haematology Flashcards
types of haematologists
benign
blood transfusion
malignant
haemostasis + thrombosis
definition of anaemia
haemoglobin conc below normal range
male <125g/l
female <115g/l
due to either low red cell mass or increased plasma volume (preg)
symptoms of anaemia
fatigue reduced exercise tolerance SOB post hypotension dizziness angina palps hf - SOB, peripheral oedema
signs of anaemia
pallor + conjunctiva tachycardic heart murmurs koilonychia - iron deficiency angular stomatitis glosssitis - B12/folate
classes of anaemia
microcytic - iron deficient, thalassaemia, anaemia of chronic disease, sideroblastic
macrocytic - vit B12 deficient, folate deficient, without anaemia = liver disease, hypothyroid,
normocytic - acute bleeding, haemolysis, chronic disease, haemolytic anaemia, primary marrow problem, pregnancy, renal failure
myelodysplasia
found in elderly
what doses of oral ferrous sulphate would you prescribe for iron deficient anaemia
200mg OD
BNF says TDS but recently been found OD works just as good but with less s/e
most common preventable error with blood transfusions
incorrect blood product
- most couldve been prevented with the final identification check
what antibodies would someone produce if they had type 0 blood
anti-A
anti-B
what antibodies would someone produce if they had type AB blood
none
what antibodies would someone produce if they had type B blood
anti-A
what antibodies would someone produce if they had type A blood
anti-B
what happens if you transfuse the wrong blood to someone
triggers massive immune response leading to shock and DIC
Individuals may die from circulatory collapse, severe bleeding or renal failure, often within minutes or hours.
which blood type can be safely given to anyone and why
blood group O
as there are no A or B antigens for the recipient’s antibodies to react with
what antigen do people who are rhesus positive create
D-antigen
talk through the steps in the decision to transfuse
- is the patient at risk of transfusion associated circulatory overload - low body weight, >70, pre-existing conditions eg cardiac/renal failure
- use of single unit recommended in non bleeding adult
- signed consent isnt a legal requirement in UK and Ireland - but patient should be informed in a timely manner for indication/risks/benefits
- record of this discussion documented in notes
- The patient should have the opportunity to raise any concerns and discuss alternative therapies, e.g. oral iron therapy (BSH 2017) have stated that a record of the administration of each blood component is essential (i.e., reason for transfusion, number of units prescribed and outcome)
what needs to be included to reach the minimum patient identification data set when requesting blood
full name dob unique identifier eg NHS number adress gender middle name
what information is required to request blood in someone who cannot be identified
the assigned unique hospital identification number e.g. ED number / Major Incident Number and gender are required as a minimum
who is responsible for checking for previous transfusion history/ specific requirements?
the person making the request
what information is needed when requesting a pre-transfusion test or blood component
minimum patient identification data set
the reason for the request, the pre-transfusion test or number and type of component required, urgency of request, location of patient, blood group antibodies (if known), previous transfusion history and/or transfusion in the past three months, any special requirements, the date and time required
what specific blood should be requested for neonates up to 28 days post expected date of delivery
cytomegalovirus negative blood
what specific blood should be requested for patients who are immunocompromised and why
irradiated blood
Is used to destroy any T lymphocytes remaining in the blood donation, which may cause graft-versus-host disease in vulnerable patients. If an immunocompromised patient receives blood components that are not irradiated, the donors T cells can cause tissue and organ damage leading to death.
worried about potassium overload - what blood should be requested
blood of specified age
For example, blood of less than 5/7/10 days is required because of concerns of the potassium content in older units.
what blood is used for transfusion in children
paedipacks
One adult unit divided between 4 - 8 aliquots. Several aliquots are allocated to one child to allow sequential transfusions from the same donor, reducing donor exposure.
what is the difference between the group and save and crossmatch tests
group and save
- is the sample processing that determines the patient blood group (ABO and RhD) and screens for any atypical antibodies.
The process takes around 40 minutes and no blood is issued
crossmatch
- is the final step of pretransfusion compatibility testing, to request blood from the laboratory.
Crossmatching involves physically mixing of patient’s blood with the donor’s blood, in order to see if any immune reaction occurs
After ensuring that donnor blood is compatible, the donor blood is issued and can be transfused to the patient.
This process takes around 40 minutes, in addition to the 40 minutes required to G&S the blood.
what blood do you prescribe in an emergency setting when not knowing the patients blood type
type O D negative
how long can a pre-transfusion testing sample be used for repeat cross-matching purposes
7 days
sampling procedure for pre-transfusion testing
1 - identify patient
2 - complete minimum indentification requiements on blood form
3- Take the blood sample and immediately after hand-write on the tube unless using a computer prepared label generated by an electronic bar-coding system. If electronic systems are used the bar-coded label must be printed at the bedside from the patients ID band. Re-check that the details on the sample tube and request form match before putting them in the transport bag
who is responsible for ensuring that the patient identification details on the sample tube and request form match when taking for blood transfusion
the person taking the sample
what must be included on the sample tube when taking blood for transfusion
date
time
signature
blood availability - timescales
OD negative - emergency immediate 5 mins
group compatible blood - 10-15 mins
fully crossmatched blood - 30-40 mins (maybe hours if antibody found)
if someone has no history of transfusions what may also be required as a pre-transfusion test?
a secondary confirmatory blood group sample - as long as it doesn’t impede on delivery of urgent blood components
red cells storage
- time
- temp
- if removed
35 days
2-6 degrees
alarmed fridge
transfused within 4 hours of removal from fridge
if removed and not transfused sent back to lab with the length of time it was out to see if it can be reused
platelets storage
- time
- temp
- if removed
20-24 degrees
not in fridge as they aggregate
5-7days
if removed and not used returned to lab
FFP + cryoprecipitate
- time
- temp
- if removed
-25 degrees
- 3 years
transfused as soon as possible
if unused return to lab
collection steps before transfusion
ensure patient has identification band in situ
check minimum patient identification data set
ensure informed consent
IV access?
pre-tranfusion obs taken within 60 mins of the transfusion
only collect one unit at a time
only pass over the blood to the person who requested it
Clinical staff are required to check the correct component is received upon delivery, and to sign and time receipt.
what do you need to do if you use group O cells in an emergency
inform the lab so they can replace it
blood transfusion bedside checklist
- blood integrity eg no clots, leaks, damage, discoloration, expirary etc
- informed consent documented
- positive patient identification
- check unit tag against unit label, prescription, patient ID band and PPID
- perform obs - temp, pulse, resp, bp
what venous access is required for transfusions
central line normally
when using this the blood should be warmed through a blood warming device
venous access for blood transfusions big no no’s or do do’s
must be a CE-marked tranfusion set with an integral mesh filter to remove microaggregates
do not prime with 0.9 saline
do not administer meds or other IV fluids through the access for the tranfusion as there is a risk of incompatibility (e.g. dextrose & calcium containing solutions can cause haemolysis or lead to clotting of the transfusion components
the administration set should be changed every 12 hours
never use the same admin set for platelets as red cells as will cause aggregation
administration of blood components steps
- full patient identification data set with patient and on the laboratory generated label attached to the blood component against the patient’s identity band
- check the laboratory generated label attached to the blood component against the label affixed to the unit to ensure all the following is the same:
- donation number
- patients blood group
- component type
methods for patient identification for transfusion best practise points
NO WRISTBAND NO TRANSFUSION
in the unconscious/compromised patient (e.g. neonates or paediatric practice or confused patients) it is imperative that greater vigilance should be taken to identify these patients,
unidentified patients in A&E should use unique identification number and gender
documenting a transfusion
sign the transfusion documentation
record the donation number
complete traceability documentation
treatment of choice for emergency reversal of warfarin
prothrombin comples concentrate
signs and symptoms of a transfusion reaction
patients should be transfused in an area where they can observed
- advise pt on signs symps to look out for
- stop transfusion immediately following any sign
- check the blood component against the wrist band
- antipyretic or antihistamine may be required
can you restart a transfusion if they have only had mild reaction to the first component?
yes after 30 mins if the patient has responded to symptomatic treatment
management of a severe transfusion reaction?
- stop transfusion
- check compatibility of unit
- assess patient - ABCDE
-Replace the administration set and preserve IV access with normal saline to maintain systolic BP
Check urine for signs of haemoglobinuria
Commence appropriate treatment
Maintain airway and give high flow Oxygen.
If appropriate administer adrenaline and/or diuretic and resuscitate if/as required.
Reassess patient and treat appropriately - Seek expert advice if patient’s condition continues to deteriorate
document it as adverse event
delayed haemolytic transfusion reaction
-what is it?
signs/symps
rare
usually seen in patients who have developed red cell antibodies in the past from transfusion or pregnancy. A combination of the features occurs days after the transfusion, suggesting that the red cells are being destroyed abnormally quickly
signs/sympts
- fever
- falling haemoglobin or a rise less than expected
- jaundice
- haemoglobinuria
what should be measured 15 mintues after starting a transfusion
temp
bp
hr
rr
alternatives to a donor blood transfusion
sometimes can have autologous transfusion - recycling your own blood
allogenic - drug therapies eg oral or IV iron, erythropoietin and tranexamic acid
when should you crossmatch blood?
only when a transfusion is likely to be required
what is the universal donor for plasma?
group AB
has no anti-A or anti-B antibodies in it
what percent of the population are rhesus positive or resus neg
85% rhesus pos
15% neg
how much blood can someone donate in blood per year
470mLs of whole blood three times a year
what is a bag of red blood cells?
red cells in additive solution - contains up to 20 mLs of plasma
leucocyte-depleted
haematocrit typically 0.55
stored for up to 5 weeks at 4 degrees +/- 2 degrees
can be irradiated +/or CMV neg
when would you prescribe transfusion of red cells?
improve oxygenation to tissues by increasing circulating red cell mass
main indications =
- bleeding
- anaemia
- haemoglobin disorders
- loss of 30-40% volume
- if hb is below 70g/L in fit pt
- if below 80-90 g/L in pt with CVS
transfusing red cells will give a rise of haemoglobin to what ratio?
for 4mL/kg of red cells = rise of 10g/L of Hb
this works for people with body weights of 70-80kg if very low then use smaller volumes
define apheresis donation
a single donor
pooled donation
whole blood derived - 4 donations
adult therapeutic dose
one pack
one adult therapeutic dose of platelets should increase the platelet count by what?
