Haematology Flashcards
1
Q
Commonest 3 causes of malabsorption leading to iron deficiency anaemia in GI?
A
- Coeliac disease
- Gastrectomy
- H Pylori
2
Q
Commonest 4 causes of occult blood loss leading to iron deficiency in GI?
A
- NSAIDs/Aspirin use
- Cancer- colon or gastric
- Benign gastric ulcer
- Angiodysplasia
3
Q
When would you refer patients with a changed bowel habit for urgent colonoscopy?
A
40 years + and loose bowels + rectal bleeding for 6 weeks
60 years + rectal bleeding for 6 weeks
60 years + looser bowels for 6 weeks
4
Q
Cause of megaloblastic macrocytic anaemia
A
Low B12
Low folate
Megaloblast= large immature nucleated RBC progenitor seen on blood films
5
Q
Haemolysis causes what kind of anaemia?
A
Normocytic- normal MCV
6
Q
For a patient with macrocytic anaemia, what four outcomes from bone marrow biopsy may arise and what causes do they indicate?
A
Megaloblastic- vit B12 + folate deficiency
Normoblastic- liver disease, hypothyroidism
Impaired erythropoesis- sideroblastic anaemia, aplasia, leukaemia
Increased erythropoesis- haemolysis
Producing odd cells (megaloblast), not producing enough or wiping them out
7
Q
Patient has macrocytic anaemia, how can the cause be uncovered using investigations?
A
Blood film- hypersegmented polymorphs = vit B12 + folate deficiency
Target cells- liver disease
Sideroblasts (can also cause microcytic anaemia)
LFTs- may indicate alcoholism/liver problems
Raised bilirubin- haemolysis
TFTs- hypothyroidism
Bone marrow biopsy if still not elucidated (leukaemia, aplasia, haemolysis)
8
Q
What is sideroblastic anaemia?
A
Bone marrow produces ringed sideroblasts rather than healthy red blood cells, granules of iron accumulate around the nucleus as a result of dysfunctional haem synthesis or processing.
Consider if iron-deficiency anaemia isn’t responding to iron supplements
9
Q
3 common causes of a macrocytic anaemia:
A
B12/folate deficiency (megaloblastic)
Alcohol
Myelodysplasia
10
Q
What is the inheritance of G6PD deficiency as a cause of haemolytic anaemia?
A
X linked, may be drug linked
11
Q
What is different about the pathophysiology of thalassaemia compared to haemaglobinopathies like sickle cell, or HbC?
A
Thalassaemia = reduced rate of Hb synthesis (low MCV + MCH)
Others= abnormal Hb chains
12
Q
Which clotting factor is implicated in haemophilia A?
A
Factor 8 (commoner than haemophilia B)
13
Q
What chromosomal translocation is associated with Burkitt’s lymphoma?
A
8 + 14
14
Q
Which translocation is associated with acute promyelocytic leukaemia
A
15 and 17
15
Q
Which translocation is associated with CML and ALL (philadelphia chromosome)?
A
9 and 22
16
Q
What defines anaemia in men and women?
A
Men- Hb < 135g/L
Women Hb < 115g/L
17
Q
How can anaemia present?
A
Dyspnoea
Palpitations, angina (if coronary artery disease)
Fatigue, anorexia
Headache, faintness, tinnitus
18
Q
Signs of anaemia:
A
<80g/L hyperdynamic circulation- tachycardia, flow murmurs (ejection systolic)
Conjuctival pallor
Iron deficiency: koilonychia, angular stomatitis, atrophic glossitis
19
Q
Causes of microcytic anaemia:
A
MCV < 76
Low ferritin = Iron deficiency
High ferritin = Thalassaemia Sideroblastic anaemia (ineffective erythropoesis, more iron absorption)
20
Q
Causes of normocytic anaemia:
A
MCV 76-96
Blood related: acute blood loss, haemolysis
Failures: renal, bone marrow, hypothyroidism
General: pregnancy, chronic disease
21
Q
Causes of macrocytic anaemia:
A
MCV >96
Megaloblastic: B12 or folate deficiency
Drugs: cytotoxics, antifolates (phenytoin), alcohol excess
Haem related: myelodysplasia (variable cell production), marrow infiltration, reticulocytosis
Failures: liver failure, hypothyroidism
22
Q
3 groups of causes of an iron deficiency anaemia:
A
Iron intake:
Diet (in babies + children, poverty)
Malabsorption (coeliacs, pancreatitis)
Blood loss (menorrhagia, GI bleeding, hookworm)
23
Q
Patient has an iron deficiency anaemia and a history of menorrhagia. What is the next step?
A
Ferrous sulphate 200mg TDS
If old, or no obvious cause, a full GI work up of colonoscopy and gastroscopy is needed to exclude GI cancer
24
Q
What is the pathophysiology of anaemia of chronic disease?
A
Hepcidin mediated: prevents iron overload
- Reduced production of erythropoietin
- Reduced response to erythropoietin
- Poor use of iron in erythropoiesis
- Cytokine-induced shortening of RBC survival
25
What different treatment can be tried for the different types of microcytic anaemia?
Iron deficiency- ferrous sulphate
Chronic disease- underlying disease and erythropoietin
Sideroblastic- pyridoxine ± transfusions
26
If iron is low, but ferritin is high what is the cause of the microcytic anaemia?
Anaemia of chronic disease:
Body tries to store iron away inside cells as ferritin to protect against bacteria so ferritin is high (acute phase response) and iron is low
Total iron binding capacity (transferrin levels) are low as there is enough iron, but it is not being effectively utilised
This is in contrast to iron-deficiency where iron will be low, but ferritin will also be low as there are not many iron stores and TIBC is high.
