All lectures Flashcards
Glycolysis is the ____ step in the breakdown of glucose to extract energy.
first
Glycolysis does not use ?
Oxygen
Describe the first phase of glycolysis
First traps the glucose molecule and uses energy to modify it: the six-carbon sugar molecule is split into two three-carbon molecules
Describe the second phase of glycolysis
The second extracts energy from the molecules and stores it in the form of ATP and NADH (one enzyme is pyruvate kinase)
What do reactive oxygen species do?
- Converts ferrous of haemoglobin to ferric of methaemoglobin
- Damage lipid membrane: short life span
What does glutathione do?
Scavenges reactive oxygen species
- Oxidized form is regenerated by glutathione reductase
- Hexose monophosphate shunt generates the necessary NADPH and uses G6PD
What is EPO or erythropoietin?
The hormone which controls red cell production: it works on red cell precursors in the bone marrow and promotes differentiation
EPO is produced where?
Kidney under hypoxic stress
Where is EPO produced in the foetal and perinatal period?
Liver
Where is EPO produced in adults?
Kidney
What is the definition of anaemia?
- Reduction in red cell number and haemoglobin concentration of blood
- Haemoglobin is the oxygen carrying pigmented protein in red cells
- Consequently anaemia is important as it results in a reduction in the oxygen carrying capacity of the blood
Symptoms of anaemia
- Tiredness, headaches
- Dizziness
- Shortness of breath
- palpitations
- Chest pain
What are signs of anaemia?
- Pallor: conjunctivae, palmar creases
- Cardiac decompensation: tachycardia, postural hypotension, congestive cardiac failure
Which signs of anaemia which provide a clue to aetiology?
- Angular stomatitis, glossitis, koilonychia
- Jaundice
- Underlying illness: systemic illness, primary bone marrow pathology
How is anaemia defined by laboratory indices?
Reduction in red cell number and haemoglobin concentration of blood
Useful laboratory indices for anaemia ?
- Haemoglobin (Hb)
- Mean corpuscular volume (MCV)
- Blood film
- Reticulocyte count
Describe properties of full blood count or FBC
- EDTA anticoagulated venous blood sample
- Objective
- Accurate and reproducible
- Rapid
How is haemoglobin measured?
Aliquot lysed by laurel sulphate, read by sphectrophotometry @ 540 nm
How is Red blood cell count measured?
Directly measured by particle counter (impedance: passage of cell impedes current and creates a pulse)
How is mean corpuscular volume measured? (MCV)
Directly measured electronically (impedance)
How is MCHC measured?
Calculated from haemoglobin and haematocrit
How is haematocrit measured?
Calculated from red cell number and MCV
How are white cells and platelets measured?
Measured optically via electrical impedance, light scatter, fluorescence and laser
Haemoglobin levels in pregnancy?
10-20 lower due to disproportionate rise in plasma and red cell volumes
Normal haemoglobin levels (g/L) in newborn?
145-220
Normal haemoglobin level (g/L) in 3-6 months?
110-135
Normal haemoglobin levels (g/L) in 6-12 years?
115-155
Normal haemoglobin levels in males?
130-170
Normal haemoglobin levels in females?
120-160
Normal reference range for MCV?
80-100
Reduced MCV means?
Microcytic anaemia
Normal MCV means?
Normocytic anaemia
Increased MCV means?
Macrocytic anaemia
Purpose of blood film?
- It validates machine cell counts and indices
- Looking for specific morphological findings
Blood smears are?
Dried and stained
Principle of Romanowsky stains?
- Basic cellular elements react with an acidic dye (eosin) and stain red-orange, e.g. haemoglobin
- Acidic cellular elements react with a basic dye (methylene) and stain blue, e.g. nuclear DNA
Describe journey of red cell development
- proerythroblast
- Basophilic erythroblast
- Polychromatic erythroblast
- Pyknotic erythroblast
- Reticulocyte
- Mature red blood cell
Length of bone marrow proliferation and maturation?
3-5 days
Length of reticulocytes from bone marrow to blood?
3-4 days
How long does a mature red cell circulate for?
120 days
What nutrients are required for DNA synthesis and nuclear maturation?
Vitamin B12 and folate
What are reticulocytes ?
- Young immature red cells
- Residual RNA
- Therefore they have a blue blush
- On a blood film this is called polychromasia
Reticulocyte count is identified by?
Staining residual RNA
Manual way of identifying reticulocyte count?
Residual RNA precipitated and stained with a supravital dye (New methylene blue) and manually counted)
Automated way of counting reticulocyte?
