Haematology and immunology Flashcards
ALL - high yield information?
- Most common cancer of childhood
- Bone pain, CNS involvement and orchidectomy are common + lymphadenopathy
- B-cell ALL: CD19+
- T-cell ALL: CD3+
CLL - high yield information?
- Smear cells on microscopy
- Lymphaedenopathy - often found incidentally
AML - High yield information?
- More common in adults: poor prognosis
- Gum hypertrophy
- MPO +ve
- Auer rods on microscopy
- May be a result of progression from myelodysplastic syndrome
CML - high yield information?
- Poor prognosis
- Numerous myeloid cells on microscopy
- Massive splenomegaly
- > 80% have philadelphia chromosome (t(9;22) - associated with better prognosis
Hodgkins leukaemia high yield information?
- proliferation of Reed-Sternberh cells (owl-eye nuclei)
- Young adults and older adults
- neck mass, pain on alcohol consumption
Non-Hodgkins leukaemia high yield information?
All other lymphomas without Reed-sternberg
cells.
* Monomorphic sheets of lymphoma cells on a
slice.
* More likely to experience B-symptoms
* Better prognosis than Hodgkin’s
* Split into high grade and low grade
Auer rods -AML
Smudge cells (CLL)
Popcorn cells - NHSL
Classical reed-stern berg cell - HL
‘Starry sky’ - Burkett’s lymphoma
Approach to a blood film?
1) What is the size
2) What is the shape
3) What is the colour
4) Are there any inclusions
Sickle cell anaemia
- Sickle cells
- Aniscytosis
- Polikilocytosis
Iron deficiency anaemia
- Anisopoikilocytosis
- Poikilocytes (pencil cells)
- Target cells
Thalassaemia
- Mild hypochromic, microcytic anaemia
- Target cells
Hyposplenism
Asplenism/hyposplenism leads to different INCLUSIONS.
1) Howell jolly bodies
2) Siderotic granules (also seen in disorders of iron utilization
like sideroblastic anaemias).
3) Heinz bodies
Liver Disease
* Macrocytic cells
* Target cells
* Somatocytes (coffee-bean)
* Echinocytes (burr)
* Acanthocytes (spur)
Schistocytes (RBC fragment):
* DIC
* Microangiopathic haemolytic anaemia (HUS, TTP),
* Burns,
* Metallic Heart valve
Tear drop poikilocytes:
* Myelofibrosis (characteristic!)
* Extramedullary haematopoeisis
Things which cause EPO differences?
EPO may be low in CKD or polycythaemia vera
EPO high in EPO-secreting kidney malignancies
Reticulocytosis causes?
Acute bleeding
Reticulocytopenia causes
- AOCD
- CKD (eGFR <60) due to decreased renal synthesis of EPO
- Parvovirus B19 espeically in sickle cell anaemia
Microcytic anaemia causes?
- iron deficiency
- Anaemia of chronic disease
- Sideroblastic anaemia
Normocytic anemia causes?
Hyperproliferative:
- Acute blood loss
- haemolytic anaemia
Hypoproliferative
- Anaemia of chronic disease
- Bone marrow failure
- Renal failure
Macrocytic anaemia causes?
megaloblastic
- Vit B12 deficiency
- Folate deficiency
- Anti-folate drugs
Non megaloblastic
- Hypothyroidism
- Alcohol
- Myelodysplasia
When should patients with IDA be referred to gastroenterology clinic?
- All men and post-menopausal women (unless
overt non-GI bleeding) - All >50 or FH of colorectal carcinoma
When should premenopausal women be referred to gastroenterology clinic for IDA?
- Colonic symptoms, strong FH OR persistent
despite tx
When should IDA be referred to 2ww endoscopy?
Either:
- >60
- <50 + rectal bleeding
Which investigations should be carried out for serious anaemia?
Should mention in your answers:
* Coeliac serology screen +/- OGD with a biopsy of the second part
of the duodenum
* Colonoscopy – especially if male and >60y/o
Consider:
* CT – renal, small bowel and pancreas
Summarise ALL the coeliac serology
- Total IgA +IgA anti-TTG + IgA anti-EMA
- AND IgA anti-DGP
- AND IgG anti-DGP
IgG is used to further screen for celiac disease in individuals with
IgA deficiency
Causes of B12 deficiency
Malabsorption:
1) GASTRIC
* Autoimmune (pernicious anaemia – atrophic gastritis)
* Gastrectomy/Bariatric surgery
* Chronic inflammation of gastric mucosa
2) INTESTINAL CAUSES
* Ileal resection or severe Crohn’s disease with terminal ileitis
* Fish tapeworm
* Metformin
Causes of folate deficiency
- DIETARY !!
