Haematology Flashcards
1
Q
What’s the colour of the blood sample bottle used for FBC
A
Purple
2
Q
What is the yellow blood sample bottle used for
A
Urea and electrolytes
3
Q
What tests are in an FBC for RBCs (selected)
A
- Haemoglobin
- Haematocrit
- Mean Corpuscular Volume
- Red cell count & distribution width
- Reticulocyte count
4
Q
Haemoglobin in FBC
- affected by
A
high = polycythaemia; low = anaemia
→ grams per litre
- Iron deficiency
- active bleeding
check for pancytopenia (marrow issue)
5
Q
Haematocrit in FBC
- what is it
A
→ L / L
- % of sample made up of RBC
- affected by number of RBC and volume of blood plasma
→ watch for hyperviscosity syndrome (too thick) during polycythemia
6
Q
Mean Cell/Corpuscular Volume in FBC
- what is it
- what is it useful for
A
→ phenol litres
- average size of RBC in sample
- useful in anaemia: indicates cause
- classified macrocytic / normalcytic / microcytic
7
Q
Red cell count & distribution width
- what are they & what are they useful for
A
RCC
= # of RBC present per unit volume of blood
- use with Hb & Hct to confirm anaemia / polycyth
RDW
= in depth look at MCV, provided in range (big-small) so useful when mixed cell size (anisocytosis - associated with iron deficiency) and anemia
8
Q
Reticulocyte count
- what is it
- a brief interpretation of results
A
= shows # of fresh, newly produced RBC (in the bone marrow)
so if anaemia:
→ a raised rc count = marrow is producing, but rbc is getting destroyed
→ a low rc count = marrow not producing enough
no anaemia:
→ a raised rc count = compensating for blood loss or adapting to oxygen demand
9
Q
A raised WBC is known as
A
Leukocytosis
- to treat: determine rate and which type (typically neutrophils and lymphocytes)
10
Q
A lower WBC is known as
A
Leukopenia
- to treat: determine rate and which type (typically neutrophils and lymphocytes)
11
Q
What is in a ‘differential’?
A
Tests separately for different types of WBC but most importantly **counts blasts in circulation**
12
Q
Neutrophils:
- function
- lifespan
- structure & % of leukocyte
A
- early phagocytosis of pathogen, involved in acute infect (partt bacteria) & inflamm
- 10 hours
- multi-lobed nucleus, 40-60%
13
Q
Lymphocytes
- subtypes & function
- lifespan
- structure & % leukocytes
A
- B lymphocytes - plasma / memory cells & produce antibodies
- T lymphocytes: T helper / cytoxic / natural killer: kills virus infected cells
- 8-12 hours
- fried egg appearance
- perinuclear hoff around golgi, 20-40%
14
Q
Monocytes
- function
- structure & % of leukocyte
A
- differentiates into macrophages → tissue resident
- major phagocytotic role
- can become antigen presenting cells
- reniform nucleus
- 2-10%
- Kupffer, osteoclast & alveolar macrophages
15
Q
Eosinophils
- function
- lifespan
- structure & % of leukocyte
A
- Neutralises histamine
= antagonist to basophils & mast cells - bi-lobed, pink lozenge, distinctive granules
- 1%
16
Q
Basophils
- function
- lifespan
- structure & % of leukocyte
A
- Involved in allergic reaction & inflammation
- produces histamine
= release vasoactive substances
= antagonist to eosinophils - bi-lobed, dark blue granules of histamine
- 0.5%
17
Q
Blasts
- what are they
- where are they usually found?
A
= immature cells
- typically found in bone marrow where they mature (are then released)
→ so blasts in circulation = abnormal!
can be caused by
- leukaemia
- myeloproliferative disorders
- chemo or treatment with G-CSF
18
Q
Define thrombocytosis
A
raised platelet count
19
Q
What’s in an iron study?
A
- ferritin
- serum iron
- transferrin saturation / total iron binding capacity
- most useful for patients with anaemia and a chronic disorder
20
Q
Ferritin
- what does it measure
- when would it be abnormal?
A
- measure of iron stores
- may be increased in: inflammation, tissue destruction, liver disease, malignancy, iron replacement
- used to diagnose iron deficiency and anaemia
21
Q
Serum iron
- what does it measure
- what can it be affected by
A
- amount of iron in the blood
- can be affected by circadian rhythm so usefulness?
22
Q
Transferrin
- what is it?
- what is it like in iron deficiency?
A
- protein used to transport iron around the body
- in iron deficiency: synthesis is increased but saturation is low (less of it is occupied)
23
Q
TIBC
- what is it
A
Total iron binding capacity
- measures all of the proteins in the serum that binds iron, transferrin being the principle
24
Q
Define anaemia
A
where there is decrease of haemoglobin in the blood below the reference level for the age and sex of individual
25
Two pathological cause of anaemia
- decreased production: deficiencies iron / folate / B12 OR bone marrow failure
- increased loss: is the patient bleeding OR are RBC being destroyed (haemolysis) - vascular system or spleen?
26
How are anaemia classified
Based on **mean corpuscular volume** - how big the cells are: macrocytic / normocytic / microcytic
27
What is macrocytic anaemia and what causes it?
- RBC is bigger than normal
- Depending on the size of the erythroblasts (megaloblastic or non), it can be caused by folate / B12 deficiencies or others
28
How is macrocytic anaemia classified by cause?
- **megaloblastic**: vitamin B12 deficiency (pernicious anaemia) / folate deficiency
- **normoblastic**: alcohol, liver disease, hypothyroidism, haemolysis, marrow issues, myeloma, azathioprine
29
Folate physiology:
- where is it found
- how is it used in the body
found in
**green vegetables, e.g spinach and brocco**
low body stores of around 4 months, essential for **DNA synthesis**
_deficiency_ =
delayed nuclear maturation so **larger RBC** and **decreased RBC production in marrow**
**& neural tube defect in foetus**
30
Presentation of folate deficiency
- **anaemia symptoms** = pallor, fatigue, dyspnoea, anorexia, heachache
- glossitis (red sore tongue can occur)
- **no neuropathy unlike B12**
31
What causes folate deficiency?
- poor nutrition
- malabsorption: coeliac, crohn’s, pregnancy, haemolysis
= main cause of macrocytic anaemia
32
How would you treat folate deficiency
→ check for vitamin B12, if deficient replace B12 first
- replace orally
33
What causes B12 deficiency?
