acquired
140
What would see you see on FBC and peripheral blood smear of sideroblastic anemia?
FBC - low MCV
Peripheral blood smear - dimOrphic population of normal and hypochromic RBCs. Basophilic stippling and pappenheimer bodies
141
What would iron studies show in sideroblastic anaemia?
High serum iron
Increased ferritin
Decreased total iron binding capacity
142
How does sideroblastic anaemia present differently to iron deficiency/
In 1/3rd of cases there is splenomegaly
143
How is sideroblastic anaemia managed?
Avoiding alcohol and vitamin C to reduce iron absorption (both increase acidity so turn Fe3+ into its absorbable Fe2+ state)
Remove causative agents
Red cell transfusions for symptomatic anaemia
EPO, pyridoxine and Ciclosporin can be used
144
What are the thalassaemias?
Defective synthesis of globin chain leads to imbalanced globin chin production, cause precipitation of the excess globin chains within the red cell precursors and resulting in ineffective erythropoeisis. This precipitation leads to haemolysis of red cells.
There are alpha and beta thalassaemias
145
Outline the pathophysiology of beta thalassaemia?
Either no normal beta chains are produced or beta chain production is very reduces
This leaves an excess of alpha chains with precipitate in erythroblasts and red cells, causing ineffective erythropoeisis and haemolysis
In the carrier state, excess alpha chains combine with delta and result in modestly increased quantities of HbA2 which i used for screening.
146
Thalassaemia carries may be confused with iron deficiency anaemia as red cells are hypochromic and microcytic. How can these be distinguished?
In thalassemia trait, the serum ferritin and iron stores are normal
147
What is non-transfusion dependant thalassaemia?
Symptomatic patients with moderate anaemia but do not require regular transfusions
Patient may have seen omega lay, bone deformities, recurrent leg ulcers, gallstones and infections
148
What is transfusion-dependant thalassemia?
Thalassaemia major
Present during the first year of life with FTT, recurrent bacterial infections, severe anaemia, hepatosplenomegaly and bone expansion, hair on end appearance on skull X-ray
149
How do you investigate sickle cell anaemia?
FBC - low Hb, high reticulocyte count
Blood films - sickling
Sickle solubility test
Haemoglobin electrophoresis - 80-95% HbS
Parents having sickle cell trait
150
How do you teat sickle cell anaemia?
Iv fluids and adequate analgesia for acute painful attacks - morphine
Infection prophylaxis with penicillin 500mg daily and vaccination for those without a functioning spleen
Folic acid
Blood transfusions
Hydroxycarbamide
Stem cell transplantation
Counselling
151
Typically, how much HbS does someone with sickle cell trait have?
60% HbA and 40% HbS
152
What can aplastic anemia evolve into?
Myelodysplasia
Paroxysmal nocturnal haemoglobinuria
AML
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How do we investigate aplastic anaemia?
Look for pancytopenia, absence of reticulocyte and hypocellularity in the bone marrow with increased fat spaces
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How do you manage aplastic anaemia?
Treat cause
Treat any signs of infection with broad spec antibiotics
Haematopoeitic stem cells for those under 40 with severe aplastic anaemia who have a HLA identical sibling donor, where it gives 75-90% chance of long term survival
Otherwise immunosuppressive treatment with antithymocyte globulin and Ciclosporin can be given or a stem cell transplant can be used
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Whats the difference between extravascular and intravascular haemolysis?
Extravascular haemolysis - red cells are removed from the circulation by macrophages in the reticuloendothelial system
Intravascular haemolysis - red cells are rapidly destroyed within circulation and Hb is liberated.
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What are the causes of inherited haemolytic anaemias?
Red cell membrane defects - hereditary spherocytosis, elliptocytosis and stomatocytosis
Haemoglobinopaties - thalassaemia and sickle syndromes
Metabolic disorders of the red cell - G6PD deficiency or pyruvate kinase deficiency
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What are the causes of acquired haemolytic anaemias?
