Haem Flashcards
What drug should be given urgently to a patient on LMWH therapy who has significant, life threatening bleeding?
Protamine sulfate
Heparin works by increasing the action of antithrombin III.
Antithrombin III inactivates thrombin and factors IX, X and XI.
There are two main types in clinical practice - low molecular weight heparin - LMWH- (does not require monitoring) and unfractionated heparin (requires APTT monitoring).
Heparins predominantly affects the intrinsic pathway of clotting. Heparins
In severe bleeding an antidote, protamine sulfate, may be given. It doesn’t completely reverse LMWH, however.
What molecule, secreted by the liver, inhibits iron absorption from the gut by inhibiting transferrin?
Hepcidin
A recently immigrated 5 year old girl is seen in secondary care after concerns from her GP about an undiagnosed congenital condition.
She is short (below 5% percentile for age), has malformed fingers and flat, pigmented birthmarks all over her body.
Blood tests show a pancytopenia.
What is the likely diagnosis?
Fanconi anaemia
Fanconi anaemia is the most common type of inherited primary bone marrow failure. It presents between the ages of 5-9 with skeletal abnormalities (abnormal thumbs), short stature, cafe au lait spots and pancytopenia.
The disease is due to dysfunctioning DNA repair genes such as FANCA.
There is a high risk of developing acute myeloid leukaemia, approximately 10% of patients diagnosed with fanconi anaemia will develop this. 30% will develop some myelodysplastic syndrome.
Please note this is different to Fanconi syndrome, which is a renal disease
Which cell type has a giant nucleus taking up most of the cell?
Lymphocyte
How to differentiate leukocytes on a peripheral blood smear - look at the nucleus, size and granules.
Neutrophil
Very common. 3x larger than erythrocytes. Multisegmented nucleus (2-5 lobes). Nucleus looks “speckly”/ isn’t solidly stained because chromatin is condensed.
Monocyte
Relatively common. >3x larger than erythrocytes. Large, kidney bean shaped nucleus.
Basophil
Rare. 3x large than erythrocytes. Deep blue (basic) granules. Bilobed nucleus
Eosinophil
Rare. 3x larger than erythrocytes. Reddish purple (acidic) granules. Bilobed nucleus
Lymphocyte
About the same size as erythrocytes (so, small). Giant nucleus taking up most of the cell. No granules. Nucleus is not kidney shaped.
What score is used to aid clinical decision making with respect to DVT risk?
Well’s Score
The Well’s score (two versions exist - one for DVT and one for PE) allows a physician to classify the risk of DVT/PE.
It uses factors such as active cancer, mobility status etc. and produces a numerical value which guides further treatment
What dysfunctional gene is common to myelofibrosis, essential thrombocytosis and polycythaemia rubra vera?
JAK2
Which cofactor is required for synthesis of the anticoagulant proteins C and S?
Vitamin K
Vitamin K dependent clotting factors
The vitamin K dependent clotting factors are factors 2, 7, 9 and 10. In addition, the anticoagulants protein C and S also rely on vitamin K.
Warfarin inhibits the enzyme Vitamin K epoxide and prevents recycling of vitamin K - leading to a net reduction in levels of vitamin K dependent clotting factors.
If initiating warfarin treatment, for the first few days there is a PRO-coagulant effect. This is due to the different half lifes of the anticoagulants protein C + S relative to the clotting factors. Protein C and S have a shorter half life, so these anticoagulant proteins disappear - leaving normal levels of the other clotting factors. This means there is a net procoagulant effect.
Typically, people are bridged with low molecular weight heparin for the first few days of warfarin treatment.
What is the term given to describe spherical erythrocytes which may be congenital or due to autoimmune haemolytic anaemia?
Spherocyte
What protein is typically defective in hereditary elliptocytosis?
Spectrin
What drug inhibits the fusion protein BCR-ABL and is used in the treatment of Chronic Myeloid Leukaemia?
Imatinib
Chronic Myeloid Leukaemia (CML)
CML is the overlap point between full blown leukaemias and the other myeloproliferative diseases.
The median age of diagnosis is around 50 years old.
Often, CML is diagnosed incidentally. Classically it causes massive splenomegaly due to splenic infiltration of myeloid cells.
A white cell count will show an elevated neutrophil count. If CML is suspected, genetic testing for the philadelphia chromosome (9;22 translocation) or the BCR-ABL fusion gene should be performed.
