Haematology Flashcards
What do lymphocytes look like?
Condensed (purple) nucleus with a thin rim of cytoplasm
How are reticulocytes different from erythrocytes?
Residual ribosomal RNA
They are still able to synthesise Hb
Where is erythropoietin (EPO) produced?
In the kidneys which has a ‘hypoxia sensor’
This is the hormone that regulates red cell production in the bone marrow
Average life span of RBCs
120 days
What cell can sense old red blood cells and removes them?
Macrophages
What happens to the globin chains when a RBC is broken down?
Recycled into amino acids
What happens to haem when RBCs are broken down?
Broken down into iron and bilirubin (from porphyrin ring)
Bilirubin is taken to liver where it is conjugated and excreted in bile
Iron is recycled and put back in storage
How does glycolysis keep haemoglobin functional?
Glycolysis produces 2ATP, 2 pyruvate and 2 NADH
The NADH reverses Fe3+ to Fe2+
This is called Embden-Myerhof Pathway
What is a Hexose Monophosphate Shunt / Pentose Pathway?
A parallel pathway to glycolysis that produces NADPH
NADPH regenerates glutathione
Both NADPH and glutathione protect the RBC from oxidative stress
Rate limited by enzyme G6PD
There is an X-linked disorder which produces faulty G6PD so you get more oxidative stress and premature RBC destruction
How does iron deficiency lead to microcytic anaemia?
Precursor RBCs keep dividing until they have enough haemoglobin so if theres not enough Fe to make haem then they’ll keep dividing until theres enough and end up smaller than normal
Causes of macrocytic anaemia
Vit. B12 or folate deficiency
Needed for DNA synthesis so cells don’t divide normally and increased apoptosis so there’s less of them
How is iron absorbed and regulated?
Haem iron is absorbed through a dedicated haem transporter
Non-haem iron (from cereals) is absorbed through DMT-1
Ferroportin helps pass iron onto transferrin for transport
Hepcidin is produced in the liver in response to increased iron and this binds to ferroportin causing its degradation, trapping iron in duodenal cells and macrophages
What is primary iron overload?
Haemochromatosis
Autosomal recessive
Chromosome 6, mutation in HFE gene causing decreased hepcidin resulting in increased iron absorption
Treat with venesections
Treatment for secondary iron overload
Iron-chelating drugs e,g, desferrioxamine
Side effects of iron supplements
Nausea Diarrhoea Constipation Vomiting Abdo pain Dark stools
Dose-dependant
Best given on an empty stomach
Examples of iron supplements
Ferrous sulfate, fumarate and gluconate are oral
Sodium feredetate liquid prep (syntron) has lower iron conc and is used in paediatrics
IV iron only if oral not tolerated or malabsorption issue
Which chromosome has alpha-like genes for globin?
Chromosome 16
2 alpha genes per chromosome (4 per cell)
Which chromosome has beta-like genes for globin synthesis?
Chromosome 11
1 beta gene per chromosome (2 per cell)
What are haemoglobinopathies?
Hereditary conditions affecting globin chain synthesis
Autosomal recessive
Thalassaemias involve decreased rate of globin chain synthesis but the chains are normal
Sickle cell involves the production of abnormal globin chains
Alpha thalassaemia trait
-a/-a OR aa/-a OR - -/aa
1 or 2 alpha genes are missing
Asymptomatic carrier but may have mild anaemia
No treatment usually required
HbH Disease
- -/-a
More severe alpha thalassaemia where only one alpha gene
Excess beta chains form tetramers called HbH, causes haemolysis and HbH doesn’t offload O2 as well as HbA
Moderate to severe anaemia
Hepatosplenomegaly
Jaundice
May need transfusions
Hb Barts Hydrops Foetalis Syndrome
- -/- - (no alpha genes)
Tetramers of beta and gamma chains are produced
Almost all die in utero as can’t make foetal haemoglobin
Beta thalassaemia trait /minor
One beta gene has either reduced production or no production
Usually asymptomatic or mild anaemia
RAISED HbA2 IS DIAGNOSTIC
Beta thalassaemia major
No beta chains
Appears from 3-6 months of age as body starts moving from HbF to HbA
Haemopoiesis which leads to hepatosplenomegaly and bone expansion
Skull xray shows “hair on end appearance” due to expansion of cortical bone. Looks fuzzy like there a slight buzz cut on the skull
Treat with regular transfusions and long-term folic acid
Describe how sickle cell anaemia occurs
Single point mutation at codon 6 in beta globin gene that substitutes a glutamine to valine
HbS polymerises if exposed to low O2 levels for a prolonged period which distorts the RBC and damages membrane
Describe symptoms and treatment for sickle cell crisis
Chronic haemolysis Vascular occlusion (cells get stuck) which leads to infarcts Hyposplenism due to infarcts Jaundice Acute pain
Treat with opiates, hydration and rest, O2, antibiotics if sign of infection, may need red cell exchange transfusion
How do you diagnose a haemoglobinopathy?
