Haematology and oncology Flashcards
At what platelet level should you considered giving platelet transfusion ?
<10 and no bleeding
<30 with active bleeding e.g. epistaxis, melaena
<100 if severe bleeding or bleeding from critical site e.g. CNS
What is one problem with platelet transfusion that occurs more so than with other blood products?
Bacterial contamination of platelets is more common than with other blood products.
What should target platelet levels be pre-op?
for any patient - >50
For those at risk of bleeding 50-75
those at risk of bleeding from critical site >100
What conditions are contraindicatory for platelet transfusion?
Autoimmune thrombocytopenia
Heparin induced thrombocytopenia
Thrombotic thrombocytopenia purpura
chronic bone marrow failure
name 3 types of porphyria’s ?
acute intermittent porphyria
porphyria cutanea tarda
variegate porphyria
What is the common pathogenesis with the porphyrias?
abnormalities in enzymes synthesising Heme resulting in the accumulation of intermediates = porphyrins
how does porphyria cutanea tarda present?
photosensitive bullae
skin fragility on face and dorsal aspect of hands
what form is porphyria cutanea tarda (i.e. which organ?) and how is it caused?
hepatic form
can be caused by hepatocyte damage - alcohol, oestrogens
defect in uroporphyrinogen decarboxylase
how can you investigate porphyria cutanea tarda?
elevated uroporphyrinogen
pink florescence urine under wood lamp
How do you manage Porphyria cutanea tarda (PCT)?
Chloroquine
what enzyme is defective in variegate prophyria?
protoporphyrinogen oxidase
what pattern of inheritence is variegate porphyria?
autosomal dominant
How does variegate porphyrias present?
photosensitive blistering rash
abdominal and neuro symptoms
most common in south aftrican
How does a PET scan work?
flurodeoxyglucose used as a radiotracer.
tumours are active and take up this marker
images are combined with CT to give an idea of if lesions are metabolically active
At what stage of pregnancy is risk of DVT/VTE the highest?
3rd trimester
what is the cause of increased risk of VTE in pregnancy?
hypercoaguable state - increase in factors VII, VIII, X and fibrinogen
decrease in protein S
stasis in legs - uterus compressing on veins. progesterone dilates veins.
what treatment is used for DVT in pregnancy?
LMWH
warfarin contraindicated
causes of splenomegaly including massive splenomegaly….
massive spenomegaly: myelofibrosis CML visceral leishmaniasis malaria gauchers syndrome
other causes: (not massive)
- EBV, hepatitis
- malaria
- sickle cell/ thalassemia
- haemolytic anaemia
- portal hypertension
- CLL, hodgekins
- rheumatoid arthritis (feltys)
- infective endocarditis
Where are thymomas located? what age do they present?
most common tumour of anterior mediastinum
Occur during 6th and 7th decades of life
what diseases are thymomas associated with?
Myasthenia gravis (30-40%)
Dermatomyositis
Red cell aplasia
SLE, SiADH
what are the causes of death with a thymomas?
compression of airway
cardiac tamponade
what is transexamic acid?
antifibrinolytic
lysine derivative
binds plasminogen and plasmin preventing the breakdown of fibrin
used in menorrhagia
which type of central venous catheter gives a higher risk of VTE?
femoral > subclavian
which underlying conditions increase risk of VTE?
malignancy thrombophilia: e.g. Activated protein C resistance, protein C and S deficiency heart failure antiphospholipid syndrome polycythaemia nephrotic syndrome
Behcet's sickle cell disease paroxysmal nocturnal haemoglobinuria hyperviscosity syndrome homocystinuria
which medications increase risk of VTE?
Oestrogens
Raloxifene
tamoxifen
antipsychotics
what is waldernstrom’s macroglobulinaemia?
lymphoplasmacytic lymphoma - rare malignant lymphoma with monoclonal IgM paraproteinaemia
who is waldenstroms macroglobulinaemia most common in?
older men
what are the symptoms of waldenstroms macroglobulinaemia? How does this relate to pathophysiology
IgM is a large pentamer of 5 IgM molecules - causes hyperviscosity
- blurred vision, headaches, tireness, hypercoaguability, mucosal bleeding, peripheral neuropathy
systemic symptoms - weight loss, fatigue
IgM deposit in organs - splenomegaly, hepatomegaly, lymphadenopathy.
overcrowds other blood components - low RBC and platelets.
can lead to cryoglobulinaemia - e.g. raynauds
what genes are mutated in waldenstroms macroglobulinaemia?
MYD88
CXCR4
How is waldenstroms macroglobulinaemia diagnsoed?
electrophoresis and immunofixation to show monoclonal band of IgM
CT - organomegaly
FBC
how is waldenstroms macroglobulinaemia managed?
assymptomatic - monitor
otherwise plasmaelectrophoresis or chemotherapy
What is usually the cause of tumour lysis syndrome?
can occur in anyone but mainly occurs after combination chemotherapy.
death of cells and release of contents - urea, phosphate, potasium
How are patients at high risk of tumour lysis syndrome managed?
IV allopurinol or rasburicase immediately prior or in first few days of chemo
what is the mechanism of action of
- rasburicase
- allopurinol
Rasburicase - similar to urate oxidase - converts urate to allantoin. allantoin is more soluble that urate and can be excreted by kidneys
how are low risk patients of tumour lysis managed?
oral allopurinol during chemotherapy
why can allopurinol and rasburicase not be given together?
Reduces affect of rasburicase
In any patient with AKI in presence of high uric acid and phosphate levels, what should we suspect?
tumour lysis syndrome
what scoring system grades tumour lysis syndrome?
Cairo-bishop scoring system
what is the cairo bishop scoring system?
labarotory tumour lysis syndrome…
K: >6 (or 25% increase)
uric acid: >475 (or 25% increase)
PO4: >1.125 (0r >25% increase)
Ca: <1.75 (or >25% decrease)
how is clinical tumour lysis syndrome classified using laboratory tumour lysis ?
laboratory tumour lysis syndrome + one of the following:
- Creatinine >1.5 upper limit
- cardiac arrhythmia/sudden death
- seizure
what is the most common and second most common type of thrombophilia?
Factor V leiden
second = prothrombin gene mutation
List the causes of thrombophilia?
genetic:
- factor V leiden
- Protein C/S deficiency
- antithrombin III
- prothrombin gene mutaton
acquired
- antiphospholipid syndrome
- COCP
which type of thrombophilia gives the largest risk of VTE?
ATIII deficiency largest risk
followed by Protein S and C deficinecy
then homozygous for Factor V leiden
then heterozygous for factor V leiden
causes of thrombocytosis..
reactive - surgery, infection, bleeding essential thrombocythemia malignancy as part of another myeloproliferative disorder e.g. leukaemia hyposplenism
how is thrombocytosis defined?
platelets >400
what is essential thrombocythaemia?
myeloproliferative disorder where bone marrow produces too many platelets. Due to JAK 2 mutation and activation of JAKSTAT pathway. Slowly progressive
can lead to myelofibrosis or acute leukaemia
what symptoms are found with essential thrombocythemia?
high viscosity:
- tinnitus, blurred vision, peripheral neuropathy, headaches, fatigue, dizziness, nausea.
VTE , stroke, MI , miscarriages.
may get bleeding events when platelets are really high.
most likley to be assymptomatic
why can essential thrombocythemia cause bleeding?
excess platelets mop up vWF
how is essential thrombocythemia managed?
low risk VTE - aspirin high risk : - hydroxyuria - IFNa - anagrelide
OR platelet plasmaphoresis
which organs normally release thrombopoietin ?
liver and kidneys
what tumour produce the following markers:
Ca125 Ca15-3 Ca19-9 PSA AFP
ca125 - ovarian Ca15-3 - breast Ca19-9 - pancreatic PSA - prostate AFP - HCC, teratoma
what tumours produce the following markers:
CEA
S100
Bombesin
CEA - colorectal
S100 = melanoma, schwanoma
Bombesin - Small cell lung Ca, gastric, neuroblastoma.
what chains is normal adult Hb made of?
2a , 2b
what chains is sickle cell HB made up of
2a and 2 mutated B
HBSS
(heterozygous - one mutated B = HbAS
what is the pathogenesis behind sickle cell anaemia?
point mutation in B globulin gene
changes glutamic acid to valine (hydrophilic to hydrophobic)
when deoxygenated these Hb molecules aggregate:
- sickling of the cells which has low affinity to O2
- damages RBC membranes - intravascular haemolysis
predisposing factors to a crisis - low O2, dehyrdration, acidosis, infection.
bone marrow - reticulocytosis
expansion of medullary cavities e.g. enlarged cheeks and skull has hair on end appearance on Xray.
extramedullary haematopoesis - hepatomegaly
when do symptoms of sickle cell anaemia start?
4-6 months after birth (when fetal Hb is replaced)
what does the heterozxygous form of sickle cell protect against?
Falciparium malaria
Sickle cell anaemia causes vaso-occlusion.. what are the consequences of this?
RBC are sickled shaped and get stuck in cappillaries causing occlusion/ ischaem
- in extremities (esp in children) - dactylitis (swelling of digits)
- in bones - avascular necrosis and painful crisis
- in lungs - acute chest syndrome
- in spleen - splenic infarct and hyposplenism. also splenic sequestration.
- in penis - priapsim
- cerebral vasculature - strokes
- renal papillae - necrosis . haematuria and proteinura
what types of organisms does the spleen protect against?
encapsulated bacteria Neisseria meningitides S. pneumonia salmonella H.influenza
what is moya-moya disease?
occulusion of cerebral vessles can lead to dilation of adjacent capillaries and these look like puffed out smoke on scan
how is sickle cell crisis managed?