Residual RNA stained with fluorescent dyes (green) and enumerated by flow cytometry
Reference range of reticulocyte count ?
50-100 x 10^9 / L or 0.5-2.0%
List cause of anaemia
- Decreased production: deficiencies of iron, B12, folate
- Systemic illness, primary bone marrow pathology
- Increased loss of blood (bleeding)
- Shortened life span or increased destruction (haemolytic anaemias), either inherited (e.g. thalassaemias) or acquired autoimmune)
Anaemia with decreased or increased white cells and/or platelets due to primary bone marrow pathology when?
When more than one cell line is abnormal
Anaemia is NOt a?
Diagnosis
MCV < 80fL means?
Iron deficiency due to chronic blood loss.
Inherited Hb abnormality: the thalassaemias
MCV normal means?
- Acute blood loss
- Systemic illness
- Primary BM pathology
MCV > 100 fL means?
- B12 and folate deficiency
- Haemolysis
- Liver disease
What is anisopoikilocytosis?
Iron deficiency anaemia. Hypochromic microcytic cells.
In B12 or folate deficiency, what happens to RBCs?
Macrocytes
Spherocytes occurs?
Haemolysis
What happens in polychromasia?
Abnormally high number of immature red bloo cells
What happens in sickle cell anaemia?
An inherited abnormal haemoglobin, aren’t enough red blood cells to carry oxygen because they’re mishapen and break down faster than normal.
Rouleaux disease is?
RBCs stacking together due to discoid shape and flat surface. Occurs in myeloma
What happens in acute leukaemia?
Immature white blood cells (blast cells) continue to divide but doesn’t mature
Increased reticulocytes means?
Increased bone marrow production
What can increase bone marrow production?
- Acute haemorrhage
- Reduced red cell life span: haemolysis
- Response to replenished iron, B12 and folate
Normal or reduced reticulocytes means?
Reduced bone marrow production
What can reduce bone marrow production?
- Not enough iron, B12 and folate
- Systemic illness
- Bone marrow pathology
Iron studies can test for?
Transferrin saturation and ferritin
Haemolytic screen can test for?
- Bilirubin, LDH, haptoglobin, DCT
Tests of inherited causes of haemolysis look at?
Haemoglobin, red cell membrane and red cell enzymes.
Lab test for creatinine looks at?
Renal impairment
Serology tests look for?
Autoimmune diseases
Liver function tests look for? (LFT’s)
Hepatic dysfunction
Which diseases should be considered when primary bone marrow pathology is diagnosed? (more than one cell line is affected)
- Leukaemia
- Lymphoma
- Myeloma
- Myeloproliferative disease
- Secondary carcinoma
Bone marrow biopsy are performed to?
Confirm or exclude a suspected diagnosis
Procedure of bone marrow biopsy?
- Site: posterior iliac crest or sternum, tibia in neonates
- Aspirates: to assess cell number, maturation and morphology
- Trephine: to assess cellularity, architecture and abnormal cellular infiltrate
Treatments of anaemia?
- Transfusion: only indication is circulatory compromise: acute severe blood loss, circulatory failure especially in the elderly
- Replace missing iron, B12 and folate
- Rectify shortened life span, in case of haemolysis
- Treat underlying condition
Life span of neutrophils?
3-4 days unless digesting bacteria
Life span of eosinophils?
3 weeks
Life span of basophils?
3-10 days
Life span of B cells?
4 days to 5 weeks
Life span of T cells?
Couple days to months
Life span of monocytes?
1 week
Life span of platelets?
7-10 days
Lymphoid stem cells develop into?
Lymphoblast, which then develops into:
- B lymphocyte
- T lymphocyte
- Natural killer cells
Myeloid stem cells develop into?
- Red blood cells
- Platelets
- Myeloblast which develop into: granulocytes (basophils, eosinophils, neutrophils)
0-2 months foetus blood production?
In yolk sac
2-7 months foetus blood production?
Liver, spleen
5-9 months foetus blood production?
Bone marrow
Infants blood production where?
Mostly bone marrow (long and flat bones)
Adults blood production where?
- Bone marrow in all regions of flat bones and extremities of long bones (e.g. vertebrae, ribs, sternum, skull, sacrum and pelvis, proximal ends of femur)
- Extra-medullary depends on need
Mature RBC does not have?
- No DNA
- No RNA
- Cannot synthesize Hb
Reticulocytes does not have?
- Doesn’t have nucleus,
- Reduced size
- Still contains some RNA
Reticulocyte moves into peripheral blood and final maturation by?