27
What is sideroblastic anaemia and how is it treated:
Abnormal haem synthesis or ineffective erythropoiesis leads to a microcytic anaemia with more iron absorption, iron loading in marrow, liver and heart
Histology: ring sideroblasts in the marrow- perinuclear ring of iron granules
Causes:
Congenital- x linked, rare
Acquired- idiopathic, following chemo/anti-TB drugs, EtoH, irradiation
IHx: ferritin (up), iron (up), TIBC (N)
Blood fil, marrow aspiration
Rx: cause + Pyridoxine ± transfusions
28
In haematinic studies of normocytic anaemias, what findings are expected for those with anaemia of chronic disease, chronic haemolysis and pregnancy?
All have high ferritin as all pro-inflammatory states
Anaemia of chronic disease- low iron (iron sequestered in cells), TIBC low (adequate iron levels, poorly utilised)
Chronic haemolysis- high iron (increased Hb breakdown) low TIBC
Pregnancy- high iron, high TIBC (more protein synthesis)
29
What is anicytosis and what causes it?
Variation in RBC size:
Megaloblastic anaemia (B12 or folate lack)
Iron deficiency anaemia
Thalassaemia
30
On blood film what abnormalities in RBC distribution may be seen and what causes it?
Irregular RBC collections = cold agglutinins
EBV, mycoplasma, SLE, CLL
Rouleaux formation = stacks
Inflammation, multiple myeloma
31
What types of poikilocytosis are seen on blood film in terms of membrane abnormalities and overall shape change?
Membrane abnormalities (liver disease or splenectomy)
Acanthocytes- spiculated RBCs from unstable membrane
Liver disease, spherocytosis, splenectomy
Burr cells- serrated smaller uniform RBC projections
Liver failure, renal failure, artifact
Target cells- increased surface area: volume ratio
Liver disease, haemaglobinopathy (more Hb), splenectomy
Cell shape:
Spherocytes- haeolytic anaemia or spherocytosis
Schistocytes- fragmented RBCs from TTP, DIC, heart valves
Teardrop cells- myelofibrosis, thalassaemia
Bite cells- oxidant sensitivity denatures Hb (Heinz bodies) then removed by spleen = G6PD
32
What intracellular extras might be seen in RBCs on a blood film and what causes them?
Basophilic RBC stippling: denatured RNA (defective Hb synthesis)
Megaloblastic anaemia, myelodysplasia, haemaglobinopathy, liver disease
Howell-Jolly bodies: DNA remnant (removed by spleen normally)
Megaloblastic anaemia, myelodysplasia, splenectomy
Heinz bodies: aggregates of denatured Hb (oxidant sensitivity)
G6PD or thalassaemia (extra Hb)
Pappenheimer bodies: granules of siderocytes containing iron
Sideroblastic anaemia, lead poisoning, splenectomy
Cabot rings: figure of 8 ?microtubules
Lead poisoning, pernicious anaemia
33
Causes of left shift vs right shift and what is it?
Shift describes overall proportions of stages of neutrophils
Left shift- more immature neutrophils (infection)
Right shift- more mature neutrophils (abnormal production of new neutrophils- megaloblastic anaemia, liver disease, uraemia)
34
Cause of blast cells on the blood film?
Leukaemia
Myelofibrosis
Malignant infiltration
35
Causes of neutrophilia:
Bacterial infection
Inflammation- MI, polyarteritis nodosa, disseminated cancer, stress (surgery, burns, haemorrhage)
Myeloproliferative disorders
Steroids
36
Causes of neutropenia:
Reduced production:
Chemo, carbimazole, sulphonamides, cytotoxics
Bone marrow failure
Increased destruction:
Viral infections, severe sepsis
Neutrophil antibodies- SLE, haemolytic anaemia
Hypersplenism- Felty's (RA)
37
What is the hyper-eosinophilic syndrome?
Idiopathic disease where raised eosinophil count for 6 weeks leads to end organ damage resulting in:
```
Restrictive cardiomyopathy
Skin lesions
Thromboembolisms
Lung disease
Neuropathy
Hepatosplenomegaly
```
Rx: steroids, anti-IL5 antibody biologic)
38
Causes of eosinophilia?
I MADeR
Infections: parasites, helminths
Malignant: lymphoma, eosinophilic leukaemia
Autoimmune: atopy, eczema, asthma, psoriasis, pemphigus, dermatitis herpetiformis, polyangitis nodosa, Loffler's syndrome (pulmonary infiltration)
Adrenal insufficiency
Drugs reactions: erythema multiforme
39
How many lobes in a neutrophil's nuclei is normal?
5 or less
Anymore = hypermature
A nucleus shaped like a horse shoe = band form = immature
40
What is a megaloblast?
A cell where the nucleus is delayed in it's development compared to the cytoplasm of the same shape
41
What types of anaemia are seen in BM failure, myelodysplasia and marrow infiltration?
BM failure: making less RBCs, but the RBCs made are normal
= normocytic
Myelodysplasia: clonal progenitor cell dominates cell production, resulting in ineffective erythropoiesis and reduced RBCs
= normocytic (BM failure) or macrocytic (immature cells)
Marrow infiltration: pushes immature cells out earlier
= macrocytic
42
Investigations for a macrocytic anaemia:
LFTs- EtoH
B12/folate
TFTs- hypothyroidism
Blood film- membrane abnormalities (liver), intracellular extras (megaloblastic, myelodysplasia)
2nd line: bone marrow aspirate
43
Causes of folate deficiency
Poor intake: alcoholics, poverty
Malabsorption: coeliac disease, tropical sprue
Anti-folate drugs: methotrexate, anti-epileptics (phenytoin)
Increased use: more cell turnover (inflammation, cancer, haemolysis), pregnancy
44
How do antifolate drugs work?