A rationally designed small molecule inhibitor, imatinib (when BCR-ABL is present) can induce remission in nearly every case in the chronic phase of the disease.
What are inclusions of denatured haemoglobin within erythrocytes commonly called when seen in a peripheral blood film?
Heinz bodies
What blood film finding may be found in multiple myeloma and is reflective of a paraproteinaemia?
Rouleaux
Multiple Myeloma is a malignancy of plasma cells.
It is differentiated from the related conditions MGUS and Smouldering Myeloma by the presence of end organ damage, the so called “CRAB” symptoms. Calcium (elevated), Renal failure, Anaemia and Bone lesions. MGUS has <10% plasma cells in the bone marrow on biopsy, where as SM and multiple myeloma have >10%.
Most commonly, the plasma cells will produce large amount of defective immunoglobulins - mostly IgG (less commonly IgA). These may be detected by serum electrophoresis - producing a graph of the molecular weights of proteins in the blood. There will be a large, single, spike. Urinary bence jones proteins are also used in the diagnosis of MM - these are the light chains of immunoglobulins which may be secreted in urine - but not always.
Other diagnostic factors include: an elevated ESR and rouleaux formation on a blood film (both due to the increased protein [immunoglobulin] concentration in the blood).
What condition is stereotypically associated with a “dry tap” on bone marrow biopsy?
Myelofibrosis
A 1 month old child is investigated for the cause of a macrocytic anaemia, identified during routine workup for surgery for treatment of her cleft palate. She is noted to be quite underweight. Her brother has suffered from similar issues.
Vitamin B12 and folate levels were normal. Haemoglobin electrophoresis showed elevated fetal haemoglobin, but no other abnormalities. Her reticulocyte count was low.
What is the most likely underlying diagnosis?
Diamond-Blackfan anaemia
Diamond-Blackfan anaemia is a congenital disorder affecting haematological stem cells.
Typically, only red blood cells are affected rather than other blood cell lineages.
Symptoms are usually detected in infancy and diagnosis is made off the results of blood tests (showing anaemia, low reticulocytes and elevated fetal haemoglobin). A bone marrow biopsy would also reveal decreased erythroid precursors.
Other features which may be present include craniofacial malformations, such as cleft palate or cardiac defects.
Please note, this syndrome is different from Shwachman-Diamond syndrome, which predominantly affects neutrophils.
What is the classical finding on a full blood count for a patient suspected of dyskeratosis congenita?
Pancytopenia
To differentiate the commonest primary bone marrow failures on blood film, here is a helpful table:
Fanconi anaemia Pancytopenia Most common
Diamond-Blackfan anaemia Red cells only
Shwachman-Diamond syndrome Neutropenia
Dyskeratosis congenita Pancytopenia
A patient has a normocytic anaemia, an elevated unconjugated bilirubin, elevated LDH and low haptoglobin.
A peripheral blood film reveals spherocytes. Direct Coomb’s test is negative.
What investigation will confirm the diagnosis?
Eosin-5-maleimide test
What is the collective term for the following collection of symptoms:
Drenching Night Sweats Fever Weight loss
B symptoms
Hodgkin’s Lymphoma (HL) [20% of lymphomas]
Typically occurs in two groups of people - young adults and elderly patients. Men are disproportionately affected.
A key precipitating factor is prior infection with Epstein Barr Virus (EBV). Malignant cells are predominantly mature B cells from a lymph node’s germinal centre. It is staged using the Ann-Arbor system.
Often, it is symptomless until the development of “B” symptoms - fever, drenching night sweats and weight loss. There will be asymmetrical lymphadenopathy, usually in the neck. Classically, there is lymph node pain after alcohol - though this is very rare. There is also the risk of developing SVC syndrome if left untreated.
For diagnosis, clinical suspicion and CT-PET followed by lymph node biopsy is used. A blood film may show the presence of Reed-Sternberg cells.
There are multiple subtypes of HL, the most common of which is the nodular sclerosing subtype (good prognosis).
A 6 year old boy is seen by his GP.
His dentist said that he should have his blood tested.
At his most recent dentist appointment, gentle manipulation of the patient’s gums caused bleeding disproportionate to the injury and took a long time to stop.
Blood tests arranged by the GP show a normal INR, prolonged APTT, normal PT, normal number of platelets, normal factor IX but low Factor VIII. Bleeding time is prolonged.