MALABSORB
- surgery: gastrectomy / ileal resection
- **pernicious anaemia** (= autoimmune malabsorp)
- diseases: **crohn's, coeliac**
INSUFFICIENT DIET INTAKE
OTHERS
- metformin, PPI, H2 receptors
- nitric oxide recreational use
= marocytic, megaloblastic anaemia
34
Presentation of vitamin B12 deficiency anaemia
**anaemia symptoms**
fatigue, headache, pallor, dyspnoea, anorexia, tachy & palp
**glossitis, angular stomatitis / cheilosis**
ulcers in corner of mouth
**lemon yellow skin** due to pallor + jaundice
from excess breakdown of Hb
**_! neurological symptoms !_**
_differentiate_ from folate deficiency
- **Peripheral neuropathy** with numbness or **paraesthesia** (pins and needles)
Loss of **vibration sense** or **proprioception**
Visual changes
Mood or cognitive changes
35
What is pernicious anaemia?
autoimmune condition where gastric parietal cells (produces intrinsic factor needed to absorb vitamin B12) are destroyed or lost
→ need IM replacement and not oral
36
How would you
- diagnose general B12 deficiency
- differentiate pernicious anaemia from general B12 deficient anaemia
- FBC, blood smear, reticulocyte count, serum vitamin B12
→ macrocytic, megaloblastic anaemia
- test for intrinsic factor antibodies
37
How would you treat vitamin B12 deficiency
- replace **intramuscularly** (esp for pernicious anaemia), then needed for maintenance
- **IM** **hydroxocobalamin**
- for _dietary deficient_ people → _oral_ replacement
38
Cause of normocytic anaemia
- acute blood loss
- anaemia of chronic disease
- aplastic & haemolytic
- endocrine disorders (hypothyroidism )
- renal failure
- pregnancy
39
Clinical presentation of normocytic anaemia
- fatigue, headaches and faintness
- dyspnoea and breathlessness
- angina if preexisting coronary disease, palpitations
- anorexia
- palpitations
40
How would you diagnose normocytic anaemia
principle of exclusions:
- normal B12 and folate
- raised reticulocytes
- Hb down
- blood count and film: **RBC are normocytic**
41
How would you treat normocytic anaemia
- treat underlying cause
- improve diet with plenty of vitamins
- erythropoietin injections
42
Cause of microcytic anaemia
= TAILS
- **t**halassaemia
- **a**naemia of chronic disease
- **i**ron deficiency anaemia
- rarely: **l**ead poisoning/ congenital **s**ideroblastic anaemia
43
What is sideroblastic anaemia?
when red cells fail to completely form haem
iron deposits which form a ring around nucleus = sideroblast
→ ‘**basophilic stippling of RBC**’
supportive tx,
if acquired = alcohol
44
Common causes of iron deficiency
- **impaired absorption**: coeliac, gastrectomy, diet: v's, the elderly
- assume **blood loss** until proven otherwise!
- **gastrointestinal malignancy** for everyone
- women = **menstruation**, **pregnancy** (transfer to foetus)
45
Presentation iron deficiency
**anaemia** = fatigue, dyspnoea on exertion
glossitis, angular stomatitis / cheilosis
**restless legs syndrome**
**pica** = ED, eating non-food
**nail changes**: thinning, flattening then spooning (last is rare)
46
Iron physiology
- function
- absorption to function
required for the **formation of the haem of haemoglobin**
transported into duodenum by HCP1,
intracellular storage form **= ferritin** (intracellular store for iron)
circulate around the body = bound to **transferrin**
47
Results needed to diagnose iron deficiency
RBC = **microcytic**, **hypochromic** (pale)
poikilocytes (vary in shape), anistocytes (vary in size)
**serum ferritin** = low (simple i.a.) /
normal in malignancy
* *→ low transferrin saturation** (\<16%)
* *high** total iron binding capacity
* *low** reticulocyte count
48
How would you manage iron deficiencies
- investigate / treat source of blood loss
- replace iron → \*\*oral is preferred (safer), IV is no faster than oral\*\*!
- Hb should rise approx 20g every 3-4 weeks
- \*\*ferrous sulphate\*\* 200mg 1-3x daily
- after normal: continue supplementation for further 3 months to replenish stores
49
Side effects of ferrous sulphate // alternative therapy
- nausea, abdominal discomfort, diarrhoea / constipation and black stools
- IV or deep IM iron not absorbing or intolerant
- ferrous gluconate if bad SE
50
What is haemolytic anaemia and how is it classified?
premature breakdown of RBCs before their normal lifespan of around 120 days
- **compensated** - increased destruction matched by increased synthesis
- **decompensated** - rate of destruction exceeds rate of synthesis
51
Cause of haemolytic anaemia
**Hereditary**
spherocytosis / elliptocytosis /
Hb disease = sickle cell, A/B thalassaemia
G6PD deficiency
**Acquired**
autoimmune / prosthetic valve related
52
Tests used to investigate haemolytic anaemia
**_FBC_: normocytic anaemia**
**_blood films_**
reticulocyte ++, **bilirubin** (**unconj** +++),
RBC fragments = schistocytes / spherocytes / sickle cell, haptoglobin
**_direct Coomb test_**: to see if autoimmune
**_Liver function test_**
(but liver might be able to compensate and conj)
Lactose dehydrogenase ++
53
Presentation and results for diagnosing haemolytic anaemia
**Anaemia** = fatigue, glossitis, pallor (pale)
**Splenomegaly** = congested Hb
**Jaundice** = haemolysis
Abdo pain = **gallstones**
**Dark urine = Hb uria**
54
Physiology of bilirubin and how would you use it to diagnose haemolytic anaemia
- yellow bile pigment from breakdown of Hb (haemolysis)
- **unconjugated (indirect)** - insoluble, travel in bstream bound to albumin
- **conjugated (direct)** - processed in the liver so soluble & excretable
- **urobilinogen** = end product of conjugated haemoglobin
usually in haemolytic anaemia, **unconjugated is increased** = as increased Hb breakdown, faster than liver can process
55
Physiology of haptoglobin and how would you use it to diagnose haemolytic anaemia
protein made in the liver trying to **mop up free haemoglobin** (loose in blood stream can cause problems) therefore if values are low = busy = issue!
56
G6PD
- what is it
- pathophysio for \*\*deficiency\*\*
Glucose-6-Phosphate-Dehydrogenase deficiency
- vital enzyme to **ensure normal lifespan of RBC**, protect from oxidative damage
- (inherited) deficiency will mean **sudden destruction of RBC** and can lead to haemolytic anaemia
- malaria protective trait as parasites cannot survive on these RBC
57
Presentation of G6PD deficiency
most are _asymptomatic_ but may have **_oxidative crisis_** due to reduced glutathione (partner of G6PD in protecting RBC) production.
Mostly precipitated by **acute drug-induced haemolysis** from
aspirin, antimalaria (-quine drugs), antibac's, fava beans
Attacks are due to **rapid intravascular haemolysis** → **anaemia, jaundice and haemoglobinuria**
58
Investigate and diagnose for G6PD deficiency
- blood count normal between attacks
- blood film **_during attack_** has irregularly contracted cells, bite cells and increased reticulocytes
- **G6PD enzyme will be low**, but immediately after attack might have false high concentration
59
Treatment G6PD deficiency
- stop drugs / fava beans
- blood transfusion
- splenectomy isn't usually helpful
60
What is Hereditary spherocytosis
inherited - **autosomal dominant** but 25% spontaneous
defects in Hb membrane → cells become **spherocytic**
= **more rigid, less deformable**
trapped in spleen → destroyed via **extravascular haemolysis**
| (risk = family history)
61
Present hereditary spherocytosis
- **jaundice** - at birth but may be delayed
- may eventually develop anaemia
- **ulcers** on the leg, **splenomegaly, gall stones** (from **chronic haemolysis**)
- course of illness may be interrupted by either _aplastic anaemia_ (sudden stop in BC production) or m_egaloblastic anaemia_ (folate) caused by hyperactivity of the bone marrow
62
How would you diagnose hereditary spherocytosis
- blood film showing spherical RBCs and reticulocytes
- blood count with low Hb and increased retic
- haemolysis: serum bilirubin and urinary urobilinogen is raised
- direct antiglobulin (Coomb's test): negative, thus ruling out autoimmune haemolytic anaemia
63
What is Hereditary Elliptocytosis?
