Haem/Imunity Flashcards
1
Q
Protein that transfers iron through the blood
A
Transferrin
2
Q
If transferrin is high, and ferretin is normal:
A
Suggests iron deficiency
Ferretin is an “acute phase reactant” - ie may have low ferretin, but infection/ inflamation etc is driving level up artificially
3
Q
If transferrin is high, and ferretin is normal:
A
Suggests iron deficiency
Ferretin is an “acute phase reactant” - ie may have low ferretin, but infection/ inflamation etc is driving level up artificially
4
Q
Types of Thalassemia
A
Alpha and Beta - in regards to body’s genetic inability to create associated globin chains
4 alpha genes - deletion of 1 gene generally asymptomatic, 2 moderate, deletion of 3 is severe anaemia, deletion of 4 alpha genes is incompatable with life
2 beta genes - minor to major anaemia, requiring no - frequent infusions
5
Q
Most common type of hereditary haemochromatosis
A
- Hereditary Haemochromatosis type 1
- HFE gene related
- Excessve intestinal absorption of dietary iron
- Most common Northern European descent - especially Celtic
- Excessive expression of DMT1 (Divalent Metal Transporter 1) - Which is the major iron transporter that contributes non-heme iron uptake in most types of cell.
5
Q
Hemachromatosis inheritance traits and management for men and women
A
Autosomal recessive
Women generally do not need venesection due to menstrual blood loss until menopause
6
Q
How is Hemachromatosis heritable?
A
Autosomal recessive
Women generally do not need venesection due to menstrual blood loss until menopause
7
Q
Summarise development of aquired immune response to an antigen (flowchart Dr Raj)
A
8
Q
Key physical exam check for thrombocytopaenia
A
Thrombocytopaenia - Abnormally low levels of platelets (thrombocytes)
Mucosal membranes for bleeding/petecchia
Statistically significant correlation for intracerebral haemorrhage
More important than “dependent” areas - gravity dependent such as ankles, legs, etc
9
Q
Primary vs Secondary Neutropenia
A
Neutropenia = Abnormally low Neutrophils
Primary autoimmune neutropenia (AIN) -
When seen in infancy:
- Neutropenia is the sole abnormality
- Rarely associated with serious infections and exhibits a self-limited course.
Chronic idiopathic neutropenia of adults is characterized by occurrence in late childhood or adulthood
Secondary AIN
More commonly seen in adults
Underlying causes include:
- Collagen disorders
- Drugs
- Viruses
- Lymphoproliferative disorders.
10
Q
Common presenting symptoms of severe neutropenia
A
- Low-grade fever
- Sore mouth
- Odynophagia - pain swallowing
- Gingival pain and swelling
- Skin abscesses
- Recurrent sinusitis and otitis
- Symptoms of pneumonia (eg, cough, dyspnoea)
- Perirectal pain and irritation
11
Q
Patients with agranulocytosis usually present with the following:
A
Agranulocytosis - Insufficient granulocytes (Neutrophils, Basophils, Eosinophils, Mast cells)
May be asymptomatic for a time, but when patients present they have:
- Sudden onset of malaise
- Sudden onset of fever, possibly with chills, sweats and prostration
- Stomatitis and periodontitis accompanied by pain
- Pharyngitis, with difficulty swallowing
- Lung infections are usually bacterial or fungal pneumonias
12
Q
Physical findings on examination of a patient with neutropenia may include the following:
A
- Fever
- Stomatitis
- Periodontal infection
- Cervical lymphadenopathy
- Skin infection: Rashes, ulcers, or abscesses
- Splenomegaly; Associated petechial bleeding;
- Peri-rectal infection
13
Q
Anaphylaxis 2nd line therapies
(AFTER ADRENALINE/EPINEPHRINE)
A
- Corticosteroids -have a delayed effect (4–6 hours), generally used to reduce duration of reaction & prevent relapse (should not be used instead of adrenaline)
-
Antihistamines- used as adjuncts helpful for associated urticaria, angioedema & itch.
– including H-2 blockers e.g. Ranitidine if H-1 blockers ineffective - Beta2 agonists -Inhaled (via MDI and spacer) or nebulised short-acting beta2 agonists may help relieve bronchospasm that is resistant to adrenaline.