- MALABSORPTION (coeliac disease)
- DRUGS
* Anticonvulsants: phenytoin, valproate, carbamazepine
* Methotrexate, trimethoprim (do not co-prescribe) and sulphasalazine - MIXED: liver disease, alcoholism
- Excess utilisation
* Physiological – pregnancy, lactation, prematurity
* Pathological - haematological eg haemolytic anaemias, malignancy,
inflammatory disease, psoriasis, rheumatoid
Atrophic gastritis mucosa
histology:
* Loss of parietal cells
* Chronic inflammatory infiltrate
* Goblet cell metaplasia
* ECL hyperplasia
Classically, coeliac disease has
the triad of:
1. Intraepithelial
lymphocytosis (IEL>30/100
epithelial cells),
2. Lamina propria
inflammation
3. Villous atrophy
Sickle Cell Anaemia – Genetics
Genetics:
- AUTOSOMAL RECESSIVE mutation of the beta-
globin chain - Mutant haemoglobin S (HbS) sickles at low
PO2/acidic environments.
Sickle Cell Anaemia – Pathology
- Fetal haemoglobin (HbF) is usually replaced by haemoglobin A (HbA) at ~6 weeks of age, and is entirely replaced by 6months.
- Sickling makes RBCs more fragile, leading to a haemolytic anaemia, microvascular occlusion and other crises
Vaso-occlusive painful crisis
PRESENTATION: Symptoms are typically pain, fever and those of the triggering infection.
Areas affected: swollen painful joints, mesenteric ischaemia, CNS infarction, avascular necrosis (especially of femoral head), renal papillary necrosis (loin pain), dactylitis
Vaso-occlusive painful crisis - pathophysiology?
Due to microvascular occlusion, causes ischaemia and infarction especially in the bone marrow causing severe pain
Acute chest syndrome
Vaso-occlusive crisis in the lungs
Acute chest syndrome is a medical emergency with a high mortality.
Aplastic crisis - trigger
Usually due to parvovirus B19 infection, often in children
Aplastic crisis - pathophysiology
Sudden reduction in marrow production, especially RBCs
* Sudden fall in Hb, low reticulocytes. THIS IS HOW YOU DIFFERENTIATE WITH ACUTE SEQUESTRATION CRISIS
Splenic sequestration crisis - pathophysiology
sickling of RBCs in the spleen → pooling and sequestration of blood → acute fall in haemoglobin, severe anaemia and potential circulatory collapse (hypovolaemic shock)
Associated with an increased reticulocyte count
Splenic
sequestration
crisis - presentation?
organomegaly, severe anaemia and shock
Splenic
sequestration
crisis - presentation?
organomegaly, severe anaemia and shock
Kidney - Sickle cell crisis
Histology: Classically glomerular
capillary occlusion and extensive
peritubular capillary congestion by
sickled cells
‘Special requirements’ on form when requesting blood transfusion
Among others
* Severe congenital immunodeficiencies
* Certain types of chemotherapy (lymphoma)
* Hodgkin’s lymphoma
* Females of below and current reproductive age
Name the different blood
groups that are ‘grouped’
or ‘screened’
Different antigens:
* ABO
* Rh
* Kell
* Several others e.g. Duffy
Extrinsic
pathway - test?
PT time
Intrinsic
pathway - test?
aPTT time
PT time affected by?
- Warfarin
- Extrinsic
- Liver disease
- K vitamin deficiency (1972 - II, VII, IX, X)
aPTT time affected by?
- Antiphospholipid syndrome
- Haemophilia
- Von Willebrand disease
- Heparin
Warfarin - MOA?
Vitamin K antagonist, hence inhibits clotting factor II, VII, IX and X
Warfarin - Side-effects?
- haemorrhage
- teratogenic, although can be used in breastfeeding mothers
Warfarin - clinical use?
specific circumstances we use Warfarin over DOACs
* mechanical heart valves
* APLS secondary prophylaxis
* Generally, 2nd line after DOACs
* Severe renal failure where DOACs are not appropriate
Warfarin reversal?
