Haematology Flashcards
Give the reticulocyte percentage in RBC underproduction compared to destruction
<3% in underproduction as decreased bone marrow response
>3% in destruction as increased bone marrow activity
What does MCV stand for and what should it be for a normal RBC/ in normocytic anaemia?
Mean corpuscular volume = 80-100 micro meters cubed
What is the MCV in macrocytic anaemia?
> 100
What is the MCV in microcytic anaemia?
<80
What causes microcytic anaemia?
Decrease in haemoglobin which leads to the splitting of RBCs in order to try and increase haemoglobin concentration
Give the 4 general causes of Iron deficiency anaemia
Decreased intake
Increase in the body’s demand
Decrease in absorption
Increase in blood loss
Why might someone’s intake of iron decrease?
Infants <6 months, generally feed on breast milk which lacks iron
Why might the body’s demand for iron increase?
Child/ adolescent- growing
Pregnant women
Why might there be a decrease in iron absorption?
Decrease in production of stomach acid if patient is on a PPI or has had a gastrectomy
Problem in the duodenum- Coeliac disease
Why might there be an increase in blood loss leading to anaemia?
Heavy menstruation
Peptic ulcer disease
Hookworm infection
Colon cancer/ polyps
How might you diagnose iron deficiency anaemia?
Symptoms of anaemia As well as: Koilonychia- spoon shaped nails Pica- desire to eat inedible things Restless leg syndrome
How is iron transported and stored in the body?
Iron binds to transferrin in the blood
Iron binds to ferritin in the liver and is stored in macrophages (Kupffer cells)
How are ferritin and transferrin levels affected in iron deficiency anaemia?
Ferritin decreases
Transferrin increases in order to compensate for iron loss and increase total iron binding capacity
What type of anaemia is anaemia of chronic disease?
Microcytic
What is hepcidin and how do levels vary in relation to iron levels?
A major iron regulator
When iron levels decrease, hepcidin decreases
When iron levels increase, hepcidin increases
This is because hepcidin decreases serum iron
How does hepcidin decrease serum iron?
It blocks ferroportin channels, inhibiting the passage of iron across duodenal cells/ absorption from the gut
What is the consequence of hepcidin preventing degration of RBCs after 120 days?
Iron cannot be released and saved/ recycled
Why is hepcidin released in response to an inflammatory disease?
Iron can be a key nutrient needed for bacterial growth so hepcidin is released in response to cytokines so that iron levels decrease
Give the potential treatments for Iron deficiency anaemia
Oral iron supplements- taken with an acidic drink (this can cause black stools)
IV iron
Blood transfusion
- With increased blood loss or decreased absorption supplements are not enough
Why would you not treat anaemia of chronic disease with iron?
May increase the rate of bacterial growth
Describe the mechanism of microcytic anaemia
Between G2 and M phase, reticulocytes grow too big and haemolysis occurs as a result
What is the compensatory mechanism that occurs as a result of macrocytic anaemia?
Bone marrow hyperplasia in order to increase reticulocytes
Give the causes of macrocytic anaemia
Folate deficiency (THF) B12 deficiency
How does folate deficiency lead to macrocytic anaemia?
THF converts to purines through a number of reactions, specifically adenine and guanine
Therefore a deficiency in folate means that DNA is not synthesised correctly
Give 3 causes of B12 deficiency
Resection of terminal ilium
Tapeworm
Lack of intrinsic factor- this is pernicious anaemia
Which cells produce intrinsic factor?
Parietal cells
Give the treatment of folate deficiency and B12 deficiency
Folate: oral folic acid
B12: Parenteral B12
Which drugs inhibit the conversion of folic acid to THF?
Methotrexate
AVT
Cyclophosphamide
Trimethoprim
Which type of haemoglobin is affected in sickle-cell disorder?
Haemoglobin A
2 alpha globin
2 beta globin
Describe what is meant by heterozygote advantage in sickle cell anaemia
Sickle trait (carrier)
No health problems unless exposed to extreme conditions
Decreases the severity of P. falciparum malaria
Describe the mutation that occurs in sickle cell anaemia
Non-conservative missense mutation
Glutamic acid (hydrophilic) is replaced with Valine (hydrophobic)
Sickle cell haemoglobin with mutated beta globin is called HbS
How do HbS form the sickle shape?