What is the diagnosis?
Von Willebrand’s Disease
Von Willebrand’s Disease
Von Willebrand’s disease is a disorder of platelet function caused by a reduction in function or number of Von Willebrand Factor (vWF). Normally, vWF is responsible for binding to other proteins, notably factor VIII, collagen and platelets directly. By binding these three things together, it stabilises the platelet plug and increases the strength of the initial platelet plug in primary haemostasis.
Factor VIII is normally bound to vWF in circulation. If vWF is not present, then Factor VIII is rapidly degraded. Hence, Von Willebrand’s disease will also decrease the function of the intrinsic clotting pathway due to reduced levels of Factor VIII.
Most Von Willebrand’s disease is mild and many people do not realise they have it. If they are symptomatic, then usually it will present as easy bruising and nosebleeds. Women may experience heavy periods.
Blood tests will reveal a prolonged bleeding time (as this measures platelet function directly) and a prolonged APTT (due to increased degradation of Factor VIII).
Platelet count, PT and INR will be normal. Haemophillia does not affect the bleeding time
Levels of vWF may be normal OR low - depending if the issue is with the function of vWF or if the issue is with a lack of production of vWF
A bone marrow biopsy for a patient suspected of having multiple myeloma shows 15% clonal plasma cells in the bone marrow. She does not have any symptoms of end organ damage.
What is the diagnosis?
Smouldering Multiple Myeloma
Multiple Myeloma is a malignancy of plasma cells.
It is differentiated from the related conditions MGUS and Smouldering Myeloma by the presence of end organ damage, the so called “CRAB” symptoms. Calcium (elevated), Renal failure, Anaemia and Bone lesions. MGUS has <10% plasma cells in the bone marrow on biopsy, where as SM and multiple myeloma have >10%.
Most commonly, the plasma cells will produce large amount of defective immunoglobulins - mostly IgG (less commonly IgA). These may be detected by serum electrophoresis - producing a graph of the molecular weights of proteins in the blood. There will be a large, single, spike. Urinary bence jones proteins are also used in the diagnosis of MM - these are the light chains of immunoglobulins which may be secreted in urine - but not always.
Other diagnostic factors include: an elevated ESR and rouleaux formation on a blood film (both due to the increased protein [immunoglobulin] concentration in the blood).
What stereotypical description relating to erythrocytes can be seen on a blood film with a patient with myelofibrosis?
Dacrocyte
A long term alcoholic presents to their GP for a review.
The doctor orders a panel of blood tests.
A FBC reveals a normocytic anaemia.
The results of Iron Studies are below. Serum iron Elevated Total Iron Binding Capacity (TIBC) Normal Ferritin Elevated C Reactive Protein 3 (NR 2-8)
A blood film is ordered and reveals the presence of immature red blood cells with inclusions of iron deposits in a ring formation.
What type of anaemia does this patient have?
Sideroblastic anaemia
A 71 year old woman is seen by her GP due to progressive tiredness. She also thinks she has been losing weight.
On examination, there was cervical lymphadenopathy.
A full blood count showed a low haemoglobin and an elevated white cell count, predominantly lymphocytes.
A blood film was performed and did not show any immature cells.
What is the likely diagnosis?
Chronic Lymphocytic Leukaemia
Chronic Lymphocyte Leukaemia (CLL)
CLL is a slow lymphoproliferative disease, typically presenting in elderly men. Often asymptomatic and only detected incidentally on blood tests.
Symptoms include Bone Marrow Failure (anaemia, thrombocytopenia and neutropenia) in the end stages, however typically the only symptoms will be generalised lymphadenopathy with weight loss, fever and night sweats.
Richter’s transformation may occur, where a low-grade CLL converts to a high grade, aggressive Diffuse Large B Cell Lymphoma.
Blood tests will show a high WCC with elevated (mature) lymphocytes. A blood film may show smudge cells.
Watchful waiting is usually the management of choice for early-moderate disease. Ibrutinib (a tyrosine kinase inhibitor) may be used for advanced or symptomatic cases.
A 3 year old child is seen by her GP.
Her mother has been concerned about her gums bleeding often recently. She has also been suffering from nosebleeds and her mother says that she is not acting her normal self.
The GP sends off a panel of bloods including full blood count and a clotting screen.