O2, opioids, rehydration
Abx
may require transfusion - however try to limit due to iron overload and development of Abx
how are patients with sickle cell managed in the long term?
prophylactic Abx
Vaccinations - pneumococcal
hydroxyurea - increases gamma globulin - to convert Hb to fetal form - used as prophylaxis against acute attacks.
how is sickle cell anaemia diagnosed?
new born blood spot screen
blood smear
electrophoresis
What are the different forms of sickle crisis?
Thrombotic acute chest aplastic haemolytic sequestration
what is the thrombotic (aka painful crisis)? (in sickle cell)
vaso-occlusive crisis
infarcts within bones often joints causing avascular necrosis, swelling, pain.
infarcts also can be in lung, spleen, brain
what is sequestration crisis? (in sickle cell)
pooling of blood within the spleen
low blood pressure
worsening anaemia
splenomegaly
what is the aplastic crisis?(in sickle cell)
caused by parvovirus
dramatic drop in Hb
no reticulocytosis
how does acute chest syndrome present (in sickle cell)?
dyspnoea, chest pain, low O2
pulmonary infiltrates
most common cause of death after childhood
what is sideroblastic anaemia? including genetic pathophysiology
a form of anaemia whereby iron is not correctly incorporated into RBC and thus there is a build up of iron and immature RBC.
ALAS2 gene is mutated resulting in defective delta ALA synthase –> defective protoprphin IX synthesis leading to poor heme production.
Iron deposits in mitochondria of RBC and excess iron in blood.
how can sideroblastic anaemia be acquired?
alcohol, lead poisoning, myelodysplasia, pyroxidine deficiency
what are pappenheimer bodies? what stain is used to view them?
pappenheimer bodies are the deposits of iron within mitochondria. - seen on blood film
Mitochondria circulate the nucleus – ringed sideroblasts on histology
stained with prussain blue stain for bone marrow
how is sideroblastic anaemia diagnosed?
FBC
iron and ferritin increased
blood smear - basophillic stipling and pappenhiemer bodies.
clinically
how does sideroblastic anaemia present?
presents like haemochromatosis:
- fatigue
- liver failure
- heart failure
- kidney faulure
- diarrhoea
- large spleen
how is sideroblastic anaemia treated?
phlebotomy
deforoxamine (iron chelating)
pyroxidine , thymine or folic acid can be given
how does spinal metastasis present?
back pain worse on lying down/ nocturnal
worse on cough/sneeze
How quickly should an MRI be organised for an individual with suspected spinal metastasis?
If no risk of cauda equina or neuro symptoms - 1 week.
if signs of cauda equina - 24 hours
what type of malignancy is superior vena cava obstruction most likely causes by?
lung cancer
also lymphoma, breast cancer, kaposi sarcoma, seminoma
what are the clinical features of SVC obstruction?
dyspnoea, cough facial plethora swelling of arms and neck headache - worse in morning blurred vision increased JVP
other:
stridor, dysphagia, cerebral oedema/ischaemia
other than malignancy what are the other causes of SVC obstruction?
aortic aneuryms
SVC thrombosis
goitre
mediastinal fibrosis
how is SVC obstruction managed?
STAT high dose steroid
urgent CT
Endovascular stenting
radio/chemo
what is the pemberton sign?
raise arms above head - obstructs SVC further
cyanosis, swelling of face and SoB = positive sign
what is the most common inherited bleeding disorder? what pattern of inheritance does this follow?
Von willibrand disease
Autosomal dominant
what are the symptom of von willibrand disease?
epistaxis and menorrhagia - behaves like a platelet disorder
rather than coagulopathy - haemarthrosis and haematomas.
what is the normal function of von willibrand factor?
promotes platelet aggregation
stabilises factor 8
what are the different types of von wilibrand disease?
type 1 - most common, partial reduction in vWF
type 2 - abnormal form
type 3 - total lack of (autorecessive)
what is found on Ix for Von Willibrand disease?
increased bleding time
increased APTT
defective platelet aggregation with ristocetin
how is Von willibrand disease managed?
transexamic acid
factor VIII concentrate
Desmopressin (DDAVP) - increases levels of vWF by reducing release from endothelial cells.
what is Wiskott Aldrich syndrome?
X linked genetic Condition were by there is a dysfunction of the WASP protein resulting in a classic triad:
Eczema
Microthrombocytopenia
immunodeficiency
what is the genetics behind Wiskott Aldrich syndrome?
WASP gene (found on chromosome X) is mutated. This normally is stabilised by a ligand but once WASP protein is mutated it can no longer be stablised.
WASP is produced by all haematopoetic cells and is important for cytoskeletal functions (phagocytosis and cell division).
Wiskott Aldrich syndrome type 2 is caused by mutation in WIPF1 gene which encodes the ligand
what conditions are individuals with Wiskott Aldrich syndrome more prone to?
leukaemias and ITP
describe the triad seen in Wiskott Aldrich syndrome
eczema
microthrombocytopenia - small few platelets
immune deficiences - especially for encapsulated bacteria
what antibodies patterns are seen in Wiskott Aldrich syndrome?
increase in IgA/E
Descrease in IgM/G
What is thrombotic thrombocytopenia purpura?
abnormal vWF causes platelets to clump within vessels causing thrombosis.
Caused by deficiency in ADAMTS13 (mellanoprotease enzyme) which breaks down large vWF
rare
mainly in adult females
what are the features of thrombotic thrombocytopenia purpura?
pentad of fever, fluctuating neuro signs, thrombocytopenia, renal failure, microangiopathic haemolytic anaemia
what are the causes of thrombotic thrombocytopenia purpura?
pregnancy post infection SLE tumour HIV drugs - COCP, penicllin, aciclovir, ciclosporin, clopidogrel
how is thrombotic thrombocytopenia purpura managed?
plasma exchange - treatment of choice.
no Abx
steroids
vincistine
how is vit b12 absorped?
binds intrinsic factor
active absorption by terminal ilium
what are the causes of vitamin B12 deficiency?
vegan pernicious anaemia chrons/ terminal ilium disease post gastrectomy metformin - rare
what type of anaemia is vit B12 deficiency?
macrocytic
how does Vit B12 deficiency present?
sore tongue/ mouth
neuro signs
- dorsal column first e.g. joint positon and vibration
mood disturbance
How is Vit B12 deficiency managed?
IM injections of hydroxycobalamin 3x for 2 weeks then once every 3 months
how is combined B12 and folate deficiency managed?
replace B12 first (24 hours prior to folate deficiency).
This avoid subacute combined degeneration of the cord.
What is usually the cause of malignant spinal cord compression?
vertebral body metastasis
usually due to lung, breast or prostate
How is suspicion of spinal cord compression managed?
high dose oral dexamethasone
oncology assessment - radiotherapy/surgery
urgent MRI within 24 hrs
what are the symptoms of malignant spinal cord compression?
back pain - worse at night, worse on lying/coughing. usually earliest symptoms
lower limb weakness
sensory changes
above L1 - upper neuron signs
below L1 - lower neuron signs
what is IFNa used to treat?
Hep B/C Thrombocythemia metastatics RCC hairy cell leukaemia Kaposi sarcoma
Describe the pathogenesis of multiple myeloma:
cyclin D mutation or chromosomal abnormalities result in dysregulation of plasma cells.
progression from normal to MGUS to MM
Monoclonal population of B cells divide rapidly and produce monoclonal Ab (paraprotein)
These Ab can crowd other cells causing increased bleeding and infections.
IL6 is high which stimulates RANK ligand. This causes osteoclast stimulation and inhibition of osteoblasts
this leads to lytic bone lesions and raised calcium
what is the M spike?
Spike seen on electrophoresis corresponding to a monoclonal Ab band.
Then use immunofixation to detect the exact Ab causing this spike
what are some risk factors for developing myeloma?
benzene and petroleum
Who does myeloma commonly present in?
M>W
>70yrs
<40yrs very unlikely
african americans
what is the most common type of myeloma (i.e. Ab expressed)
IgG kappa
then IgA
How does myeloma present clinically?
Disseminated bone disease:
- high Ca - pathalogical # - bone pain (vertebrae and ribs)
Kidney failure due to Ca, Bence jones, amyloidosis and NSAID use/ chemotherapies
- stones, renal tubular acidosis, pyelonephritis
Hyperviscosity syndrome
Ab overcrowd other Ab - immunodeficiency
Ab coat platelets - bleeding
Plasmacytoma - local tumours can cause local symptoms
amyloidosis - macroglossia, carpal tunnel
normocytic normochromic anaemia
lethargy
How is myeloma investigated?
electrophoresis - of serum and urine
- urine - bence jones proteins (light chains)
- serum - M spike
Immunofixation
Whole body MRI
why is ALP normal in myeloma? what does this mean about the use of a bone scan?
bone lysis occurs but osteoblasts are inhibited and thus new bone is not formed. so ALP is normal.
Thus activity also wont be picked up on bone scan
Name two prognostic markers in multiple myeloma
B2 macroglobulin - high levels associated with poor prognosis
Albumin - low levels associated with poor prog
how is myeloma staged?
stage 1: B2 macroglobulin <3.5 and albumin >35
stage 2 - not stage 1 or 3
Stage 3: B2 macroglobulin >5.5
how is myeloma managed?
high dose chemo
Stem cell transplant
radiation for plasmacytoma
what are the causes of microcytic anaemia?
iron deficiency thalassemia lead poisoning sideroblastic anaemia anaemia of chronic disease
why can polycythaemia ruba vera present as microcytic RBC?
normal Hb but microcytic due to iron deficiency secondary to increased bleeding risk
what are the causes of neutropenia?
viral - EBV, HIV, hepatitis Drugs - cytotoxic, carbimazole, clozapine Haematological malignancy Rheumatology - RA and feltys Severe sepsis haemodialysis
what are the causes of normocytic anaemia?
chronic disease haemolytic anaemia blood loss asplastic anaemia CKD
what is myelofibrosis?
bone marrow undergoes fibrosis and looses function
What are the causes of myelofibrosis?
