Haematology Flashcards
Causes of Anaemia with MCV<80
TAILS
Thalassaemia
Anaemia of chronic disease
Iron deficiency
Lead poisoning
Sideroblastic
Causes of Anaemia with MCV: 80-100
ABCD
Acute blood loss
Bone marrow disorders
Chronic disease
Destruction - haemolysis
Causes of Anaemia with MCV>100
RALPH - non megaloblastic
Reticulocytosis - haemolysis
Aplastic anaemia
Liver disease, alcoholism
Pregnancy
Hypothyroidism
B12/Folate deficiency - megaloblastic
What is the predominant haemoglobin in a fetus?
Haemoglobin F
2 alpha chains and 2 gamma chains
(gamma chain production dips from 3-6 months old)
What is the predominant haemoglobin in life?
Haemoglobin A
2 alpha chains and 2 beta chains
(Small amounts of Haemoglobin A2 -> 2 alpha + 2 delta) chains)
(beta chains reach peak levels from 3-6 months old)
What is the need for different haemoglobin in a fetus than an adult?
Foetal haemoglobin has higher oxygen affinity = oxygen flows from maternal to foetal circulation more readily across the placenta
On which chromosomes are alpha and beta chains found?
Alpha - chromosome 16 (twice as many alpha genes - life can not be sustained beyond embryonic stage without alpha chains)
Beta - chromosome 11
What are the 3 manifestations of alpha thalassaemia?
- Thalassaemia trait (carrier - asymptomatic)
- Haemoglobin H disease (3/4 genes deleted, excess beta chains form beta4 tetramers = haemoglobin H = high affinity for oxygen + damage RBC membrane = hypoxia)
- Thalassaemia- Alpha Major (hydrops fetalis)
What is the inheritance of thalassaemia and sickle cell disease?
Autosomal Recessive
What is the consequence of alpha/beta chain precipitants in red blood cells
Higher affinity for oxygen = hypoxia
Precipitate in RBC = haemolysis in bone marrow and spleen
– Stimulates extra-medullary erythropoiesis = enlarged bone marrow and spleen = jaundice, deformities of long bones and facial bones
– Damaged RBC + haemoglobin spill into plasma = increased bilirubin, iron - secondary haemochromatosis
What would you find in haemoglobin electrophoresis in B Thalassaemia trait and major?
Trait: Decreased HbA, Increased HbA2
Major: Absence HbA, Increased HbA2 + HbF
What would you find in haemoglobin electrophoresis in Alpha Thalassaemia trait and disease?
Trait: unable to pick up and decreased of all types so ratio is technically the same.
Disease: Presence of HbH
How does chronic disease cause anaemia?
- Decreased RBC lifespan - direct cellular destruction via toxins from cancer cells, infections, inflammation
- Decreased RBC production- impaired iron metabolism and regulation due to cytokines and ILs.
- TNF-alpha + IFN-Y = Inhibit EPO production
- IFN-y = increase expression of DMT on surface of macrophages to allow iron to enter - less available for haemoglobin
- IL-10 mediates expression of increased ferritin receptors on surface of macrophages
- IL-6 increases hepcidin
How do distinguish anaemia of chronic disease from iron deficiency anaemia?
Chronic disease anaemia
- Starts normocytic but eventually becomes microcytic
- LOW serum iron levels, LOW TIBC, HIGH ferritin
- Presence of chronic disease state - infection, diabetes, autoimmune, malignancy, critical illness, trauma
Iron Deficiency
- LOW serum iron levels, HIGH TIBC, LOW ferritin
- Pica - abnormal craving or appetite for non-food substances - soil, paint, clay
- Restless leg syndrome
- Pencil cells - blood film
4 main causes of iron deficiency anaemia?
- Inadequate diet
- Increased requirements - growth, pregnancy
- Malabsorption - GI issues
- Blood loss - surgery, GI, menstrual
Typical Findings in Microcytic Anaemia?
RBC
- Microcytic
- Hypochromic
- Target cells - thalassaemia
- Pencil cells - iron deficiency
Why are RBC more easily damaged and removed early from circulation in hereditary spherocytes?
They have an inherited membrane defects - autosomal dominant
Abnormalities in membrane proteins…
1. Spectrin protein
2. Band-3 protein
Intrinsic haemolysis
What is the significance of the G6PD enzyme and if deficient?
G6PD reduces NADP+ back into NADPH
Glutathione is oxidised when mops up free radicals
Glutathione reductase uses NADPH -> NADP+ to reduce oxidised glutathione
G6PD reduces NADP+ back to NADPH to repeat process
No G6PD = no NADPH = no glutathione reductase = build up of free radicals = unstable red cell membrane = haemolysis
(Typically asymptomatic until exposed to oxidative stressors)
What cells can be seen on a blood smear in G6PD deficiency?