Repeated passage through spleen/marrow in peripheral blood circulation ~ 48 hours
Orthochromatophilic erythroblast/normoblast haemoglobin percentage?
35%
What are basophilic erythroblast?
Nucleus condensing, haemoglobin formation
What are polychromatophilic erythroblast?
Cells getting smaller, losing organelles, nucleus shrinking, producing Hb
Haemoglobin is broken down into ?
Globin and heme, and amino acids.
Heme becomes bilirubin, which is?
Bilirubin is picked up from blood by liver, secreted into intestine in bile, metabolized to stercobilin by bacteria and excreted in feces.
Iron is stored as?
Ferritin and haemosiderin in liver
Essential factors of erythropoiesis?
- Hypoxia inducible factors
- Haematinics (e.g. b12, cobalamin, B9, folic acid/folates, iron - transferrin - macrophages
Control of erythropoiesis:
- Hypoxia, anaemia
- Thyroid hormones, androgens, growth hormone, corticosteroids
Essential organs of erythropoiesis?
- Bone marrow
- Kidney, liver, spleen, gastrointestinal
Destruction of erythrocytes?
Macrophages, haem breaks down to iron and bilirubin (colour)
Critical biosynthesis in erythropoiesis?
DNA synthesis, Hb synthesis
Causes of iron deficiency anaemia?
- Increased iron requirements: growth demands
- Limited external supply: poor intake, malabsorption
- Blood loss: bleeding, venesection
Stain for haemoglobin?
Hb is basic component, so use acidic dye (eosin) - red/orange .
Stain for DNA?
DNA is acidic, so use basic dye (methylene) - blue
MCV is?
Mean corpuscular volume or the average volume of red cells.
Causes of microcytic anaemia?
- Iron deficiency anaemia
- Thalassaemia (genetic disorder, abnormal Hb)
Describe vitamin b12 absorption
- Dietary B12 intake,
- Dietary protein separated from B12 due to HCl and pepsin secretion
- Haptocorrin binds to B12 protein
- Complex goes to intestine where B12 binds to intrinsic factor
- B12- intrinsic factor complex binds to cubman receptor which then allows it to separate, and be absorbed through MDR1 channel into blood vessels.
Vitamin B12 or folate deficiency leads to?
Macrocytic anaemia due to impaired DNA synthesis
Lack of Vitamin B12 or folate are caused by?
- Insufficient intake
- Deficient absorption: due to gastrectomy and/or autoimmune attack such as pernicious anaemia
Causes of normocytic anaemia?
- Decreased production: anaemia of chronic disease (common)
- Increased destruction or loss: acute bleeding, hypersplenism, haemolytic disorders
- Increased plasma volume: pregnancy
What are the prevalence of anaemia?
- ~8% of preschool children
- 12% of pregnant women
- 15% of non-pregnant women of reproductive age
- Highly prevalent in Indigenous communities
Symptoms of anaemia? (subjective phenomenon)
- Tiredness
- Dizziness
- Palpitation
- Headache
Signs of anaemia (objective phenomenon)
- Pallor: conjunctivae, skin, oral mucosa
- Jaundice
- Koilonychia (spoon nails)
What does atrophic glossitis look like? (due to anaemia)
- Smooth glossy appearance with red or pink background tongue
What does angular cheilitis as a oral manifestation of anaemia?
- Inflamed and cracked skin at the angles of the mouth
What’s lymphoma?
Malignant disease in which lymphocytes proliferate in an uncontrolled manner leading to lymphocyte accumulation in lymph nodes (one or more of neck, axillae, thorax, abdomen, inguinal) and/or lymphocyte accumulation in bone marrow
Lymphoma results in?
Lymph node enlargement (isolated or generalised) and occasionally
- Marrow failure (anaemia, lecopenia, thrombocytopenia)
Epidemiology of lymphoma
5th and 6th most common cancers among males and females in Australia and USA.
Lymph node groups exist where?
- Adenoid
- Tonsils
- Thymus
- Spleen
- Bone marrow
- Lymphatics of mammary gland
Common lymphoid progenitor differentiates into?
- T-lymphocyte
- B-lymphocyte
- NK cells
Common myeloid progenitor differentiates into?
- MEP -> Megakaryocyte, erythrocyte
- GMP -> Granulocyte, monocyte
Which lymphoma is more common?
B cell lymphomas are much more common than T cell lymphomas.
T cell lymphomas are much more common than NK cell lymphomas.
B cells function?
Make antibodies
T cells function?
Fight viruses, fungi and tumours (specific)
NK cells function?
Fight viruses, fungi and tumours (non-specific)
Each lymphocyte (B or T) has one receptor for antigen on its surface and responds to only?