Immune causes e.g. alloantobodies and autoantibodies
Non-immune causes e.g, paroxysmal nocturnal haemoglobinuria, prosthetic heart valves, secondary to systemic disease
Miscellaneous causes e.g. toxins, malaria, hypersplenism,burns, drugs, ingested chemicals
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What is glucose-6-phosphate dehydrogenase deficiency?
An x-linked recessive disorder characterised by defective G6PD enzymes with shorter half lives which leads to the destruction of RBCs
It causes crises triggered by infections, medications and broad beans (fava beans)
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Outline the genetic basis of G6PD deficiency?
mutation on G6PD gene which is on the X chromosome, and thus us an X-linked recessive condition
So almost exclusively manifests in men - as they have 1 X chromosome
Females are only carries and only transmit disease to their sons
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Why does G6PD deficiency protect an individual from falciparum malaria?
Because it makes the RBCs more susceptible to oxidants and therefore will also kill malaria parasites (only the Mediterranean variant)
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What can increase free radical production and cause haemolytic enzymes in those with G6PD deficiency?
Metabolic acidosis
Infections - viral hepatitis and pneumonia
Foods/drinks - fava beans, soy products, red wine
Certain meds - primaquine and chloroquine (malaria treatment), aspirin, ibuprofen, ibuprofen and sulfonamide drugs
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What’s the genetic basis of pyruvate kinase deficiency?
Autosomal recessive disorder causing a defect in pyruvate kinase
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Whats the pathophysiology of pyruvate kinase deficiency?
Deficiency in PK means it cannot help in glycolysis and therefore RBCs are deficient in ATP
This means Na+/K+ ATPase pump cannot work, making K+ leak out and water moves out also. The cell shrinks and forms echinocytes (burr cells)
These RBCs get trapped in the spleen causing extravascular haemolysis
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What is Coombs test?
The direct Coombs test detects antibodies that are stuck to the surface of the red blood cells
The indirect Coombs detects antibodies that are floating freely in the blood
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How is haemolytic anaemia treated?
Corticosteroids
Splenectomy 2nd line
Rituximab in those who fail to respond to steroids
Blood transfusion if severe anaemia
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Whats the most common type of haemolytic disease of the newborn?
ABO - mother is group O and foetus is group A
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Whats the pathophysiology of haemolytic disease of the newborn?
Maternal alloantibodies against foetal red cell antigens pass from the maternal circulation via the placenta into the foetus, where they destroy foetal red cells.
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What is paroxysmal nocturnal haemoglobinuria?
a rare condition that occurs when a specific genetic mutation in the haematopoietic stem cells in the bone barrow occurs during the patients lifetime. The specific mutation results in a loss of the proteins on the surface of red blood cells that inhibit the complement cascade. The loss of protection against the complement system results in activation of the complement cascade on the surface of red blood cells and destruction of the red blood cells.
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Why is reticulocytosis macrocytic?
Reticulocytosis : An elevation in the number of reticulocytes in blood, a sign of unusually rapid red blood cell production.
Reticulocytes are incompletely processed RBCs and, therefore, are slightly larger than the average RBC.
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What is Wilson’s disease?
an autosomal recessive disorder characterised by excessive copper deposition in the tissues
Causes haemolysis
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Outline the pathology of intravascular haemolysis?
free haemoglobin is released which then binds to haptoglobin. As haptoglobin becomes saturated haemoglobin binds to albumin forming methaemalbumin (detected by Schumm's test). Free haemoglobin is excreted in the urine as haemoglobinuria, haemosiderinuria
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What type of anaemia does myelodysplasia usually cause?
Macrocytic normbolastic
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What are tear drop poikilocytes associated with?
Myelofibrosis
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What are spherocytes associated with?
Hereditary spherocytosis
Autoimmune haemolytic anaemia
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What is basophilic stippling associated with?
Lead poisoning
Thalassaemia
Sideroblastic anaemia
Myelodysplasia
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What are Howell-Jolly bodies associated with?
