Haematology (inc oncology) Flashcards
1
Q
What is the process of red blood cell formation?
A
Erythropoeisis:
- Haematopoietic stem cells –>Myeloid progenitor cell–> Erythrocyte
- Hemocytoblast –>Proerythroblast (committed) Developmental pathway:Early erythroblast – ribosome synthesis–>Late erythroblast – Hb accumulation –>normoblast–> Ejection of nucleus–> reticulocyte–>mature Erythrocyte released into blood stream
2
Q
Do mature erythrocytes produce globin?
A
No – hence the globin chains need to be stable so they can survive for 120 days
3
Q
What are the characteristics of the mature erythrocyte?
A
Ability to bind oxygen + be compressed an squeezed into narrow capillaries:
- Lost its nucleus
- Full of Hb
4
Q
Key driver of erythropoiesis
A
Erythropoietin - EPO
5
Q
Where is EPO produced?
A
Mainly kidney
6
Q
When does EPO production increase?
A
When RBC count lowers
7
Q
All the controls of erythropoiesis?
A
- Hormones: EPO, Testosterone, thyroid
- Nutrients: Iron, folate, B12
8
Q
How much can the marrow increase its Red cell production?
A
Up to 8x the normal rate . If red cell loss/ destruction continues after this point –> anaemia
9
Q
Structure of Hb?
A
Tetramer protein:
- 4 linked globin chains – 2 pairs
- Central haem molecule – with iron at its centre (4 per molecule of Hb)
- Gives blood the red colour
10
Q
What is the normal level of Hb?
A
- Women: 12-16g/dL – g/L in hospitals so 120-160
* Men: 13.5-17.5g/dL
11
Q
What are the different types of Hb?
A
- Adult
- Fetal (portland and gower)
- Embryonic (HbF)
12
Q
What is embryonic Hb?
A
Hb Portland and Hb Gower
13
Q
When does fetal Hb replace embryonic Hb?
A
By 5 weeks gestation
14
Q
What is embryonic Hb?
A
HbF: 2 alpha and 2 gamma chains – 85% of total Hb
15
Q
After birth what happens?
A
HbF production starts to decline and HbA – adult Hb starts taking over
16
Q
What is adult Hb?
A
HbA- majority 97%, small amount of HbA2 and even tinier amount of HbF.
- 2 alpha globin chains
- 2 beta globin chains
17
Q
what is the inheritance of Hb?
A
- Chr 16: 2 genes on each chromosome that code for alpha chains – alpha globin –>4 genes in total (2 from each parent)
- Chr 11: 1 gene on each chromosome that code for beta globin chains –>2 genes in total (1 from each parent)
18
Q
2 broad types of Hb disorders?
A
o Thalassemia: Quantiative defect , structurally normal globin chain
o Sickle cell disease: Qualiative defect – abnormal Hb chains
19
Q
What are thalassaemias?
A
Due to low/absent production of a particular chain of Hb – either alpha or beta. Phenotypically vary greatly. Cause Anaemia
20
Q
Why do thalassaemias cause anaemia?
A
Multifactorial:
o Insufficient globin chains –> excess of one type–>causes precipitation of dominant chain within the cell –>whole cell is less structurally stable (bc globin chains like to be paired – an alpha chain will preferentially pair with a beta chain etc)
o Causes abnormalities in the red cells
o These reds cells are then destroyed (apoptose in the bone marrow / if escape into the circulation –>prone to be lysed –>chronic haemolytic anaemia)
o Additional ineffective erythropoiesis
21
Q
Thalassaemias cause what type of anaemia?
A
Chronic haemolytic anaemia
22
Q
What are the types of thalassaemia’s?
A
- Alpha Thalassaemia – deletion of one or more of the genes coding for alpha chains
- Beta thalassaemia – mutation within the genes encoding the beta chains
23
Q
Why is alpha thalassemia a phenotypically heterogenous condition?
A
- 4 genes control its production – 2 inherited from each parent on Chr 16
- Most people with it only inherit 1 or 2 affected/ deleted genes –> produces a very mild disease
24
Q
What does the offsprings phenotype depend on?
A
- Number of deleted genes inherited
* Location of deletion ( both deletations on one chromosome/ on 2 different chromosomes)
25
What are the alpha thalassaemia phenotypes and genotypes?