Heinz bodies - free radicals damage haemolgobin molecules = damaged proteins precipitate inside RBC
Bite cells - spleen macrophages try to remove the cells by taking a bite
What is the genetic inheritance of G6PD deficiency?
X-linked recessive
What is the mutation in sickle cell?
Amino acid substitution from glutamine to valine in beta chains
Valine - more hydrophobic = cause haemoglobin to polymerise
What haemoglobin is present in sickle cell?
Haemoglobin S
- 2 alpha chains and 2 mutated beta chains
What is a consequence of Haemoglobin S in sickle cell anaemia?
HbS can polymerise when triggered by hypoxia
Become crescent shape - rigid and distorted
Aggregate with other HbS to form polymers that distort red cells = sickling - sickle cell crises
Repeated sickling weakens red cell membrane = premature destruction = intravascular haemolysis
What is a crises in sickle cell?
Vaso-occlusion -> Sickle cells get stuck in capillaries - infarct - pain crises
Block spleen = Spleen sequestration
- Howell-Jolly bodies
Lung sickling - life threatening
Causes of non-immune extrinsic haemolytic anaemia?
Malaria
Burns
Microangiopathic - TTP, DIC, HUS
Hypersplenism
Mechanical heart valve
Drugs - dapsone, toxin from snake/spider bites, copper
What are typical signs of haemolysis?
Jaundice
Dark urine
Gallstones - chronic haemolysis
Signs of anaemia
Splenomegaly
What are classical blood findings of haemolysis?
Raised reticulocytes
Raised LDH
Raised bilirubin
Low haptoglobin
Low Hb
What are classical findings on a blood film for haemolytic anaemia?
Reticulocytes
Schistocytes - DIC, TTP, HUS
Spherocytes - hereditary spherocytosis
Sickle cells
Howell-jolly bodies - splenic atrophy
Bite cells + Heinz bodies- oxidative haemolysis - G6PD deficiency
What are triggers of oxidative stress in G6PD deficiency?
Infections,
Fava beans, soy products
Primaquine, chloroquine, aspirin, NSAIDs, quinidine
What are the 2 important structural proteins in red cell membranes?
Band-3 protein and Spectrin
What occurs in warm autoimmune haemolytic anaemia?
IgG reacts with RBC at 37 degrees -> Leads to extravascular haemolysis - in liver and spleen
Idiopathic, SLE, RA, CLL
What occurs in cold autoimmune haemolytic anaemia?
IgM reacts with RBC below 37 degrees -> leads to intravascular haemolysis, complement activated
Idiopathic, EBV, malignancy
What are the 2 pathophysiologies behind paroxysmal nocturnal haemoglobinuria
- Somatic mutation in haematopoietic stem cell
- Mutation in PIG-A gene = GPI protein anchor cannot be synthesised = unable to anchor defence proteins(CD55, CD59) to surface of RBC that normally protect from lysis by complement = MAC-mediated intravascular haemolysis - Background of bone marrow hypoplasia - aplastic anaemia, myelodysplasia
How can you distinguish autoimmune haemolytic anaemias from the other types of haemolytic anaemias?
DAT - direct antiglobulin test to identify antibodies
Common triad of symtptoms for aplastic anaemia?
Anaemia symptoms - pallor, fatigue
Increased bruising/bleeding
Recurrent infections
How do you get reticulocytosis in haemolysis?
Haemolysis stimulates EPO production - erythropoietic hyperplasia = reticulocytosis
What leads to increased absorption of iron?
acids, ascorbate, solubilising agents - sugars, amino acids, vitamin C
pregnancy
increased erythropoiesis
haemochromatosis
Increased DMT-1 and ferroportin receptors
What is TIBC?
Total/Transferrin Iron-Binding Capacity
Determines the amount of iron that can be bound to unsaturated transferrin - amount of transferrin binding sites per unit
High in iron deficiency (increased transferrin production)
Low in inflammation, iron overload (increased transferrin degradation)
What decreases absorption of iron?
Alkalis, phytates, phosphates, tetracyclines
Tea - tanins
Infections - increased hepcidin
High body iron stores
What is the process of iron absorption?
- Iron reduced from ferric to ferrous form(Fe3+ -> 2+) via vitamin C reductase
- Ferrous iron transported into lumen via DMT-1 receptor on lumen membrane
- Ferrous iron transported out of enterocyte via ferroportin receptor
- Ferrous iron converted to ferric iron via hephaestin
- Ferric iron circulates in blood bound to transferrin
What is the role of hepcidin in iron regulation?
Hepcidin is an iron regulator made in the liver.
- Blocks reuptake of iron into the circulation from the liver.