Exact management depends on urgency of reversal, size of bleed and INR
- Tranexamic acid
- Vitamin K (oral or IV)
- Prothrombin complex concentrate (PCC) - Beriplex
Warfarin - bridge?
Warfarin preferentially decreases protein C and S first causing a transient increase in thrombosis risk so LMWH bridge is always given when starting Warfarin (usually for at least a few days until INR >2 for 2 consecutive readings)
Heparin - MOA?
Heparin binds to antithrombin and POTENTIATES its action of inhibiting factor 10a and thrombin
Heparin types?
- Low molecular weight: Frequent monitoring needed, can be rapidly reversed
- Unfractionated heparin: Okay in renal failure
Heparin - Contraindications?
known hypersensitivity, active bleeding (excluding menstruation), bleeding disorder, severe hepatic impairment
Heparin - complications?
- Osteopenia if long-term
- Heparin-induced thrombocytopenia
(HIT) - Heparin-induced skin necrosis
- Systemic anaphylactoid reaction
Direct Oral Anticoagulants (DOACs/NOACs) - advantages?
- Fixed once or twice daily dosing
- No routine monitoring required
- Predictable pharmacology
- Peak effect occurs in HOURS vs days in Warfarin
Direct Oral Anticoagulants (DOACs/NOACs) - caution?
NOT METALLIC HEART VALVES (warfarin), in pregnancy, in
severe renal failure or APLS.
DOAC reversal agents:
- Xa inhibitors = PCC
- Dabigatran = Idarucizumab
(Praxbind) - Rivaroxaban = Andexanet Alfa
Investigations you should do in NAI
Initial blood tests:
* FBC and blood film
* Clotting screen (PT, aPTT, fibrinogen and
thrombin time)
Further bloods:
* Discuss with haematology about the need for 2nd line investigations:
* VWF
* Factor assays (especially factor VIII),
* platelet aggregation and
Rarer causes of bleeding/clotting disorders:
* Vitamin C deficiency
* Connective tissue disorders e.g. Ehlers Danlos
* Copper deficiency
* Zinc deficiency
Imaging:
* Skeletal survey
* CT head scan
* Bone profile
* Rule out leukaemia, ITP etc.
* Fundoscopy (retinal haemorrhages)
Thrombin time (TT)- Measures?
measures the common pathway
measures fibrinogen to fibrin
Beware of heparin contamination
Reptilase time?
To get around the heparin contamination
If TT is prolonged, but Reptilase time is normal, there is heparin contamination
Causes of thrombocytopenia – Framework
1) Reduced production -> congenital or Aquired
2) Increased consumption -> Immune or Non-immune
CONGENITAL causes of thombocytopaenia?
- Bone marrow failure syndromes -Fanconi anaemia
- Rare inherited platelet disorders e.g. Wiscott Aldrich
ACQUIRED causes of thrombocytopenia
- Aplastic anaemia
- Infection: CMV, HIV,
parvovirus - Liver disease
- Bone marrow infiltration in
cancer
IMMUNE causes of thrombocytopenia?
- ITP (diagnosis of
exclusion) - Drug-induced
- Other autoimmune
disease e.g. SLE
NON-IMMUNE causes of thrombocytopenia
- DIC
- Thrombotic microangiopathies
e.g. TTP, HUS - Mechanical loss e.g. dialysis,
ECMO
Haemophilia - definition?
Inherited deficiency of a clotting
factors 8/9/11
* Usually INHERITED X-LINKED
* aPTT!!
Haemophillia 3 subtypes?
- Haemophilia A: factor 8 deficiency
- Haemophilia B: factor 9 deficiency
- Haemophilia C: RARE - factor 11 deficiency
Haemophillia presentation?
Symptoms usually begin in neonates or early childhood
* Typically very DEEP bleeding (unlike e.g. vWD
which presents with platelet-bleeding i.e. Epistaxis,
menorrhagia etc)
* Untreated haemoarthroses lead to joint contractures.
Haemophillia - management?
IV factor infusions +/- desmopressin
Emicizumab (Hemlibra)
Complications of donor clotting factors in the
management of haemophilia
Production of recipient antibody against factor VIII or IX - Results in treatment becoming ineffective
Blood born viruses - HIV and Hep C
Von Willebrand Disease - definition?