- Glucagon - if still hypotensive in spite of fluids & adrenaline, give Glucagon IV – which exerts positive inotropic & chronotropic effects by directly activating adenylyl cyclase & bypassing β-adrenergic receptor
14
Q
Corticosteroid effects on immune response - especially in anaphylaxis
A
Antiinflammatory - reduce production of many cytokines such as IL-4,5,17, TNF-a
Immune suppressant - to avoid continuous presence of anaphylactic reaction after allergen removed
Doesn’t work as quickly as epinephrine -
15
Q
Histamine receptors and actions
A
16
Q
What is central tolerance?
A
Central tolerance occurs in the Thymus (T cells) or the Bone marrow (B cells) and removes lymphocytes that respond too strongly to self antigens
17
Q
What is peripheral tolerance?
A
Peripheral tolerance further regulates the immune response and protects the body from any lymphocytes that do respond to self but have made it into the circulation
18
Q
What are the mechanisms of autoimmunity?
A
1- Reversal of anergy
- Failure to inhibit peripherally autoreactive T-cell clones
2- Local tissue damage
- Can release intracellular antigens
- Can expose new antigens arising from self proteins perviously unseen by immune system
3- Alteration of self-antigens
- Alteration of shape of self protein - ie citrulination in RA
- Infectious organisms alter self antigens - ie viral infection proceeds pancreatic B-cell autoimmunity in T1DM
4- Hypersensitivity reactions
- Autoimmune diseases may result in hypersensitivity reactions - RA, SLE
5- Molecular mimicry
- T-cells activated by infectious agents with structural similarities to self-proteins
- T cells then re-activated due to only exposure of self peptide with MHC complex
19
Q
What is Anergy?
A
Mechanism of inactivating peripheral self reactive T-cell clones
Anergy occurs through disruption of signals, failure to express co- stimulatory signals or inhibition of the activation signal
Reversal of anergy can lead to autoimmune disease
20
Q
Most common cause of severe malaria and survival rates
A
Plasmodium Falciparum
Mortality is 10-20% despite optimal Rx
Nearly 100% without treatment
Mortality in pregnant women 2 & 3 trimester ~ 50%
21
Q
Diagnosis of malaria
A
- Microscopic analysis of thick and thin films (3) - gold standard
- Rapid Diagnositc Test - remain positive for 1 month after infection
- PCR - most accurate, research test only
22
Q
What is the most effective antimalarial
A
- IV Artesunate - short half life, reaches peak concentration in ~10 minutes
- Parasite clearance with Artesunate typically occurs within 72 hours.
- Should be documented with thick and thin blood smears every 12 hours
- After 24 hours can commence oral medications
- Kills young circulating ring staged parasites which quinine does not
23
Q
Specific Rx consideration for Plasmodium Vivax and Ovale infections
A
Primaquine or Tafenoquine - Kills early stage oocytes
- These subtypes can lay dormant in hepatocytes and pop up years later without further exposure
Primaquine also given to Falciparum infections in Northern Australia - prevent acute onspreading
24
MOA of LMWH (low molecular weight heparin)
Examples too
Inhibits factor Xa
Enoxaparin (Clexane), Dalteparin
25
MOA of Heparin
Inhibits
XIIa
XIa
IXa
(mostly intrinsic pathway)
26
What the hell is a NOAC?
Newer Oral AntiCoagulants (aka DOAC - direct-acting oral anticoagulants, as they are actually >15yo)
* Direct thrombin inhibitor (dabigatran)
* Factor Xa inhibitors (apixaban and rivaroxaban)
* For most indications, one or all three have been demonstrated in clinical trials to be as effective as warfarin
* Fewer drug and food interactions than warfarin
According to Judy, Don't need monitoring
27
Measurement of PT vs aPTT
PT ~ Extrinsic Pathway - Unique factor VIIa
aPTT ~ Intrinsic Pathway - Unique factor VIIIa
28
Risk factors associated with VTE
Venous ThromboEmbolism
– Older age
– Immobility
– Malignancy
– Obesity
– Previous VTE
– Family history of VTE
– Oral contraceptive pill, hormone replacement, tamoxifen, strontium (Protos™ - for osteoporosis)
– Venous insufficiency/varicose veins
Hip or Knee replacement!