20x10(9)/L
when will platelets be tranfused?
to prevent bleeding not stop it
when platelet count drops below 10x10(9)
for example in:
- Reversible bone marrow failure including allogeneic stem cell transplant and critical illness
- Chronic bone marrow failure if patient is receiving intensive treatment or to prevent persistent bleeding
- to prevent bleeding prior to a procedure
- thrombocytopenia
dont have to cross match but preferre
do you need to match the group when tranfusing fresh frozen plasma
yes as a first choice
fine tho as long as its ‘low-titre’ and another group
when is fresh frozen plasma given?
inherited coagulation factor deficiency where no suitable factor concentrate is available, e.g. Factor V deficiency
Acute disseminated intravascular coagulation (with evidence of bleeding)
Thrombotic thrombocytopenic purpura (TTP)
Major haemorrhage*
Prophylaxis before surgery (or another invasive procedure) if abnormal coagulation test results AND one or more additional risk factors for bleeding:
i) Personal or family history of abnormal bleeding
ii) Procedure associated with major blood loss
iii) Procedure involves critical tissues such as eye, brain or spinal cord
iv) Concurrent thrombocytopenia.
dose of fresh frozen plasma for:
- prophylaxis for surgical or invasive procedure
- major haemorrhage
- proph - 15ml/kg
- major - 15-20ml/kg
when should FFP not be used
As a plasma expander to correct hypovolaemia.
For the reversal of warfarin anticoagulation, treatment of bleeding in this circumstance is vitamin K, with or without prothrombin complex concentrate.
To non-bleeding patients with liver disease*
To critically ill patients with prolonged PT or APPT in the absence of bleeding.
For patients with liver disease: there is no evidence that prophylactic FFP reduces the risk of bleeding from percutaneous liver biopsy or variceal haemorrhage.
how much cryoprecipitate should be used to increase fibrinogen levels by approx 1g/l in non-bleeding average-sized adult of 70kg
2 x 5-donor pools
which blood component is the most likely to cause an allergic or serious reaction
FFP
define major haemorrhage
- loss of one blood volume within a 24 hour period
- 50% blood volume loss within 3 hours
- rate of loss of 150mLs/min
Bleeding which leads to a heart rate of >110 bpm and/ or a systolic BP < 90 mm Hg is a useful indicator of major blood loss of 1000 mL or more in an adult.
commonest causes of major haemorrhage
GI haemorrhage]trauma
ruptured AA
obstetric haemorrhage
management of major haemorrhage in adults
Activate major haemorrhage protocol
Administer high flow oxygen
Insert 2 wide bore peripheral cannulae and provide fluid resuscitation.
Contact key personnel, including experts to treat bleeding cause.
Arrest bleeding and treat underlying cause as soon as possible.
Request laboratory investigations and perform Point of Care Tests where available, including blood gas analysis and viscoelastic tests (ROTEM/ TEG).
Transfuse red cells to maintain a haemoglobin level of 70-90 g/L
Administer tranexamic acid within 3 hours of onset of haemorrhage unless complicated by disseminated intravascular coagulation
Transfuse FFP empirically if estimated blood loss greater than 20% blood volume or if microvascular bleeding
Anticipate the need for additional blood components (including red cells, FFP, platelets and cryoprecipitate)
Use cell salvage where available and appropriate
When bleeding is under control additional doses of FFP should be based on results
procedure to maintain Hb between 70-90g/L
Give group O D negative uncrossmatched red cells in cases of life-threatening bleeding, until patient’s ABO group and D status is known. The clinical assessment of the urgency of the transfusion needs of the patient is key to ensure blood availability specifically meets the needs of patient
Cross-matched red cells can be transfused if already prepared for patient concerned
Group specific red cells should be requested on the group and screen sample, since a full cross match will take time for serological testing.
A blood warmer with rapid infusion facility should be used to reduce the risk of hypothermia.
Consider use of cell salvage , where available, to reduce requirement for allogenic red cells
The patient’s haemoglobin level should be checked regularly (minimum of hourly intervals during active bleeding) to monitor transfusion therapy and to avoid excessive red cell transfusion. A blood gas analyser or other point of care test eg haemocue may be used. Similarly coagulation tests/ POCT should be regularly repeated.
Administer 10% calcium gluconate if ionised calcium less than 1.13 mmol/l to optimise coagulation.
complications of major haemorrhage
thrombocytopenia hypothermia hypocalcaemia hyperkalaemia adult resp distress syndrome coagulopathy
what is included in plasma albumin solution
95% albumin and electrolytes but no clotting factirs or BG antibodies - so crossmatching not required
how much does concentrated 20% human albumin solution expand the circulation by?
3-4
what are the two concs that albumin comes in and the volumes and infusion rates for them
4.5-5% - 400mLs 5-15mLs/min
20-25% - 100mLs 1-2 mLs/min
why would conc 20-25% albumin solution be needed?
restore plasma volume in pts with interstitial oedema
acute lung injury with severe resp failure
promote diuresis in patients with severe hypoalbuminaemia eg hepatic cirrhosis
vital signs should be closely monitored due to risk of circ overload
what is prothrombin complex concentrate and when is it used
conc of three or four inactivated clotting factors - II, IX, X or II, VII, IX, X and Protein S and C anticoagulant factors
treats - bleeding, peri-op proph of bleeding
common s/e of IV IG
fever
muscle pain
headaches
these can be resolved by slowing rate of infusion and administering paracetamol
toxicity with IV IG
The total dose per course must not exceed 2g / kg body weight, usually administered over 2-5 days.
define acute transfusion reaction
are adverse reactions occurring at any time up to 24 hours after a transfusion of blood or blood components
what is a delayed transfusion reaction + examples
defined as a fever and other signs of haemolysis more than 24 hours after
confirmed by
- fall in Hb or failure of increment
- raise in bilirubin and LDH
- incompatible crossmatch not detectable pre-transfusion
- iron overload
name 4 myeloproliferative disorders
polycythaemia rubra vera - red cell proliferation
chronic myeloid leukaemia - white cell proliferation
essential thrombocythaemia - platelet proliferation
myelofibrosis - marrow stroma proliferation
what level of platelets will cause spont bleeding or haemostasis
spont bleeding <20
haemostatic >80
causes of thrombocytopenia
Failure of platelet production
- Vitamin B12 or folate deficiency
- Bone marrow infiltration (leukaemia or metastases)
- Radiation, cytotoxic therapy
Increased consumption of platelets
- Immune thrombocytopenia (ITP)
- Disseminated intravascular coagulation (DIC)
- HIV infection
Hypersplenism
causes of thrombocytosis
Secondary
Bleeding, Infection, Inflammation, malignancy
Primary: Essential Thrombocythaemia
- Uncontrolled malignant proliferation of megakaryocytes
- Platelets >600 persistently
- Arterial and venous thrombosis
- Bleeding with very high counts eg >1500
- Treatment with aspirin, hydroxycarbamide, anagrelide, interferon
normal haemostasis pathophys
Localized vasoconstriction at the site of injury
Adhesion of platelets to damaged vessel wall and
formation of a platelet aggregate or plug
Activation of the coagulation cascade leading to fibrin
formation, reinforcing the platelet plug
Activation of the fibrinolytic system which digests the
haemostatic plug, re-establishing vascular patency
two types of thrombosis and their differences/treatment
arterial circ - MI/stroke, platelet rich, antiplatelet
venous circ - DVT/PE, fibrin rich, anticoags
RF for venous // arterial thrombosis
venous Acquired Age, previous VTE Surgery/trauma, immobility, obesity Cancer, serious illness Pregnancy, contraceptive pill, HRT Inherited (Thrombophilia)
ARTERIAL Smoking Obesity Hypertension Diabetes mellitus Older age Not inherited thrombophilia
DOACs vs Warfarin
Advantages of DOACs
Rapid onset of action
Fixed oral dosing with predictable anticoagulant effect
Low potential for food or alcohol interactions
Low potential for drug interactions
No need for blood monitoring
Disadvantages of DOACs
Renal elimination
No specific antidotes for the Xa inhibitors
Licensed for only specific indications
severe anaemia classification and waht it causes
<8g/dl
causes signs of hyperdynamic circulation:
- tachycardia
- flow murmur
- cardiac enlargement
- increased cardiac output
approach to normocytic anaemia to find differential
- check reticulocyte count
- > increased -> haemolysis? yes = haemolytic anaemia, no = recent bleed
- > decreased or normal -> any evidence of renal or endocrine failure or chronic inflam? then = anaemia of renal, endocrine or chronic disease
- > if not then consider a primary bone marrow problem (pure red cell aplasia, MDS, MM, infiltration) -> bone marrow ix
where is absorption of iron folate and B12 take place
iron = duo/jejunum
folate = jejunum
b12 = ileum
what is iron transported as and stored as
trans = transferrin
stored = ferritin, haemosiderin
iron deficiency anaemia pres causes ix differentials mgmt
pres Fatigue Pallor Pica Nail changes - koilonychia (spoon nails), brittleness Hair loss Mouth changes - angular stomatitis, atrophic glossitis (burning) Faintness Dyspnoea
causes
Inadequate intake - poor diet, poverty
Poor absorption - poor acid production, gastric surgery, coeliac
Excessive loss - GI bleeding (unknown loc), peptic ulcer, diverticulosis, neoplasm, menorrhagia