Can be primary
or due to secondary cause:
Essential thrombocythaemia and polycythaemia ruba vera
what is the pathogenesis behind myelofibrosis?
JAK STAT pathway mutation and overdrive
many megakaryocytes
produce platelet derivred growth factor and fibroblast GF
results in activation of fibroblasts
fibsosis of bone marrow
haematopoietic stem cells migrate to liver, spleen and lung for extramedullary haematopoiesis
enlargement and dysfunction of these organs
bone marrow dysfunction - pancytopenias
what are the symptoms of myelofibrosis?
hypermetabolic symptoms 0 fever, tiredness, weight loss
pancytopenia - anaemia, bleeding, infections
bone pain
hepatospenomegaly (massive splenomegaly)
excess platelets - VTE
itching
what is seen on blood film for myelofibrosis?
tear drop RBC
early on increase cell number
but later decrease
what is the function of ruxolitinib ?
blocks JAK STAT pathway and relieves symptoms
what is seen on bone marrow aspirate in myelofibrosis?
dry tap - bone marrow unobtainable
what blood markers are high in myelofibrosis?
LDH and urate
What is paroxysmal nocturnal haemoglobinuria? which gene is mutated and pathogenesis?
Acquired chronic haemolytic anaemia due to defect in myeloid stem cells
PIGA gene mutation (on X chromosome)
PIGA codes for enzyme that synthesises proteins that regulate completement e.g. DAF and GPI. These are reduced meaning complement regulatory proteins CD55 and CD59 are reduced.
This results in MAC complex formation on RBC and intravascular haemolysis.
What are the symptoms of paroxysmal nocturnal haemoglobinuria?
haemolytic anaemia - throughout day but in mornings urine is most concentrated and thus get haemaglobinuria at night (hence the name) splenomegaly pancytopenia and aplastic anameia fever of unknown origin thrombosis
what are the complications of paroxysmal nocturnal haemoglobinuria?
iron deficiency anaemia
AML
Thrombosis - venous (most common cause of death)
What lab findings do we see in paroxysmal nocturnal haemoglobinuria?
low HB high reticulocytes normal MCV high LDH low haptoglobin
what diagnostic tests can be used for paroxysmal nocturnal haemoglobinuria?
flow cytometry for CD55 and CD59
Acidified serum test (HAM) - acid induced haemolysis (normal RBC wont haemolyse) - now gold standard
how is paroxysmal nocturnal haemoglobinuria managed?
Transfusion
Eculizumab - binds C5 prevents cleavage so no MAC and no attack of RBC
what vaccination is needed if using Eculizumab ?
Eculizumab - is used for paroxysmal nocturnal haemoglobinuria
Need to give N.meningites vaccine if using
What gene is mutated in polycythaemia ruba vera?
JAK 2
What protein normally activates JAK 2?
EPO in erythrocytes
Thrombopoetin in megakaryocytes
what is meant by the stent phase in polycythaemia ruba vera?
in polycythaemia ruba vera bone marrow is initially active and producing lots of cells. eventually becomes replaced by fibrotic tissue and no longer prodcuing RBC. leads to pancytopenia = STENT Phase
a.k.a myelofibrosis
what are the symptoms of polycythaemia ruba vera?
headaches in morning facial flushing tiredness tinnitis blurred vision dizzinss increased sweating
itching especially after hot shower
splenomegaly
gout
increased risk of clots
when does polycythaemia ruba vera present?
6th decade
what lab findings are found in polycythaemia ruba vera?
high RBC, haemocrit, HB, high platelets, high WCC
low ESR
low EPO
high ALP
what is the management for polycythaemia ruba vera?
phlebotomy
ruxolitinib - JAK STAT pathway inhibitor - releives itching
hydroxyurea - reduces RBC formation
antihistamines, hydroxyzine and aspirin - reduces itching
STENT phase - blood transfusion
what are the secondary causes of polycythaemia?
COPD, high altitude OSA Excess EPO hypernephroma hepatoma
what is relative polycythaemia?
e. g. dehydration
e. g Stress - Gaisbock syndrome
what can polycythaemia ruba vera progress to?
myelofibrosis
Acute leukaemia
How is neutropenic sepsis defined?
neutrophil count <0.5
high temp
sepsis
When does neuropenic sepsis normally present?
7-14 days post chemo?
what is the most common pathogen causing neutropenic sepsis?
gram positive cocci
how is neutropenic sepsis managed?
Abx - Tazocin
if still unwell - mero+/- vancomycin
GCSF in some patients
what is the prophylaxis for neutropenic sepsis?
can give fluoroquinolone if high risk
Which type of lymphocyte is most commonly the cause of Non-hodgekins lymphoma? Which cell marker does it express?
B cell
CD20
Name the different forms of Non-hodgekins lymphoma.
diffuse large B cell mantle cell marginal zone follicular Burkitts T cell lymph plasmocytic
where do the majority of Non-hodgekins lymphoma develop?
lymph nodes - nodal lymphomas
some develop in other organs - extranodal
Which is the most common Non-hodgekins lymphoma? Is this an aggressive or slow growing tumour?
diffuse large B cell lymphoma
aggressive
Which translocation in seen in Burkitts lymphoma?
t (8:14) - increase in MYC gene
Is burkitts lymphoma slow growing or aggressive?
highly aggresive
What pattern do we see between burkits lymphomas and ethnicity?
in africans - involves jaw (extranodal)
outside africa - ileocaecal junction
what is seen under microscopy for burkits lymphoma?
starry sky appearance
what translocation is seen in follicular lymphoma?
t (14:18 ) - bcl-2 next to Ig promotor
large B cells
is follicular lymphoma slow growing or agressive ?
slow growing
What translocation is seen in mantle cell lymphoma? is this slow or aggressive?
t (11:14) - BCL2 (cyclin D)
aggresive
What is lymphoplasmocytic lymphoma?
slow growing tumour
M proteins produced
Waldenstroms macroglobulinaemia
what is marginal cell lymphoma? give one example?
slow growing extranodal lymphoma
e..g MALT gastric lymphoma caused by H.pylori
What is an example of a T cell lymphoma? What virus is linked to this?
Adult T cell lymphoma /leukaemia - HTLV1
what is sezary syndrome? which lymphoma causes this?
Caused by a T cell lymphom = mycosis fungoides
T cell lymphoma of the skin
sezary syndrome - generalised red itchy rash
what staging is used for lymphomas?
ann arbour
what is the management of Non-hodgekins lymphoma ?
Rituximab - CD20 binding to induce apoptosis
How do B type symptoms differ in hodgekins vs Non-hodgekins lymphoma?
Occur earlier in hodgekins
which markers are used for prognosis in Non-hodgekins lymphoma?
ESR and LDH
what types of conditions is follicular lymphomas associated with?
autoimmunity
what is oral allergy syndrome?
cross reaction with food and pollen allergen
such that food causes allergy
Has seasonal variation with pollen
Only affects oral mucosa where pollen may be.
IgE hypersensitivity
what symptoms are seen in oral allergy syndrome?
mild tingling/pruritis of mouth/lips and tongue
Hx of hayfever
develops minutes after eating
resolves within 1 hr
how is oral allergy syndrome investigated?
IgE RAST and skin prick
how is oral allergy syndrome managed?
avoid
antihistamine
how does oral allergy syndrome compare to food allergy?
food allergy caused by direct sensitivity to protein whereas OAS depends on pollen cross reactivity
food allergy can cause more systemic symptoms / anaphylaxis
What is MGUS?
monoclonal gammaglobinopathy
benign paraproteinaemia
many Ig (monoclonal) but not enough to cause symptoms
what are the features of MGUS?
assymptomatic
what differentiates MGUS and myeloma?
IN MGUS.... normal immune function normal B2 microglobulin levels lower stable levels of paraproteins no clinical features
What is methaglobinaemia?
increased levels of methaglobin in blood
Methaglobin = Oxidised Hb (Fe3+) which cant bind O2 as easily or release sas easily. One of 4 Hb is Fe3+. The others compensate and increase their affintiy. Therefore reduced release at tissues …. tissue hypoxia.
disruption of enzymes involved in reduction of Fe3+ to Fe2+ leads to methaemaglobinaemia
What are the causes of methaglobinaemia?
can be inherited (congenital) or acquired)
Congenital:
- autosomal recessive
- type 1 mutation in cytochrome B5 reductase - absent in RBC
- Type 2 - cytochrome B5 reductase absent in all cells - much more methaglobin in this form.
acquired - much more common e.g. local anaesthetic benzocaine e.g. primaquine e.g. nitrates/ nitrites e.g. dapsone all of these act as oxidants and overwhelm the cytochome B5 reductase
How does methaglobinaemia present?
type 1: cyanosis and otherwise assymptomatic
type 2: developmental delays and neuro symptoms. fatal after 1 yr of life
acquired - depends on level - cyanosis, CNS (confusion, headache, seizure), CVS (dyspnoea, chest pain, palpitations, MI)
worse in infants as their Hb oxides more readily and have less of the enzyme
what is found on Ix for methaglobinaemia?
low O2
normal PaO2
chocolate brown coloured blood
‘chocolate cyanosis’
how is methaglobinaemia managed?
asorbic acid
avoid worsening agesnts
O2
IV methylene blue (convers MHb to Hb) - a.k.a methlinium chloride
what can methaglobinaemia be used to treat?
cyanide poisoning
give nitrites to promote metHB
what is the function of methaglobin reductase?