29
Measures for VTE prophylaxis
Venous ThromboEmbolism Prophylaxis
- Anticoagulants (injections and/or oral)
- Graduated compression stockings (GCS)
- Intermittent pneumatic compression (IPC)
- Inflatable pneumatic pump provides intermittent cycles of compressed air, enhancing venous return
- Pneumatic foot compression or pump
30
What is Atopy?
The genetic tendency to develop classic allergic diseases - atopic dermatitis, allergic rhinitis (hay fever) and asthma
Atopy involves the capacity to prroduce IgE in response to common environmental proteins
From Greek - "atopos" - out of place
31
Define *Allergy*
A misguided reaction to foreign substances by the immune system
32
Describe the "Normal" inflammatory response
**Vascular Events**
- Initial *vasodilator response*
- *Increase in capillary permeability - leakage of plasma proteins* (antibodies, complement, clotting factors)
- Increase in extravascular protein content -> *accumulation of interstitial fluid*
- Increased blood viscocity due to leakage of fluid -> slow blood flow through vessels -> *increase contact of white blood cells with vessel endothelium*
**Cellular Events**
- White blood cells adhere to endothelium - due to slower flow
- WBCs respond to chemotactic factors -> diapedesis - migrate into interstitial space
33
Activation of the complement cascade causes which main effects
A. Opsonisation of bacteria
B. Release of factors that are chemotactic for phagocytes
C. Release of factors that activate phagocytes and other white cells
D. Lysis of bacterial cells
34
How do phagocytes know what to digest?
By recognising:
**Pathogen-associated molecular patterns (PAMPs)**
- Carbohydrates or lipopolysaccharides in the bacterial cell wall, bacterial DNA or viral RNA
**Complement surrounding bacteria (opsonisation)**
- C3b receptors on the phagocyte recognise C3b surrounding the bacteria
35
What are the two classes of MHC and where are they present?
Major Histocompatability complex
**MHC class I**
- Present on virtually every cell in the body
- Marker of self that the body recognizes
- Cytotoxic T cells recognize MHC class 1 in combination with foreign antigen
**MHC class II**
- Appear mainly on macrophages and B cells, helper T cells
36
Describe the structure of an antibody molecule
- Light chain
- Heavy chain
- Fc
- Fab
37
Summarise major immunoglobulin classes in humans
38
Functions of antibodies in the acquired immune response
- Activate B lymphocytes
- Act as opsonins
- Cause antigen clumping and inactivation of bacterial toxins
- Activate antibody-dependent cellular activity (NK cell and eosinophils)
- Trigger mast cell degranulation
- Activate complement
39
MOA of LMWH and Fondaparinux
Factor Xa Inhibitor
40
Summarise Oral Anticoagulants and their main targets
- **Direct thrombin inhibitor**
- Dabigatran (Pradaxa)
- **Direct factor Xa inhibitors**
- Apixaban (Eliquis)
- Rivaroxaban (Xarelto)
- **Vitamin K antagonist**
- Warfarin (coumadin, marevan)
41
Summarise pros and cons of warfarin
- Vit k antagonist (reversible)
- Oral medication (easy at home)
- Low therapeutic index (requires regular monitoring)
- Teratogenic
- Metabolised by cytochrome P 450 in liver (many drug interractions due to common metabolism pathway)
42
3 most common indications for warfarin therapy
- Atrial Fibrilation (AF)
- Venous thromboembolism (VTE)
- Prosthetic heart valves
43
General target INR for warfarin
INR of 2-3.5 depending on clinical indication and other risk factors - can be different given patients coorbidities and requirements
At least 5 days required to achieve therapeutic INR
More regular INR monitoring is required at initiation of therapy
44
Drugs that may have a potentiation effect on warfarin (increase effect)
- **Inhibitors of hepatic drug metabolism**
- Amiodarone, several antibiotics & antifungals
- **Drugs with antiplatelet effect**
- NSAIDs, Aspirin
- **Drugs that displace warfarin from binding sites on plasma proteins**
- NSAIDs
45
Plasma is composed of:
- Water
- Ions
- Trace elements and vitamins
- Gases - O2, CO2
- Organic molecules (such as)
- Glucose
- Lipids
- Nitrogenous Waste
- Amino acids
- Proteins (such as)
- Albumins
- Globulins
- Fibrinogen
46
General summary of what mast cells release
(3 key factors, and their general effects)
Histamine, Prostaglandins, Leukotrienes
- Vasodilation
- Increase capillary permeability
- Bronchial constriction
- Neutrophil and Eosinophilic chemotaxis
47
People with allergies/atopy have much higher serum levels of what immunoglobulin?
