Module 2A - Haematology Flashcards
What are the components of plasma?
- red blood cells
- white blood cells
- platelets
- clotting factors (eg. fibrinogen)
Once clotting factors are removed from blood plasma, what is left is called the serum, what does serum contain?
- Glucose
- Electrolytes –> sodium and potassium
- Proteins –> immunoglobulins (antibodies) and hormones
Thrombopoiesis/erythropoeisis/granulopoiesis/monopoiesis
Blood cells are produced and developed in the bone marrow, this process is called haematopoiesis, draw the lineage starting with a blood stem cell (pluripotent haematopoietic stem cell).
- Thrombopoiesis: megakaryoblasts –> megakaryocytes –> platelets
- Erythropoiesis: erythroblasts –> reticulocytes –> erythrocytes –> RBCs
- Granulopoiesis: granulocytes –> basophils + eosinophils + neutrophils
- Monopoiesis: monocytes –> macrophages + dendritic cells
- B cells –> plasma cells
- NK cells = large granular lymphocyte
What are reticulocytes? and how long do red blood cells survive on average?
- reticulocytes are immature red blood cells
- 120 days (4 months)
B lympocytes (B cells) mature in the ______ ________ and differentiate into; _______ _____ and ________ ______.
T lymphocytes (T cells) mature in the ________ ______ and differentiate into; CD4 cells (T _______ cells), CD_ cells (cytotoxic T cells), and _______ ______ cells
B lymphocytes (B cells) mature in the bone marrow and differentiate into; plasma cells and memory B cells.
T lymphocytes (T cells) mature in the thymus gland and differentiate into; CD4 cells (T helper cells), CD8 cells (cytotoxic T cells), and Natural killer cells.
What are antigens? and name the most relevant antigens in blood transfusions.
- Antigens –> molecules present on the surface of red blood cells (RBCs) that can trigger an immune response if recognized as foreign by the immune system
- ABO system –> Includes A and B antigens. Blood types are A (A antigen), B (B antigen), AB (both A and B antigens), and O (no A or B antigens).
- Rh system –> Includes the D antigen. Blood can be Rh-positive (D antigen present) or Rh-negative (D antigen absent).
What are antibodies? and name the most important antibodies in the context of blood transfusions.
- Antibodies are proteins produced by the immune system that specifically recognize and bind to antigens. In the context of blood transfusions, antibodies can react against foreign blood group antigens.
- Anti-A and Anti-B Antibodies: Present in individuals who lack the corresponding antigens (e.g., a person with blood type A has anti-B antibodies).
- Anti-D Antibodies: Can be produced by Rh-negative individuals if they are exposed to Rh-positive blood.
What is the importance of anti-D in the context of blood transfusions?
- Anti-D is an antibody against the Rh(D) antigen
- Hemolytic Disease of the Newborn (HDN): If an Rh-negative mother is sensitized to Rh-positive blood (e.g., from a previous pregnancy with an Rh-positive baby), she can produce anti-D antibodies that can cross the placenta and destroy the Rh-positive red blood cells of the foetus in subsequent pregnancies.
- Transfusion Reactions: If an Rh-negative person receives Rh-positive blood, they can develop anti-D antibodies, leading to complications in future transfusions.
What is a ‘group and screen’?
A pre-transfusion test.
- Blood Grouping: Determining the ABO and Rh blood type of the patient.
- Antibody Screening: Detecting any unexpected antibodies in the patient’s plasma that could react with transfused blood.
2 types
What is ‘crossmatching’?
- Crossmatching is a compatibility test between the donor’s and recipient’s blood. It involves mixing a small sample of the recipient’s plasma with a sample of the donor’s red blood cells to check for agglutination (clumping) or hemolysis (destruction of red blood cells). There are two types:
- Immediate Spin Crossmatch: A rapid test that detects ABO incompatibility.
- Antiglobulin Crossmatch (Coombs’ test): A more detailed test that detects other antibodies that might cause transfusion reactions.
Describe the ABO blood group system
- AB: universal recipient for ABO system (but can only donate to AB)
- O: universal donor for ABO system (but can only receive from O)
What pre-transfusion (blood transfusion) tests should be done?
- Group and Screen –> Determine ABO and Rh blood type, and screen for unexpected antibodies
- Crossmatch –> Ensure compatibility between donor and recipient blood
What are the 4 blood components that can be given by transfusion?
- Red blood cells
- Platelets
- FFP (Fresh Frozen Plasma)
- Cryoprecipitate
Indications for red blood cell transfusions
- acute blood loss (to restore oxygen-carrying capacity)
- chronic anaemia and symptomatic (Hb levels need to be <70/80g/L)
Indications for platelets transfusions
- thrombocytopenia –> low platelet count
- surgical/procedural prophylaxis –> to prevent bleeding in pts with low platelet counts
- active bleeding –> when platelet count is significantly reduced and patient is actively bleeding or undergoing major surgery
Indications for FFP transfusions
- coagulopathy –> when there is bleeding and abnormal clotting tests (INR >1.5 or APTT >1.5 times normal)
- massive transfusion protocols
- liver disease –> with significant bleeding or before invasive procedures
Indications for cryoprecipitate transfusions
- Fibrinogen deficiency –> cryoprecipitae is rich in clotting factors
- Massive haemorrhage –> as part of massive transfusion protocols to maintain fibrinogen levels
- 71yr old man. pale and tired
- Hb 70g/L (130-170)
- MCV 69fl (83-101)
- Differential diagnosis?
- Next tests?
Findings: microcytic anaemia
Differentials:
- iron-deficiency anaemia
- thalassaemia
- anaemia of chronic disease
- (sideroblastic anaemia, lead poisoning)
Next tests:
- Iron studies –> serum ferritin (low in iron-deficiency anaemia), serum iron (low in iron-deficiency anaemia), Total iron-binding capacity (elevated in iron-deficiency anaemia), transferrin saturation (low in iron-deficiency anaemia)
- Peripheral blood smear
- FIT (faecal immunochemical test) –> checks for blood –> GI bleeding in men with unexplained iorn-deficiency anaemia –> cancer
- reticulocyte count –> assess bone marrow function
- Haemoglobin electrophoresis –> identify thalassaemias
- Inflammatory markers –> CRP/ESR –> anaemia of chronic disease
- 70yr old woman. Pale. Glossitis (inflammation of the tongue)
- Hb 68g/L (120-150)
- MCV 112fl (83-101)
- Differential diagnosis?