Excessive iron requirement - infancy, preg, hookworm
ix Hb and haematocrit <13g/dL (men), <12g/dL (women) MCV <80fL = microcytic MCHC Low = hypochromic Peripheral blood smear - Hypochromic - Microcytic - Anisocytosis (different size) - Poikilocytosis (different shape, pencil) Iron studies (FITT) - Serum iron - low - Serum ferritin - low (<12ng/mL is diagnostic, but dont forget its an acute phase protein so raised in any infection, inflam, malignancy) - Total Iron Binding Capacity - increased - Transferrin saturation - low Investigations for cause - Coeliac serology, H. pylori/urease breath test, UGI/LGI endoscopy (rule out malignancy)
ddx
chronic disease - 20%
sideroblastic
mgmt
oral iron replacement - ferrous sulphate 2-3mg/kg/day in 4 doses, for 3-6 months SE = constipation, black stools, vomiting
diet - dark-leafy green veg, meat, iron-fortified bread
consider transfusion - if symptomatic at rest or hb <70 or <80 with cardiac illness, old etc
sideroblastic anaemia when to suspect define sideroblast mechanism causes ix mgmt haemosiderosis
when to suspect
microcytic hypochromic anaemia not responding to iron
sideroblast = Atypical abnormally nucleated erythroblast with perinuclear iron accumulation
mech
Ineffective erythropoeisis. Increased
iron absorption but can’t incorporate
to haemoglobin
causes
Congenital - inherited XLSA (x-linked)
Acquired - MDS (myelodysplastic syndrome), myeloma, PRV, pyridoxine (B6) deficiency, alc, anti-TB meds
ix Hb and haematocrit <13g/dL (men), <12g/dL (women) MCV <80fL = microcytic MCHC - Low = hypochromic Peripheral blood smear - Dimorphic population of normal and hypochromic red blood cells Iron studies (FITT) - Serum iron - high - Serum ferritin - high - TIBC - low Marrow aspirate - Perinuclear ring of iron granules with Prussian Blue
mgmt mainly supportive iron chelation = desferrioxamine repeat transfusion - if sympt at rest avoid alc + vit c as these increase iron absorption if hereditary consider pyridoxine (B6)
haemosiderosis = iron deposition at liver kidney and heart
thalassaemia haemoglobin
normal - 2x alpha 2x beta chains
HbF = 2 x alpha 2 x gamma
HbA2 = 2xa 2x delta
beta thalassaemia what is it patho epi TYPES investigations mgmt comps
what is it Inherited microcytic anaemia caused by mutation in beta-globin gene. autosomal recessive chromosome 11 β0 - complete absence β+ - some beta-globin
epi
med, africa, south east asia
patho
Decreased/absent synthesis of beta-globin leads to excess alpha production + membrane damage/cell destruction
Ineffective erythropoeisis
cells cant survive - 1. anaemia
2. erythroid hyperplasia - bony changes in skull (flat bones, air space sinus, vertebral bodies)
skull bossing + Extramedullary hematopoiesis - hepatosplenomegaly
TYPES
- silent carrier -> normal haem
- minor/trait -> B/B+ or B/B0, usually asymp, mild anaemia (confused with IDA)
- intermedia -> β+/β+ or β0/β+, similar pres as maj but as toddler
- major (aka cooleys anaemia) β0/β0, Complete absence HbA, presents at months with progressive pallor and abdo distension + skull bossing (or chipmunk face) + failure to thrive
ix
FBC- microcytic anaemia
Peripheral blood smear:
- Microcytic
- Target cells
- Nucleated red cells
Reticulocyte count- Elevated (haemolytic)
Haemoglobin analysis (electrophoresis)
- Major: No HbA, elevated HbF and HbA2
- Intermedia: Decreased HbA, elevated HbF and HbA2
- Minor/Trait: Mostly HbA, elevated HbF and HbA2
LFT - Elevated total and unconjugated bilirubin (haemolytic)
XRay skull - Hair on end sign, widening of diploeic space
AUSS - Hepatosplenomegaly
mgmt
minor - genetic counselling + iron advice
inter - genetic counselling + transfusion at symptomatic anaemia (infection, perioperative) + iron monitoring with chelation (desferrioxamine)
3. maj - Genetic counselling + regular transfusion to >10g/dL + iron monitoring with chelation
+/- splenectomy
+/- assessment for haematopoeitic stem cell transplant
comps
1. Thrombotic
2. Complications of iron overload
a - Arthropathy (MSK)
b - Pigmentation and bronzing
c - Arrhythmias and contractile dysfunction -> congestive heart failure
d - Endocrine
anterior pituitary -> slow growth, delayed sexual maturation
pancreatic islet cells -> impaired insulin secretion (T1DM)
3. Transfusion reactions + transmission acquired infections (HIV, HBV, HCV)
4. Splenectomy complications
causes of splenomegaly
Splenomegaly results from multiple transfusions, iron deposition and extramedullary erythropoeisis and can lead to hypersplenism.
This leads to an increased transfusion requirement and a decreased red cell survival as well as leukopenia and thrombocytopenia.
alpha thalassaemia what is it patho epi types pres ix mgmt
what is it
Inherited microcytic anaemia caused by mutation in alpha-globin genes.
autosomal recessive
chromosome:
16
Different mutations:
α0 (–/) - both alpha genes on same chromosome deleted
α+ (α-/) - one of two alpha globin genes is deleted on same chromosome
patho
- Decreased/absent synthesis of alpha-globin leads to excess beta production
- There are 2 copies/alleles of the alpha globin gene on each chromosome 16 (α1 and α2)
- Ineffective erythropoeisis - anaemia and haemolysis
epi
Corresponds to malaria distribution -
sub-saharan africa + middle east + south east asia
TYPES
- silent carrier - 1 of 4 alpha globin genes affected - asymptomatic
- trait - 2 of 4 alpha globin genes affected - heterozygous (α0/α) or (α+/α+) - mild anaemia (hypochromic, microcytic) or normal Hb, confused IDA
- HbH disease - 3 deletions (α0/α+) - leads to beta tetramers - detected on electrophoresis - anaemia + splenomeg
- major or bart hydrops fetalis - Homozygous (α0,α0), all 4 alleles affected death in utero
pres
RF - fh, malaria, geo
Symptoms of anaemia - fatigue, dizziness, SOB
Splenomegaly
Presentation in childhood - more severe, growth retardation
Symptoms of gallstones - bloating, abdo pain, gallstones common in HbH
ix FBC - Microcytic anaemia (MCV low, MCHC low) Peripheral blood smear: - Microcytic/hypochromia - Target cells - Basophilic stippling in HbH Reticulocyte percentage- Elevated (haemolytic) Haemoglobin analysis (electrophoresis): - Presence of HbH, Hb Bart, will not detect silent carrier or trait Iron studies: - Serum iron - normal or elevated - Serum ferritin - normal or elevated
mgmt
genetic counselling + iron advice (avoid unless deficient)
HbH - + folic acid (1mg, PO) + education + regular transfusion to >10g/dL + iron monitoring with chelation
+/- splenectomy
+/- assessment for haematopoeitic stem cell transplant
crisis - identify cause + monitor + folic acid +/- red cell transfusion
haemolytic anaemias
what is it
when can it happen
Haemolysis is the premature destruction of RBC. It can happen in two places:
1. Within circulation/Intravascular:
a. Trauma e.g. mechanical heart valve
b. Complement mediated lysis
Reticuloendothelial system/Extravascular:
a. Macrophages of liver
b. Spleen
c. Accelerated red cell destruction due to immune targeting by antibodies
haemolytic anaemia causes accquired explained pres ix mgmt
causes
1. Hereditary:
a - Enzyme defects - Glucose 6 phosphate dehydrogenase deficiency
b - Membrane defects - Hereditary spherocytosis, elliptocytosis
c - Abnormal Hb production - Sickle cell anaemia, thalassaemia
- Acquired:
a - Immune mediated
b - Non-immune mediated
ACCQUIRED
Immune mediated:
- Caused by autoantibodies and direct antiglobulin +ve (Coombs’ positive)
- Often part of other AI cond (SLE/reactive arthritis/scleroderma)
- Divide into 2 subtypes depending on temperature at which antibody binds to RBC:
1. Warm
IgG mediated - Rx: steroids
2. Cold
IgM mediated - Rx: keep warm
Non-immune mediated:
- Direct antiglobulin -ve
- Infection (e.g. malaria), trauma, microangiopathic haemolytic anaemia (DIC, TTP, HUS, HELLP), hypersplenism, liver disease
- Paroxysmal nocturnal haemoglobinuria:
a - Rare membrane defect
b - Haemoglobinuria, marrow failure + thrombophilia, Dx: urinary haemosiderin
pres anaemia symps jaundice splenomeg episodic dark urine presence of RF - AI disorders, prosthetic heart valve, family origin Med or middle east, family history haemoglobinopathy or RBC membrane defect, PND, Cephalosporins, fava beans
ix
FBC + MCHC + reticulocyte count:
- Low Hb
- Increased MCHC suggestive of spherocytes and reticulocytes
- Reticulocyte count >2%
Unconjugated bilirubin - Mildly elevated
Urinalysis - Haemoglobinuria
LDH and Haptoglobin: (this will bind free haemoglobin in intravascular causes)
High and Low, n.b. High LDH and low haptoglobin is 90% sensitive for haemolytic anaemia
Peripheral blood film:
- Sickle cells
- Spherocytes
- Elliptocytes
- Heinz bodies: bite and blister cells - G6PDD
- Hypochromic - thalassaemia
Coombs test - blood cells washed and incubated with Coombs’ reagent - look for agglutination, Positive for immune mediated
Other tests - creatanine/urea (raised in TTP or HUS), LFT (elevated in liver disease), Donald-Landsteiner antibody in cold-immune disease
mgmt
coombs posi - Treat underlying + support (packed RBC transfusion, if symps + folic acid for RBC prod)
combs neg:
- valve - cardiology eval
- TTP - plasma exchange
- Paroxysmal Nocturnal Haemoglobinuria - corticosteroids + anticoag
- hypersplenism - splenectomy
membrane disorder - splenectomy + support
G6PDD - avoid triggers + support
haemoglobinopathies - support + disease specific
in haemolytic anaemias what does the… cause:
increased breakdown?
increased production?
extravascular or intravascular?
Increased breakdown?
- Increased bilirubin, increased urobilinogen, increased LDH
Increased production?
- Increased MCV by increased reticulocytes, marrow hyperplasia
Extravascular or intravascular?