RBC are ellipse shaped
autosomal dominant
presents & manages same as hereditary spherocytosis
64
How would you treat hereditary spherocytosis & elliptocytosis
- **splenectomy** will relieve symptoms due to anaemia or splenomegaly, reverse growth failure and prevent recurrent gallstones (if issue = **cholecystectomy**)
- best to postpone until after childhood due to infections post-op
- after operation: do appropriate immunisation and **lifelong penicillin prophylaxis, folate supplements**
65
Source of RBC?
Bone marrow
Made from erythroblasts
66
What is erythropoietin?
- Hormone made in the kidneys
- Used by bone marrow to stimulate production of RBC
67
Structure of haemoglobin
- general structure formula
- Adult, foetal and delta
- % composition of an adult
haemoglobin + enzymes + membrane
- **HbA** = haem + 2 alpha + 2 beta chains
- **HbFoetal** = haem + 2 alpha + 2 gamma chains
- **HbA2** = haem + 2 alpha + 2 delta chains
- HbA 97%, HbA2 2%, HbF = 1%
68
Foetal haemoglobin
- where is it made
- when does the shift to adult haemoglobin occur
- made in liver and spleen, relied on in utero
- upgrade to adult haem production before delivery
- survives fully on adult haemoglobin up to 6 months
69
Haemoglobinopathies: disease principle (how do things go wrong?)
- **thalassaemias** are disorders of quantity (reduced production)
- **sickle** **cell** **anaemia** is a disorder of quality
70
Sickle cell anaemia
- cause
- subdivision
- single point mutation in beta globin gene.
- inherit from both \*\*autosomal recessive\*\* or carrier
- so - sickle cell anaemia (homozygous) or compound heterozygous with different abnormality from each parent but may still present like sickle cell disease
71
Patho for sickle cell anaemia
- instead of HbA, HbS are made
- in deoxygenation: HbS - polymerises → changes to sickle shape
- blocks blood vessels
- chronic haemolysis (low baseline Hb)
- acute complications & chronic organ damage
- normal Hb for child with sickle cell is 60-100
72
Nature of onset of sickle cell anaemia?
- Will not present until **patient is at least 6m (switch to HbA)**!
- any acute presentation = medical emergency
- urgent analgesia for painful crisis
73
Present - short term for sickle cell anaemia
- **vaso-occlusive crises** - acute _pain in hand and feet_ due to vasoocclusion (children), pain in long bones (femur, spine, ribs and pelvis) due to avascular necrosis (adult)
- **Splenic sequestration** (trap in spleen) = megaly + fall in Hb
- **acute chest syndrome** - shortness of breath, chest pain, hypoxia
- **pulmonary hypertension** - mean pulmonary artery pressure \> 25 mmHg by right heart catheterisation, → **stroke, dactylitis, priapism**
74
Present - long term for sickle cell anaemia (5)
- **delay in growth**:
weight, sex maturation
avascular necrosis of bones, dactylitis, osteomyelitis due to infections,
- **neurological TIA**, fits and cerebral infarction 25%
- **splenic infarctions** over time → **autosplenectomy** (acute = splenic sequestration)
- liver - **chronic hepatomegaly** and liver **dysfunction** bc trapping of sickle cells
- cardio - normally **hypertrophy** → works hard to pump blood → more at risk for systolic and diastolic disorders
75
Aetiology for sickle cell anaemia
- protects against malaria
- african, afro carribean, southern asian
- family history
76
How would you diagnose sickle cell anaemia
* *Antenatal** = molecular genetics test → preg mums
* *Heel prick test** = 5 days after birth
**_for types of Hb_**
High performance liquid chromatography
Gel / Hb electrophoresis
**_for the trait_**
Sickle solubility test
77
treatment options for sickle cell anaemia
- treat infections if needed
- transfuse
- exchange
- top up
- pharma
- \*\*hydroxycarbamide\*\*
- switches back on patient’s foetal haemoglobin production
- reduce sickle cell complications as foetal usually no problems
- folic acid to all haemolysis patients!
- bone marrow transplant only curative option available
- gene therapy
- lentiviral (uses virus to bring in new gene)
- crispr / cas9 genome edit
78
Subtypes and pathology of thalassaemia?
- alpha & beta thalassaemia
- for each type there is under or no synthesis for that chain (normal = balanced 1:1 production)
- consequence = ineffective erythropoiesis and haemolysis
- autosomal recessive - if carriers might still have mild anaemia
79
Beta thalassaemia: cause, if heterozygous?
- little to no B chains - so lots of alpha therefore more HbA2 and HbF
- due to point mutations
- if heterozygous then asymptomatic microcytosis with or without mild anaemia
80
Presentation - Beta thalassaemia major (homozygous)
- recurrent bacterial infections
- severe anaemia from 3m - 6m (switch from gamma to beta)
- \*\*extramedullary haematopoiesis\*\* (ineffectve RBC production outside marrow) resulting in hepatosplenomegaly and bone expansion
- \*\*thalassaemia face\*\*: small face, smooth philtrum, short nose, thin upper lip, underdeveloped jaw
- hypertrophy of ineffective bone marrow = bone abnormalities
- hair on end sign
- Bloods: microcytic, irregular, hyperchromic RBC, normal ferritin
= lifelong transfusion dependent!
81
Presentation - Beta thalassaemia minor (heterozygous)
= common carrier state
- asymptomatic
- anaemia is mild or absent
- RBC is hypochromic (pale), and microcytic with a low MCV
- \*\*distinguish from iron deficiency\*\*: serum ferritin and iron stores normal
- raised HbA2 and often HbF
82
Presentation classified as beta thalassaemia intermedia
= includes those who are symptomatic with moderate anaemia that do not require regular transfusions
- splenomegaly
- bone deformities
- recurrent leg ulcers
- gallstones
- infections
83
Treatment beta thalassaemia - general plan?
- transfusion - depends on type but goal is to keep Hb above 90g/L to suppress extramed haematopoeisis
- iron-chelating agents \*\*or DEFRIPRONE or sc DESDERRIOXAMINE\*\* to prevent iron overload / ascorbic acid increase urinary excretion of iron
- splenectomy but not in childhood (infection)
- bone marrow transplant
- long term folic acid
84
Complications of transfusions
- progressive increase in body iron load
- in liver and spleen: liver fibrosis and cirrhosis
- in endocrine glands and heart: diabetes, hypothyroid/calcaemia & premature death
85
alpha thalassaemia: cause
- gene deletions on chromosome 16
- can be one or both alpha chain gene deletions
86
presentation alpha thalassaemia
* *4 gene deletion** (both genes both chromosomes, **--/--**)
- only Hb Barts present = 4 gamma chains, cannot carry O2 and incompatible with life
- stillborn or shortly after birth. pale, oedematous and enormous livers and spleens (**hydrops fetalis**)
* *3 gene deletion** (a-/--)
- **HbH** disease with 4 beta chains
- moderate anaemia and splenomegaly
- usually not transfusion dependent
* *2 gene deletion** - **trait carrier** (aa/-- or a-/a-)
- microcytosis with or without mild anaemia
* *single gene deletion** - **silent carrier** (aa/a-)
- usually a normal blood picture
87
Aplastic anaemia due to bone marrow failure
- what is it
**_Pancytopenia_**
= reduction in all major cell lines, red / white / platelets; with
aplasia (hypocellularity) of the bone marrow
= marrow stops making cells
88
Cause of aplastic anaemia
- idiopathic acquired (67%)
- benzene, toluene and glue sniffing
- chemo drugs
- antibiotics, infections
89
Pathophysio of aplastic anaemia
- due to reduction in number of pleuripotent stem cells, together with fault in those remaining
- or immune reaction against pleuripotent stem cells - unable to repopulate bone marrow
90
Present of aplastic anaemia
- symptoms from the deficiency of the three: anaemia, infection, bleeding - gums, bruising with minimal trauma, blood blisters in mouth
91
How would you diagnose aplastic anaemia?