- Next tests?
Findings: macrocytic anaemia
Differentials:
- Vit B12 deficiency (often associated with glossitis)
- Folate deficiency
- alcoholism
- livre disease
- hypothyroidism
- myelodysplastic syndromes
- drugs (methotrexate, azathioprine)
Next tests:
- Vit B12 and Folate levels
- Peripheral blood smear
- Reticulocyte count (assess bone marrow response to anaemia)
- Thyroid function tests
- Liver function tests (LFTs)
- serum iron studies (to rule out concurrent iron-deficiency)
- 83yr old woman. Tiredness. PMH (RA, Type 2 DM)
- Hb 85g/L (120-150)
- MCV 89fl (83-101)
- Differential diagnosis?
- Next tests?
Findings: Normocytic anaemia
Differentials:
- anaemia of chronic disease
- acute blood loss
- chronic kidney disease (renal failure)
- Mixed B12/folate and iron deficiency
- bone marrow disorders (aplastic anaemia)
- haemolytic anaemia
Next tests:
- FBC
- Reticulocyte count (low - inadequate production, high - increased destruction or loss of RBCs)
- Iron studies (check for iron-def anaemia)
- Renal function tests
- Inflammatory markets (CRP, ESR)
- Stool occult blood test (check for GI bleeding)
- Bone marrow biopsy
- 63yr old man. Tiredness. Dark urine.
- Hb 85g/L (130-170)
- MCV 105fl (83-101)
- Differential diagnosis?
- Next tests?
Findings: macrocytic anaemia, dark urine suggests possible haemolysis or liver dysfunction
Differentials:
- Haemolytic anaemia
- Vit B12 deficiency
- Folate deficiency
- Liver disease
- alcoholism (liver damage can cause dark urine)
- Myelodysplasia
Next tests:
- FBC
- Peripheral blood smear (haemolysis)
- Reticulocyte count
- Lactate dehydrogenase (LDH)
- Bilirubin (indirect unconjugated, direct conjugated)
- Vit B12 and Folate lvls
- LFTs
- Urinalysis
- Coombs test
- G6PD assay
- Bone marrow biopsy
- 60yr old woman. Hypertension - annual review.
- Hb 120g/L (120-150)
- MCV 65fl (83-101)
- Differential diagnosis?
- Tests?
Findings: microcytic anaemia
Differentials:
- iron-deficiency anaemia
- thalassaemia
- anaemia of chronic disease
- (sideroblastic anaemia, lead poisoning)
Next tests:
- Iron studies: serum ferritin (low in iron-deficiency anaemia), serum iron (low in iron-deficiency anaemia), Total iron-binding capacity (elevated in iron-deficiency anaemia), transferrin saturation (low in iron-deficiency anaemia)
- Peripheral blood smear
- Stool occult blood test: check for GI bleeding)
- reticulocyte count (assess bone marrow function)
- Haemoglobin electrophoresis (identify thalassaemias)
- Inflammatory markers (CRP/ESR - anaemia of chronic disease)
- 26yr old newlywed. Brother has sickle cell disease
- Concerned about risk of child with sickle cell disease
- Normal FBC, no sickle cells on blood film
- Questions?
- What is the risk of having a child with sickle cell disease?
Questions:
- Any hx of sickle cell disease, or any symptoms?
- Family hx of sickle cell?
- Partner’s hx?
- Have you or your partner undergone sickle cell testing, ever had a Hb electrophoresis test?
.
Autosomal recessive:
- risk depends on sickle cell status of both parents
- both have normal Hb: no risk
- one parent has sickle cell trait: 50% risk of inheriting sickle cell trait
- both parents have sickle cell trait: 50% chance sickle cell trait and 25% chance sickle cell disease
- One parent has sickle cell disease: each child will have sickle cell trait, but none will have disease
- one parent has sickle cell disease and other has sickle cell trait: each child has 50% chance of sickle cell disease and 50% chance of sickle cell trait
- 59yr old woman with tiredness and abdominal swelling
- O/E mass in left upper quadrant. Moves on inspiration. Has a notch in it. Can’t get above it
- What is it?
- What might be causing it?
- Questions?
- Tests?
Diagnosis: Splenomegaly
Potential causes:
- Haem disorders (CLL, NHL, myelofibrosis, sickle cell disease)
- Infections (EBV, malaria, TB)
- liver cirrhosis
- Inflammatory disorders (RA, SLE, sarcoidosis)
Questions:
- PMH: hx of haem disorders, infections, autoimmune disorders?
- SH: recent travel (infection risk?), alcohol intake (liver cirrhosis)
- FH: haem disorders, autoimmune disorders
Tests:
- Bloods: FBC, LFTs, blood cultures
- Imaging: abdo ultrasound or CT scan
- bone marrow biopsy (if haem disorders suspected)
- Serology (autoimmune antibodies)
- 21yr old man. Lump in neck. O/E lymph node 1.5cm
- Differential diagnosis?
- Questions?
- Tests?
Differentials:
- Infection (reactive lymphadenopathy)
- Inflammation: autoimmune (RA, SLE), sarcoidosis
- Malignancy: lymphoma
Questions:
- Red flag symptoms (weight loss, malaise, night sweats, fatigue)
- recent travel? smoking hx
- family hx of cancer or autoimmune disorders?
