Haematology Flashcards
What is tumour lysis syndrome?
Tumour lysis syndrome is a common oncological emergency.
It is associated with rapid cell death, causing release of uric acid, on starting chemotherapy and is common in tumours which are rapidly proliferating.
The uric acid can form crystals in the interstitial tissue and tubules of the kidneys and causes acute kidney injury.
These are classically haematological malignancies such as leukaemia and lymphoma.
What happens physiologically in tumour lysis syndrome?
It results in an increase in serum urate, potassium and phosphate, precipitating renal failure.
Symptoms of tumour lysis syndrome?
Nausea
Vomiting
Muscle pain
Prevention of tumour lysis syndrome?
Management focuses on preventing this from occurring through giving:
Prophylactic allopurinol
In some cases a recombinant urate oxidase rasburicase is given
Good hydration should be maintained.
What is lymphadenopathy and what are the general causes?
Lymphadenopathy refers to enlarged lymph nodes. There are a long list of causes of enlarged lymph nodes, which can be generally grouped into:
Reactive lymph nodes (e.g., swelling caused by viral upper respiratory tract infections, dental infection or tonsillitis)
Infected lymph nodes (e.g., tuberculosis, HIV or infectious mononucleosis)
Inflammatory conditions (e.g., systemic lupus erythematosus or sarcoidosis)
Malignancy (e.g., lymphoma, leukaemia or metastasis)
Lymphadenopathy - features suggesting malignancy?
Unexplained (e.g., not associated with an infection)
Persistently enlarged (particularly over 3cm in diameter)
Abnormal shape (normally oval shaped where the length is more than double the width)
Hard or “rubbery”
Non-tender
Tethered or fixed to the skin or underlying tissues
Associated symptoms, such as night sweats, weight loss, fatigue or fevers
Lymphadenopathy of which of the cervical lymph nodes are most concerning for malignancy?
Supraclavicular - . They may be caused by malignancy in the chest or abdomen and require further investigation.
Infectious mononucleosis is a cause of lymphadenopathy. What cause is it and what are the features?
It is caused by infection with the Epstein Barr virus (EBV) and most often affects teenagers and young adults. It is found in the saliva of infected individuals and may be spread by kissing or sharing cups, toothbrushes and other equipment that transmits saliva.
It presents with
Fever
Sore throat
Fatigue
Lymphadenopathy
Mononucleosis can present with an intensely itchy maculopapular rash in response to amoxicillin or cefalosporins.
The first-line investigation is the Monospot test. It is also possible to test for IgM (acute infection) and IgG (immunity) to the Epstein Barr virus.
Management is supportive. Patients should avoid alcohol (risk of liver impairment) and contact sports (risk of splenic rupture).
What are lymphomas and how do they cause lymphadenopathy?
Lymphomas are a group of cancers that affect the lymphocytes inside the lymphatic system. These cancerous cells proliferate within the lymph nodes and cause the lymph nodes to become abnormally large
What are the two categories of lymphoma and which is more common?
Hodgkin’s lymphoma (1/5) and non-Hodgkin’s lymphoma (4/5).
Hodgkin’s lymphoma is a specific disease and non-Hodgkins lymphoma encompasses all the other lymphomas.
What causes Hodgkin’s lymphoma (physiologically, in simple terms)?
Proliferation of lymphocytes
In which ages does lymphoma most commonly present?
bimodal age distribution with peaks around aged 20 and 75 years
Typical presentation of Hodgkin’s lymphoma?
Lymphadenopathy: key presenting symptom
The enlarged lymph node or nodes might be in the neck, axilla (armpit) or inguinal (groin) region.
They are characteristically non-tender and feel “rubbery”.
Some patients will experience pain in the lymph nodes when they drink alcohol.
B symptoms are the systemic symptoms of lymphoma:
Fever
Weight loss
Night sweats
Fatigue
Itching
Cough
Shortness of breath
Abdominal pain
Recurrent infections
What are B symptoms?
B symptoms are the systemic symptoms of lymphoma:
Fever
Weight loss
Night sweats
What is the key finding from lymph node biopsy in patients with Hodgkin’s lymphoma.
The Reed-Sternberg cell
What staging system is used for lymphoma?
The Ann Arbor staging system is used for both Hodgkins and non-Hodgkins lymphoma.
The presentation of leukaemia is quite non-specific.
Some typical features are what?
Fatigue
Fever
Pallor due to anaemia
Petechiae and abnormal bruising due to thrombocytopenia
Failure to thrive (children)
Abnormal bleeding
Lymphadenopathy
Hepatosplenomegaly
What is leukaemia and how is it classified?
Leukaemia is the name for cancer of a particular line of the stem cells in the bone marrow.
This causes the unregulated production of certain types of blood cells.
They can be classified depending on how rapidly they progress (chronic is slow and acute is fast) and the cell line that is affected (myeloid or lymphoid) to make four main types:
Acute myeloid leukaemia
Acute lymphoblastic leukaemia
Chronic myeloid leukaemia
Chronic lymphocytic leukaemia
What are the components of blood and serum?
Blood is made up of plasma (the liquid of the blood) that contains red blood cells, white blood cells and platelets. The plasma also contains lots of clotting factors such as fibrinogen.
Once the clotting factors are removed from the blood what is left is called the serum. Serum contains:
Glucose
Electrolytes such as sodium and potassium
Proteins such as immunoglobulins and hormones
Where do blood cells develop from?
Bone marrow
Where is bone marrow mostly found?
Pelvis
Vertebrae
Ribs
Sternum
What are Pluripotent Haematopoietic Stem Cells and what do they become?
These are undifferentiated cells that have the potential to transform into a variety of blood cells. They initially become:
Myeloid Stem Cells
Lymphoid Stem Cells
Dendritic Cells (via various intermediate stages)
Reticulocyte vs red blood cell?
Red blood cells (RBCs) develop from reticulocytes that comes from the myeloid stem cells.
Reticulocytes are immature red blood cells that are slightly larger than standard erythrocytes (RBCs) and still have RNA material in them. The RNA has a reticular (“mesh like”) appearance inside the cell. It is normal to have about 1% of red blood cells as reticulocytes.
Where do reticulocytes come from?
Myeloid stem cells
RBC lifespan?
120 days
Platelet lifespan?
10 days
What are platelets made by?
Megakaryocytes
What is the role of platelets
Their role is to clump together (platelet aggregation) and plug gaps where blood clots need to form
What can promyelocytes become?
Monocytes then macrophages
Neutrophils
Eosinophils
Mast Cells
Basophils
What do myeloid stem cells become?
Promyelocytes
What do myeloid stem cells become?
Promyelocytes
Where do lymphocytes come from?
Lymphoid stem cells
What do lymphocytes become?
B cells or T cells
Where do B lymphocytes mature?
Bone marrow
Where do T lymphocytes mature?
Thymus gland
What do B lymphocytes differentiate into?
After maturing in the bone marrow:
Plasma Cells
Memory B cells
What do T lymphocytes differentiate into?
After maturing in the thymus gland
CD4 cells (T helper cells)
CD8 cells (Cytotoxic T Cells)
Natural Killer Cells
What is a blood film?
A blood film involves a specialist examining the blood using a microscope to manually check for abnormal shapes, sizes and contents of the cells and note abnormal inclusions in the blood
Blood film findings: what is anisocytosis and when might it be seen?
Variation in size of red blood cells
Myelodysplastic syndrome, some types of anaemia
Blood film findings: what are target cells and when might they be seen?
RBC that have a central pigmented area, surrounded by a pale area, surrounded by a ring of thicker cytoplasm on the outside. This makes it look like a bull’s eye target.
These can be seen in iron deficiency anaemia and post-splenectomy.
What is seen here and why might it be present?
Anisocytosis refers to a variation in size of the red blood cells. These can be seen in myelodysplasic syndrome as well as some forms of anaemia
What are seen here and why might they be present?
Target cells - have a central pigmented area, surrounded by a pale area, surrounded by a ring of thicker cytoplasm on the outside. This makes it look like a bull’s eye target. These can be seen in iron deficiency anaemia and post-splenectomy.
What are seen here and why might they be present?
Howell-Jolly bodies are individual blobs of DNA material seen inside red blood cells. Normally this DNA material is removed by the spleen during circulation of red blood cells. They can be seen in post-splenectomy and in patients with severe anaemia where the body is regenerating red blood cells quickly.
What are Howell-Jolly bodies and why might they be seen?
Howell-Jolly bodies are individual blobs of DNA material seen inside red blood cells. Normally this DNA material is removed by the spleen during circulation of red blood cells. They can be seen in post-splenectomy and in patients with severe anaemia where the body is regenerating red blood cells quickly.
Why might % of reticulocytes be higher than normal (aprox 1%) and what does this demonstrate?
Rapid turnover of RBC - rapid turnover of red blood cells, such as haemolytic anaemia. They demonstrate that the bone marrow is active in replacing lost cells.
What are schistocytes?
Schistocytes are fragments of red blood cells. They indicate the red blood cells are being physically damaged by trauma during their journey through the blood vessels.
Why might schistocytes be seen on blood film?
They may indicate networks of clots in small blood vessels caused by:
Haemolytic uraemic syndrome
Disseminated intravascular coagulation (DIC) or Thrombotic thrombocytopenia purpura.
They can also be present in replacement metallic heart valves and haemolytic anaemia.
What is seen here and why might they be seen?
Schistocytes are fragments of red blood cells. They indicate the red blood cells are being physically damaged by trauma during their journey through the blood vessels. They may indicate networks of clots in small blood vessels caused by haemolytic uraemic syndrome, disseminated intravascular coagulation (DIC) or thrombotic thrombocytopenia purpura. They can also be present in replacement metallic heart valves and haemolytic anaemia.
What are sideroblasts and why might they be seen on blood films?
Sideroblasts are immature red blood cells that contain blobs of iron. They occur when the bone marrow is unable to incorporate iron into the haemoglobin molecules. They can indicate a myelodysplasic syndrome.
What is seen here and why might they be present?
Sideroblasts are immature red blood cells that contain blobs of iron. They occur when the bone marrow is unable to incorporate iron into the haemoglobin molecules. They can indicate a myelodysplasic syndrome.
What are smudge cells and why might they be seen?
Smudge cells are ruptured white blood cells that occur during the process of preparing the blood film due to aged or fragile white blood cells.
They can indicate chronic lymphocytic leukaemia.
What are seen here and why might they be present?
Smudge cells are ruptured white blood cells that occur during the process of preparing the blood film due to aged or fragile white blood cells.
They can indicate chronic lymphocytic leukaemia.
What are spherocytes and why might they be seen on blood film?
Spherocytes are spherical red blood cells without the normal bi-concave disk space. They can indicated autoimmune haemolytic anaemia or hereditary spherocytosis.
What are seen here and why might they be present?
Spherocytes are spherical red blood cells without the normal bi-concave disk space. They can indicated autoimmune haemolytic anaemia or hereditary spherocytosis.
Causes of microcytic anaemia?
T – Thalassaemia
A – Anaemia of chronic disease
I – Iron deficiency anaemia
L – Lead poisoning
S – Sideroblastic anaemia
Causes of normocytic anaemia?
There are 3 As and 2 Hs for normocytic anaemia:
A – Acute blood loss
A – Anaemia of Chronic Disease
A – Aplastic Anaemia
H – Haemolytic Anaemia
H – Hypothyroidism
What are the two types of macrocytic anaemia and what is the difference??
Megaloblastic or normoblastic
Megaloblastic anaemia is the result of impaired DNA synthesis preventing the cell from dividing normally. Rather than dividing it keeps growing into a larger, abnormal cell. This is caused by a vitamin deficiency.
Normblastic is not related to DNA synthesis
What are the causes of megaloblastic anaemia?
B12 deficiency
Folate deficiency
What are the causes of normoblastic macrocytic anaemia?
Alcohol
Reticulocytosis (usually from haemolytic anaemia or blood loss)
Hypothyroidism
Liver disease
Drugs such as azathioprine
Causes of macrocytic anaemia
Megaloblastic:
B12 deficiency
Folate deficiency
Normoblastic:
Alcohol
Reticulocytosis (usually from haemolytic anaemia or blood loss)
Hypothyroidism
Liver disease
Drugs such as azathioprine
Generic SYMPTOMS of anaemia?
Tiredness
Shortness of breath
Headaches
Dizziness
Palpitations
Worsening of other conditions such as angina, heart failure or peripheral vascular disease
SYMPTOMS specific to iron deficiency anemia?
Pica describes dietary cravings for abnormal things such as dirt and can signify iron deficiency
Hair loss can indicate iron deficiency anaemia
Generic SIGNS of anaemia?
Pale skin
Conjunctival pallor
Tachycardia
Raised respiratory rate
SIGNS specific to iron deficiency anaemia?
Koilonychia (spoon shaped nails)
Angular cheilitis (swollen red patches at corners of the mouth)
Atrophic glossitis ( smooth tongue due to atrophy of the papillae)
Brittle hair + nails
Post-cricoid webs
What sign may be specific to a haemolytic anaemia?
Jaundice
What specific clinical signs indicate CKD as the underlying cause of anaemia?
Oedema, hypertension and excoriations on the skin
What specific clinical sign indicates thalassaemia as the underlying cause of anaemia?
Bone deformities
When anaemia is found, what further initial investigations will be performed?
Haemoglobin
Mean Cell Volume (MCV)
B12
Folate
Ferritin
Blood film
When anaemia is found and initial investigations (MCV, B12, Folate, Ferritin, Blood film) have been performed, what further investigations might be considered?
Oesophago-gastroduodenoscopy (OGD) and colonoscopy to investigate for a gastrointestinal cause of unexplained iron deficiency anaemia. This is done on an urgent cancer referral for suspected gastrointestinal cancer.
Bone marrow biopsy may be required if the cause is unclear
The bone marrow requires iron to produce haemoglobin. There are several scenarios where iron stores can be used up and the patient can become iron deficient, such as?
Insufficient dietary iron
Iron requirements increase (for example in pregnancy)
Iron is being lost (for example slow bleeding from a colon cancer)
Inadequate iron absorption
Where is iron absorbed?
Duodenum and jejunum
How can PPIs cause iron deficiency?
Acid from the stomach to keep the iron in the soluble ferrous (Fe2+) form.
When the acid drops it changes to the insoluble ferric (Fe3+) form.
Therefore, medications that reduce the stomach acid such as proton pump inhibitors (lansoprazole and omeprazole) can interfere with iron absorption
What is the soluble form of iron?
Ferrous Fe2+
What is the insoluble form of iron?