Hyposplenism
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What are Heinz bodies associated with?
G6PD deficiency
Alpha thalassaemia
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What are helmet cells/schistocytes associated with?
Intravascular haemolysis
Mechanic heart valve
Disseminated intravascular coagulation
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What are ‘pencil’ poikilocytes associated with?
IDA
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What are burr cells/echinocytes associated with?
Uraemia
Pyruvate kinase deficiency
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What are hypersegmented neutrophils associated with?
Megaloblastic anaemia
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What vitamin deficiency can cause haemolytic anaemia?
Vit E
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What are the causes of intravascular haemolysis?
Mismatched blood transfusion
G6PD deficiency
Red cell fragmentation - heart valves, TTP, DIC, HUS
Paroxysmal nocturnal haemoglobinuria
Cold autoimmune haemolytic anaemia
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What are the causes of extravascular haemolysis?
Haemoglobinopathies
Hereditary spherocytosis
Haemolytic disease of the newborn
Warm autoimmune haemolytic anaemia
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What causes target cells?
Haemoglobinopathies
IDA
Hyposplenism
Liver disease
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What hypersensitivity react is autoimmune haemolytic anaemia?
Hypersensitivity type 2 - IgG or IgM binds to antigen on cell surface
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How does sickle cell anaemia affect kidney?
Causes renal papillary necrosis
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What is haemolytic uraemic syndrome?
A triad of AKI, microangiopathic haemolytic anaemia and thrombocytopenia
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If the Hb is disproportionately low compared to MCV, what does this suggest?
Thalassaemia
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How do acute and chronic blood loss present differently?
Acute presents as normochromic normocytic
Chronic presents as hypochromic microcytic
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What are the 2 biggest causes for hypochromic microcytic anaemia?
Iron deficiency
Thalassaemia
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What is diamond black fan anaemia?
an inherited blood disorder that affects the ability of the bone marrow to produce red blood cells - pure red cell aplasia
Manifests in early infancy
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Where do you collect a bone marrow biopsy from?
Posterior iliac crest
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What can cause a macrocytosis without blood cell abnormalities?
Alcoholism
Liver disease
Hypothyroidism
COPD
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What can cause a raised haemoglobin?
Congenital cyanosis heart disease
high altitudes or deep sea diving
COPD
Renal cell carcinoma
Polycythemia Ruben vera
Dehydration
Heart failure
Liver cancer.
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How does spherocytosis present?
Recurrent episodes of jaundice and anaemia and splenomegaly
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What causes haemolytic uraemic syndrome?
Most cases are secondary (termed 'typical HUS'):
classically Shiga toxin-producing Escherichia coli (STEC) 0157:H7. This is the most common cause in children, accounting for over 90% of cases
pneumococcal infection
HIV
rare: systemic lupus erythematosus, drugs, cancer
Primary HUS ('atypical') is due to complement dysregulation.
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Why can PPIs cause IDA?
HCL is required for iron adsorption in the duodenum and proximal jejunum. The low pH of gastric acid allows a ferric reductase enzyme to convert insoluble ferric to absorbable ferrous iron.
PPIs reduce the production of HCL so they reduce the absorption of iron
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What should be given to pt with IDA prior to surgery?
Oral iron or if not possible then IV iron
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What does hypersegmented neutrophil polymorphs suggest?
Megaloblastic anaemia
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Can IDA cause pruritus?
Yes
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What can give a falsely low HbA1c?
Anything that decreases the lifespan of a RBC - haemodialysis, haemolytic anaemia, renal anaemia, renal dialysis, chronic malaria, acute blood loss, recent transfusion, drugs e.g. anti-psychotics, corticosteroids, management of HIV, alcohol consumption and aspirin
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What should you do for Men of any age with a Hb below 110g/L?
Upper and lower GI endoscopy as a 2ww
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What can cause basophilic stippling of RBCs?
lead poisoning, sideroblastic anaemia, impaired Hb synthesis, alcoholism, and megaloblastic anemias
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How do you test for pernicious anaemia?