Tests:
- Lymph exam
- Bloods: infection/haematoloigcal abnormalities, serology for specific infections (EBV, HIV, CMV)
- Ultrasound neck
- Lymph node biopsy
What does this histology show?
neutrophils
What does this histology show?
lymphocytes
What does this histology show?
basophil - high in CML (chronic myeloid leukaemia)
What does this histology show?
monocyte
What does this histology show?
eosinophil
Draw out the coagulation cascade
Coag cascade –> Extrinsic pathway
- Tissue factor is expressed on surface of many cells outside blood vessels –> but not on surface of circulating blood cells or endothelium
- When endothelium damaged –> tissue factor comes into contact with blood and combines with circulating factor VII to form a complex –> leads to activation of factor X –> triggering the common pathway
Coag cascade –> Common pathway
- Begins with activation of factor X to factor Xa via either extrinsic pathway or intrinsic pathway
- It is final stage of coagulation cascade –> leads to formation of thrombin and fibrin
- Factor Xa combines with factor V, platelet membrane phospholipids, and Ca2+ ions to convert prothrombin to thrombin
- Thrombin then converts fibrinogen into fibrin strands which form an important structural component of a thrombus
- In addition to the formation of fibrin, thrombin activates many parts of the coagulation cascade via a positive feedback loop through the intrinsic pathway leading to formation of large amounts of additional thrombin –> ‘thrombin burst’
Coag cascade –> Intrinsic pathway
- can be activated by surface contact, when damage to the vascular endothelium leads to exposure of clotting factors to negatively charged subendothelial surfaces –> mediated by the molecule Kallikrein
- thrombin generated from previous activation of the extrinsic pathway also activates the intrinsic pathway and there is a positive feedback loop which causes amplification of thrombin production
- This continuous cycle means that vast amounts of thrombin can be generated from a single initial stimulus and a thrombus can be formed quickly after injury to limit blood loss
Actions of thrombin
- Fibrin generation –> thrombin converts fibrinogen into fibrin
- Intrinsic pathway activation –> via positive feedback loop
- Factor XIII activation –> thrombin converts factor XIII into factor XIIIa (fibrin stabilising factor) which then cross-links fibrin to generate a ‘fibrin mesh’ which encapsulates activated platelets creating a thrombus and stopping bleeding
- Platelet activation –> thrombin receptors on platelets cause activation and aggregation, further enhancing the haemostatic effects of the coagulation cascade
- Regulation of clot formation
Regulation of the coagulation cascade –> without these the +ve feedback loop triggered by thrombin would lead to dangerous lvls of clotting in the blood
- Protein C is produced in response to thrombin binding to the receptor thrombomodulin on the vascular endothelium –> this leads to protein S activation which then breaks down factors Va and VIIIa in a negative feedback loop
- Antithrombin is a natural anticoagulant that is produced by the liver and destroys factors Xa, XIa, and thrombin
- (Heparin and fondaparinux enhance the natural effects of antithrombin in inhibiting thrombin and factor Xa) - Tissue factor pathway inhibitor is a protein that binds to and inactivates factor VIIa and factor Xa
What clotting factors does Warfarin act on
Warfarin is a vitamin K antagonist which prevents the synthesis of vitamin K-dependent clotting factors (II, VII, IX and X)
range
Which pathway does prothrombin time (PT) measure?
- PT measures the time taken for fibrin to form via the extrinsic pathway
- normal range –> 9-12 seconds
Causes of a prolonged PT
- Disseminated intravascular coagulation (DIC)
- Vitamin K deficiency –> Factor VII is the vitamin K dependent clotting factor with the shortest half-life
- Chronic liver disease
INR –> what is it?
- a ratio of the patient’s PT compared to a normal PT
- The INR is used to monitor the levels of anticoagulation in patients on Warfarin and adjust the dosage as necessary
normal range
Which pathway does (activated thromboplastin time) APTT measure?
- APTT measures the time taken for fibrin to form via the intrinsic pathway
- normal range is 23-38 secs
Causes of a prolonged APTT
- Disseminated intravascular coagulation (DIC)
- Clotting factor deficiencies (e.g. haemophilia A or B)
- Von Willebrand’s disease
3 conditions that cause dysfunction of the coag cascade
- Haemophilia –> a congenital deficiency in either factor VIII (haemophilia A), factor IX (haemophilia B) or factor XI (haemophilia C) –> leading to defective clotting and therefore a tendency to bleed
- Chronic liver disease –> can lead to defective coagulation as many coagulation factors are depleted as the liver’s synthetic function is impaired
- Factor V Leiden –> a common genetic mutation to the gene coding for Factor V –> it increases the resistance of factor V to activated protein C making it more difficult to break down and therefore leading to an increased tendency to clot
Haemostasis and the clotting cascade –> why vitamin K and calcium are important –> video
Dr Matt and Dr Mike video:
https://www.youtube.com/watch?v=8FTuOjO7j-s
Causes of microcytic anaemia –> MCV < 80
T – Thalassaemia
A – Anaemia of chronic disease
I – Iron deficiency anaemia
L – Lead poisoning
S – Sideroblastic anaemia
Causes of normocytic anaemia –> MCV 80-100
A - Acute blood loss
A - Anaemia of chronic disease
A - Aplastic anaemia
H - Haemolytic anaemia
H - Hypothyroidism
R - Renal failure –> reduced EPO production –> low RBCs
Causes of macrocytic anaemia –> MCV > 100
- B12 and folate deficiency –> vegan diet ?
- Reticulocytosis
- Hypothyroidism
- Liver disease
- Drugs –> azathioprine and meds that reduce B12 absorption (PPIs and metformin) + alcohol
Symptoms/signs of anaemia + specific signs of iron-deficiency anaemia
- Symptoms –> tiredness, SOB, headaches, dizziness, palpitations, worsening of other conditions
- Iron-def –> Pica, hair loss
- Signs –> pale skin, conjunctival pallor, tachycardia, raised resp. rate
If there is unexplained iron-deficiency anaemia –> what should you investigate next?
- Faecal Immunochemical Test (FIT) –> check for blood before colonoscopy
- Colonoscopy –> GI cancer as a source of bleeding
If there is unexplained anaemia –> next step?
Bone marrow biopsy –> malignancy?
Iron deficiency anaemia –> causes
- Dietary iron –> red meat, fortified cereals
- Malabsorption of iron –> coeliac disease
- Pregnancy –> increased iron requirements
- Blood loss –> heavy menstruation? peptic ulcer or bowel cancer?
Iron deficiency anaemia –> management
- Oral iron –> ferrous sulphate or ferrous fumarate
- Vitamin C can be given –> helps iorn absorption
- Iron transfusion or blood transfusion (severe anaemia)
Common side effects of oral iron
Constipation and black stools
Pernicious anaemia –> what is it?
autoimmune condition –> involves antibodies against parietal cells or intrinsic factor –> resulting in a lack of absorption of vitamin B12
Vitamin B12 deficiency symptoms
- Neurological symptoms –> peripheral neuropathy (numbness, paraesthesia) …
- Glossitis –> ‘beefy red tongue’
Autoantibodies used to diagnose pernicious anaemia
Intrinsic factor antibodies
Management of vit B12 deficiency
IM hydroxocobalamin:
- No neurological symptoms –> 3 times weekly for two weeks
- Neurological symptoms –> alternate days until there is no further improvement in symptoms
- Pernicious anaemia –> injections for life every 2/3 months
In B12 and folate deficiency –> which do you treat first?