- Blocks ferroportin receptor to prevent iron being released into the circulation from enterocyte
What increases hepcidin production?
Infection/inflammation
High iron plasma levels
HFE
What happens to the iron circulating in the blood?
75% iron sent to the bone marrow for erythropoeisis
10-20% iron sent to liver and stored as ferritin.
What is the role of HFE gene?
HFE regulates hepcidin production - regulates iron absorption
Mutation in HFE = low hepcidin = iron overload = secondary haemochromatosis
How is B12 absorbed?
Intrinsic factor made by parietal cell
IF binds to B12 in stomach + travels through intestine
Absorbed in terminal ileum to circulation
B12 travels in blood bound to transcobalamin + IF degraded
Why is B12 required in folate metabolism?
B12 required for methylation of Methyl THF to THF
Deficiency in B12 = functional folic acid deficiency - metabolism pathway blocked at methylation point
What occurs in pernicious anaemia?
Autoimmune disease
Antibodies against intrinsic factor or against parietal cells.
Impaired absorption of B12 - become deficient = anaemia
What are complications associated with blood transfusions in anaemia?
Iron overload risk - organ failure
Tx = Iron chelation therapy - desferrioxamine
What are characteristics on a blood film for B12/Folate deficiency?
Hypersegmented polymorphonucleated neutrophils (>5 lobes of nucleus)
Macro-ovalocytes - large, oval RBCs
What can precipitate an aplastic crises?
parvovirus infection
What drugs cause folate deficiency?
phenytoin
primidone
methotrexate
sulfasalazine
What drugs cause B12 deficiency?
colchicine
neomycin
metformin
anticonvulsants
PPI
What drugs cause B12 deficiency?
colchicine
neomycin
metformin
anticonvulsants
PPI
How can kidney damage cause anaemia?
Reduced production of EPO
What enzymes are inhibited by lead poisoning in haemoglobin production?
ALA dehydratase
Ferrochelatase
How can a diagnosis of porphyria be made?
Serum levels of enzyme raised
Stool and urinalysis - increased porphyrins
What enzyme inhibition/deficiency is linked to acute intermittent porphyria?
PBG deaminase
Accumulation of delta aminolaevulinic acid + porphobillinogen - toxic
Unexplained abdominal pain
Nausea, vomiting, constipation
Neuropschiatric symptoms
Port-wine coloured urine
What enzyme inhibition/deficiency is linked to Porphyria cutanea tarda?
Uroporphyrinogen decarboxylase
… Via inherited defect or liver damage(alcohol, oestrogen, HIV, HepC)
Skin manifestation
- blisters and erosions on sun-exposed skin
- hypertrichosis
- hardened yellow skin
- hypermelanosis
What is the first-rate limiting step in Haemoglobin production that can be blocked?
Inhibition of ALA Synthase
Blocked by B6 deficiency - pyridoxine, glucose
Leads to sideroblastic anaemia - iron accumulation
Presents similar to haemochromatosis
What is a red blood cell broken up into for metabolism?
Globin - amino acids reused for erythropoiesis
Iron - stored or reused
Protoporphyrin - metabolised
What is the metabolism of protoporphyrin?
Biliverdin - cleaved haem and iron released
Unconjugated bilirubin - fat soluble, taken to fatty tissues (can accumulate in brain = kernicterus) - circulates in blood bound to albumin
Conjugated bilirubin - water soluble -(conjugated in liver ER by glucoronidation)
Urobilinogen - in urine - blood and kidneys
Stercobilinogen - brown faeces from action of bacteria in gut
Why can liver damage cause anaemia?
Portal hypertension
Low hepcidin release - similar to chronic disease
Alcohol toxic to bone marrow
What are 4 mechanisms behind jaundice in bilirubin metabolism?
Haemolytic jaundice - increased unconjugated bilirubin in blood (conjugation mechanism overload)
Impaired hepatocytes/liver damage - more unconjugated bilirubin in blood as liver unable to uptake
Impaired bilirubin conjugation - increased unconjugated bilirubin in blood - deficiency in enzymes for glucoronidation in ER
Obstruction - more conjugated bilirubin in blood - normally gallstones or pancreatic carcinoma blocking canaliculi for conjugated bilirubin = pale, chalky faeces, colicky pain
Above what % of blasts are seen in acute leukaemia?
20%
What condition can Auer rods be seen?
Acute myeloid leukaemia
What are complications of chronic lymphocytic leukaemia?
Warm autoimmune haemolytic anaemia
Richter’s Transformation - high grade non-hodgkins lymphoma
What is the pathophysiology behind CML and what is the definitive diagnosis?
Philadelphia chromosome - 9:22
Fusion of BCR-ABL - tyrosine kinase constantly activated
FISH - used to detect
In which diagnosis can you see smudge/smear cells on a blood film?