One antigen
T or B lymphocyte antigen receptor remains?
Remains unchanged for the whole of the lymphocyte’s life.
Describe what happens in a lymphoma
- All cells share the same B cell (or T cell) receptor and the same B cell (or T cell) receptor gene sequence
- If B cell, all cells express a single type of light chain (k/l) kappa or lamda
- All cells express the same differentiation proteins on their surface
- If the parent B cell produces antibody, all lymphoma cells produce that same antibody (paraprotein)
List two types of lymphoma
- Non-Hodgkins lymphoma
- Hodgkins lymphoma
Typical histological appearance of lymphocyte
Small cells with little cytoplasm
Flow cytometry for identifying lymphocyte populations
Examining the surface proteins (most have been assigned CD (or cluster of differentiation) numbers. A monoclonal population of mature B cells expresses either kappa or lambda light chains, not both.
List tests for cytogenetics and molecular genetics - changes in chromosomes or genes that are on chromosomes
- Cytogenetic analysis - karyotype
- Fluorescence in situ hybridisation (FISH)
- Polymerase chain reaction (PCR) ie DNA amplification
How does FISH (fluorescence in situ hybridisation) work?
Probes to specific genetic locations are used to track the position of those locations in the cell: identifies translocations such as those involving bcl-2, c-myc etc
How does polymerase chain reaction (PCR) work?
Identifies stretches of DNA by amplifying an intervening section through forward and reverse primer sequences e.g. translocation of bcl-2 and IgH in follicular lymphoma
List major classes of non-hodgkin’s lymphomas
- Indolent (low-grade, slow-growing): follicular, marginal zone, other
- Aggressive (intermediate and high-grade, fast-growing): diffuse large B cell lymphoma, Burkitt’s lymphoma, other
How do indolent NHLs present?
Slow growing but often widespread.
Typically asymptomatic at diagnosis.
“watch and wait” strategy can be used with low tumour burden of disease.
Responds to treatment but relapses.
Not considered curable.
can transform to higher grade lymphoma (3% annually)
Most common type of indolent lymphoma?
Follicular lymphoma is the most common indolent lymphoma. Others include marginal zone lymphoma, Waldenstrom’s macroglobulinaemia)
Describe aggressive NHLs
- Most often symptomatic at diagnosis
- Quite often localised at diagnosis
- Progresses relatively rapidly without treatment
- Cause death within months to 1-2 years if not effectively treated
- Always aggressively treated in fit patients
Most common aggressive lymphoma?
diffuse large B cell lymphoma,
Describe DLBCL (diffuse large B cell lymphoma)
- Diffuse infiltrate of large B-cells in node
- Patients of all ages
- 50% curable with chemotherapy, those that relapse progress and die of lymphoma
- some relapsing patients can be salvaged with a stem cell transplant usually the patient’s own stem cells
Describe Burkitt’s lymphoma
- Aggressive lymphoma with a particular genetic alteration involving a translocation between chromosomes 8 and 14 or (t8:14) that juxtaposes the c-myc oncogene and the IgH gene
- Cells have a very high mutation rate
- Specific morphology (starry sky appearance)
- Affects all ages and has a predilection to involve the ileum and the nervous system
- Requires aggressive multiagent chemotherapy that can be curative
Describe Waldenstroms macroglobulinaemia
- An indolent lymphoma of lymphoplasmacytoid cells in the bone marrow
- Characterised by lymphoplasmacytoid morphology and the presence of an IgM paraprotein
Waldenstroms macroglobulinaemia is frequently associated with which mutation?
L265P in the MyD88 signalling pathway protein
Waldenstroms macroglobulinaemia is often associated with?
Anaemia and splenomegaly.
Waldenstroms macroglobulinaemia is not treated?
Not treated aggressively as many cases slow to progress
3 types of biopsy available for lymph nodes?
- Fine needle biopsy
- Core biopsy
- Surgical biopsy (partial or complete excision)
Surgical biopsy provides what details?
- Cell detail
- Architecture
- Flow cytometry
- Immunohistochemistry
- Genetics
- Accurate diagnosis and classification
Core biopsy provides what details?
- Uses ultrasound
- CT if excision is difficult e.g. node site, age, patient co-morbidities
- Limited material and architecture
Fine needle biopsy gives what details?
- Only cytology and flow cytometry, but never gives architecture and is inadequate for initial diagnosis
- Used as an initial screen to exclude other cancers or to confirm relapse in a case of a known lymphoma.
Immunopehnotyping is important for?