Testing for auto-antibodies is used to diagnose pernicious anaemia.
Intrinsic factor antibody is the first line investigation
Gastric parietal cell antibody can also be tested but is less helpful
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How do you manage pernicious anaemia?
1mg of intramuscular hydroxycobalamin 3 times weekly for 2 weeks, then every 3 months. More intense regimens are used where there are neurological symptoms
(Not its IM not oral as problem is with absorption)
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How do you manage a patient who has both, a B12 and a folate deficiency?
Treat b12 deficiency first with IM hydroxycobalamin
Then treat folate deficiency
(Treating patients with folic acid when they have a B12 deficiency can lead to subacute combined degeneration of the cord. This is because folic acid will correct ther anaemia so delay diagnosis of vitamin B12 deficiency but will not prevent progression of neurological damage)
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Whats the main cause of folate malabsorption?
Gluten-induced enteropathy
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What are some good dietary sources of vitamin B12?
Eggs
Foods fortified with B12
Meat
Milk and dairy
Salmon and cod
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What are some good dietary sources of folic acid?
Asparagus
Broccoli
Brown rice
Brussel sprouts
Chickpeas
Peas
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How does hereditary spherocytosis present?
It presents with jaundice, gallstones, splenomegaly and notably aplastic crisis in the presence of the parvovirus
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How do you manage hereditary spherocytosis?
Folate supplementation and splenectomy
Cholecystectomy if gallstones are a problem
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How does G6PD deficiency present?
Jaundice in neonatal period
Gallstones
Anaemia
Splenomegaly
Heinz bodies on blood film
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What medications can trigger haemolysis in G6PD deficiency?
primaquine (an antimalarial), ciprofloxacin, sulfonylureas, sulfasalazine and other sulphonamide drugs.
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How do you manage autoimmune haemolytic anaemia?
Blood transfusions
Prednisolone
Rituximab
Splenectomy
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How does PNH present?
Red urine in the morning (due to concentrated urine from overnight)
Anaemic
Predisposed to thrombosis and smooth muscle dystonia ( oesophageal spasm, erectile dysfunction)
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How do you manage PNH?
Management is with eculizumab or bone marrow transplantation. Eculizumab is a monoclonal antibody that targets complement component 5 (C5) causing suppression of the complement system. Bone marrow transplantation can be curative.
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What are signs and symptms of thalassaemia?
Microcytic anaemia (low mean corpuscular volume)
Fatigue
Pallor
Jaundice
Gallstones
Splenomegaly (spleen collects all destroyed RBCs)
Poor growth and development
Pronounced forehead and malar eminences (due to bone marrow expanding to try to produce extra RBCs to compensate for the chronic anaemia)
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How do you diagnose thalassaemia?
Full blood count shows a microcytic anaemia.
Haemoglobin electrophoresis is used to diagnose globin abnormalities.
DNA testing can be used to look for the genetic abnormality
Pregnant women in the UK are offered a screening test for thalasseamia at booking.
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Why does iron overload occur in thalassaemia?
as a result of faulty creation of red blood cells, recurrent transfusions and increased absorption of iron in response to the anaemia.
Patients with thalassaemia have serum ferritin levels monitored to check for iron overload. Management involves limiting transfusions and iron chelation.
221
Which chromosome contains the gene coding for alpha-thalassaemia?
Which chromosome contains the gene coding for beta-thalassaemia?
16
11
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What are the 3 types of beta-thalassaemia?
Thalassaemia minor - carriers of abnormally functioning beta globin gene. They have 1 abnormal and 1 normal gene = causes mild microcytic anaemia (often require monitoring and no active treatment)
Thalassaemia intermedia - 2 abnormal copies of gene which are either both defective or 1 defective and 1 deletion gene. Causes a more significant microcytic anaemia and pt require monitoring and occasional blood transfusions
Thalassaemia major - homozygous for deletion gene. Most severe and presents with severe anmaemia and FTT in early childhood. It causes splenomegaly and bone deformities. May require a curative bone marrow transplant
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How do you best manage sickle cell anaemia?
