haem Flashcards
1
Q
diagnosis?
A
thalassaemia trait
- microcytosis and hypochromia with normal Hb
2
Q
possible diagnoses? (2)
what if B12 and folate were in normal range?
What if there were macro-ovalocytes and hyper-segmented neutrophils?
A
haemolytic anaemia
megaloblastic anaemia
If normal B12 + folate = haemolysis or acute blood loss i.e. reticulocytosis
if macro-ovalocytes and hyperseg neutrophils = B12/folate deficiency
3
Q
polychromasia?
macro ovalocytes and hyperseg neutrophils?
A
reticulocytes
b12/folate deficiency
4
Q
what parameter on blood count is likely to be raised in patient with spherocytosis?
A
MCHC because hyperchromic
5
Q
how can you differentiate between acute blood loss and haemolysis?
A
spherocytes
spherocytes are marker of membrane damage
will NOT see them in acute blood loss
6
Q
what blood count parameters would be raised in haemolytic anaemia? (4)
A
MCHC (spherocytes)
urinary haemosiderin
serum lactate dehydrogenase
DECREASED serum haptoglobin
7
Q
when to suspect haemolytic anaemia? (3)
A
anaemia with polychromasia (reticulocytes) - either ACUTE* blood loss or haemolysis
spherocytes - not seen in acute blood loss
haemosiderin/haemoglobin in urine = intravascular
** chronic blood loss associated with microcytic anaemia due to iron deficiency - reticulocytes will not be present
8
Q
how to confirm autoimmune haemolysis?
A
DAT test (Coombs)
Dx = autoimmune haemolytic anaemia
9
Q
Ax autoimmune haemolytic anaemia? (3)
Tx?
A
infection (CMV, HIV, EBV)
autoimmune disease (lupus)
lymphoma
Tx = steroids 1st line + FOLIC ACID!
10
Q
blood film shows:
abnormally shaped red cells, neutrohpil segmentation
diagnosis?
A
myelodysplastic syndrome
i.e. macrocytic anaemia
11
Q
components of normal haemostatic system? (4)
A
formation of platelet plug - primary haemostasis
fibrin clot - secondary haemostasis
fibrinolysis
anticoagulant defences - protein C, S, anti-thrombin
12
Q
when should antiplatelet drugs be stopped prior to surgery?
examples of drugs
A
approx a week prior to surgery (platelet lifespan 7-10 days)
aspirin, clopidogrel, ticagrelor
13
Q
steps in primary haemostasis
A
endothelial damage = expresses VWF
platelets adhere to VWF
aggregation of platelets
14
Q
failure of primary haemostasis consequences? (4)
A
spontaneous bruising and purpura (often seen on lower limbs, will blanche)
mucosal bleeding (epistaxes, GI, conjunctiva, menorrhagia)
intracranial haemorrhage
retinal haemorrhage
15
Q
whats this?
A
purpura (seen in thrombocytopenia)
16
Q
causes of primary haemostasis FAILURE? (3)
A
scurvy, elderly
thrombocytopenia (or reduced platelet function)
VWF defieincy - most common inherited deficiency
17
Q
secondary haemostasis steps
A
tissue factor (TF) released from damaged endothelium
TF activates clotting factor VII
VII activates V and X
V and X stimulate prothrombin to become thrombin
thrombin stimulates fibriogen to form fibrin
thrombin also activates clotting factors 8+9
8+9 activate more V and X
18
Q
causes of FAILURE of secondary haemostasis? (3)
A
single clotting factor deficiency (usually heridirary e.g. haemophilia)
multiple clotting factor deficiencies (usually acquired e.g. DIC, liver disease, vit K deficiency/Warfarin therapy)
increased fibrinolysis
NB: in multiple clotting factor deficiencies will have prolonged PT and APTT
19
Q
fibrinolysis process
D-dimer?
A
TPA converts plasminogen to plasmin
plasmin breaks fibrin into fibrin degredation products (FDPs)
in blood, FDPs show up as D-dimers
20
Q
consequences of FAILURE of secondary haemostasis?
A
no characteristic clinical syndrome
bleeding into joints and muscles - haemophilia
DIC - severe bleeding
21
Q
screening tests for fibrin clot formation
screening test for primary haemostasis?
A
prothrombin time
activated partial thromboplastin time
primary = platelet count
22
Q
prolonged PT?
prolonged APTT?
A
prolonged PT = 7, 5, 10, prothrombin or fibrinogen
prolonged APTT = 8 and 9
e.g. if deficient in factor VII
APTT normal, PT prolonged
23
Q
clinical approach to bleeding disorders
A
history - primary or secondary?
purpura, mucosal bleeding = primary
joint bleeds, muscle bleeds = secondary (haemophilia)
duration of bleeding - hereditary will be lifelong
previous surgery/dental extractions + menstrual periods!
drug history - aspirin, anticoagulants, NSAIDs
examination - purpura, mucosal bleed, retinal exam, enlarged spleen (low platelets in circulation)
24
Q
naturally occuring anticoagulants?
what happens to thrombin?
A
antithrombin - switches off thrombin
protein C, protein S - switch off factor 5 and 8
thrombin recognises when haemostasis is achieved and binds to thrombomodulin (switches on protein C and S)
25
thrombophilia?
deficiency of naturally occuring anticoagulants (antithrombin, protein C, protein S)
tendency to develop DVT/PE
26
markers of normal tissue perfusion?
Blood pressure
consciousness
urine output
lactate
27
causes of shock?
hypovolaemic (severe dehydration, burns)
cardiogenic (MI!!, cardiomyopathy, valve problems, dysrhythmias)
distributive (massive vasodilation - "hot" shock, sepsis, anaphylaxis, acute liver failure, spinal cord injury)
obstructive (PE, air/fat/amniotic fluid embolism, tamponade, tension pneumothorax)
endocrine (hypothyroid, thyrotoxicosis, addisonian crisis)
there are more but whatever
28
hypovolaemia classification
29
monitoring shock patients?
Examination - pale, cold skin, prolonged cap refill
Urine output - sensitive indicator of renal perfusion
Neurological - disturbed consciousness -\> cerebral hypoperfusion
Biochemical - acidosis, lactate levels
Blood pressure
Central venous pressure - rarely useful except to assess “**fluid responsiveness”**
Cardiac output monitoring = **gold standard is thermodilution with PA catheter**
30
management shock?
ABCDE
wide bore IV access
Tx underlying cause
31
target MAP shock?
fluid challenge?
when fluids dont work?
when this fails?
Target for MAP = **65-70 mmHg** (normal = 70-100)
fluid challenge = **500ml over 10-20 mins**, want to see increased MAP, decreased HR, increased UO
when fluids don't work = **adrenaline** (^ HR, contractility), **noradrenaline** (vasoconstriction), vasopressin
when drugs fail = LVAD, ECMO
32
2 types of fluids used in shock?
**Crystalloids - convenient, cheap, safe**
But rapidly lost from circulation - need significantly larger volumes!!
**Colloids - cheapish, reduce the volume required**
Albumin most common
Can cause anaphylaxis
33
side effect of resuscitation?