Lymphoma diagnosis and classification
- Detects antigen expression (e.g. CD19, CD20, CD5, CD23) and monoclonality using kappa and lambda
- Can be done on tissue by flow cytometry and immunohistochemistry
- Blood and BM using flow cytometry
What is Ann Arbor Staging system?
- Originally used for staging HL; adopted for NHL
- Accounts for: number of disease sites, presence of disease above or below diaphragm, presence of extranodal disease, systemic symptoms
- Used to distinguish local from extensive disease
Risk factors for diffuse large B cell lymphoma?
- AGe > 60 years
- Stages 3 or 4
- More than 2 extranodal sites
- ECOG performance status greater or equal 2
- LDH > normal
Chemotherapy for lymphoma include:
- Chlorambucil
- Cyclophosphamide (C)
- Doxorubicin (H)
- Vincristine (O)
- Prednisone (P)
Immunotherapy for lymphoma include:
Rituximab (R)
What is CD20 molecule
- Transmembrane phosphoprotein
- Single extracellular loop
- Natural ligand not identified
- Physiologic function uncertain
- Expressed on most B-cell malignancies
- Resistant to internalisation or shedding after ligation by antibody.
What is the drug for CD20
Rituximab: a therapeutic anti-CD20 antibody
Function of rituximab
Binds CD20 molecule present on normal and malignant B cells.
Improves response rate in B cell lymphomas when given with chemotherapy
Rituximab is used routinely as maintenance therapy in?
Low grade lymphoma after completion of chemo-immunotherapy where it prolongs survival
Rituximab is used routinely in DLBCL where it?
Improves response rate and overall survival
Rituximab is also used in many ?
Non-lymphoma situations especially where pathological auto-antibodies are formed.
Example of immunomodulating drugs in treatment of lymphoma
Lenalidomide
Proteosome inhibitor in treatment of lymphoma
Bortezomib
List B cell receptor signalling inhibitors in treatment of lymphoma
Ibrutinib, idelalisib
List BH3 mimetics that induce apoptosis in treatment of lymphoma
ABT-199
Describe inhibitors of B cell receptor signalling pathways
- Fostamatinib inhibit SYK,
- GS-1101 inhibits PI3ko
- Ibrutinib inhibits BTK which inhibits NF-kb production
Lenalidomide inhibits IR4F because?
If IR4F is not inhibited, it upregulates CARD11 and downregulates IRF7 and IFN-beta
Sickle cell anaemia is caused by the homozygous haemoglobin mutation?
Glu6 Beta- > val, which aggregates as rigid 14-strand fibres.
Which haemoglobin causes sickle cell anaemia?
haemoglobin S
Function of quinoline?
These anti-malarial drugs such as quinine, chloroquine, and mefloquine inhibit the chemical polymerisation of haem which accumulates in the parasite and kills it.
Malarial parasites does what?
Proteolyse haemoglobin, and synthesizes parasitic proteins.
What’s thalassaemia?
Normal globin chains are produced but in reduced quantity
Examples of abnormal globin chains produced in normal quantity?
Sickle cell anaemia, haemoglobin C or haemoglobin E disease
In thalassaemia, what are the major consequences of reduced production of one type of globin chain are:
- The reduced production of functional haemoglobin tetramers
- An imbalance in synthesis of individual alpha and beta subunits
What is beta thalassaemia?
If an abnormal gene reduces the rate of production of beta globin chains and excess alpha chains accumulate.
What is alpha thalassaemia?
When alpha globin chain production is reduced, and excess beta chains accumulate
Which chromosome encodes for alpha globin chain production?
Chromosome 16, making for a total of 4 genes encoding alpha chains (2 genes per chromosome)
Which chromosome encodes for beta globin chain production?
Chromosome 11, total 2 genes (1 gene per chromosome)
Most cases of beta thalassaemia are due to?
point mutations
Most cases of alpha thalassaemias are due to?
Deletions, although some point mutations are also recognised.
What is SOCRATES method?
Site, onset, character (type of pain), radiation, associated feature, timing, exacerbation or relieving factors, severity
Associated symptoms with anaemia
Fatigue, weakness, dyspnoea, palpitations, headache, dizziness, tinnitus
Associated symptoms with neutropenia
Unusually severe or recurrent infections
Associated symptoms with thrombocytopenia
Easy bruising, excessive bleeding after trauma, spontaneous bleeding from mucous membranes
Associated symptoms with defective coagulation
Excessive bleeding after trauma, spontaneous bleeding into joints and muscles
Associated symptoms with leukaemia and lymphoma
Lumps caused by lymphadenopathy, pain
Pallor possibly means?