- Treat B12 deficiency first –> giving folic acid when they have a B12 deficiency can lead to subacute combined degeneration of the cord
Symptoms of haemolytic anaemia –> premature destruction of RBCs
- Anaemia symptoms
- Splenomegaly –> spleen becomes filled with destroyed RBCs –> spleen acts like a mesh –> if RBC abnormal shape then won’t fit through and gets destroyed, cells get broken down and recycled here too
- Jaundice –> unconjugated bilirubin is released during destruction of RBCs
FBC, blood film, direct Coombs test
Investigation findings in haemolytic anaemia
- FBC –> normocytic anaemia, raised reticulocytes
- Blood film –> schistocytes (fragments of red blood cells)
- Direct Coombs test –> positive in autoimmune haemolytic anaemia (not in other types)
Hereditary spherocytosis is the most common inherited haemolytic anaemia –> what inheritance pattern
Autosomal dominant
Chronic haemolytic anaemia –> causes?
- Hereditary spherocytosis
- Thalassaemia
- Sickle cell anaemia
- G6PD deficiency
- (Hereditary elliptocytosis)
Symptoms of hereditary spherocytosis
- Anaemia, jaundice, gallstones
- Splenomegaly –> due to fragile sphere-shaped RBCs that easily break down when passing through spleen –> cause blockage
- Aplastic crisis in the presence of parvovirus
G6PD deficiency –> what is it + inheritance pattern
- caused by a defect in the gene coding for glucose-6-phosphate dehydrogenase (G6PD) –> an enzyme responsible for protecting the cells from oxidative damage
- X-linked recessive
triggers, symptoms, blood film
Consequences of G6PD deficiency
- Results in acute episodes of haemolytic anaemia –> triggered by infection, drugs, or fava beans
- (triggering meds –> ciprofloxacin, sulfasalazine, and anti-malarials)
- Results in neonatal jaundice, gallstones, anaemia, splenomegaly
- Blood film –> Heinz bodies
G6PD deficiency –> blood film finding + diagnosis
- Heinz bodies on blood film
- G6PD enzyme assay –> diagnosis
For management think what drugs would suppress the immune system
Autoimmune haemolytic anaemia –> what is it + types (+ aetiology) + management
- Occurs when antibodies are created against the patient’s own RBCs –> leads to haemolysis
- Warm (more common) –> haemolysis occurs at normal/above normal temp. –> usually idiopathic
- Cold –> haemolysis occurs at lower temps –> can be secondary to lymphoma, leukaemia, SLE, and infections
Management:
- Blood transfusions
- Prednisolone
- Rituximab –> monoclonal antibody against B cells
- Splenectomy
Prostehtic valve haemolysis
- caused by turbulence flow around the valve and the shearing of the red blood cells
- the valve churns up the cells, and they break down
Iron deficiency anaemia vs anaemia fo chronic disease
- Iron deficiency –> TIBC is high (reflecting production of more transferrin to increase iron-binding)
- Anaemia of chronic disease –> TIBC is low (iron stores are elevated)
Thalassaemia –> what is it + types + inheritance pattern
- Alpha- thalassaemia –> defect in alpha-globin chains
- Beta-thalassaemia –> defect in beta-globin chains
(defect in one chain is trait, in both is major) - Autosomal recessive
Consequences of thalassaemia
- Haemolytic anaemia –> RBCs more fragile so break down easily
- Splenomegaly –> spleen collects all the destroyed RBCs
Investigations for suspected thalassaemia
- FBC –> microcytic anaemia, raised ferritin (iron ovreload)
- Hb electrophoresis –> diagnosis
- DNA testing can look for genetic abnormality
Management for alpha-thalassaemia and beta-thalassaemia
- Alpha-thalassaemia –> blood transfusions, bone marrow transplant, splenectomy
- Beta-thalassaemia –> limiting blood transfusions and iron chelation
Pathophysiology of sickle cell disease + genetics
- At around 32-36 weeks gestation, HbF production decreases and HbA increases –> at birth half the Hb is HbF and half is HbA –> by 6 months RBCs should contain entirely HbA
- Sickle-cell –> HbS which is sickle-shaped RBCs
- Autosomal recessive condition affecting the beta-globin on chromosome 11
- one abnormal copy of the gene –> sickle cell trait
- two abnormal copies of the gene –> sickle cell disease
How is sickle cell disease picked up ?
newborn blood spot screening test at around 5 days of age
What type of anaemia does sickle cell disease cause?
Haemolytic anaemia –> abnormal shape of RBCs makes them more fragile and easily destroyed
Sickle cell crisis –> what is it + couple of types + managements
- Acute exacerbations –> triggered by dehydration, infection, stress, or cold weather
- Managed supportively –> IV fluids and analgesia
- Vaso-occlusive (most common type) –> sickle-shaped RBCs cloggin capillaries –> causing distal ischaemia and of vital organs
- Splenic sequestration –> RBCs block flow in spleen –> acutely enlarged and painful spleen –> can lead to splenic infacrtion and hypovolamic shock –> IV fluids and blood transfusions (for anaemia)
- Aplastic crisis –> parvovirus B19 is usual trigger
- Acute chest syndrome –> clot in lungs –> emergency and high mortality –> risk of ARDS
General management of sickle cell disease
- Avoid triggers –> dehydration
- Up-to-date vaccinations
- Antibitoic prophylaxis
- hydroxycarbamide –> stimulates HbF
- regular exchange transfusions
- bone marrow transplant can be curative
Raised eosinophils (eosinophilia) –> 2 causes
- allergies/atopy
- parasitic infection
Causes of neutropenia (low neutrophils)
- Infection - sepsis?
