Haematology Flashcards
What is von Willebrand’s Disease?
Most (c) inherited bleeding disorder
AD inheritance
Low levels of vWF in the blood
vWF -> promotes platelet adhesion to damaged endothelium, carrier for F8
Investigation for von Willebrand’s Disease?
prolonged bleeding time
APTT may be prolonged
factor 8 levels may be moderately reduced
defective platelet aggregation with ristocetin (for an unknown reason this antibiotics causes vWF to bind to plts. This is reduced if less vWF in blood)
Management of von Willebrand’s Disease?
Tranexamic acid for mild bleeding
desmopressin (DDAVP): raises levels of vWF by inducing release of vWF from Weibel-Palade bodies in endothelial cells
factor VIII concentrate
What is antithrombin 3 deficiency?
an inherited cause of thrombophilia - AD
Antithrombin III inhibits several clotting factors, primarily thrombin, factor X and factor IX
Features of antithrombin 3 deficiency?
Recent venous thromboses
arterial thromboses do occur but are uncommon
Management of antithrombin 3 deficiency?
Warfarin
Heparinisation during pregnancy (monitor FXa)
Antithrombin III concentrates (often used during surgery or childbirth)
What is the inheritance pattern of haemophilia and what is the difference between A and B?
Haemophilia is a X-linked recessive disorder of coagulation. Up to 30% of patients have no FH. Haemophilia A = deficiency of factor 8 whilst in haemophilia B = lack of factor 9
Features of haemophilia?
- haemoarthroses, haematomas
* prolonged bleeding after surgery or trauma
Blood tests in haemophilia?
- prolonged APTT
* bleeding time, thrombin time, prothrombin time normal
When would you use irradiated blood products?
Irradiated blood products are used to avoid transfusion-associated graft versus host disease
Three main RF for transfusion-associated graft versus host disease (TA-GvHD)?
- Volume and age of transfused blood
- Immunodeficiency, especially that involving T-cells and cell-mediated immunity e.g. Hodgkin’s disease
- Similar HLA haplotype sharing
What is the presentation of transfusion-associated graft versus host disease (TA-GvHD) and what might you see on biopsy?
diarrhoea, liver damage, and rash
A biopsy of skin or BM can be diagnostic. A biopsy specimen of the skin will show abundant NECROTIC KERATINOCYTES. BM shows marked hypocellularity with macrophage infiltration
ta-GVHD is a rare and usually fatal complication of blood transfusion in which lymphocytes from the transfused blood component attack the recipient’s tissues, especially the skin, BM and GI tract
What is the MOA of Cyclophosphamide and are its adverse effects?
Alkylating agent - causes cross-linking in DNA
SEs: Haemorrhagic cystitis (incidence reduced by the use of hydration and mesna), myelosuppression, transitional cell carcinoma
What is the MOA of Methotrexate and are its adverse effects?
Inhibits dihydrofolate reductase and thymidylate synthesis
Myelosuppression, mucositis, liver fibrosis
NOT lung fibrosis
Doses of adrenaline in anaphylaxis?
< 6 months -> 100 - 150 micrograms (0.1 - 0.15 ml 1 in 1,000)
6 months - 6 years -> 150 micrograms (0.15 ml 1 in 1,000)
6-12 years -> 300 micrograms (0.3ml 1 in 1,000)
Adult and child > 12 years -> 500 micrograms (0.5ml 1 in 1,000)
What is refractory anaphylaxis?
Resp/CVS problems that persist despite two doses of adrenaline
What blood test can you take to see if a patient had a true anaphylactic reaction and how long after?
Serum tryptase up to 12hrs after attack
In what percentage of patients does a biphasic reaction occur following anaphylaxis?
20%
Which patients need 12 (instead of 6hrs) of post-anaphylaxis monitoring?
severe reaction requiring > 2 doses of IM adrenaline
patient has severe asthma
possibility of an ongoing reaction (e.g. slow-release medication)
patient presents late at night
patient in areas where access to emergency access care may be difficult
observation for at 12 hours following symptom resolution
What is the most common inherited thrombophilia?