IgE
48
How does IgE facilitate mast cell degranulation?
(picture)
49
Which cell is largely responsible for late stage allergic response?
**Eosinophils**
- Associated with long term tissue damage from chronic allergic reactions
- They release:
- Reactive oxygen species
- Cytokines
- Growth fators
All contribute to tissue damage in chronic allergic reactions
- Also elicit chronic T helper 2 cells in maintaining inflammation
50
Which cell is secondarily responsible for late stage allergic reactions?
T helper 2 cells
- Attracted by Eotaxin along with eosinophils
- Once recruited, release:
- IL-4 which increases IgE synthesis
- IL-5 - chemotactic for eosinophils
Basically, they keep the ball rolling, compounding damage
51
A hypersensitivity reaction can be defined as an immune response that is
---------------------- or is ---------------------------
A hypersensitivity reaction can be defined as an immune response that is **inappropriate because it is directed at a self antigen** (i.e. autoimmunity) or is **directed at an antigen that poses no significant risk to the body** (e.g. pollen or transfused blood cells)
52
Summary of 4 types of hypersensitivity reactions, and an example of each
53
Major functions of the Innate Immune System are:
- Physical and chemical barrier
- Recruit immune cells to infection sites via chemotaxis
- Activate complement cascade - opsonisation and MAC
- Identify and remove foreign substances via WBCs
- Activate adaptive immune system via antigen presentation
54
Short summary of Type-4 hypersensitivity
T-Cell activation of the immune response following recognition of an antigen.
More than likely occurs after prior exposures, which sensitise people to subsequent exposures.
54
What are the 2 major types of ingredients in vaccines?
**Antigens**
Can contain:
- Killed whole pathogen - killed by heat/chemicals (Hep A, polio)
- Components of pathogen
- Genetic engineering (Hep B, Human papiloma virus)
- Purifying from whole bacterium/virus
- Derivative of toxin produced by pathogen - harmless toxoid (tetanus, diptheria)
**Adjuvants**
- Amplify immune response - aluminium hydroxide widely used
55
Cell precursors of erythrocytes
56
What are some factors that decrease tissue oxygenation, and what does the body do as a result of this?
1. Low blood volume
2. Anaemia
3. Low Hb
4. Poor blood flow
5. Pulmonary disease
Results in Erythropoiesis
57
What is "Secondary Polycythemia"?
**Secondary Polycythemia** is a physiological condition:
An over production of Erythrocytes!
At high altitude or under other conditions that result in poor tissue oxygenation, **secondary polycythemia** may develop.
As opposed to **polycythemia vera** which is a pathological defect in regulation of erythropoiesis - resulting in higher RBC count
58
IgM and IgG
Primary vs Secondary Response
59
Sickle cell disease is a genetic defect in which ----------, the 6th out of 146 amino acid chain for --------- haemoglobin is replaced by ---------
Sickle cell disease is a genetic defect in which **Glutamate**, the 6th out of 146 amino acid chain for **Beta** haemoglobin is replaced by **Valine**
Glutamic acid - hydrophilic
Valine - hydrophobic
Hence, lack of polarity here changes the shape of the protein and thus shape of RBC
60
What is Granulation Tissue?
Granulation tissue is formed as the last stage of the inflammatory response.
Granulation tissue replaces the tissue that has undergone necrosis as part of the inflammatory response with connective tissue which makes up the scar.