Tx?
fluid overload - oedema, ARDS (wet lung), bowel oedema
young healthy people will just pee it out
elderly = diuretics, dialysis
34
what is massive haemorrhage?
massive haemorrhage protocol?
One blood volume (5L) in 24 hours OR
50% blood volume in 3 hours OR
blood loss of 150ml/minute
(obstretrics = \>1000ml)
ABCDE
call blood bank and state "massive haemorrhage"
send urgent FBC, coag screen, fibrinogen, Xmatch, U+E, calcium
blood bank will issue: 4 units red cells, 4 units FFP, 1 unit platelets
35
what is FFP?
cryoprecipitate?
transfusion target?
FFP = replaces clotting factors
cryoprecipitate = replaces fibrinogen
aim 2RBC : 1 FFP
in trauma = 1 : 1!!
36
Mx PPH?
most common cause = uterine atony
uterine massage
uterotonic drugs
**cryoprecipitate** (fibrinogen much higher in pregnant women)
**+ tranexamic acid**
37
trauma haemorrhage Tx?
Variceal bleed?
ruptured AAA?
trauma = tranexamic acid within 3 hours!!
Variceal bleed = **terlipressin**, **FFP very important**, band ligation of varices!!
ruptured AAA = blood component support until **emergency surgery (EVAR)**
38
what should **NOT** be used in GI haemorrhage?
tranexamic acid!!
39
when to suspect DVT?
d-dimer
doppler
WELLS score
40
types of thrombocytopenia?
hereditary i.e. **VWF deficiency** (most common)
aquired:
reduced production (marrow problem) - pancytopenia
increased destruction = DIC, ITP, portal hypertension (hypersplenism)
41
Ax platelet **functional** deficits (i.e. normal number)?
hereditary
acquired = drugs (aspirin, NSAIDs), renal failure
42
von willebrand factor deficiency?
most common hereditary bleeding disorder (failure of platelet plug fomration but normal platelet count)
autosomal dominant
43
commonest cause of primary haemostatic failure?
thrombocytopenia - usually ITP or portal hypertension
44
clotting factor synthesis?
what is essential for function?
ALL synthsised in hepatocytes (reduced in liver failure)
factor 2, 7, 9 + 10 carboxylated by vitamin K whcih is essential for function
45
vitamin K absoprtion?
Ax vit K deficiency?
absortped in small bowel, requires **bile salts** for absorption
Ax deficiency
\* poor diet
\* malabsorption
\* obstructive jaundice (no bile)
\* Warfarin
\* haemorrhagic disease of the newborn
46
disseminated intravascular coagulation?
S/s?
blood count will show?
coag screen?
Excessive activation of haemostatic system - **primary, secondary and fibrinolysis**
S/s = bruising, purpura, generalised bleeding, **end organ failure**
blood count = **thrombocytopenia**, reduced clotting factors, **lots of D-dimer (FDPs)**
coag screen = **prolonged PT and APTT**
47
Ax DIC?
Tx?
basically anything that leads to massive tissue damage and so excess haemostatic activity = sepsis, obstetric emergencies, malignancy, hypovolemic shock
Tx = treat underlying cause, **platelets, FFP, cryoprecipitate**
48
haemophillia?
inheritance?
Types?
severity?
Hereditary **single** clotting factor deficiency
X-linked
Hemophilia A (factor VIII deficiency) - 5 x more common than hemophilia B
Hemophilia B (factor IX deficiency)
3 types: mild, moderate, severe (severe is most common)
49
features haemophilia?
No abnormality of primary hemostasis
Depending on if hemophilia A or B, will only have deficiency of **factor VIII or IX**
So **prothrombin time will be normal**
**APTT will be prolonged**
50
clinical features of severe haemophilia?
complication?
Recurrent hemarthrosis
Recurrent soft tissue bleeds
Bruising in toddlers
Prolonged bleeding after dental extractions, surgery and invasive procedures
comp: recurrent bleeds within the joint can lead to significant joint damage (can see loss of joint space + fusion)
51
isolated prolonged APTT?
suspect haemophillia
52
categories thrombosis?
Arterial = coronary, cerebral, peripheral
Venous = deep venous thrombosis, pulmonary embolism
53
arterial thrombosis Ax?
thrombus?
Tx?
Ax = atherosclerosis
platelet rich thrombus
Tx = aspirin and other antiplatelet drugs
modify risk factors for atherosclerosis - smoking, weight
54
venous thrombosis Ax?
thrombus?
Ax = Virchow's triad
\* stasis + endothelial damage + hypercoagulability
platelets not activated so **fibrin-rich** clot
Tx = anticoagulants e.g. heparin, wafarin, DOACs
55
risk factors VTE?
elderly
obesity
pregnancy + puerperium
HRT, COCP
previous DVT/PE
trauma, surgery
malignancy
thrombophillia
56
thrombophillia?
commonest thrombophillia?
Deficiency of anticoagulant defences (protein S, C, antithrombin)
commonest thombophilia = facotr V Leiden
\* change in factor V protein, **cannot be switched off by proten C or S**
57
Hereditary thrombophilias?
Factor V Leiden
Prothrombin 20210 mutation
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
58
when to suspect hereditary thrombophillia?
Tx?
Venous thrombosis \<45 years old
Recurrent venous thrombosis
Unusual venous thrombosis
Family history of venous thrombosis
Family history of thrombophilia
Tx = avoid COCP
**short term prophylaxis** to prevent thrombotic events during period of known risk
**short term anticoagulation** to treat thrombotic events
**long term anticoagulation** if **_recurrent_** thrombotic events
59
acquired thrombophillia?
S/s?
features?
Dx?
Antiphosphilipid antibody syndrome
s/s = recurrent thrombosis (arterial i.e. TIAs, venous), recurrent foetal loss, mild thrombocytopenia
Dx = aCL + LA
will see prolonged APTT (confusing but just know this)
60
conditions associated with APS?
Tx?
Autoimmune disorders
Lymphoprilifative disorders
Viral infections
Drugs
**Primary** - most common
**Tx = aspirin + Warfarin**
(remember different in pregnancy - **LMWH**)
61
indications for anticoagulant drugs?
Examples?
Venous thrombosis
Atrial fibrillation
anticoagulants = heparin + LMWH, Warfarin, DOACs
62
heparin mechanism?
benefit?
2 types?
mechanisms of types?
heparin = increases antithrombin effect
benefit = immediate effect
2 forms = unfractioned + LMWH
LMWH = antithrombin-Xa reaction
unfractioned = antithrombin-thrombin reaction
63
herpatin complications?
reversal?
Bleeding
Heparin induced thrombocytopenia (with thrombosis) HITT - so if patient on heparin and platelet count DROPS they are actually at risk of thrombosis
Osteoporosis with long term use
Heparin - reversal
\* **stop herparin** (short half-life)
\* in emergency = **protamine sulphate**
64
mechanism of action Warfarin?
what do you have to give warfarin with initially?
why?
inhibition of vit K
warfarin must be given with **herparin** initially as inhibits protein C and protein S for a while
65
Warfarin therapy cons?