- Normal alpha genes on Chr 16
- a+ thalassaemia trait: one deletion on one chromosome - normal /minimal change
- a+ thalassameia homozygote - MCH<25pg
- Hb H disease: 3 deleted genes: moderate severe
- Hydrops Fetalis: all deleted, fatal
26
If both deletions are on the same chromosome what is it termed (thalassemia)?
Alpha 0
27
If a deletion is on each chromosome what is it termed (thalassaemia)?
Alpha +
28
Phenotype of alpha+ trait?
normal/minimal changes to Hb, MCV and MCH
29
Does alpha 0 or alpha + show a worse phenotype?
Both alpha 0 and alpha + are phenotypically indistinguishable -->both will have more marked changes. Mean cell Hb <25pg
30
What happens if an alpha 0 carrier has a child with an alpha+ carrier?
Potential for offspring to have a clinically significant disease:
- Hb H disease or
- Hydrops Foetalis
31
What are the clinically signidicant alpha thalassemia diseases?
- Hb H disease or
| - Hydrops Foetalis
32
What is Hb H disease?
alpha thalassemia
• Results from inherited 3 deleted genes
• Causes moderate severe anaemia: Hb 30-100g/L, MCH 15-120pg
33
What is Hydrops Fetalis?
alpha thalassemia
• Fatal syndrome in babies: once they’re embryonic Hb disappears --> become more and more severely anaemic--> ascites and oedema
• Predominant Hb becomes Hb barts- tetramer of gamma globin chains – can bind oxygen but wont release it
• Most babies will die in utero or shortly after birth
34
What can be done to improve survival in Hydrops Foetalis?
In utero transfusions
35
40. How would you diagnose alpha thalassemia?
- Typically blood film features – small, pale, microcytic, hyperchromic red cells
- PCR is the only diagnostic test (Hb electrophoresis will show variant Hbs but not diagnose it). PCR is not always required
36
41. What is the Treatment for alpha thalassemia?
o Alpha thalassemia trait: no treatment – often just incidental finding on blood test – microcytosis/ mild microcytic anaemia
o HbH disease: Folic acid supplementation, particularly when pregnant. Prompt treatment of infection. May require transfusions
37
Why is folic acid given for HbH disease Tx?
Folic acid depletes rapidly when haemolysing + folate deficiency will worsen their anaemia
38
What is the carriage of alpha thal like?
Very common carriage worldwide
39
What is the prevalence of severe alpha thal disease?
Rare – bc of distribution of a0 thal. Significant a thal disease (HbH or Barts hydrops) confined to Eastern Med and Far East
40
During antenatal screening for alpha thal, what is important to consider?
Individuals from high risk areas will require partner testing
41
What is the phenotype of beta thalassaemia like?
Wide heterogeneity:
- Severity not always associated with genotype.
- Hundreds of diff mutations which all cause reduction of beta globin production to a different degree
- Phenotype affected by other factors – coinheritance of other Hb disorders (alpha thal, sickle cell)
42
What are the distinct entities of beta thalassaemia?
o Thalassaemia carrier / heterozygote - asymptomatic
Inheritence of 2 copies:
o Thalassaemia Intermedia – less severe anaemia and can survive without regular blood transfusions
o Thalassaemia Major – Transfusion dependant
43
What is the B thal trait?
Carrier state – inherit one copy of faulty Hb beta gene.
Usually asymptomatic + Hb> 10g/dL
- Microcytic – rbc smaller than normal
- Abnormal blood film – red cells look like targets
- Usually abnormal Hb electrophoresis (also useful to exclude co-inheritance of Hb variant) – Hb A2 will be slightly higher in b thal carriers
44
In people with B thal trait, what is it important to check?
Iron levels – should be normal (as the other characteristics can be confused with Iron deficiency anaemia) Exclused iron deficiency as the cause of the microcytosis
45
Tx of b thal trait?
No usually required. B thal trait usually picked up incidentally
46
What is B thal intermedia
More anaemic than carrier state but not requiring transfusion
47
Inheritance of B thal intermedia?
Several diff mechanisms:
- Inheritance of 2 mild allelels
- Inheritance of 1 severe allele
- Co-inheritance of alpha thal --> makes homozygous beta thal milder
48
Clinical presentation of B thal intermedia?