61
Summary of the steps in the activation of
the acquired immune response
1. Macrophage/ APC engulfs bacteria and **presents antigen**
2. **Helper T cell activated** by macrophage/ APC with a MHC complex
3. B cell bind antigen and receives a **cytokine** signal from T helper cell
*(Or recognition of foreign antigen by naïve circulating B cells can autoactivate (T-independent))*
4. B cells undergo **clonal expansion** and differentiation, affinity maturation
5. B cell matures into antibody secreting **plasma cells**
6. **Memory B cells** remain behind once the infection is cleared. If the
body is re-exposed to the antigen, the memory cells will recognize the antigen and respond quickly
62
What are the intermediate steps from
Haematopoetic stem cell - Specialised Blood Cells
63
What is Myeloid?
Having to do with the bone marrow, or certain types of haematopoietic cells found in bone marrow
64
4 types of Leukaemia
65
What is Multiple Myeloma?
"Multiple Myeloma represents a malignant proliferation of **plasma cells** derived from a single clone"
Ie - we end up with excessive plasma B cells accumulating in the bone marrow, and producing excessive amounts of antibody proteins
65
How does Polycythaemia Vera (PV) start?
PV is a clonal stem cell disorder in which there is an **alteration in the pluripotent progenitor cell** leading to **excessive proliferation of erythroid, myeloid and megakaryocytic progenitor cells**
66
What is Polycythaemia (Rubra) Vera?
- A disorder where too many red cells are produced in the bone marrow, without any identifiable cause.
- These cells accumulate in the bone marrow and in the blood stream
- Cause increase in blood volume and viscocity
- In many people with polycythaemia vera, excess platelets and white cells are also produced
67
What is "Urticaria?"
Urticaria is also known as “hives” and is characterized by itchy, raised, swollen areas on the skin or mucous membranes, often a manifestation of an allergic reaction.
68
How are the different antigens formed in the ABO blood group model?
What antibodies are formed as a result of this?
A - N-acetylgalactosamine (NAGA) is added
B - Galactose is added
AB - Both!
O - Neither!
Naturally occurring IgM anti-A and anti-B antibodies are called **isoagglutinins** or **isohaemagglutinins**
O forms antibodies against both
AB against neither
69
What is VEGF
Vascular Endothelial Growth Factor
- Key factor for angiogenesis as the name suggests
Increases:
- Migration of endothelial cells
- Matrix metalloproteinase activity - break down connective tissue scaffolding
- Mitosis of endothelial cells
70
How are MMPs relevant to neoplastic outcomes?
MMP = Matrix Metallo Proteinases
Increased expression of MMPs in human malignant tissue are often correlating with poor prognosis
They break down connective tissue scaffolding
71
Difference on smear seen in ALL vs AML
Remember:
Acute Myeloblastic Leukaemia
Acute Lymphoblastic Leukaemia
**AML**: Myeloblasts are larger with more cytoplasm and Irregular Shaped Nuclei
Commonly have Auer Rods
Myeloid - more prominent nuclei
**ALL**: Smaller with Scant Cytoplasm
72
3 most common types of Myeloproliferative neoplasms (MPNs)
Some key driver mutations too (pie graph)
- Polycythemia Vera (PV)
- Essential Thrombocythemia (ET)
- Primary Myelofibrosis (PMF)
Classic DRIVER mutations are -
JAK -26V1F - Gene on chromosome 9
CALR exon 9
MPL exon 10
NOTE. -Not a strict category though, this is a SPECTRUM of disease and category!
TREATMENT often W TYROSINE KINEASE INHIBITORS
72
Sites of Hematopoiesis age changes graph
73
Summary of the coagulation cascade
74
Self antigens associated with autoimmunity include:
75
Symptoms and signs of Leukaemia
- Asymptomatic
- Anaemia
- Neutropaenia - fever, infections
- Thrombocytopaenia - Petechia (pinpoint like haemorrhages) , Purpura (bruising)
- Bone Pain
- Splenomegaly
- Hepatomegaly
- Lymphadenopathy
- Testicular enlargement
- Gum infiltration
- Skin deposits
- CNS involvement
76
Diagnosis of Leukaemia involves:
- Full blood count - FBC
- Stain blood sample/ blood smear - microscope view
- Bone marrow biopsy - Commonly around PSIS
- Bone marrow Trephine biopsy - ratio cells:fat
- Surface antigen expression
77
Basic requirements for Graft Versus Host Disease (GVHD)
- **Graft** must contain immune competent cells - relevant for TAGVHD (Transfusion Associated Graft Vs Host Disease)
- **Host** must have antigens lacking in the graft so the host appears foreign to graft - lacking in syngenergic transplant (identical twin graft)
- **Host** must be incapable of mounting an immune response against the graft - hence need for conditioning
Note - you can still get GVHD with a perfectly matched sibling donor and aggressive immunosuppressive therapy.