Benefits?
requires INR monitoring (every few weeks)
risk of haemorrhage
drug interactions - aspirin, antibiotics, NSAIDs, spinach, kale, cranberry juice
cant take in pregnancy
benefits = reversible with vitamin K (or in emergency = clotting factors, as vit K takes a few hours)
66
DOACs?
benefits?
cons?
new anticoagulants
oral Xa inhibitors = edoxaban, rivaroxiban, apixiban
direct thrombin inhibitors = dabigatran
benefits = no monitoring
cons = not reversible + cannot be used in renal disease (Warfarin can)
67
DOACs used for?
DVT/PE
## Footnote
**stroke prevention in AF patients**
68
PSIS
69
immunophenotyping
70
ESRD and erythropoetin
71
haemopoesis?
types?
production of RBCs, WBCs + platelets
erythropoiesis = RBC
Thrombopoesis = platelets
Lymphopoiesis = WBC
granulopoiesis/myelopoiesis = production of granulocytes
72
lifespan of blood cells?
therefore?
RBC = 120 days
neutrophils = 7-8 hours
platelets = 7-10 days
So if haemopoiesis switched off, would expect neutrophils to fall, then platelets then red cells
73
ancestry of blood cells?
RBC
Pro-**normoblast** → late normoblast → reticulocyte → erythrocyte
Neutrophil
**Myeloblast** → promyelocyte → myelocyte → metamyelocyte → band neutrophil → mature neutrophil
Platelet = **megakaryocyte**
74
where do precursors (erythroblasts, myeloblasts) come from?
haemopoetic **proginitor cells**, which come from haemopoetic **stem cells**
75
myelocytes?
**nucleated** precursor between **myeloblasts** and **neutrophils**
76
myeloid terminology?
77
haemopoetic stem cells originate from?
sites of haemopoesis?
originate in **mesoderm**
**yolk sac is first site of haemopoeisis**
week 6 = liver
week 16 = bone marrow
in adults, haemopoesis restricted to **axial skeleton, pelvis, and proximal long bones**
in children, haemopoesis occurs in **all bones**
78
bone marrow cellularity?
subtract age from 100
so 20 year old has 80% cellularity
79
where to collect bone marrow biopsy?
adults = PSIS
children = anterior tibia
80
red vs yellow marrow?
myeloid:erythroid ratio?
normal ratio?
when will it change?
Red (haemopietically active) vs yellow (fatty inactive) marrow: increase in yellow marrow with age results in reduction in marrow cellularity in older individuals
myeloid:erythroid ratio = proprtion of neutrophils/precursors to proportion of **nucleated** red cell precursors
Normal = 1.5:1 to 3.3:1
ratio reverses in haemolysis as compensation
81
neutrophil precursor maturation regulated by?
platelets?
erythropoeisis?
neutrophil precursor maturation regulated by G-CSF (granulocyte colony stimulating factor)
thrombopoetin regulates development of **magakaryocytes**
erythropoesis = erythropoetin, iron (haem), folate, globin synthesis
82
Ix haemopoesis?
Routinely undertaken = FBC, cell indices, morphology (blood films)
Less common (specialist) - bone marrow examination
83
investigations for non-lymphoid cells vs lymphoid?
For non-lymphoid = blood count/morphological assessment often sufficient
lymphoid cells = **immunophenotyping**
84
how to harvest stem cells?
G-CSF injections stimulate mobilisation of stem cells form bone marrow into blood
85
ancestry lymphoid cells?
86
lymphoid system?
Central (primary) lymphoid tissues = bone marrow + thymus
Peripheral (secondary) lymphoid tissues = lymph nodes, spleen, tonsils (waldeyer’s ring), epithelio-lymphoid tissues
87
lymph node anatomy?
afferent channels drain lymph into peripheral sinus where it is filtered
efferent vessel exits hilum, drains to:
cisterna chyli/thoracic duct
or left subclabian vein
into venous system :)
arterial and venous supply to nodes enter/exit via hilum
88
lymphoid system function?
immune function
prevents oedema
89
cell populations in lymph nodes?
Lymphocytes
* B cells
* Associated with follicles and germinal centres
* Interfollicular
* Plasma cells - mainly in medulla
* T cells
* T helper cells + cytotoxic
* Natural killer cells
Macrophages, antigen presenting cells, and dendritic cells
Endothelial cells
90
lymphadenopathy Ax?
(INDAM = infectious/inflammatory, neoplastic, drugs, autoimmune, metabolic)
Local inflammation
* Infection (some have typical features e.g. TB, toxoplasma)
* Others e.g. vaccination, dermatopathic
Systemic inflammation
* Infection e.g. viral infections
* autoimmune/CT disorders
Malignancy
* Haematological e.g. lymphoma/leukemia
* Metastatic
Others
* E.g. sarcoidosis, Castleman's disease, IgG4 related disease
91
red lines extending from inflamed node?
lymphangitis
92
generalised lymphadenopathy suggests?
systemic infection
**lymphoma/leukemia** - must check FBC
autoimmune
93
lymph node response to autoimmune? tumour? viral infection?
94
spleen palpable?
surfaces?
vascular supply?
rupture?
spleen not palpable unless substantially enlarged
2 key surfaces: diaphragmatic + visceral (left kidney, gastric fundus, tail of pancreas, splenic flexure of colon)
supplied by **splenic artery** (branch of coelic)
* drained by **splenic vein** (forms portal vein alongside SMV)
rupture is a **surgical emergency**
95
structure of spleen?
function?
red pulp + white pulp
* red pulp = sinusoids + cords
* sinusoids = fenestrated
* cords = contain macrophages
* white pulp = contains CD4+ cells + PALS
**functions as a** **filter** = eliminates unwanted material, facilitates immune response to blood-borne antigens
96
how does spleen facilitate immune repsonse?
APCs in white pulp present antigen to immune cells
When stimulated by antigen, T and B cell responses may occur
97
splenomegaly symptoms?
Traid of hypersplenism?
Dragging sensation in LUQ
Discomfort with eating
Pain if infarction
**Triad of hypersplenism** = splenomegaly + fall in one or more cellular components of blood + correction of cytopenias by splenectomy
98
causes of splenomegaly?
infection = EBV, malaria, TB, typhoid, brucellosis, lesihamniasis, trypanosomiasis
congestion = portal hypertension, cirrhosis, splenic vein thrombosis, cardiac failure
haemotological diseases = lymphoma/leukemia, haemolytic anaemia, ITP, myeloproliferative disorders
inflammatory conditions = RA, SLE
storage diseases = Gaucher's, Neimmann-Pick disease
miscellaneous = amyloid, tumours, cysts
99
Ax hypersplenism vs hyposplenism?
hypersplenism
* conditions associated with splenomegaly
hyposplenism
* most commonly from splenectomy (need immunopsuppression)
* other causes = coeliac disease, sickle cell, sarcoidosis, iatrogenic
100
features of hyposplenism?