- blood count - pancocytopenia with low reticulocyte count
- bone marrow exam: hypocellular marrow with increased fat spaces
92
How would you treat aplastic anaemia?
- TUC
- main concern = **infection** - so any with severe neutropenia & fever give **broad spectrum parenteral antibiotics urgently**
- RC transfusion and platelet
Long term
- if under 40: bone marrow transplant: HLA identical sibling or donor
- over 40 / with severe disease and no sibling donor / transfusion dependent: immunosuppresive therapy with **antithymocyte globulin (ATG) and cyclosporin**
93
What does it mean if a haematological condition is lymphocytic / lymphoblastic
cancerous change takes place in mature blood stem cell in the marrow that normally develops into \*\*lymphocyte\*\*
94
What does it mean if a haematological condition is myeloid
mutation occurs in bone marrow cell that would develop into \*\*RBC, WBC or platelet (aka not lymphocyte)\*\*
95
What does it mean if a haematological condition is acute
progresses rapidly and affect cells that are not fully developed
96
What does it mean if a haematological condition is chronic
progress slowly, patients have a greater number of mature cells
97
Acute Lymphocytic Leukaemia
- What is it
- What cells do they affect
- Common incidence
= malignancy of the lymphoblast → gives rise to T cells and B cells!
- precursor cell, which predominantly lives in the marrow
- bimodal incidence, lots in \<20 then more later on
98
Risk for Acute Lymphocytic Leukaemia
- age - less than 5 (2-4), mid 30’s, mid 80’s
- radiation esp during pregnancy
- benzene - solvents
- smoking
- down syndrome
- immunodeficiency
99
Acute Lymphocytic Leukaemia - pathology
arrest maturation of lymphocytes and promotes controlled proliferation of immature blast cells in marrow
B cells = in children T cells = in adults
genetics and environmental trigger
100
Acute Lymphocytic Leukaemia - Present
anaemia, thrombocytopenia (easier bleeding), leukopenia (+ infections)
**enlarged lymph nodes** (!!)
**enlarged spleen/liver** due to infiltration
**thymus enlargement**
= mediastinum masses with SVC obstruction
**neuro palsies / involvement**
(if gum enlargement = AML!)
101
Signs of Marrow failure
- low Hb = **Anaemia** = breathlessness, fatigue, angina and claudication / pallor, murmur
- low WBC = **infection** = fever and mouth ulcers
- low platelets = **bleeding** & **bruising**
102
Acute Lymphocytic Leukaemia - Investigations
| (& what is it again?)
1st line bloods = FBC + UE,
**peripheral blood smear → diff M or L**
HLA typing
* *CXR** - look for mediastinal and abdominal lymphadenopathy
* *lumbar puncture / pleural tap** for CNS involvement
103
Acute Lymphocytic Leukaemia - Treatment options
chemotherapy = in course & diff dose
**focus on the brain**: will relapse and chemo doesn't get through blood brain barrier = **intrathecal therapy** - chemo delivered through lumbar puncture
* *supportive**
- blood and platelet transfusions
- antiviral / bac / fungals from neutropenia
* *GOLD = transplant = stem cell / bone marrow**
- molecular MRD (minimal residual disease) - decide based on this aka tech to look for remaining disease
104
Acute Lymphocytic Leukaemia - complications - 3i's
- induction mortality - 4.7% (dying in the first month)
- interact of chemo with other drugs
- infection
105
Acute Lymphocytic Leukaemia - new drug options (4) and their mechanisms
**Monoclonal antibodies**: attach to CD20 via link molecule
brentuximab, **inotuzumab**
liver tox
**BiTE** - similar to monoclonal antibody
= uses T cell to kill B cell
* *Autologous CAR-T production**
- take out T cell, genetically engineer and put back, kills cancer
106
Chronic Lymphocytic Leukaemia
- What is it
= accumulation of CLL cells (**partially mature B cells** that have escaped apoptosis and undergone cell arrest) in the body from acquired genetic mutation → **crowd out healthy cells**
107
Subtypes of Chronic Lymphocytic Leukaemia
- does it matter?
→ **Small Lymphocytic Lymphoma** = when abnormal B cells in lymphoid tissues
→ **Chronic Lymphocytic Leukaemia** = when abnormal B cells are deposited in blood and bone marrow, and often in spleen and lymph nodes
→ same type of cells and treatment, just location
108
Risk of Chronic Lymphocytic Leukaemia
- normally later in life
- pneumonia may be triggering event
- mutations, trisomies and deletions influence risk
109
Presentation Chronic Lymphocytic Leukaemia
- elevated WBC = most common finding
- fatigue / shortness of breath during normal physical activity
- **lymph node enlargement**\*\*
* *If severe**
- low grade fever
- unexplained weight loss
- night sweats
- feeling of fullness due to enlarged spleen or liver
- infection of skin, lungs or sinuses
110
Differentiate CML from CLL on a blood smear?
CLL = **smudge cells**
immature B cells broken during the smear
CML = increased granulocytes and monocytes
111
Complications of Chronic Lymphocytic Leukaemia
- autoimmune haemolysis
- increased risk of infection due to hypogammaglobulinaemia (low lgG)
- marrow failure
112
Treatment for Chronic Lymphocytic Leukaemia
- blood transfusions
- human IV immunoglobulins
- chemo or radio
- stem cell transplant
113
Prognosis of Chronic Lymphocytic Leukaemia
- may stay stable for years, but death is often due to complication of infection
- may transform into aggressive lymphoma = Richter’s syndrome
Rule of 3rd's
- 1/3 will never progress
- 1/3 progress slowly
- 1/3 progress actively
114
What is intrathecal therapy?
chemo delivered into the brain (so it will cross blood brain barrier) through lumbar puncture
115
What is Acute Myeloid Leukaemia
= heterogenous clonal malignancy characterised by
- immature myeloid cell proliferation (≥ 20% blasts in peripheral blood!)
- bone marrow failure
116
What do myeloid cells give rise to?
Myeloid cells gives rise to basophils, neutrophils and eosinophils
117
Aetiology of Acute Myeloid Leukaemia?
- about 3-4k cases every year, but increasing over time
- 85-89 yo peak age of AML cases
- majority are not hereditary
118
Symptoms of Acute Myeloid Leukaemia?
- hepatomegaly and splenomegaly
- **gum hypertrophy \*\*** → unique!!
- **anaemia** (fatigue, shortness of breath, lightheadedness) and **thrombocytopenia** (bleeding / bruising) symptoms
- **Disseminated intravascular coagulation** (bruising, blood clots, confusion) occur in subtype of AML where there is release of thromboplastin
119
how would Acute myeloid Leukaemia present on an FBC?
**white cell counts can be anything!**
risk of frequent and / or severe infections → large proportion of whites are normal
**other** blood counts **unusually low**
_Red_: fatigue, shortness of breath, lightheadedness
_Platelets_: bleeding / bruising
**blasts in peripheral blood!**
deterioration in FBC parameters is very rapid, in days / weeks!