Ferric - Fe3+
What autoimmune conditions can cause iron deficiency?
Conditions that result in inflammation of the duodenum or jejunum such as coeliac disease or Crohn’s disease can also cause inadequate iron absorption.
What the the main causes of iron deficiency?
Blood loss is the most common cause in adults (commonly menorrhagia, oesophagitis, gastritis)
Dietary Insufficiency is the most common cause in growing children
Poor iron absorption (consider Crohn’s, coeliac)
Increased requirements during pregnancy
What should iron deficiency anaemia arise suspicion for?
GI tract cancer
How does iron travel around the blood?
Ferric ions (insoluble) bound to transferrin (carrier protein)
What is TIBC?
Total iron binding capacity
The total space on the transferrin molecules for the iron to bind.
Therefore, total iron binding capacity is directly related to the amount of transferrin in the blood.
Calculating transferrin saturation?
Transferrin Saturation = Serum Iron / Total Iron Binding Capacity
Expressed as a percentage
Ferritin levels in iron deficiency anemia?
LOW - highly suggestive of iron deficiency
NORMAL - possible, if there are reasons to have raised ferritin such as infection
HIGH - If ferritin is high then this is difficult to interpret and is likely to be related to inflammation rather than iron overload. Ferritin is released from cells in inflammation, such as infection or cancer
Why is serum iron not a useful measure when used alone?
Serum iron varies significantly throughout the day with higher levels in the morning and after eating iron containing meals. On its own serum iron is not a very useful measure.
What does transferrin saturation indicate?
Transferrin saturation gives a good indication of the total iron in the body. In normal adults it is around 30%, however if there is less iron in the body transferrin will be less saturated and if iron levels go up transferrin will be more saturated. It can temporarily increase after eating a meal rich in iron or taking iron supplements so a fasting sample gives the most accurate results.
What can TIBC be used as a marker for, and when might you expect it to be hig/low?
Total iron binding capacity can be used as a marker for how much transferrin is in the blood.
It is an easier test to perform than measuring transferrin.
Both TIBC and transferrin levels increase in iron deficiency and decrease in iron overload.
Supplementation with iron and acute liver damage (lots of iron is stored in the liver) can give the impression of iron overload, increasing all iron related markers in the blood - except for?
TIBC - which will be low
What two things can increase the values of serum ferritin, serum iron, and transferring saturation, giving the impression of iron overload?
Supplementation with iron
Acute liver damage (lots of iron is stored in the liver)
TIBC will be low
Management of iron deficiency anemia?
New iron deficiency in an adult without a clear underlying cause (for example heavy menstruation or pregnancy) should be investigated with suspicion. This involves doing a oesophago-gastroduodenoscopy (OGD) and a colonoscopy to look for cancer of the gastrointestinal tract.
- Blood transfusion.
- Iron infusion e.g. “cosmofer”
- Oral iron e.g. ferrous sulfate 200mg three times daily
When correcting iron deficiency anaemia with iron you can expect the haemoglobin to rise by around 10 grams/litre per week.
When correcting iron deficiency anaemia with iron you can expect the haemoglobin to rise at what rate?
Around 10 grams/litre per week.
What are the options for correcting iron deficiency anaemia?
Blood transfusion. This will immediately correct the anaemia but not the underlying iron deficiency and also carries risks.
Iron infusion e.g. “cosmofer”. There is a very small risk of anaphylaxis but it quickly corrects the iron deficiency. It should be avoided during sepsis as iron “feeds” bacteria.
Oral iron e.g. ferrous sulfate 200mg three times daily. This slowly corrects the iron deficiency. Oral iron causes constipation and black coloured stools. It is unsuitable where malabsorption is the cause of the anaemia.
Correcting iron deficiency: blood transfusion advantages and disadvantages?
Advantages:
Immediately corrects the anaemia
Disadvantages:
Does not correct the underlying iron deficiency
Risks and complications of blood transfusion:
- Blood borne infections like HIV, hepatitis are possible but rare
- Other reactions like graft- versus- host disease, delayed hemolytic reaction and acute immune hemolytic reaction are also seen
- Allergic reactions, anaphylactic reaction
- Fever
Correcting iron deficiency: iron infusion e.g. ‘‘cosmofer’’ advantages and disadvantages?
Advantages:
Quickly corrects the anaemia iron deficiency
Disadvantages:
'’Feeds’’ bacteria in SEPSIS
Small risk of anaphylaxis
Correcting iron deficiency: iron infusion e.g. ‘‘cosmofer’’ advantages and disadvantages?
Advantages:
Quickly corrects the anaemia iron deficiency
Disadvantages:
'’Feeds’’ bacteria in SEPSIS
Small risk of anaphylaxis
Correcting iron deficiency: oral iron e.g. ferrous sulfate advantages and disadvantages?
Advantages:
Least invasive
Treats underlying iron deficiency (if not due to malabsorption)
Disadvantages:
Does not work if cause if malabsorption
Cn cause constipation and black coloured stools
Hodgkin’s lymphoma risk factors?
HIV
Epstein-Barr Virus
Autoimmune conditions such as rheumatoid arthritis and sarcoidosis
Family history
Features of lymphadenopathy in Hodgkin’s lymphoma?
Neck, axilla or inguinal lymph nodes typically affected
Non-tender, rubbery
May be painful when drinking alcohol
Symptoms of lymphoma other than lymphadenopathy and B symptoms?
Fatigue
Itching
Cough
Shortness of breath
Abdominal pain
Recurrent infections
How is ?lymphoma investigated?
Lymph node biopsy is the key diagnostic test.
LDH (often raised in HL but not specific)
CT, MRI and PET scans can be used for diagnosing and staging lymphoma and other tumours.
What marker is often raise in Hodgkin’s lymphoma?
Lactate dehydrogenase (LDH)
Key finding on lymph node biopsy in patient’s with Hodgkin’s lymphoma?
REED-STERNBERG CELL
They are abnormally large B cells that have multiple nuclei that have nucleoli inside them.
This can give them the appearance of the face of an owl with large eyes.
What is seen here, and what is this characteristic of?
Abnormally large B cell with multiple nuclei with nucleoli inside them - REED STERNBERG CELL
The Reed-Sternberg cell is the key finding from lymph node biopsy in patients with Hodgkin’s lymphoma.
The Ann Arbor staging system is used for both Hodgkins and non-Hodgkins lymphoma. What stages does it classify disease into?
Stage 1: Confined to one region of lymph nodes.
Stage 2: In more than one region but on the same side of the diaphragm (either above or below).
Stage 3: Affects lymph nodes both above and below the diaphragm.
Stage 4: Widespread involvement including non-lymphatic organs such as the lungs or liver.
The Ann Arbor staging system is used for both Hodgkins and non-Hodgkins lymphoma. What does it put importance on?
The system puts importance on whether the affected nodes are above or below the diaphragm
Management of Hodgkin’s lymphoma and the associated risks of concern?
The key treatments are chemotherapy and radiotherapy.
The aim of treatment is to cure the condition.
This is usually successful however there is a risk of relapse, other haematological cancers and side effects of medications.
Chemotherapy creates a risk of leukaemia and infertility.
Radiotherapy creates a risk of cancer, damage to tissues and hypothyroidism.
Notable types of NHL?
Burkitt lymphoma
MALT lymphoma
Diffuse large B cell lymphoma
What infections if Burkitt lymphoma associate with?
Epstein-Barr virus
Malaria
HIV
What does MALT lymphoma affect?
Affects the mucosa-associated lymphoid tissue, usually around the stomach.
It is associated with H. pylori infection.
How does diffuse large B cell lymphoma present and in what age group?
Diffuse large B cell lymphoma often presents as a rapidly growing painless mass in patients over 65 years.
What type of lymphoma is associated with H.pylori infection?
MALT lymphoma (affects the mucosa-associated lymphoid tissue, usually around the stomach)
Risk factors for non-Hodgkin’s lymphoma?
HIV
Epstein-Barr Virus
H. pylori (MALT lymphoma)
Hepatitis B or C infection
Exposure to pesticides and a specific chemical
called trichloroethylene used in several industrial processes
Family history
What chemical exposures increase the risk of NHL?
Pesticides
Trichloroethylene (used in industrial processes)
Differentiating between HL and NHL?
The presentation is similar, often they can only be differentiated when the lymph node is biopsied.
Management of non-Hodgkin’s lymphoma?
Management involves a combination of treatments depending on the type and staging of the lymphoma:
Watchful waiting
Chemotherapy
Monoclonal antibodies such as rituximab
Radiotherapy
Stem cell transplantation
Relationship between age and subtype of leukaemia?
“ALL CeLLmates have CoMmon AMbitions” to remember the progressive ages of the different leukaemia from 45-75 in steps of 10 years. Remember that ALL (the first in the mnemonic) most commonly affects children under 5 years.
Under 5 and over 45 – acute lymphoblastic leukaemia (ALL)
Over 55 – chronic lymphocytic leukaemia (CeLLmates)
Over 65 – chronic myeloid leukaemia (CoMmon)
Over 75 – acute myeloid leukaemia (AMbitions)
What type of leukaemia is most common in children under 5?
Acute Lymphoblastic Leukaemia (ALL)
What ages are typically affected by Acute Lymphoblastic Leukaemia (ALL)?
Under 5s, over 45s
What ages are typically affected by Acute Myeloid Leukaemia (AML)?
Over 75s
What ages are typically affected by Chronic Myeloid Leukaemia (CML)?
Over 65s
What ages are typically affected by Chronic Lymphocytic Leukaemia?
Over 55s
Differentials for a presentation of bruising and petechiae?
Leukaemia
Meningococcal septicaemia
Vasculitis
Henoch-Schonlein Purpura (HSP)
Idiopathic Thrombocytopenia Purpura (ITP)
Non-accidental injury
Diagnostic tests in leukaemia (and their reasoning)
Full blood count is the initial investigation. NICE recommend a full blood count within 48 hours for patients with suspected leukaemia.
Children or young adults with ptechiae or hepatosplenomegaly should be referred immediately to the hospital.
Blood film can be used to look for abnormal cells and inclusions.
Lactate dehydrogenase (LDH) is a blood test that is often raised in leukaemia but is not specific to leukaemia. It can be raised in other cancers and many non-cancerous diseases.
Bone marrow biopsy can be used to analyse the cells in the bone marrow. This is the main investigation for establishing a definitive diagnosis of leukaemia.
Chest xray may show infection or mediastinal lymphadenopathy.
Lymph node biopsy can be used to assess lymph node involvement or investigate for lymphoma.
Lumbar puncture may be used if there is central nervous system involvement.
CT, MRI and PET scans can be used for staging and assessing for lymphoma and other tumours.
What is the main investigation for establishing a definitive diagnosis of leukaemia?
Bone marrow biopsy
NICE recommend a full blood count within what time period for patients with suspected leukaemia?
48hrs
Under what circumstances should suspected leukaemia be referred immediately to hospital?
Children or young adults with ptechiae or hepatosplenomegaly should be referred immediately to the hospital.
What are the various techniques used to obtain bone marrow biopsy?
Bone marrow aspiration: involves taking a liquid sample full of cells from within the bone marrow.
Bone marrow trephine: involves taking a solid core sample of the bone marrow and provides a better assessment of the cells and structure.
Samples from bone marrow aspiration can be examined straight away however a trephine sample requires a few days of preparation.
Bone marrow biopsy is usually taken from the iliac crest. It involves a local anaesthetic and a specialist needle.
What happens in Acute Lymphoblastic Leukaemia?
Acute lymphoblastic leukaemia is where there is malignant change in one of the lymphocyte precursor cells. It causes acute proliferation of a single type of lymphocyte, usually B-lymphocytes. Excessive proliferation of these cells causes them to replace the other cell types being created in the bone marrow, leading to a pancytopenia.
Around what ages does ALL peak
2-4 years
What conditions is ALL associated with?
Downs Syndrome
Philadelphia chromosome (t(9:22) translocation) - in 30% of adults and 3-5% of children with ALL.
What is seen on blood film of ALL
Blast cells
- a partially differentiated cell, usually referred to as a unipotent cell that has lost most of its stem cell properties
What happens in CLL?
Chronic lymphocytic leukaemia is where there is chronic proliferation of a single type of well differentiated lymphocyte, usually B-lymphocytes.
How might CLL present?
Often it is asymptomatic but it can present with infections, anaemia, bleeding and weight loss.
It can cause warm autoimmune haemolytic anaemia.
What type of leukaemia can cause warm autoimmune haemolytic anaemia?
Chronic Lymphocytic Leukaemia
- lymphoma
- chronic lymphocytic leukaemia
What can CLL transform into?
high-grade lymphoma.
This is called Richter’s transformation.
What is seen in blood film in CLL?
Smear or smudge cells
What happens in CML?
Chronic myeloid leukaemia has three typical phases: the chronic phase, the accelerated phase and the blast phase. The chronic phase can last around 5 years, is often asymptomatic and patients are diagnosed incidentally with a raised white cell count.
How is CML often diagnosed?
Incidentally, with raised WCC
What are the phases of CML?
CHRONIC
Can last around 5 years, asymptomatic
ACCELERATED
abnormal clast cell take up a high proportion of the cells in the bone marrow and blood (up to 20%), patients become more symptomatic, develop anaemia and thrombocytopenia and become immunocompromised.
BLAST PHASE
An even high proportion of blast cells and blood (>30%). This phase has severe symptoms and pancytopenia. It is often fatal.
What cytogenetic change is characteristic of CML?
The Philadelphia chromosome, which is a translocation of genes between chromosome 9 and 22: it is a t(9:22) translocation.
What is the most common acute leukaemia in adults?
Acute Myeloid Leukaemia
It can present at any age but normally presents from middle age onwards.
AML blood film
A blood film will show a high proportion of blast cells.
These blast cells can have rods inside their cytoplasm that are named Auer rods.
What might AML be the result of?
It can be the result of a transformation from a myeloproliferative disorder such as polycythaemia ruby vera or myelofibrosis.
Most common leukaemia in children. Associated with Down syndrome.
Acute lymphoblastic leukaemia
Most common leukaemia in adults overall. Associated with warm haemolytic anaemia, Richter’s transformation into lymphoma and smudge / smear cells.
Chronic lymphocytic leukaemia
Leukaemia which has three phases including a 5 year “asymptomatic chronic phase”. Associated with the Philadelphia chromosome.
Chronic myeloid leukaemia
What type of leukaemia can be the result of a transformation from a myeloproliferative disorder, associated with Auer rods?
Acute myeloid leukaemia
What is seen here and what is this characteristic of?