**Howell-Jolly bodies**
also some immune deficiency
101
basophilia seen in?
polycythaemia rubra vera
chronic myeloid leukaemia
102
monocytosis seen in?
chronic bacterial infections
malignancy (chromic myelomonocytic leukaemia)
connective tissue disease (SLE + RA)
103
are monocytes raised in smoking?
No - will see mild neutrophilia tho
104
features of monocytes?
precursor?
large monolobular cells
same precursor as granulocytes but **unlike granulocytes** do not have prominent granules
105
functions monocytes?
phagocytosis + antigen presenting
106
lymphocyte origins and development?
lymphocytosis?
arise in bone marrow + develop in primary lymphoid organs (bone marrow + thymus)
lymphocytosis in response to infection or malignancy
can also be seen after removal of spleen
107
EBV mononucleosis characteristic appearance?
T cells blue cytoplasm wraps around neighbouring cells
(can also be seen in HIV, CMV, viral hepatitis + toxoplasma)
108
stable plaques can cause?
unstable plaques?
stable plaques = stable angina (coronary artery) + PVD claudication
unstable plaques = MI, stroke
109
risk factors arterial thrombosis?
Hypertension
Smoking
High cholesterol
Diabetes
110
platelets bind to?
platelet aggregation chemicals?
platelets bind to VWF (released by damaged vessel wall)
ADP, thromboxane A2
111
e.g. antiplatelet drugs?
Aspirin - inhibits cyclooxygenase which is necessary to produce thromboxane A2 (prevents platelet aggregation i.e. stops them sticking together)
Clopidogrel, prasugrel - ADP receptor antagonists
Dipyridamole - hosphodiesterase inhibitor, reduced production of cAMP which is “second messenger” in platelet activation
abciximab - GP II2b/IIIa inhibitor (surface proteins platelets use to bind to each other)
112
side effects aspirin?
Bleeding
Blocks production of prostaglandins
* GI ulceration
* Bronchospasm (contraindicated in asthma)
113
which drug is contraindicated in asthma?
aspirin!!!
114
side effects antiplatelet drugs?
Tx?
bleeding!
will affect platelets for 7-10 day lifespan so stop antiplatelets approx a week before surgery
in emergency = can reverse with platelet transfusion
115
A - acute leukemia
116
D - chronic lymphocytic leukemia
117
???
118
how are proginitor/stem cells identified?
**immunophenotyping**
119
acute leukaemia pathophys?
Blood count?
bone marrow?
Proliferation of abnormal progenitors PLUS
Lack of differentiation/maturation of RBCs, platelets, and granulocytes
high white cell count + low RBC, platelets, granulocytes
tons of abnormal cells in bone marrow
120
chronic myeloproliferative disorders pathophys?
e.g.?
blood count?
why?
in contrast to acute leukemia = proliferation of abnormal proginitors but **no differentiation/maturation** failure
e.g. **chronic myeloid leukemia**
so blood count = very high white cells (due to **neutrophils**), low RBC, low/high platelets
the platelets and red cells may be low because all the neutrophils will take up space in bone marrow - **there is no problem with maturation!!!**
121
main cell type that differentiates CML and AML?
neutrophils!!
In AML = low
in CML = high
122
haematological malignancy divided into?
myeloid or lymphoid
developmental stage i.e. lymphoblastic vs lymphocytic vs myeloma
anatomical site
* blood = leukemia
* lymph node = lymphoma
123
myeloma?
malignancy of plasma cell in marrow
124
differences in histology/progression of haematological malignancies?
Acute leukaemias and high grade lymphomas are more aggressive (histologically and clinically) than chronic leukaemias and low grade lymphomas
in acute leukemias + high grade lymphomas more likely to see: high nuclear:cytoplasmic ratio, prominent nucleoli, rapid proliferation
125
what do all leukemias present with?
All Leukaemias present (more commonly than chronic leukaemia) with significant bone marrow failure
126
malignant haemopoesis
myeloid vs lymphoid?
myeloid malignancies tend to involve more primitive progenitor cells
lymphoid malignancies can turn malignant at various stages
127
acute leukemia features?
Types?
Rapidly progressive malignancy of bone marrow + blood
With **maturation defects**
Defined as excess of “blasts” **\>20%** in blood or bone marrow
Loss of normal blood cell production (RBC, platelets, neutrophils, basophils + eosinophils)
Types
* Acute myeloid leukaemia (AML)
* Acute Lymphoblastic leukemia (ALL)
128
acute lymphoblastic leukemia?
clinical presentation?
Malignant disease of primitive lymphoid cells (lymphoblasts)
(most common childhood cancer!)
clinical presentation
* bleeding (nosebleeds), bruising, anaemia + infections (due to marrow failure)
* fever
* fatigue, weakness
* weight loss
* bone pain
129
commonest childhood cancer?
acute lymphoblastic leukemia
130
acute myeloid leukemia epidemiology?
S/s?
elderly \>60 y/o
presentation same as ALL (marrow failure)
some have characteristic presentation
* **DIC in acute promyelocytic leukemia**
* gum infiltration
131
Ix acute leukemia?
Blood count (increase in WBC - reduction in Hb, neutrophils, platelets)
Blood film (will see "blasts", large size, huge nucleus, prominent nucleolus)
Coagulation screen (d-dimers and fibrinogen for DIC)
Bone marrow aspirate (same as blood film)
Cytogenetic analysis
132
Auer rods?
AML!!!
133
how to differentiate between AML and ALL?
why is this important?
bone marrow aspirate sub-optimal?
Immunphenotyping used to differentiate between AML and ALL even if there are **Auer rods** in the blasts
important because **treatment of AML is different from ALL**
Trephine (piece of bone) - enables better assessment of cellularity and helpful when aspirate sub-optimal
134
so definitive diagnosis of acute leukemia?
**immunophenotyping!!**
(only definitive way to distinguish between AML and ALL)
135
Tx acute leukaemia?
ALL - can last up to 2-3 years
* chemo
AML - between 2-4 cycles of chemotherapy (5-10 days of chemo followed by 2-4 weeks recovery)
* Prolonged hospitalisation
* Often need long-term central venous access
136
CVC placement for AML?
tip should sit at junction of SVC and right atrium
137
acute leukaemia (marrow failure) complications?
Tx?
Anaemia
**Neutropenia**
* Gram NEGATIVE infections can be life-threatening
* Therefore if **neutropenic patient develops fever**, broad spectrum antibiotics are initiated **IMMEDIATELY**
* **DO NOT WAIT FOR CULTURE RESULTS** (but do take blood culture before administering antibiotics)
* In patients with neutropenic fever that does not resolve with antibiotics, assume **fungal infection**
thrombocytopenia
* bleeding, purpura, petechiae
* prophylactic platelet infusions **even if no evidence of bleeding**
138
chemo side effects
late effects?