Inhibit dihydrofolate reductase needed to produce folate
Folate acts a cofactor for enzymes producing purines and amino acids (like serine or methionine) so when synthesis is inhibited it reduces cell turnover and repair.
Examples:
Methotrexate (autoimmune conditions)
Pemetrexed (non-small cell lung cancer + mesothelioma)
Proguanil (protozoal DHFRi)
Trimethoprim (microbial DHFRi)
Phenytoin may compound these effects by inhibiting enzyme that enables uptake of folate in the gut
45
What needs to be given first B12 or folate, if patient is deficient?
B12 (alphabetical)
Can precipitate subacute combined degeneration of the cord
Pregnancy dose 400micrograms, unless high risk = 5mg
46
How is B12 absorbed?
Digestion releases B12 from it's protein carrier (needs acidic environment to activate pepsin for cleavage)
Intrinsic factor in the stomach binds it
Complex absorbed in terminal ileum
47
Causes of B12 deficiency?
Lack of dietary intake- Vegans, alcoholics, elderly
Digestion of B12 from it's protein carrier in the stomach requires acid for pepsin activation- PPIs, gastrectomy
Intrinsic factor- pernicious anaemia, atrophic gastritis
Absorption- ileal resection, Crohn's, bacterial overgrowth, tapeworms
48
Signs of B12 deficiency:
Lemon tinge- anaemic pallor + mild jaundice (haemolysis)
Angular cheilosis
Glossitis
49
Features of B12 deficiency:
Neuropsych: depression, dementia, irritability, psychosis
Neurological: peripheral neuropathy, SCDC*, paraesthesiae
SCDC= dorsal column loss (LMN) + corticospinal (motor UMN)
Absent ankle + knee jerks with upgoing plantars
Ataxia + spastic weakness
50
What is pernicious anaemia?
Autoimmune atrophic gastritis leads to destruction of parietal cells- without which there is reduced intrinsic factor and acid secretion (and hence achlorhydria)
Resulting in low B12
May be caused by anti-parietal cell antibodies, anti-intrinsic factor antibodies
51
Patient has vitiligo and a macrocytic anaemia, what could be the cause?
Think autoimmune associated conditions:
```
Pernicious anaemia (B12 level)
Hypothyroidism (TFTs- Hashimoto's or primary atrophic)
```
52
Tests and Rx in suspected pernicious anaemia?
IHx:
Anti-parietal cell Abs
Anti-intrinsic factor Abs
However may be -ve in 50%, so look at plasma B12 levels after IM if no PO response in B12 levels
NB: autoimmune unlikely in under 40s, suspect coeliac instead (duodenal biopsy)
Rx:
Malabsorptive cause: hydroxocobalamin IM then every 3 months
Dietry cause: oral B12 after initial hydrocobalamin
53
What is haemolysis and how can it's causes be split?
Early breakdown of RBCs before their normal 120 day lifespan
Intravascular- in the circulation
Extravascular- in the reticuloendothelial system, macrophages of liver, spleen and bone marrow
54
What blood test results suggest haemolysis has taken place?
Normocytic or macrocytic (reticulocytic) anaemia
High unconjugated bilirubin
High urinary urobilinogen
High serum LDH (released from RBC breakdown)
55
How can an intravascular haemolysis be differentiated from extravascular?
Extravascular: splenomegaly
Intravascular:
High free plasma Hb
Presence of methaemalbuminaemia (Free Hb combines to albumin)
Low plasma haptoglobin (mops up free Hb, uptaken by liver)
Haemaglobinuria- red/brown urine but no RBCs
Haemosiderinuria- free Hb stored by tubular cells as haemosiderin, then sloughed off (Prussian blue stain 1 week post haemolysis)
56
Patient is jaundiced, which tests will enable diagnosis of haemolysis and confirm a cause?
Bloods: LFTs, conjugated + unconjugated bilirubin, LDH, haptoglobin levels, free Hb levels, methaemalbumin levels
Urine: urobilinogen, haemosiderin on microscopy, urine dip negative for RBCs despite red/brown urine
Blood film: thick + thin
Coombs test- direct antiglobulin test
```
Optional extras: osmotic fragility testing (membrane abnormalities)
Hb electrophoresis (haemaglobinopathies)
Enzyme assays (enzymatic causes)
```
57
Describe Coombs direct and indirect antiglobulin test:
Direct: wash patient's RBCs
Add antihuman Abs
If RBC's are coated by the patient's anti-RBC antibodies, RBC will agglutinate
Indirect: get patient's serum (containing anti-RBC ab's potentially)
Add RBCs
Add anti-human Abs
RBC's will agglutinate if serum has anti-RBC antibodies in
58
Patient has haemolysis and a positive Coombs test.
| What could the 4 groups of causes be?
Acquired immune-mediated haemolysis:
1. Drug induced: penicillin (binds membranes), quinine (forms complexes)
2. Autoimmune: autoantibodies causing extravascular haemolysis (ie splengomegaly)
Warm AIHA- IgG binds at 37 degrees
Idiopathic, CLL, lymphoma, SLE
Cold AIHA- IgM binds <4 degrees, activates cell-surface compliment
EBV, mycoplasma
3. Paroxysmal cold haemoglobulinuria: Abs stick to RBCs when cold and cause self-limiting complement-mediated haemolysis on rewarming. Viruses + syphilis
4. Isoimmune- transfusion reactions or haemolytic disease of newborns
59
How does the cause of warm autoimmune haemolytic anaemia and cold autoimmune haemolytic anaemia differ?
Warm AIHA: idiopathic, CLL, lymphoma, SLE, drugs
| Cold AIHA: EBV, mycoplasma
60
Name 2 drugs causing autoimmune haemolytic anaemia (+ve Coombs test)?