Avoid things that can trigger a sickle cell crisis e.g. dehydration, sudden temperature changes, high altitudes etc
Ensure vaccines are up to date
Antibiotic prophylaxis to protect against infection with penicillin V (phenoxymethypenicillin)
Hydroxycarbamide can be used to stimulate production of fetal haemoglobin (HbF). Fetal haemoglobin does not lead to sickling of red blood cells. This has a protective effect against sickle cell crises and acute chest syndrome.
Blood transfusion for severe anaemia
Bone marrow transplant can be curative
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What is sickle cell crisis?
An umbrella term for a spectrum of acute crises related to the condition e.g. Vaso-occlusive crisis, splenic sequestration crisis, aplastic crisis, acute chest syndrome. These range from mild to life threatening. They can occur spontaneously or be triggered by stresses such as infection, dehydration, cold or significant life events.
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What is Vaso-occlusive crisis?
AKA painful crisis
caused by the sickle shaped blood cells clogging capillaries causing distal ischaemia.
It is associated with dehydration and raised haematocrit.
Symptoms are typically pain (typically hands and feet), fever and those of the triggering infection.
It can cause priapism in men by trapping blood in the penis causing a painful and persistent erection. This is a urological emergency and is treated with aspiration of blood from the penis.
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What is splenic sequestration crisis?
caused by red blood cells blocking blood flow within the spleen. This causes an acutely enlarged and painful spleen. The pooling of blood in the spleen can lead to a severe anaemia and circulatory collapse (hypovolaemic shock).
It’s an emergency!
Splenectomy is often used in cases of recurrent crisis
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What is aplastic crisis?
Aplastic crisis describes a situation where there is a temporary loss of the creation of new blood cells. This is most commonly triggered by infection with parvovirus B19.
It leads to significant anaemia.
Management is supportive with blood transfusions if necessary.
It usually resolves spontaneously within a week.
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What is acute chest syndrome?
a new radiodensity on chest imaging accompanied by fever and/or respiratory symptoms. It is an acute complication of sickle cell disease (SCD) that is potentially fatal and requires immediate intervention regardless of the patient's age
Management - Antibiotics or antivirals for infections, blood transfusions for anaemia, incentive spirometry using a machine that encourages effective and deep breathing, artificial ventilation with NIV or intubation may be required
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What can be seen on an x-ray of the skull in thalassaemia?
Hair on end appearance
Aka crew cut appearance
(It’s a characteristic feature of chronic haemolysis e.g. thalassaemia and sickle cell anaemia)
230
Why does thalasssaemia cause secondary haemochromatosis?
Due to excessive accumulation of iron in tissues and organs
The iron comes from the break down of RBC as well as excessive iron absorption and regular blood transfusions
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How is a diagnosis of beta-thalassemia confirmed?
Haemoglobin electrophoresis will show low HbA but increased HbF and HbA2 levels (as excess alpha chains bind to beta and delta chains)
232
What is classified as transfusion dependant beta thalassaemia?
Beta thalassaemia major
Sometimes intermediate beta-thalassemia with decreased beta chain synthesis
233
Why dont symptoms of sickle cell appear in homozygotes until 4-6 months?
Because this is when the abnormal HbSS molecules take over from HbF
234
What is basophilic stippling?
Indicative of ineffective haemotpoeisis
It’s the presence of numerous basophilic granules that are dispersed through the cytoplasm of erythrocytes
235
What are pappenheimer bodies?
Abnormal basophilic granules of iron found inside RBCs
Appear as dense, blue-purple granules within the RBCs
Found in sideroblastic anaemia, myelodysplastic syndrome, haemolytic anaemia, lead poisoning and sickle cell disease
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What is a siderocyte?
A RBC containing no haemoglobin iron i.e. containing a pappenheimer body