* Hepatosplenomegaly: common feature
* High Hb and very few symptoms – in some people
* Low Hb and skeletal deformaties + impaired growth – in some people
49
When does B thal major present?
Childhood, usually 6-12months
50
Clinical presentation of B thal major?
Severe symptoms:
- Anaemia + failure to thrive
- Failure to feed
- Listless
- Crying
- Pale
51
Severity of anaemia in B thal major?
Moderate to severe. Hb 30-70g/l
52
Blood signs in B thal major?
* Hb 30-70g/L, MCV and MCH very low
* Abnormal blood film: large and small (irregular) very pale red cells, NRBC
* Hb F>90% on Hb electrophoresis. Normally you would only see this in a neonatal blood sample
* Normal ferritin
53
Why are there complications in B thal major (pathophysiology)?
As Erythropoeisis is ineffective --> unchecked feedback of severe anaemia--> attempted increased erythropoiesis -->soon expands out of the bone marrow – extra medullary haematopoeisis (liver and spleen)
54
Complications of untreated B thal major?
- Skeletal abnormalities: bone marrow expansion also erodes through bony cortex . typical facial bone changes
- Multi-organ issues: hepatosplenomegaly, wasting
- Secondary haemochromatosis: ineffective erythropoiesis interrupts normal Iron metabolism diabetes, delayed puberty, affects fertility
55
Tx of B thal major?
* Blood transfusions: Every 2-4 weeks
* Endocrine hormone replacements
* Tx and prevention of osteoporosis
* Prompt tx of infections – bc theyre at higher risk of serious bac infections
newer Tx:
- Allogenic bone marrow transport: rare but successful
- Gene editing therapies being developed
56
Aim of transfusion in B thal major?
Maintain a pre-transusion Hb between 95 and 100g/L -->should suppress ineffective erythropoiesis--> avoid hepatosplenomegaly and skeletal abnormalities. Children should grow and develop normally
57
What are the risks of Blood transfusion?
Risk of huge toxicity of excess iron burden. Patients regularly monitored for signs of Iron dysfunction. Sites most sensitive to iron loading regularly monitored – by cardiac MRI, hormone and diabetes screening, Liver MRI
58
What is the sickled haemoglobin – HbS?
Variant of the beta Hb chain
59
Inheritance of sickled cellHb (HbS)?
Autosomal recessive
60
What does sickle cell disease refer to?
- The homozygous state – (SS)
- Combined heterozygotes (SC or SD - Thalassaemia) – if the other beta globin is also abnormal in some way (another Hb variant or beta thalassaemia)
61
Where is carriage and the disease distributed worldwide?
Predominantly in areas where malaria is endemic. 15,000 SS in UK
62
What do sickle cell carriers have?
1 abnormal beta globin gene but will still produce normal beta globin chains (as the condition is autosomal recessive)
63
What advantage do HbS carriers have?
Carriage offers protection against falciparum malaria
64
What is the genetic abnormality in the beta globin gene (in HbS)?
Single amino acid substitution: missesense Glu --> Val
65
Describe the pathophysiology of sickle cell disease?
- Red cells containing HbS deform in low oxygen conditions bc the Hb easily polymerises --> deforming the rbc’s--> form characteristic ‘sickle shape’
- Sickled cells don’t pass through blood vessels easily – sticky and lodge themselves on vascular endothelium -->vascular occlusions: acute and longer term crisis
- Chronic haemolysis: depletes NO- needed for healthy vascular endothelium--> pulmonary hypertension + skin ulceration
66
Phenotype of sickle cell disease?
Highly variable: Few -->severe symptoms
67
Characteristics of sickle cell disease?
- Chronic hameolytic anaemia
- Vascular problems: occlusions, hypertension, skin ulceration
- Spleen infacrtion in childhood--> asplenism + increased risk of infections
68
Why does the spleen usually infarct in childhood in sickle cell disease?
Repeated crisis
69
Characteristics of anaemia in sickle cell disease?
Chronic haemolytic anaemia:
• Usually 60g/dL-90g/dL
• High reticulocyte count – goes up further in acute haemolytic crisis
• No HbA on Hb electrophoresis (90%HbS with variable HbF)
• Anaemia usually well tolerated
70
Why is the anaemia in sickle cell disease usually well tolerated?