Penicillin binds membranes
| Quinine forms immune complexes
61
Rx for different types of autoimmune haemolytic anaemia depending on whether it is due to cold or warm agglutinins?
Warm AIHA: IgG mediated- steroids ± splenectomy (Extravascular haemolysis causes splenomegaly)
Cold AIHA: IgM mediated- Keep warm, chlorambucil maybe
62
What could cause an autoimmune haemolytic anaemia that was Coombs negative?
2% of AIHA
Autoimmune hepatitis (anti-SM)
Hepatitis B + C
Post flu or rituximab
63
Which conditions are considered microangiopathic haemolytic anaemias?
Where intravascular haemolysis occurs from mechanical trauma to RBCs resulting in schistocyte formation:
Haemolytic-uraemic syndrome (shiga toxin inactivates ADAM13)
Thrombotic thrombocytopenic purpura (autoantibodies against ADAM13, metalloprotease that cleaves vWF)
Disseminated Intravascular Coagulation (widespread clotting)
Pre-eclampsia + eclampsia (HELLP)
64
What is paroxysmal nocturnal haemoglobinuria?
Acquired mutation in haematopoietic stem cell/precursor
Abnormal surface glucosylphosphatidylinositol means complement is not removed from RBC surface
Leads to haemolysis, marrow failure (from clonal proliferation) and thrombophilia
IHx: immunophenotyping
Rx: anticoagulation, eculizumab (complement inhibitor)
65
4 broad causes of acquired haemolytic anaemia?
Immune, infection, vascular, malignancy in essence
1. Immune mediated
Coombs positive- drug induced, autoimmune (cold + warm), paroxysmal cold Hb-uria
Coombs negative
2. Infective- malaria
3. Microangiopathic- TTP, HUS, eclampsia, DIC
4. Paroxysmal nocturnal Hb-uria
66
Hereditary causes of haemolytic anaemia?
1. Enzyme defects
Glucose-6-Phosphate Dehydrogenase (X linked)
Pyruvate kinase deficiency (AR)
2. Membrane defects
Hereditary spherocytosis (AD)
Hereditary elliptocytosis
Hereditary ovalcytosis
3. Haemoglobinopathy- sickle cell or thalassaemia
67
What triggers oxidative crises in G6PD deficiency?
Defect in RBC enzyme responsible for sorting oxidative stress may be precipitated by:
Drugs- sulphonamides (diuretics, gliclazide), aspirin
Broad beans
Henna
Denatured Hb forms Heinz bodies in RBCs, which is removed by the spleen to leave Bite cells
68
A Greek patient becomes jaundiced following aspirin intake, which you suspect to be haemolysis. How would you test for G6PD deficiency?
X linked
Rapid anaemia + jaundice
Enzyme assay 8 weeks after crisis (as young RBCs may have normal levels of enzyme)
Measure enzyme activity on reagent
69
What in the inheritance of congenital causes of haemolytic anaemia?
Enzymes:
G6PD deficiency- X linked
Pyruvate kinase deficiency- Autosomal recessive
Membranes:
Spherocytosis- Autosomal dominant
Eliptocytosis- Autosomal dominant
Haemaglobinopathy:
Sickle cell- Autosomal recessive amino acid substitution
Thalassaemia- Autosomal recessive point mutation, but may have some penetrance in heterozygotes
70
What are the genetics underlying sickle cell disease?
Amino acid substitution in Beta globin chains
| At position 6 glutamic acid is exchanged for valine (hydrophobic, causing the Hb to collapse in on themselves)
71
What is sickle cell trait and when can it be a problem?
Heterozygosity for sickle cell amino acid substitution (glutamic acid for valine at position 6)- HbAS
Problematic in hypoxia- anaesthesia or unpressurised aircrafts
Can lead to vaso-occlusive events occurring
Or if other Hb variants have been inherited
72
What is needed for definitive diagnosis of sickle cell disease?
Hb electrophoresis- distinguishing homozygosity vs heterozygosity and presence of any other Hb variants.
73
What are the 4 ways sickle cell disease may manifest?
1. Vaso-occlusive crisis: microvascular occlusion
Dactylitis, avascular necrosis, leg ulcers
Priaprism
Stroke, seizure, cognitive defects
2. Aplastic crisis: Sudden reduction in marrow production
Due to parvovirus B19
3. Sequestration crisis: splenic pooling of blood, severe anemia and shock. Transfusion is urgently required, mainly occurs in children when spleen has not yet undergone auto-splenectomy
4. Acute chest syndrome: pulmonary infiltrates in lung segments
74
How can CNS infarctions be assessed for signs of impending stroke in children with sickle cell disease?
Transcranial Doppler Ultrasonography
75
Management of priaprism:
Conservative: Hydration
Medical: a-agonists (phenylephrine)
Surgical: aspiration of blood + irrigation with saline
76
What causes aplastic crises in sickle cell patient?
Parvovirus B19
| Usually self-limiting, may need tranfusion
77
What are the complications of sickle cell disease?
General: Impaired growth, anaemia
```
Retinal disease
Lung fibrosis (± pulmonary hypertension)
```
Abdo: Chronic renal failure
Splenic infarction- before age 2 (susceptible to disease)
Gallstones
Iron overload
78
Management of sickle cell disease?
Frequent crises- hydroxyurea
BM transplant is curative but controversial
Conservative: genetic counselling, parental education for signs of sequestration crisis
Vaso-occlusive crises- analgesia, hydration, Rx infection
Aplastic crises- self limiting
Sequestration crises- urgent transfusion (also for CNS involvement)
Dilutes HbS levels
79
DR ABC for sickle cell, what should be included?