When deoxygenated, it changes shape allowing it to aggregate with other HbS proteins and form long polymers in a sickle shape
Give two conditions that promote sickling
Acidosis as this decreases Hb affinity for oxygen
Low flow vessels as Hb has time to dissociate from lots of oxygen
How can repeated sickling cause scleral icterus, jaundice and gallstones?
Repeated sickling leads to weakened cell membranes and therefore premature destruction where Hb spills out
Recycled haptoglobin yields unconjugated bilirubin
What is the effect of an increased production of reticulocytes by the bone marrow in anaemia?
New bone formation as increased activity of bone marrow
Expansion of medullar cavities in skull causing enlarged cheeks
Describe extra medullary hematopoiesis and what this causes
In anaemia there may be RBC production outside the bone marrow which travel to the liver and cause hepatomegaly
What happens when sickle cells clog blood flow in infants?
Obstruct supply to hands and feet causing dactylitis in infancy
What happens when sickle RBCs clog up the spleen?
Infarct leading to autosplenectomy (fibrosis) and splenic sequestration
The patient is therefore susceptible to encapsulated bacteria since encapsulated bacteria are usually opsonised and phagocytised by macrophages in the spleen
What can occur if sickle cells become stuck in cerebral vasculature?
Stroke
Moya-moya disease- “puff of smoke” collateral vessels that bypass blocked arteries
What can occur if sickle cells become stuck in the vessels of the following organs:
Lungs
Kidneys
Penis
Lungs: acute chest syndrome
Kidneys: Necrosis leading to haematuria and proteinuria
Penis: priapism- painful and prolonged erection
How would you diagnose sickle cell anaemia?
Newborn blood spot screen
Blood smear
Protein electrophoresis
How would you treat sickle cell anaemia?
Oxygen and fluids
Opioids to manage pain
Abx to treat underlying bacterial infection from acute chest syndrome
Blood transfusion
Hydroxyurea- increases alpha globin and HbF (no beta globin so no mutation), which gets in the way of HbS
Bone marrow transplant
Gene therapy
Describe the process of DVT formation
Damage to endothelium
Vasoconstriction
Platelets: adhere, are activated by collagen and tissue factor, recruit more forming a plug
Clotting factors are activated, terminally activating fibrinogen to convert to fibrin forming a mesh over the platelet plug
This plaque can break off and form a clot
Give the three factors of Virchow’s triad that lead to DVT
Slowed blood flow
Hypercoagulation (genetics, surgery, medications)
Damage (Infections, chronic inflammation, tobacco smoke)
Describe the symptoms and diagnosis of DVT
Symptoms:
Pain, swelling, redness, warm
Diagnosis:
US, Venography, D dimer blood test
Define acute leukemia
The precursor “blasts” can’t differentiate any further, normally % of blasts in bone marrow is 1-2 %
In leukaemia it is >20%
What is the effect of an increased number of precursor cells in the bone marrow in leukaemia?
Cytopoeina as normal cells are “crowded out”
Anaemia: fatigue
Thrombocytopenia: bleeding
Neutropenia: Infection
How would you test for lymphoblasts?
TdT positive
How do you differentiate between B-ALL and T-ALL?
B- expresses surface markers CD10, 19 and 20
T- expresses surface markers CD2-CD8
How would you test for myeloblasts?
Auer rods
Positive myeloperoxidase seen via cytoplasmic staining
What is the Philadelphia chromosome and how does it affect prognosis in leukaemia?
t(9;22) Ph +ve
Poor prognosis
How would you classify acute myeloid leukaemia by lineage?
Mono blast AML
Megakaryoblast AML
Erythroblast AML
Which type of leukemias are associated with Down’s syndrome and at what age?
0-5 years- megakaryoblastic leukaemia
>5 years- acute lymphoblastic lymphoma
Give 2 conditions that can lead to AML
Myelodysplastic syndrome- blast build up in bone marrow
Myelodysplasia- poor formation of bone marrow cells
What is the most common cause of leukaemia?
Chromosomal abnormality in haematopoietic stem cells which will affect leukocytes so that they only mature partially and don’t work effectively
Describe the difference between chronic myeloid and chronic lymphocytic leukaemia
CML:
Affects granulocytes
Cells divide too quickly
CLL:
Affects lymphocytes
Cells don’t die when they should
How can chronic leukaemia progress to acute leukaemia?