HbS has a reduced oxygen affinity ie: it gives up oxygen more easily
71
What is the association with HbF and sickle cell disease?
HbF is protective – those with a higher F percentage (e.g if they have hereditatory persistence of fetal Hb) -->likely to have less severe symptoms
72
16. What are the acute complications of sickle cell disease?
o Painful crises: dactylitis in children. Can be triggered by temp changes, infection, dehydration
o Sequestration crises: spleen (common) and liver
o Infections: Hyposplenism
o Chest complications: Acute chest syndrome
o Abdominal: gallstones, cholangitis
o CNS: acute strokes
73
17. When does sequestration occur (sickle cell disease)?
Generally in childhood (can occur in pregnancy).
74
What does sequestration in the spleen cause?
splenic infarction
75
Patients with sickle cell disease are prone to what infections?
- Pneumococcal
- Neisseria meningitidis
- E.coli
76
Why is there manifestations of acute chest syndrome in sickle cell disease (pathophysiology)?
Sickling in the pulmonary vasculature. Can be fatal if not treated daily
77
Why are gallstones common in sickle cell disease>
Chronic haemolysis and release of bilirubin-->accumulates as bile pigment stains
78
22. What are the consequences of gallstones?
Pain + can lead to infection of the biliary tract
79
23. What are the chronic complications of sickle cell disease?
o CNS: silent infarcts cognitive deterioration over time
o Eyes: Proliferative retinopathy, retinal detachments
o Bones/Joints: Avascular necrosis and chronic pain. Arthritis
o Kidneys/Genituorinary:
- Sickle nephropathy
- Chronic renal impairement contributed by hypertension, drugs, recurrent renal crisis
- Reccurent priapism can lead to erectile dysfunction if not managed early
80
Acute management of sickle cell disease?
- Pain control. Multimodal anaelgesia. Opiods first line Tx in severe pain (opposite to traditional anaelgesic ladder)
- Fluid hydration – if needed
- Supplemenatary oxygen – if needed
81
26. What is the acute management of patients (HbS) with severe uncontrolled pain crisis/ strokes / chest syndrome?
Exchange transfusion – patients red cells are venessected away + cross matched blood is used to replace the volume
82
27. How are chronic complications managed (HbS)?
Regular follow up , monitoring and modifying of any potential risk factors e.g BP , blood glucose
83
what is the disease modifying Tx in Sickle cell disease?
o Regular exchange transfusion
o Hydroxycarbamide – increasing HbF percentage
o Allogenic bone marrow transplant – use is limited
o New hope – gene therapy
84
1. What are the 2 important membranopathies?
o Hereditary Spherocytosis
| o Hereditary eliptocytosis
85
Most common membranopathy?
Hereditory Spherocytosis
86
Inheritance of heriditory spherocytosis?
o Autosomal dominant mutations mostly (75%), Recessive forms – have a more severe phenotype
87
Pathophysiology of hereditory spherocytosis?
structural protein losses --> unstable RBC membrane – not bioconcave , they are spheres- smaller surface area for oxygen diffusion + RBCs don’t survive for as long
88
How is diagnosis of heridatory spherocytosis made?
- Blood film
- Biochemical markers of haemolysis
- Family History
- Clinical findings
- If doubts – further tests can be done inc osmotic fragility test
89
Where is heridatory spherocytosis most common?
Northern European origin
90
what are the clinical features of hereditaroy spherocytosis?
o Mild : compensated haemolysis (Hb 110-150), raised reticulocytes
o Mod-severe: Hb 80-110 60%, splenomegaly becomes detectable during childhood, gallstones common
91
What is the treatment for hereditary spherocytosis?
Supportive care with folic acid replacement
- Splenectomy if severe
- Vaccination
92
How do red cells produce energy?
Glycolysis – anaerobic
93
Key enzymes needed for glycolysis?
- Glucose-6-phosphate dehydrogenase (G6PD)
| - Pyruvate kinase
94
What are 2 enzymeopathies?
- G6PD deficiency
| - Pyruvate Kinase deficiency
95
What is the most common enzymopathy?
G6PD deficiency
96
What is the cause of G6PD deficiency??
Wide variety of mutations in the G6PD gene
97
What is the inheritance of G6PD deficiency?
X linked – predominantly affects men but women may also be
98
Pathophysiology of G6PD deficiency?