120
How would you diagnose Acute Myeloid Leukaemia & how would you differentiate it from ALL
* *peripheral blood smear** (→ myeloblast or lymphoblast) **& bone marrow biopsy**
- Differentiation from ALL is based on **microscopy**, immunophenotyping and **molecular methods**
121
Differential diagnosis for Acute Myeloid Leukaemia
- B12 or folate or mixed haematinic deficiency
- infection - retroviral disease, herpesvirus
- medication / autoimmune
- liver disease (e.g. cirrhosis)
122
How would you treat Acute Myeloid Leukaemia
- **allopurinol** for tumour lysis syndrome prevention
- **chemo**
- usually a combination, manage dose carefully to optimise balance between destroyed leukaemic cells and not damaging other normal cells
- usually administered on **IV, anthracycline, cytarabine**
- may suggest patient to have **a Hickman / PICC line / portacath**
123
Alternative to allopurinol and mechanism?
febuxostat
xanthine competitive inhibitor
(allopuinol is direct xanthine inhibitor)
124
What is a Hickman / PICC line / portacath
= central venous catheters, inserted into the veins at chest or neck area
Useful for
- giving meds / fluids that can't be taken by mouth or would hurt a small vein
- obtaining bloods when often needed
125
General supportive measures for chemotherapy?
- fertility cryopreservation - semen storage for men
- transfusion (red cells, platelets, treatment of infection)
- clinical trial availability: offer novel therapeutic options for patients
- offer diagnostic / test modalities not necessarily offered as standard of care
- bystander damage to other organs can occur!
126
What is the less intensive treatment regime for AML?
- usually for older / less fit individuals
outpatient
- azacytidine
- low dose subcut cytarabine
- with supportive measures
127
Typical 'anaemia' symptoms
fatigue, headache, pallor, dyspnoea, anorexia, tachy and palpitations
128
What is Chronic Myeloid Leukaemia
= abnormal (**partially mature**) and overproduction of granulocytes caused by chromosomal genetic mutation BCR-ABL1 gene
= **myeloproliferative** neoplasm
129
Risk factors for Chronic Myeloid Leukaemia
- disease of adults, rare in childhood
- most often 40-60, male
130
Pathology of Chronic Myeloid Leukaemia - how does it start?
- translocation chromosomal error during which a fusion gene is produced → BCR-ABL1 gene
- translocation between parts of chromosome 9 & 22 in a single bone marrow cell during cell division
= **9 is longer, 22 is shorter** → **Philadelphia chromosome**
131
Function of the BCR ABL Gene?
BCR-ABL creates protein → produces excessive tyrosine kinase = constant cell division
→ myeloid cells divide quickly & partially mature!
= buildup & symptoms of AML
132
How is Chronic Myeloid Leukaemia categorised?
- patients with detectable philly chromosome = Ph+ CML (95%), none = PH- CML
- may also be atypical CML not caused by BCR-ABL1 gene! must assess as poor prognosis and may not respond to treatment
133
Signs and Symptoms Chronic Myeloid Leukaemia
- ymptomatic anemia: weakness, fatigue, shortness of breath during basic everyday activities
- fever, bone pain
- unexplained weight loss
- \*\*pain or feeling of fullness below the ribs on the left\*\* due to \*\*enlarged spleen\*\*
- fullness on the LUQ
- palpable spleen?
- night sweats
- gout due to purine breakdown
- bleeding due to platelet dysfunction
134
Investigations for Chronic Myeloid Leukaemia
full FBC & blood film
bone marrow biopsy = hypercellular
Genetics
karyotyping → checks for chromosomal abnormalities or cytogenetics!
**PCR** for most sensitive test used to detect and measure the quantity of BCR-ABL1 gene (Ph does not matter here)
135
Diagnosing criteria for Chronic Myeloid Leukaemia
- increased WBC (granulocytes)
- with spectrum of myeloid cells (3 phils and myelocytes)
- blasts in smears!
- normally not present in blood of healthy individuals!
136
Treatment plan for Chronic Myeloid Leukaemia
- use PCR results to determine baseline BCR-ABL1 gene amount
**biological therapy**: **tyrosine kinase inhibitor**
= _Imatinib_ (dasatinib, nilotinib, etc )
Monitoring
FVC, spleen size, PCR repeat for BCR-ABL-1
gold is probably stem cell transplant
137
Prognosis of Chronic Myeloid Leukaemia depends on:
- phase of CML
- age
- spleen size
- platelet count
- blasts in the blood & increased number of basophils
138
What are Myeloproliferative Neoplasms (with 3 examples!)
= group of blood cancers in which too many blood cells are made in bone marrow
= e.g. primary thrombocytosis = essential thrombocythaemia // polycythaemic vera // myelofibrosis
139
Main cause of myeloproliferative neoplasms
**JAK2 mutation**
JAK2 protein → signals for promotion of growth and division of cells
helps control big3 blood cells
increased production of big 3 + prolonged survival
overproduction of cytokines too = + inflammation
140
Targeted treatment for cause of myeloproliferative neoplasms?
**_Ruxolitinib_**
= Janus Kinase inhibitor
= cancer growth blocker
for intermediate to high risk
intolerance to hydroxyurea & steroid refractory GvHD
141
Polycythaemia Vera - what is it?
RBC count above the normal range
142
Inflammatory symptoms for Myeloproliferative Neoplasms
- unexplained fevers
- night sweats
- itchy skin = **pruritus** - esp after hot **shower**
- reddening of face
- bone pain
143
Neurological symptoms for Myeloproliferative Neoplasms
- headaches, dizziness and weakness
- difficulties concentrating
- peripheral neuropathy (numbness, tingling or burning in the feet)
144
Symptoms and signs - Polycythaemia Vera
- inflammatory and neurological symptoms for MN's
- **Conjunctival plethora** (excessive redness to the conjunctiva in the eyes)
- A “**ruddy**” complexion
- **erythromelalgia**: burning in fingers and toes
- **hepatosplenomegaly**: due to extramedullary haemopoiesis → distinguishes PV from secondary causes!
- uncontrolled bleeding or excessive bruising
- abnormal blood clots
- weight loss with no known reason
- full after eating small amounts of food
145
Complications Polycythaemia Vera
- stroke
- heart attack
- thrombus / DVT
- enlarged spleen
- progression to myelofibrosis, MDS or AML
146
Pathology of Polycythaemia Vera
**mutation in the JAK2 gene**
JAK2 protein made signals for promotion of growth and division of cells
- helps control big3 blood cells
**_→ mutation_**
- increases production and prolongs survival
- erythroid progenitor offspring **_do not need**_ (=unusual) _**erythropoietin_**
→ avoids apoptosis // erythropoietin levels low
- **overproduction of cytokines**: increases **inflammation**
147
Major criteria Polycythaemia Vera
- complete blood count with differential
→ high RBC = diagnose
→ high WCC and platelets = distinguish PV from secondary causes
- presence of JAK2 mutation on genetic screen
148
Minor criteria Polycythaemia Vera
- bone marrow biopsy: **prominent erythroid, granulocytic & megakaryocytic proliferation**
- serum erythropoietin low
149
Treatment goals Polycythaemia Vera
→ no cure, aims to maintain normal blood count
150
Treatment plan Polycythaemia Vera
**venesection** = symptom relief
lower PCV and platelet count, 400-500ml/week
often sole tx
**chemo**
intolerant to venesection / uncontrolled others e.g. thrombocytosis
- **hydroxycarbamide** and low dose **bulsulfan**
* *low dose aspirin** alongside above
- **radioactive phosphorus** but only in over 70 due to + risk of acute leukaemia
- **allopurinol** to block uric acid production thereby reducing gout / tumor lysis
- **lifestyle** - smoke, cardio health
151
What is thrombocytosis aka thrombocythaemia?