A- O2 if sats <95%
B- Empirical Abs if temperature of chest signs
C-rehydrate with IV fluids, keep warm, patient controlled analgesia
Bloods: FBC, reticulocytes, crossmatch, blood cultures, MSU ± CXR
80
Sickle cell patient comes in with pain, temperature and is wheezy and dyspnoeic. How should it be treated?
CXR but symptoms may precede chest signs
A- O2
B- antibiotics (can be caused by mycoplasma, chlamydia, viruses, fat emboli from bone marrow)
Bronchodilators if wheeze.
C- cultures, analgesia, blood transfusion if severe
81
What are thalassaemias are what types are there?
Group of genetic diseases resulting in unbalanced Hb synthesis
Unpaired Hb aggregates damaging RBC membranes causing haemolysis from within the bone marrow.
Common in Mediterranean and Far East (china)
B thalassaemia minor = B/B+ heterzygous mutation
B thalassaemia intermedia = mild homozygous B mutations or heterozygotes with another Hb-opathy
B thalassaeia major = both B chains severely affected
A thalassaemia = --/-a 3 out of 4 genes are mutated
A thalassaemia carrier = 2/4 alpha genes mutated
82
Which forms of thalassaemia are likely to be asymptomatic?
B thalassaemia minor (heterozygous B mutation)
A thalassaemia carrier state (2/4 a mutation)
83
Presentation, examination signs and investigations (apart from Hb electrophoresis) that indicate patient has beta thalassaemia major?
PC: Onset before age 1- failure to thrive, severe anaemia
EHx:Extramedullary haemopoiesis: skull bossing, hepatosplenomegaly
IHx: Xray, osteopenia + 'hair on end' sign
Blood film, microcytic cells, teardrop RBCs (extramedullary), Heinz bodies (Hb), target cells (abnormal Hb to membrane), nucleated RBCs
84
Management of thalassaemia?
Conservative: fitness, healthy diet, folate supplements
Medical:
> Life-long fortnightly transfusions
> Iron-chelators (desferrioxamine)
> Endocrine complications of iron depositions requires Hormone replacement- insulin for DM, testosterone gel to reduce hypogonadism, levothyroxine
Surgical:
> Splenectomy for splenomegaly
> Histocompatible marrow transplant
85
What is Haemaglobin H disease?
Alpha thalassaemia, where 1 out of a possible 4 alpha genes are functional.
PC: jaundice, leg ulcers, hepatosplenomegaly
IHx: blood film- B4 tetramers and y4 tetramers (HbBarts)
86
What comprises HbA, HbA2 and HbF haemoglobin molecules?
HbA- alpha 2, beta 2 (absent in b thalassaemia major)
HbA2- alpha 2, delta 2 (variable in b thalassaemia major)
HbF- alpha 2, gamma 2 (hugely raised in b thalassaemia major)
87
How can bleeding disorders be categorised?
Vascular defects:
Congenital- Osler Weber Rendu, connective tissue disease
Acquired- senile purpura, infection (meningococcal, measles, dengue, fever), steroids, Henoch-Schönlein
Platelet disorders:
Low production- BM infiltration or suppression, megaloblastic anaemia, aplastic anaemia
High destruction- Immune (ITP, SLE, CLL, heparin)
Non-Immune (DIC, TTP, HUS, sequestration in spleen)
Poor function- myeloproliferative, uraemia, NSAIDs
Coagulation defects:
Congenital- Haemophilia, von Willebrand's disease
Acquired- anticoagulants, live disease, DIC, Vit K deficiency
88
Signs of Ehlers Danlos:
Skin is easily bruised or torn, wide scars, fragile
Elastic skin
Hypotonic, hypermobile joints
Mitral valve prolapse (systolic murmur), aortic dissection
GI bleeds/perforation
Flat feet
89
What is Ehler's Danlos syndrome?
Autosomal dominant disease of collagen leading to hyperelasticity.
There are six types
IHx:urine pyridinolines may be found
Complications: mitral valve prolapse, aortic dissection, GI bleeds
90
Cause of ITP vs TTP vs HUS vs DIC?
Platelet disorders:
Immune
ITP = acquired platelet destruction from platelet autoantibodies
Non-immune
TTP = ADAMS13 protease deficiency
HUS = E Coli 0157 verotoxin inactivates ADAM13 needed for vWF cleavage
Coagulation disorder:
DIC = widespread activation of clotting from pro-coagulant release
91
What is the difference between contusions and purpura and petechiae and eccymosis?
Contusions = bruise, as blood escapes into interstitium, should blanch (eccymosis is another name for it)
Petechiae = < 2mm pinpoint spot caused by intradermal haemorrhage
Purpura = > 1cm non-blanching rash caused by bleeding into the skin
92
36 year old woman has noticed a purpuric rash in pressure areas, she often gets nosebleeds and has very heavy periods. What tests can be done to determine if ITP is the cause?
Antiplatelet antibodies
| Increased megakaryocytes in marrow
93
Management of immune thrombocytopenic purpura?
Medical: prednisolone
If symptomatic- bleeding, epistaxis etc or platelets <20
IV Ig- temporary for pregnancy or surgery
Immunosupression if all else fails- azathioprine
Avoid platelet transfusions- destroyed by Ab's
Surgical: splenectomy (cures 80%)
94
Inheritance of haemophilia A and B?
Haemophilia A: X linked deficiency in factor 8
| Haemophilia B: X linked deficiency in factor 9
95
Management of haemophilia A:
Conservative: avoid NSAIDs and IM injections (SC okay), genetic counselling
Medical:
Minor bleed- pressure, elevation, Desmopressin (ADH)
Major bleed- recombinant Factor 8 to 50% normal
Life-threatening bleed- recombinant Factor 8 to 100% normal
NB: haemarthrosis = major bleed, obstructing airway = life-threatening bleed
96
Vitamin K dependent clotting factors?