Catalyses the reduction of NADP NADPH in the pentose phosphate pathway. NAPDH protects the cell membrane and Hb from oxidative damage – in erythrocytes its only produced via this pathway. G6PD deficiency makes them prone to cell lysis
99
Prevalance and global distribution of G6PD deficiency?
Middle east, SE asia, southern Europe and West Africa
100
How is G6PD deficiency diagnosed?
Screening test for NADPH
101
Clinical features of G6PD deficiency?
- Haemolysis after exposure to oxidants and infections
- Most asymptomatic
- Crisis characterised by haemolysis, jaundice and anaemia
- Picked up in neonate as neonatal jaundice
102
Why is there haemolysis in G6PD deficiency?
Abnormal rbc’s caught and picked up by the spleen
103
What else can G6PD deficinecy be precipiated by?
o Broad beans --> Favism (people experience haemolysis after eating broad beans)
o Drugs
o Infection
104
What drugs can cause drug induced haemolysis?
- Primaquine
- Sulphonamides
- Nitrofurantoin
- Quinolones
- Dapsone
105
WHat is the presentation of drug induced haemolysis?
Usually occurs 1-3 days after drug is administered. Anaemia is at its most severe 7-10 days after the drug.
- Crisis: jaundice, dark urine, haemolysis, anaemia --> usually self limiting
106
What is the presentation of favism?
Can occur within hours of injesting broad beans, can be much more severe--> crisis. Investigations will show spherocytes and fragments on the blood film. Unconjugated bilirubin will be high + reticulocyte count will be high
107
Management of favism?
Avoid broad beans / drugs , transfusion if anaemia is severe
108
Inheritance of pyruvate kinase deficinecy?
Autosommal recessive
109
Pathophysiology of Pyruvate Kinase deficiency?
PK is a enzyme in glycolysis. Deficiency causes reduced ATP production in the red blood cell and increased 23DPG --> Causes Hb to have a lower affinity for oxygen
110
What are the clinical features of PK deficiency?
* Congenital haemolytic anaemia, can also present later in life
* Variable chronic haemolysis
* Prone to aplastic crisis in Parvovirus B19 Infection
* Classical features of hameloysis on investigation inc high reticulocyte count
111
Definitive diagnosis of PK deficiency requires??
PK level
112
Tx of Pyruvate Kinase deficiency?
- Folic acid
- Transfuse during severe crisis
- Consider splenectomy if high transfusion requirements
113
What does FBC include?
o Haemoglobin
o MCV – mean cell volume (how big rbc)
o Haematocrit – what proportion of blood volume is made up of rbc
o Platelets – count
```
o White cell count - overall
o Neutrophils
o Lymphocytes
o Monocytes
o Basophils
o Eosinophils
```
114
What is the normal haematocrit?
About 45%
115
What happens to haematocrit in polycythaemia?
Rises
116
When does neutrophil count increase?
Infection and inflammation
117
Where does haematopoiesis normally occur?
Bone marrow – confided to central skeleton and proximal ends of the long bones
118
What is extramedullary haematopoiesis?
Cells that make RBCs form colonies elsewhere in the body e.g spleen – could contribute to splenic enlargement
119
What is the haematopoetic stem cell?
Can self renew and differentiate into progenitor cells
120
2 routes of the haematopoietic stem cell?
Early commitment to either: Lymphoid or myeloid route
121
How is haematopoiesis regulated?
By cytokines : EPO, G-CSF,GH, IL-2, TPO
122
EPO is illegally used in what group of people?
Performance enhancing drug by elite sports people – cyclers
123
What is the important signalling pathway in haematopoiesis?
JAK/STAT signalling
124
How does JAK/STAT signalling work?
Act on cell surface receptors -->activate the JAK/STAT signalling pathway -->activates the inactive enzymes by phosphorylation--> cascade--> changes in gene transcription – switches on genes involved in cell proliferation
125
JAK/STAT signalling goes wrong in what group of disorders?
Myeloproliferative neoplasms
126
What signalling pathway goes wrong in MPNs?
JAK/STAT
127
What are Myeloproliferative neoplasms?
Group of blood cancers, generally considered to be chronic conditions and can evolve over many years. Characterised by uncontrolled proliferation of one or more cell lines in the bone marrow – usually: eryhthroid, myeloid and/or megakaryocyte lines
128
What is the main manifestation of MPNs?