= platelet count above the normal range = 450 x 10^9 / L in adults
cythaemia = result of proliferation of megakaryocytic cell line
152
How to differentiate thrombocytosis from polycythaemia vera?
besides a raised platelet, check if hematocrit is also raised - if yes → polycythaemia vera
153
types of thrombocytosis / thrombocythaemia?
→ **Primary** = essential
= **JAK2 mutation** (others: MPL / CALR gene)
= autonomous production
→ **Secondary** = reactive
= caused by conditions
= triggers release of cytokines → mediate an increase in platelet production
= TUC then transient
154
Presentation thrombocytosis / thrombocythaemia?
- what are thrombus symptoms? (4)
**_thrombus symptoms_**
DVT // Pulmonary embolism // MI from clot // Stroke or TIA
Other symptoms
- fatigue, weight loss, low grade fevers, night sweats
* *erythromelalgia**: pain, redness and swelling in hands or feet
* *enlarged spleen**
155
investigations for thrombocytosis / thrombocythaemia?
1. platelet count raised - from blood count
2. review blood film, acute phase reactants, iron status
156
Possible outcomes from investigations for thrombocytosis / thrombocythaemia?
- reactive thrombocytosis
- essential thrombocytosis
- iron deficiency
157
Based on investigations for thrombocytosis, if everything is normal but with symptoms: - what to do next
- if symptoms persist with no explanation?
- if normal: repeat blood count
- if persistent unexplained thrombocytosis: molecular genetics screen for JAK2, CALR, MPL. Diagnose if fulfils criteria
158
Based on investigations for thrombocytosis, if it's iron deficiency?
treat iron deficiency ( replace iron → **oral is preferred (safer), IV is no faster than oral**! - ferrous sulphate 200mg 1-3x daily) then repeat blood count
159
If Acute Phase response (??)
Diagnose as reactive thrombocytosis
160
Diagnostic criteria for Essential Thrombocythaemia?
4M or 1-3M + m
* *Major**
1. platelet count ≥ 450x10^9 / l
2. bone marrow biopsy showing increased megakaryocytes (forms platelets) with abnormal nuclei
3. exclusion of other diseases, e.g philly+ CML, PV, myelofibrosis, myelodysplastic syndromes, m - neoplasms
4. presence of JAK2, CALR, or MPL mutation
**Minor**
Presence of clonal marker (chromosome abnormality) or NO evidence that disorder is caused by reactive thrombocytosis
161
Treatment goals thrombocytosis / thrombocythaemia?
→ prevent thrombosis = main goal!
→ anyone with venous blood clot will require lifelong treatment with anticoag
162
Treatment plan for thrombocytosis / thrombocythaemia based on risk category? (4)
* *Very low**
- under 60, no thrombo, no JAK2 mut
- observation only
* *Low**
- under 60, no thrombo, no JAK2 mut
- low dose aspirin
* *Intermediate**
- over 60, no thrombo, no JAK2 mut
- low dose aspirin with or without cytoreductive therapy
* *High**
- over 60, yes thrombo, yes JAK2 mut
- low dose aspirin with cytoreductive therapy
163
Medications for thrombocytosis / thrombocythaemia? (1+2+emerg)
* *Aspirin**
- low dose: 80-100mg per day
- reduces clotting and complications
- SE = GI upset and heartburn
first line = **Hydroxycarbamide** (hydroxyurea)
- decrease number of blood cells made in the bone marrow
- succeeds in decreasing in weeks, minimal and short term SE
- SE: low white blood cell count, nausea, vomiting, diarrhoea and oral ulcers
second line - **bulsulfan** (chemo!)
- used in older patients who are resistant or intolerant to hydroxyurea
- SE low counts, nausea and vomiting, diarrhoea, poor appetite and mouth sores
* *emergency - plateletpheresis**
- circular patient-machine cycle where machine collects platelets, returning the rest to patient’s blood strea
- temporary effect! only used for emergencies e.g. clotting complications
164
Complications thrombocytosis / thrombocythaemia?
- myelofibrosis
- less common - myelodyplastic syndrome or acute myeloid leukemia
165
What is Idiopathic Thrombocytopenic Purpura (ITP)?
= Immune thrombocytosis
= easy or excessive bruising and bleeding from unusually low level of platelets
166
What is petechiae?
superficial bleeding into skin that appears as pinpoint sized reddish-purple spots
167
Purpura vs petechiae?
Petechiae are very small, pinpoint sized reddish purple spots less than 4 millimeters (mm) in size.
Purpura are larger areas of bleeding under the skin, typically between 4 mm and 10 mm
168
Signs & symptoms for Idiopathic Thrombocytopenic Purpura (ITP)
- easy or excessive bruising
- petechiae / purpura
- bleeding from gum & nose
- blood in urine or stools
- unusually heavy menstrual flow
169
Acute causes for Idiopathic Thrombocytopenic Purpura (ITP)
- esp in children
- **history or recent viral infection** → may be immunisation!
- varicella zoster (chickenpox) or measles
- flu
- present as muco-cutaneous bleeding!
- may be severe but rarely life-threatening
- sudden self limiting purpura → red or purple spots on skin
170
Chronic causes for Idiopathic Thrombocytopenic Purpura (ITP)
- less acute than children’s
- most commonly in women - may be associated with other autoimmune disorders
- chronic lymphocytic leukaemia (CLL), SLE, thyroid disease & autoimmune haemolytic anaemia
- from infection
- HIV, hep, H pylori (causes stomach ulcers)
- platelet autoantibodies detected in 60-70% of patients
171
Investigations and criteria for diagnosis - Idiopathic Thrombocytopenic Purpura (ITP)
- bone marrow exam
- thrombocytopenia shown
- with increased or normal megakaryocytes in marrow
- platelet autoantibody - present in 60-70% but not needed to diagnose
172
Medications for Idiopathic Thrombocytopenic Purpura (ITP) - (2)
- mild - regular monitoring and platelet checks. children mostly improves without treatment.