Fe3+ to Fe2+
What type of lymphoma is mantle cell lymphoma?
B cell, non hodgekins.
aggressive
who is mantle cell lymphoma seen in?
median age 60
M>W
what is the median survival of mantle cell lymphomas?
1-2 yrs
responds well to chemo but very aggressive
what translocation is seen in mantle cell lymphoma?
t (11:14) - bcl2 (cyclin D) is put next to Ig promotor
what markers does mantle cell lymphoma express?
CD5, CD19. CD22 - positive
CD10, CD23 - negative
what are the symptoms of mantle cell lymphoma?
B symptoms - more common in this type of lymphoma
painless lymphadenopathy
may have bone marrow/ blood involvement - leukaemic phase
GIT involvement - waldenyers ring
how is mantle cell lymphoma managed?
chemo and radiation
Ibrutinib
what is the function of ibrutinib?
BTK inhibition prevents development of Pre-B cells
how is mantle cell lymphoma diagnosed?
Excisional biopsy/ core needle
NEVER fine needle
CT/ PET scan
what are the causes of macrocytic anaemia with a megaloblastic bone marrow?
B12 deficiency
folate deficiency
what are the causes of macrocytic anaemia with a normoblastic bone marrow?
alcohol liver disease hypothyroid pregnancy reticulocytosis myelodysplasia
what are the different types of lung cancer? which is most/ least common?
small cell - least common non small cell: = adenocarcinoma - most common = squamous cell = large cell
which form of lung cancer has the worst prognosis?
small cell
out of the non-small cell lung cancers which has the worst prognosis?
large cell carcinoma
how do the different forms of lung cancers relate to smoking?
all linked to smoking
Adenocarcinoma is the most common in non-smokers (but still more common in smokers)
which location are the different non-small cell lung cancers found?
squamous - central
large cell and adenocarcinoma - peripheral
which form of lung cancer can secrete B HCG?
Large cell
where do lung cancers metastasise?
brain
bone
liver
adrenals
what are the symptoms of lung cancer?
cough haemoptysis chest pain weight loss may get SVC compression
what are the symptoms of a pancos tumour?
compression of brachial plexus - weakness in arm and abnormal sensation
compression of SVC - facial flushing
Compression of sympathetic chain - horners
what are the different paraneoplastic syndromes of lung cancer?
SMALL CELL:
ADH - siADH
ACTH - cushing
Squamous cell:
PTH - high Ca
hypertrophic pulmonary osteoarthropathy - clubbing
what Ix can be done for lung cancer?
CT scan bronchoscopy needle aspiration CT guided fine needle biopsy Thoracocentesis
what Mx options are available for lung Ca?
surgery
radio/ chemo for stage III
Laser therapy and stenting.
what is Immune thrombocytopenia (ITP)?
an autoimmune attack of platelets
IgG against GPIIb/IIIa
these Ab are produced by the spleen
what are the symptoms of ITP?
purpura
assymptomatic
mucosal bleeding if severe
What are the two forms of ITP and who do these mainly occur in?
acute - mainly in children post viral infection./vaccine . lasts <6months and resolves spontaneously
chronic: usually in females of reproductive age. can be primary with no underlying trigger or secondary to HIV, HepC or lupus.
what is evans syndrome?
ITP associated with autoimmune haemolytic anaemia
what Ix can be done for ITP?
antiplatelet AutoAb
bone marrow Aspiration - megakaryocytes in marrow
what are the laboratory finding with ITP?
low platelets only
how is ITP managed?
1st line - oral prednisolone
if platelets <30 and bleeding can give IV steroids or IVIg
transfuse platelets if <10
splenectomy if platelets <30 after 3 months of steroids
what two diagnosis could be a result of abdo pain and neurological signs?
lead poisoning
acute intermittent porphyria
what is the pathogenesis behind lead poisoning?
results in deffective ferrochelatase and ALA dehydratase activity
which inhibits heme production
what are the symptoms of lead poisoning?
abdominal pain peripheral neuropathy constipation fatigue blue lines on gums (rarely in children)
how is lead poisoning investigated?
increased lead levels (>10)
microcytic anaemia
increased delta aminoleuvulic acid in serum and urine
increased coproporphyrin in urine
what is seen on blood film in lead poisoning?
basophillic stipling
clover leaf morphology
how is lead poisoning managed?
DMSA
D. penicillamine
EDTA
Dimercaprol
Who does Hodgkin’s lymphoma mainly occur in?
M>F
15-34yr (second peak >50)
caucasions
what cell type is characteristics of Hodgkin’s lymphoma ?
Reed sternberg - owl eye nucleus
bilobed nuclei appearance , eosinophilic infusion like nuclei
Which is better for survival Hodgkin’s or non hodgkins lymphoma
hodgkins
what carcinogens increase risk of Hodgkin’s lymphoma ?
HIV, EBV, benzene
how does EBV increase risk of Hodgkin’s lymphoma ?
NF-KB transcription factor can be activated by EBV
what are the different classifications of Hodgkin’s lymphoma ?
Nodular lymphocyte predominant
Classic Hodgekins - more common
- mixed cellularity
- lymphocyte rich
- nodular sclerosis
- lymphocyte depletewhich type of Hodgkin’s lymphoma has best and worst prognosis?
best - lymphocyte rich / nodular sclorosis
worst lymphocyte deplete
which subtype of Hodgkin’s lymphoma is most common in women and children? what cell is seen in this type?
nodular sclerosis
lacunar type of reed sternberg cells
which subtype of Hodgkin’s lymphoma is mainly seen in elderly and what cells are seen here? where does it present?
Mixed cellularity
eosinophils, plasma cells, histocytes
abdo, spleen, lymph nodes
which is the least common and most aggressive subtype of Hodgkin’s lymphoma ?
lymphocyte depleted
what is the hasen clever score?
Poor progostic factors:
- Male
- age >45
- WCC>15
- low lymph <0.6
- anaemia <10.5
- albumin <40
- stage 4
increased LDH is also linked to poor prognosis
what are the B symptoms?
fever
weight loss >10% in 6 months
night sweats
what are the symptoms of Hodgkin’s lymphoma ?
painless cervical lymphadenopathy B symptoms Splenomegaly (not massive) itching fever - pal ebstein fever (comes and goes) nephrotic syndrome autoimmune haemolytic anaemia painful lymph nodes on alcohol consumption - not common but very specific
how does Hodgkin’s lymphoma spread?
starts in cervical
contaginous spread - one lymph node to the next
what is the ann arbor staging?
stage 1: single lymph node
stage 2: 2 on same side
stage 3: opposite sides of diaphragm
stage 4: involving extra lymph node sites
A= no B symptoms
B - B type symptoms
how is Hodgkin’s lymphoma diagnosed?
core needle biopsy microscopy - reed sternberg immunohistochemistry - CD15 and CD30 bloods CT/ CXR
how is Hodgkin’s lymphoma managed?
radiation and chemo
AVBD regime
What is the pathogenesis behind haemophilia?
X linked recessive
mutation of F8 or F9 (for haemophilia A and B respectively)
F8 - defect and reduced factor 8
F9 - defect and reduced factor 9
both are part of intrinsic pathway and result in defective coagulation and bleeding.
Why does Von willibrand disease mimic haemophilia?
VWF normally stabilises factor 8. if vWF is deplete, factor 8 is broken down quicker and becomes deplete
how can haemophilia be acquired?
DIC , liver disease, autoimmunity against clotting factors.
what are the symptoms of haemophilia?
bruising haematomas GI bleeding Haematuria severe nose bleeding brain haemorrhage
what are the lab findings in haemophilia?
normal PT and thrombin time
normal platelets
increased APTT
which factors do the following tests look at: Prothrombin time (PT) Activated partial thromboplastin time (APTT)
PT - 1,2,5,7,10
APTT- 1,2,5,8,9,10,11,12
how is haemophilia managed?
injection of clotting factor
DEsmopressin - stimulates vWF (good for mild VIII deficiency
avoid contact sports and aspirin
what are the different forms of latex allergy?
type 1 - anaphylaxis
type 2 - dermatitis
which condition makes latex allergy more common?
children with myelomeningocele spina bifida
which fruits are associated with latex fruit syndrome?
latex allergy is linked to fruit allergy:
banana, kiwi, strawberry
mango, avocado
pinapple , passionfruit
chesnut
which conditions does leukocyte alkaline phosphatase increase in?
myelofibrosis polycythaemia ruba vera infection pregnancy / COCP steroids/ cushings leukaemoid reactions
which conditions does leukocyte alkaline phosphatase decrease in ?
CML
EBV
pernicious anaemia
paroxysmal nocturnal haemoglobinuria
what is a leukaemoid reaction?
immature WCC in peripheral blood
caused by infiltration of bone marrow and pushing immature cells out or sudden need for new cells
what are the causes of a leukamoid reaction?
haemolysis
haemorrhage
infection
metastatic bone Ca
what is the difference between a leukaemoid reaction and CML?
in CML leukocyte alkaline phosphatase is not increased
In leukmoid reaction the is also a left shift of neutrophils and toxic granulation in white cells (Dohle bodies)
what symptoms are seen in factor 12 deficiency?
assymptomatic
who is hereditary spherocytosis most common in?
northern europe
what type of inheritance is hereditary spherocytosis?
autosomal dominant
how does hereditary spherocytosis present?
gall stones and jaundice
splenomegaly
failure to thrive
haemolysis - low Hb, destroyed by spleen
what virus can trigger aplastic anaemia in hereditary spherocytosis?
parvovirus
how is hereditary spherocytosis diagnosed?