- Intravascular - increased free plasma Hb and decreased haptoglobin, increased haemoglobinuria (no blood cells)
- Extravascular - splenomegaly
G6PDD what is it patho pres triggers ix mgmt
what is it
An inherited X-linked recessive (G6PD gene) enzyme deficiency common among parts where malaria (protective) is common: Mediterranean, sub-Saharan Africa, Asia
patho
G6PD catalyses step one of pentose phosphate pathway (similar glycolysis) which generates NADPH (important for red cells to protect from oxidative stress)
pres prolonged neonatal jaundice or haemolytic anaemia pallor dark urine - suggests intravascular haemolysis nausea vom dehydration AKI - haemoglobin precip
triggers:
infection
broad beans
drugs that cause oxidative stress - sulphonamides, cephalosporins
ix
See haemolytic anaemia investigations
Peripheral blood smear:
- Blister/bite cells - suggestive of oxidative stress as cause of haemolysis
- Heinz bodies - fragments of denatured haemoglobin
Genetic testing for G6PD variants
mgmt
treat as acute haemolysis:
- Maintain fluid intake
- Folic acid 5mg orally (for RBC production)
- Blood transfusion if severe anaemia (<7g/dL)
- Renal support if renal impairment by haemoglobinuria (EPO)
anaemia of chronic disease characteristic features why? ix patho causes mgmt
characteristic
anaemia and evidence of immune system activation
due to
Inflammation mediated reaction and decreased RBC production + decreased survival
ix
Normocytic normochromic/microcytic hypochromic hb
Low reticulocyte count as of underproduction by marrow (typical in ACD) due to EPO
Low serum iron
Low TIBC
Low transferrin saturation
Elevated ferritin
patho
Release of pro-inflammatory cytokines by infection, neoplasm, autoimmune, trauma (VITAMIN CDEF)
Cascade leads to fall in serum iron and decreased RBC survival
IL-1 and IL-6:
1. upregulate hepcidin synthesis
Hepcidin is a regulator of iron metabolism produced by the liver
2. Down regulates ferroportin (which exports iron from enterocyte)
Less free iron for erythropoeisis (and micro-organism growth) and cytokine induced shortening of RBC life
causes - VITAMIN CDE
Vascular
Infective/inflammatory - Chronic: TB, fungal, hepatitis, HIV, Acute: pneumonia, pyelonephritis, endocarditis, cellulitis
Traumatic
Autoimmune - RA, SLE, dermatomyositis, PMR, scleroderma
Metabolic
Iatrogenic
Neoplastic - lymphoma, carcinoma
Congenital
Degenerative - CKD, CHF, chronic lung disease
Endocrine - DM
mgmt
treat underlying disease
RBC trans if symptomatic
aplastic anaemia def pres causes assocs pathophys ix mgmt
def
TRIAD:
Pancytopenia (BM failure) with hypocellular bone marrow and no abnormal cells (aka On BM biopsy
Hypocellularity with no dysplasia or blasts)
pres:
1. neutropenia - infections (<1.5) (lymphocytes are typically spared)
2. normochronic, normocytic anaemia - fatigue, pallor, dyspnoea, faintness (<100)
3. thrombocytopenia - bleeding, bruising (<50)
30 yrs old
causes acquired: - Idiopathic (50%) - Drug or toxin exposure -> NSAIDs, penicillamine, gold, chloramphenicol, phenytoin - Post virus (especially hepatitis + parvovirus) inherited: - Fanconi anaemia (AR) - Shwachman-Diamond syndrome (AR)
assocs
PNH, pregnancy, coeliac, SLE
patho
autoimmune attack on hematopoietic
system
DNA damage repair mechanisms
ix
FBC - At least 2 cytopenias
Reticulocyte count - <1%
Bone marrow biopsy - Hypocellular marrow with no abnormal cell population
mgmt
If asymptomatic:
- Give neutropenic regimen (MASSC risk assessment if NP< 0.5, Full barrier nursing, Avoid IM injections, Look for infection, Check bloods and cultures, Vitals 4 hourly)
If severe:
- Matched related allogeneic BM transplant (If BM cellularity < 25% can be curative
Worry about Graft vs host disease (GVHD)) + RBC and Pt transfusion + ABX (Antibiotics and antifungals to local guidelines)
neutropenia when immunocomp/severe? causes sepsis triad mgmt
when immunocomp = 0.5-1.0
severe = <0.5
causes
Aplastic anaemia, immunosuppression, chemotherapy, HIV, BM infiltration,
Neoplastic disease, infections…… (think decreased prod and increased destruct)
sepsis triad
T > 38.5 or 2 readings >38.0 (an hour apart) + NP < 0.5 x 10^9/L + hypotension
mgmt
Sepsis work up (FBC, BC, CRP, ESR etc) + Sepsis 6 with tazocin (tazobactam [beta lactamase inhib] + piperacillin) +fluid challenge + G-CSF (Given S/C to stimulate NP production)
where does the bone marrow do haemopoiesis?
where would you get a sample
axial skeleton - vertebrae, sternum, ribs, skull
long bones
biopsy taken from iliac crest
sickle cell anaemia what is it patho epi types precipitants symps crisis pres ix mgmt + crisis gen management comps
what is it
Disease of RBC caused by AR single gene defect in beta chain of Hb (HbA) (valine replaces glutamine in sixth amino acid) resulting in sickle cell haemoglobin (HbS)
patho
crescent shaped haemoglobin = disrupted blood flow + break (haemolysis), cause varying degrees anaemia, obstruction of small blood caps = painful crises, organ damage, increased vulnerability to infection
HbS will polymerise at periods of hypoxia + acidosis
epi
very common in sub-saharan africa
types
- sickle cell trait = HbSA - protective falciparum malaria, disability @ hypoxia. Venous occlusion may occur at operation therefore require testing before if black.
- sickle cell disease = HbSS
- haemoglobin SC disease = HbSC - sickle gene from one parent and haemoglobin C (lysine for glutamine at 6) from other. Make no HbA.
- sickle cell beta thal
precipitated by CHIDS Cold Hypoxia Infection Dehydration Stress
symps parents have it jaundice pallor lethargy tachycardia vaso-occlusion - Dactylitis, visual floaters (retinal arterioles), persistent pain in skeleton, chest and abdomen, chronic renal failure, CNS infarct
crisis pres
- Acute chest syndrome: pneumonia like syndrome (due to sickling in pulmonary vasculature) - chest pain, fever, dyspnoea, tachypnoea, ?collapse
- painful, ischaemia - bone/ abdo - Bone infarction and avascular necrosis femoral head, mesenteric ischaemia
- aplastic - temp bone marrow failure - severe anaemia - trig = PARVOVIRUS B19
- splenic sequestration - life threatening sudden enlargement of the spleen leading to hypovolaemia
- cerebrovascular
- priaprism - nocturnal + risk of long-term impotence
ix
Hb- low
Reticulocytes - High (10-20%)
Bilirubin - high
Peripheral blood film - Sickled cells and Howell-Jolly bodies. Target cells at HbSC
Sickle solubility test - Doesn’t distinguish HbSS from HbSA - turbid appearance, normal Hb is clear
GOLD - Hb electrophoresis - To diagnose variant
Iron studies - Normal
Other - LFTs, Renal function, LuFT at diagnosis for baseline
SHOULD BE DIAGNOSED AT NEWBORN BLOOD SPOT
mgmt
Give pneumococcal vaccine 5 yrly and penicillin prophylactically for pneumococcus + genetic counselling + parental education
*Sequestration prevents blood from leaving spleen -> acute splenic engorgement
trigger avoidance
manage daily pain
Hydroxyurea (with monthly blood tests) - Increases production of fetal haemoglobin - reduces painful crises
Repeat blood transfusion to maintain HbS below 30% and Hb > 10g/dL
CRISIS GEN MGMT PRINCIPLES:
1. hydration - IV fluids
2. oxygenation
3. pain relied
4. abx as indicated by local guidelines
5. consider exchange transfusion
comps
Anaemia
Liver complications - jaundice, hepatomegaly and gallstones
Iron overload from chronic transfusion
Dactylitis
Leg ulcers
Priapism - requires urgent urological aspiration if >4 hours
CV - hyperdynamic precordium, flow murmur, cardiomegaly. Treat for heart failure and HTN
megaloblastic anaemia
what is it
causes
symps
what is it
Unusually large, structurally abnormal RBCs
Defective DNA synthesis which also leads to leukopenia and thrombocytopenia
macrocytic anaemia
causes
B12/folate deficiency + drugs (hydroxyurea)
symps
Tend to be asymptomatic as slow onset of decreased Hb due to fall in B12 and folate allowing the body to adjust
folate deficiency what is it what is folate used for present in? absorbed in? causes pres ix mgmt
what is it
A type of macrocytic anaemia with absence of neurological signs
what is folate used for
DNA synthesis + repair (@pregnancy = NT defects)
present in
Green vegetables, nuts and liver
absorbed in
prox jejunum + duodenum
caused by
- poor diet - pov, alc, elderly
- increased demand - preg, renal disease/dialysis, chronic haemolytic anaemia
- malabsorption - coeliac, tropical sprue
- drugs, alc, methotrexate - inhibits synthesis folic acid
symps
Pallor, fatigue, dyspnoea, faintness, tachycardia, heart murmur
headache - hallmark sign of megaloblastic anaemia
GI - loss of apetite/ weight loss (from increased energy demand of ineffective erythropoeisis) - hallmark sign of megaloblastic anaemia. Diarrhoea if coeliac.