First line - \*\*corticosteroids e.g. prednisolone\*\*
- IV immunoglobulin e.g. IV IgG - raises platelet count more rapidly than steroids thus useful for surgery
Second line - \*\*splenectomy\*\*
- eliminates source of platelet destruction
- increases susceptibility to infection
- if splenectomy fails then immunosuppression e.g. oral or IV azathioprine
Others:
rituximab: increases platelet count as an immunosuppressant, but may reduce effectiveness of vaccine
173
What is Thrombotic Thrombocytopenia Purpura (TTP)
→ this is quite rare
= widespread adhesion and aggregation of platelets leading to microvascular thrombosis; thus profound consumption of platelets and thrombocytopenia
174
Causes for Thrombotic Thrombocytopenia Purpura (TTP)
- acquired (idiopathic) and congenital (familial)
- lack of ADAMTS 13 enzyme
- responsible for breaking down large strings of VWF into smaller units, which reduces the small blood vessel clots
- often stops working because body makes antibodies to it
- cancer, pregnancy, drug induced - quinine
175
Risk for Thrombotic Thrombocytopenia Purpura (TTP)
- women more than men
- peak in 40’s
176
Presentation - Thrombotic Thrombocytopenia Purpura (TTP)
- florid purpura - discolouration of the skin or mucous membranes due to haemorrhage from small blood vessels
- fluctuating cerebral dysfunction
- headaches, mental changes, confusion, speech abnormalities, slight or partial paralysis, seizures or coma
- \*\*haemolytic anaemia\*\* with red cell fragmentation, often accompanied by acute kidney injury
- fever
- blood plasma protein and small number of RBC in urine may also occur
177
Diagnosis - Thrombotic Thrombocytopenia Purpura (TTP)
- blood test and film
- coag screen is normal
- lactate dehydrogenase is raised as a result of haemolysis
- in about half: increased creatinine
- \*\*ADAMTS13\*\* level check
178
Treatment for Thrombotic Thrombocytopenia Purpura (TTP)
- plasma exchange
- tablets or drip
- IV rituximab
- IV methylprednisolone
179
What is Myelofibrosis
= blood cancer characterised by the buildup of scar tissue = fibrosis in the bone marrow
→ bone marrow cannot make enough healthy blood cells so spleen and liver compensates through cell making and increase in size
180
Types of myelofibrosis
- primary
- as a JAK mutation
- secondary - as a result of PV or ET - 10-20%
- complication - acute myeloid leukemia, portal hypertension (from cell production), extramedullary hematopoiesis (production of BC), gout
181
3 major symptoms of myelofibrosis
- usually slow developing and does not cause symptoms early on
→ \*\*not enough blood cell symptoms\*\*
- Fatigue, weakness, shortness of breath, or pale skin
- Frequent infections due to a low white blood cell count
- Bleeding or bruising easily due to a low platelet count
→ \*\*splenomegaly / hepatomegaly (liver)\*\*
- abdominal pain, feeling of fullness, decreased appetite, weight loss
→ \*\*general\*\*
- early satiety / cachexia
- night sweats
- itchy skin
- problems concentrating
- fever, bone or joint pain
- weight loss
182
Investigations for Myelofibrosis
- FBC & blood film
- leucoerythroblastic =
- tear drop poikilocytes
- normal b12 / folate / ferritin
- ultrasound (enlarge of spleen or liver)
- bone marrow biopsy
183
Diagnosis criteria for myelofibrosis
at least 3M + 1m!!
* *major**
1. typical megakeryocyte changes accompanied by ≥ grade 2 reticulin / collagen fibrosis
2. presence of JAK2, CALR, MPL mutations or others; or rule out reactive bone marrow fibrosis
3. no other myeloid neoplasms
* *minor**
1. anemia not otherwise explained
2. leukocytosis ≥ 11x10^9
3. palpable splenomegaly
4. increased serum lactate dehydrogenase (LDH)
5. leukoerythroblastic blood smear
184
Differential Diagnosis for myelofibrosis
- lactate dehydrogenase - (association found - raised for myeloproliferative diseases)
- b12 / folate / ferritin (normal)
- hep B / c / HIV (rule out!)
185
Treatment principle for myelofibrosis
→ depends on prognostic scoring: Dynamic International Prognostic Scoring System (DIPSS), IPSS, DIPSS plus, MIPSS-70
186
Danazol - what is it and what are the SEs?
- androgen drug, help increase RBC production
187
Hydroxyurea - what is it and what are the SEs?
- chemo drug, reduce spleen size or high platelet & WBC count in those not eligible for others
- SE low count (+ infection & bleeding), nausea, vomitting, diarrhea & oral ulcers
188
Ruxolitinib - what is it and what are the SEs?
- JAK 1 /2 inhibitor.
- for Pri MF, Post PV MF, Post ET-MF.
- SE low counts, bruising, dizziness and headaches. major tox. increase risk of infections
189
Prenisolone - what is it and what are the SEs?
- corticosteroid
- mainly used for ITP, also for other inflammatory diseases e.g. Crohn's & arthritis
190
Treatment plan for myelofibrosis
- Depend on prognostic scoring system
\*\*Very low risk\*\*
- no symptoms: no anaemia / enlarged spleen / comp's = generally not treated
\*\*Low risk\*\*
- some symptoms: may be observational or cytoreductive treatment for symptom relief
\*\*Intermediate risk\*\*
- INT-1 risk with symptoms
→ Ruxolitinib
→ allogeneic stem cell transplant
- INT-2 with symptoms
→ Ruxolitinib
→ Fedratinib
→ Allogeneic stem cell transplant
→ treatment for anemia
\*\*High Risk\*\* = depend on classification, see above
191
Allogenic stem cell transplant - what is it and what are the SEs?
- high dose of chemo to kill off abnormal, but will also kill off normal
- infusion of blood stem cells and replace defective cells
- creates new immune system
- high SE and mortality
- Comp: GVHD
192
Fedratinib - what is it and what are its side effects?
- kinase inhibitor with activity against JAK2 and FLT3, thereby reducing the abnormal production of blood cells and associated symptoms.
- for Prim MF, post-PV MF, or post-essential thrombocythaemia myelofibrosis
- SE nausea very common (counter w/antiemetics), constip, diarr, vom, HT, headache, infect, pain
193
Drugs for splenomegaly
- hydroxyurea
- ruxolitinib
- Splenectomy - not med lol
194
Identify the rash on picture?
| (& name the possible condition?)
Purpura
idiopathic thrombocytopenic purpura ITP
195
Identify the rash in picture
| (and name the possible condition?)
petechiae
idiopathic thrombocytopenic purpura
196
Diagnosis based on the following presentation?
- spikey paraprotein
- high Ca \> 0.25mmol/l above limit
- renal impairment, creatine \> 173 mmol/l
- anaemia
- bone disease
multiple myeloma
197
What is multiple myeloma?
- cancer of differentiated b-lymphocytes, known as plasma cells
- a bone marrow cancer, leads to progressive bone marrow failure
- characteristic spikey paraprotein production
- incurable
198
on the **characteristic spikey protein**
- produced by?
- type of protein?
- how to determine which type?
paraprotein
- produced by myeloma cells
- immunoglobulins - usually IgG (70) or IgA (30), others rare
- serum electrophoresis / densitometry
199
Specific presentations of multiple myeloma?
Spikey = paraprotein = immunoglobulin
Old = average age of incidence is 70
C = high Ca, \> 2.75 mmol/l
R = renal imapirment, creatine \>173 mmol/l
A = anaemia, ?
B = bone disease - lytic lesions, osteoporosis, spinal cord compression
200
Diagnostic threshold of paraproteins for multiple myeloma?
\> 30g / dl !
201
Other possible presentation of multiple myeloma besides spikey old crab?
hyperviscosity
recurrent infection \> 2 episodes in past 2 years
amyloid
raised ESR
& globulin frequent signals
202
Diagnosis based on the following presentations?
- paraproteins are an incidental finding, \< 30g / dl
- \< 10% plasma cells in bone marrow
- no related organ or tissue damage
- no evidence of amyloid or other lymphoproliferative disorder (LPD)
Monoclonal gammopathy of undetermined significance (MGUS)
- thought to be preceeding myeloma
203
Subtypes of myeloma (2) and how would you treat?