FHx, clinical, spherocytes on blood film
EMA binding test
cryohaemolysis test
electrophoresis analysis of erythrocyte membrane
what is the management for hereditary spherocytosis?
folate replacement
transfusion
splenectomy
what is hairy cell leukaemia? who is it most common in?
rare malignant leukaemia of B cells.
More common in males
what are the features of hairy cell leukaemia ?
- symptoms
- Ix
pancytopenia splenomegaly pancytopenia 1/3 dry tap on bone marrow TRAP stain positive
what are the causes of hyposplenism?
splenectomy sickle cell graves SLE Amyloid Coeliacs/ dermatitis herpetiformis
what type of inheritance is hereditary angioedema?
autosomal dominant - mutation in C1-INH (C1 esterase inhibitor)
what are the laboratory findings in hereditary angioedema?
low C2 and C4 during attack and between attacks
C1 - INH low during attack
what type of molecule is a C1 inhibitor (C1-INH) , what is its function?
protease inhibitors
stops uncontrolled release of bradykinin
which marker is the most reliable screening tool for hereditary angioedema?
serum C4 levels
what are the symptoms of hereditary angioedema?
painful macular rash prior to attack
painless swelling of submucosal tissue
upper airways/ abdomen (abdo pain)
no urticaria
how is hereditary angioedema managed?
steroids, adrenaline and antihistamines have no effect
IV C1 inhibitor concentrate, FFP
anabolic steorids (danazol) may help
which organs does IgG4 related disease affect?
almost every organ
histologically similar appearance in each of these organs
e.g. Riedals thyroiditis autoimmune pancreatitis mediastinal retroperitoneal fibrosis periaortitis kuttners tumour - submandibular glands Mikulicz syndrome - salivary and lacrimal glands
how is IgG4 related disease diagnosed?
increased IgG4 concentrates in tissue and serum
not very specific for diagnosis
what are the causes of intravascular haemolysis?
ABO mismatching cold autoimmune HA G6PD deficiency heart valves TTP DIC HUS paroxysmal nocturnal haemoglobinuria
what are the causes of extravascular haemolysis?
sickle cell thalassemia hereditary spherocytosis warm HA haemolytic anaemia of new born
what blood findings are found in intravascular haemolysis?
low haptoglobin
haem binds albumin –> methaemalbumin
how is methaemalbumin detected?
Schumm’s test
EBV is linked to which haematological malignancies?
Burkitt’s, Hodgkin’s
nasopharyngeal
HTLV1 is linked to which haematological malignancies?
adult T cell leukaemia/ lymphoma
H.pylori is linked to which haematological malignancies?
MALT gastric lymphoma
HIV is linked to which haematological malignancies?
High grade B cell lymphoma
malaria is linked to which haematological malignancies?
Burkitts
how does malt gastric lymphoma present?
gastritis symtpms
fever and night sweats
found in antrum of stomach
for the following translocations which malignancies are they associated with and what protein is made... t (9:22) - philedelphia chrom t (8:14) t (14:18) t(11:14) t (15:17)
9: 22 - CML, (also ALL and associated with poor prognosis). BCRABL (tyrosine kinase)
8: 14 - burkitts - MYC oncogene next to Ig promoter
14: 18 - follicular - BCL2 (cyclin D)
11: 14 - mantle cell lymphoma - BCL2 (cyclin D)
15: 17 - acute promyleocytic leukaemia. PML with RARa gene
what is fanconis anaemia?
autosomal recessive
aplastic anaemia
what cancer is an increased risk in fanconis anaemia
AML
what are the symptoms of fanconis anaemia?
short stature microcephaly neurological symtpoms - developmental delay thumb abnormalities - aplastic thumb cafe au lait spots
Pancytopenia - in fanconis anaemia patients can get aplastic anaemia
what is granulocyte colony stimulating factor?
increases neutrophil count
what are the risks in using GCSF?
can stimulate myeloid malignacy
give an example of a GCSF drug?
filgrastrim
when is GCSF used?
high risk neutropenia
e.g. elderly, previous neutropenia, certain malignancy/chemos
when is MCHC increased./decreased?
mean corpuscular hemoglobin concentration is a measure of the concentration of haemoglobin in a given volume of packed red blood cel
Increased
hereditary spherocytosis
autoimmune haemolytic anemia*
Decreased microcytic anaemia (e.g. iron deficiency)
what are the causes of aplastic anaemia?
idiopathic genetic e.g. fanconis anaemia acquired - radiation - drugs - chemo, indomethacin, antiepileptics, antithyroid - HIV/EBV
which are the main bones that undergo haematopoeisis ?
spine
pelvis
ribs
how is aplastic anaemia diagnosed?
FBC - pancytopenia
increased EPO
bone marrow biopsy
what are the symptoms of aplastic anaemia ?
symptoms of pancytopenia
how is aplastic anaemia managed?
<50 yrs - stem cell transplant
>50 - immunosupression, GCSF
supportive - blood products , Abx
anti-thymocyte globulin (ATG) and Antilymphocyte globulin (ALG) - highly allergenic so use steroids too.
is autoimmune haemolytic anaemia extrinsic or intrinsic haemolytic anaemia? intravascular or extravascular
extrinsic - the problem isnt of the RBC itself but Ab against them.
extravascular - haemolysis occurs in spleen and liver. However acute cold haemolytic anaemia can be intravascular (in this case it can cause raynauds due to microemboli)
what are the causes of autoimmune haemolytic anaemia?
idiopathic
other disease states
medication
what are the features of warm haemolytic anameia? inc causes?
> 37 degrees
more common
idiopathic
mainly in children - triggered by SLE, virus, lymphomas and leukaemias
can also occur in CLL and lymphomas
what are the features of cold haemolytic anaemia?
0-10 degrees
less common
can be acute(viral, glandular fever)
or chronic(leukaemia, lymphoma)
acute - more common in children
which type of haemolytic anaemia is more common (cold or warm)
warm
which Ab is involved in cold/warm haemolytic anaemia what antigen are involved
IgG - warm (antigen is RH and stimulates phagocytosis in spleen)
IgM - cold (antigen L, I, P - stimulate complement. )
what are the lab findings for autoimmune haemolytic anaemia?
high: reticulocytes, LDH
reduced: haptoglobin
urine: urobilinogen (dark urine), haemoglobinuria, haemosiduria (only when intravascular)
direct coombs - Ab bound to RBC, if present RBC will agglutinate
direct antigen test
which type of autoimmune haemolytic anaemua is C3D ab found in?
both
in warm positive for both IgG and C3D
in cold only C3D
How is autoimmune haemolytic anaemia managed?
transfusion
if severe plasmapheresis to remove Ab
warm: steroids, splenectomy (to reduce phagocytosis), immunosuppressants
cold: no Tx
What is B thallaesemia?
autorecessive
mutation and deficiency in B chains of Hb
on chrom 11
if one gene mutated - B thal minor
if 2 mutated coding for reduced B chain - B thal intermediate
if 2 mutants for no B chain - B thal major
who is B thal most common in?
Mediterranean, African , S.E Asian
what is the pathogenesis behind B thal?
defective Hb - haemolysis inta/extravascular
iron and heme released into blood stream - leads to secondary haemochromatosis and jaundice
hypoxia
production of new RBC - enlarged bones and extramedulary organs - hepatosplenomeg
what are symptoms of B thal
haematopoisis - chip munk face from enlarged cheek and forehead bones, splenomegaly
hypoxias
symptoms related to haemochromatosis and haemolysis
symptoms dont develop until after 3-6 m of life
how is B thal managed?
transfusions
s/c deferoxamine to prevent iron overload
what are the Ix findings for B thal?
high fe, high ferritin, high transferritin saturation
low haptoglin
diagnosed via electrophoresis - HbA2 and HbF increased
blood smear - target cells
xray - hair on end appearance on skull xray
what are the doses of adrenaline in anaphylaxis per age group?
<6months - 150 ug
6m-6yrs - 150 ug
6-12yrs - 300ug
>12yrs 500ug
what are the doses of hydrocortisone in anaphylaxis per age group?
<6months 250ug /kg
6m-6yrs - 50ug
6-12yrs - 100ug
>12yrs - 200ug
what are the doses of chlorphenamine in anaphylaxis per age group?
<6months - 250 ug/kg
6m-6yrs 2.5mg
6-12yrs 5mg
>12yrs 10mg
why do we need to observe after anaphylaxis?
need to observe for 6-12 hours later as often get biphasic reactions.
Which marker is elevated in anaphylaxis?
serum tryptase
elevated for up to 12 hours after.
Give an example of a SERM (selective oestrogen receptor modifiers)
tamoxifen - antagonist AND partial agonist
given an example of an aromatase inhibitors
anastrozole
what are the side effects of tamoxifen?
hot flushes
VTE
menstrual disturbance
endometrial cancer
what are the side effects of anastrozole?
osteoporosis - needs DEXA scan before starting.
arthralgia / myalgia
hot flushes
insomnia
Which anti-oestrogen drug is used in post menopaual women?
aromatase inhibitors - reduces peripheral O.synthesis.
what are the features of antiphospholipid syndrome in pregnancy?
IUGF recurrent misscarriage pre-eclampsia placental abruptions VTE
what are the features of antiphospholipid syndrome?
recurrent thrombosis - arterial and venous
recurrent fetal loss
thrombocytopenia
what are the causes of antiphospholipid syndrome?
can be primary
or secondary e.g. lupus
how is antiphospholipid syndrome managed?
low dose aspirin as soon as pregnant
LMWH - once fetal heart seen on USS and discontinued at 34 weeks
Where is Antithrombin III made? what is its normal function?
liver
normally binds thrombin and factor X and inhibits coagulation
How does ATIII deficiency present?