Auer rods, associated with acute myeloid leukaemia
Management of leukaemia?
Treatment will be coordinated by an oncology multi-disciplinary team. Leukaemia is primarily treated with chemotherapy and steroids.
Other therapies include:
Radiotherapy
Bone marrow transplant
Surgery
Potential complications of chemotherapy management in leukaemia?
Failure
Stunted growth and development in children
Infections due to immunodeficiency
Neurotoxicity
Infertility
Secondary malignancy
Cardiotoxicity
Tumour lysis syndrome
What is released in tumour lysis syndrome?
Uric acid
Potassium, phosphate (can lead to hypocalcemia)
What can be are to reduce the high uric acid levels in tumour lysis syndrome?
Allopurinol or rasburicase
What is myeloma?
Myeloma is a cancer of the plasma cells. These are a type of B lymphocyte that produce antibodies. Cancer in a specific type of plasma cell results in large quantities of a single type of antibody being produced. Myeloma accounts for around 1% of all cancers.
What are plasma cells and what happens to them in myeloma?
These are a type of B lymphocyte that produce antibodies.
Cancer in a specific type of plasma cell results in large quantities of a single type of antibody being produced.
What are the premalignant conditions that may progress to myeloma?
Monoclonal gammopathy
Smouldering myeloma
What is multiple myeloma
Multiple myeloma is where the myeloma (multiple myeloma is where the myeloma affects multiple areas of the body) affects multiple areas of the body.
What is monoclonal gammopathy of undetermined significance?
Where there is an excess of a single type of antibody or antibody components without other features of myeloma or cancer.
This is often an incidental finding in an otherwise healthy person and as the name suggests the significance is unclear.
It may progress to myeloma and patients are often followed up routinely to monitor for progression.
What is smouldering myeloma?
Smouldering myeloma is where there is progression of MGUS with higher levels of antibodies or antibody components.
It is premalignant and more likely to progress to myeloma than MGUS.
Waldenstrom’s macroglobulinemia is a type of smouldering myeloma where there is excessive IgM specifically.
In what type of smouldering myeloma where there is excessive IgM specifically?
Waldenstrom’s macroglobulinemia
Pathophysiology of myeloma?
Genetic mutation of plasma cells (B lymphocytes that have become activated to produce a certain antibody) causing it to rapidly and uncontrollably multiply.
These plasma cells produce one type of antibody (also called immunoglobulins. They are complex molecules made up of two heavy chains and two light chains arranged in a Y shape. They help the immune system recognise and fight infections by targeting specific proteins on the pathogen. They come in 5 main types: A, G, M, D and E)
This single type of antibody that is produced by all the identical cancerous plasma cells can be called a monoclonal paraprotein. This means a single type of abnormal protein.
The “Bence Jones protein” that can be found in the urine of many patients with myeloma is actually a part (subunit) of the antibody called the light chains.
What are the 5 main types of antibodies?
A
G
M
D
and
E
Immunoglobulins in myeloma?
When you measure the immunoglobulins in a patient with myeloma, one of those types will be significantly abundant.
More than 50% of the time this is immunoglobulin type G (IgG).
This single type of antibody that is produced by all the identical cancerous plasma cells can be called a monoclonal paraprotein. This means a single type of abnormal protein.
What is the most common immunoglobulin excess in myeloma?
IgG
What can be found in the urine of many patients with myeloma?
“Bence Jones protein”
What is the Bence Jones protein that can be found in the urine of many patients with myeloma?
A part (subunit) of the antibody called the light chains
What is low in myeloma and why?
The cancerous plasma cells invade the bone marrow. This is described as bone marrow infiltration.
This causes suppression of the development of other blood cell lines leading to anaemia (low red cells), neutropenia (low neutrophils) and thrombocytopenia (low platelets).
What happens in myeloma bone disease?
Myeloma bone disease is a result of increased osteoclast activity and suppressed osteoblast activity.
Osteoclasts absorb bone and osteoblasts deposit bone.
This results in the metabolism of bone becoming imbalanced as more bone is being reabsorbed than constructed.
This is caused by cytokines released from the plasma cells and the stromal cells (other bone cells) when they are in contact with the plasma cells.
Common sites off myeloma bone disaese?
Skull
Spine
Long bones
Ribs
Myeloma bone disease - osteolytic lesions
The abnormal bone metabolism is patchy, meaning that in some areas the bone becomes very thin whereas others remain relatively normal.
These patches of thin bone can be described as osteolytic lesions.
How can myeloma cause pathological fractures?
Myeloma bone disease is a result of increased osteoclast activity and suppressed osteoblast activity.
This results in the metabolism of bone becoming imbalanced as more bone is being reabsorbed than constructed
The abnormal bone metabolism is patchy, meaning that in some areas the bone becomes very thin (osteolytic lesions) whereas others remain relatively normal.
These weak points in bone lead to pathological fractures.
For example, a vertebral body in the spine may collapse (vertebral fracture) or a long bone such as the femur may break under minimal force.
What electrolyte disturbance may be seen in myeloma and why?
Increase in osteoclast activity caused by cytokines released from the plasma cells and the stromal cells (other bone cells) when they are in contact with the plasma cells.
Calcium is reabsorbed from the bone into the blood. This results in hypercalcaemia (high blood calcium).
What are plasmacytomas and where can they occur?
People with myeloma can also develop plasmacytomas.
These are individual tumours made up of the cancerous plasma cells.
They can occur in the bones, replacing normal bone tissue or can occur outside bones in the soft tissue of the body.
Why might patients with myeloma develop renal impairment (Myeloma Renal Disease)
High levels of immunoglobulins (antibodies) can block the flow through the tubules
Hypercalcaemia impairs renal function (increase osteoclast activity)
Dehydration
Medications used to treat the conditions such as bisphosphonates can be harmful to the kidneys
What issues can plasma viscosity cause?
Easy bruising
Easy bleeding
Reduced or loss of sight due to vascular disease in the eye
Purple discolouration to the extremities (purplish palmar erythema)
Heart failure
Why is there hypeviscosity in myeloma?
Plasma viscosity increases when there are more proteins in the blood.
These are proteins like immunoglobulins and fibrinogen, both of which increase with inflammation.
In myeloma there are large amounts of immunoglobulins in the blood causing the plasma viscosity to be significantly higher.
Four key features of myeloma?
C – Calcium (elevated)
R – Renal failure
A – Anaemia (normocytic, normochromic) from replacement of bone marrow.
B – Bone lesions/pain
What type of anemia occurs in myeloma?
Normocytic, normochromic - from replacement of bone marrow
Risk factors for myeloma?
Older age
Male
Black African ethnicity
Family history
Obesity
In what patients do NICE suggest considering myeloma in?
Over 60s with persistent bone pain (particularly back pain) or unexplained fractures
Myeloma - initial investigations
FBC (low white blood cell count in myeloma)
Calcium (raised in myeloma)
ESR (raised in myeloma)
Plasma viscosity (raised in myeloma)
If any of these are positive or myeloma is still suspected:
B – Bence–Jones protein (request urine electrophoresis)
L – Serum‑free Light‑chain assay
I – Serum Immunoglobulins
P – Serum Protein electrophoresis
FBC in myeloma
Anaemia (normocytic + normochromic)
Low white blood cell count
What is used to confirm the diagnosis of myeloma?
Bone marrow biopsy
Imaging in myeloma?
Imaging is required to assess for bone lesions. The order of preference to establish this is:
- Whole body MRI
- Whole body CT
- Skeletal survey (xray images of the full skeleton)
Patients only require one investigation but may not tolerate or be suitable for MRI or CT.
Myeloma X ray signs?
Punched out lesions
Lytic lesions
“Raindrop skull” caused by many punched out (lytic) lesions throughout the skull that give the appearance of raindrops splashing on a surface
Aim of treatment in myeloma/disease course?
The aim of treatment is to control disease. It usually takes a relapsing-remitting course and treatment aims to improve quality and quantity of life.
Management will be undertaken by the haematology and oncology specialist multidisciplinary team.
What is the first line treatment of myeloma?
First line treatment usually involves a combination of chemotherapy with:
Bortezomid
Thalidomide
Dexamethasone
Management of myeloma?
Chemotherapy is first line: bortezomid, thalidomide, dexamethasone
Stem cell transplantation (as part of a clinical trial, where patients are suitable)
VTE with aspirin or LMWH whilst on certain chemotherapy regimes (e.g. thialidomide) as there is a higher risk of developing a thrombus
Myeloma bone disease can be improved using bisphosphonates.
Radiotherapy to bone lesions can improve bone pain
Orthopaedic surgery can stabilise bones or treat fractures.
Cement augmentation can improve spine stability and pain
Specific management of myeloma bone disease
Myeloma bone disease can be improved using bisphosphonates. These suppress osteoclast activity.
Radiotherapy to bone lesions can improve bone pain.
Orthopaedic surgery can stabilise bones (e.g. by inserting a prophylactic intramedullary rod) or treat fractures.
Cement augmentation involves injecting cement into vertebral fractures or lesions and can improve spine stability and pain
What are the complications of myeloma itself and the treatments?
Infection
Pain
Renal failure
Anaemia
Hypercalcaemia
Peripheral neuropathy
Spinal cord compression
Hyperviscocity
What are the three main myeloproliferative disorders?
Primary myelofibrosis
Polycythaemia vera
Essential thrombocythemia
What are myeloproliferative disorders?
Conditions occurring due to uncontrolled proliferation of a single type of stem cells consider a type of bone marrow cancer
Primary myelofibrosis is the result of proliferation of what?
Hematopoietic stem cells
Polycythaemia vera is the result of proliferation of what?
The erythroid cell line
Essential thrombocythaemia is the result of proliferation of what?
The megakaryocytic cell line
What disease is the result of proliferation of the megakaryocytic cell line?
Essential thrombocythaemia
What disease is the result of proliferation of the erythroid cell line?
Polycythaemia vera
What disease is the result of proliferation of the hematopoietic stem cells?
Primary myelofibrosis
Mutations in which genes are associated with myeloproliferative disorders?
JAK2
MPL
CALR
Myeloproliferative disorders have the potential to progress and transform into what?
acute myeloid leukaemia
What drug is used to target the JAK2 mutation?
ruxolitinib
JAK2 inhibitor
What can myelofibrosis be the result of?
Myeloproliferative disorders: primary myelofibrosis, polycythaemia vera or essential thrombocythemia
What happens in myelofibrosis and what can this lead to?
Myelofibrosis is where the proliferation of the cell line leads to fibrosis of the bone marrow.
The bone marrow is replaced by scar tissue in response to cytokines that are released from the proliferating cells.
One particular cytokine is fibroblast growth factor.
This fibrosis affects the production of blood cells and can lead to anaemia and low white blood cells (leukopenia).
When the bone marrow is replaced with scar tissue the production of blood cells (haematopoiesis) starts to happen in other areas such as the liver and spleen.
This is known as extramedullary haematopoiesis and can lead to hepatomegaly and splenomegaly.
This can lead to portal hypertension.
If it occurs around the spine it can lead to spinal cord compression.
Presentation of myeloproliferative disorders?
Initially, myeloproliferative disorders can be asymptomatic.
They can present systemic symptoms:
Fatigue
Weight loss
Night sweats
Fever
There may be signs and symptoms of underlying complications:
Anaemia (except in polycythaemia)
Splenomegaly (abdominal pain)
Portal hypertension (ascites, varices and abdominal pain)
Low platelets (bleeding and petechiae)
Thrombosis is common in polycythaemia and thrombocythaemia
Raised red blood cells (thrombosis and red face)
Low white blood cells (infections)
What three signs are key O/E for polycythaemia vera?
Conjunctival plethora (excessive redness to the conjunctiva in the eyes)
A “ruddy” complexion
Splenomegaly
Myeloproliferative disorder various FBC findings?
Polycythaemia Vera:
Raised haemoglobin (more than 185g/l in men or 165g/l in women)
Primary Thrombocythaemia:
Raised platelet count (more than 600 x 109/l)
Myelofibrosis (due to primary MF or secondary to PV or ET) can give variable findings:
- Anaemia
- Leukocytosis or leukopenia (high or low white cell counts)
- Thrombocytosis or thrombocytopenia (high or low platelet counts)
What might be seen on a blood film in myelofibrosis?
Teardrop-shaped RBCs,
Varying sizes of red blood cells (poikilocytosis)
Immature red and white cells (blasts).
Diagnosis of myeloproliferative disorders?
Bone marrow biopsy is the test of choice to establish a diagnosis. Bone marrow aspiration is usually “dry” as the bone marrow has turned to scar tissue.
Testing for the JAK2, MPL and CALR genes can help guide management.
Management of Primary Myelofibrosis
Patients with mild disease with minimal symptoms might be monitored and not actively treated.
Allogeneic stem cell transplantation is potentially curative but carries risks.
Chemotherapy can help control the disease, improve symptoms and slow progression but is not curative on its own.
Supportive management of the anaemia, splenomegaly and portal hypertension.
Management of Polycythaemia Vera
Venesection can be used to keep the haemoglobin in the normal range. This is the first line treatment.
Aspirin can be used to reduce the risk of developing blood clots (thrombus formation).
Chemotherapy can be used to control the disease.
Management of Essential Thrombocythaemia
Aspirin can be used to reduce the risk of developing blood clots (thrombus formation).
Chemotherapy can be used to control the disease.
What is myelodysplastic syndrome?
Myelodysplastic syndrome is caused by the myeloid bone marrow cells not maturing properly and therefore not producing healthy blood cells.
There are a number of specific types of myelodysplastic syndrome.
Myelodysplastic syndrome causes low levels of blood components that originate from the myeloid cell line, including?
Anaemia
Neutropenia (low neutrophil count)
Thrombocytopenia (low platelets)
In which patients is myelodysplastic syndrome more common?
It is more common in patients above 60 years of age and in patients that have previously had treatment with chemotherapy or radiotherapy.
What does myelodysplastic syndrome have a risk of transforming into?
There is an increased risk of transforming into acute myeloid leukaemia.
?Presentation of myelodysplastic syndrome
Patients may be asymptomatic and incidentally diagnosed based on a full blood count.
They may present with symptoms of anaemia (fatigue, pallor or shortness of breath), neutropenia (frequent or severe infections) or thrombocytopenia (purpura or bleeding).
How might myelodysplastic syndrome be diagnosed?
Full blood count will be abnormal. There may be blasts on the blood film.
The diagnosis is confirmed by bone marrow aspiration and biopsy.
Blood film in myelodysplastic syndrome
Blasts
Management of myelodysplastic syndrome?