It's a balancing act, as if there is no T-lymphocyte action against the host, there will be a relapse of leukaemia, and too my action against the host is GVHD
78
Summarise Major Histocompatability Complex (MHC)
- Cell surface glycoproteins
- Highly variable between individuals
**Class 1**
- HLA-A, HLA-B, HLA-C
- Expressed on virtually all nucleated cells
- Present antigens to CD8+ cytotoxic/suppressor cells
**Class 2**
- HLA-DQ and HLA-DRB1
- Restricted to cells of the immune system (B-cells and monocytes)
- Molecules on macrophages that present antigenic fragments to CD4+ T-helper cells
79
Types of Graft Versus Host Disease (GVHD)
**Acute < 100 days**
Usually at time of engraftment
Skin, GIT - malabsorption, diarrhoea, Liver (abnormal LFTs)
**Chronic > 100 days**
Skin
Liver
Lung and other tissues
80
Describe Delayed Haemolytic Transfusion Reaction
(DHTR)
- Haemolysis is more mild than severe AHTR (acute haemolyric transfusion reaction)
- Patient may make a red cell antibody to a red cell antigen they lack after transfusion, transplantation or pregnancy
- May be reaction between recipient antibodies and Rh (anti D) or minor Rh group antigens (C,E,c,e) - or non ABO antigens (Kidd, Duffy, Kell, MNS antigen system)
**Symptoms**
- Fever, declining Hb, mild jaundice - occuring days to weeks after transfusion
80
What is the most common cause of transfusion related death in developed countries?
**Transfusion Related Acute Lung Injury - (TRALI)**
- Resp distress disproportionate to volume of blood
- Fever, chills, dyspnoea, tachypnoea, cyanosis, hypotension and new onset pulmonary oedema (non cadriogenic)- leading to resp failure within 6 hours of transfusion
- Hypotension - helps distinguish from Transfusion Associated Circulatory Overload (TACO)
All products that contain plasma can cause this
Often underreported in minor cases - must inform lab though as these donors should be excluded from becoming future donors
Pathogenesis not exactly understood, but involves reaction activation of neutrophils in pulmonary microcirculation, releasing oxidases and proteases that damage vessels - leaky vessels
80
Describe Transfusion - Related Circulatory Overload (TACO)
- Potentially lethal volume overload
- Due to rapid or massive transfusion, or too much fluid
- Even a single unit can precipitate TACO in cardiac compromised patients
- Avoid by administering components slowly (over 2-3 hrs)
**Signs and symtoms**
- Dyspnoea
- Orthopnoea
- Tachycardia
- Hypoxia
- Increased BP - helps theoretically distinguish from TRALI (Transfusion Related Acute Lung Injury)
**Individuals at increased risk include:**
- Diminished cardiac reserve
- Very young or very old
- Chronic anaemia
- Renal impairment
80
Summary of 5 Immunoglobulins table
81
Summary of heavy vs light chain locations in antibodies/immunoglobulins
82
Summary of α-thalassemias
- The α-thalassemias involve genes HBA1 & HBA2
- Autosomal recessive
- Two genetic loci exist for α-globin, thus four alleles are in diploid cells. Two maternal and two paternal alleles.
- Severity is correlated with number of affected α-globin
- Alpha-thalassemias -> decreased alpha-globin production -> fewer alpha-globin chains are produced, resulting in an excess of β chains in adults and excess γ chains in newborns.
- The excess β chains form unstable tetramers (called hemoglobin H or HbH of 4 beta chains), which have abnormal oxygen dissociation curves.
- Alpha thalassemias often are found in people from Southeast Asia, the Middle East, China, and in those of African descent.
83
Summary of β thalassemia
- β thalassemias are due to HBB gene on chromosome 11 mutaations
- Autosomal recessive inheritance
- Severity of disease depends on nature of mutation and presence of mutations in one or both alleles
- Mutated alleles are called β+ when partial function is conserved (either the protein has a reduced function, or it functions normally but is produced in reduced quantity) or βo, when no functioning protein is produced.