2, 7, 9, 10
7 (PT-extrinsic)
9 (APTT- intrinsic)
10 (both)
As factor 7 has the shortest half-life, PT will be more markedly abnormal than aPTT tests
97
Management of acute haemorrhage for vitamin K abnormalities?
IV vitamin K
| Fresh frozen plasma (contains clotting factors)
98
How do thrombolytic agents work?
Normally fibrinogen is broken down into fibrin to make fibres of the clot.
Firbin stimulates endothelium to produce tissue plasminogen-activator
t-PA activates plasminogen into plasmin, which breaks down fibrin.
Alteplase imitates t-PA
Streptokinase binds plasminogen, which activates it once complex has formed
99
Causes of a long prothrombin time?
PT = extrinsic system (activated by endothelial damage)
factor 7 involved
Vitamin K deficiency / warfarin
Factor 7 has shortest half-life out of all the Vit-K dep factors
APTT high also: liver disease, DIC
100
Causes of a long APTT?
Intrinsic system- factor 8, 9, 11, 12 (activated by platelets)
Haemophilia
Heparin (PT reagents bind heparin unlike aPTT reagents)
Von Willebrand's involved in platelet aggregation
APTT also high: DIC, liver disease
101
Patient keeps bleeding from cuts and doesn't seem to be coagulating effectively. What blood tests can help elucidate a cause?
FBC- low platelets?
Immune- ITP, SLE, or Non-immune causes- HUS, TTP,
APTT- intrinsic pathway (haemophilia, heparin, vW disease)
PT- extrinsic pathway (vit K deficiency)
D-dimers- DIC, DVT
Blood film- schistocytes
PFA-100- platelet dysfunction
Specialise: vWf antigen, antiplatelet antibodies
102
What are the types of early complications following transfusion:
AAAABC
Within 24 hours:
Acute haemolytic reaction- ABO incompatibility, shock, chest pain
Anaphylaxis- bronchospasm
hlA Antibodies (Febrile reaction)- shivering + fever, non haemolytic
Acute lung injury (TRALI)- antileukocyte antibodies in donor plasma
Bacterial contamination- temperature, rigors
Congestion- fluid overload
103
What are the late complications of blood transfusions?
| After 24 hours
Infections- viruses, hep C+B, HIV, bacteria, protozoa, prions
Iron overload
Invasion- Graft vs host disease
Post-transfusion purpura (non-blanching rash, 5days after)
104
In which early transfusion reactions might you consider slowing the transfusion rather than stopping it?
Non-haemolytic febrile reaction: give paracetamol, ensure no signs of shock
Allergic reactions (urticaria or itch): give chlorphenamine, ensure no anaphylaxis
Fluid overload: furosemide IV, consider CVP line
105
Patient is having a transfusion, when they become dyspnoeic and develop a cough. What could be the cause and how could this be confirmed?
TRALI- transfusion related acute lung injury
CXR shows white out
ARDS with infiltrates due to antileukocyte antibodies in donor plasma
106
Side effects of heparins:
1. Bleeding
2. Heparin-induced-thrombocytopenia (immune mediated, less in LMWH)
3. Osteoporosis in long term (less-so in LWMH)
107
Mechanism of the oral anticoagulant agents?
LMWH- activates antithrombin to inhibit Factor Xa (Dalteparin)
Fondaparinux- ultra LMWH (similar to LMWH)
Unfractionated Heparin- activates antithrombin to inhibit Factor Xa and Thrombin
```
Direct Oral Anticoagulants- Factor Xa binding (Rivaroxiban, Apixiban)
Thrombin binder (Dabigatran)
```
Warfarin- inhibits vitamin K reductase enzyme
108
How long is heparin needed for when starting Warfarin?
Until Warfarin is within range
AND
At least up to day 5 (Warfarin has a pro-thrombotic effect initially)
109
What counters unfractionated heparin if patient starts bleeding?
Protamine sulfate (binds to heparin, leading to its removal by the reticulo-endothelial system)
110
What are the typical targets of INR in Warfarin therapy for different indications?
AF: 2-3
Single PE: 2-3
Recurrent PE: 3.5
Metallic heart valve: 3-4
111
```
How long is anti-coagulation needed in
A. Provoked below knee DVT
B. Provoked above knee DVT or PE
C. Unprovoked DVT/PE
D. Unchanging Thrombophilia's
```
A. At least 3 months
B. At least 3 months
C. At least 6 months
D. Potentially life-long
112
Patient has a red swollen calf, what investigations should you do?
Two level- Wells score
2+ means DVT likely: aim for USS within 4 hours + if negative, D dimer
<2 means DVT unlikely: do D-dimer + aim for USS in 4 hours if positive
In the above scenarios, if USS not possible within 4 hours, give LWMH and aim for USS within 24 hours
```
If unprovoked look for cause:
Physical exam
CXR
Bloods- FBC, serum calcium, LFTs, urinanalysis ± anti-phospholipid
± CT abdo-pelvis if over 40 years
```
113
How do you manage a patient with a high INR on Warfarin, depending on whether they are bleeding or not?
BNF guidelines
INR above 5 or major bleed: stop Warfarin + restart when < 5
Major bleed: Prothrombin complex concentrate + IV Vitamin K
> 8 + minor bleed: IV Vit K
> 8 + no bleed: oral Vit K
> 5 + minor bleed: oral Vit K
114
Leukaemic patient has AKI + bruising occurring at venepuncture sites and around the body.
Platelets low, aPTT + Pt high, fibrinogen low.
Management?
Likely DIC:
Treat the cause- malignancy, sepsis, trauma, labour
Platelets if <50
Cryoprecipitate (for fibrinogen)
FFP (coagulation factors)
Activated protein C (if sepsis)
115
What Rx can be given to those with acute promyelocytic leukaemia to reduce the incidence of DIC?