Depending on the symptoms, risk of progression and overall prognosis the treatment options are:
Watchful waiting
Supportive treatment with blood transfusions if severely anaemic
Chemotherapy
Stem cell transplantation
How might blood product transfusion complications be broadly classified?
immunological: acute haemolytic, non-haemolytic febrile, allergic/anaphylaxis
infective
transfusion-related acute lung injury (TRALI)
transfusion-associated circulatory overload (TACO)
other: hyperkalaemia, iron overload, clotting
Why might non-haemolytic febrile reaction occur in blood product transfusion?
Thought to be caused by antibodies reacting with white cell fragments in the blood product and cytokines that have leaked from the blood cell during storage
due to white blood cell HLA antibodies
often the result of sensitization by previous pregnancies or transfusions
Features of non-haemolytic febrile reaction?
Fever, chills
Red cell transfusion (1-2%)
Platelet transfusion (10-30%)
Management of non-haemolytic febrile reaction?
Slow or stop the transfusion
Paracetamol
Monitor
Why might minor allergic reaction occur in blood product transfusion?
Causes by foreign plasma proteins
Why might anaphylaxis occur in blood product transfusion?
Can be caused by patients with IgA deficiency who have anti-IgA antibodies
Management of minor allergic reaction in blood product transfusion?
Temporarily stop the transfusion
Antihistamine
Monitor
Management of anaphylaxis in blood product transfusion?
Stop the transfusion
IM adrenaline
ABC support
oxygen
fluids
During blood product transfusion, what might suggest anaphylaxis?
Hypotension, dyspnoea, wheezing, angioedema.
Features of minor allergic reaction in blood product transfusion?
Pruritus, urticaria
Why might acute haemolytic reaction occur in blood product transfusion?
ABO-incompatible blood e.g. secondary to human error
Features of acute haemolytic reaction
Fever, abdominal pain, hypotension
Management of acute haemolytic reaction
Stop transfusion
Confirm diagnosis
check the identity of patient/name on blood product
send blood for direct Coombs test, repeat typing and cross-matching
Supportive care
fluid resuscitation
Why might transfusion-associated circulatory overload (TACO) occur?
Excessive rate of transfusion, pre-exisiting heart failure
Transfusion-associated circulatory overload (TACO) features
Pulmonary oedema, hypertension
Transfusion-associated circulatory overload (TACO) management
Slow or stop transfusion
Consider intravenous loop diuretic (e.g. furosemide) and oxygen
Why does Transfusion-related acute lung injury (TRALI) occur?
Non-cardiogenic pulmonary oedema thought to be secondary to increased vascular permeability caused by host neutrophils that become activated by substances in donated blood
Features of Transfusion-related acute lung injury (TRALI)
Hypoxia, pulmonary infiltrates on chest x-ray, fever, hypotension, acute respiratory sidress syndrome
Transfusion-related acute lung injury (TRALI) management
Stop the transfusion
Oxygen and supportive care
What happens in acute hemolytic transfusion reaction?
Acute haemolytic transfusion reaction results from a mismatch of blood group (ABO) which causes massive intravascular haemolysis.
This is usually the result of red blood cell destruction by IgM-type antibodies.
When do the symptoms occur in acute haemolytic transfusion reaction?
Symptoms begin minutes after the transfusion is started and include a fever, abdominal and chest pain, agitation and hypotension.
Complications of acute haemolytic transfusion reaction?
Disseminated intravascular coagulation, and renal failure
When do allergic/anaphylaxis reactions occur in blood transfusion?
Symptoms typically arise within minutes of starting the transfusion and severity can range from urticaria to anaphylaxis with hypotension, dyspnoea, wheezing, and stridor, or angioedema.
Management of simple urticaria in blood transfusion?
Simple urticaria should be treated by discontinuing the transfusion and with an antihistamine. Once the symptoms resolve, the transfusion may be continued with no need for further workup.
Within how long does TRALI occur?
within 6 hours of transfusion
Key differences between TRALI and TACO
TRALI - HYPOTENSION
TACO - HYPERTENSION
Concerns with vCJD transmission in blood transfusion?
although the absolute risk is very small, vCJD may be transmitted via blood transfusion
a number of steps have been taken to minimise this risk, including:
from late 1999 onward, all donations have undergone removal of white cells (leucodepletion) in order to reduce any vCJD infectivity present
from 1999, plasma derivatives have been fractionated from imported plasma rather than being sourced from UK donors. Fresh Frozen Plasma (FFP) used for children and certain groups of adults needing frequent transfusions is also imported
from 2004 onward, recipients of blood components have been excluded from donating blood
Blood products: whole blood fractions?
Packed red cells
Platelet rich plasma
Platelet concentrate
Fresh frozen plasma
Cryoprecipitate
SAG-MAnnitol Blood
What is SAG-Mannitol blood, and how much can be used?
Removal of all plasma from a blood unit and substitution with:
Sodium chloride
Adenine
Anhydrous glucose
Mannitol
Up to 4 units of SAG M Blood may be administered. Thereafter whole blood is preferred. After 8 units, clotting factors and platelets should be considered.
Blood transfusuion: What is cryoprecipitate and what does it allow for?
Formed from supernatant of FFP.
Rich source of Factor VIII and fibrinogen.
Allows large concentration of factor VIII to be administered in small volume.
What is FFP prepared from?
Single units of blood
FRESH FROZEN PLASMA
Prepared from single units of blood.
Contains clotting factors, albumin and immunoglobulin.
Unit is usually 200 to 250ml.
Usually used in correcting clotting deficiencies in patients with hepatic synthetic failure who are due to undergo surgery.
Usual dose is 12-15ml/Kg-1.
It should not be used as first line therapy for hypovolaemia.
How is platelet concentrate prepared and used?
Prepared by high speed centrifugation and administered to patients with thrombocytopaenia.
Which patients are administered platelet rich plasma?
Usually administered to patients who are thrombocytopaenic and are bleeding or require surgery.
How is platelet rich plasma obtained?
It is obtained by low speed centrifugation.
When are packed red cells used?
Used for transfusion in chronic anaemia and cases where infusion of large volumes of fluid may result in cardiovascular compromise.
How are packed red cells obtained?
Product obtained by centrifugation of whole blood.
What whole blood fractions MUST be cross matched?
Packed red cells
Fresh frozen plasma
Cryoprecipitate
Whole blood
What whole blood fraction can be ABO incompatible in adults?
Platelets
What are cell saver devices?
These collect patients own blood lost during surgery and then re-infuse it. There are two main types:
Those which wash the blood cells prior to re-infusion. These are more expensive to purchase and more complicated to operate. However, they reduce the risk of re-infusing contaminated blood back into the patient.
Those which do not wash the blood prior to re-infusion.
Advantage of cell saver devices?
Their main advantage is that they avoid the use of infusion of blood from donors into patients and this may reduce risk of blood borne infection.
It may be acceptable to Jehovah’s witnesses.
When are cell saver devices contraindicated?
It is contraindicated in malignant disease for risk of facilitating disease dissemination.
Stepwise management when immediate or urgent surgery is required in patients taking warfarin?
- Stop warfarin
- Vitamin K (reversal within 4-24 hours)
IV takes 4-6h to work (at least 5mg)
Oral can take 24 hours to be clinically effective - Fresh frozen plasma
Used less commonly now as 1st line warfarin reversal
30ml/kg-1
Need to give at least 1L fluid in 70kg person (therefore not appropriate in fluid overload)
Need blood group
Only use if human prothrombin complex is not available - Human Prothrombin Complex (reversal within 1 hour)
Bereplex 50 u/kg
Rapid action but factor 6 short half life, therefore give with vitamin K
What are the two causes of B12 deficiency?
insufficient dietary intake of vitamin B12 or pernicious anaemia.
What is pernicious anaemia?
Pernicious anaemia is a cause of B12 deficiency anaemia. B12 deficiency can be caused by
Autoimmune condition - antibodies form against the parietal cells or intrinsic factor
A lack of intrinsic factor prevents the absorption of vitamin B12 and the patient becomes vitamin B12 deficient.
What is intrinsic factor and where is it produced?
Parietal cells of the stomach produce a protein called INTRINSIC FACTOR - essential for the absorption of vitamin B12 in the ileum
What neurological symptoms can B12 deficiency cause?
PERIPHERAL NEUROPATHY WITH NUMBNESS OR PARAESTHESIA (PINS AND NEEDLES)
Loss of vibration sense or proprioception
Visual changes
Mood or cognitive changes
What can be tested for to diagnose pernicious anemia?
Autoantibodies -
INTRINSIC FACTOR ANTIBODY - first line investigation
Gastric parietal cell antibody can also be tested but is less helpful
Management of B12 deficiency
DIETARY DEFICIENCY (if not severe): oral replacement with cyanocobalamin
PERNICIOUS ANEMIA - IM hydroxocobalamin
They can be treated with 1mg of intramuscular hydroxocobalamin 3 times weekly for 2 weeks, then every 3 months.
(Oral replacement is inadequate because the problem is with absorption rather than intake)
More intense regimens are used where there are neurological symptoms (e.g. 1mg every other day until the symptoms improve).
What is important in management of folate deficiency and why?
If there is also folate deficiency it is important to check and treat B12 deficiency first before correcting the folate deficiency.
Treating patients with folic acid when they have a B12 deficiency can lead to subacute combined degeneration of the cord.
If there is also folate deficiency it is important to check and treat B12 deficiency first before correcting the folate deficiency - why?
Treating patients with folic acid when they have a B12 deficiency can lead to subacute combined degeneration of the cord.
Must correct B12 deficiency quickly
What is haemolytic anaemia and what are the two general reasons it occurs?
Haemolytic anaemia is where there is destruction of red blood cells (haemolysis) leading to anaemia.
There are a number of inherited conditions that cause the red blood cells to be more fragile and break down faster than normal leading to chronic haemolytic anaemia.
There are also a number of acquired conditions that lead to increased breakdown of red blood cells and haemolytic anaemia.
Inherited causes of haemolytic anaemia?
Hereditary Spherocytosis
Hereditary Elliptocytosis
Thalassaemia
Sickle Cell Anaemia
G6PD Deficiency
Acquired causes of haemolytic anaemia?
Autoimmune haemolytic anaemia
Alloimmune haemolytic anaemia (transfusions
reactions and haemolytic disease of newborn)
Paroxysmal nocturnal haemoglobinuria
Microangiopathic haemolytic anaemia
Prosthetic valve related haemolysis
What are the features that might be seen in a patient with a haemolytic anaemia due to the destruction of RBC - and why?
(prehepatic) jaundice (unconjugated bilirubin released in breakdown of RBC)
Anaemia (reduction in circulating RBC)
Splenomegaly (spleen becomes filled with destroyed red blood cells)
Investigations + findings haemolytic anaemia?
FULL BLOOD COUNT
Full blood count shows a normocytic anaemia
BLOOD FILM
Blood film shows schistocytes (fragments of red blood cells)
DIRECT COOMBS TEST
Direct Coombs test is positive in autoimmune haemolytic anaemia
What is the most common inherited haemolytic anaemia in northern Europeans?
Hereditary spherocytosis
What is hereditary spherocytosis and how is it inherited?
It is an autosomal dominant condition.
It causes sphere shaped red blood cells that are fragile and easily break down when passing through the spleen.
- most common hereditary haemolytic anaemia in people of northern European descent
- autosomal dominant defect of red blood cell cytoskeleton
- the normal biconcave disc shape is replaced by a sphere-shaped red blood cell
- red blood cell survival reduced as destroyed by the spleen
What is seen here?
Spherocytosis (fragments of RBC) seen in haemolytic anaemia
How might hereditary spehrocytosis present?
It presents with jaundice, gallstones, splenomegaly, failure to thrive, MCHC elevated, and notably aplastic crisis in the presence of the parvovirus.
What infection does hereditary spherocytosis notably present with in aplastic crisis?
Parovirus
How is hereditary spherocytosis diagnosed?
It is diagnosed by family history and clinical features with spherocytes on the blood film.
The mean corpuscular haemoglobin concentration (MCHC) is raised on a full blood count.
Reticulocytes will be raised due to rapid turnover of red blood cells.
the British Journal of Haematology (BJH) guidelines state that ‘patients with a family history of HS, typical clinical features and laboratory investigations (spherocytes, raised mean corpuscular haemoglobin concentration [MCHC], increase in reticulocytes) do not require any additional tests
if the diagnosis is equivocal the BJH recommend the EMA binding test and the cryohaemolysis test
for atypical presentations electrophoresis analysis of erythrocyte membranes is the method of choice
Investigation findings - hereditary spherocytosis?
Spherocytes on the blood film.
The mean corpuscular haemoglobin concentration (MCHC) is raised on a full blood count.
Reticulocytes will be raised due to rapid turnover of red blood cells.
What is hereditary elliptocytosis and how does it compare to hereditary spherocytosis?
Hereditary elliptocytosis is very similar to hereditary spherocytosis except that the red blood cells are ellipse shaped.
It is also autosomal dominant.
Presentation and management are the same:
- It presents with jaundice, gallstones, splenomegaly and notably aplastic crisis in the presence of the parvovirus. elliptocytosis on the blood film.
- The mean corpuscular haemoglobin concentration (MCHC) is raised on a full blood count. Reticulocytes will be raised due to rapid turnover of red blood cells.
- Treatment is with folate supplementation and splenectomy. Removal of the gallbladder (cholecystectomy) may be required if gallstones are a problem.
What is G6PD deficiency and how is it inherited?
G6PD deficiency is a condition where there is a defect in the red blood cell enzyme G6PD.
It is more common in Mediterranean and African patients and is X LINKED RECESSIVE
It causes crises that are triggered by infections, medications or fava beans (broad beans).
Presentation of G6PD deficiency?
It presents with jaundice (usually in the neonatal period), gallstones, anaemia, splenomegaly and Heinz bodies on blood film. May also see bite and blister cells.
How is G6PD enzyme deficiency diagnosed?
G6PD enzyme assay
levels should be checked around 3 months after an acute episode of hemolysis, RBCs with the most severely reduced G6PD activity will have hemolysed → reduced G6PD activity → not be measured in the assay → false negative results
What might trigger a crisis (sudden onset of jaundice and haemolytic anaemia) in a patient with G6PD deficiency?
Infections
Fava beans (broad beans)
Medications
Medications that trigger haemolysis include:
- Primaquine (an antimalarial)
- Ciprofloxacin
- Sulfonylureas
- Sulfasalazine and other sulphonamide drugs.
What is Autoimmune haemolytic anaemia and what are the two ‘types’?