Anaemia
Lemon tint on face means?
Megaloblastic anaemia
Jaundice on face means?
Haemolytic anaemia
Plethora on face means?
Polycythaemia
Ulcers in mouth possibly means?
Neutropenia
Glossitis in mouth possibly means?
Megaloblastic anaemia; iron deficiency anaemia
Angular chelitis in mouth possibly means?
Megaloblastic anaemia; iron deficiency anaemia
Oral thrush in mouth possibly means?
Immunosuppression
Excessive bruising on skin possibly means?
Coagulation disorder, thrombocytopenia
Purpuric or petechial rash possibly means?
Thrombocytopenia
Leg ulcers possibly means ?
Sickle cell anaemia
Localised lymphadenopathy common causes?
Local bacterial, or viral infection, lymphoma, metastatic malignancy
Generalised lymphadenopathy common causes?
Systemic infection, lymphoma, leukaemia, inflammatory disease, disseminated malignancy
Slightly enlarged spleen are caused by?
Various acute and chronic infection
Moderate enlarged spleen are caused by?
Haemolytic anaemia; infectious mononucleosis; portal hypertension
Massive enlarged spleen are caused by?
Myelofibrosis; chronic myeloid leukaemia; polycythaemia vera; lymphoma; malaria; leishmaniasis
Consistent markers of malnutrition in measuring weight?
> 2% in 1 week, 5% loss in 30 days, > 7.5% in 3 months, 10% loss in 180 days BMI <21
Jaundice is due to?
Release of unconjugated bilirubin from lysed red cells
All patients with haemolytic anaemia are at risk of?
Developing aplastic anaemia
Aplastic anaemias are often associated with which oral manifestations?
Oral petechiae, gingival hyperplasia, spontaneous gingival bleeding and increased incidence of oral herpetic lesions
Iron deficiency signs include?
Koilonychia (spoon-shaped nails) pruritis and pica.
Epithelial atrophy of the oral mucosa, loss of filiform and fungiform papillae, red shiny smooth atrophic tongue which is often painful (glossodynia), oral ulcerations, angular cheilitis, candidosis, xerostomia
Plummer-Vinson syndrome features?
Dysphagia, presence of a ‘pharyngeal web’ and a high incidence of oral and oro-pharyngeal carcinoma.
Painful glossitis or burning tongue may be a manifestation of?
Vitamin B12 or folate deficiency
Painless glossitis is generally associated with?
Iron deficiency.
What is the most common metabolic disorder of red blood cells?
X-linked glucose-6-phosphate dehydrogenase deficiency (G6PD)
Haemolytic crisis may be facilitated by?
Decreased oxygenation, oxidative drugs such as sulphonamides, chloramphenicol, aspirin by infections or eating fava beans.
Congenital haemolytic anaemias features?
Delayed eruption of teeth or discoloured teeth.
Anaesthetic medication for patients with anaemia?
Prilocaine and articaine could cause methaemoglobinaemia.
What is methaemoglobinaemia?
Rare blood disorder where the blood is unable to carry oxygen to cells in the body
How is methaemoglobinaemia caused?
The condition occurs when normal haemoglobin which containing Fe2+ is changed to abnormal haemoglobin called methaemoglobin which contains Fe3+.
Analgesic medication for patients with anaemia
Aspirin/NSAIDs could cause platelet dysfunction, gastritis, acidosis; acidotic drugs cause haemolysis in congenital anaemias, so avoid paracetamol and codeine in the G6PD patient.
Sedation medication for patients with anaemia?
Myelopathy and neuropathy caused by nitrous oxide toxicity. Nitrogen dioxide inactivates the cobalamin form of Vitamin B12 by oxidation. It can occur within days or weeks of exposure to nitrogen dioxide anaesthesia in people with subclinical vitamin B12 deficiency
Antibiotics for patients with anaemia?
No sulpha drugs with G6PD deficiency
Arterial supply of spleen?
Splenic artery and venous blood into portal circulation
In the spleen, the arteries supplying blood to the spleen are surrounded by a sleeve of lymphocytes consisting principally of?
T cells
Along the sleeve of lymphocytes surrounding arteries to spleen, the follicles consisting of mantle zones and germinal centres containing B cells form.
True
Mantle zones and germinal centres containing B cells are known as?
White pulp
Arteries that open out onto the splenic cords, a meshwork of fibroblasts and macrophages and terminate in close proximity to the splenic sinuses are known as?
Red pulp
spleen function?
Serves as a filter culling defective or abnormal red blood cells and retaining platelets, reticulocytes and lymphocytes.