All-transretinoic acid
APML= M3 subtype, chromosome 15 + 17
116
What do the chronic leukaemia's transform into?
CML transforms into blast crisis
| CLL transforms into high grade lymphoma (Richter's syndrome)
117
What chromosome translocations have relevance for haem malignancies?
9 and 22- philadelphia chromosome in CML
| 8 and 14- Burkitt's lymphoma (+EBV)
118
Tests for suspected ALL?
| Little leukaemia
```
Bloods- FBC + platelets
Blood film- blasts
Bone marrow aspirate
CXR + CT scan (mediastinal + abdo lymphadenopathy)
Lumbar puncture- CNS involved
```
119
Management of acute lymphoblastic leukaemia:
Conservative: education, nursing help
Medical: blood + platelet transfusions, IV fluids, allopurinol
Chemotherapy
Transplant: Matched allogenic marrow transplants
120
Causes of bilateral parotid swelling:
Cancer: acute lymphocytic leukaemia
Infection: mumps, HIV
Bulima
Endocrine: hypothyroid
121
What age do the leukaemia's commonly occur at?
ALL- children
AML- 50s
CML- 50-70s
CLL- 70+
122
Which leukaemia is DIC commonly associated with?
Acute Promyelocytic Myeloid Leukaemia
All-tansretinoic acid reduces risk
123
How does bone marrow transplant work?
HLA-matched pluripotent stem cells taken from marrow
Cyclophosphamide and whole body irradiation destroys leukaemic cells
Stem cells infused in to repopulate bone marrow
Reduces relapses by 60% but may have 10% mortality
124
What is myelodysplasia and findings on blood film?
Malignant haematopoietic stem cell disorder so less cells may be made and those produced may be defective.
30% transform to AML
IHx: pancytopenia
Film: Howell Jolly bodies (DNA nuclear remnants from abnormal production)
Basophilic RBC stippling (denatured RNA)
125
Which leukaemia do you get gum hypertrophy in?
AML (m for mouth)
126
In CLL, which finding is associated with the worst prognosis? (Aside from transformation into lymphoma)
Platelets <100
| Suggests marrow infiltration
127
How is Hodgkin's lymphoma staged?
1- one group of lymph nodes
2- two + groups of lymph nodes on same side of diaphragm
3- groups of lymph nodes on different sides of diaphragm
4- involvement beyond lymph nodes- liver/bone marrow
128
Name some low grade non-hodgkins lymphomas:
Indolent, incurable, widely disseminated:
FoLLicuLar lymphoma
MALT
Lymphocytic lymphoma
Lymphoplasmacytoid lymphoma (produces IgM- Waldenstrom's macroglobulinaemia)
129
What are examples of high grade non-hodgkins lymphoma?
Aggressive, often curable, all the B's:
Burkitt's lymphoma (jaw lymphadenopathy)
Diffuse large B-cell lymphoma
LymphoBlastic lymphoma
130
Causes of pancytopenia:
```
Marrow failure:
Aplastic anaemia (stem cell disorder)
Infiltration- ALL/AML, myelodysplasia, myeloma, lymphoma, TB
Megaloblastic anaemia
Myelofibrosis
SLE
```
Increased destruction: hypersplenism
131
What drugs cause agranulocytosis?
```
Lack of eosinophils, basophils and neutrophils - 4 C's:
Carbamazepine
Clozapine
Colchicine
Carbimazole
```
132
What platelet level does a patient need for biopsy or lumbar puncture?
>50 x 10^9/L
133
What are myeloproliferative disorders of the following known as?
A. RBC
B. WBC
C. Platelets
D. Fibroblasts
A. Polycythaemia
B. CML
C. Thrombocythemia
D. Myelofibrosis
134
Causes of polycythaemia:
Primary- JAK2 driven clone proliferation
```
Secondary- hypoxia (altitude, smoking, chronic lung disease)
Erythropoietin secretion (HCC or renal cell carcinoma)
```
135
Patient complains of itching when getting out the bath and has facial plethora, what symptoms suggest polycythaemia rubra vera?
Hyperviscosity signs: tinnitus, dizziness, headache, visual disturbance
Burning pain in the fingers: erthyromelagia- due to intermittent blockage of capillaries
136
What is the difference between a bone marrow trephine and aspiration?
Trephine takes a core of bone to assess architecture and infiltration (posterior iliac crest)
Aspirate provides a film for analysis (anterior iliac crest or sternum)
137
Marrow aspirate shows hypercellularity with erythroid hyperplasia, what is the diagnosis?
Polycythaemia rubra vera
138
Rx for polycythaemia rubra vera?
Low dose aspirin
To keep haemocrit down
Young: venesection
Old or previous DVT: hydroxyurea or a-IFN
139
What is myelofibrosis?
Whereas thrombocythaemia is due to clonal proliferation of megakaryocytes, myelofibrosis = hyperplasia of them
Increased PDGF
Marrow fibrosis and myeloid metaplasia
Haeatopoiesis in the spleen and liver result
140
Test findings of myelofibrosis:
BM failure- pancytopenia
Blood film- leukoerythroblastic cells (nucleated RBCs), teardrop RBCs
Bone marrow trephine, 13% dry tap
141
Features of myeloma:
Calcium- myeloma cell signals to activate osteoclasts
Renal disease- bence jones proteins or rarely AL amyloid
Anaemia- marrow infiltration
Bones- osteolytic lesions
Infection
142
What screening investigations are needed for suspected multiple myeloma?
FBC, ESR
U+Es
Serum + urine electrophoresis
B2-microglobulin (high levels suggest more advanced myeloma)
143
What is myeloma?