Factor V Leiden (activated protein C resistance)
What is Factor 5 Leiden and what can it cause?
Due to a gain in function mutation
Factor 5 is part of the clotting cascade and contributes to clot formation
In this condition Factor 5 is broken down 10x more slowly than usual
‘Activated protein C’ is responsible for the breakdown in factor 5. Therefore it is the resistance to ‘activated protein C’ that causes the condition
Results in an increased risk of VTEs
What is a leukaemoid reaction?
A rise in WCCs (>50) that results from an insult/infection (and not a malignancy)
How do you differentiate between a leukomoid reaction and CML?
Leukaemoid reaction:
high leucocyte alkaline phosphatase score (substance found within mature WBCs)
toxic granulation (Dohle bodies) in the white cells
‘left shift’ of neutrophils i.e. three or fewer segments of the nucleus
CML: low leucocyte alkaline phosphatase score (WBCs are underdeveloped and not mature)
What is the most common age for patients to develop CML?
40-60yrs
What are the three phases of CML?
Chronic phase - >90% Dx, median 3yrs long, few symptoms
Accelerated phase - 2-15months, increasing arrest of cell maturation
Blastic phase -> 3-6months, leads to death (resembles an acute leukaemia)
Investigations for CML?
Raised granulocytes - neutr, eosino, basophils (at different stages of maturation +/- thrombocytosis)
Decreased leukocyte alkaline phosphatase (substances found within mature WBCs - as more are at immature stages then less alk phosphatase will be found)
Blood film
BM aspirate
Philadelphia chromosome - due to a translocation between the long arm of chromosome 9 and 22 - t(9:22)(q34; q11), BCR
Management of CML?
Targeted molectular therapy - tyrosine kinase inhibitors e.g. imatinib
SC transplant
What are the investigations for CLL?
Raised lymphocytes
Blood film (mature lymphocytes, SMUDGE cells)
Immunophenotyping
Management of CLL?
Do nothing!
FCR
SC transplant
Poor prognostic factors for CLL?
male sex age > 70 years lymphocyte count > 50 prolymphocytes comprising more than 10% of blood lymphocytes lymphocyte doubling time < 12 months raised LDH CD38 expression positive TP53 mutation
What is a good prognostic factor for CLL?
Deletion of the long arm of chromosome 13 (del 13q)
What is methaemoglobinaemia?
Describes haemoglobin which has been oxidised from Fe2+ to Fe3+, there is tissue hypoxia as Fe3+ cannot bind oxygen
Which way is the oxygen dis curve shifted in methaemoglobinaemia?
to the left
The subunits of hemoglobin that are not oxidized bind oxygen more tightly, and, therefore, release it less readily. These hemoglobin have a high affinity for oxygen and shift the oxygen dissociation curve to the left
Congenital and acquired causes of methaemoglobinaemia?
Congenital:
haemoglobin chain variants: HbM, HbH
NADH methaemoglobin reductase deficiency (which is normally involved in converting methaemoglobin to haemoglobin)
Acquired causes (met = meth so all drugs)
drugs: sulphonamides, nitrates (including recreational nitrates e.g. amyl nitrite ‘poppers’), dapsone, sodium nitroprusside, primaquine (all p’s)
chemicals: aniline dyes
What are features of methaemoglobinaemia?
‘chocolate’ cyanosis (colour of blood)
dyspnoea, anxiety, headache
severe: acidosis, arrhythmias, seizures, coma
normal pO2 but decreased oxygen saturation
Management of methaemoglobinaemia?
Congenital: NADH - methaemoglobinaemia reductase deficiency: ascorbic acid
Acquired: IV methylthioninium chloride (methylene blue)
What is ITP?
Body produces Abs to platelet antigens (© glycoprotein 2b/3a) -> platelet destruction
Also marrow failure -> means plt production is not appropriately increased
What are the two forms of ITP?