CLL
What is small lymphocytic lymphoma?
A low grade Non-Hodgkins lymphoma
CLL but when lymphadenopathy with no lymphocytosis
Which group of diseases can transform into AML?
Myeloproliferative disorders
- CML
- PV
- ET
Can transform into myelofibrosis – AML
In which lymphoma can Reed-Sternberg Cells be seen on a blood film?
Hodgkins Lymphoma
What kind of biopsy should not be used in lymphoma?
Fine needle aspirate
What 3 disorders is the JAK2 mutation found?
Polycythaemia
Myelofibrosis
Essential thrombocythemia
In which disorder can tear drop cells be seen on a blood film?
Myelofibrosis
Which disorder can show hypersegmented neutrophils on a blood film?
Megaloblastic anaemia
Which disorder can show schistocytes on a blood film?
Intravascular haemolysis
Which disorder can show pencil cells on a blood film?
Iron deficiency anaemia
Which disorders can show howell-jolly bodies on a blood film?
Hyposplenism
- Sickle cell
- Coeliac disease
What’s the criteria for MGUS?
<10% malignant plasma cells in bone marrow
Paraprotein: 10-30g/L
No CRAB symptoms
What is the CRAB criteria in MM?
C - hypercalcaemia
R - renal failure
A - anaemia
B - bone lesions
How do myeloma cells impact bones?
Myeloma cells produce OPG and RANK-L
Activation of osteoclasts to increase resorption
Inhibition of osteoblasts to reduce production
net result = bone resorption
What investigations should be done in MM?
Blood film - rouleaux
Bone marrow biopsy >10% plasma cells
Skeletal survey - MRI, CT
Serum protein electrophoresis - paraproteins, IgG, IgA
Serum free light chain immunoassay
Immunophenotyping
What is the management in MM?
Chemotherapy + Stem cell transplant(if <70)
Fractures - bisphosphonates, prophylactic surgery
Renal failures - dialysis, IV fluids
Hypercalcaemia - IV fluids, radiotherapy
Anaemia - transfusion, EPO
Hyper-viscosity - plasma exchange, chemo
Spinal cord compression - steroids
What light chain protein can be found in urine in MM?
Bence-Jones Protein - light chain
What is Multiple Myeloma?
Abnormal proliferation of a single clone of plasma cell.
Immunoglobulin involved normally - IgG or IgA
In which disease is a ‘rain drop skull’ seen on an x-ray?
Multiple Myeloma
What is Waldenstrom’s Macroglobulinaemia and what is the risk of this disease?
Monoclonal proliferation of IgM Paraprotein made by lymphoma cells.
Seen as a low grade lymphoma.
Pentameric configuration of IgM = Hyperviscosity Syndrome
What is the cause of Renal Failure in MM?
Light chain deposition in tubules
Hypercalcaemia
NSAID usage treating pain
Recurrent infections
What is a plasmacytoma?
Mass of clonal plasma cells
- in bones = solitary plasmacytoma
- in soft tissues = solitary extra-medullary plasmacytoma
What are the 2 light chain and how can these be measured in myelomas?
Lambda chain
Kappa chain
Testing serum free light chain in myelomas = monoclonal cells will only make 1 type of light chain
What is primary amyloidosis?
Clonal plasma cells make abnormal light chains (normally lambda) - deposit in organs as insoluble amyloid proteins = organ damage
- heart - congestive cardiomyopathy
- kidneys - nephrotic syndrome, renail failure
- nerves - neuropathy
- liver - hepatomegaly, liver failure
- gut - macroglossia, malabsorption
- skin - deposits
What stain is used for amyloidosis on liver tissue?
Congo Red Stain
Apple green birefrigence under polarised light
What is myelodysplastic syndrome?
Abnormal maturation and proliferation of haematopoietic stem cells.
Production of deformed cells = dysplastic = blasts = Reduced survival and improper maturation
Pancytopenia
When >20% blasts in bone marrow = transformed into AML
What occurs in myelofibrosis?
JAK2 gene mutation = overstimulation of haematopoeisis
Large amounts of megakaryocytes = release fibroblast growth factor = cause fibrosis = scarring of bone marrow = no space of haematopoeisis = pancytopenia
Extra-medullary haematopoiesis in spleen, kidneys, liver for compensation = hepatosplenomegaly
Which haematological cancers is down syndrome a risk factor of?
Myelodysplastic syndrome
ALL
AML
Which leukaemia presents with increased neutrophils and basophils?
CML
What is the pentad of problems in TTP?
Fever
Microangiopathic haemolytic anaemia
Renal impairment
Fluctuating neurological signs - headache, seizures, coma, confusion
Thrombocytopenia
What is the aetiology behind TTP?