DVT/VTE
arterial thrombosis
How is ATIII deficiency caused?
liver disease
DIC
Nephrotic syndrome
acquired:
- type 1 - deficiency
- type 2- defective protein
How is ATIII deficiency managed?
direct thrombin inhibitor - argatroban
direct Xa inhibitor - rivaroxaban
warfarin
replacement of ATIII (if not controlled by above)
how is ATIII deficiency investigated?
AT - heparin cofactor assay - if <80% of normal
why can heparin not be used in ATIII deficiency?
Heparin works by binding ATIII and increasing its affinity for the clotting factors.
which thrombophilia’s are most common (order in prevelance) how does each compare for risk of VTE?
factor V leiden Prothrombin gene mutation protein C deficiency Protein S deficiency ATIII deficiency
increases in risk of VTE as you go down
which is the most common childhood cancer?
ALL
what are group does ALL most commonly present in?
2-5yrs
what are the good prognostic factors for ALL?
FAB L1 type common ALL pre-B phenotype low initial WCC del 9p
what are the bad prognostic factors for ALL?
male CNS involved FAB L3 type WCC >100 at presentation non-Caucasian philedelphia chrom TIB surface markers <2yrs >10yrs
what are the symptoms of AML?
mainly that of bone marrow failure
splenomegaly
bone pain
What are the poor prognostic factors of AML?
> 60
20% blasts after first chemo
deletion of chrom 5 or 7
what is the FAB classification used for AML?
french american british association
Mo - undifferentiated M1 - without maturation M2 - granulocytic maturation M3 - promyelocytic maturation M4 - granulocytic and monocytic maturation M5 - monocytic M6 - erythroleukaemia M7 - megakaryoblastic
what genetic abnormality is seen in acute promyelocytic leukaemia ?
t(15:17) - fusion of PML with RARa genes
who does acute promyelocytic leukaemia (M3 subtype) occur in?
younger people (23yr average) classically presents as DIC/ thrombocytopenia
what is the prognosis of acute promyelocytic leukaemia ?
good prognosis
what is seen on blood film for acute promyelocytic leukaemia ?
Auer rods - seen with myeloperoxidase stain.
In an allergy test what are the controls used?
negative control - water
positive control - histamine
how long do you need to wait before interpreting an skin prick test?
15 mins
what is the RAST test?
radioallergosorbant test
- amount of IgE that is made after known allergen
- score of 0 to 6 given (6 = strongly positive)
when might RAST be better than skin prick?
when skin prick is not possible e.g. severe eczema or on antihistamine medication.
what allergy test is used for contact dermatitis ? how is this performed?
skin patch test. Patched placed for 48 hours and interpreted for further 48 hours
what is alpha thalassemia ?
deficiency of alpha chains of Hb
what subunits are seen in adult and fetal hb?
fetal 2a and 2g
adult: 2a2b or 2a2d
which chromosome are the alpha genes for Hb held on?
chromosome 16 - 2 genes a1 and a2 i.e. two gene loci
explain the genetics of alpha thal…
a thal major - 2 deleted genes - either on same chrom or different chroms
a thal moderate disease = HbH = 3 defective genes
silent carrier = one mutation
Hb Barts = all 4 mutated
auto recessive
what happens when 3 alpha genes of alpha thal are missing?
excess B chains made
= HbH
these clump in RBC
HbH can damage RBC membrane - intramedullary haemolysis and extravascular haemolysis
HbH has high affinity for O2 and doesnt release it at tissues.
increase in Hb synthesis so enlargment of spleen, liver and bone
what happens in Hb barts (alpha thal)
all 4 alpha genes mutated
gamma chains of fetal Hb form tetramers
very high affinity for O2
leads to tissue hypoxia and high cardiac output/failure
leads to hydrops fetalis
oedema and death in utero/just after birth.
what are the symptoms of alpha thalaessemia ?
anaemia
hepatosplenomegaly
How is alpha thal diagnosed?
Hb test - hypochromic microcytic anaemai MCH/ MCV target cell Hb Electrophoresis genetic testing
how is alpha thal managed?
blood transfusions
What is virchows triad?
stasis - turbulent flow, inactivity
damage to endothelium - infection, chronic inflammation, tabacco
coagulopathy - genetic, medications, surgery
What is the two level wells score?
Each 1 point:
- active cancer / treatment within 6m
- paralysis/ immoblisation of lower
- bed ridden>3 days/ major surgery within 12 weeks
- localised tenderness along deep vein
- swollen leg
- calf swelling atleast 3cm more than other side
- pitting oedema confined to symptomatic side
- collateral superficial leg vein swelling
- previous DVT
minus 2:
alternative diagnosis as likely.
How does the WELLS score for DVT determine management/ investigation for DVT?
if >2 points:
- USS within 4 hours
- if cant be performed within 4 hours then start anticoag (LMWH/doac) and do interim d dimer
if 1 or less
- d dimer
- if positive USS leg within 4 hours (if cant be done in 4 hours start doac)
if scan negative and D dimer positive. Repeat scan in 1 week.
new NICE guidelines to use DOAC while waiting results as well as for treatment.
How is DVT treated?
DOACs = first line = apixaban/rivaroxaban
- if not suitable can give LMWH/warfarin
IVC filter placed in vena cava to prevent clots getting into lungs
routine cancer screening no longer recommended
if active cancer - DOAC
if renal failure - LMWH/ warfarin
if antiphospholipid syn - LMWH/warfarin
how long should anticoagulation be used for following a DVT?
all patients ateast 3 months
provoked - 3 to 6 m
unprovoked - 6 months may need lifelong
has bled to weigh up bleeding risk
What is DIC? what is the pathogenesis?
coagulation lead to clotting factors being used
bleeding due to no clotting factors
tissue factor plays a role - bind to coagulation factors and triggers clotting (normally found exposed after vascular damage)
what are the lab findings in DIC?
increased PT/ PTT
decreased platelets and fibrinogen
increased D dimers
schistocytes - from microangiopathic haemolytic anaemia
what are the causes of DIC?
Sepsis, trauma, malignancy, obstetric complications - amniotic fluid embolism, HELLP
what are the lab finding i.e. APTT, PT, platelets for use of:
a) warfarin
b) aspirin
c) heparin
warfarin - increased PT, normal platelets and normal APTT
asprin - all normal
heparin - increased APTT, normal platelets
what is factor V leiden? explain pathogenesis…
Factor V normally potentiates the ability for factor 10 to initiate coagulation.
fctor V is normally bound and cleaved by protein C to prevent excess clotting. The products of this clevage them increase activity of protein C/S
factor V leiden is a genetic disease with a single point mutation in the protein - it now cannot bind or be cleaved by protein C and thus continue to increase coagulation.
what is the difference in disease severity between homozygous and heterozygous factor V leiden?
autosomal dominance and thus heterozygous = disease state
homozygous gives even more risk for VTE
what are the symptoms of factor V leiden?
DVT/ VTE
Does factor V leiden require anticoagulation prophylaxis?
no prophylaxis required
how is factor V leiden diagnosed?
clinical suspicion - recurrent DVT, young age, FHx
lab findings
DNA sequencing
what race is factor V leiden most common in?
caucasions
what is cryoglobulinaemia?
immunoglobulins that precipitate at 4 degrees and dissolve at 39
how many types of cryoglobulinaemia are there?
3
what is type 1 cryoglobulinaemia?
monoclonal IgG/M
associated with waldenstroms macroglobulinaemia and multiple myeloma
what is type 2 cryoglobulinaemia?
mono and polyclonal mix of Ab
RF present
associated with RA, sjrogens, lymphoma, hep
what is type 3 cryoglobulinaemia?
polyclonal
RF present
associatd with RA and sjrogrens
most common
what are the symptoms of cryoglobulinaemia?
raynauds - type 1 only
vascular purpura, ulcerations
arthralgia
renal involvment
what are the tests for cryoglobulinaemia?
low complement especially C4
high ESR
how is cryoglobulinaemia managed?
immunosupression
plasmaphoresis
what is cyclophosphamide?
alkylating agent - cross links DNA
what are the side effects of cyclophosphamide?
haemorrhagic cystitis
transitional cell carcinoma
myelosupresssion
how is haemorrhagic cystitis secondary to cyclophosphamide managed?
hydration
mesna - binds acrolein (toxic metabolite of cyclophosphamide) and prevents toxic effects on bladder
what is the function and side effects of the following:
a) bleomycin
b) anthacyclines (doxorubicin)
c) methotrexate
a) degrades DNA, causes lung fibrosis
b) Stabilises the DNA topoisomerase complex to inhibit DNA/RNA synthesis. Can cause cardiomyopathy
c) inhibits DHFR and thymidylate synthesis. Can cause myelosuppression, hepatoxic and lung fibrosis
what is the function and side effects of the following:
a) flurouracil
b) 6- mercaptopurine
c) cytarabine
a) Pyrimidine analogue . blocks thymidylae synthesis - cell cycle arrest. Can cause myelosupression, mucositis and dermatitis
b) reduced purine synthsis (purine analogue). Can cause myelosupression.
c) Pyrimidine analogue. Can cause myelosupression and ataxia
what is the function and side effects of the following:
a) vincistrine
b) docetaxel (taxane)
c) irinotecan
a) inhibits microtubule fomration. Can cause peripheral neuropathy and paralytic ileus
b) prevents polymerisation of microtubules. Can cause neutropenia
c) topoisomerase inhibitor - can cause myelosupression
what is the function and side effects of the following:
a) cisplatin
b) hydroxyura
a) cross links DNA. Ototoxicity, hypoMg, peripheral neuropathy
b) inhibits ribonucleotide reductase and reduced DNA synthesis. can cause myelosupression
what is glucose 6 phosphate dehydrogenase deficiency?