More divisions leads to increased mutations
This progression is often caused by trisomy of chromosome 8 or doubling of Philadelphia chromosome
Describe the mechanism of chronic lymphocytic leukaemia
Mutations interfere with B cell receptors which should only be signalled during inflammation
Excess B cells in the bone marrow are forced into the blood and lymphatic system leading to lymphadenopathy
This is a lymphoma
Give 5 symptoms of chronic leukaemia
Fatigue
Easier bleeding
More infections
In CML hepatosplenomegaly- feeling of fullness
In CLL lymphadenopathy- pain in the lymph node
How would you diagnose CML?
Increased granulocytes and monocytes in blood smear
How would you diagnose CLL?
Smudge cells- immature B cells, broken during smear in blood smear
How would you treat chronic leukaemia?
Biological therapy: tyrosine kinase inhibitor (less effective for CLL)
Chemo
Stem cell transplant
Bone marrow transplant
What is the key feature of non-Hodgkin lymphoma?
Absence of Reed-Sternberg cell
Describe the differentiation of B cells in lymph nodes
B cells grouped into follicles in the cortex of lymph nodes
Some differentiate directly into plasma cells and produce IgM antibodies
Memory B cells travel to the blood, lymph nodes, spleen and mucosa-associated lymphoid tissue
Describe the mechanism of non-Hodgkin lymphoma
A genetic mutation occurs where cells which should usually undergo apoptosis instead divide uncontrollably forming nodal lymphomas
How does NHL affect the following:
GI tract
Bone marrow
Spinal cord
GI: Bowel obstruction
Bone marrow: crowds out normal cells
Spinal cord: spinal cord compression
Give 4 general symptoms of lymphoma
Painless lymphadenopathy
Fever
Night sweats
Weight loss
How would you diagnose lymphoma?
Imaging studies (CT scan) to establish stage Lymph node biopsy
How would you treat lymphoma?
Chemo/ radiation therapy
If CD20 +ve rituximab can be used to induce complement-mediated lysis as well as direct cytotoxicity and apoptosis
What is multiple myeloma?
Malignant disease of plasma cells in the bone marrow
What differences can be seen in the bone marrow of someone with multiple myeloma?
> 10% plasma cells
Producing abnormal antibodies and only light chains produced (paraproteins)
Give 5 symptoms of multiple myeloma
Back pain Lytic bone lesions Anaemia Dehydration Infections Fractures Renal failure Proteinuria
Give the three types of bone cells
Osteoblasts
Osteoclasts
Bone marrow stroll cells- regulate haematopoeisis
Which immunoglobulins are produced in high amounts in multiple myeloma?
IgG and IgA
How do osteoclasts break down bone?
Releasing HCl
What do osteoblasts release in order to build bone?
Osteoid and minerals (calcium and phosphate)
How is osteoclast activation regulated by osteoblasts?
Rank on osteoclasts binds to rank ligand on osteoblasts
How do bone marrow stromal cells help myeloma cells survive and grow?
Adhesion of bone marrow cells to myeloma cells stimulates cytokine mediated growth, survival, drug resistance and migration
What is osteoprotegerin?
It inhibits the differentiation of osteoclast precursors
How do multiple myeloma cells reduce osteoblast activity?
Release IL-3 which inhibits osteoblast progenitor cells
How do multiple myeloma cells increase osteoclast activity?
Release DKK1 which inhibits OPG
Expression of rank ligand
What are the problems caused by hypercalcaemia as a result of multiple myeloma?
Nerve problems
Dehydration
What are the problems caused by paraproteinaemia in multiple myeloma?
Can pass through the glomerulus and cause renal failure
What is the name for the light chain proteins in the urine in multiple myeloma?
Bence-Jones proteins
Why do you get anaemia from multiple myeloma?
Shift from myeloid to lymphoid progenitor to make more plasma cells
Over-production of plasma cells clogs up bone marrow
Kidney failure- decreased erythropoiesis, so decreased RBC production
What would be the results of a blood and urine test in multiple myeloma?
Anaemia Paraproteinaemia Decrease in normal antibodies Hypercalcaemia Increase in urea and nitrogenous bases- renal failure Increase in creatinine Bence- Jones proteins in urine
What bone investigations would you carry out for multiple myeloma?
Bone aspiration Bone marrow biopsy X-ray CT scan- lesions of bone and soft tissue MRI
How would you diagnose multiple myeloma?