- Medications - antibiotics, immunosuppressants, chemotherapy (cytotoxic)
- B12/folate deficiency or iron deficiency
- Autoimmune disease
- HIV - any cytopenia could be due to HIV
- Bone marrow failure - seen with low Hb and low platelets
Causes of neutrophilia (high neutrophils)
- Basically infection or leukaemia
Acute leukocytosis:
- Reactive - infection, inflammation, post-surgery
- Steroids - stress response (endogenous) or medication (exogenous)
- Haematological - acute leukaemias
Chronic leukocytosis:
- Reactive - chronic infection, smoking
- Haematological - leukaemia, lymphoma (some subtypes)
- Hyposplenism - typically mild
- Pregnancy
Polycythemia (raised Hb) –> causes
- Primary –> polycythaemia vera (myeloproliferative neoplasm) –> JAK2 mutation
- Secondary: conditions that increase amount of erythropoietin (EPO) circulating in the blood (EPO is hormone produced by kidneys which stimulates bone marrow to make more RBCs) –> smoking and alcohol excess (most common), COPD, OSA, lung fibrosis, Cushing’s, EPO abuse (athletes)
Causes of thrombocythaemia (raised platelets)
- Reactive –> inflammation/infection (count will normalise after treatment)
- Myeloproliferative disorders –> essential thrombocythaemia
- Hyposplenism/post-splenectomy (asplenia)
4 main differentials for excessive/easy bleeding
- Thrombocytopenia
- Von Willebrand disease
- Haemophilia A and haemophilia B
- Disseminated intravascular coagulation –> usually secondary to sepsis
Immune thrombocytopenic purpura (ITP) –> what is it + presentation + management
- a condition where antibodies are created against platelets –> an immune response against platelets leads to their destruction and a low platelet count (thrombocytopenia)
- Characteristically presents with purpura –> non-blanching lesions caused by bleeding under the skin
- Management –> spontaneous remission common, prednisolone, Rituximab, splenectomy can be considered
Thrombotic thrombocytopenic purpura (TTP) –> what is it + protein dysfunction + treatment
- a condition where tiny thrombi develop throughout the small vessels, using up platelets –> microangiopathy
- Dysfunction of ADAMTS13 –> can be genetic or autoimmune
- Treatment –> plasma exchange (FFP), steroids, rituximab
von Willebrand disease –> what is it + presentation + management
- an inherited disorder causing a problem with a glycoprotein called von Willebrand factor –> important for platelet adhesion…
- Decreased factor VIII activity –> normal PT, prolonged APTT
- Presentation –> bleeding gums withbrushing, nosebleeds (epistaxis), easy bruising, menorrhagia etc.
- Management –> factor VIII + von Willebrand factor infusion
Haemophilia A and haemophilia B –> deficiency in which factor? + inheritance pattern + symptoms + diagnosis + management
- Haemophilia A –> deficiency in factor VIII
- Haemophilia B –> deficiency in factor IX
- X-linked recessive
- Typically presents early in life with deep and severe bleeding into soft tissues, joints and muscles
- Diagnosis –> coagulation factor assays and genetic testing
- Management –> clotting factors (VIII or IX) can be given by IV infusion, for minor bleeds (desmopressin)
What mutation is polycythaemia vera associated with
JAK2 mutation
Elevated HbA2 is a characteristic trait of what condition? –> elevated haemoglobin A2 level on electrophoresis
Beta-thalassaemia trait
Blood groups video –> ABO and Rh (Rhesus)
Dr Matt and Dr Mike video:
https://www.youtube.com/watch?v=Amn2EWTY2Lk
- Rh +ve can receive both Rh +ve and Rh -ve blood
- Rh -ve can only receive Rh -ve blood
Blood transfusion reaction - Allergy –> presentation + management
- Acute transfusion reaction
- can present as urticaria, angioedema or anaphylaxis
- Stop transfusion –> give fluids + adrenaline (if anaphylaxis), chlorphenamine (antihistamine), and hydrocortisone
Blood transfusion reaction - Acute haemolytic reaction –> Cause + Presentation + Management
- caused by ABO incompatibility –> wrong blood type given
- Signs –> fever, abdo pain, hypotension
- Stop transfusions –> give fluids + treat any complications
Blood transfusion reaction –> Febrile non-haemolytic reaction –> presentation + management
- presents with fever, rigor/chills –> patient otherwise well
- Slow transfusion –> give 1g paracetamol
+ serious complication that can lead to
Blood transfusion reaction –> TRALI (transfusion-associated acute lung injury) –> presentation + management
- Dyspnoea, have pulmonary oedema –> can cause ARDS
- Stop transfusion –> start pt on high flow oxygen + give fluids –> treat ARDS (antibx? ventilation?)
Blood transfusion reaction –> TACO (transfusion-associated circulatory overload) –> presentation + management
- Dyspnoea and fluid overload (hypertension, raised JVP)
- Slow transfusion –> give furosemide + oxygen if need
what are the 3 delayed blood transfusion reactions?
- Delayed haemolytic transfusion reaction –> caused by an exaggerated response to a foreign red cell antigen, presents with jaundice, anaemia and fever, usually day 5 post transfusion
- Transfusion-associated graft versus host disease –> caused by donor blood lymphocytes attacking the recipient’s body (usually non-irradiated blood to immunocompromised recipient) –> rare but high mortality
- Iron overload –> most common in pts that receive repeated transfusions –> desferrioxamine (lowers iron lvls)
Draw the haematopoiesis lineage diagram
Red cell maturation –> diagram
Blood film shows target cells –> …
Iron-deficiency anaemia and post-splenectomy
Blood film shows Heinz bodies and bite cells –> …
G6PD deficiency and alpha-thalassaemia
–> damaged Hb
Blood film shows Howell-Jolly bodies –> …
Post-splenectomy or non-functioning spleen
–> spleen would usually remove the little piece of DNA seen
Blood film shows reticulocytes –> …
Haemolytic anaemia –> bone marrow trying to replace lost cells
–> immature RBCs
Blood film shows schistocytes –> …
DIC, HUS, TTP, metallic heart valve replacement
–> fragments of RBCs
defective ________ synthesis
Sideroblastic anaemia –> what is it
- defective protoporphyrin synthesis
- bone marrow cannot incorporate iron into Hb molecules –> even though there is adequate iron
- due to genetic defect or myelodysplastic syndrome
(sideroblasts shown in image)
Blood film shows smudge cells –> …
Chronic lymphocytic leukaemia (CLL)
–> ruptured WBCs
Blood film shows sickle cells –> …
sickle cell anaemia –> HbS
Blood film shows spherocytes –> …
autoimmune haemolytic anaemia or hereditary spherocytosis
–> sphere-shaped RBCs –> without biconcave disc
Blood film shows tear drop cells –> …
bone marrow cancer –> myelofibrosis
Hepatomegaly —> Differentials
- Liver cirrhosis
- Malignancy —> metastatic spread or primary hepatoma
- Right-sided heart failure
- Infection —> EBV
- Haem malignancies
- Sarcoidosis, amyloidosis
Splenomegaly —> Differentials
- Portal hypertension (secondary to cirrhosis)
- Infection —> EBC, hepatitis
- Myelofibrosis, lymphoproliferative disease (CLL, Hodgkin’s)
- CML
Lymphadenopathy —> Differentials
- Reactive —> infection (EBV)
- Lymphoma
- Autoimmune —> SLE, RA, sarcoidosis
Anterior triangle anatomical borders
- Inferior border of the mandible —> superiorly
- Anterior border of the sternocleidomastoid —> laterally
- Sagittal line down the midline of the neck —> medially
Posterior triangle anatomical borders
- Posterior border of the sternocleidomastoid —> anterior
- Anterior border of the trapezius muscle —> posteriorly
- Middle 1/3 of the clavicle —> inferior
4 types of leukaemia…
- which results from transforamtion of myeloporliferative disorders and is associated with auer rods?