Acute –
• mainly in children, lasts <6 months, d/t immune complexes
• Follows a viral infection (© varicella)
• Equal genders
Chronic –
• mainly in adults, lasts >6 months, d/t specific IgG antiplatelet Abs
• Women > men
Features of ITP?
Mucosal/skin bleeding – epistaxis, oral bleeding, menorrhagia
Characteristic purpuric rash
Afebrile
Signs of raised ICP (d/t increased brain bleeds)
Investigations in ITP?
Low platelets Megathrombocytes (enlarged plts) Megakaryocytes – platelet precursors found in the bone marrow (normal/raised) PT, PTT, coagulation time = normal Platelet IgG
Management of ITP?
Acute –
Children: usually resolves spontaneously (w/in 2 months)
Adults: rarely resolves spontaneously
Chronic –
Plts <30 but no catastrophic bleeding:
Prednisolone
o Mandatory to perform a BM biopsy before commencing steroids (r/o leukaemia)
Catastrophic bleeding:
IV methylprednisolone
Platelet transfusion
IV Ig - raises plt level quicker than steroids so can be used in acute bleeding/pre-operative
Splenectomy prev required in 50%, now less common (plts that have been bound by autoAbs are taken up by macrophages in the spleen so removal keeps more plts in circulation)
30% of these relapse – may benefit from cyclophosphamide, azathioprine, vincristine etc
Platelet transfusion only required in emergencies to induce haemostasis
What is Evan’s syndrome?
ITP in association with autoimmune haemolytic anaemia (AIHA)
What percentage of factor 8 activity would give you a diagnosis of haemophilia?
Factor Activity in Hemophilia depending on severity
Mild: 5-30% of Normal Activity
Moderate: 1-5% of Normal Activity
Severe: <1% of Normal Activity
What can causes hereditary angioedema and what is the inheritance pattern?
What is the probable mechanism?
C1 esterase inhibitor deficiency
Autosomal dominant
Probably caused by uncontrolled release of bradykinin
What would you do to investigate in hereditary angioedema?
C1-INH level is low during an attack
low C2 and C4 levels are seen, even between attacks. Serum C4 is the most reliable and widely used screening tool
Symptoms of hereditary angioedema?
First sign may be a painful maculopapular rash
Followed by painless, non-pruritic swelling (of upper airways/skin/abdo organs occasionally)
Usually no urticaria
Management of hereditary angioedema?
IV C1-inhibitor concentrate, FFP if this is not available
Prophylaxis: anabolic steroid Danazol may help
Indications for treatment of CLL?
progressive marrow failure: the development/worsening of anaemia +/or thrombocytopenia
massive (>10 cm) or progressive lymphadenopathy
massive (>6 cm below left costal margin) or progressive splenomegaly
progressive lymphocytosis: > 50% increase over 2 months or lymphocyte doubling time < 6 months
systemic symptoms: WL > 10% in previous 6 months, fever >38ºC for > 2 weeks, extreme fatigue, night sweats
AI cytopaenias e.g. ITP
When would you use RAST testing?
Radioallergosorbent test (RAST)
Determines the amount of IgE that reacts specifically with suspected or known allergens through a blood test
Chosen > skin prick if v young infant, risk of severe reaction to skin prick, severe eczema/psoriasis, pts taking antihistamines
What is the inheritance pattern of G6PD deficiency?
X-linked recessive
What is the mechanism of action in G6PD deficiency?
↓ G6PD (metabolite of glucose) occurs because the genetic condition causes G6PD to form with a shorter half-life → ↓ reduced NADPH (which is responsible for reactivating glutathione) → without activated glutathione free radicals aren’t mopped up which can directly break down RBCs and haemoglobin
What are the features of G6PD deficiency?
neonatal jaundice, intravascular haemolysis, gallstones are common
splenomegaly may be present
What would you see on investigation in G6PD deficiency?