Defects in either the
amount, structure or function of vWF.
Inherited AUTOSOMALLY (both
recessive and dominant).
Von Willebrand Disease = Pathophysiology
vWF produced in endothelial cells and megakaryocytes.
* Role of von Willebrand factor
1. Cofactor for platelet adhesion to damaged endothelium (vWF in the multimeric form is required)
2. Carrier protein for factor 8 (vWF stabilises factor VIII).
THREE subtypes of von Willebrand disease:
o Type 1 (80%) - low levels of normal vWF - AUTOSOMAL
DOMINANT
o Type 2 - normal levels of vWF but abnormal function -
AUTOSOMAL DOMINANT
o Type 3 - there is NO von Willebrand factor and low/no
Factor VIII - AUTOSOMAL RECESSIVE, most severe form
Von Willebrand Disease - Diagnosis?
- Stress releases vWF into the blood stream → masking low levels
- Differences with blood group O (naturally lower levels)
Von Willebrand Disease - Management?
- Avoid anti-platelet drugs
- Antifibrinolytics e.g. tranexamic acid (TXA)
- Desmopressin (DDAVP)
Primary haemostasis - what is it?
Think of this as a problem with the initial
platelet plug forming (and therefore presenting
broadly like a platelet issue).
Secondary haemostasis = what is it?
Think of this as a problem with the secondary
coagulation cascade (and presenting like a
‘coagulation’ issue).
Primary haemostasis presentation?
PRESENTATION: superficial bruises/petechiae,
bleeding of mucosal membranes, epistaxis,
menorrhagia.
Secondary haemostasis presentation?
bruising in deeper tissues,
muscles, joints (haemarthroses).
Primary haemostasis - causes?
vWD, ITP, Glanzmans
Secondary haemostasis - causes?
Deficiency of factor VIII, IX, factor XIII
(Haemophilia)
Liver problems
Neutrophils - pathogens?
Bacteria: especially Staph. aureus
Fungi: invasive fungal species e.g. aspergillus, disseminated candida
Signs of Immunodeficiency?
“SPUR”
- Serious infections
- Persistent infections
- Unusal infections
- Recurrent infections
SCID - what is it?
a group of rare disorders
caused by mutations in genes involved in
the development and function of B and T
cells.
SCID - genetics?
Most SCID is an autosomal recessive
Some are X linked
SCID - treatment?
HSC transplant, ideally from a
sibling who is a close tissue match. Transplants
from matched siblings lead to the best
restoration of immune function,
BTK deficiency - also known as?
(X-linked
agammaglobulinemia)
BTK deficiency presentation?
BTK deficiency leads to an absolute deficiency of mature B cells (and hypogammaglobulinaemia).
Symptoms present as soon as the protective effect of maternal
immunoglobulins wanes at around six months of age.
BTK deficiency - PATHOPHYSIOLOGY?
- Bruton’s tyrosine kinase is expressed during the pre-B cell stage.
- Signalling through it is ESSENTIAL for B-cell survival and differentiation.
Flow cytometry in BTK deficiency?
If flow cytometry shows no mature B cells (CD19+), and there is a hypogammaglobulinaemia, think BTK.
Chronic granulomatous disease - definition?
Primary immunodeficiency caused by X-linked recessive mutation in NADPH oxidase gene.
Remember that this effectively leads to lack of neutrophils → this means that you are unable to clear bacterial infections, and form lots of chronic granulomas (hence the name)!
Chronic granulomatous disease - pathophysiology
- NADPH is required to produce the oxidative
burst in neutrophils that usually kills and lyses
ingested bacteria. - Deficiency results in an inability to form the
oxidative burst in neutrophils = inability to clear
infections
Chronic granulomatous
disease presentation?
NEUTROPHIL deficiency so especially
susceptible to Catalase positive organisms
(Staphylococci, Listeria, Corynebacterium diphtheriae).
Presents with abscesses, periodontal disease
INVARIABLY CAUSED BY STAPH AUREUS → fibrosis of
viscera.
Chronic granulomatous
disease - diagnosis?
Diagnosis can occur by either nitroblue tetrazolium test
negativity or dihydrorhodamine flow cytometry