- which is most common in children and Down’s syndrome?
- Which is associated with the Philadelphia chromosome and is usually symptomatic?
- Which is usually picked up on routine blood tests (asymptomatic)?
- AML –> rapidly progressing cancer of the myeloid cell line (may result from transformation of myeloproliferative disorder and is associated with Auer rods)
- ALL –> rapidly progressing cancer of the lymphoid cell line (most common in children and Downs)
- CML –> slowly progressing cancer of the myeloid cell line (associated with Philadelphia chromosome)
- CLL –> slowly progressing cancer of the lymphoid cell line (associated with warm haemolytic anaemia, Richter’s transformation, and smudge cells)
Pathophysiology of leukaemia
- a genetic mutation in one of the precursor cells in the bone marrow leads to excessive production of a single type of abnormal white blood cell
- The excessive production of a single type of cell can suppress the other cell lines, causing the underproduction of different cell types –> pancytopenia (anaemia, leukopenia, thrombocytopenia)
- .
Presentation of leukaemia
Non-specific –> urgent FBC needed if leukaemia is a dx
- fatigue, fever, pallor due to anaemia, failure to thrive …
Differentials of petechiae
- Leukaemia
- Meningococcal septicaemia
- Vasculitis
- Henoch-Schönlein purpura (HSP)
- ITP
- TTP
Investigation for definitive diagnosis of leukaemia and staging
- Bone marrow biopsy –> diagnosis
- CT and PET scans –> staging
details of what happens –> creates abnormal gene sequence ____ + …..
CML is associated with what chromosome?
- Philadelphia chromosome –> abnormal chromosome 22 –> translocation (swapping) of a section of chromosome 9 and chromosome 22
- this creates an abnormal gene sequence called BCR-ABL1 –> codes for tyrosine kinase enzyme –> drives proliferation of abnormal cells (cell growth and division cell)
associated with?
Auer rods
- characteristic finding in AML
General management of leukaemias
- MDT
- Chemotherapy
- Targeted therapies –> Tyrosine kinase inhibitors (e.g., ibrutinib, imatinib), Monoclonal antibodies (e.g., rituximab, which targets B-cells)
Risk factors for Hodgkin’s lymphoma
- HIV
- Epstein-Barr virus
- Autoimmune conditions –> RA and sarcoidosis
- Family hx
B symptoms are systemic symptoms of lymphoma
- Fever
- Weight loss –> >10% body weight in 6 months
- Night sweats
Hodgkin’s lymphoma blood film characteristic finding
Reed-Sternberg cells –> large multinucleated cancerous B lymphocytes
Lugano (used to be Ann Arbor) classification for Hodgkin’s and non-Hodgkin’s lymphoma
- Stage 1 –> Confined to one node or group of nodes
- Stage 2 –> In more than one group of nodes 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
Note: presence of B symptoms –> ‘B’
Symptoms of Hodgkin’s lymphoma
- Painless, asymmetrical lymphadenopathy, alcohol-induced pain
prognosis?
Management of Hodgkin’s and non-Hodgkin’s lymphomas
Hodgkin’s:
- chemotherapy and radiotherapy –> curative disease –> good prognosis
non-Hodgkin’s –> depends on type and stage:
- Watchful waiting
- Chemotherapy
- Radiotherapy
- Monoclonal antibodies –> e.g., rituximab, which targets B cells
- Stem cell transplantation
Myeloma –> what is it + multiple myeloma? + MGUS
- cancer affecting the plasma cells in the bone marrow
- Plasma cells are B lymphocytes that produce antibodies
–> Cancer in a specific type of plasma cell results in the production of large quantities of a specific paraprotein (or M protein), which is an abnormal antibody or part of an antibody - Multiple myeloma is where the myeloma affects multiple bone marrow areas in the body
- MGUS (monoclonal gammopathy of undetermined significance) –> involves the production of a specific paraprotein without other features of myeloma or cancer –> can progress to myeloma
4 features of myeloma
C – Calcium (elevated)
R – Renal failure
A – Anaemia –> most common complication
B – Bone lesions and bone pain
Myeloma bone disease –> pathophysiology and common sites
- increased osteoclast activity and suppressed osteoblast activity –> osteoclasts absorb bone, osteoblasts deposit bone
- common sites –> skull, spine, long bones, and ribs
Presentation of myeloma
- Persistent bone pain (e.g., spinal pain)
- Pathological fractures
- Unexplained fatigue
- Unexplained weight loss
- Fever of unknown origin
- Hypercalcaemia –> due to increased osteoclast activity
- Anaemia
- Renal impairment
including blood film finding
Diagnostic investigations for myeloma
- Bone marrow biopsy
- Electrophoresis to detect paraproteinaemia –> paraprotein spike
- Bence Jones poteins –> serum-free light-chain assay (in urine)
- Rouleaux formation on blood film
potential to turn into what type of leukaemia?