skin/mouth - exfoliative dermatitis, glossitis, painful swallowing (inflamed oral mucosa)
ix FBC - low haem, raised MCV + MCH, thrombocytopenia, neutropenia reticulocyte count - low peripheral blood smear - macrocytic RBCs and hypersegmented neutrophils serum folate - low RBC folate - low serum B12 - normal LFT - ?alc liver disease
mgmt
macrocytosis without anaemia - oral folic acid 1-5mg + treat disorder
macrocytosis + pancytopenia - oral folic + treat disorder + packed RBC transfusion
folic acid for 4 months +/- B12
B12 deficiency aka what is it B12 used for present in absorbed in/how causes pres ix mgmt
aka
cobalamin
what is it
A type of macrocytic anaemia with peripheral neuropathy and neuropsych complaints
used for: DNA synth, myelination of nerves and red blood cells (without = megaloblastic anaemia + neuropathy)
present in - meat, fish, dairy
absorbed in - ileum (combined with intrinsic factor)
how - 1. B12 released from food in stomach by peptic acid
2. Parietal cells at gastric fundus produce intrinsic factor (IF)
3. IF binds B12 to form an IF-B12 complex
4. Complex travels to terminal ileum
5. Endocytosis occurs and complex binds to transcobalamin which is released into the blood stream
caused by -
- poor diet - vegan, vege, old age
- decreased gastric breakdown - hx of gastric surg, atrophic gastritis
- malabsorption - pernicious anaemia, crohns, coeliac
- drugs - metformin (decreases absorption), PPI, H2 antagonists
pres
pallor
fatigue
dyspnoea
faintness
mild jaundice
haemolysis
NEURO - Paresthesias, ataxia + loss vibration (posterior column degeneration), peripheral neuropathy, dementia, psychosis
SUBACUTE DEGENERATION SPINAL CORD - upgoing plantars, loss knee jerk, loss ankle jerk
GI - chronic GI illness, surgery
mouth signs - glossitis, angular chelitis
ix
FBC - Elevated MCV, low haematocrit, 25% do not have anaemia, if severe = pancytopenia
Serum B12 - Low
Peripheral blood smear - Megalocytes (RBC precursor) and hypersegmented neutrophils -> megaloblastic anaemia
Reticulocyte count - Low (decreased production)
IF antibody
+ve if cause is pernicious anaemia
mgmt
Symptomatic + severe i.e. pancytopenia + anaemia + neurological = IM hydroxycobalamin 1mg (daily) + refer to
neuro/haem + oral folic acid (1mg PO OD) will correct Hb
not neuro + admit and blood transfusion
mod + no neuro involve -
IM hydroxycobalamin 1mg 3x/week for 2 weeks then
once every 3 months
Need for lifelong therapy
pernicious anaemia what is it associated with risk of pres specific test mgmt
what is it
Autoimmune atrophic gastritis -> Atrophy of gastric mucosa with failure of IF and acid production due to autoantibodies to IF
leads to B12 deficiency
pernicious = causing harm, especially in a gradual or subtle way
assoc with other AI diseases -> Thyroid (25%) Vitiligo T1DM Addisons group A blood Women > men x 1.6
risk of GASTRIC CANCER
pres
anaemia features:
lethargy, pallor, dyspnoea
neurological features:
peripheral neuropathy: ‘pins and needles’, numbness. Typically symmetrical legs > arms
subacute combined degeneration of the spinal cord: progressive weakness, ataxia and paresthesias that may progress to spasticity and paraplegia
neuropsychiatric features: memory loss, poor concentration, confusion, depression, irritabiltiy
other features
mild jaundice: combined with pallor results in a ‘lemon tinge’
glossitis → sore tongue
specific tests:
FBC + vit b12 + folate
1. IF antibody
2. Antiparietal cell antibody:
- 90% sensitive (not specific - elevated in atrophic gastritis)
3. Serum gastrin (fasting)
4. Schilling test (NO LONGER DONE) (radiolabeled B12)
- Oral radiolabelled B12 with IM unlabelled B12 @1 hour later
- Collect urine over 24 hours
- Normal result shows 10% of radiolabelled B12 in urine, if = impaired absorption there will be less
- If impaired absorption give oral radiolabelled B12 with IF
- If urinary radiolabelled B12 is high = pernicious anaemia, if low = malabsorption
mgmt
B12 replacement as in B12
folic acid supplements
two main types of haematological malignancies
- bone marrow - myeloid (haematopoietic stem cells - blood forming system)
- lymphatic - lymphoid (can be B/T cell)
what is leukaemia
Excess of abnormal white cells in peripheral blood - myeloid or lymphoid
what is lymphoma
Tumour presentation with local or scattered lumps in lymphatic system
what is myeloproliferative disorders
Involve BM, liver and spleen with peripheral blood features
for haematological malignancies what are the differentials for Acute onset with rapid
progression -> life-threatening
in weeks/months
myeloid - AML
lymphoid - ALL (T or B cell origin). high grade lymphoma (DLBCL)
for haematological malignancies what are the differentials for Slowly progressive disorders with usual interval of years between presentation and clinically relevant condition
myeloid - CML myeloproliferative neoplasm (polycythaemia rubra
vera, myelodysplastic syndrome)
Lymphoid - CLL, low grade lymphoma (follicular, marginal
zone), myeloma
acute leukaemia
pres
pres
tumour - bone pain, fever, lethargy, fatigue, night sweats, weight loss
bone marrow failure - anaemia (pallor, SOB, fatigue), thrombocytopenia (petechial rash, bleeding, bruising), neutropenia (freq/recurrent infections) eg candida
circ cell related - hyperviscocity (headache, neurology eg cranial nerves), infiltration (tissues, organs), skin/gums @ monoblastic AML, hepatosplenomeg, lymphadenopathy, testicular enlargement
DIAGNOSE:
A 58-year-old man presents to his primary care physician with increasing tiredness, accompanied by bruising on his legs. He also complains of aching bones. He has no previous illnesses. On examination, he is pyrexial and pale, has bony tenderness over the sternum and tibia, and has petechiae on his legs. There are no palpable lymph nodes. He has crepitations at the left base. The liver and spleen are not palpable.
AML
AML what is it diagnostic feature epi assocs ix ddx mgmt prog
what is it
Clonal expansion of myeloid blasts in bone marrow, peripheral blood or extramedullary tissue, unable to differentiate into neutrophils
diagnostic feature
Bone marrow blasts > 20% or peripheral blood
epi
most common ADULT leukaemia (>65) - can be comp of chemo
assoc
Myelodysplastic syndrome, Down’s syndrome, bone marrow failure syndromes (e.g. Fanconi, Diamon-Blackfan, aplastic anaemia), smoking
ix
FBC - Leukocytosis (increase in WCC) with neutropenia, thrombocytopenia, anaemia
Peripheral blood film - Blasts + Auer rods (crystallised granules in myeloid blasts)
Coagulation panel- As baseline: PT and PTT may be prolonged with normal fibrinogen and D-dimer
U+E, LFT, renal function- For baseline
Bone marrow biopsy/aspirate (for definitive diagnosis) + immunophenotyping:
- Hypercellularity, blasts > 20%, Auer rods
- Flow cytometry immunophenotyping/FISH
CXR - Pulmonary infiltrates
ddx
ALL - clinically indistinguishable, requires BM biopsy + immunophenotyping
myelodysplastic syndrome - based on number of blasts (blood film >10%, bone marrow <20%)
aplastic anaemia - hypocellular bone marrow
mgmt
Supportive care:
Hydration - electrolyte abnormalities
Allopurinol - for acute tumour lysis syndrome (increased urate)
Leukoreduction - hydroxycarbamide/leukapheresis
Transfusions - RBC + platelets
Treat infections (complication)
INDUCTION CHEMO:
Cytarabine and daunorubicin (interferes with all stages of cell cycle)
+/- STEM CELL TRANSPKANT AT FIRST REMISSION - allogenic
prog 5 yr survival 25% poor prog factors - > 60 years > 20% blasts after first course of chemo cytogenetics: deletions of chromosome 5 or 7
what is tumour lysis syndrome
Electrolyte and metabolic disturbance due to breakdown of large number leukaemic cells (hyperuricaemia, hyperphosphataemia, hyperkalaemia, hypocalcaemia,
renal impairment)
diagnose
A 4-year-old girl presents with lethargy, dyspnoea, fever, and bruising. On examination she has hepatosplenomegaly. CXR shows a mediastinal mass and pleural effusion.
ALL
acute promyelocytic leukaemia M3
associated with t(15;17)
fusion of PML and RAR-alpha genes
presents younger than other types of AML (average = 25 years old)
Auer rods (seen with myeloperoxidase stain)
DIC or thrombocytopenia often at presentation
good prognosis
ALL what is it diagnostic epi assocs chromosomes classification extra pres types ix mgmt comps prog + poor factors
what is it
Malignancy of lymphoid cells (B or T). Undergoes somatic change and undergoes uncontrolled proliferation. Lymphoid cells replace hematopoietic cells.
diagnostic
Bone marrow blasts > 20%, blood smear leukaemic lymphoblasts
epi
Rare in adults. Most common childhood leukaemia (75% < 6), girls > boys
assoc
Down’s syndrome, ionising radiation, Kleinefelter’s, Fanconi anaemia, smoking
chromosome
Most common cytogenetic abnormality in adults is Philadelphia chromosome - translocation (9,22). BCR-ABL fusion oncogene = poor prognosis
CLASSIFICATIONS 1. FAB (french american british): L1 - small homogenous blasts (children) L2 - large heterogenous blasts (adults) L3 - Burkitt large basophilic B cells with vacuoles
- Immunological - uses surface markers
- Cytogenetic - chromosomal analysis, Ph chromosome is a poor prognosis
extra pres
CNS involvement - CNS infiltration by leukaemoid cells presents as papilloedema, nuchal rigidity and meningismus
May also have a focal neurology (CN 3, 4, 6, 7)
TESTICULAR SWELLING!