Abnormal clone of plasma (or lymphoplasmacytic) cells
Leading to secretion of an Ig fragment
2/3 IgG
1/3 IgA
2/3s Bence Jones proteins- free Ig light chains of kappa or lambda
144
What is a pepper pot skull a sign of?
Increased activation of osteoclasts
Hyperparathyroidism
Multiple myeloma looks similar (raindrop skull- myeloma cells stimulate osteoclasts)
145
Management of Myeloma:
Supportive:
Bone pain- analgesia, bisphosphonates (+ reduce fractures), vertebroplasty
Renal- adequate fluids, antibiotics (infection) or IV Ig
Low Hb- blood transfusion, erythropoietin
Medical:
Chemotherapy- palliative or intensive
Surgical:
Allogenic or autologous stem cell transplant
146
Diagnostic Criteria of Myeloma:
MyELOma:
Monocloncal protein band on serum or urine electrophoresis
Evidence of end organ damage- hypercalcaemia, renal insufficiency, anaemia
Lesions of the bone- CXR of spine, skull, pelvis ± PET, Tech scan
Overwhelming plasma cells on marrow biopsy
147
Causes of bone tenderness/pain?
Vascular- sickle cell anaemia, osteonecrosis (microemboli)
Infective- osteomyelitis,
Trauma- fracture (steroids, osteopenia)
Autoimmune- CREST, Srögrens,
Metabolic- hyperparathyroidism, Paget's, renal osteodystrophy
Iatrogenic
Neoplastic- myeloma, sarcoma, secondary's (breast, lung, prostate)
148
Raised IgM on serum electrophoresis and ESR, what is the likely haem cause?
Waldenström's macroglobulinaemia:
Circulation of Ig produced by a single clone
Hyperviscosity is common (needs plasmaphoresis)
May not Rx if no symptoms
Chemo optional
149
What is monoclonal gammopathy of uncertain significance? (MGUS)
Paraprotein in serum
No other criteria of myeloma or primary haem malignancy (no bone lesions, Bence Jones, low paraprotein level, BM <10% plasma cell)
150
Name the 4 main causes of inherited thrombophilia?
1. Factor 5 Leiden- factor 5 resistant to breakdown by Protein C + S. Usually a single point mutation
2. Protein C + S deficiency- vit K dep, cleave factors 5 + 8
3. Prothrombin increase- high prothrombin, less activation of fibrinolysis (by thrombin-activated fibrinolysis inhibitor)
4. Antithrombin deficiency- inhibits thrombin, homozygous = incompatible with life
151
Patient has had a number of DVTs previously and when put on Warfarin develops skin necrosis, what inherited thrombophilia do they have?
Protein C + S deficiency (Vit-K dependent clotting factors)
152
Antiphospholipid antibodies?
Anti-cardiolipin
| Lupus anticoagulant Abs
153
Who warrants thrombophilia testing for acquired or inherited causes of arterial/venous thrombosis?
```
PC: arterial thrombosis/MI before age 50
VTE under 40 with no RFs
Neonatal thrombosis
Unexplained recurrent VTE
At least 3 miscarriages
Unusual site- mesenteric or portal vein thrombosis
```
FHx: Familial VTE in pregnancy or with contraceptives
154
What things do patients need to know if starting high dose steroids?
Steroid rules: double dose if sick, IM if vomiting, don't stop
Steroid card
PMH- conditions worsened include O DiTCH
osteoporosis, diabetes, TB, chicken pox, hypertension
DHx- take PPI, calcium + vit D supplements, bisphosphonates
Avoid NSAIDs + aspirin (ulcer disease risk)
SEs: infection, cataracts, glaucoma, psych, pancreatitis, ulcers, myopathy
155
Main SEs of ciclosporin?
The h's:
| Gum hyperplasia, hepatotoxicity, hyperkalaemia, hypertrichosis, hurting the kidneys,
156
Causes of massive splenomegaly:
My mate chrissy likes gateaus:
```
Mylofibrosis
Malaria
CML
Leishmaniasis
Gaucher's- lysosomal storage disease
```
157
Causes of moderate splenomegaly:
Vascular- portal hypertension, CCF
Infection- EBV, TB, malaria, leishmaniasis, schistosomiasis
(T)
Autoimmune- RA, SLE, sarcoid, haemolytic anaemia
Metabolic- Gaucher's (lysosomal storage)
Idiopathic
Neoplasm- CML, lymphoma
158
Features suggesting a large spleen is palpated rather than kidneys:
Palpation:
1. RUQ, can't get above it
2. Moves down with inspiration
3. Medial notch
Percussion:
Dull (also kidney would be, but colon wouldn't)
159
Blood film seen in splenectomy's?
Howell-Jolly bodies- denatured DNA seen as not removed when Hb synthesis is abnormal
Papenheimer bodies- granules of iron (siderocytes)
Target cells- abnormal Hb to membrane ratio, should be removed
160
Prophylactic Rx of patients post-splenectomy:
```
Immunisations- encapsulated organisms:
Strep pneumo
N. Meningitidis
Haemophilus inflenzae type B (HIB)
Influenza
```
Prophylaxic penicillin OD
Prevention: alert bracelet of infection risk, meticulous malaria prophylaxis when traveling abroad
161
Features of amyloidosis:
General: malabsorption > weight loss
Hands: carpal tunnel, peripheral neuropathy
Face: periorbital purpura, macroglossia
Chest: restrictive CM, angina, arrhythmias
Abdomen: hepatopmegaly, obstruction, nephrotic syndrome
162
Hows is the Schilling test used to illicit the cause of B12 malabsorption?
Radiolabelled B12 taken orally + excretion into urine measure over 24 hours.
Illustrates malabsorption present, then give injected B12 and chect excretion, a rise above 10% of total B12 excreted proves it's due to lack of intrinsic factor not terminal ileal disease or bacterial overgrowth