Myeloproliferative disorders –> what is it + 3 types + mutation associated
- Bone marrow cancer –> uncontrolled proliferation of a single type of stem cell
- They have the potential to turn into AML
All associated with JAK2 mutation:
- Primary myelofibrosis –> haematopoietic stem cells
- Polycythaemia vera –> erythroid cells
- Essential thrombocythaemia –> megakaryocyte cells
Myelofibrosis –> what is it + blood film findings + bone marrow aspiration finding
- Myelofibrosis can result from primary myelofibrosis, polycythaemia vera, or essential thrombocytothaemia
–> Bone marrow is replaced with collagen, becoming fibrosed - Teardrop-shaped RBCs + anisocytosis + blasts
- bone marrow aspiration –> ‘dry tap’
can transform into what type of leukaemai
Myelodysplastic syndrome –> what is it + presentation + diagnosis + management
- cancer cuased by a mutation in the myeloid cells in bone marrow –> inadequate production of blood cells (ineffective hematopoiesis)
- Can transform into AML
Pancytopenia:
- Anaemia –> fatigue, pallor or shortness of breath
- Neutropenia –> recurrent and severe infections
- Thrombocytopenia –> bleeding and purpura
- Diagnosis –> bone marrow biopsy
Management:
- Watchful waiting
- Supportive treatment –> transfusions
- Erythropoietin –> stimulates RBC production
- GCSF –> stimulates neutrophil production
- Chemotherapy
- Allogenic stem cell transplantation –> risky but potentially curative
Rituximab MOA
monoclonal antibody against B cells (targeting CD20)
Blood tests –> order of draw
what conditions is this used to detect?
Osmotic fragility test
Used to detect hereditary spherocytosis and thalassaemia –> measure of how fragile RBCs are
Elevated erythropoietin –> causes
Erythropoietin –> stimulates production of RBCs
- Iron deficiency anaemia
- Thalassaemia
- Haemolytic anaemia
and what is it?
Why would you use a direct antiglobulin test –> Coombs test ?
- To investigate possible haemolytic transfusion reactions or autoimmune haemolytic anaemia
- Looks for antibodies that are stuck to RBCs
A 62-year-old female patient has been admitted to hospital with a diagnosis of an abdominal aortic aneurysm (AAA). She is told that she must have the aneurysm repaired due to risk of rupture. The Doctor explains to her that an artery will be occluded in the procedure but resassures her that another artery will be able to supply the area.
What artery that branches from the aorta at the vertebral level L3 will most likely be occluded during the procedure?
A - Coaeliac axis
B - Inferior mesenteric
C - Left renal artery
D - Right renal artery
E - Superior mesenteric
B - Inferior mesenteric artery
Anaemia –> an overview
Dr Matt and Dr Mike video:
https://www.youtube.com/watch?v=Lek2zAOhOTg
which contains platelet?
plasma, buffy coat, haematocrit
- Blood is split into plasma (55%), buffy coat (1%), and erythrocytes (RBCs –> 45%)
- Buffy coat –> WBCs, thrombocytes, platelets
Haematopoiesis video
Dr Matt and Dr Mike video:
https://www.youtube.com/watch?v=anfpX7NzExg
What receptors does von Willebrand’s factor (vWF) bind to on platelets and what receptor on the platelet is activated which leads to increased expression of glycoprotein IIb/IIIa?
- Glycoprotein Ib receptors
- ADP (P2Y12) receptor
How are fibrin clots later dissolved?
- tPA (tissue plasminogen activator) turns plasminogen –> plasmin (activated form)
- Plasmin then breaks down the fibrin mesh
what does it measure
PT/INR –>
APTT –>
Thrombin time –>
- PT/INR –> measure of time taken for blood to clot via EXTRINSIC pathway –> factor VII pathology is rare, so better used as a measure of overall clotting
- APTT –> measure of time taken for blood to clot via INTRINSIC pathway
- Thrombin time –> how fast fibrinogen is converted to fibrin by thrombin
What effects do anticoagulants have on coagulation screen?
Anticoagulants (warfarin, heparins, DOACs) –> will increase PT/INR and the APTT
PT/INR ↑ , APTT ↑ , platelet count —
Vitamin K deficiency/Warfarin use
PT/INR — , APTT ↑ , platelet count —
–> with hx of prolonged bleeding after dental surgery
Haemophilia A/B/C
PT/INR — , APTT —/↑ , platelet count —
–> hx of petechiae, bruising, contact bleeding (e.g. gums), menorrhagia
von Willebrand’s disease
PT/INR ↑ , APTT ↑ , platelet count ↓
–> hx of sepsis
DIC
–> primary cause must be treated, give platelets and clotting factors
PT/INR —, APTT —, platelet count ↓
- ITP/TTP/HUS
–> Lack of PT/APTT derangement is a good differentiator from DIC –> NEVERgive platelets to these patients
DIC –> what is it + most common risk factor
- a rare but serious condition that causes abnormal blood clotting throughout the body’s blood vessels –> may develop DIC if you have an infection or injury that affects the body’s normal blood clotting process
- Sepsis is most common risk factor
Interpreting serum ferritin
- Ferritin is an intracellular protein that binds to and stores iron + an acute-phase protein that increases in inflammatory states
–> therefore, we need to do CRP with ferritin
Transferrin –> what is it + increased transferrin indicates?
- Transfers iron through the blood to destinations within body
- If transferrin increased –> low iron –> iron deficiency anaemia
Vitamin B12 (cobalamin) deficiency FBC findings
- Macrocytic anaemia
- Low reticulocyte counts –> bone marrow cannot make new cells without B12
Main investigation for pernicious anaemia
- Anti-intrinsic factor antibodies (Anti-IF)
- Anti-IF are found in pernicious anaemia and have a high positive predictive value
Iron-deficiency treatment
- oral iron (ferrous sulphate) with vitamin C supplement to improve absorption of iron
–> a response in Hb count should be seen within a few weeks
Treatment of B12 deficiency
- Intramuscular (IM) vitamin B12 injections
- If no neurological symptoms –> 1mg three doses a week for 2 weeks, then every 3 months
- If neurological symptoms present –> 1mg alternate days until no further improvement in symptoms (minimum 3 weeks), then every 2 months
Causes of folate deficiency
- Dietary: folate-rich foods (legumes, broccoli, asparagus, brown rice, folate fortified foods)
- Alcoholism
- GI disorders: eg. coeliac
- Pregnancy: preferential delivery of folate to foetus rather than mother’s tissues, deficiency in utero increases the risk of neural tube defects
- Haematological disorders: increased red cell destruction (sickle cell anaemia, haemolytic anaemias) and those with abnormal haematopoiesis
Treatment of folate deficiency
Folic acid 5mg OD 3-4 months
(Note: if mixed folate/B12 deficiency –> give B12 first due to risk of worsening neruo symptoms (subacute spinal cord degeneration)
What can go wrong in this pathway?