TYPES from most to least common: Pre B CD10 phenotype Pre T T B
ix
FBC - Leukocytosis (increase in WCC) with lymphopenia, thrombocytopenia, anaemia
Peripheral blood film - Leukaemic lymphoblasts
Coagulation panel (for bleeding/petechiae)
U+E, LFT, renal function - For baseline
Bone marrow biopsy/aspirate (for definitive diagnosis) + immunophenotyping - Hypercellularity, lymphoblasts > 20-25% + Flow cytometry immunophenotyping/FISH/ PCR for t(9,22)
CXR + LP + pleural tap - Mediastinal widening (T), leukaemic lymphoblasts, leukaemic lymphoblasts
mgmt
Supportive care:
- Hydration - electrolyte abnormalities
- Allopurinol - for acute tumour lysis syndrome (increased urate)
- Prophylactic antimicrobials (aciclovir + fluconazole + ciprofloxacin + co-trimoxazole - pneumocystis pneumonia)
- Transfusions - RBC + platelets (if pt<10 x 10^9)
- Beware neutropenic sepsis
Induction chemotherapy (kill leukaemic cells):
- Prednisolone, vincristine, daunorubicin (anthracycline) +- tyrosine kinase inhibitor (imatinib)
- Intrathecal methotrexate (for CNS disease)
Consolidate remission (weeks)
Maintain remission (years) - mercaptopurine (daily), methotrexate (weekly), vincristine + pred (monthly)
comps Tumour lysis syndrome Neutropenic sepsis Pancytopenia Chemotherapy side effects
prog
Complete remission 90% at < 30
worst prog: male, <2 >10, WCC > 20, T or B type, philly, black
CML what is it pres diagnosis pathophys course epi ix mgmt
what is it
Uncontrolled proliferation of myeloid cells in bone marrow
pres 1/3 may be asymp typical early: Malaise Fever Wt loss Abdominal discomfort due to splenomegaly (elevated WBC count) Night sweats Arthralgia - increased uric acid from cell turnover
diagnosis
Presence of Philadelphia chromosome/ BCR-ABL fusion gene
patho
- Philadelphia chromosome t(9,22) produces BCR-ABL fusion oncogene (chromosome 22)
- Produces p210 BCR-ABL protein (p190 @ ALL)
- Expresses constitutionally active tyrosine kinase on surface of myeloid cells
- Unregulated cell division
course
Chronic phase may transform to accelerated (symptomatic) or blast phase (AML) in 10%
epi
15 - 20% of adult leukaemias. Median age 50
ix
FBC - Leukocytosis (increase in WCC), anaemia, normal platelets, thrombocytosis (chronic/accel), thrombocytopenia (accel/blast crisis)
Peripheral blood film:
- Almost all WBCs are mature myeloid cells (NP, basophil, eosinophil)
- Blasts > 10% - accelerated + basophils > 20%
- Blasts > 20% - blast phase
Metabolic profile - Raised potassium, LDH, uric acid due to cell turnover
Bone marrow biopsy/aspirate
- Granulocytic hyperplasia
Cytogenetics (FISH)
- Philadelphia chromosome
mgmt
FIRST LINE- Tyrosine kinase inhibitor (imatinib - muscle cramps/heart failure or dasatinib - pleural effusion) +- allogeneic haematopoeitic stem cell transplant + high-dose induction chemotherapy
- Blast crisis (see AML) -> leads to pancytopenia
- Presence of philadelphia chromosome is GOOD prognosis - event free survival 95%, able to use tyrosine kinase inhibitor for older people who may not tolerate chemotherapy
CLL what is it epi triggers ix ddx criteria/staging mgmt comps
what is it
A malignant disorder of B lymphocytes that escape cell death (apoptosis) involving bone marrow and peripheral blood. Leukaemic cells may infiltrate lymphatic tissue and haemopoietic organs (liver, spleen, bone marrow)
epi
most common leukaemia
triggers
pneumonia,
increasing age
ix
FBC - Lymphocytosis (marked), low Hb, low pt
Peripheral blood film:
- Smudge and smear cells (damage to lymphocytes in slide prep)
- Flow cytometry: CD5, CD19, CD23 positive
CT scan - Hepatosplenomegaly, retroperitoneal, mediastinal lymph node
ddx
leukaemic phase of lymphoma
criteria/staging
BINET:
A - < 3 lymphadenopathy + normal Hb and Pt,
B - >=3 lymphadenopathy + normal Hb and Pt
C - anaemia or thrombocytopenia with any lymphadenopathy
mgmt
A + B + asymptomatic - watch and wait. Monitor with FBC, flow cytometry every 3 months
C - chemotherapy: rituximab + cyclophosphamide + fludarabide +- stem cell transplant
comps
- Hypogammaglobulinaemia - lymphocytes are dysfunctional and can’t produce antibodies. Pt deficient in IgG, IgA, IgM therefore increased infection risk (can give monthly IVIG)
- Autoimmune haemolytic anaemia - dysfunctional antibodies directed towards RBCs. Give prednisolone
- transformation to high grade lymphoma - richters transformation (become very unwell very suddenly)
diagnose
A 55-year-old male farmer presents with worsening shortness of breath, night sweats, fevers, bilateral axillary lymphadenopathy, and a 7.7 kg (12%) total body weight loss over 3 months. Recently, he has not been able to work because of fatigue. Physical examination reveals a 3.5 cm left axillary mass; enlarged cervical, axillary, and inguinal lymph nodes; splenomegaly; and no hepatomegaly.
non-hodgkin’s lymphoma
Non-hodgkin's lymphoma what is it most common epi/rf subtypes assoc pres ix ddx staging mgmt comps prog
what is it
basically all the ones that aren’t hodgkins
Lymphomas are solid, leukaemias are circulating
most common
Most common is diffuse large B-cell lymphoma (mainly from B cell lines) -May produce immunoglobulins. T cells can travel to extranodal sites e.g. skin and CNS
epi
5x more common than hodgkins
older, caucasians, hx of chemo/radio, fh, recent viral infection, AI, immunodeficient
subtypes
- Diffuse large B-cell lymphoma (30%) - aggressive/high grade
- Follicular lymphoma (20%) - indolent/low grade
- Burkitt’s (HG) (1%) - EBV - characteristic jaw lymphadenopathy (child)
- Primary CNS lymphoma (1%) - EBV with AIDS
- MALT (LG) (gastric mucosa associated lymphoid tissue) - H.pylori
- Marginal zone - massive splenomegaly
- T cell
assoc
AI disorders - sjogren’s, RA, SLE, coeliac
immunodeficiency
pres
nodal - painless lymphadenopathy, asymmetrical (can be rapid)
extranodal (MUCH more common than in hodgkins):
1. Bone marrow - pancytopenia (fatigue, dyspnoea), bone pain
2. Splenomegaly (massive in marginal zone) + hepatomegaly
3. Dry cough - mediastinal mass/pneumonia
4. Skin (T cell)
5. Gut: diarrhoea, vomiting, abdo pain (MALT)
6. Bone pain
7. CNS - nerve palsies
B symptoms ( less so than in hodgkins)
ix
FBC + blood film - Thrombocytopenia (liver or BM), or pancytopenia (BM)
Lymph node core biopsy/skin biopsy/bone marrow biopsy (for flow cytometry - tumour surface markers and cytogenetics) +ve
LDH: Elevated - proliferative rate of lymphoma
ESR
CT scan/MRI - For staging
Other - LP, LFT (mets), HIV test
ddx
- Hodgkin’s lymphoma (bimodal 20s and 60s, pruritus and alcohol pain) - Reed Steenberg cells
- ALL (acute onset, purpura, bleeding, infection) - blast cells
- Infectious mononucleosis - with pharyngitis and rash
staging ANN ARBOR 1 - Single lymph node group 2- Multiple on same side diaphragm 3 - Multiple on opposite side diaphragm 4 - Multiple extranodal sites or lymph nodes and extranodal disease E - extranodal extension B - weight loss > 10%, fever, drenching night sweats A - no B symptoms (B symps = worst prog
mgmt
for diffuse large b cell lymphoma or stage 3-4 follicular lymphoma
R-CHOP-21 (6-8 cycles)
+/- CNA proph - intrathecal methotrexate
+/- growth factor - G-CSF - filgastim
+/- antimicrobial proph - cipro + acic + fluconazole
prog
DLBCL - S1/2 - 80% cure rate, S3/4 - 40% cure rate
FL - incurable
comps
Bone marrow infiltration causing anaemia, neutropenia or thrombocytopenia
Superior vena cava obstruction
Metastasis
Spinal cord compression
Complications related to treatment e.g. Side effects of chemotherapy
philidelphia chromosome
It is due to a translocation between the long arm of chromosome 9 and 22 - t(9:22)(q34; q11). This results in part of the ABL proto-oncogene from chromosome 9 being fused with the BCR gene from chromosome 22. The resulting BCR-ABL gene codes for a fusion protein which has tyrosine kinase activity in excess of norma
hodgkins lymphoma what is it pres diagnostic epi most common type causes patho key RF staging ix mgmt
what is it
malignant proliferation of lymphocytes
arises from mature B cells
pres
cervical or supraclavicular lymphadenopathy (painless)
Risk factors
B symptoms (25%) - pel ebstein fever
Pruritus (10%)
Alcohol induced pain
Symptoms of mediastinal adenopathy - Dry cough, Dyspnoea, Chest pain, Superior vena cava syndrome (facial and upper limb oedema, dilated vessels)
diagnostic
Presence of Reed-Sternberg cells (large, multinucleated, mirror image nuclei, may contain EBV)
epi
bimodal @ 25 + 50
most common type
nodular sclerosing - 70%
others - mixed cellularity
lymphocyte rich/ depleted
causes
Primary immunodeficiency - ataxia-telangiectasia, Wiscott-Aldrich
Secondary immunodeficiency - HIV/transplants
Infection - EBV
Autoimmune disorders - SLE
patho
Impaired immunosurveillance of EBV infected cells. B cells escape regulation and proliferate
RF
EBV
Positive hamily history
Young adult from higher socioeconomic class
staging - ann arbor
ix FBC - low hb, pt, WCC high or low ESR - raised is poor prog excisional lymph node biopsy CXR - mediastinal mass PET-CT - staging PCR - EBV baseline liver/renal function
mgmt
Chemotherapy (ABVD) + Radiotherapy (mainly for the chest) (80% curative)
Doxorubicin
Bleomycin
Vincristine
Dacarbizine
Be aware of the side effects of chemotherapy and radiotherapy
multiple myeloma what is it pres diagnosis 3 main assocs epi classification ix criteria comps + rx when to transplant
what is it
Plasma dyscrasia: Clonal proliferation of plasma cells in the bone marrow associated with monoclonal element (Ig or Ig fragment) in serum or urine
It arises due to genetic mutations which occur as B-lymphocytes differentiate into mature plasma cells
pres
chronic relapse/remit
Bone pain (esp back pain!) - osteolytic lesions + fractures, vertebral collapse (high osteoclast activity)
Anaemia
Fatigue
recurrent bact Infections
Hypercalcaemia - bone break down babes
Renal impairment - due to light chain deposition and precipitation of light chains with Tamm-Horsfall protein in ascending loop of Henle
Bleeding -bone marrow crowding also results in thrombocytopenia which puts patients at increased risk of bleeding and bruising
diagnosis
serum and urine protein electrophoresis
3 main assocs
- Osteolytic bone disease + hypercalcaemia
- Anaemia - by accumulation plasma cells in BM
- Renal disease
epi
Most common haematological malignancy
Mean age is 60/70
classification
spectrum: m-protein is monoclonal component
1. MGUS - monoclonal gammopathy of unknown significance (may progress): M-protein < 30g/L, bone marrow clonal cells <10%
2. SMOULDERING myeloma - asymp: M-protein > 30g/L OR bone marrow clonal cells >10%, No related organ or tissue involvement (including bone lesions)
3. ACTIVE myeloma - symps -
A - M-protein > 30g/L OR bone marrow clonal cells >30% (10% = minor, 30% = major) 1 major + 1 minor
B - CRAB (tissue/organ involvement):
Calcium elevation (>2.75mmol/L)
Renal insufficiency (Cr > 173mmol/L)
Anaemia (Hb < 10g/dL or 2g/dL below normal)
Bone disease - lytic or osteopenic
ix
REMEMBER EVIDENCE OF END ORGAN DAMAGE
1. serum electrophoresis - GOLD (Paraprotein spike IgG > 30g/L, IgA > 20g/L, light chain urinary excretion >1g/day Bence Jones, hypogammaglobulinaemia)
2. skeletal survey, whole body MRI - Osteopenia, osteolytic lesions (e.g. pepper pot/raindrop skull), pathological fractures
3. BM aspirate + trephine biopsy - Plasma cell infiltrate >10% (minor) or >30% major
4. blood film - rouleaux formation
5. serum ca -> raised
6. FBC - anaemia
7. creatinine/urea - raised
8. ESR - raised with increased viscosity
mgmt
must begin immediately
TREAT COMPS
Bone disease: Hypercalcaemia + pain - bisphosphonates + analgesics
Anaemia - blood transfusion/EPO
Spinal cord compression - dexamethasone
Hyperviscosity (reduced cognition/blurred vision) - plasmapheresis
AKI - rehydration/ preserve good hydration
Infection - antibiotics + pneumonia/flu vaccine, IVIG
VTE proph
MGUS - Monitor closely with urine/serum electrophoresis 6 monthly
considering transplant (younger/healthier): (bortezomib) based induction + dexamethasone + DVT prophylaxis (aspirin 75mg OD) + autologous/allogeneic stem cell transplant
no transplant:
Thalidomide + an Alkylating agent + Dexamethasone
completion of treatment - monitor every 3 months- bloods, electropheresis
relapse - bortezombin monotherapy
explain assoc of osteolytic bone disease and multiple myeloma
Rapid growth of myeloma cells (in BM) inhibits formation of osteoprogenitor cells and osteoblasts
Production of macrophage inflammatory protein 1 alpha (MIP1a) stimulates osteoclastogenesis and Dkk-1 inhbits osteoblasts
Imbalance leads to hypercalceamia and hypercalciuria
50 with back pain
serum electrophoresis and ESR
major and minor criteria in MM
Criteria: req 1 major and 1 minor
Major
Plasmacytoma on BM biopsy
BM plasmacytosis > 30%
Monoclonal spike as 1a.