* *Smouldering myeloma** = \>30g/l paraprotin and \>10% plasma cells in BM, but no related organ or tissue impairment
- 20% risk of progression to MM 1st year
**Symptomatic myeloma** = hits diagnostic criteria and/or ROTI and/or tissue amyloid
**Only** treat _symptomatic myelomas_
204
Investigations for Multiple Myeloma?
_Main_
- bone marrow biopsy
- serum electrophoresis (where densitometry is a step)
- FBC for renal function, UE (serum calcium)
- urine
_Others_
- imaging is MRI
205
Treatment principles and options for Multiple Myeloma
_P__rinciple_:
- control and live with as incurable.
- reduce number of cells, reduce symptoms and complications
_Options_
- **Bisphosphonates:** Aledronic acid (for those potentially osteo frag frac), pamidronate, zoledronic acid (for hypercalcaemia)
- _CI_ renal impairment, _SE_ oseophagitis, osteonecrosis in jaw, non healing lesions
- **generic chemo**
- **stem cell transplant**
206
Options of generic chemo for multiple myeloma? (5)
- monoclonal antibodies
- immunomodulatory drugs (thalidomide & analogues SE birth defects)
- corticosteroids - reduce most cancers
- alkylating agents
- proteasome inhibitors
207
Briefly describe the stem cell transplant process?
- stem cell harvested
- high dose melphalan
- stem cell transplant
- is a chronotoxic procedure but keeps disease away for longer
- SE infection
208
What are amyloids?
Proteins of an abnormal shape which deposits into tissues
stains blue with iodine
209
What is systemic amyloidosis?
Tissue damage from extra amyloid deposits
can occur as a result of multiple myeloma
210
Symptoms of systemic amyloidosis?
Nephrotic syndrome ± renal impairment, congestive cardiomyopathy, neuropathy
bleeding, raccoon eyes & microglossia
211
Investigations for systemic amyloidosis?
proteinuria, hypoalbuminuria
biopsy of the tissues
212
Treatment for systemic amyloidosis?
No cure, cannot remove amyloid from organs :(
Organ transplant if needed.
Treat multiple myeloma
213
What is a lymphoma & how are they classified?
Haem malignancy arising from lymphoid tissue / cells
Commonly categorised as _Hodgkin_ and _non-Hodgkin_ lymphoma
| (= WBC cancer)
214
What is the difference between Hodgkin and non-Hodgkin lymphoma
Presence of Hodgkin / Reed Sternberg cells
215
Besides Hodgkin & Non-Hodgkin, how else are lymphoma classified?
according to cells of origin
B cell = more common
or NK/T cell
216
How might you differentiate Hodgkin's from non-Hodgkin's lymphoma?
Hodgkin = bimodal, 20's & 60's
Non Hodgkin = 50's
Hodgkin also has **pruritus** & **alcohol triggered pain**
217
What are Hodgkin/Reed-Sternberg cells (HRS) like?
Hodgkin = mononucleated
Reed-Sternberg = multinucleated, like an owl
218
Presentations for Hodgkin's lymphomas?
**Lymphadenopathy** = typically painless, firm, enlarged lymph nodes in the neck
**B symptoms** = fever, night sweats & weight loss
**_Pruritus_** = differentiate from non-H!!!
Mediastinal mass / hepatosplenomegaly, malaise, fatigue
219
How might you diagnose a Hodgkin's lymphoma?
Lymph node scans
Blood smear / FBC
Skin biopsy
biopsy of lymph nodes
fine needle aspiration, core biopsy or excision
220
What would the blood picture be like if there was bone marrow involvement?
high WBC
low haemo & platelets
bone marrow biopsy if needed
221
How might you stage a Hodgkin's lymphoma?
**_Lugano system_** = for HL!
**limited** = single / group of adjacenet / 2 or more same side
**Stage II bulky** = II with bulky disease
**Advanced** = nodes on both sides, above diaphragm with spleen
222
Methods used in staging of Hodgkin's lymphoma?
CT scans
Bloods, bone marrow
extranodal involvement / B symptoms
223
Main treatment for Hodgkin's Lymphoma?
ABVD Chemo (4x chemo agents)
A = Doxorubicin
B = Bleomycin
inhibit DNA synthesis
V = Vinblastine
inhibit microtubule formation
D = Dacarbazine
224
Other tx options & support for Hodgkin's Lymphoma?
**Monoclonal antibodies**
esp anti CD20 = rituximab etc
**Blood transfusions** = irradiated blood
avoid graft-vs-host disease
225
Prognosis for HL?
75% cured, and minimum survival for all stages = about 5 years
226
Presentation for Non-Hodgkin lymphoma?
More common than Hodgkin's!
50's
may present with only one system
227
Main treatment for non-Hodgkin's lymphoma?
R-CHOP Chemo
R - **Rituximab** (CD20)
C - **Cyclophosphamide**
= inhibit DNA Synthesis
**Doxorubicin**
= inhibit topoisomerase II = DNA synthesis
**Vincristine**
= inhibit microtubule formation to tubulin
**Prednisolone**
228
Most common form of Non Hodgkin's Lymphoma?
Diffuse large B cell lymphoma
229
Presentation for DLBCL?
Rapidly enlarging mass, commonly in the neck, abdomen or mediastinum
B symptoms in a third of patients
may lead to superior vena cavae obstruction & cord compression
230
2nd most common form of B cell NHL?
Presentation?
Follicular lymphoma
85% have a translocation
between chromosome 14 and 18
Gradually worsening, painless lymphadenopathy
231
What is a Burkitt's lymphoma?
high grade, rapidly proliferating B cell NHL
commonly affects children
232
Subtypes / causes of Burkitt's lymphoma?
**Endemic** = Epstein-Barr virus
follows distribution of malaria
**Sporadic**
**Immunodeficiency** = AIDs / immunosuppressive meds
233
Presentation - Burkitt's lymphoma?
**rapidly enlarging tumour**
in **jaw** of a child
alt: enlarged lymph nodes, abdo mass
GI pres common e.g. bowel obstruction
fever, weight loss & night sweats
234
What is superior vena cava obstruction? How will it present?
dyspnoea, face swelling, head fullness
**cyanosis**, **stridor**, upper limb oedema, distended neck and chest wall veins
**symptoms exacerbated by bending forwards / lying down**
235
Tests for SVC obstrustion?
**Pemberton's sign**
patient asked to elevate both arms above head for 1-2min
**_positive_** if causes cyanosis, respiratory distress or congestion
Chest CT = diagnostic!!
236
Tx SVCO?
Stent if stridor
Get help!
237
What is tumour lysis syndrome?
metabolic disturbances arising from the breakdown of malignant cells following the initiation of treatment for malignancy
238
How might tumour lysis syndrome present?
fluid overload
haematuria
tetany & paraesthesia
bronchospasm
**AKI**! from uric acid & calcium phosphate in renal tubules
esp if using _allopurinol & rasburicase_
239
Tests for TLS?
Electrolytes, Serum urate, Renal function
= essential
ECG monitor, additional as need
240
What is a TLS diagnosis based on?
**increases in uric acid, potassium, phosphate & calcium levels**
alt - serum creatinine +, cardiac arrhythmia, seizure which cannot be tagged to a med
| (25% increase each)
241
Prevent and treat TLS?
**Allopurinol** = xanthine oxidase
= prophylactic only
**Rasburicase** = recombinant uric oxidase = treat + prophy
Supportive as needed