Nausea and vomiting
Hair loss
Liver + renal dysfunction
Tumour lysis syndrome (hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia)
Infection
* **Bacterial - empirical treatment with broad spectrum antibiotics (esp covering gram neg) as soon as neutropenic fever (IMPORTANT)**
* Fungal (if prolonged neutropenia and persisting fever unresponsive to anti-bacterial agents) - IMPORTANT
* Protozoal e.g. PJP (more relevant in **ALL therapy**)
* **So patients with ALL often offered prophylaxis against pneumocystis** (co-trimox?)
Late effects e.g. loss of fertility, **cardiomyopathy with anthracyclines**
139
D - urgent biopsy followed by steroids
140
B - excision biopsy of lymph gland
I THINK
141
symptoms of lymphoma?
when to suspect Hodgkins?
lump
B symptoms - fever, night sweats, weight loss (10% over a 6 month period)
**itch without rash + alcohol-induced pain = suspect Hodgkin's lymphoma**
142
lymphadenopathy features
143
Ix lymphadenopathy?
FBC - chronic lymphocytic leukaemia (CLL) is one disease where FBC is diagnostic = **lymphocytosis**
* then do **immunophenotyping** (do not need biopsy in CLL)
Biochemical profile - hypercalcaemia
General investigations for INDAM
**Biopsy** “**the only way” for diagnosis and treatment**
Imaging - extent of lymphadenopathy and/or associated pathology
144
diagnostic approach lymphadenopathy?
145
imaging for lymphoma?
**CANNOT be diagnosed by CT**
but still useful
Dx = biopsy!!
146
Dx lymphoma
**Dx = incision biopsy!!!!**
| (FNA + core biopsy **not acceptable**)
147
...
148
immunohistochemistry lymphoma?
antibodies against proteins in biopsy
brown = positive
149
reed sternberg cells?
Hodgkins lymphoma
150
genetics analysis of lymphoma biopsy?
Fluorescence in situ hybridisation (FISH) or PCR for specific abnormalities:
* t(14;18) in follicular lymphoma
* t(8;14) in Burkitt's lymphoma
* Myc rearrangements in high-grade B cell lymphoma
151
types of B cell lymphoma?
**Hodgkins**
non-hodgkins:
**Burkitt's**
diffuse large cell B cell lymphoma
Mantle cell lymphoma
Follicular lymphoma
152
classifications of lymphoma?
153
risk factors lymphoma?
In many patients there is no identifiable risk factor
Immunosuppression (e.g. HIV, inherited immunodeficiency states)
Autoimmune disorders (e.g. Sjogren’s, coeliac)
Infections (EBV, H.pylori, HHV-8, HTLV-1)
Genetic predisposition
Environment
154
staging of lymphoma using?
system?
CT + PET
Ann Arbor staging system:
* stage 1 = only one lymph node or one extra-nodal area
* stage 2 = 2 or more lymph nodes on one side of diaphragm
* stage 3 = 2 or more lymph nodes on both sides of diaphragm
* stage 4 = disseminated, or multiple extra-nodal areas
155
prognosis lymphoma?
lactate dehydrogenase (LDH) = prognostic
156
hodgkin's lymphoma associated with?
spread?
hallmark?
Tx?
prognosis?
link with **EBV infection**
spread to lymph node groups is orderly
hallmark = **reed-Sternberg cell** (variant “lacunar” cell)
Tx = multi-agent chemotherapy +/- radiotherapy
* Immunotherapy/stem cell transplant is an option for patients not responding to chemo
prognosis:
* good cure rates - particularly in younger patients
157
complication chemo?
Bleomycin can cause pneumonitis
Long term toxicity including secondary cancers, cardiovascular disease, infertility
158
non-Hodgkin's subtype associated with high-grade lesions?
Extranodal disease?
Tx?
prognosis?
diffuse large B cell lymphoma = common high-grade NHL
Extranodal disease = T cell NHL, Burkitt lymphoma
Tx
* multi-agent chemo +/- radiotherapy
* Monoclonal antibody therapy
* **Ritixumab** in B cell NHL
* **Brentuximab** in T cell NHL
* stem cell transplant when unresponsive to therapy
High grade NHL = usually curable
Low-grade is incurable but many patients may not need treatment (unless rapidly progressive lymphadenopathy, B symptoms etc)
159
burkitt's lymphoma?
Ax?
disease sites?
genes?
complication?
Fastest growing human tumour!
Ax = **EBV**, HIV, sporadic
Disease sites = **jaw** or **abdominal tumour**, bone marrow, CNS, kidney or testis
genes = c-myc!!
comp = tumour lysis (usually following treatment)
* **hyperkalaemia, hypocalcaemia, hyperphosphataemia, hyperuricaemia, renal failure**
160
steroid use lymphoma?
used in **emergency management** of suspected lymphoma i.e. in **compression symptoms** (SVC, spinal cord, respiratory tract)
* Always try to avoid steroids before biopsy
* Can cause cell necrosis making it hard for pathologist
161
Dx?
pancytopenia - not a diagnosis on its own (must find cause)
162
pancytopenia?
rules?
Pancytopenia = deficiency of blood cells of ALL lineages (but generally **excludes** lymphocytes)
so **anaemia + neutropenia + thrombocytopenia**
* Pancytopenia is NOT a diagnosis
* It does NOT always mean bone marrow failure or malignancy
163
erythrocyte precursor?
164
pancytopenia Ax?
reduced production or increased destruction
* reduced production = acquired or inherited
* increased destruction = **hypersplenism**
165
triad inherited bone marrow syndromes?
congenital anomalies + impaired haemopoeisis (pancytopenia) + cancer predisposition
166
Ax reduced production pancytopenia?
**inherited** bone marrow syndromes e.g. Fanconi's anaemia
**acquired** causes:
* primary bone marrow failure
* idiopathic aplastic anaemia - autoimmune attack against haemopoetic stem cells
* myelodysplastic sysndromes (MDS)
* acute leukaemia
* secondary bone marrow failure
* drug-induced (chemo, alcohol, azathiprine, methotrexate, chloramphenicol) = aplasia
* B12/folate deficiency (nuclear maturation can affect all lineages)
* infiltrative - metastasis, lymphoma
* viral
* storage diseases
167
Fanconi's anaemia S/s?
Ax?
S/s = short stature, hypogenitalia, GI defects, cardio disease, renal disease
**haematological abnormalities!**
* marrow failure by 20 years old
* **macrocytosis, thrombycytopenia, neutropenia**
Ax = unable to fix DNA damage
168
idiopathic aplastic anaemia?
Ax?
features?
cause of primary pancytopenia
Ax = auto-reactive T cells to HSC
will have no RBCs, neurophils or platelets
(different to B12/folate deficiency + MDS when u see **hyper**cellular marrow)
169
myelodysplastic syndromes?
feature?
why do you get pancytopenia?
compliation MDS?
Dysplasia!! - cause of primary pancytopenia
**Hypercellular marrow (despite low cellularity in blood)**
Increased apoptosis of progenitor and mature cells (**ineffective haemopoeisis**)
complication = **evolution into AML**
170
why can acute leukaemia cause pancytopenia?
171
secondary bone marrow failure?