Heinz bodies on blood films. Bite and blister cells may also be seen
Heinz bodies are abnormal proteins on the wall of the cell membranes. These are recognised by macrophages which ‘bite’ a chunk out of the RBCs
G6PD enzyme assay -> levels checked 3m after acute episode
What can precipitate an attack in G6PD deficiency?
Broad (fava) beans
anti-malarials: primaquine
ciprofloxacin
sulph- group drugs: sulphonamides, sulphasalazine, sulfonylureas
Which ethnicities are more likely to suffer from G6PD deficiency?
African + Mediterranean
Which ethnicities are more likely to suffer from spherocytosis?
Northern Europeans
What occurs in spherocytosis and what is the inheritance pattern?
AD
Defect of RBC cytoskeleton -> the normal biconcave disc shape is replaced by a sphere-shaped RBC
RBC survival reduced as destroyed by the spleen
Results in extravascular haemolysis
Presentation of spherocytosis?
failure to thrive
jaundice, gallstones
splenomegaly
aplastic crisis precipitated by parvovirus infection
What might you see in the blood results in spherocytosis?
spherocytes
Raised mean corpuscular haemoglobin concentration [MCHC]
Increase in reticulocytes
What are the definitive investigations for spherocytosis?
If the diagnosis is ambiguous -> EMA binding test (EMA binds to proteins on RBCs, less so in SC as less RBCs) and the cryohaemolysis test (measure the rate of RBC breakdown at different temps - in SC, RBCs breakdown at lower temps)
for atypical presentations -> electrophoresis analysis of RBC membranes is the method of choice
If you have significant lab test, clinical features and FH, no more investigations are needed
What would be the result of a direct coombs test in spherocytosis?
Direct coombs test = negative
Management of spherocytosis?
acute haemolytic crisis:
treatment is generally supportive
transfusion if necessary
longer term treatment:
folate replacement
splenectomy
What medication do you use to treat CLL?
Fludarabine, Cyclophosphamide and Rituximab (FCR)
What is protein C deficiency and what is the inheritance pattern? Defining symptom?
Autosomal codominant
Causes an increase in VTEs
Skin necrosis occurs on starting warfarin -> warfarin causes a reduction in biosynthesis of protein C, results in a temporary procoagulant state. Thrombosis occurs in venules which leads to skin necrosis
Concurrent use of heparin usually stops this
Skin necrosis can also occur with protein S def (however this is a less common condition)
What is haptoglobin and what is its significance in sickle cell disease?
Haptoglobin is made in the liver and binds to free haemoglobin in the blood in order to assist its clearance
If there is RBC breakdown, there will be more haemoglobin to bind to, and therefore the levels of haptoglobin go down in SCA
What is responsible for increased/decreased MCHC?
Increased
hereditary spherocytosis
autoimmune haemolytic anemia
Decreased microcytic anaemia (e.g. iron deficiency)
What is Chediak Higashi Syndrome?
AR inheritance
Results in a decrease in phagocytosis
Affected children have ‘partial albinism’ and peripheral neuropathy. Recurrent bacterial infections are seen
What is Wiskott Aldrich Syndrome?
Primary immunodeficiency due to a combined B- and T-cell dysfunction
Condition caused by reduced number and size of platelets -> these defective platelets are cleaned up, leading to thrombocytopenia
Results in increased bleeding (thrombocytopaenia), infection risk and cancer risk (lymphomas)
Also get eczema
Mnemonic WATER - WAsp gene, Thrombocytopaenia, Eczema, Recurrent infection
X-linked, defect in WAS gene
Tx = stem cell transplant
What do you see on microscopy in Chediak Higashi Syndrome?
Giant granules in neutrophils and platelets
What are the common features of DiGeorge syndrome?
Common features include congenital heart disease (e.g. tetralogy of Fallot), learning difficulties, hypocalcaemia, recurrent viral/fungal diseases, cleft palate
What is common variable immunodeficiency?
Due to defect in B cell maturations
Hypogammaglobulinemia is seen. May predispose to autoimmune disorders (e.g. IBD) and lymphoma
What is a follicular lymphoma?