Accumulation of mature blood cells in the circulation – that arise from haematopoietic stem cells. The cells look normal
129
Cause of MPNs?
Something has gone wrong in the haematopoietic stem cells – acquisition of genetic mutations in haematopoietic stem cells --> JAK/STAT signalling ‘switched on’ inappropriately
130
Are MPNs inherited or aquired?
Aquired
131
In MPNs, what are the mutations in?
- CALR- calreticulin: lots of receptors clumped together --> swtiches on even without cytokine
- MPL: point mutations -->change 3d shape of receptor--> permanently on
- JAK2V617F: kinase – enzyme that phosphorylates --> mutation--> no auto-inhibition-->permanently active and phosphorylating
132
What diseases are MPNs?
- Polycythaemia Vera (PV)
- Essential Thrombocytosis (ET
- Myelofibrosis (MF)
- Chronic Myeloid Leukemia (CML)
- Rare MPNs (chronic neutrophilic leukemaia, eosinophilic leukaemia)
133
What is Polcythaemia Vera (PV)?
Clonal stem cell disorder in which there is an excessive proliferation of erythroid, myeloid and/or megakaryocytic progenitor cells.
-Elevated haematocrit and Hb – may have splenomegaly. Too much RBC.
134
What is the most common mutation in Polycythaemia Vera?
JAK2 (over 95%). Point mutation that causes the substitution of phenylalanine--> valine at position 617 – JAK2V617F
135
Describe the onset of disease in Polycythaemia Vera?
Insidious
136
What age group is Polycythaemia Vera most common in?
>60
137
Clinical presentation of Polycythaemia Vera?
```
o Fatigue
o Itching
o Vertigo
o Headache
o Visual disturbance
o Complications of the disease – thrombosis or haemorrhage
```
Since these symptoms are common in the older population , diagnosis of PV is commonly missed
138
What is the main complication of Polycythaemia Vera?
Blood clots -->risk of stroke, MI, DVT .
139
What is disease transformation?
Relatively chronic indolent disease--> switches to aggressive acute leukemia/ myeloid fibrosis. Occurs in small proportion
140
What is the disease transformation like in Polycythaemia Vera?
- 12-21% develop into myeloid fibrosis
| - 5% develop into AML
141
Median prognosis in Polycythaemia Vera?
13 yrs
142
Causes of elevated haematocrit?
- Primary PV
| - Secondary: lung disease, alcohol, 'apparent erythrocytosis', EPO producing tumours, COPD patients
143
What is apparent erythrocytosis?
Not too many RBC, just not enough liquid -dehydrated, SGLT-2 inhibitors
144
What tumours can produced EPO?
Rare – liver and kidney cancer
145
35. How do you differentiate between secondary causes and primary PV?
Spleen is palpable in 70% in Primary PV
146
36. What is the diagnostic criteria for PV?
o JAK-2 Positive PV: requires mutation in JAK-2 + elevated haematocrit or raised red cell mass
o JAK-2 Negative PV: Just look at BSH guidelines (basically exclude secondary causes + look for other signs/ symptoms, other blood evidence)
147
What is the aim of Tx in Polycythaemia Vera?
Maintain normal blood count and prevent complications of disease particularly thromboses and haemorrhage. Aim to keep haematocrit <0.45
148
What is the management of Polycythaemia Vera?
Focus to reduce risk of blood clots:
• Venesection: inital removal of 400-500mL of blood weekly--> relieves symptoms, aim of haematocrit <0.45
• Hydroxycarbamide – mild chemotherapy continuous or intermittent. Reduces RBC production. Used in patients who do not tolerate venesection or have poorly controlled features – e.g thrombocytosis, symptomatic splenomegaly or thrombosis
• Low dose Aspirin: 75mg daily with the above Tx is routinely given in patients with PV in the absence of contraindications
• Management of other CV risk factors: BP control ,cholesterol, diabetes: need to have an annual check
149
When is Allopurinol given in PV?
If they have gout, allopurinol blocks uric acid production. Gout is due to increased cell turnover
150
In patients with PV, what should be done before surgery?
PV should be controlled. High operative risk. In emergency, haematocrit must be reduced by venesection and appropriate fluid replacement