Ax?
cause of pancytopenia
* Drug-induced (e.g. chemotherapy, alcohol, azathioprine, methotrexate, chloramphenicol) - causes aplasia
* B12/folate deficiency (nuclear maturation can affect all lineages) - marrow is hypercellular
* Infiltrative - metastatic malignancy, lymphoma
* Misc - viral (HIV), storage diseases
172
increased destruction pancytopenia?
S/s?
Ax?
**HYPERSPLENISM**
s/s = splenomegaly
Ax:
* splenic congestion - portal hypertension
* systemic diseases - rheumatoid arthritis
* haematological = splenic lymphoma
173
summary pancytopenia
174
s/s pancytopenia?
Anaemia
* Fatigue
* SOB
Neutropenia = infections
Thrombocytopenia
* Bleeding
* Purpura
* Petechiae
* “Wet” bleeds i.e. visceral bleeds
175
Ix cause of pancytopenia?
History
Clinical findings - skeletal abnormalities (Fanconi)
FBC, blood film
B12/folate, LFTs, virology, autoantibody tests
Bone marrow examination (hyper vs hypocellular)
Specialised tests guided by above (cytogenetics, e.g. chromosome fragility testing in Fanconi’s syndrome, NGS, WES)
176
marrow cellularity in pancytopenia?
**Hypo**cellular in aplastic anaemia
**Hyper**cellular in:
* Myelodysplastic syndromes
* B12/folate deficiency
* Hypersplenism
177
Tx pancytopenia?
supportive
* Red cell transfusions, platelet transfusions
* for neutrophils tranfusions are not routine - instead = **antibiotic prophylaxis**
* **TREAT NEUTROPENIC SEPSIS IMMEDIATELY**
specific = related to cause
* **primary bone marrow disorders**
* malignancy = chemo
* congenital = bone marrow transplant
* idiopathic aplastic anaemia = immunosuppression
* **secondary bone marrow disorder**
* drug reaction = stop
* viral = treat HIV
* replace B12/folate
* hypersplenism = treat cause (e.g. portal hypertension) or **splenectomy**
178
immediate cytotoxic drug side effects?
long term?
Tx?
immediate (affects rapidly dividing organs)
* Bone marrow suppression, gut mucosal damage, hair loss (alopecia)
* Vinca alkaloids = neuropathy
* Anthracyclines = cardiotoxicity
* Cis-platinum = nephrotoxicity
long term
* Alkylating agents = infertility, secondary malignancy
* Anthracyclines = cardiomyopathy
Tx for immunosuppression = **haemopoetic growth factors**! + combine suppressive vs non-suppressive drugs
179
what is used to monitor response to therapy in Hodgkin's lymphoma?
PET scan
180
haematological uses of biologics?
e.g.?
**multiple myeloma!!**
e.g. thalidomide, lenalidomide (revlimid)
181
Tx CML?
tyrosine kinase inhibitors
182
myeloproliferative disorders (neoplasms)?
what do they result in?
Myelo = bone marrow (granulocytes, red cells and platelets)
Proliferative = rapid multiplication
MPNs result in overproduction of **mature, differentiated** cells as opposed to primitive blast cells seen in AML (acute leukaemia)
183
myeloproliferative neoplasm types?
**BCR-ABL1 negative**
* Primary myelofibrosis
* Polycythaemia vera (overproduction of red cells)
* Essential thrombocytopenia (overproduction of platelets)
**BCR-ABL1 positive = CML**
* CML = overproduction of granulocytes
* **Philadelphia chromosome!!! (chromosome 22)**
184
when to consider MPN?
High granulocyte count
High red cell count/Hb
High platelet count
Eosinophilia/basophilia
Splenomegaly
Thrombosis in an unusual place (i.e. toe)
NO REACTIVE EXPLANATION
185
suspect MPN - polycythaemia vera?
* raised Hb
* raised eosinophils + basophils
* significantly raised haematocrit
186
this patient has severe COPD
this is NOT myeloproliferative disorder as there is a reactive cause for the symptoms
* significantly raised Hb + haematocrit
* neutrophilia
**so Dx is** **secondary polycythaemia due to hypoxia from COPD**
187
chronic myeloid leukaemia?
clinical features?
Proliferation of myeloid cells
* Granulocytes and their precursors
* Other lineages (platelets)
S/s = asymptomatic, splenomegaly, hypermetabolic symptoms (weight loss, sweats), gout, problems related to hyperleukocytosis e.g. priapism
188
lab features CML?
**Blood count changes**
* normal/decreased Hb
* Leukocytosis with neutrophilia and myeloid precursors (myelocytes)
* eosinophilia, basophilia
* thrombocytosis
**Bone marrow biopsy**
* Increased cellularity
* Increased granulocytes
189
early satiety + weight loss
Dx = CML
* weight loss
* moderate anaemia
* very high WCC (neutrophillia, eosinophillia + basophilia)
* raised platelets
190
empyema
Dx = reactive picture seconary to empyema
* moderate anaemia
* high WCC (neutrophilia)
* thrombocytosis
191
hallmark of CML?
philadelphia chromosome
(chromosome 9 + 22 translocation)
**BCR-ABL1 positive!!**
192
pathophys CLM?
thus Tx?
Philadelphia chromosome results in new gene: **BCR-ABL1**
Gene product is a **tyrosine kinase** which causes haematological changes
Tx = tyrosine kinase inhibitors (**e.g. imatinib**)
193
BCR-ABL1 negative MPN?
symptoms?
Polycythaemia vera
Essential thrombocythemia
Primary myelofibrosis (very rare)
symptoms common to MPN = can be **asymptomatic**
* gout, fatigue
* weight loss, sweats
* marrow failure (anaemia)
* thrombosis (arterial or venous including TIA, MI, abdominal vessels, claudication)
* erethromelalgia - pain and redness in hands and feet
194
polycythaemia vera features?
must distinguish from?
**High haemoglobin + haematocrit!**
**Erythrocytosis** (true increase in red cell mass)
Rest of blood count probably normal
MUST DISTINGUISH FROM **secondary polycythaemia**
* Chronic hypoxia
* Smoking
* Erythropoietin-secreting tumour
AND **pseudopolycythaemia**
* Dehydration
* Diuretics
* Obesity
195
pseudopolycythaemia?
actually a normal amount of red blood cells - however haematocrit high due to decreased volume of blood
196
clinical features polycythaemia vera?
Clinical features common to MPN (see before)
Plus
* Headache, fatigue (remember blood viscosity raised NOT plasma viscosity)
* Itch (aquagenic pruritus) - i.e. itch in response to warm water
197
Ix polycythaemia vera?
History (e.g. history suggestive of secondary polycythaemia?)
Examination e.g splenomegaly + investigation of secondary/pseudo causes e.g. **CXR, SaO2**
FBC, film
**JAK2 mutation status (IMPORTANT)**
198
JAK2 mutation?
Present in \>95% of patients with PV
**NOT present in patients with secondary or pseudopolycythaemia**
199
Tx polycythaemia vera?