Autoimmune haemolytic anaemia occurs when antibodies are created against the patient’s red blood cells.
These antibodies lead to destruction of the red blood cells.
There are two types based on the temperature at which the auto-antibodies function to cause the destruction of red blood cells:
- Warm Type Autoimmune Haemolytic Anaemia
- Cold Type Autoimmune Haemolytic Anaemia
Warm vs cold AIHA - which is more common?
Warm
What is meant by warm autoimmune haemolytic anaemia and why does it occur?
Autoimmune haemolytic anaemia occurs when antibodies are created against the patient’s red blood cells.
These antibodies lead to destruction of the red blood cells.
Haemolysis occurs at normal or above normal temperatures.
In warm AIHA the antibody (usually IgG) causes haemolysis best at body temperature and haemolysis tends to occur in extravascular sites, for example the spleen.
It is usually idiopathic, meaning that it arises without a clear cause.
Other causes:
autoimmune disease: e.g. systemic lupus
erythematosus*
neoplasia
lymphoma
chronic lymphocytic leukaemia
drugs: e.g. methyldopa
What is cold agglutinin disease and what occurs?
Also known as cold autoimmune haemolytic anemia.
At lower temperatures (e.g. less than 10ºC) the antibodies against red blood cells attach themselves to the red blood cells and cause them to clump together.
This is called agglutination.
This agglutination results in the destruction of the red blood cells as the immune system is activated against them and they get filtered and destroyed in the spleen.
The antibody in cold AIHA is usually IgM and causes haemolysis best at 4 deg C. Haemolysis is mediated by complement and is more commonly intravascular. Features may include symptoms of Raynaud’s and acrocynaosis. Patients respond less well to steroids
What might cold AIHA/cold agglutinin disease occur secondary to?
Conditions such as:
- Lymphoma
- Leukaemia
- Systemic lupus erythematosus
Infections such as:
-Mycoplasma
- EBV
- CMV
- HIV
Management of AIHA?
Blood transfusions
Prednisolone (steroids)
Rituximab (a monoclonal antibody against B cells)
Splenectomy
What is Alloimmune Haemolytic Anaemia and in what senarios does it occur?
Alloimmune haemolytic anaemia occurs where an there is either foreign red blood cells circulating in the patients blood causing an immune reaction that destroys those red blood cells or there is a foreign antibody circulating in their blood that acts against their own red blood cells and causes haemolysis.
The two scenarios where this occurs are transfusion reactions and haemolytic disease of the newborn.
In hemolytic transfusion reactions red blood cells are transfused into the patient. The immune system produces antibodies against antigens on those foreign red blood cells. This creates an immune response that leads to the destruction of those red blood cells.
In haemolytic disease of the newborn there are antibodies that cross the placenta from the mother to the fetus. These maternal antibodies target antigens on the red blood cells of the fetus. This causes destruction of the red blood cells in the fetus and neonate.
What is the abnormality in paroxysmal nocturnal haemoglobinuria and what occurs subsequently?
Paroxysmal nocturnal haemoglobinuria is a rare condition that occurs when a specific genetic mutation in the haematopoietic stem cells in the bone marrow 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.
Presentation of paroxysmal nocturnal haemoglobinuria?
The characteristic presentation is red urine in the morning containing haemoglobin and haemosiderin.
The patient becomes anaemic due to the haemolysis.
They are also predisposed to thrombosis (e.g. DVT, PE and hepatic vein thrombosis) and smooth muscle dystonia (e.g. oesophageal spasm and erectile dysfunction).
Management of paroxysmal nocturnal haemoglobinuria?
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.
What is MAHA?
Microangiopathic haemolytic anaemia (MAHA) is where the small blood vessels have structural abnormalities that cause haemolysis of the blood cells travelling through them.
What might microangiopathic haemolytic anaemia occur secondary to?
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
What is Prosthetic Valve Haemolysis and why does it occur?
Haemolytic anaemia is a key complication of prosthetic heart valves.
It occurs in both bioprosthetic and metallic valve replacement.
It is caused by turbulence around the valve and collision of red blood cells with the implanted valve (the valve churns up the cells and they break down)
What is the management Prosthetic Valve Haemolysis?
Monitoring
Oral iron
Blood transfusion if severe
Revision surgery may be required in severe cases
What is thalassaemia and what occurs?
Thalassaemia is related to a genetic defect in the protein chains that make up haemoglobin.
Normal haemoglobin consists of 2 alpha and 2 beta-globin chains.
Defects in alpha-globin chains leads to alpha thalassaemia. Defects in the beta-globin chains leads to beta thalassaemia. Both conditions are autosomal recessive. The overall effect is varying degrees of anaemia depends on the type and mutation.
In thalassaemia, the red blood cells are more fragile and break down more easily. The spleen acts as a sieve to filter the blood and remove older blood cells.
The bone marrow expands to produce extra red blood cells to compensate for the chronic anaemia.
Thalassemia - signs and symptoms
Microcytic anaemia (low mean corpuscular volume)
Fatigue
Pallor
Jaundice
Gallstones
Splenomegaly
Poor growth and development
Pronounced forehead and malar eminences
Physical features seen in thalassemia?
Susceptibility to fractures and prominent features such as a pronounced forehead and malar eminences (cheekbones) due to bone marrow expansion (to compensate for the chronic anaemia)
Splenomegaly - in thalassaemia the spleen collects all the destroyed red blood cells and swells, resulting in
Pallor
Jaundice
Thalassaemia - investigations and results?
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.
Iron abnormalities in thalassaemia?
Iron overload occurs 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.
Iron overload in thalassaemia causes effects similar to haemochromatosis - such as?
Fatigue
Liver cirrhosis
Infertility and impotence
Heart failure
Arthritis
Diabetes
Osteoporosis and joint pain
What is the defect in alpha-thalassemia?
Alpha-thalassaemia is caused by defects in alpha-globin chains. The gene coding for this protein is on chromosome 16.
Management of alpha-thalassemia?
Monitoring the full blood count
Monitoring for complications
Blood transfusions
Splenectomy may be performed
Bone marrow transplant can be curative
What is the defect in Beta-thalassaemia?
Beta-thalassaemia is caused by defects in beta-globin chains. The gene coding for this protein is on chromosome 11.
What are the three types of beta-thalassaemia and how do they differ?
- Thalassaemia minor - carriers of an abnormally functioning beta globin gene, they have one abnormal and one normal gene, mild microcytic anaemia
- Thalassaemia intermedia - two abnormal copies of the beta-globin gene (x2 defective genes or x1 defective gene + x1 deletion gene), causes a more significant microcytic anaemia
- Thalassaemia major - patients are homozygous for the deletion genes & have no functioning beta-globin genes at all.
This is the most severe form and usually presents with severe anaemia and failure to thrive in early childhood.
Beta-thalassemia management?
- Thalassaemia minor - usually patients only require monitoring and no active treatment
- Thalassaemia intermedia - patients require monitoring and occasional blood transfusions.
If they need more transfusions they may require iron chelation to prevent iron overload. - Thalassaemia major regular transfusions, iron chelation and splenectomy. Bone marrow transplant can potentially be curative.
What does thalassaemia major cause?
- Severe microcytic anaemia
- Splenomegaly
- Bone deformities
Likely to present with failure to thrive in childhood
What is sickle cell anaemia and what is the underlying abnormaliy?
Sickle cell anaemia is a genetic condition that causes sickle (crescent) shaped red blood cells. This makes the red blood cells fragile and more easily destroyed leading to an haemolytic anaemia. Patients with sickle cell anaemia are prone to various types of sickle cell crises.
Patients with sickle-cell disease have an abnormal variant called haemoglobin S (HbS). HbS causes red blood cells to be an abnormal “sickle” shape.
Sickle cell anaemia is an autosomal recessive condition where there is an abnormal gene for beta-globin on chromosome 11.
One copy of the gene results in sickle-cell trait.
Patients with sickle-cell trait are usually asymptomatic.
Two abnormal copies are required for sickle-cell disease.
Why is sickle cell disease more common in patients from areas traditionally affected by malaria such as Africa, India, the Middle East and the Caribbean?
Having one copy of the gene (sickle-cell trait) reduces the severity of malaria.
As a result, patients with sickle-cell trait are more likely to survive malaria and pass on their genes.
Therefore, there is a selective advantage to having the sickle cell gene in areas of malaria.
This leads to a high proportion of the population in these areas having the gene.
Diagnosis of sickle cell anaemia/sickle cell trait?
Pregnant women at risk of being carriers of the sickle cell gene are offered testing during pregnancy.
Sickle cell disease is also tested for on the on the newborn screening heel prick test at 5 days of age.
Complications of sickle cell anaemia?
Anaemia
Increased risk of infection
Stroke
Avascular necrosis in large joints such as the hip
Pulmonary hypertension
Painful and persistent penile erection (priapism)
Chronic kidney disease
Sickle cell crises
Acute chest syndrome
General management of sickle cell anaemia?
Avoid dehydration and other triggers of crises
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
What are sickle cell crises and why might they occur?
Sickle cell crisis is an umbrella term for a spectrum of acute crises related to the condition.
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.
Management of sickle cell crisis?
There is no specific treatment for sickle cell crises and they are managed supportively:
Have a low threshold for admission to hospital
Treat any infection
Keep warm
Keep well hydrated (IV fluids may be required)
Simple analgesia such as paracetamol and ibuprofen
Penile aspiration in priapism
NSAIDs such as ibuprofen should be avoided where there is renal impairment.
Specific types of sickle cell crisis?
Vaso-occlusive Crisis (AKA painful crisis)
Splenic sequestration crisis
Aplastic crisis
Acute chest syndrome
Why does vaso-occlusive crisis occur?
Vaso-occlusive crisis is caused by the sickle shaped blood cells clogging capillaries causing distal ischaemia. It is associated with dehydration and raised haematocrit.
Vaso-occlusive crisis - symptoms and management
Symptoms are typically pain, 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.
Supportive management:
Have a low threshold for admission to hospital
Treat any infection
Keep warm
Keep well hydrated (IV fluids may be required)
Why does splenic sequestration crisis occur + what are the potential consequences?
Splenic sequestration crisis is 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).
Recurrent crises can lead to splenic infarction and therefore susceptibility to infections.
Splenic sequestration crisis - management?
Splenic sequestration crisis is considered an emergency.
Management is supportive with blood transfusions and fluid resuscitation to treat anaemia and shock.
Splenectomy prevents sequestration crisis and is often used in cases of recurrent crises.
Management of aplastic crisis in sickle cell anaemia?
It leads to significant anaemia.
Management is supportive with blood transfusions if necessary. It usually resolves spontaneously within a week.
What is aplastic crisis in sickle cell anaemia and what is it commonly triggered by?
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.
Management of sickle cell crisis: ACS
Is a medical emergency with a high mortality and requires prompt supportive management and treatment of the underlying cause:
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
Sickle cell crisis: why might ACS occur?
Infection (e.g. pneumonia or bronchiolitis)
Non-infective causes (e.g. pulmonary vaso-occlusion or fat emboli).
Sickle cell crisis: what does a diagnosis of ACS require?
Fever or respiratory symptoms with
New infiltrates seen on a chest xray
What is thrombocytopenia and what are the two general causes?
Thrombocytopenia describes a low platelet count.
The normal platelet count is between 150 to 450 x 109/L.
Problems with production or destruction.
Thrombocytopenia - causes related to problems with production?
Sepsis
B12 or folic acid deficiency
Liver failure causing reduced thrombopoietin production in the liver
Leukaemia
Myelodysplastic syndrome
Thrombocytopenia - causes related to problems with destruction?
Medications (sodium valproate, methotrexate, isotretinoin, antihistamines, proton pump inhibitors)
Alcohol
Immune thrombocytopenic purpura
Thrombotic thrombocytopenic purpura
Heparin-induced thrombocytopenia
Haemolytic-uraemic syndrome
What medications can causes thromocytopenia?
Sodium valproate
Methotrexate
Isotretinoin
Antihistamines
Proton pump inhibitors
Heparin-induced thrombocytopenia
How might thrombocytopenia present?
Mild thrombocytopenia - may be asymptomatic and found incidentally on a full blood count.
Platelet counts below 50 x 109/L will result in easy or spontaneous bruising and prolonged bleeding times:
- Nosebleeds
- Bleeding gums
- Heavy periods
- Easy bruising or blood in the urine or stools.
Platelet counts below 10 x 109/L are high risk for spontaneous bleeding:
- Spontaneous intracranial haemorrhage
- GI bleeds are particularly concerning
Platelet counts below what will result in easy or spontaneous bruising and prolonged bleeding times - i.e.
- Nosebleeds
- Bleeding gums
- Heavy periods
- Easy bruising or blood in the urine or stools.
50 x 109/L
Platelet counts below what are high risk for spontaneous bleeding, making haemorrhage or GI bleeds particularly concerning?
10 x 109/L
Key differentials for prolonged bleeding?
Thrombocytopenia (low platelets)
Haemophilia A and haemophilia B
Von Willebrand Disease
Disseminated intravascular coagulation (usually secondary to sepsis)
What is ITP (immune thrombocytopenic purpura) and what is it also known as?
autoimmune thrombocytopenic purpura
idiopathic thrombocytopenic purpura
primary thrombocytopenic purpura
ITP is a condition where antibodies are created against platelets.
This causes an immune response against platelets, resulting in the destruction of platelets and a low platelet count.
Management + patient advice for IPT
Management options include:
Prednisolone (steroids)
IV immunoglobulins
Rituximab (a monoclonal antibody against B cells)
Splenectomy
The platelet count needs to be monitored and the patient needs education about concerning signs of bleeding such as persistent headaches and melaena and when to seek help.
Additional measures such as carefully controlling blood pressure and suppressing menstrual periods are also important.
What is Thrombotic Thrombocytopenic Purpura?
This is a condition where tiny blood clots develop throughout the small vessels of the body using up platelets and causing thrombocytopenia, bleeding under the skin and other systemic issues. It affect the small vessels so it is described as a microangiopathy.
Why happens in Thrombotic Thrombocytopenic Purpura and why does this occur?
Tiny blood clots develop throughout the small vessels clots develop due to a problem with a specific protein called ADAMTS13
This protein normally inactivates von Willebrand factor and reduces platelet adhesion to vessel walls and clot formation.
A shortage in this protein leads to von Willebrand factor overactivity and the formation of blood clots in small vessels
This causes platelets to be used up leading to thrombocytopenia.
The blood clots in the small vessels break up red blood cells, leading to haemolytic anaemia.