Deficiency of ADAMTS13 = leads to ultra-large vWF multimers = thrombosis in microcirculation
Immune mediated - antibodies against ADAMTS13
Congenital - Inherited autosomal recessive mutation of ADAMTS13
What is seen on a blood film and blood count in TTP?
Film - Schistocytes + Reticulocytes
Count - Low Hb, Low platelets, Low haptoglobin, Raised LDH
Proteinuria
What happens in ITP?
The spleen produces IgG autoantibodies against GPIIb/IIIa on platelets
Auto-reactive T cell mediated destruction of platelet and megakaryocyte in the bone marrow
Isolated thrombocytopenia <100
Typically asymptomatic
Can get purpura and gum bleeding and nose bleeding
What blood results are indicative of DIC?
Low platelets
Prolonged PT and APTT time
Decreased fibrinogen
Elevated D-dimer
What is the management of DIC?
Platelets
FFP - if PT 1.5x normal
Cryoprecipitate - if fibrinogen < 2
RBC
Fluids
What blood group is the universal donor?
O group
What blood group is the universal recipient?
AB group
Which 2 patient groups are at increased risk of side effects for future transfusions due to alloantibodies
Women with previous pregnancies
Multiply transfused patients
When should diuretics be given with red blood cell transfusions?
When 2 or more units given
In elderly patients
Patients high risk circulatory overload - heart failure etc
What levels of Hb are indications for red blood cell transfusion in certain patients?
In a stable patient: <70
In a patient with cardiovascular disease: <80
Patient receiving radiotherapy: must maintain Hb>100
What other substance can be given when transfusing red blood cells to avoid a specific side effect?
Iron chelation therapy - desforrioxamine
Transfusion with which blood product has the highest risk of bacterial contamination?
Platelet transfusions
What are the platelet count indications for transfusion in different scenarios?
No bleeding - platelet count <10
Active bleeding - platelet count<30
Severe bleeding or bleeding at CNS - platelet<100
Prophylactic before surgery - aim platelet count >50
Prophylactic before surgery if high risk bleeding - aim platelet count 50-75
Prophylactic before Surgery at critical site - aim platelet count >100
What are the main substances found in cryoprecipitate and what is the main indication to give?
High in fibrinogen, factor 8 and 13, vWF
Usually given with FFP
Given when low fibrinogen, with or without bleeding
What is the universal donor group for plasma?
AB group
When is fresh frozen plasma necessary?
When PT and APTT ratio >1.5, treating DIC, TTP, massive haemorrhage, liver failure
Contains all clotting factors
What are alternative therapies instead of transfusions?
Oral or IV iron - if iron deficient anaemia
EPO - stimulate RBC production
IM B12
Tranexamic acid - help stabilise clots and reduce need for platelet transfusions
Cell salvage
How much can one unit of RBC increase a patients Hb?
By 10g/L
How does irradiated red blood cells alter the components?
Reduced shelf life from 35 days to 14 days
Reduced red cell membrane stability = Increase in potassium leakage from cells - risk of hyperkalemia not clinically significant unless large volume rapidly transfused or a patient with lower circulating volume, e.g. in neonates
How and why does blood need to be irradiated?
Done by exposing to gamma or x-ray irradiation - destroys donor lymphocytes - prevents transfusion associated graft vs host disease
Indicated severe T cell immunodeficiency of hodgkins lymphoma, stem cell transplants, certain chemotherapies, patients receiving HLA matched
Which patient groups require CMV negative blood products?
All neonates - up to 28 days post expected delivery date
Elective transfusions for pregnant women
Intrauterine transfusions
What is a group and save and how long can samples be kept for?
Blood group and antibody screen tested
Up to 7 days
72 hours if patient pregnant or transfused in previous 3 months
What is crossmatching?
Mixing patients serum against known donor and suspended in saline to ensure compatibility
If sample agglutinates = cannot use this donor
Can be kept for 72 hours
What is an electronic issue?
Patient had group and screen on 2 separate occasions
Antibody screens negative + no pregnancy or transfusions in between tests
Donor blood can be issued directly via electronic system - no need to physically cross match donor and recipient blood
What is the pathophysiology behind a non-haemolytic febrile reaction and how is it managed?
Action of recipients WBCs releasing cytokines and bringing about immune response
Slow or stop transfusion and give paracetamol
Much less common now that RBCs are leukodepleted
Who is at risk for TACO?
Patients with…
Congestive heart failure
Chronic kidney disease
Severe aortic stenosis
Pulmonary oedema
Neonates
What is the main difference between TACO and TRALI in their presentation?
TACO will present with HYPERtension, elevated BNP, diuretics have dramatic effect, NO fever
TRALI will present with HYPOtension, fever, normal BNP and pulmonary infiltrates on chest x-ray, pink stained frothy sputum, diuretics have no effect
Who is at risk of delayed transfusion reactions?