Venesect to haematocrit **\<0.45**
Aspirin (thrombosis risk)
Cytotoxic oral chemotherapy e.g. hydroxycarbamide (also used in sickle)
200
essential thrombocythaemia?
overproduction of platalets + abnormally large platelets
i.e. **uncontrolled production of abnormal platelets**
201
* clinical features ET?
platelet function abnormal so thrombosis + at high levels can result in **bleeding** due to acquired Von Willebrands disease
* can be asmptomatic
* clinical features common to MPN (particularly thrombosis)
* bleeding
202
does high platelet count = essential thrombocytopenia?
example
High platelet count **DOES NOT** equal essential thrombocythemia
on left = high platelet, normal Hb + WBC = ET
on right = low Hb, neutrophillia = reactive thrombocytosis secondary to major surgery (AAA repair)
203
ET diagnosis?
Exclude reactive thrombocytosis - IMPORTANT (blood loss, inflammation, malignancy, iron deficiency)
Exclude CML - can present with high platelet count
Genetics (about 50% have JAK2)
204
ET Tx?
Antiplatelets = aspirin
Cytotoxic = hydroxycarbamide, anagrelide, interferon alpha
205
myelofibrosis?
Ax?
rare cause of BCR-ABL1 negative MPN
Ax
* primary = idiopathic
* secondary = post-polycythaemia vera or post-ET
206
idiopathic myelofibrosis clincal features?
Marrow failure (variable degrees)
Bone marrow fibrosis (no alternative cause)
Extramedullary haemopoesis (liver and spleen)
**Leukoerythroblastic film appearances** - IMPORTANT
**Teardrop-shaped RBCs in peripheral blood**
207
myelofibrosis symptoms?
Clinical features common to MPN
Marrow failure = nnaemia, bleeding infection
Splenomegaly (LUQ pain) + hepatomegaly
* complications e.g. portal hypertension
Night sweats
Unexplained weight loss
208
myelofibrosis Dx?
Typical blood film (**teardrop RBC** and leukoerythroblastic)
Trephine (unable to aspirate bone marrow due to underlying fibrosis)
* **Fibrosis on trephine biopsy**
JAK2, CALR, MPL mutations (majority JAK2)
209
leukoerythroblastic blood film?
Ax?
neutrophil precursors (myelocytes) + red cell precursors (erythroblasts) in peripheral blood
Ax
* reactive - sepsis
* marrow infilration
* **myelofibrosis**
210
fibrosis in bone marrow trephines?
Dx = myelofibrosis
211
myelofibrosis Tx?
Different from ET and PV
* Supportive care (blood transfusion, platelets, antibiotics)
* Allogeneic stem cell transplantation in young, fit patients (only potentially curative option but extremely high morbidity)
* JAK2 inhibitors (improve spleen size, symptoms) - ruxolitinib
212
....
213
....
214
neutrophil maturation?
myeloblast \> promyelocyte \> myelocyte \> neutrophil
215
RBC maturation?
earliest site of entry to bloodstream?
pronormoblast \> normoblast \> reticulocyte \> eryethrocyte
earliest site of entry to blood = reticulocyte (also first nucleus free cell)
216
granulocytes?
Eosinophils
Basophils
Neutrophils
217
neutrophil features?
function?
Segmented nucleus (polymorph)
function = phagocytose invaders, kill with granule contents, attract other cells
218
eosinophil features?
function?
Bi-lobed + bright orange/red granules
Function = fight parasitic infections, allergic reactions
219
basophil features?
function?
Large deep purple granules obscuring nucleus
Function
* Basically circulating version of tissue mast cell
* Mediates hypersensitivity reactions
* FcE Receptors bind IgE
* Granules contain histamine
220
monocytes features?
function?
Large single (mono) nucleus, often vacuolated
Function
* Enter tissues to become macrophages
* Phagocytose invaders
* Kill them and present antigen to lymphocytes
Much longer lived than neutrophils
221
lymphocytes mature vs atypical?
Mature
* Small with condensed nucleus
Activated (atypical) - seen in glandular fever!!
* Large with plentiful blue cytoplasm
Atypical shown here:
222
structure of RBCs
full of Hb to carry oxygen
No nucleus - can’t divide, can’t replace damaged proteins
No mitochondria either - limited to glycolysis for energy generation (no Kreb’s cycle)
High surface area/volume ratio to allow for gas exchange
Flexible to squeeze through capillaries
223
oxidation RBC?
Oxidation (Fe3+) is BAD for RBCs!!
224
Hb structure?
2 alpha + 2 beta chains
haeme group is Fe2+ in flat porphyrin ring
one haem per subgroup (4)
one oxygen molecule binds to one Fe2+
(oxygen does NOT bind to Fe3+)
225
red cell production regulated by?
Red cell production regulated by erythropoietin
* Hypoxia sensed by kidney
Erythropoietin produced
Stimulates RBC production
226
red cell destruction?
aged cells taken up by macrophages in spleen + liver
red cell contents recycled (amino acids + iron)
* haem broken down to iron + bilirubin
* globin chains broken down to amino acids
bilirubin then taken to liver and **conjugated**
then excreted in bile (colours faeces and urine)
227
redistribution of blood cells?
Low cell count
* Chronic liver disease -\> portal hypertension -\> splenomegaly
High cell count
* Steroids - neutrophils will leave tissues and enter circulation instead
* Splenic trauma
228
...
229
erythroid hyperplasia?
hypoxia results in increased **erythropoetin** production
result is **erythroid hyperplasia**
230
...
231
glycolysis pathway
232
free radicals?
what protects body?
what is needed to regenerate?
problem?
Superoxide and hydrogen peroxide are free radicals - damages DNA structure
**glutathione** - protects us from **hydrogen peroxide** by reacting with it to form water and an oxidised glutathione product (GSSG)
Glutathione eplenished by **NADPH** (which is generated by **hexose monophosphate shunt**)
Rate limiting enzyme is **glucose-6-phosphate dehydrogenase!**
**can get GPD6 deficiency resulting in oxidative damage to RBCs**
233
G6PD deficiency?
X-linked male disorder
* oxidative damage to RBCs, thus **ANAEMIA**
234
CO2 transport?
Only 10% dissolved in solution
Around 30% bound directly to Hb as carbamino-Hb
**60% as bicarbonate** - RBC very important for generating that bicarbonate
235
foetal Hb?
2 alpha, 2 gamma
236
allosteric effect?
Oxygen binding to Hb = **allosteric effect**
When one oxygen binds to subunit, the Hb shape changes
This makes it easier for next O2 to bind to different subunit
**Cooperative binding**
237
oxygen dissociation curve?
Dissociation curve for haemoglobin is sigmoidal!
238
curve shifted right by?
results in?
significance?
Curve shifted _right_ by **2,3-BPG, H+** and **CO2**
this results in more O2 delivered to tissues - think, when H+ and CO2 are high, its good to have more O2 in tissues
significance = 2,3-BPG (sometimes called DPG) is increased in **chronic anaemia**
239
what shifts curve to the left?
increased pH (low H+), **low** DPG, **low** temperature
240
when are Hb/hct not a good marker of anaemia?
rapid haemorrhage
or when fluids are given
241
polychromasia?
reticulocytes!!