RBC, Hb
Blood film
HPLC - quantifies Hb present and type of Hb
Lifetime of B12 and folate
B12 2-4 years
Folate 4 months
What is pernicious anaemia?
Autoimmune conditions which damages gastric parietal cells, less intrinsic factor, can’t absorb as much vit. B12
Most common cause of B12 deficiency
Associated with hypothyroidism, addisons and vitiligo
Signs of B12 and folate deficiency
Mild jaundice
Red, beefy, sore tongue = glossitis
B12 neuropathy: dorsal column abnormalities, peripheral neuropathy, can be irreversible
4 steps of haemostasis
- Formation of platelet plug (primary haemostasis)
- Formation of fibrin clot (secondary haemostasis)
- Fibrinolysis
- Anticoagulation defences
Describe primary haemostasis
Platelets are formed in bone marrow from megakaryocytes
Endothelial damage exposes collagen and releases con willebrand factor
Platelets have receptors to these and bind
Chemicals are secreted (ADP and thromboxane A2) which leads to aggregation of platelets
Describe secondary haemostasis
Damaged endothelium releases tissue factor (TF) which binds to factor VII and activates it
This activates factors V and X which activates pro-thrombin (extrinsic pathway)
Thrombin activates fibrinogen which forms a fibrin clot
The activation of thrombin activates factors VIII and IX which activates more V and X in a positive feedback loop (intrinsic pathway)
Describe fibrinolysis
As soon as bleeding stops the body starts breaking down the clot
Tissue plasminogen activator (TPA) activates plasminogen which forms plasmin which breaks down a fibrin clot
D-dimers are cross-linked breakdown products of fibrin
What is thrombocytopenia?
Low platelets
What clotting factors are affected by haemophilia
XIII (haemophilia A, more common)
IX (haemophilia B, less common)
Describe the thrombus formed in veins
No platelet activation but activation of the coagulation cascade resulting in a red thrombus rich in fibrin
What is the most common factor affected in hereditary thrombophilias?
Factor V
Describe anti-phosphololipid syndrome
Auto-immune disease making you more likely to clot
Auto-antibodies present are lupus anticoagulant and anti-cardiolipin
Livedo reticularis skin caused by small clots that make skin look blotchy red or blue
Causes thromboses, recurrant fetal loss and mild thrombocytopenia
Counter-intuitively, APTT is actually prolonged
What is the MOA of heparin?
Potentiates the action of anti-thrombin
Immediate effect
Monitor with APTT
How do the DOACs ‘-oxabans’ work?
Directly inhibit factor X
Why does warfarin interact with so many other drugs?
It is metabolised by cytochrome P450
MOA of aspirin
Inhibits cyclo-oxygenase which is necessary to produce thromboxane A2 (which usually causes platelet aggregation)
MOA of clopidogrel
ADP receptor antagonists (ADP causes platelet aggregation)
How long before surgery should you stop anti-platelet drugs?
7 days before as platelets have a lifespan of 7-10 days
Which chromosome codes for ABO blood types?
Chromosome 9
What type of antibodies are anti-ABO and anti-D?
Anti-ABO are IgM (acute reactions)
Anti-D are IgG (delayed reactions)
What is acquired thrombophilia?
Anti-phospholipid syndrome
Stronger risk than hereditary
2 main auto-antibodies are lupus anticoagulant and anti-cardiolipin
Causes livedo reticularis = derm. condition caused by small clots, blotchy appearance
What is leukemia?