Deficiency in the ADAMTS13 protein can be due to an inherited genetic mutation or due to autoimmune disease where antibodies are created against the protein.
Management of thrombotic thrombocytopenic purpura?
Treatment is guided by a haematologist and may involve plasma exchange, steroids and rituximab (a monoclonal antibody against B cells).
Basic pathophysiology of heparin induced thrombocytopenia?
Heparin induced thrombocytopenia (HIT) involves the development of antibodies against platelets in response to exposure to heparin.
These heparin induced antibodies specifically target a protein on the platelets called platelet factor 4 (PF4).
These are anti-PF4/heparin antibodies.
The HIT antibodies bind to platelets and activate clotting mechanisms.
This causes a hypercoagulable state and leads to thrombosis.
They also break down platelets and cause thrombocytopenia.
Therefore there is an unintuitive situation where a patient on heparin with low platelets forms unexpected blood clots.
How is heparin induced thrombopenia diagnosed?
Diagnosis is by testing for the HIT antibodies in the patients blood.
How is heparin induced thrombopenia managed?
Management is by stopping heparin and using an alternative anticoagulant guided by a specialist.
What is the role of ADAMTS13 and why might it be deficient?
This protein normally inactivates von Willebrand factor and reduces platelet adhesion to vessel walls and clot formation (shortage in this protein leads to von Willebrand factor overactivity and the formation of blood clots in small vessels)
Deficiency in the ADAMTS13 protein can be due to an inherited genetic mutation or due to autoimmune disease where antibodies are created against the protein.
What is the most common inherited cause of abnormal bleeding (haemophilia)?
Von Willebrand disease
Underlying causes of Von Willebrand disease?
Most causes are autosomal dominant.
The causes involve:
- a deficiency
- absence
- malfunctioning
of a glycoprotein called von Willebrand factor (VWF).
There are three types based on the underlying cause and ranging from type 1 to type 3. Type 3 is the most severe.
Von Willebrand Disease - presentation?
Patients present with a history of unusually easy, prolonged or heavy bleeding:
Bleeding gums with brushing
Nose bleeds (epistaxis)
Heavy menstrual bleeding (menorrhagia)
Heavy bleeding during surgical operations
Family history of heavy bleeding or von Willebrand disease is very relevant.
Diagnosis of Von Willebrand Disease
History of abnormal bleeding, family history
Bleeding assessment tools and laboratory investigations
Due to all the underlying causes there is no easy von Willebrand disease test. This can make diagnosis challenging
Management of Von Willebrand Disease
Von Willebrand disease does not require day to day treatment.
Management is required either in response to major bleeding or trauma (to stop bleeding) or in preparation for operations (to prevent bleeding):
- Desmopressin can be used to stimulates the release of VWF
- VWF can be infused
- Factor VIII is often infused along with plasma-derived VWF
Women with VWD that suffer from heavy periods can be managed by a combination of:
Tranexamic acid
Mefanamic acid
Norethisterone
Combined oral contraceptive pill
Mirena coil
Hysterectomy may be required in severe cases.
What is the deficiency in Haemophilia A?
Haemophilia A is caused by a deficiency in factor VIII.
What is the deficiency in Haemophilia B?
Haemophilia B (also known as Christmas disease) is caused by a deficiency in factor IX.
Inheritance pattern of Haemophilias A and B?
Both haemophilia A and B are X linked recessive.
This means in order to have the condition all of the X chromosomes need to have the abnormal gene.
Men only require one abnormal copy as they only have one X chromosome.
Women require abnormal copies on both their X chromosomes, and if only one copy is affected they are a carrier of the condition.
Therefore haemophilia A and B almost exclusively affect males.
For a female to be affected they would require an affected father and a mother that is either a carrier or also affected.
How and when might haemophilia A and B present?
Both haemophilia A and B are severe bleeding disorders. Patients can bleed excessively in response to minor trauma and are also at risk of spontaneous haemorrhage without any trauma.
Most cases present in neonates or early childhood. It can present with intracranial haemorrhage, haematomas and cord bleeding in neonates.
Spontaneous bleeding into joints (haemoathrosis) and muscles are a classic feature of severe haemophilia. If untreated this can lead to joint damage and deformity.
Abnormal bleeding can occur in other areas:
Gums
Gastrointestinal tract
Urinary tract causing haematuria
Retroperitoneal space
Intracranial
Following procedures
Management of haemophillia
Management should be coordinated by a specialist.
The affected clotting factors (VIII or IX) can be replaced by intravenous infusions. This can be either prophylactically or in response to bleeding. A complication of this treatment is formation of antibodies against the clotting factor resulting in the treatment becoming ineffective.
Acute episodes of bleeding or prevention of excessive bleeding during surgical procedures involve:
Infusions of the affected factor (VIII or IX)
Desmopressin to stimulate the release of von Willebrand Factor
Antifibrinolytics such as tranexamic acid
What is diagnosis of haemophilia based on?
Bleeding scores
Coagulation factor assays
Genetic testing
Acute episodes of bleeding or prevention of excessive bleeding during surgical procedures in patients with haemophilia involve what?
- Infusions of the affected factor (VIII or IX)
- Desmopressin to stimulate the release of von Willebrand Factor
- Antifibrinolytics such as tranexamic acid
Deficiency in factor IX
haemophilia b
Deficiency in factor VIII
haemophilia A
What is VTE and what might it progress to?
Venous thromboembolism (VTE) is a common and potentially fatal condition. It involves blood clots (thrombi) developing in the circulation. This usually occurs secondary to stagnation of blood and hyper-coagulable states. When a thrombus develops in the venous circulation, it is called a deep vein thrombosis (DVT).
Once a thrombus has developed, it can travel (embolise) from the deep veins, through the right side of the heart and into the lungs, where it becomes lodged in the pulmonary arteries. This blocks blood flow to areas of the lungs and is called a pulmonary embolism (PE).
If the patient has a hole in their heart (for example, an atrial septal defect), the blood clot can pass through to the left side of the heart and into the systemic circulation. If it travels to the brain, it can cause a large stroke.
Risk factors for VTE/PE
Immobility
Recent surgery
Long haul travel
Pregnancy
Hormone therapy with oestrogen (combined oral contraceptive pill and hormone replacement therapy)
Malignancy
Polycythaemia
Systemic lupus erythematosus
Thrombophilia
Thrombophilias are conditions that predispose patients to develop blood clots. There are a large number of these, such as?
Antiphospholipid syndrome
Factor V Leiden
Antithrombin deficiency
Protein C or S deficiency
Hyperhomocysteinaemia
Prothombin gene variant
Activated protein C resistance
What thrombophillia might you suspect in a patient with recurrent VTE + miscarriage
Antiphospholipid syndrome, diagnosed by testing for antiphospholipid antibodies
VTE prophylaxis
Every patient admitted to hospital should be assessed for their risk of venous thromboembolism (VTE). If they are at increased risk of VTE, they should receive prophylaxis unless contraindicated.
Prophylaxis is usually with low molecular weight heparin, such as enoxaparin. Contraindications include active bleeding or existing anticoagulation with warfarin or a DOAC.
Anti-embolic compression stockings are also used, unless contraindicated. The main contraindication for compression stockings is significant peripheral arterial disease.
DVT presentation
DVTs are almost always unilateral. Bilateral DVT is rare and bilateral symptoms are more likely due to an alternative diagnosis such as chronic venous insufficiency or heart failure. DVTs can present with:
Calf or leg swelling
Dilated superficial veins
Tenderness to the calf (particularly over the site of the deep veins)
Oedema
Colour changes to the leg
Diagnosing DVT/PE
Wells Score
The Wells score predicts the risk of a patient presenting with symptoms having a DVT or PE. It includes risk factors such as recent surgery and clinical findings such as unilateral calf swelling 3cm greater than the other leg.
Diagnosis
D-dimer is a sensitive (95%), but not specific, blood test for VTE. This makes it helpful in excluding VTE where there is a low suspicion. It is almost always raised if there is a DVT; however other conditions can also cause a raised d-dimer:
Pneumonia
Malignancy
Heart failure
Surgery
Pregnancy
Doppler ultrasound of the leg is required to diagnose deep vein thrombosis. NICE recommends repeating negative ultrasound scans after 6-8 days if a positive D-dimer and the Wells score suggest a DVT is likely.
Pulmonary embolism can be diagnosed with a CT pulmonary angiogram (CTPA) or ventilation-perfusion (VQ) scan. CTPA is usually preferred, unless the patient has significant kidney impairment or a contrast allergy.
Measuring legs in ?DVT
To examine for leg swelling, measure the circumference of the calf 10cm below the tibial tuberosity.
More than 3cm difference between calves is significant.
DVT: initial management
The initial management for a suspected or confirmed DVT or PE is with anticoagulation. In most patients, NICE (2020) recommend treatment dose apixaban or rivaroxaban. It should be started immediately in patients where DVT or PE is suspected, and there is a delay in getting the scan.
The NICE guidelines (2020) recommend considering catheter-directed thrombolysis in patients with a symptomatic iliofemoral DVT and symptoms lasting less than 14 days. This involves inserting a catheter under x-ray guidance through the venous system to apply thrombolysis directly into the clot.
LONG TERM ANTI COAGULATION - VTE
The options for long term anticoagulation in VTE are a DOAC, warfarin, or LMWH.
DOACs are oral anticoagulants that do not require monitoring. They were called “novel oral anticoagulants” (NOACs), but this has been changed to “direct-acting oral anticoagulants” (DOACs). Options are apixaban, rivaroxaban, edoxaban and dabigatran. They are suitable for most patients, including patients with cancer.
Warfarin is a vitamin K antagonist. The target INR for warfarin is between 2 and 3 when treating DVTs and PEs. It is the first-line in patients with antiphospholipid syndrome (who also require initial concurrent treatment with LMWH).
Low molecular weight heparin (LMWH) is the first-line anticoagulant in pregnancy.
Duration of long term anticoagulation following VTE?
3 months if there is a reversible cause (then review)
Beyond 3 months if the cause is unclear, there is recurrent VTE, or there is an irreversible underlying cause such as thrombophilia (often 6 months in practice)
3-6 months in active cancer (then review)
What is an inferior vena cava filter, and when might it be used?
Inferior vena cava filters are devices inserted into the inferior vena cava, designed to filter the blood and catch any blood clots travelling from the venous system, towards the heart and lungs.
They act as a sieve, allowing blood to flow through whilst stopping larger blood clots.
They are used in unusual cases of patients with recurrent PEs or those that are unsuitable for anticoagulation.
Investigating unprovoked DVT?
When patients have their first VTE without a clear cause, the NICE guidelines from 2020 recommend reviewing the medical history, baseline blood results and physical examination for evidence of cancer.
In patients with an unprovoked DVT or PE that are not going to continue anticoagulation (they have finished 3-6 months of treatment and are due to stop), NICE recommends considering testing for:
- Antiphospholipid syndrome (check antiphospholipid antibodies)
- Hereditary thrombophilias (only if they have a first-degree relative also affected by a DVT or PE)
What is Budd-Chiari syndrome?
Budd-Chiari syndrome is where a blood clot (thrombosis) develops in the hepatic vein, blocking the outflow of blood. It is associated with hyper-coagulable states. It causes acute hepatitis.
Triad of symptoms in Budd-Chiari syndrome?
Abdominal pain
Hepatomegaly
Ascites
Management of Budd-Chiari syndrome?
Management involves anticoagulation (heparin or warfarin), investigating for the underlying cause of hyper-coagulation and treating hepatitis.
Cytomegalovirus (CMV) is transmitted in leucocytes. As most blood products (except granulocyte transfusions) are now leucocyte depleted CMV negative products are rarely required - in which cases are they indicated?
Granulocyte transfusions
Intra-uterine transfusions
Neonates up to 28 days posts expected date of delivery
Pregnancy: elective transfusion during pregnancy (not labour or delivery)
Irradiated blood products are depleted of T-lymphocytes and used to avoid transfusion-associated graft versus host disease (TA-GVHD) caused by engraftment of viable donor T lymphocytes. When are they indicated?
Granulocyte transfusion
Intra-uterine transfusions
Neonates up to 28 days post expected date of delivery
Bone marrow/stem cell transplants
Immunocompromised
Patients with/previous Hodgkin lymphoma
When is FFP used, and how does it differ from red cells?
most suited for ‘clinically significant’ but without ‘major haemorrhage’ in patients with a prothrombin time (PT) ratio or activated partial thromboplastin time (APTT) ratio > 1.5
typically 150-220 mL
can be used prophylactically in patients undergoing invasive surgery where there is a risk of significant bleeding
In contrast to red cells, the universal donor of FFP is AB blood because it lacks any anti-A or anti-B antibodies
What does cryoprecipitate contain?
contains concentrated Factor VIII:C, von Willebrand factor, fibrinogen, Factor XIII and fibronectin, produced by further processing of Fresh Frozen Plasma (FFP).
much smaller volume than FFP, typically 15-20mL
When is cryoprecipitate used?
Clinically it is most commonly used to replace fibrinogen
most suited for patients for ‘clinically significant’ but without ‘major haemorrhage’ who have a fibrinogen concentration < 1.5 g/L
example use cases include disseminated intravascular coagulation, liver failure and hypofibrinogenaemia secondary to massive transfusion.
It may also be used in an emergency situation for haemophiliacs (when specific factors not available) and in von Willebrand disease
can be used prophylactically in patients undergoing invasive surgery where there is a risk of significant bleeding where the fibrinogen concentration < 1.0 g/L
When is prothrombin complex concentrate used?
used for the emergency reversal of anticoagulation in patients with either severe bleeding or a head injury with suspected intracerebral haemorrhage
can be used prophylactically in patients undergoing emergency surgery depending on the particular circumstance
Transfusion thresholds for adults?
Patients without ACS - 70 g/L
Patients with ACS - 80 g/L
Transfusion targets for adults?
Patients without ACS - 70-90 g/L
Patients with ACS - 80-100 g/L
ie. up to 20 above the transfusion threshold
Red blood cells should be stored at what temperature prior to infusion?
red blood cells should be stored at 4°C
In a non-urgent scenario, a unit of RBC is usually transfused over what time period?
90-120 minutes
What is Graft Versus host disease and why does it occur?
Graft versus host disease (GVHD) is a multi-system complication of allogeneic bone marrow transplantation.
Less frequently, it may also occur following solid organ transplantation or transfusion in immunocompromised patients.
The disease occurs when T cells in the donor tissue (the graft) mount an immune response toward recipient (host) cells.
It is not to be confused with transplant rejection (in which recipient immune cells activate an immune response toward the donor tissue).