X linked genetic disorder
mutation in G6PD leading to defective protein
and thus reduced levels
what is the pathogenesis behind glucose 6 phosphate dehydrogenase deficiency?
normally free radicals (hydrogen peroxidase) need to be reduced otherwise they will damage cells.
glutathione becomes oxidised and reduces these free radicals.
Glutathione reductase regenerate glutathione to allow this process to continue.
G6PD is an enzyme that generates NADPH to enable glutathione reductase to continue to work.
glucose 6P —-> 6phosphogluconolactate (catalysed by G6PD
in RBC the G6PD is the only enzyme that can do this and thus RBC are susceptible to damage by oxidative agents if G6PD is deficient
free radicals…
- damage the membrane (haemolysis)
- damage Hb and cause it to precipitate = heinz bodeis
- macrophages remove the Heinz bodies to cause RBC to appear as bite cells.
- reduced life span of RBC
what are the two common types of glucose 6 phosphate dehydrogenase deficiency?
mediterrean type - reduced half life of G6PD, protection from malaria falciparium
African variant
what things increase free radical productions and thus worsen glucose 6 phosphate dehydrogenase deficiency?
infection, metabolic acidosis ,
flava beans, soy , red wines
primaquinine and chloroquinine
aspirin, sulphonamides, ciprofloxacin
what are the symptoms of glucose 6 phosphate dehydrogenase deficiency?
assymptomatic until oxidative stress
symptoms related to haemolysis - jaundice, anaemia, dark urine
how is glucose 6 phosphate dehydrogenase deficiency managed?
avoid triggers
transfusions
how is glucose 6 phosphate dehydrogenase deficiency diagnosed?
bloods - reduced RBC, increased reticulocytes, increased LDH, increased billirubin and reduced haptoglobin
coombs negative
bite cells and heinz bodies using heinz stain
enzyme assay for G6PD deficiency - definitive test. check levels 3 months after acute episode
what conditions are target cells seen in?
iron deficiency anaemia sickle cell thalassemia liver disease hyposplenism
what cell types are seen in myelofibrosis ?
tear drop poikilocutes
what conditions are heinz bodies seen in?
G6PD deficiency
alpha thallaessemia
which conditions is basophilic stippling seen in?
thalessemia
lead poisoning
sideroblastic anaemia
myleodysplasia
what types of cells are seen in hyposplenism (blood film)?
target cells
howell jolly bodies
when are schistocytes seen on blood film?
intravascular haemolysis
DIC
mechanical heart valve
other than heriditary spherocytosis , when else can spherocytes be seen?
autoimmune haemolytic anaemia
what are pencil poikilocytes indicative of?
iron deficiency anaemia
what are burr cells a sign of (blood film)?
uraemia
pyruvate kinase deficiency
what condition are acanthrocytes seen on blood film?
abetalipoproteinaemia
what other abnormality on blood film do you find in megaloblatic anaemia (other than RBC)
hypersegmented neutrophils
what does cryoprecipitate contain and when is it used?
fibrinogen
factor VIII:C
von willebrand
factor XIII
good for replacing fibrinogen e..g. DIC, liver failure
when is prothrombin complex concentrate used?
emergency severe bleeding
e.g. head injury
when in FFP used?
clinical significant but not major haemorrhage
PT:APTT >1.5
what are the complications of blood transfusions?
acute haemolytic reaction non-haemolytic febrile reactions allergy anaphylaxis TRALI TACO Infections Iron overload
what is a non-haemolytic febrile reactions post blood transfusion? presentation and management
WBC HLA Ab against WCC fragments in blood product . often due to sensitisation following previous transfusions/pregnancy
presents with fever and chills
managed by slowing/stopping transfusion. give paracetamol
what is a acute haemolytic reactions post blood transfusion? presentation and management
caused by ABO incompatibility
intravascular haemolysis
IgM
complications - AKI, DIC
fever, abdo pain, hypotension minutes after
stop transfusion and check blood product. fluid resusitation
how can blood transfusions cause allergies/anaphylaxis and how is this managed?
minor allergy - stop temporarily and give antihistamine
anaphylaxis - caused by patients who are IgA deficient and have anti IgA Ab - stop transfusion, adrenaline etc
what is TACO and how is it managed?
transfusion associated circulatory overload
pulmonary oedema , HTN
slow/stop transfusion, diuretics , give O2
what is TRALI and how is it managed?
non cardiogenic pulmonary oedema secondary to increased vascular permeability secondary to activation of host neurotrophils
reduced O2, chest infiltrates, fever, low BP
stop transfusion, give O2
when is CMV negative blood needed and why?
CMV can be transmitted in leukocytes and for those who are immunodeficient this can be a problem.
pregnancy required CMV negative blood
granulocyte transfusion, intrauterine transfusion and neonates up to 28 days
when is irradiated blood needed and why?
depleted of T lymphocytes to avoid graft vs host reaction
bone marrow/stem cell transplants
immunocompromised
hodgkins lymphoma
granulocyte transfusion, intrauterine transfusion and neonates up to 28 days
Causes of drug induced pancytopenia?
cytotoxics anti-rheum - penacillamine, gold trimethroprim carbimazole carbemazepine tolbutamide
what is the ECOG score?
performace status scale - functional measure. used for onco treatment
0 = fully active 1 = restricted in physical strenuous activity 2= able to self care but can carry out work 3 = self care only, in bed >50% 4 = completely disabled 5 = dead
what are the causes of eosinophilia?
pulmonary:
- asthma
- allergic broncopulmonary asperigillosis
- churg strauss
- lofflers syndrome
- tropical pulmonary eosinophilia
- eosinophilic pneumonia
- hypereosinophilic syndrome
infective - schistosomiasis, nematodes, cestodes
other - nitrofurantoin, sulphasalazine, eczema, psoriasis, eosinophilic leukaemia
what is Li Fraumeni syndrome?
autosomal dominant
p53 mutation in germline
predisposiition fo malignancy - particularly sarcoma and leukaemia
diagnosed if sarcome <45yrs OR
1st degree relative with any cancer <45yrs and another family member OR sarcoma at any age
what is gardeners syndrome?
auto dominant familial colorectal polyposis skull osteomas, thyroid cancer, epidermoid cyst desmoid tumours APC gene mutation - chromosome 5
variant of familial adenomatosis polyposis coli
Which malignancys are associated with BRCA 1/2
60% risk of breaast
ovarian
prostate (BRCA2 in men)
what is lynch syndrome?
autosomal dominant
aka. hereditary nonpolyposis colorectal cancer (HNPCC)
MMR gene
increased risk of endometrial and colonic cancer
what is the Amsterdam criteria used for?
Diagnosis of lynch syndrome
3 or more family members with CRC , one of whom is 1st degree
2 successive generations
one or more <50yrs
FAP has been excluded
what are the different forms of AML?
8 different subtypes
e.g. AML with maturation /without maturation
what translocations can be seen in ALL?
9:22 and 12:21
what is acute promyelocytic leukaemia treated with? what is the theory behind this.
ALL - trans retanoic acid ATRA
acute promyelocytic leukaemia is caused by a translocation t15:17 which gives a defective retanoic acid receptor (normally involved in cell division)
ATRA binds the receptor and causes blasts to mature to neutrophils.
what is myelodysplastic syndrome?
defective maturation of myeloid cells and build up of blasts
can lead to acute promyelocytic leukaemia if blasts >20%
how does acute acute promyelocytic leukaemia lead to DIC?
leads to disruption of clotting profile
this along with thrombocytopenia
leads to DIC
what are the symptoms of acute leukaemias?
symptoms of pancytopneia tired pain in bones hepatosplenomegaly - more so with ALL lymphadenopathy (pain) - more so in ALL
which surface antigen do B cells present?
CD10
what is acute intermittent porphyria?
rare autosomal dominant gene mutation in HMBS gene (encodes porphobilinogen deaminase)
defect in heme synthesis
what are the symptoms of acute intermittent porphyria?
majority assymptomatic
DOES NOT cause UV symptoms unlike other porphyrias (blistering in sunlight)
10% of young women get acute attacks…
- CNS: anxiety, seizures, delirium
- Autonomic: HTN, Tachycardia, GI motility - diarrhoea and vomitting, constipation
- peripheral neuropathy and paraesthesia
port wine urine - excess porphobilinogen in urine causes it to oxidise under light to red colour
what triggers an acute attack in acute intermittent porphyria?
anything triggering heme production e.g. alcohol, starvation, medications increase cytochrome p450 system
what is the pathogenesis behind an acute attack in acute intermittent porphyria?
defective porphobilinogen deaminase means that porphobilinogen builds up and is toxic.
the porphobilinogen is converted to aminoleuvlenic acid which is also toxic (more so)
aminoleuvenic acid can cross BBB
what are the 4Ps of acute intermittent porphyria?
Peripheral neuropathy
psychological
painful abdomen
port wine urine
how is acute intermittent porphyria diagnosed?
urinarlysis - 5x porphobilinogen levels (elevated between attacks and even more so during acute attack)
urine turns deep red on standing in light.
measure erythrocyte porphobilinogen deaminase activity
raised serum leuvalenic acid.