Disorder characterised by the accumulation of malignant white blood cells in the bone marrow and blood
Causes bone marrow failure and infiltrates organs
acute lymphoblastic leukemia
Malignant disease of the Primitive Lymphoid cells (lymphoblasts)
Most common childhood cancer
Symptoms of bone marrow failure = pancytopenia
Can ilfiltrate the CNS, testes and cause bone pain
Associated Downs Syndrome and with the Philadelphia Chromosome (t9:22)
Describe the bone marrow and blood of acute lymphoblastic leukemia
Bone marrow is packed with blast cells
Blood also shows blast cells, pancytopenia though WCC may be high cos of blast cells but individual WC will be low
What investigation gives you the definitive diagnosis of ALL
Immunophenotyping
Describe Acute Myeloid Leukemia
Malignant disease of primitive myeloid cells (myeloblasts)
More common in the elderly (>60)
Can be secondary after treatment for other cancer
Auer rods in blast cells
Bone marrow of acute myeloid leukemia
Marrow is full of blast cells, auer rods can be seen in the blast cells
Describe chronic lymphocytic leukemia and symptoms
Kind of like a crossover of leukemia and lymphoma
Mostly affects the middle-aged and elderly
Mostly an incidental finding on routine blood test
Enlarged lymph nodes
Splenomegaly
Anaemia
Recurrent infections
Bone marrow and blood of chronic lymphocytic leukemia
Bone marrow is packed with a monotonous population of small lymphocytes
Blood also has a high lymphocyte count and smudge cells (fragile lymphocytes)
Describe the distribution of B and T cells in lymph nodes
B cells are found in follicles -> cause follicular hyperplasia
T cells are found in the interfollicular area -> cause expansion of the interfollicular area
Describe Hodkin’s Lymphoma
Characterised by Reed-Sternberg cells = Owl-eye appearance (abnormally large B cell with multiple nuclei with a nucleolus inside them)
1/4 of patients will have B symptoms
Associated with EBV
Better prognosis than non-hodkins lymphoma
Describe non-hodgkin’s lymphoma
Less consistently lymph node specific than Hodgkin’s lymphoma
90% are B cell cancers
Less likely to get B symptoms than hodgkins
Mostly middle-age to elderly patients
Differences between Hodgkin’s and Non-Hodgkin’s Lymphoma
Hodgkins is always lymph node in origin and spreads consistently
Non-hodgkins commonly has extra-nodal involvement and can crossover with leukemia
Hodgkins peaks in adolescence or late middle-age, Non-Hodgkins is usually middle-age to elderly
1/4 of Hodgkin’s will have B symptoms, Non-hodgkin’s are less likely to have B symptoms
Hodgkin’s has a better prognosis
Describe Follicular Lymphoma (a type of B cell NHL)
Most common B cell lymphoma
Translocation between chromosomes 14 and 18 which affects the bcl-2 gene
Can be identified with FISH or PCR
Progresses slowly but is fatal
Describe Burkitt’s Lymphoma
Presents with massive lymphadenopathy of the jaw, mostly in children -> facial swelling
Associated with EBV, HIV and malaria
C-myc gene, (t8:14)
Histology will show a Starry Sky appearance
Which lymphoma involves with c-myc gene?
Burkitt’s Lymphoma
Which lymphoma involves the bcl-2 gene?
Follicular Lymphoma, a type of B cell Non-Hodgkin’s Lymphoma
Which staging is used for Lymphomas?
Ann Arbor Staging
Describe Chronic Myeloid Leukemia
3 phases;
Chronic = asymptomatic raised WCC, particularly basophils
Accelerated = abnormal blast cells take over causing anaemia and thrombocytopenia and immunocompromise
Blast = >30% blast cells causing pancytopenia. Often fatal
Associated with Philadelphia Chromosome (t9:22), causing the formation of the BCR-ABL gene
Which Lymphoma is associated with H.pylori infection?
MALT Lymphoma (mucosa-associated lymphoid tissue), usually affects the stomach
What is Tumour Lysis Syndrome?
When tumours start to breakdown (due to chemo or can be spontaneous) they release purines -> uric acid
The increase in uric acid causes uric acid nephropathy and AKI
Ions are also released that cause hyperkalaemia and hyperphosphataemia (can cause clacium phosphate crystals in kidneys causing hypocalcaemia)
Purines->uric acid and ions-> hyperkalaemia, hyperphosphatamaemia, hypocalcaemia -> Renal Failure
What does a monoclonal increase in immunoglobulins mean?
Identical antibodies are produced from the clonal expansion of a single B cell
Indicates an underlying B cell or plasma cell disorder
What is multiple myeloma?
Malignant disease of bone marrow plasma cells that causes multiple tumours
Incurable, relapses are common
Generally males >60, more common in black africans
Symptoms of multiple myeloma plus identifiable features
Bony pain (from tumours, punched out skull ‘pepper pot’ or ‘raindrop’) Hypercalcaemia (bone destruction, bones, stones, moans, groans) Renal failure (Bence Jones Proteins)
Rouleax formations (stacks of RBCs)
What is polycythaemia?
High Hb and RBCs
Can be:
primary (vera): Will have Splenomegaly
Secondary: chronic hypoxia, EPO tumour
Pseudo: reduced plasma volume gives a false picture (dehydration/diuretics)
Symptoms of polycythaemia vera and treatment
Aquagenic pruritis Thrombosis Fatigue Headache Visual disturbance Hepatosplenomegaly
Treatment: venesection and aspirin
What is Sideroblastic anaemia?
You’ve got iron but you’re unable to make it into haem
Leads to deposits of iron in mitochondria (where part of Hb biosynthesis takes place) and they form a ring around the nucleus
Can be congenital or acquired
Symptoms of sideroblastic anaemia
Hypochromic microcytic anaemia
High ferritin and transferrin saturation
Hepatosplenomegaly
Basophilic stippling of red blood cells
Triad of HUS
Haemolytic anaemia
Acute kidney injury
Thrombocytopenia (low platelets)
Causes of HUS
Caused by Shiga Toxin which can be produced by E.coli 0157 or Shigella
Can be caused by giving antibiotics or anti-motility (loperamide) drugs to someone with gastroenteritis
Symptoms of HUS
5 days after gastroenteritis Haematuria Abdo pain Lethargy/irritability Confusion Hypertension Decreased urine output (AKI) Bruising