Prognosis is generally poor.
What criteria is used to diagnose graft versus host disease?
Three conditions required for diagnosis of GVHD, known as the Billingham criteria 1:
The transplanted tissue contains immunologically functioning cells
The recipient and donor are immunologically different
The recipient is immunocompromised
GVHD - risk factors
Poorly matched donor and recipient (particularly HLA)
Type of conditioning used prior to transplantation
Gender disparity between donor and recipient
Graft source (bone marrow or peripheral blood source associated with higher risk than umbilical cord blood)
Within what timeframe does acute GVDH occur?
100 days
Within what timeframe does chronic GVDH occur?
Classically 100 days following transplantation
May occur following acute disease, or can arise de novo
Clinical features of chronic GVHD
Has a more varied clinical picture: often lung and eye involvement in addition to skin and GI, although any organ system may be involved
Skin: Many manifestations including poikiloderma, scleroderma, vitiligo, lichen planus
Eye: Often keratoconjunctivitis sicca, also corneal ulcers, scleritis
GI: Dysphagia, odynophagia, oral ulceration, ileus.
Oral lichenous changes are a characteristic early sign (2)
Lung: my present as obstructive or restrictive pattern lung disease
Clinical features of acute GVDH
Usually affects the skin (>80%), liver (50%), and gastrointestinal tract (50%)
Multi-organ involvement carries a worse prognosis**
Painful maculopapular rash (often neck, palms and soles), which may progress to erythroderma or a toxic epidermal necrolysis-like syndrome
Jaundice
Watery or bloody diarrhoea
Persistent nausea and vomiting
Can also present as a culture-negative fever
Investigating GVHD?
Investigations (largely dependent on which organs are involved):
LFTs may demonstrate cholestatic jaundice. Hepatitis screen/ultrasound may be useful to exclude other causes
Abdominal imaging may reveal air-fluid levels and small bowel thickening (‘ribbon sign’)
Lung function testing
Biopsy of affected tissue may aid in diagnosis if there is uncertainty
Management of GVHD
Management consists of immunosuppression and supportive measures.
Intravenous steroids are the mainstay of immunosuppressive treatment in severe cases of acute GVHD.
Extended courses of steroid therapy are often needed in chronic GVHD and dose tapering is vital.
Second-line therapies include anti-TNF, mTOR inhibitors and extracorporeal photopheresis.
Excessive immunosuppression may predispose patients to infection, and also limit the beneficial graft-versus-tumour effect of the transplant.
Topical steroid therapy may be sufficient in mild disease with limited cutaneous involvement.
Features of aplastic anaemia?
Characterised by pancytopenia and a hypoplastic bone marrow
Peak incidence of acquired = 30 years old
Features:
normochromic, normocytic anaemia
leukopenia, with lymphocytes relatively spared
thrombocytopenia
may be the presenting feature acute lymphoblastic or myeloid leukaemia
a minority of patients later develop paroxysmal nocturnal haemoglobinuria or myelodysplasia
What electrolyte abnormalities may be present in tumour lysis syndrome?
hyperkalaemia, hyperphosphataemia, hyperuricaemia and hypocalcaemia.
What is the mainstay of treatment for those with beta-thalassaemia major?
Fortnightly blood transfusions
First line recommendation from NICE for neutropenic sepsis
Piperacillin with tazobactam is recommended as the first-line antibiotic by NICE,
What is the roles of hydroxycarbamide in sickle cell anaemia?
Hydroxycarbamide (previously known as hydroxyurea) is a ribonucleotide reductase inhibitor that increases the levels of foetal haemoglobin (Hb F) in the blood, which has been shown to reduce the frequency of sickle cell crises, reduce hospitalisation and decrease mortality.
What clotting factors do heparins affect and how?
Prevents activation factors 2,9,10,11
What clotting factors does warfarin affect and how?
Affects synthesis of factors 2,7,9,10
What clotting factors are involved in DIC?
Factors 1,2,5,8,11
What clotting factors are affected by liver disease?
Factors 1,2,5,7,9,10,11
Interpretation blood clotting test results:
APTT INCREASED
PT INCREAED
BLEEDING TIME NORMAL
VITAMIN K DEF
Interpretation blood clotting test results:
APTT INCREASED
PT NORMAL
BLEEDING TIME NORMAL
Haemophilia
Interpretation blood clotting test results:
APTT INCREASED
PT NORMAL
BLEEDING TIME INCREASED
von Willebrand’s disease
What is acute intermittent porphyria + what is the abnormality + in which patients does it present?
Acute intermittent porphyria (AIP) is a rare autosomal dominant condition caused by a defect in porphobilinogen deaminase, an enzyme involved in the biosynthesis of haem.
The results in the toxic accumulation of delta aminolaevulinic acid and porphobilinogen.
It characteristically presents with abdominal and neuropsychiatric symptoms in 20-40-year-olds.
AIP is more common in females (5:1)
Presentation of acute intermittent porphyria?
abdominal: abdominal pain, vomiting
neurological: motor neuropathy
psychiatric: e.g. depression
hypertension and tachycardia common
Acute intermittent porphyria:: diagnosis and management
Diagnosis
classically urine turns deep red on standing
raised urinary porphobilinogen (elevated between
attacks and to a greater extent during acute attacks)
assay of red cells for porphobilinogen deaminase
raised serum levels of delta aminolaevulinic acid and porphobilinogen
Management
avoiding triggers
acute attacks
IV haematin/haem arginate
IV glucose should be used if haematin/haem arginate is not immediately available
Features of AML?
Features are largely related to bone marrow failure:
anaemia: pallor, lethargy, weakness
neutropenia: whilst white cell counts may be very
high, functioning neutrophil levels may be low leading to frequent infections etc
thrombocytopenia: bleeding
splenomegaly
bone pain
AML - poor prognostic factors
> 60 years
20% blasts after first course of chemo
cytogenetics: deletions of chromosome 5 or 7
Acute promyelocytic leukaemia M3
associated with t(15;17)
fusion of PML and RAR-alpha genes
presents younger than other types of AML (average = 25 years old)
Auer rods (seen with myeloperoxidase stain)
DIC or thrombocytopenia often at presentation
good prognosis
The importance of identifying APML lies in both the presentation (classically disseminated intravascular coagulation) and management
AML CLASSIFICATION
Classification - French-American-British (FAB)
MO - undifferentiated
M1 - without maturation
M2 - with granulocytic maturation
M3 - acute promyelocytic
M4 - granulocytic and monocytic maturation
M5 - monocytic
M6 - erythroleukaemia
M7 - megakaryoblastic
Antiphospholipid syndrome is an acquired disorder characterised by a predisposition to both venous and arterial thromboses, recurrent fetal loss and thrombocytopenia. It may occur as a primary disorder or secondary to other conditions, most commonly systemic lupus erythematosus (SLE).
What complications may occur during pregnancy?
recurrent miscarriage
IUGR
pre-eclampsia
placental abruption
pre-term delivery
venous thromboembolism
Management of antiphospholipid syndrome?
low-dose aspirin should be commenced once the pregnancy is confirmed on urine testing
low molecular weight heparin once a fetal heart is seen on ultrasound. This is usually discontinued at 34 weeks gestation
these interventions increase the live birth rate seven-fold
Causes of aplastic anaemia?
idiopathic
congenital: Fanconi anaemia, dyskeratosis congenita
drugs: cytotoxics, chloramphenicol, sulphonamides, phenytoin, gold
toxins: benzene
infections: parvovirus, hepatitis
radiation
What is aplastic anaemia and what are the features?
What might it be a presenting feature of?
Characterised by pancytopenia and a hypoplastic bone marrow
Peak incidence of acquired = 30 years old
Features
- normochromic, normocytic anaemia
- leukopenia, with lymphocytes relatively spared
thrombocytopenia
may be the presenting feature acute lymphoblastic or myeloid leukaemia
a minority of patients later develop paroxysmal nocturnal haemoglobinuria or myelodysplasia
Mgx of warm AIHA?
treatment of any underlying disorder
steroids (+/- rituximab) are generally used first-line
Investigations: AIHA
general features of haemolytic anaemia
anaemia
reticulocytosis
low haptoglobin
raised lactate dehydrogenase (LDH) and indirect bilirubin
blood film: spherocytes and reticulocytes
specific features of autoimmune haemolytic anaemia
positive direct antiglobulin test (Coombs’ test).
Features of Beta-thallasemia major?
presents in the first year of life with failure to thrive and hepatosplenomegaly
microcytic anaemia
HbA2 & HbF raised
HbA absent
HOW is Beta-Thalasemia major managed and how can this cause complications?
repeated transfusion
this leads to iron overload → organ failure
iron chelation therapy is therefore important (e.g. desferrioxamine)
Blood abnormalities in thalassemia?
mild hypochromic, microcytic anaemia - microcytosis is characteristically disproportionate to the anaemia
HbA2 raised (> 3.5%)
BLOOD FILM: ABNORMALITY AND ASSOCIATED CONDITION
TARGET CELLS
Sickle-cell/thalassaemia
Iron-deficiency anaemia
Hyposplenism
Liver disease
BLOOD FILM: ABNORMALITY AND ASSOCIATED CONDITION
POIKILOCYTES ‘Tear-drop’
Myelofibrosis
BLOOD FILM: ABNORMALITY AND ASSOCIATED CONDITION
SPHEROCYTES
Hereditary spherocytosis
Autoimmune hemolytic anaemia
BLOOD FILM: ABNORMALITY AND ASSOCIATED CONDITION
BASOPHILLIC STRIPPING
Lead poisoning
Thalassaemia
Sideroblastic anaemia
Myelodysplasia
BLOOD FILM: ABNORMALITY AND ASSOCIATED CONDITION
Howell Jolly bodies
Hyposplenism
BLOOD FILM: ABNORMALITY AND ASSOCIATED CONDITION
HEINZ BODIES
G6PD deficiency Alpha-thalassaemia
BLOOD FILM: ABNORMALITY AND ASSOCIATED CONDITION
Schistocytes (‘helmet cells’)
Intravascular haemolysis
Mechanical heart valve
Disseminated intravascular coagulation
BLOOD FILM: ABNORMALITY AND ASSOCIATED CONDITION
‘Pencil’ poikilocytes
Iron deficency anaemia
BLOOD FILM: ABNORMALITY AND ASSOCIATED CONDITION
Burr cells (echinocytes)
Uraemia
Pyruvate kinase deficiency
BLOOD FILM: ABNORMALITY AND ASSOCIATED CONDITION
Acanthocytes
Abetalipoproteinemia
When might hypersegmented neutrophils be seen?
megaloblastic anaemia
What might be seen on a typical blood film in hyposlenism?
target cells
Howell-Jolly bodies
Pappenheimer bodies
siderotic granules
acanthocytes
What might be seen on a typical blood film in iron def anemia?
target cells
‘pencil’ poikilocytes
if combined with B12/folate deficiency a ‘dimorphic’ film occurs with mixed microcytic and macrocytic cells
What type of lymphoma is Burkitts Lymphoma?
high-grade B-cell neoplasm
What are the two main types of Burkitts Lymphoma?
endemic (African) form: typically involves maxilla or mandible
sporadic form: abdominal (e.g. ileo-caecal) tumours are the most common form. More common in patients with HIV
Two specific risk factors for Burkitts lymphoma?
Burkitt’s lymphoma is associated with the c-myc gene translocation, usually t(8:14).
The Epstein-Barr virus (EBV) is strongly implicated in the development of the African form of Burkitt’s lymphoma and to a lesser extent the sporadic form
Microscopic findings In Burkitt’s lymphoma?
‘starry sky’ appearance: lymphocyte sheets interspersed with macrophages containing dead apoptotic tumour cells
What emergency complication may occur as a result of Burkitt’s lymphoma?
Management is with chemotherapy. This tends to produce a rapid response which may cause ‘tumour lysis syndrome’.
Rasburicase (a recombinant version of urate oxidase, an enzyme which catalyses the conversion of uric acid to allantoin*) is often given before the chemotherapy to reduce the risk of this occurring.
Complications of tumour lysis syndrome include:
hyperkalaemia
hyperphosphataemia
hypocalcaemia
hyperuricaemia
acute renal failure
*allantoin is 5-10 times more soluble than uric acid, so renal excretion is more effective
Potential complications of CLL?
anaemia
hypogammaglobulinaemia leading to recurrent infections
warm autoimmune haemolytic anaemia in 10-15% of patients
transformation to high-grade lymphoma (Richter’s transformation)
What is Richter’s transformation?
Ritcher’s transformation occurs when leukaemia cells enter the lymph node and change into a high-grade, fast-growing non-Hodgkin’s lymphoma. Patients often become unwell very suddenly.
Ritcher’s transformation is indicated by one of the following symptoms:
lymph node swelling
fever without infection
weight loss
night sweats
nausea
abdominal pain
Features of CLL?
often none: may be picked up by an incidental finding of lymphocytosis
constitutional: anorexia, weight loss
bleeding, infections
lymphadenopathy more marked than chronic myeloid leukaemia
What proliferates in CLL?
monoclonal proliferation of well-differentiated lymphocytes which are almost always B-cells (99%)
CLL investigations + findings
full blood count:
- lymphocytosis
- anaemia: may occur either due to bone marrow replacement on autoimmune hemolytic anaemia (AIHA)
- thrombocytopenia: may occur either due to bone marrow replacement on immune thrombocytopenia (AIHA)
blood film: smudge cells (also known as smear cells)
immunophenotyping is the key investigation:
most cases can be identified using a panel of antibodies specific for CD5, CD19, CD20 and CD23
CML: genetic abnormalities
The Philadelphia chromosome is present in more than 95% of patients with chronic myeloid leukaemia (CML).
It is due to a translocation between the long arm of chromosome 9 and 22 - t(9:22)(q34; q11).
This results in part of the ABL proto-oncogene from chromosome 9 being fused with the BCR gene from chromosome 22.
The resulting BCR-ABL gene codes for a fusion protein that has tyrosine kinase activity in excess of normal.
CML: presentation
Presentation (60-70 years)
anaemia: lethargy
weight loss and sweating are common
splenomegaly may be marked → abdo discomfort
an increase in granulocytes at different stages of
maturation +/- thrombocytosis
decreased leukocyte alkaline phosphatase
may undergo blast transformation (AML in 80%, ALL in 20%)
Management of CML?
imatinib is now considered first-line treatment
inhibitor of the tyrosine kinase associated with the BCR-ABL defect
very high response rate in chronic phase CML
hydroxyurea
interferon-alpha
allogenic bone marrow transplant
What is Cryoglobulinaemia and what types exist?