Spherocytes
- Hereditary spherocytosis
- Autoimmune haemolysis
Elliptocytes
hereditary elliptocytosis
Schistocyte (helmet cell)
DIC, TTP, HUS
Haematopoeisis video
Dr Matt and Dr Mike video:
https://www.youtube.com/watch?v=anfpX7NzExg&t=27s
Imatinib MOA
Tyrosine kinase inhibitor
Which immunoglobulin is associated with an acute transfusion reaction –> eg. anaphylactic shock
IgA –> IgA deficiency increases the risk of anaphylactic blood transfusion reactions
Basophils and eosinophils are associated with…
Allergic/atopic reactions + parasitic infections
How does the kidney regulate RBC production?
- Kidney produces EPO (erythropoeitin) –> hormone that stimulates RBC production
- Kidney detets lvls of oxygen within blood and uses this as a measure of how much EPO to produce to regulate RBC production
2 weeks gestation/3 months gestation/birth to adult
Where are pluripotent haematopoeitic stem cells produced?
- 2 weeks –> yolk sac
- 3 months –> liver/spleen
- Birth to adult –> red bone marrow (medulla) –> axial skeleton (skull, vertebrae), end of long bones (femur, humerus), and flat bones (ribs, sternum)
give details of each phase
Haemostasis 3 stages
- Vascular spasm (vasoconstriction) –> due to release of prostaglandins (Thromboxane A2), serotonin, noradrenaline
- Platelet plug –> exposed negatively charged collagen –> platelets stick to it and vWF helps platelets to stick together and form the clot
- Clotting cascade –> stable fibrin clot formation
Why can liver disease cause clotting problems?
- Proteins produced by liver –> therefore if liver damaged then clotting cascade affected
- Prothrombin also made in liver!
Role of vitamin K and Ca2+ in coagulation cascade
- Vit K carboxylates clotting factors II, VII, IX, and X –> Ca2+ then binds to negatively charged carboxyl group on the clotting factors
- Clotting factors can now bind to collagen, platelets etc. with the Ca2+ acting as a tether
CML vs CLL –> how they present
- CML –> massive splenomegaly, splenomegaly, pallor, fatigue, loss of appetite, weight loss, easy bruising
- CLL –> usually asymptomatic, picked up on routine bloods, increased risk of recurrent infections
Imatinib is used for CML treatment –> MOA?
Tyrosine kinase inhibitor
What drug is given to polycythaemia vera patients to reduce the risk of thrombotic events (note: polycythaemia vera often has associated raised platelets)?
Low-dose aspirin
Repeated blood transfusions –> what drug should be given to reduce the risk of iron overload
Desferrioxamine –> iron chelation
Drug that causes folate deficiency
Methotrexate
Drug classes that are associated with haemolysis in G6PD deficiency
- sulph- drugs –> sulphonamides, sulphasalazine and sulfonylureas can trigger haemolysis
- Malaria prophylaxis (eg. primaquine) can also trigger haemolytic anaemia in G6PD def.
What is the single most important factor in determining whether cryoprecipitate should be given?
- A low fibrinogen level
How long should antibiotics (topical or oral) be used for max in treatment of acne vulgaris?
6 months
Definitive diagnosis of sickle cell anaemia
Haemoglobin electrophoresis –> presence of HbS
Hypersegmented neutrophils on blood film suggest –>
Megaloblastic anaemia –> B12/folate def.
Blood tests show anti-tGA antibodies +ve, blood film shows target cells and Howell-Jolly bodies –> main differential?
Coeliac disease → hyposplenism
Basophilic stippling on blood film, with FBC showing microcytic anaemia with high ferritin and high transferrin –> ?
Sideroblastic anaemia
The three JAK 2 mutation-associated conditions
- Polycythaemia vera
- Essential thrombocythaemia
- Primary myelofibrosis
Felty syndrome –>
- RA
- Splenomegaly
- Neutropenia
Secondary erythrocytosis –> causes?
- Chronic hypoxia can cause the kidneys to produce more EPO –> secondary erythrocytosis
–> COPD, smoking, high altitude, obesity …
What autoimmune condition is thymoma associated with
Myasthenia gravis
Asplenia –> why are patients at risk of infections from encapsulated bacteria + examples of encapsulated bacteria
- The white pulp of the spleen houses approximately half of the body’s immunoglobulin-producing B lymphocytes, which are critical for producing antibodies that target polysaccharide antigens on the surface of encapsulated bacteria
- Examples –> Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis
Aortic dissection on CT
Tennis ball appearance –> ascending aorta
How long should stop taking oral contraceptive pill before a surgery?
- 4 weeks before –> risk of blood clots (PE)
CLL can undergo Richter’s transformation, what is Richter’s transformation?
Richter’s transformation = when CLL transforms into high-grade non-Hodgkin’s lymphoma (diffuse large B cell lymphoma)
Most common causative organism of neutropenic sepsis
Staphylococcal epidermidis –> coagulase -ve gram +ve cocci
Neutropenic sepsis empirical antibx management
IV piperacillin with tazobactam (Tazocin)
how long is a unit of RBCs tranfused over –> non-urgent vs urgent (trauma, major haemorrhage)
- non-urgent –> 90-120 minutes
- urgent –> STAT
Which type of blood product is most likely to cause an iatrogenic infection with gram +ve infections VS with gram -ve infections
- Gram +ve –> platelets are stored at room temp. so increased risk of culturing gram +ve organisms
- Gram -ve –> packed red cells (stored at 4 degrees)
Suspected Non-Hodgkins lymphoma –> what type of lymph node biopsy for diagnosis?
Excisional node b iopsy
Positive green birefringence of rectal tissue with Congo red staining
Primary amyloidosis
Desmopressin MOA
Desmopressin stimulates the release of vWF from its storage sites in endothelial cells, improving the stability of Factor 8
Polycythaemia vera first-line treatment
Venepuncture/Phlebotomy
Management of acute chest syndrome in sickle cell disease
- pain relief
- oxygen therapy
- antibiotics
- transfusion