Patients with previous pregnancy or transfusions
Will need more transfusions to manage
What is the pathophysiology behind TRALI?
2 hit theory
- Stressor - primes neutrophils and sequesters them in pulmonary capillaries
- Transfusion activates neutrophils - release cytokines - fluid accumulates in lung interstitium = non-cardiogenic pulmonary oedema
What occurs in an acute haemolytic transfusion reaction?
Due to ABO mismatch - recipients pre-formed antibodies attack donor blood cells leading to intravascular haemolysis
Fever, hypotension, tachycardia, generally unwell
AKI, DIC, flank pain, red/brown urine, jaundice, reduced urine output
How is an acute haemolytic transfusion reaction managed?
Stop transfusion
Maintain blood pressure and renal perfusion
Fluids, furosemide, corticosteroid, adrenaline
Repeat all checks
Repeat testing of all bloods from donor and recipient - cross match
Perform direct coombs test
Perform tests for DIC - coagulation screen
Examine for bacterial examination - if suggestive start IV abx
What are the two lymph ducts?
Thoracic duct (begins at cisterna chyli)
Right lymphatic duct
How does the lymph fluid reach the heart from the lymph ducts?
Lymph ducts drain into the venous angle - between jugular and subclavian vein (good bc low pressure)
Enter superior vena cava to reach right atrium of the heart
What is virchow’s node?
Left supraclavicular lymph nodes
Can be a sign of abdominal or gastric cancer - due to the draining of the thoracic duct
What cells predominant in the cortex, paracortex and medulla of the lymph nodes?
Outer cortex - B cells
Inner/paracortex - T cells
Medulla - B cells, plasma cells, macrophages
What ensures a one way flow system in the lymphatic vessels?
Valves
Movement facilitated by skeletal muscles, smooth muscles of large vessels and thoracic pressure changes pushing on lymphatic vessels
Are there more afferent or efferent vessels in a lymph node and why?
Many afferent vessels arriving into lymph node
Only one efferent vessel leaving lymph node
To ensure all lymph fluid coming in is forced through lymphatic nodules and germinal centres to illicit immune response if necessary before leaving node
What lymph nodes are linked to cervical/ovarian issues?
Para-aortic - lumbar lymph nodes
What are the 4 steps of haemostasis?
Vasoconstriction
Primary haemostasis - platelet aggregation
Secondary haemostasis - coagulation
Fibrinolysis
What are the 3 mechanisms behind vasoconstriction in haemostasis?
Smooth muscle contraction occurs after injury to reduce blood flow = vasospasm/constriction
- Endothelial cells secrete endothelin
- Nerve reflex
- Myogenic spasm from direct injury
What are 3 mechanisms that prevent blood from clotting normally?
- Endothelial cells secrete prostaglandin and nitric oxide which inactivates platelets + stimulates vasodilation
- Heparan sulfate binds to heparin enhancer to activate Anti-thrombin which inactivates factors II, IX, X
- Thrombomodulin on endothelial cell binds to Thrombin(II) to activate Protein C which inactivates and degrades factor V and VII
How do platelets plug to an injured vessel?
vWF bound to collagen exposed in injured vessel.
Collagen binds to platelets via Gp1b = activated platelets
How to platelets aggregate to form a platelet plug?
Platelets link together via GpIIIb/IIa via fibrinogen
What do activated platelets release?
ADP = platelet aggregation
Thromboxane - vasoconstriction + platelet aggregation
Serotonin = vasoconstriction
What are the factors in the intrinsic pathway of the coagulation cascade and how is it activated?
Platelet plug has negative charge surrounding it - this activates factor 12 -> 11 -> 9 -> 8
To then activate factor 10 in common pathway
What are the factors in the extrinsic pathway of the coagulation cascade and how is it activated?
Tissue factor released in tissue injury activates factor 7
Which then activates (with help of more tissue factor) factor 10 in common pathway
What occurs in the common pathway?
Factor 10 and 5 activates prothrombin to thrombin(2)
Thrombin converts fibrinogen to fibrin(1)
Fibrin mesh around platelet plug to stabilise clot = bleeding stopped
What 2 steps need calcium for help in activation in the coagulation cascade?
Activation of factor 10
Factor 10 and 5 for activation of thrombin from prothrombin
How does fibrinolysis occur?
tPA activates plasminogen into plasmin
Plasmin degrades fibrin mesh
What are some fibrin degradation products?
D-dimer
Fibrinogen
What does PT test and when is it prolonged?
Tests secondary haemostasis - the extrinsic and common pathway - factor 7
Prolonged in DIC, Warfarin, Heparin, Liver disease, Vitamin K deficiency
What does the aPTT test and when is it prolonged?