Under normal circumstances, there is no ______ in the spleen beyond the 5th month of in utero life.
Haemopoiesis
Describe congestion as a cause of splenomegaly
Any cause of increased portal pressure (portal hypertension) will lead to splenomegaly. These include right heart failure, hepatic vein thrombosis, hepatic cirrhosis from any cause, hepatic sinusoidal obstruction and portal vein thrombosis
Describe increased phagocytic activity in splenomegaly
This may be due to abnormal red cells such as hereditary spherocytosis, thalassaemia, autoimmune haemolytic anaemia or to acute or chronic infections, including Epstein Barr infection, cytomegalovirus or malaria. Lymphoid hyperplasia may play a role in the splenomegaly associated with infections.
List other causes of splenomegaly
Infiltration by abnormal cells, haemopoietic or lymphoid type. Acute and chronic leukaemias, lymphoma, myeloproliferative disorders.
Rarely: rheumatoid arthritis, sarcoidosis, thyrotoxicosis.
Which viruses cause bone marrow failure?
Parvovirus, hepatitis viruses
Which drugs cause bone marrow failure
Anti-cancer drugs
What is SCT?
Stem cell transplantation
List types of SCT?
Autologous, syngeneic, unrelated donor, and haplo-identical parent.
Stem cells can be obtained from?
Bone marrow, peripheral blood and umbilical cord blood
Allogeneic grafts does what?
Initiate immune reactions related to histocompatibility.
The aggregate of oligopeptides displayed is determined by?
Binding specificities of a person’s HLA molecules.
T cell receptors interact with?
Surface glycoproteins and bound peptides
Donor T cells recognise recipient antigens and can cause?
Graft versus host disease (GVHD)
List complications of stem cell transplantation?
- Mucositis: oropharyngeal mucositis is painful and can involve the supraglottic area and require intubation. Intestinal mucositis causes nausea, cramping and diarrhea.
- Hepatic veno-occlusive disease, a potentially fatal syndrome of painful hepatomegaly, jaundice and fluid retention.
- Lung injury
- Related infections
- Acute GVHD damages the skin, gut and liver
- Profound immunodeficiency,
- Predisposing patient to fatal infection
- HA mismatch
Hodgkin’s disease presents most commonly as?
As a group of firm, non-tender, enlarged lymph nodes and in more than half of cases. It is mediastinal or cervical nodes that are involved.
People with Sjogren syndrome are at increased risk of?
Lymphoma
Intraoral lymphoma usually involves?
Waldeyer’s ring (oropharynx and soft palate), but may appear anywhere in the oral cavity as a rapidly expanding swelling.
Multiple myeloma may present with?
Normochromic, normocytic anaemia.
Multiple myeloma can develop?
Renal impairement and hypercalcaemia can develop with the formation of osteolytic lesions.
Chemotherapy for myeloma?
Biphosphonates and these drugs are associated with BONJ (biphosphonate-associated osteoradionecrosis of the jaws)
Impaired vitamin K absorption or metabolism can lead to?
Profound coagulopathy, manifested by haemorrhagic episodes and a prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT)
Impaired vitamin K absorption can occur?
can occur in malabsorption, liver disease, vitamin K deficiency (e.g. in malignancy), and oral anticoagulant.
LIver disease can result in?
Bleeding diathesis which includes depletion of vitamin K-dependent clotting factors, failure to clear activated clotting facotrs, thrombocytopenia due to portal hypertension and hypersplenism and abnormal fibrinogen.
In severe liver disease, what does it manifest as?
Prolonged PT, APTT, with variable but usually mild thrombocytopenia.
Defibrination syndrome or disseminated intravascular coagulation (DIC) in general has one or two possible causes?
- Release of pro-coagulant material into the circulation (amniotic fluid embolism, or metastatic malignancy)
- Widespread vascular damage (sepsis, e.g. E. coli or Meningococcus)
Resultant coagulpathy due to DIC is due to?
consumption of clotting factors, especially factors V, VIII, fibrinogen, and platelets and this may lead to significant bleeding or even thrombosis.
Therapy for DIC revolves around?
Removal of triggers, alleviation of acidosis, hypoxia, shock and correction of the coagulopathy by factor replacement with fresh frozen plasma, cryoprecipitate and platelets.
Acquired anticoagulants usually?
Factor 8 inhibitors, these are rare but may occur with rheumatoid arthritis, pregnancy or old age. May regress spontaneously or require immunosuppressive therapy.
Anticoagulant excess with heparin is not uncommon in a hospital setting and may lead to?