How is acute intermittent porphyria treated?
glucose and heme - these inhibit ALA synthase (first enzyme in pathway to prevent build up of porphobilinogen and aminoleuvlenic acid
which tumours commonly metastasise to bone and what are the common sites?
tumours - breast, prostate, lung
sites: spine, pelvis, ribs, skulls, long bones
what are the risk factors for breast cancer?
BRCA 1st degree relative that was premenopausal when diagnosed nulliparity, 1st preg >30yrs early menarche, late menopause COCP no breast feeding p53 obesity FRBB2 gene --> HER2
what type of breast cancer causes pagets disease of nipple?
ductal carcinoma in situ (epithelial tumour) - grows into lumen of alveoli
how does a lobular carcinoma grow?
Doesnt cross the basement membrane and thus doesnt become invasive.
grows within lobules without affecting the ducts.
what is burketts lymphoma?
high grade B cell neoplasm
what are the two forms of burkitts lymphoma?
endemic form - african - maxilla and mandibular invovlement. linked to EBV
sporadic - most common, linked to HIV
what gene is mutated in burkits lymphoma?
c-myc gene translocation t (8:14)
what is seen under microscopy for burkitts lymphoma?
starry sky appearance
how is burkits lymphoma managed?
chemo
HIV testing
CT scan for staging
pregnancy: if first trimester, terminate and start chemo. if 2nd/3rd start RCHOP regime.
what cancers are the following carcinogens associated with?
a) alfatoxin
b) aniline dyes
c) asbestos
d) nitrosamines
e) vinyl chloride
a) liver/HCC
b) bladder Ca
c) bronchial and mesothilioma
d) oesophageal and gastric
e) hepatic angiosarcoma
where do the majority of cervical cancers originate from?
transformation zone - junction between endo and ecto cervix.
the endocervix = columnar epithelium
ectocervix = squamous epithelium
at transformation zone there is metaplasia of columnar cells to squamous. these squamous cells can become cancerous
dysplasia starts at basal layer of transformation zone.
what type of cancer are the majority of cervical cancers?
squamous cell carcinoma
What proportion of cervical cancers is HPV responsible for?
50% are linked to HPV 16
what proteins does HPV make that lead to cancer?
E6 and E7
inhibit p53 and Retinoblastoma protein
how is cervical cancer graded?
CIN I - 1/3 of epithelium CIN II - 2/3 CIN III - almost all epithelium carcinoma insitu - whole epithelium invasive cervical cancer - through BM
how is cervical cancer screened for?
PAP smear every 3 years for 21yrs - 65yrs
check for dysplasia under microscopy
if dysplastic –> colposcopy
what are the high risk HPVs? and low risk?
HPV 16, 18, 33
HPV 6 and 11 are low risk genital warts
what are koilocytes?
infected enedocervical cells undergo changes and become koilocytes
enlarged nucleus
hyperchromasia
iregular nuclear membrane
perinuclear halo
what is the most common leukaemia of adults?
CLL
what markers does CLL express?
CD5, CD19, CD23
what is the pathogenesis behind CLL?
defective B cells due to unknown genetic changes
active tyrosine kinase and multiplying
multiplies rapidly and can migrate to lymph nodes causing lymphadenopathy and possible ritchers transformation
defective B cells can lead to autoimmune haemolytic anaemia and hypogammaglobulinaemia.
what is ritchers transformation?
when there are lots of lymphocytes in CLL they migrate to lymph nodes and can transform into a non-hodgekins lymphoma.
fast growing lymphoma
suddenly become very unwell - lymph node swelling, fever, night sweats, weight loss, abdo pain and nausea
what are the symptoms of CLL?
symptoms of pancytopenia, annorexia, weight loss, lymphadenopathy
what is seen on blood film in CLL?
smudge cells
what are the indications to treat CLL?
progressive marrow failure
massive/ progressive lymphadenopathy (>10cm)
massive/progressive splenomegaly (>6cm)
progressive lymphocytosis (>50% in 2 months or double in <6months)
weight loss (>10% in 6m), night sweats, fever for 2 weeks, extreme fatigue
autoimmune symptoms
what is the treatment regime for CLL?
FCR - fludarabine , cyclophosphamide, rituximab
if no indication - watch and wait
what are the poor prognostic factors of CLL?
male >70 yrs lymph count >50 lymphocytes doubling in <12 months CD38 expression p53 mutation prolymphocytes >10% of total lymp count increased LDH
what genetic change is associated with good prognosis in CLL?
deletion of long arm of chrom 13 (most common abnormality seen
what genetic change is associated with poor prognosis in CLL?
deletion of short arm of 17
what are the risk factors to developing N&V with chemotherapy?
anxiety
<50yrs
use of opioids
type of chemo
for high risk paients use ondansetron and dexamethasone
what cell types do the chronic leukaemias mainly affect?
CLL - mainly B lymphocytes
CML - mainly granulocytes
what translocation is characteristic of CML?
9:22
philedelphia chrom
where do excess cells deposit in CML?
spleen and liver - hepatosplenomagaly - abdominal fullness
what is meant by blast crisis?
CML can progress to acute leukaemia if excess blasts made
often caused by trisomy 8 or doubling of philedelphia chrom
what is the main treatment for CML?
imantinib - BCR ABL inhibitor
also hydroxyurea, interferona and transplant.
name 3 primary immune disorders affecting neutrophils…
Chronic granulomatous disease
Chediak-Higashi syndrome
Leukocyte adhesion deficiency
what is Chronic granulomatous disease
lack of NADPH oxidase reduces ability of phagocytes to produce reactive oxygen species Causes recurrent pneumonias and abscesses, particularly due to catalase-positive bacteria (e.g. Staphylococcus aureus and fungi (e.g. Aspergillus)
Negative nitroblue-tetrazolium test
Abnormal dihydrorhodamine flow cytometry test
what is Chediak-Higashi syndrome?
Microtubule polymerization defect which leads to a decrease in phagocytosis Affected children have ‘partial albinism’ and peripheral neuropathy. Recurrent bacterial infections are seen
Giant granules in neutrophils and platelets
what is Leukocyte adhesion deficiency?
Defect of LFA-1 integrin (CD18) protein on neutrophils Recurrent bacterial infections.
Delay in umbilical cord sloughing may be seen
Absence of neutrophils/pus at sites of infection
name 3 B cell disorders that lead to primary immunodeficiency
Common variable immunodeficiency
Bruton’s (x-linked) congenital agammaglobulinaemia
Selective immunoglobulin A deficiency
what is Common variable immunodeficiency?
Many varying causes Hypogammaglobulinemia is seen. May predispose to autoimmune disorders and lymphona
what is Bruton’s (x-linked) congenital agammaglobulinaemia?
Defect in Bruton’s tyrosine kinase (BTK) gene that leads to a severe block in B cell development X-linked recessive. Recurrent bacterial infections are seen
Absence of B-cells with reduced immunoglogulins of all classes
what is Selective immunoglobulin A deficiency?
Maturation defect in B cells Most common primary antibody deficiency. Recurrent sinus and respiratory infections
Associated with coeliac disease and may cause false negative coeliac antibody screen
Severe reactions to blood transfusions may occur (anti-IgA antibodies → analphylaxis)
Give an example of a T cell immunodeficiency disorder and explain what this is.
DiGeorge syndrome
22q11.2 deletion,
failure to develop 3rd and 4th pharyngeal pouches
Common features include congenital heart disease (e.g. tetralogy of Fallot), learning difficulties, hypocalcaemia, recurrent viral/fungal diseases, cleft palate
give 4 examples of combined T and B cell immunodeficiencies?
Severe combined immunodeficiency
Ataxic telangiectasia
Wiskott-Aldrich syndrome
Hyper IgM Syndromes
what is Severe combined immunodeficiency?
SCID
Many varying causes. Most common (X-linked) due to defect in the common gamma chain, a protein used in the receptors for IL-2 and other interleukins. Other causes include adenosine deaminase deficiency Recurrent infections due to viruses, bacteria and fungi.
Reduced T-cell receptor excision circles
Stem cell transplantation may be successful
what is Ataxic telangiectasia?
Defect in DNA repair enzymes Autosomal recessive. Features include cerebellar ataxia, telangiectasia (spider angiomas), recurrent chest infections and 10% risk of developing malignancy, lymphoma or leukaemia
what is Wiskott-Aldrich syndrome?
Defect in WASP gene X-linked recessive. Features include recurrent bacterial infections, eczema, thrombocytopaenia.
Low IgM levels
Increased risk of autoimmune disorders and malignancy
what is Hyper IgM Syndromes?
Mutations in the CD40 gene Infection/Pneumocystis pneumonia, hepatitis, diarrhoea
what is protein C deficiency? what are the features of this.
what is the effect seen with warfarin
Protein C deficiency is an autosomal codominant condition which causes an increased risk of thrombosis
Features
venous thromboembolism
skin necrosis following the commencement of warfarin: when warfarin is first started biosynthesis of protein C is reduced. This results in a temporary procoagulant state after initially starting warfarin, normally avoided by concurrent heparin administration. Thrombosis may occur in venules leading to skin necrosis
What is the pathogenesis behind protein C/S deficiency?
thrombin thrombomodulin complex is activated by protein C and S. If these arent present, factor 5 and 8 cant be cleaved by thrombomodulin
what type of genetic disease is protien C/S deficinecy?
autosomal dominant
type 1 - not enough
type 2 - defective
what are the acquired causes of protein C/S deficiency
nephrotic syndrome
liver disease - reduced production
warfarin use - reduced production
how is protein C/S deficiency tested?
serum levels
patient must not take warfarin for 2-4 weeks before test (warfarin can reduce levels)
what age does acute intermittent prophyria present?
20-40yrs.