- β thalassemia major (Mediterranean anemia or Cooley anemia) is caused by a βo/βo genotype. No functional β chains are produced, and thus no hemoglobin A can be assembled. This is the most severe form of β-thalassemia;
- β thalassemia intermedia is caused by a β+/βo or β+ β+ genotype. In this form, some hemoglobin A is produced;
- β thalassemia minor is caused by a β/βo or β/β+ genotype. Only one of the two β globin alleles contains a mutation, so β chain production is not terribly compromised and patients may be relatively asymptomatic.
- Most often in people of Mediterranean origin
84
How is peripheral tolerance maintained?
ISADS
**1. Ignorance** – antigen is invisible to the immune system
**2. Separation** – antigen is isolated from the naïve immune cells
**3. Anergy** – self-reactive cells are deleted or inhibited
**4. Deletion** – activation leads to apoptosis
**5. Suppression** – Tregs inhibit the activity of self-reactive T cells
85
Mnemonic for general DDx hypothesis
VINDICATE
(Covers literally everything that could go wrong anywhere - maybe not every letter useful in each case, but something to think about)
- **V**ascular
- **I**nfection, **I**nflammation
- **N**eoplasms
- **D**rugs (also toxins), **D**egenerative
- **I**atrogenic, **I**diopathic
- **C**ongenital (inherited, developmental)
- **A**utoimmune, **A**llergy, **A**natomical
- **T**rauma
- **E**ndocrine (metabolic), **E**nvironment (work, exposure)
86
Describe the process of non-neoplastic lymphadenopathy
- Generally due to inflammatory stimuli caused by **cellular proliferation**
- B-cell response (germinal cell hyperplasia) - Clonal expansion!
- T-cell response (paracortical expansion)
- Macrophage response (sinus hyperplasia)
- Most commonly all of the above - B cell major player, making antibodies that work in the node and will spread throughout the system
87
Describe neoplastic lymphadenopathy
Tumor secrets factors that promote **lymphangiogenesis** (along with angiogenesis)
Increases collection from the area, and makes it easier for metastisis to spread through the lymph system
88
What are Auer Rods on a blood film associated with?
Acute Myeloid Leukaemia
89
What are smudge cells on a blood film associated with?
Chronic Lymphocytic Leukaemia
- Smudge cells are not actually a cell type, but an artefact from preparing the slides - ie cells get smooshed due to poor cell membrane and being larger than normal
90
What do Reed-Sternberg cells on a lymph node biopsy indicate?
Hodgkin Lymphoma
- Large lymphocyte with "owl eyes"
91
Describe Ann Arbor Staging in Lymphoma
- **I** - Localised disease: one group of lymph nodes affected
- **II** - Two or more groups of lymph nodes are affected but they are all in the chest or abdomen
- **III** - Two or more groups of lymph nodes are affected in both the chest and the abdomen with or without involvement of a nearby organ
- **IV** - Widespread disease: lymphoma is in multiple organs or tissues (eg, bone marrow, liver or lungs) and may also be in the lymph nodes
92
Describe - Induction, Consolidation and Maintenence therapy for leukaemia
- **Induction** - To induce remission
- **Consolidation** - Get rid of any MRD and prevent recurrence
- **Maintenence** - Low dose chemotherapy for months or yearts post remission - prevent recurrence
93
Quick summary of 4 types of Leukaemia
Lymphoids are Lateral
Myeloids are Medial
A’s First (Acute = immature blast cells >20%)
C’s Second
Listed in increasing age to be commonly diagnosed
94
Summary of Methotrexate and its MOA
**Methotrexate**
Used as a:
- DMARD (Disease Modifying Anti-Rheumatic Drug) - RA, IBD, SLE, Eczema, and others
- Chemotherapy - ALL, Non-Hodgkin's lymphoma, breast, bladder
MOA
- Inhibits the body's use of folic acid which leads to->
- Interference with DNA replication - thus as a chemotherapy drug it targets quickly reproducing cells
95
Summary of lymphatic drainage and return to the venous circulation