Tests secondary haemostasis - the intrinsic and common pathway - factor 12, 11, 9, 8
Prolonged in Haemophilia, DIC, vWF Disease, Liver disease, Antiphospholipid syndrome, warfarin, heparin
What does the bleeding time test and when is it prolonged?
Tests primary haemostasis
Prolonged in thrombocytopenia, DIC, vWF Disease, Aspirin
How do the symptoms of primary vs secondary haemostasis disorders present?
Primary - prolonged bleeding from initial injury. bleeding from gums, nose, heavy periods, bruising, petechiae
Secondary disorders - bleeding into joints, muscles, tissue, more severe delayed bleeding.
What is the inheritance pattern in vWF Disease and how is it treated?
Autosomal dominant
Tranexamic acid
Desmopressin - stimulates release of vWF
Why does vW disease affect the intrinsic pathway?
Factor 8 circulates in the blood bound to vWF
Deficient/defective vWF leads to factor 8 degredation
What is the inheritance pattern in haemophilia and what factors are deficient in A and B?
X-linked recessive
A - Factor 8
B - Factor 9 - less common
What causes thrombocytopenia via increased destruction of platelets
Autoimmune - SLE, ITP
Non-immune - DIC, TTP
Why can desmopressin be given in Haemophilia A?
Desmopressin stimulates release of vWF
vWF can help stabilise factor 8
What tests can be abnormal in Haemophilia?
Increased aPTT
Decreased serum factor 8/9 assay activity
Genetic mutation testing
How does liver disease induce coagulopathy?
Inability to produce clotting factors - affect secondary haemostasis
Collects platelets - affect primary haemostasis
Unable to clear toxins in bone marrow - depression of bone marrow function
Treat underlying cause of liver disease to treat coagulopathy
What is Factor V Leiden?
Autosomal Dominant Disease - leads to functional mutation of factor 5
Unable to be inactivated by protein C
Increased active factor 5 = hyper-coagulable state = VTE risk
How does renal disease increase coagulopathy?
Depletion/loss of natural anticoagulant proteins - protein c, s, antithrombin
What is first line management in TTP?
Plasma exchange
- Removes the large vWF multimers
- Adds normal ADAMTS13
What is the driving force behind DIC?
TF activates extrinsic pathway which then activates intrinsic pathway
Inappropriate massive activation of clotting cascade = clots in microvasculature
Eventually depletion of clotting factors and platelets = bleeding
Degradation products from fibrinolysis also blocks clot formation
What is the biochemical pattern seen in myeloma - calcium, phosphate, alkaline phosphate
High calcium
Normal or high phosphate
Normal alkaline phosphate
What can trigger a sudden big drop in Hb and low reticulocyte count in anaemia?
Parvovirus - can cause aplastic crises
What can typical iron studies look like in a normocytic anaemia of chronic disease?
Low serum iron
Low TIBC
Raised Ferritin
When do you not give a platelet transfusion even if platelet count<10
TTP
HIT
Chronic bone marrow failure
Autoimmune thrombocytopenia
What interleukin do myeloma cells express a specific receptor for that acts as a major growth and survival factor?
Interleukin 6
What is the normal size of a spleen and at what size is it palpable?
Normal - 12cm
Palpable - 14cm
What are causes of splenomegaly?
Malignant - lymphoma, leukaemia, myeloproliferative disorders
Infective - TB, endocarditis, malaria, leishmaniasis
Vascular - portal hypertension - cirrhosis - alcoholism
Haematological - sickle cell, thalassaemia, haemolytic anaemia
Immunological - RA, sarcoidosis, amyloidosis, felty syndrome
Metabolic - gauchers, neumann-pick
What are causes of hepatomegaly?
Malignant - hepatocellular carcinoma, metastases, lymphoma, leukaemia, myeloproliferative disorders
Haematological - sickle cell
Infective - viral hepatitis, TB, EBV, cysts/abscesses
Congestive - right-sided heart failure, budd chiari syndrome
Inflammatory - alcoholic/autoimmune hepatitis, sarcoidosis
Metabolic - alcoholic liver disease, amyloidosis, haemochromatosis, wilsons
What are causes of bone marrow failure?
MMMMLLAh
Myeloma
Myelodysplasia
Myelofibrosis
Metastatic cancer
Lymphoma
Leukaemia
Aplastic anaemia - fanconi, DBA, drugs, radiation
Haematinic deficiency
How long should the contraceptive pill be ceased before an operation to prevent a PE?
4 weeks before the operation
What could high uric acid, renal impairment, decreased calcium, raised phosphate and potassium following chemotherapy indicate?