Slow-growing B-cell lymphoma that accounts for 20-30% of all non-Hodgkin’s lymphomas
What is TTP?
Thrombotic Thrombocytopaenic Purpura
Abnormally large + sticky multimers of vWF cause platelets to clump together that obstruct organs and result in fluctuating ischaemia
In TTP there is a deficiency of ADAMS 13 which breakdowns large multimers of von Willebrand’s factor (see image in notes)
How to manage TTP?
TTP is life threatening – must be treated as an emergency, untreated mortality of 90%
Give plasma exchange using FFP
IV methylpred - after PEX completed
How do you treat heparin-induced thrombocytopenia (HIT)?
Intravenous argatroban
What are the symptoms of TTP?
Pentad: FART N Fever Anaemia Renal impairment (haematuria, uraemia) Thrombocytopaenia Neurological (headache, confusion)
Which enzyme is responsible for TTP?
Deficiency of ADAMTS13 (cleaves vWF) – means too much vWF
What is the most common infection transmitted through platelet transfusion?
Bacterial - product stored at room temperature
What is Waldenstrom’s macroglobulinaemia?
Type of non-Hodgkin’s
Lymphoma - abnormally large numbers of B cells which differentiate into IgM
++ IgM makes the blood thick (hyperviscous)
What are the symptoms of Waldenstrom’s macroglobulinaemia?
The thickened blood causes changes in the flow through the vessels. Can cause small vessels to break resulting in bleeding gums/retina (visual disturbances) Also: systemic upset: weight loss, lethargy hepatosplenomegaly lymphadenopathy cryoglobulinaemia e.g. Raynaud's
What is the investigation of choice in Waldenstrom’s macroglobulinaemia?
Electrophoresis - look for a monoclonal IgM paraproteinaemia
What can cause a thrombocytosis?
Can act as an acute phase reactant
Malignancy
Essential thrombocytosis
Hyposplenism
What are the feature of essential thrombocytosis?
Plts >600
Venous/arterial thrombosis
Haemorrahge
Characteristic burning of the hands
How to treat essential thrombocytosis?
Hydroxyurea – reduces the platelet count
Interferon-alpha – used in younger patients, inhibits growth of megakaryotypes
Low-dose aspirin – can be used to reduce thrombotic risk
Difference between thrombocytosis, thrombophilia and thrombocytopaenia?
thrombocytosis - too many plts
thrombophilia - tendency to clot
thrombocytopaenia - too few plts
What are the different types of sickle-cell crisis?
- thrombotic, ‘painful crises’ - infarcts occur in organs incl bone
- sequestration - sickling within organs pooling of blood and worsening anaemia, assoc with increased reticulocytes
- acute chest syndrome - sickling of RBC in lungs causing pulmonary infarcts
- aplastic - body not making enough RBC to replace old ones, caused by parvovirus, BM suppression causes a reduced reticulocyte count
- haemolytic - fall in Hb due to increased rate of haemolysis
What is Deferoxamine and when is it used?
In sickle-cell patients who are regularly transfused -> it is an iron chelation therapy used to enhance iron excretion and removes excessive tissue iron
What are the features of cyanide poisoning?
‘classical’ features: brick-red skin, smell of bitter almonds
acute: hypoxia, hypotension, headache, confusion
chronic: ataxia, peripheral neuropathy, dermatitis
Treatment of cyanide poisoning?
100% O2
IV hydroxocobalamin
What happens to the oxygen dis curve in carbon monoxide poisoning?
The oxygen saturation of haemoglobin decreases leading to an early plateau in the oxygen dissociation curve (CO binding is irreversible)
Also shifts to the left as CO has a higher affinity for haemoglobin than O2
Features/symptoms of CO toxicity?
headache: 90% of cases nausea and vomiting vertigo confusion subjective weakness severe toxicity: 'pink' skin and mucosae, hyperpyrexia, arrhythmias, extrapyramidal features, coma, death