The full blood count revealed an elevated white cell count (predominantly lymphocytes) and low platelets 76 (NR: 150 - 450). A blood film showed the presence of blast cells.
A clotting screen was normal, however bleeding time was prolonged.
What is the diagnosis?
Acute Lymphoblastic Leukaemia
Acute Lymphoblastic Leukaemia (ALL)
ALL mainly affects children - aide memoire: “ALL children get sick”
Symptoms are similar to AML - Bone Marrow Failure (Anaemia, Thrombocytopenia and Neutropenia) with organ infiltration are common.
ALL has a preponderance to cause generalised lymphadenopathy and often has CNS involvement. CNS involvement is a bad prognostic factor.
A white cell count will show an elevated white cell count, mainly blasts, with a large number of lymphocytes. Immunostaining techniques can be used to further identify the subset of lymphocytes involved.
Treatment is with chemotherapy or stem cell transplanation. There is a high risk of developing tumour lysis syndrome while undergoing chemotherapy.
What are inclusions of clusters of nuclear DNA within erythrocytes commonly called when seen in a peripheral blood film?
This finding is often associated with Sickle Cell Disease in adults.
Howell-Jolly bodies
A doctor suspects that their patient may be anaemic.
The doctor orders a panel of blood tests.
A FBC reveals a microcytic anaemia.
The results of Iron Studies are below.
Serum iron Low
Total Iron Binding Capacity (TIBC) Elevated
Ferritin Low
C Reactive Protein 3 (NR 2-8)
What is the cause of this patient’s microcytic anaemia?
Iron Deficiency Anaemia
What blood test is a measure of fibrin degredation products and may reflect activity of the body’s anticoagulant system?
D Dimer
D Dimer is a measure of fibrin degradation products and hence is a proxy measure of how much “clot” is being broken down by the body.
It is not a very specific measure - it may be elevated for a large number of reasons that aren’t necessarily related to clotting. However, severely elevated levels (>1000) in the context of a patient with a clotting abnormality are suggestive of clot breakdown.
Examples of conditions with elevated D dimers include PEs, DVTs and DIC.
What abnormality is commonly seen on a full blood count of patients with fanconi anaemia?
Pancytopenia
To differentiate the commonest primary bone marrow failures on blood film, here is a helpful table: Fanconi anaemia Pancytopenia Most common Diamond-Blackfan anaemia Red cells only Shwachman-Diamond syndrome Neutropenia Dyskeratosis congenita Pancytopenia
An 18 year old presents to their GP with a neck lump.
It is approximately 3.5cm, mobile and untethered in the posterior triangle of the neck.
On further questioning, he reports weight loss and drenching night sweats.
A blood film showed the presence of multinucleated and reactive lymphocytes.
What is the most likely diagnosis?
Hodgkin’s Lymphoma
Hodgkin’s Lymphoma (HL) [20% of lymphomas]
Typically occurs in two groups of people - young adults and elderly patients. Men are disproportionately affected.
A key precipitating factor is prior infection with Epstein Barr Virus (EBV). Malignant cells are predominantly mature B cells from a lymph node’s germinal centre. It is staged using the Ann-Arbor system.
Often, it is symptomless until the development of “B” symptoms - fever, drenching night sweats and weight loss. There will be asymmetrical lymphadenopathy, usually in the neck. Classically, there is lymph node pain after alcohol - though this is very rare. There is also the risk of developing SVC syndrome if left untreated.
For diagnosis, clinical suspicion and CT-PET followed by lymph node biopsy is used. A blood film may show the presence of Reed-Sternberg cells.
There are multiple subtypes of HL, the most common of which is the nodular sclerosing subtype (good prognosis).
What first line small molecule inhibitor is used in the treatment of chronic lymphocytic leukaemia?
Ibrutinib
Chronic Lymphocyte Leukaemia (CLL)
CLL is a slow lymphoproliferative disease, typically presenting in elderly men. Often asymptomatic and only detected incidentally on blood tests.
Symptoms include Bone Marrow Failure (anaemia, thrombocytopenia and neutropenia) in the end stages, however typically the only symptoms will be generalised lymphadenopathy with weight loss, fever and night sweats.
Richter’s transformation may occur, where a low-grade CLL converts to a high grade, aggressive Diffuse Large B Cell Lymphoma.
Blood tests will show a high WCC with elevated (mature) lymphocytes. A blood film may show smudge cells.