Tumour lysis syndrome
In DVT investigation - if the D-dimer is positive but ultra sound is negative and you have started an anticoagulant, what should you do next?
Stop anticoagulant and repeat ultrasound in 7 days
What is the action of Warfarin and what factors does it interrupt the production of?
Competitive inhibitor of Vitamin K reductase
(Vit K is required for synthesis of precursor factors into functional clotting factors)
Factor 2, 7, 9, 10, + Protein C and S
What is the reversal for warfarin?
Stop warfarin
Give vitamin K
Give prothrombin complex if major bleeding and + INR>8
Which DOACs inhibit Factor Xa?
Apixaban
Edoxaban
Rivoroxaban
What drug is a direct thrombin inhibitor?
DOAC - dabigatran
What is the reversal agent of dabigatran?
Idarucizumab
What are the durations for anticoagulation in an provoked, unprovoked scenario, active cancer treatment or recurrent clots?
Provoked = 3 months
Unprovoked = 6 months
Active cancer treatment = 3-6 months
Recurrent = possibly life long
If a patient has Well Score 2+ what is the next step for suspected DVT?
Do a doppler ultrasound
Start anticoagulant if US can not be done within 4 hours
Do d-dimer if US negative
What is the next step if wells score <1 for suspected DVT?
D-dimer test within 4 hours
if raised - then do a doppler ultrasound
What is the mechanism of action of unfractionated heparin?
Activates antithrombin III = inactivates factor IIa, Xa
How is unfractionated heparin monitored and what is the reversal agent?
Monitored using APTT ratio - every 6 hours until patient stable
Reversal agent = protamine
What is the mechanism of action of LMWH?
Mainly inhibits factor Xa
Indirectly through combining with antithrombin
Which drug can cause neutrophilia?
Prednisolone
What is the mode of action of tranexamic acid?
(Synthetic derivative of lysine)
Reversibly binds to lysine receptor sites of plasminogen or plasmin
Prevents plasmin from binding to and degrading fibrin
What is the threshold of haemoglobin levels for a transfusion with red blood cells?
70g/L without ACS
80g/L with ACS
Deficiency in what increases the risk of which blood transfusion reaction?
IgA deficiency increases the risk of anaphylactic blood transfusion reactions
Which antibodies are predominantly involved in acute haemolytic transfusion reactions?
IgM antibodies cause red blood cell destruction
Which anaemia causes an increase in red blood cells?
Thalassaemia
because need more red blood cells as they are small and have less Hb
What is the translocation in APML?
15 and 17
Fusion of PML and RAR- alpha genes
Associated with DIC
What is the translocation in Burkitt’s Lymphoma?
8 and 14
What is the translocation in follicular lymphoma?
14 and 18
What is the translocation in mantle cell lymphoma?
11 and 14
What are the electrolyte changes in tumour lysis syndrome?
HIGH - potassium, uric acid, phosphate
LOW - calcium
What are symptoms of tumour lysis syndrome?
Abdominal pain
Weakness
Nausea and vomiting
Diarrhoea
Dysuria/oliguria
What are complications of tumour lysis syndrome?
AKI
Cardiac arrhythmias
Seizures
Death
What is the prophylaxis and treatment that can be used in tumour lysis syndrome?
Prophylaxis high risk:
- IV allopurinol or IV rasburicase
- Fluid hydration
TX: rasburicase + IV fluids + electrolyte imbalance correction
Prophylaxis low risk:
- Oral allopurinol
- Fluid hydration
TX: allopurinol + IV fluids + electrolyte imbalance correction
What is the triad of symptoms for Hemolytic-uremic syndrome and what commonly causes it?
- Microangiopathic haemolytic anaemia
- Thrombocytopenia
- Acute Kidney Injury
Commonly caused by strains of E.coli -> release shiga-like toxin that damages lining of blood vessels
Nonimmunologic platelet destruction. Endothelial damage is common. Loose strands of platelets and fibrin are deposited in multiple small vessels and damage passing platelets and red blood cells (RBCs), causing significant thrombocytopenia and anemia (microangiopathic hemolytic anemia). Platelets are also consumed within multiple small thrombi, contributing to the thrombocytopenia.
What is hereditary haemorrhagic telangiectasia?
Autosomal dominant condition of abnormal blood vessel formations which causes bleeding
- Telangiectasia and AVM formations
What is the immune mechanism behind heparin-induced thrombocytopenia
Heparin binds to protein on inactivated platelets to form complex ⇒ Heparin-PF4
- The Heparin PF4 complex can be immunogenic in certain people
- Recognised by circulating IgG antibodies in the blood
- IgG bind mark the H-PF4 complex for destruction within the spleen
- Antibody binding to platelet activates it → release procoagulant chemicals which triggers platelet aggregation
- Form clots within the body