Minor
Plasmacytosis 10-30%
Smaller monoclonal spike
Lytic lesions
diagnose
A 55-year-old man has had routine physical examinations for several years and has always been healthy, does not smoke, and has no history of pulmonary disease. His primary care physician has noted a gradually increasing haemoglobin level over the past few years (to a current level of 195 g/L [19.5 g/dL]), mild leukocytosis, and mild thrombocytosis. He has frequent episodes of facial flushing that are associated with slight headaches and a feeling of fullness in his head and neck. He has noted intermittent burning, stinging, and tingling sensations in his fingertips. He has recurrent, often severe, pruritus that is exacerbated by taking a hot bath. On examination, he has a red face and neck and the spleen is mildly enlarged.
polycythaemia vera
polycythaemia vera what is it/patho causes pres ix diagnosis mgmt comp
what is it
Polycythaemia is increased proportion of haemoglobin in the blood either by:
Relative - decreased plasma volume:
1. Acute - dehydration, alcohol, diuretics
2. Chronic - smoking, obesity
Absolute - increased red cell numbers:
1. Primary - polycythaemia rubra vera
2. Secondary - high altitude, chronic lung disease (hypoxia), or increased EPO due to renal carcinoma
Polycythaemia rubra vera = is a myeloproliferative (overactive BM) disorder of predominantly red cells (but also WBC and Pt)
DEFINITION: Clonal hematopoietic disorder with erythrocytosis, thrombocytosis, leukocytosis and splenomegaly
aetiology
95% JAK2 V617F somatic mutation n.b. Ph chromosome -ve (differentiates from CML)
symps
hyperviscosity = Headache, tinnitus, dizziness, visual disturbance, plethoric appearance (red and full)
thrombosis/bleeding = Stroke, MI, PE, thrombophlebitis, DVT, haemorrhage
bath = Pruritus after hot bath, erythromelalgia (pain) + redness of fingers, palms, heels toes
ix
FBC/film - Raised haemoglobin, raised haematocrit, raised WBC, raised Pt
LFT for Budd-Chiari syndrome (raised)
JAK2 gene mutation screen (e.g. PCR)
serum ferritin
U+E
low ESR
BM biopsy- Hypercellular with trilineage growth
Chromium studies - Elevated RBC mass
EPO- Low with high Hb -> PV
MCV - Low MCV with normal Hb -> PV with IDA
diagnosis
>0.52 men >0.48 women haematocrit OR raised red cell mass >25% above predicted
mutation in JAK2
mgmt
aim - to keep low haematocrit + reduce risk of thrombosis
1. Phlebotomy/venesection (for low risk, ie. <60 and no thrombosis)
2. Cytoreduction (for high risk) - hydroxycarbamide
3. Low dose aspirin (75mg)
4. Management of CV risk factors (DM, hyperlipidaemia, HTN, smoking)
comp
10-15% transform to AML
PV vs CML
PV has no philadelphia chromosome
Neutrophil alkaline phosphatase is raised in PV but decreased in CML
myelodysplastic syndrome what is it characteristics patho causes epi pres ddx diagnosis mgmt comps
what is it
group of malignant haematopoietic disorders
characteristics
- dysplastic changes in one or more cell lineages
- ineffective hematopoiesis
- predilection to develop AML
patho bone marrow becomes hyper/hypocellular peripheral blood cytopenias affects different cell lines: - myeloid WBC - erythroid RBC - megakaryocyte platelet
aetiology
primary - 90%
secondayr - worst prog - due to radio/cancer
epi
>70
male
smoker
pres
- anaemia -> Unexplained macrocytic anaemia: fatigue, exertional dyspnoea, worsening of angina, CCF
- neutropenia -> If granulocyte depletion - recurrent infections/sepsis
- thrombocytopenia -> Decreased platelets: BLEEDING, petechia, bruising, nosebleeds, bleeding gums, ecchymosis (discolouration from bleeding)
ddx macrocytic anaemia -> B12/folate def neutropenia -> viral infection, drugs thrombocytopenia -> ITP, drugs all of above -> CML, BM failure, aplastic anaemia
diagnosis
of EXCLUSION + dysplastic cell morphology
-> FBC + blood film:
Anaemia (normo/macrocytic)
Neutropenia, thrombocytopenia, neutrophilia, thrombocytosis
Dimorphic red cells, Pappenheimer bodies, anisocytosis, poikilocytosis
-> ferritin + B12 - normal
-> renal func, LFT, CXR, ECG - co-morbs
BM asp/biopsy + cytogenetics - hypercellular with blasts
mgmt
Supportive blood and platelet transfusions + monitoring iron status (ferritin)
EPO + granulocyte colony-stimulating factor (G-CSF)
If sepsis - broad spectrum ABX
If recurrent infections - G-CSF
High-intensity chemotherapy
comps
anaemia, thrombocytpenia, neutro
transfusion related iron overload -Chronic fatigue, Joint pain, Abdominal pain, Liver disease (cirrhosis), Irregular heart rhythm/heart failure, Bronze/ashen grey skin –> desferrioxamine
transform to AML
bone marrow failure - leading cause of death
median survival - 2 yrs
fanconi anaemia
what is it
pres
what is it
Mainly AR inherited bone marrow failure syndrome
Cells derived are sensitive to DNA cross-linking
pres
- Congenital dysmorphic features;
- Triangular faces
- Cafe au lait + hyperpigmented skin
- Cardiac and renal malformations
- Abnormal thumbs
- Short - Pancytopenic bone marrow failure
- Susceptibility to cancer (AML, solid tumours - head and neck squamous cell carcinoma, gynaecological cancers <50)
thrombocytopenia causes
decreased production:
- BM infiltration - leukaemia, lymphoma, myeloma, myleofibrosis
- liver disease - reduction of TPO
- decreased BM production - low B12/folate, aplastic anaemia, infection
- dysfunctional prod - myelodysplasia
increased destruction
- autoimmune - ITP
- hypersplenism
- drug related - heparin
- consumption of platelets - DIC, TTP, HUS, haemorrhage
Idiopathic thrombocytopenic purpura what is it typically occurs in symptoms important ddx ix mgmt
what is it isolated thrombocytopenia (<100) thought to be due to autoimmune phenomenon and antiplatelet autoantibodies leading to rapid clearance in spleen
typically occurs in:
children with a preceding viral illness or middle aged women
pres
bleeding - petechiae on skin or mucosal membrane, haemorrhagic bullae in oral cavity/tongue, gum/mucocutaneous bleeding, menorrhagia
ddx
must ddx from delayed visceral bleed of coag disorders
1. Pseudothrombocytopenia
2. Thrombocytopenia due to liver disease or alcohol - raised GGT, alk phos
3. TTP - may have neurological changes or fever + anaemia
4. DIC - prolonged PT and aPTT
5. Drug induced
6. Splenomegaly
ix
FBC - pt count <100
peripheral smear - rules out pseudothrombocytopenia due to clumping/poor counting
bone marrow biopsy - increased megakaryocytes, no evidence of malignancy
causes of secondary ITP - HIV serology, H.pylori, hep B/C serology, SLE, drug induced (eg quinine)
mgmt
severe active bleeding - immunosuppression:
IVIG + pred + pt transfusion (works in 1-5 days for 4 weeks)
chronic? give rituximab (anti-b cell ie antibody) + splenectomy
if <2 consider wiskott-aldrich
IN CHILDREN - usually self-limiting -2 weeks
thrombotic thrombocytopenic purpura what is it pres patho RFs CAUSES ix mgmt
what is it
MEDICAL EMERGENCY - 95% fatality
clinical syndrome with microangiopathic haemolytic anaemia and thrombocytic purpura
pres PENTAD: 1. fever 2. renal failure - raised urea + creat 3. haemolytic anaemia - pallor jaundice 4. thrombocytopenia -> purpura, ecchymosis, menorrhagia 5. neurological change - coma, focal neurology, seizure, headache, confusion \+ GI - N+V/d
patho
- Absence of VWF cleaving protein (ADAMTS-13)
- Leads to large VW multimers
- Spontaneous platelet aggregation in microvasculature (brain, kidney, heart)
- Red cells passing clots subjected to shear force and rupture -> haemolytic anaemia
RF black fat female preg
causes post infection pref drugs - ciclosporin, oral contraceptive pill, penicillin, clopidogrel, aciclovir SLE HIV
ix FBC - decreased pt, hb <80 reticulocyte count - high LDH + bilirubin - raised peripheral blood smear - microangiopathic blood film with schistocytes - RBC fragments U+E - raised urinalysis - proteinuria
mgmt
urgent plasma exchange + pred (immunosup) + antiplatelet agent (aspirin)
long-term aspirin to decrease platelet aggregation
DO NOT GIVE PLATELETS
rituximab - easy method for targeting antibody production
DIC suspect if pres how? whats decreased? whats increased? mgmt
suspect if
CRITICALLY ILL
1. Severe sepsis or obstetric or malignancy
2. Shock
3. Extensive tissue damage - trauma and burns
pres
shock - oliguria, hypotensive, tachy
bleeding - brusing, purpura, haemorrhage, petechiae, oozing, haematuria
GEN BLEEDING from 3 unrelated sites = DIC
how
coag pathways activated
diffuse fibrin deposition at microvascular circ
consumption of coag factors and platelets
dereased:
- platelet count
- fibrinogen
- factor v/8
increased: PT (extrinsic pathway) aPTT (intrinsic pathway - activated partial thromboplastin time) D-dimer fibrin degradation products
mgmt treat cause eg sepsis to intensive care supportive care -stop bleeding: - FFP - replace coagulation factors - cryoprecipitates - second line but dont require ABO match - platelet transfusion <20
haemophilia
pres in who
inheritance
bleeding pattern
toddlers
x-linked recessive so only little boys
bleed into muscles and joints
VWD
pres in who
inheritance
bleeding pattern
teenagers
AD on chromosome 12