Retroperitoneal or other haemorrhage.
What is HITS?
Heparin induced thrombocytopenia syndrome characterised by thrombocytopenia due to heparin-dependent antibodies and a paradoxical tendency to develop arterial thrombosis
What is Vitamin K essential for?
Normal synthesis of factor 2, 7, 9 and 10.
Impaired vitamin K metabolism leads to?
Profound coagulopathy, haemorrhagic episodes, prolonged prothrombin and partial thromboplastin time, e.g. malabsorption, liver disease and oral anticoagulant overdose.
Heparin overdose may lead to?
Retroperitoneal or other haemorrhage
Defibrination syndrome in general has which causes?
- Release of procoagulant material into the circulation (amniotic fluid embolism or fat embolism); or widespread vascular damage (E. coli or meningococcal septicaemia).
Resultant coagulopathy is due to?
Consumption of clotting factors, 5, 8, fibrinogen and platelets
Haemophilia A is?
Gene disorder in distal end of the long arm of X chromosome (Xq28), resulting in a deficiency of plasma factor 8 activity.
30% of haemophilia A are caused by?
Sporadic mutation
What is lyonisation?
Skewed x-inactivation
What is haemophilia B (christmas disease)
X-linked recessive genetic disorder resulting in deficiency of factor 9 activity. About 75% of mutations in haemophilia B are missense substitutions.
Where is factor 9 is synthesized exclusively in?
Liver
What happens in von Willebrand’s Disease (vWD)?
Plasma level of factor 8 may be reduced as a secondary phenomenon. Bleeding time roughly reflects vWF function and may be prolonged in vWD. Specific antibodies are used to detect the molecule as vWF:Ag.
What’s a good test for von Willebrand’s Disease?
Ristocetin co-factor test measures the agglutination of normal platelets suspended in patient plasma and is diminished in vWD.
Hallmarks of vWD?
Mucosal bleeding and occasional joint bleeds
Most prominent symptom of haemophilia?
Bleeding, particularly into the joints or muscles.
Haemarthrosis commonly affecting the hinged joints (ankles, knees, elbows)
Chronic arthropathy eventually leads to?
Fibrosis of the synovium and capsule and reduced swelling.
When does chronic arthropathy usually develops around?
Second decade of life or earlier
In a single fetus pregnancy, what happens to plasma volume?
40-50% increase
Iron absorption increases in?
Pregnancy, but not sufficient to compensate for inadequate stores commonplace in women of childbearing age.
During pregnancy, what happens to folate requirements?
Doubles, due to fetal and placental growth and the increase in red cell mass.
Pregnancy stimulates production of?
Transferrin which elevates iron binding capacity.
Most useful measures of iron and folate status in pregnancy?
Serum ferritin and red cell folate.
What is a significant complication of pregnancy and the post-partum period in coagulation?
Thromboembolism
Pregnancy’s hypercoagulable state develops as a ?
Protective mechanism such as fibrinogen rising 2 to 3 folds.
Patients who are susceptible to DVT are often?
Medicated with anti-coagulants
Patients who use aspirin may inhibit?
May inhibit platelet thromboxane production and platelet aggregation. This can increase bleeding risks.
NSAIDs also block formation of?
Blocks formation of thromboxane A by inhibition of platelet cyclooxygenase.
How does warfarin work?
It is an oral anticoagulant that inhibits the biosynthesis of vitamin K-dependent coagulation proteins (Factor 7, 9, 10 and prothrombin). It affects both intrinsic and extrinsic pathways.
Which test is used to determine safety of warfarin?
INR test, 24 hours before surgery. If below 2.2, it is safe.
Which drugs can increase warfarin effect?
- Several antibiotics: metronidazole, erythromycin, penicillin G)
- Antifungals (miconazole, and fluconazole),
- Chloral hydrate
- NSAIDs
Patients receiving haemodialysis are given?
Heparin
New Oral Anticoagulants NOACs (e.g. apixaban, dabigatran, rivaroxaban) pose?
Poses considerable patient safety risk.
Prothrombin time tests extrinsic pathway for ?
Factors 2, 5, 7, 10. Prolonged in liver disease, vitamin K deficiency, oral anticoagulants
Activated partial thromboplastin time (APTT) tests intrinsic pathway for?
Factors 8, 9, 11, 12 10.
Prolonged in factor 8, 9 deficiency (HAemophilia A, B; non Willebrand’s disease); inhibitors e.g. heparin, lupus anticoagulant)
Recommended drugs for malaria?
Atovaquone, chloroquine, doxycycline, mefloquine, primaquine, tafenoquine