Watchful waiting is usually the management of choice for early-moderate disease. Ibrutinib (a tyrosine kinase inhibitor) may be used for advanced or symptomatic cases.
What is the term given to the blood film finding of erythrocytes stacked on top of each other?
Rouleaux Formation
What blood test is used clinically to measure the activity of the extrinsic and common clotting pathways?
Prothrombin Time
Intrinsic and Extrinsic Pathways of the Clotting Cascade
The clotting cascade fundamentally exists to turn a small action into a larger action. There are two main pathways - the intrinsic and extrinsic, which converge and join the common pathway.
Fun fact: The “a” after clotting factors e.g. Xa stands for “activated”.
The intrinsic pathway starts when the vascular endothelium is disrupted, exposing collagen. This exposed collagen then sets off a chain reaction resulting in factor X being converted to Xa. Intrinsic pathway = the injury pathway. The activity of this pathway is measured clinically using the APPT.
The extrinsic pathway is much more sensitive. Heat, trauma, sepsi, chemicals and many other stimuli can begin this part of the clotting cascade. Extrinsic pathway = the “everything else” pathway. The activity of this pathway is measured clinically using the PT.
Both pathways need calcium (factor IV) in order for clotting to occur.
Both pathways then converge at the common pathway with the production of factor Xa from Factor X.
What proteins are mutated in hereditary spherocytosis?
Spectrin
What infectious organism is associated with malignancy of germinal centre B lymphocytes?
Epstein Barr Virus
Hodgkin’s Lymphoma (HL) [20% of lymphomas]
Typically occurs in two groups of people - young adults and elderly patients. Men are disproportionately affected.
A key precipitating factor is prior infection with Epstein Barr Virus (EBV). Malignant cells are predominantly mature B cells from a lymph node’s germinal centre. It is staged using the Ann-Arbor system.
Often, it is symptomless until the development of “B” symptoms - fever, drenching night sweats and weight loss. There will be asymmetrical lymphadenopathy, usually in the neck. Classically, there is lymph node pain after alcohol - though this is very rare. There is also the risk of developing SVC syndrome if left untreated.
For diagnosis, clinical suspicion and CT-PET followed by lymph node biopsy is used. A blood film may show the presence of Reed-Sternberg cells.
There are multiple subtypes of HL, the most common of which is the nodular sclerosing subtype (good prognosis).
A 1 year old has been experiencing excessive sleepiness over the last month. She now sleeps for 18 hours a day and before that her parents noticed her becoming slower and more withdrawn.
Her parents are concerned and bring her to see her GP.
On examination, there are bruises on her wrist, arms and stomach. There is palpable splenomegaly.
The GP makes an urgent safeguarding referral.
Blood tests show a low haemoglobin and low platelets. There is an elevated white cell count, reported as neutrophils. A manual differentiation reveals the presence of an abundance of myeloid precursor cells.
What is the diagnosis?
Acute Myeloid Leukaemia
Acute Myeloid Leukaemia (AML)
AML typically affects two groups of people: adults (risk increases with age) and <2 year olds
The typical presentation is of bone marrow failure - anaemia and thrombocytopenia - in combination with organ infiltration - hepatomegaly, gum infiltration or in severe cases into the CNS. There are multiple subtypes of AML.
On a FBC, there will be a high white cell count with a preponderance of blast (immature) cells. A blood film may show the presence of neutrophils with auer rods.
Treatment is mainly chemotherapy, though stem cell transplantation is an option. Symptomatic treatment with blood products is often also needed.
Of note, the M3 subtype (acute promyelocytic leukaemia) can be treated specifically with all-trans retinoic acid.
Which haematological malignancy is most commonly associated with formation of the Philadelphia Chromosome (9;22 translocation)?
Chronic Myeloid Leukaemia
Chronic Myeloid Leukaemia (CML)
CML is the overlap point between full blown leukaemias and the other myeloproliferative diseases.
The median age of diagnosis is around 50 years old.
Often, CML is diagnosed incidentally. Classically it causes massive splenomegaly due to splenic infiltration of myeloid cells.
A white cell count will show an elevated neutrophil count. If CML is suspected, genetic testing for the philadelphia chromosome (9;22 translocation) or the BCR-ABL fusion gene should be performed.
A rationally designed small molecule inhibitor, imatinib (when BCR-ABL is present) can induce remission in nearly every case in the chronic phase of the disease.