Monoclonal plasma cell in bone marrow >10% Monoclonal antibody in serum/ urine \+ 1 of CRAB: Hypercalcaemia Renal failure Anaemia Lytic bone lesions
What causes malaria infection?
Plasmodium species
Give the 5 species of plasmodium
P. falciparum P. vivax P. malariae P. ovale P. knowlesi
Which are the two main cell types affected by malaria?
Hepatocytes and RBCs
How does sickle cell anaemia protect against plasmodium vivax?
P. vivax targets the Duffy antigen, sickle RBCs have no Duffy antigen
Which other diseases provide protection against malaria and how do they do this?
Thalassemia and G6PD deficiency make parasite-infected erythrocytes more susceptible to dying from oxidative stress
What is the mosquito responsible for carrying malaria?
Female Anopheles mosquito
How does the plasmodium species enter the host?
Sporozoites in the mosquito’s salivary gland spill into the blood stream and reach the liver
What type of reproduction occurs in the liver when the plasmodium sporozoites enter in malaria?
Asexual
Which strains of malaria invade RBCs of all ages?
P. ovale and P. falciparum
Which strain of malaria invade reticulocytes?
P. vivax
Briefly describe the erythrocytic phase of malaria
Early trophozoite develops and multiplies within RBC, this ruptures and new merozoites go on the invade new RBCs
What would occur next if a merozoite undergoes gametogony?
Gametocytes remain inside RBC and may be taken up by a female Anopheles mosquito
Gametocytes reach the mosquito’s gut and mature/ fuse into zygote
Oocyst ruptures releasing sporozoites
Give 4 symptoms of haemolytic anaemia secondary to malaria
Extreme fatigue
Headaches
Jaundice
Splenomegaly
Why do you get paroxysms of fever in malaria?
The release of TNF-alpha and other inflammatory cytokines correspond to the rupture of infected RBCs
Paroxysms vary depending on the length of the erythrocytic phase
Where are most plasmodium-infected RBCs destroyed?
Sleen
How does P. falciparum avoid destruction by the spleen and cause ischaemic damage?
It generates a sticky protein that coats the surface of the infected RBCs
This protein causes RBCs to clump together and jam up blood vessels
Cytoadherence means infected cells can’t flow to the spleen
It also blocks blood flow to vital organs
Give 3 symptoms of cerebral malaria
Altered mental status
Seizures
Coma
Give 4 symptoms of bilicus malaria
Diarrhoea
Vomiting
Jaundice
Liver failure
How would you diagnose malaria?
Thick blood smear: locates parasites in RBCs
Thin blood smear: directly identifies plasmodium species
>5% of parasitemia can have worse outcomes
Thrombocytopenia
Elevated lactate dehydrogenase due to haemolysis
Normochromic and normocytic anaemia
Give the 4 general types of treatment for malaria
Suppressive treatment/ chemoprophylaxis
Therapeutic treatment
Gametocidal treatment
Radical treatment
Explain the difference between the three types of recurrent malaria
Recrudescence- from infective treatment that did not clear the infection, common with increase in antimalarial resistance
Relapse- blood cleared of merozoites but hyptozoites persist in the liver
Reinfection- treated but a new infection causes a new bout of malaria
Give 4 means of preventing malaria
Mosquito nets
Full body clothing
Indoor insecticide sprays
Empty stagnant collections of water
Define polycythaemia
Elevated haematocrit (% of RBCs in the blood)
Describe the difference between absolute and relative polycythaemia
Absolute is an increase in RBCs
Relative is due to a decrease in plasma volume
Give 4 causes of absolute polycythemia
Myeloproliferative syndrome
Reaction to chronically low oxygen levels
Malignancy
Being over-transfused
Give 3 causes of relative polycythemia
Burns
Dehydration
Stress
Give 4 causes of an increase in procoagulants
Sepsis Malignancy Trauma Obstetric complications Intravascular haemolysis
Give 3 examples of procoagulants
Tissue factor
Lipopolysaccharide
Enzymes that activate clotting factors
Give 3 consequences of new clot formation
Ischameia
Depletion of platelets and clotting factors
Fibrin degradation products in circulation interferes with clot formation
What would be the lab findings with disseminated intravascular coagulation?
Decrease in platelets and fibrinogen
Prolonged prothrombin and partial thromboplastin time (PT and PTT)
Increase in D-Dimers
What might the lab findings be in a patient with chronic DIC?
Normal results due to compensation