Immunoglobulins which undergo reversible precipitation at 4 deg C, dissolve when warmed to 37 deg C. One-third of cases are idiopathic
Three types
- type I (25%):
monoclonal - IgG or IgM
associations: multiple myeloma, Waldenstrom macroglobulinaemia
type II (25%)
mixed monoclonal and polyclonal: usually with rheumatoid factor
associations: hepatitis C, rheumatoid arthritis, Sjogren’s, lymphoma
type III (50%)
polyclonal: usually with rheumatoid factor
associations: rheumatoid arthritis, Sjogren’s
Cryoglobulinaemia features
- Raynaud’s only seen in type I
- cutaneous
vascular purpura
distal ulceration
ulceration
arthralgia
renal involvement
- diffuse glomerulonephritis
Cryoglobulinemia - investigations and management?
Investigations
low complement (esp. C4)
high ESR
Management
treatment of underlying condition e.g. hepatitis C
immunosuppression
plasmapheresis
Dabigatran - mechanism of action, excretion, reversal
Direct thrombin inhibitor
Majority Renal
Idarucizumab
Rivaroxaban - mechanism of action, excretion, reversal
Direct factor Xa inhibtor
Majority liver
Andexanet alfa
Apixiban - mechanism of action, excretion, reversal
Direct factor Xa inhibitor
Majority feacal
Andexanet alfa*
Apixiban - mechanism of action, excretion, reversal
Direct factor Xa inhibitor
Majority feacal
Andexanet alfa*
Edoxaban - mechanism of action, excretion, reversal
Direct factor Xa inhibitor
Majority feacal
None
Prothrombin time - prolonged
APTT - normal
Bleeding time - normal
Platelet count - normal
Warfarin administration
Prothrombin time - Normal
APTT - Normal
Bleeding time - Prolonged
Platelet count - Normal
Aspirin administration?-
Prothrombin time Normal (/prolonged)
APTT Prolonged
Bleeding time Normal
Platelet count Normal
Heparin
Prothrombin time Prolonged
APTT Prolonged
Bleeding time Prolonged
Platelet count Normal
DIC
Typical blood picture in DIC
↓ platelets
↓ fibrinogen
↑ PT & APTT
↑ fibrinogen degradation products
schistocytes due to microangiopathic haemolytic anaemia
Causes of DIC
sepsis
trauma
obstetric complications e.g. aminiotic fluid embolism or hemolysis, elevated liver function tests, and low platelets (HELLP syndrome)
malignancy
How does the process of coagulation and fibrinolysis differ from homeostatic conditions in DIC?
Under homeostatic conditions:
- Coagulation and fibrinolysis are coupled.
- The activation of the coagulation cascade yields thrombin that converts fibrinogen to fibrin; the stable fibrin clot being the final product of hemostasis.
- The fibrinolytic system breaks down fibrinogen and fibrin. Activation of the fibrinolytic system generates plasmin (in the presence of thrombin), which is responsible for the lysis of fibrin clots.
- The breakdown of fibrinogen and fibrin results in - polypeptides (fibrin degradation products).
- In a state of homeostasis, the presence of plasmin is critical, as it is the central proteolytic enzyme of coagulation and is also necessary for fibrinolysis.
In DIC:
- processes of coagulation and fibrinolysis are dysregulated, and the result is widespread clotting with resultant bleeding.
- Regardless of the triggering event of DIC, once initiated, the pathophysiology of DIC is similar in all conditions.
- One critical mediator of DIC is the release of a transmembrane glycoprotein (tissue factor =TF).
- TF is present on the surface of many cell types (including endothelial cells, macrophages, and monocytes) and is not normally in contact with the general circulation, but is exposed to the circulation after vascular damage.
For example, TF is released in response to exposure to cytokines (particularly interleukin 1), tumour necrosis factor, and endotoxin. - This plays a major role in the development of DIC in septic conditions.
- TF is also abundant in tissues of the lungs, brain, and placenta. This helps to explain why DIC readily develops in patients with extensive trauma.
- Upon activation, TF binds with coagulation factors that then triggers the extrinsic pathway (via Factor VII) which subsequently triggers the intrinsic pathway (XII to XI to IX) of coagulation.
What is the most common inherited thrombophilia?
Factor V Leiden (activated protein C resistance) is the most common inherited thrombophilia, being present in around 5% of the UK population.
What is the abnormality in factor V Leiden (activated protein C resistance)
It is due to a gain of function mutation in the Factor V Leiden protein.
The result of the mis-sense mutation is that activated factor V (a clotting factor) is inactivated 10 times more slowly by activated protein C than normal.
Factor V Leiden heterozygous is more common than homozygous, whereas homzygous carries a bigger risk of VTE
What inherited thrombophilia carries the highest risk of VTE?
Antithrombin III deficiency
What is Fanconi anemia?
Autosomal recessive inherited anemia.
Features
haematological:
aplastic anaemia
increased risk of acute myeloid leukaemia
neurological
skeletal abnormalities:
short stature
thumb/radius abnormalities
cafe au lait spots
G6PD DEFICIENCEY PATHOPHYSIOLOGY
G6PD is the first step in the pentose phosphate pathway, which converts glucose-6-phosphate→ 6-phosphogluconolactone
this reaction also results in nicotinamide adenine dinucleotide phosphate (NADP) → NADPH
i.e. glucose-6-phosphate + NADP → 6-phosphogluconolactone + NADPH
NADPH is important for converting oxidizied glutathine back to it’s reduced form
reduced glutathine protects red blood cells from oxidative damage by oxidants such as superoxide anion (O2-) and hydrogen peroxide
↓ G6PD → ↓ reduced NADPH → ↓ reduced glutathione → increased red cell susceptibility to oxidative stress
G6PD DEFICIENCY VS HEREDITARY SPHEROCYTOSIS
What are granulocyte-colony stimulating factors?
Recombinant human granulocyte-colony stimulating factors are used to increase neutrophil counts in patients who are neutropenic secondary to chemotherapy or other factors.
Examples include:
filgrastim
perfilgrastim
Common translocations associated with haematological malignancies
t(9;22) - Philadelphia chromosome
t(15;17)
t(8;14)
t(11;14)
t(14;18)
t(9;22) - Philadelphia chromosome - haematological malignancy associations
present in > 95% of patients with CML
this results in part of the Abelson proto-oncogene being moved to the BCR gene on chromosome 22
the resulting BCR-ABL gene codes for a fusion protein which has tyrosine kinase activity in excess of normal
poor prognostic indicator in ALL
t(15,17) - haematological malignancy associations
seen in acute promyelocytic leukaemia (M3)
fusion of PML and RAR-alpha genes
t(18,14) - haematological malignancy associations
seen in Burkitt’s lymphoma
MYC oncogene is translocated to an immunoglobulin gene
t(11,14) - haematological malignancy associations
Mantle cell lymphoma
deregulation of the cyclin D1 (BCL-1) gene
t(14,18) - Philadelphia chromosome - haematological malignancy associations
follicular lymphoma
increased BCL-2 transcription
What infections are associated with haematological mallignancies?
Viruses
EBV: Hodgkin’s and Burkitt’s lymphoma, nasopharyngeal carcinoma
HTLV-1: Adult T-cell leukaemia/lymphoma
HIV-1: High-grade B-cell lymphoma
Bacteria
Helicobacter pylori: gastric lymphoma (MALT)
Protozoa
malaria: Burkitt’s lymphoma
Indications of intravascular haemolysis (as opposed for extra-vascular)?
In 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
Causes of intravascular haemolysis?
mismatched blood transfusion
G6PD deficiency*
red cell fragmentation: heart valves, TTP, DIC, HUS
paroxysmal nocturnal haemoglobinuria
cold autoimmune haemolytic anaemia
Causes of extravascular haemolysis?
haemoglobinopathies: sickle cell, thalassaemia
hereditary spherocytosis
haemolytic disease of newborn
warm autoimmune haemolytic anaemia
What is hereditary angiodema and what is the abnormality?
Hereditary angioedema (HAE) is an autosomal dominant condition associated with low plasma levels of the C1 inhibitor (C1-INH, C1 esterase inhibitor) protein.
C1-INH is a multifunctional serine protease inhibitor - the probable mechanism behind attacks is uncontrolled release of bradykinin resulting in oedema of tissues.
Features of hereditary angiodema?
Investigation
C1-INH level is low during an attack
low C2 and C4 levels are seen, even between attacks. Serum C4 is the most reliable and widely used screening tool
Symptoms
attacks may be proceeded by painful macular rash
painless, non-pruritic swelling of subcutaneous/submucosal tissues
may affect upper airways, skin or abdominal organs (can occasionally present as abdominal pain due to visceral oedema)
urticaria is not usually a feature
How is hereditary angioedema managed?
acute
HAE does not respond to adrenaline, antihistamines, or glucocorticoids
IV C1-inhibitor concentrate, fresh frozen plasma (FFP) if this is not available
prophylaxis: anabolic steroid Danazol may help
Management of hereditary spherocytosis?
acute haemolytic crisis:
treatment is generally supportive
transfusion if necessary
longer term treatment:
folate replacement
splenectomy
What are the subtypes of HL?
Nodular sclerosing
Mixed cellularity
Lymphocyte predominant
Lymphocyte depleted
What is the most common type of HL?
Nodular sclerosing
Which type of HL has the best prognosis?
Lymphocyte predominant
Which type of HL has the worst prognosis?
Lymphocyte depleted
Which type of HL is more common in women and associated with lacunar cells?
Nodular sclerosing
Indicators of poor prognosis in HL?
Lymphocyte depleted subtype
‘B’ symptoms also imply a poor prognosis
weight loss > 10% in last 6 months
fever > 38ºC
night sweats
age > 45 years
stage IV disease
haemoglobin < 10.5 g/dl
lymphocyte count < 600/µl or < 8%
male
albumin < 40 g/l
white blood count > 15,000/µl
Most common lymphadenopathy in HL?
most commonly in the neck (cervical/supraclavicular) > axillary > inguinal
What is alcohol-induced lymph node pain characteristic of?
alcohol-induced lymph node pain is characteristic of Hodgkin’s lymphoma but is seen in less than 10% of patients
What might you expect to see on investigations for HL?
normocytic anaemia
- may be multifactorial e.g. hypersplenism, bone marrow replacement by HL, Coombs-positive haemolytic anaemia etc
eosinophilia
- caused by the production of cytokines e.g. IL-5
LDH raised
lymph node biopsy:
Reed-Sternberg cells are diagnostic: these are large cells that are either multinucleated or have a bilobed nucleus with prominent eosinophilic inclusion-like nucleoli (thus giving an ‘owl’s eye’ appearance)
How is lymphoma staging subdivided?
A = no systemic symptoms other than pruritus
B = weight loss > 10% in last 6 months, fever > 38c, night sweats (poor prognosis)
Management of HL?
chemotherapy is the mainstay of treatment. Two combinations may be used:
- ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine): considered the standard regime
- BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone): alternative regime with better remission rates but higher toxicity
radiotherapy
combined modality therapy (CMT)
chemotherapy followed by radiotherapy
hematopoietic cell transplantation
- may be used for relapsed or refractory classic Hodgkin lymphoma
Potnetial complications of HL treatment?
most patients now achieve long-term survival free of Hodgkin’s lymphoma with modern therapy
complications of treatment are therefore more of an issue for these patients:
- secondary malignancies are a risk, in particular - solid tumours: breast and lung
Causes and features of hyposplenism?
Causes
splenectomy
sickle-cell
coeliac disease, dermatitis herpetiformis
Graves’ disease
systemic lupus erythematosus
amyloid
Features
Howell-Jolly bodies
siderocytes
What is ITP, and how does it differ in adults compared to in children?
Immune (or idiopathic) thrombocytopenic purpura (ITP) is an immune-mediated reduction in the platelet count. Antibodies are directed against the glycoprotein IIb/IIIa or Ib-V-IX complex.
Children with ITP usually have an acute thrombocytopenia that may follow infection or vaccination. In contrast, adults tend to have a more chronic condition.
Features of ITP in adults
Presentation
may be detected incidentally following routine bloods
symptomatic patients may present with
petechiae, purpura
bleeding (e.g. epistaxis)
catastrophic bleeding (e.g. intracranial) is not a common presentation
Investigations
full blood count: isolated thrombocytopenia
blood film
a bone marrow examination is no longer used routinely, shows megakaryocytes in the marrow. This should be carried out prior to the commencement of steroids in order to rule out leukaemia
antiplatelet antibody testing has poor sensitivity and doesn’t affect clinical management so is not commonly done, but will usually show IgG antibodies
What is Evan’s syndrome?
ITP in association with autoimmune haemolytic anaemia (AIHA)
ITP management?
first-line treatment for ITP is oral prednisolone
pooled normal human immunoglobulin (IVIG) may also be used
- it raises the platelet count quicker than steroids, therefore may be used if active bleeding or an urgent invasive procedure is required
splenectomy is now less commonly used, indicated when if platelets < 30 after 3 months of steroid therapy
immunosuppressive drugs e.g. cyclophosphamide
What type of anemia iron deficiency
hypochromic microcytic anaemia
Blood film in iron def. anemia?
Blood film anisopoikilocytosis (red blood cells of different sizes and shapes) , target cells, ‘pencil’ poikilocytes
Haematinics in iron def. anaemia?
Serum ferritin this will likely be low, as serum ferritin correlates with iron stores. However, it is important to recognise that ferritin can be raised during states of inflammation; so a raised ferritin does not necessarily rule out iron deficiency anaemia if the is co-occurring inflammation. For patients with co-occurring inflammatory disease, other iron studies can be performed.
Total iron-binding capacity (TIBC)/transferrin this will be high. A high TIBC reflects low iron stores. . Note that the transferrin saturation will however be low
What Hb warrants a 2ww referral to gastrwoenterologist?
Post-menopausal women with a haemoglobin level ≤10 and men with a haemoglobin level ≤11 should be referred to a gastroenterologist within 2 weeks.
Iron deficiency anaemia vs. AOCD haematemics?
Haemolysis bloods?
LDH (initial + monitoring)
Bilirubin (intiial +monitoring)
Reticulocytes (initial +monitoring)
Blood film (not req. for monitoring)
Haptoglobin (not req. for monitoring)
Direct antiglobulin test (direct coombes) (not req. for monitoring)
What is indicated for platelets <100
Platelet infusion
What is indicated for INR >2.5
Vit K + prothrombin complex concentrate
What is indicated for fibrinogen <1.0g/l
Cryoprecipitate