bleed into mucus membranes and skin
haemophilia inheritance types factor 8 mgmt
inheritance
x-linked recessive - skip a gen
types
A = F8 deficient
B = F9 deficient (christmas disease)
F8
< 1% = severe - spontaneous bleeding to muscles/joints crippling arthritis
1-5% = mod - bleed post minor trauma
>5% = minor - bleed post surgery
mgmt
Treat with recombinant F8 or F9 concentrate (IV at bleed)
+ avoid IM injections, aspirin and NSAIDS
if mild haemophilia A - give desmopressin IV DDAVP -> stimulates endogenous release F8 + VWF
VWD
what is it
ckinically
mgmt
AD chromosome 12 - defective production of VWF = defective platelet plug formation and F8 deficiency
Clinically: bruising, prolonged bleeding, mucosal bleeds, epistaxis, menorrhagia
Management is severity dependent
Type 1 = DDAVP
Severe give additional recombinant F8
osler-weber-rendu syndrome aka characteristics inheritance diagnosis requirements pres mgmt
aka
HHT - hereditary haemorrhagic telangiectasia
characteristics
vascular dysplasia -> telangiectasia
inheritance
AD
diagnosis 3 of: - epistaxis (recurrent) - telangiectasia - visceral lesions - family hist
pres
sharply demarcated mucocutaneous lesions
mgmt
treat severe haemorrhage with blood transfusions
what is vit k needed for
what is it
when deficient
mgmt
synthesis of 1972
fat soluable vitamin
deficient in malabsorption especially obstructive jaundice
mgmt - IV vit K
coag cascade - v basic
Series of proteolytic enzymes that circulate in inactive state which are sequentially activated
Generate thrombin that cleaves fibrinogen creating fibrin = clot
platelet physiology
Endothelium damaged
Platelets adhere via collagen and VWF and GP1b
Binding of collagen stimulates cytoskeleton shape change
Activation causes degranulation
Alpha - PDGF, TGF-beta
Delta - ADP + ATP (amplification) + Ca2+
Aggregation: cross linking of platelets by fibrin
Activated platelet allows binding of coag factors
what do aspirin + clopidogrel work on
platelet function
what do hep and warfarin work on
coagulation cascade
antiplatelets + how they work
aspirin
Irreversibly inhibits COX1 and prevents production of thromboxane A2. TXA2 induces platelet aggregation and vasoconstriction (75-300mg od) for arterial thrombosis
clopidogrel
Irreversible P2Y12 antagonist. P2Y12 is activated by ADP and amplifies platelet activation by activating glycoprotein Gp2b3a. Inhibits ADP induced platelet aggregation.
anticoagulant: heparin what is it how does it owrk comp lmwh
works on intrinsic pathway - aPTT- measures all factors except F13 (fibrin) + F7 (tissue factor)
Heparin is a glycoaminoglycan
Binds to antithrombin and increases activity, inactivates thrombin and FXa
comp - heparin induced thrombocytopenia
LMWH - dalt is smaller and therefore renally excreted, mech inactivates FXa
anticoag warfarin:
pathway
how it works
INR range
extrinsic pathway WEPT 1972 uses PT - measures F7 + 1,2,5,10
Prevents synthesis of FII, VII, IX, X
It is a vitamin K antagonist with a long half life
It prolongs the PT
It is monitored with INR (international normalised ratio derived from prothrombin time)
Aim 2-3
DOACs examples work on indications problem
FXa inhibitors - apixaban, rivaroxiban
Thrombin inhibitors (FIIa) - dabigatran
Indicated for DVT/PE and AF
require no monitoring
The problem is they are NOT easily reversible
thrombosis
what is it
arterial
venous
Thrombosis is blood coagulation within a vessel
May occur in arterial circulation - high pressure, platelet rich (atherosclerosis + RF)
Venous circulation: low pressure, fibrin rich (DVT + PE)
hypercoagulable states
Antiphospholipid syndrome Cancer Slow flow - sickle cell, PRV Nephrotic syndrome Obesity Pregnancy
Blood transfusion complications
- INFECTION
HBV
HCV
HIV - ACUTE - non infectious
Acute haemolytic reaction - ABO incompat
Febrile, non-haemolytic reaction - hypersensitivity to allergens in plasma (IgE)
Allergic/anaphylactic reaction - Result of granulocyte activation in pulmonary vasculature - increased permeability
Transfusion-associated circulatory overload
Transfusion-related acute lung injury (TRALI)
DELAYED non infectious
Iron overload
Delayed haemolytic reaction - Non-preventable - non-ABO aB/antigen incompatability
Transfusion-associated graft vs host disease - In immunodeficient patients, transfused white cells react recipient antigens
Post-transfusion purpura - Immune thrombocytopenia occurring post transplant
of Pt containing component. Recipient prior sensitised to foreign platelet antigen. (preg)
which blood transfusion comp would pres like this
Fever, chest/abdo/flank pain, pain @ infusion site
acute haemo
discontinue blood + fluid resus
which blood transfusion comp would pres like this
Flushing + dyspnoea + pruritus + urticaria (mins), hypotension (anaphylaxis)
alllergic transfusion
discontinue blood + adrenaline + secure airway (intubate) + salbutamol ± antihistamine
which blood transfusion comp would pres like this
fever
febrile non haemolytic
stop blood + para
which blood transfusion comp would pres like this
Fever, dyspnoea (hours) + rales
TRALI
O2 +/- ventilation
IV furose
which blood transfusion comp would pres like this
Fever + jaundice
Delayed haemolytic transfusion reactions
supportive
Transfusion-associated Graft Vs Host Disease pres
fever
supportive
post transfusion purpura mgmt
IVIG
pres of splenomeg
LUQ mass, moves with respiration, enlarges towards RIF, cannot feel above, dull to percuss.
causes of hypersplenism
CHINA - MMM
Congestion - p HTN, portal vein thrombosis, budd-chiari, HF
Haematological - anamia, thalassaemia, sickle cell, leukaemia
Infection - malaria, EBV, CMV, HIV, TB, glandular fever
Neoplasm - CML, myelofibrosis, lymphoma
Autoimmune/connective tissue - RA, sarcoidosis, amyloidosis, SLE,
Chronic Myeloid Leukaemia
Myelofibrosis
Malaria
splenectomy types indications comps mgmt
types 1. Planned 2. Traumatic 3. Autosplenectomy/hyposplenism (physiological loss of function) e.g. sickle cell (splenic infarct) or coeliac -> this leads to an increased risk of infection from encapsulated bacteria (Will see Howell-Jolly bodies (basophilic) in RBC - healthy spleen would normally filter these out Might see Pappenheimer bodies (iron) )
indications
- Spontaneous rupture at massive splenomegaly (infectious mononucleosis) precipitated by trauma
- Hypersplenism: ITP, hereditary spherocytosis
- Neoplasia: lymphoma or leukaemic infiltration
- Splenic cyst or abscess
comps
Thrombocytosis - platelet count peaks at 7-10 days (? prophylactic aspirin)
*Overwhelming infection:
Encapsulated bacteria - s.pneumoniae, h. Influenza, n.meningitidis
4% if no prophylaxis
Mortality of 50% for first 2 years
mgmt
Prophylactic ABX + vaccines
Oral phenoxymethylpenicillin + or macrolides (azithromycin/clarithromycin)
Pneumococcal vaccine and influenza vaccine
Carry health alert card
Haemopoietic stem cell transplant
how
Before transplant give chemo/radiotherapy
Ablative or reduced intensity
Harvest
BM removed from pelvis under GA
Peripheral blood stem cells: from blood via apheresis
Give BM IV as inpatient
Engraftment
autologous BM transplant
Stem cells harvested from own BM
Pt undergoes ablative or reduced treatment
(+) rapid immunity, less chance infx, reduced risk rejection
(-) not suitable for AML (high relapse)
allogeneic BM transplant
Healthy donor and patient
Must match HLA to patient HLA at 3 Loci
Donor normally sibling or relative or identified match
BM transplant comps
Infection - decreased leukocytes and immunosuppression post procedure
Veno-occlusive disease - chemotherapy damages hepatic venous epithelium
Mucositis - mouth and throat
GvHD - @allogeneic, graft recognises host as non-self and begins immune response against recipients tissues. Typically @<3 months. Skin, intestine and liver commonly affected (maculopapular rash, nausea/vom, cholestatic jaundice)
Gv tumour effect - beneficial. Response of donor T lymphocytes against diseased lymphocytes of recipient lead to reduced likelihood of cancer return
when would JAK-2 be positive?
in myeloproliferative disorders
what is the difference between PT and APTT
PT on extrinsic factors
APTT on intrinsic factors
1972 WEPT - warfarin acts on extrinsic pathway and is measured by PT.
explain when you would expect the diffeent immunoglobulins to be raised
Immunoglobulin A (IgA), which is found in high concentrations in the mucous membranes, particularly those lining the respiratory passages and gastrointestinal tract, as well as in saliva and tears.
Immunoglobulin G (IgG), the most abundant type of antibody, is found in all body fluids and protects against bacterial and viral infections.
Immunoglobulin M (IgM), which is found mainly in the blood and lymph fluid, is the first antibody to be made by the body to fight a new infection.
Immunoglobulin E (IgE), which is associated mainly with allergic reactions (when the immune system overreacts to environmental antigens such as pollen or pet dander). It is found in the lungs, skin, and mucous membranes.
Immunoglobulin D (IgD), which exists in small amounts in the blood, is the least understood antibody.