242
classifying anaemia?
Decreased production (**low reticulocyte count**)
* Hypoproliferative - reduced **AMOUNT** of erythropoiesis
* Maturation abnormality - erythropoiesis **present but INEFFECTIVE**
* Cytoplasmic defects - imapired hemoglobinization
* Nuclear defects - imapired cell division
Increased loss or destruction of red cells (**high reticulocyte count**)
* Bleeding
* Haemolysis
Mean cell volume
* If MCV low (microcytic) consider problems with **haemoglobinization**
* If MCV high (macrocytic) consider problems with **maturation**
243
haemoglobin synthesis
occurs in cytoplasm
porphyrin made in mitochondria
244
hypochromic microcytic anaemias?
Causes of hypochromic microcytic anaemia (**TAILS**)
Haem deficiency:
* lack of **iron**
* Iron deficiency (low body iron)
* Anaemia of chronic disease (normal body iron but lack of available iron) - most anaemia of chronic disease **normocytic**
* Problems with **porphyrin synthesis**
* Lead poisoning
* Congenital sideroblastic anaemias
Globin deficiency
* Thalassemia
245
iron states?
Can exist in Fe2+ (ferrous) or Fe3+ (ferric) state
246
iron stored as?
transported by? - where?
Iron stored as **ferritin** in liver
Iron transported by **transferrin**
* transported to bone marrow, where macrophages “feed it” to red cell precursors
247
tests to assess iron?
Functional iron = haemoglobin
Transported iron = serum iron + transferrin
Storage iron = serum ferritin
248
% saturation transferrin?
%saturation of transferrin with iron measures **iron supply**
* Reduced in iron deficiency
* Reduced in anemia of chronic disease
* Increased in haemochromatosis
249
ferritin stores?
measures?
low?
Stores up to 4000 **ferric** ions (fe3+)
Serum ferritin = measure of storage iron
**Low ferritin means iron deficiency!!**
250
iron deficiency Dx?
reduced Hb + reduced ferritin
251
iron deficiency consequences?
**Microcytic anaemia!!**
Epithelial changes
* Skin
* Koilonychia
* Angular chelitis
252
causes of iron deficiency?
* not enough dietary iron (pregnant women + growing children)
* chronic blood loss: menorrhagia, GI (tumours, ulcers, NSAIDs), haematuria
* malabsoprtion = coeliac disease, achlorhydria
(remember iron absorbed in duodenum)
253
where is iron absorbed?
duodenum
254
B12 deficiency (macrocytic)
255
life-style
256
causes of macrocytosis?
Macrocytosis can be genuine (true) or spurious (false)
* Genuine - true increase in volume of red cells
* Megaloblastic
* non-megaloblastic
* Spurious - red cell volume normal but laboratory analyser measures MCV as high
257
what is a megaloblast?
Megaloblast - an abnormally large **_nucleated_** red cell precursor **with an immature nucleus**
258
megaloblastic anaemia occurs due to?
explain process
Due to prominent defects in DNA synthesis!!
* **Cytoplasmic development** and **haemoglobin accumulation occur normally** and so precursor cell is bigger with immature nucleus e.g. **megaloblast**
* division is reduced and apoptosis increases
* Once Hb level optimal, nucleus is extruded, leaving behind bigger than normal red cell e.g. **macrocyte**
Overall, there are still fewer macrocytes hence ANAEMIA
259
causes of megaloblastic anaemia?
**B12 deficiency** or **folate deficiency** (essential DNA synthesis and nuclear maturation)
260
how B12 absorbed?
Acid in stomach liberates B12 which then binds to rapid binder proteins
**Intrinsic factor secreted from gastric parietal cells**
B12 released from rapid binder proteins and binds to intrinsic factor protein
B12-intrinsic factor complex travels to distal small bowel (**ileum**) and is absorbed
Enters bloodstream and binds to **transcobalamin**
261
causes of B12 deficiency?
| (thus megaloblastic anaemia)
Diet (vegans)
Stomach
* **Pernicious anaemia**
* Atrophic gastritis
* PPIs
* gastrectomy/bypass
Chronic pancreatitis
Small bowel
* basterial overgrowth
* **coeliacs**
* **crohns**
Inherited deficiency
* **Cubilin receptors** (where B12 binds before being absorbed into bloodstream)
262
what is pernicious anaemia?
asociated with?
Autoimmune condition associated with destruction of **gastric parietal cells**
Results in **intrinsic factor deficiency** with B12 malabsorption and deficiency (megaloblastic anaemia)
Associated with **atrophic gastritis** and history of other autoimmune disorders (e.g. **hypothyroidism, vitiligo, Addison’s**)
263
folate absorbed?
causes of folate deficiency?
Absorbed in **jejunum**
Causes of folate deficiency - much lesser stores than B12
* **ALCOHOLICS**
* Malabsorption
* Coeliacs, crohns
* Excess utilization
* Haemolysis
* Exfoliating dermatitis
* Pregnancy
* Malignancy
* Drugs = **anticonvulsants**
264
B12 + folate sources, stores, abdorbed, daily req
265
clinical features B12/folate deficiency?
Common to both B12 and folate
* Symptoms/signs of anemia
* Weight loss, diarrhoea, infertility
* Sore tongue (glossitis), jaundice
* Developmental problems
Specific to B12
Neurological problems!!! - damages myelin sheath
* dorsal column abnormalities (sensation)
* Neuropathy
* Dementia
* Psychiatric manifestations
266
Dx B12 + folate deficiency?
Macrocytic anaemia (RBC count low) - pancytopenia in some patients
Blood film = **macro ovalocytes and hypersegmented neutrophils** (normally 3-5 nuclear segments)
autoantibodies
* **anti-gastric parietal cell (GPC)** - sensitive but not specific
* **anti-intrinsic factor** - specific but not sensitive
267
problems with B12 + folate interpretation?
268
Tx megaloblastic anaemia?
Treat cause!!
**Vitamin B12 injections for life in pernicious anaemia (IM)**
Folic acid tablets 5mg per day orally
Blood transfusion only if life-threatening anaemia
269
non-megaloblastic macrocytic anaemia Ax?
270
spurious macrocytosis Dx?
Ax?
Volume of red cell is NORMAL but MCV is measures as high
Ax
* **Reticulocytosis**
* Increase in reticulocyte numbers in response to acute blood loss or red cell breakdown (haemolysis)
* Blood film will show polychromasia
* **Cold-agglutinins**
* Produced in certain types of cancer
* Clumps of “agglutinated” red cells registered as 1 giant cell
271
approach to macrocytic anaemia
272
what chemicals are released from dead red cells?
Haemoglobin and lactate dehydrogenase (LDH)
273
earliets part of haem ring synthesised where?
Earliest part of haem ring synthesised in mitochondria
274
pernicious anaemia Tx?
lifelong B12 IM injections
275
Tx alcoholic with macrocytic anaemia?
folic acid 5mg/day
276
haemglobinopathies e.g.?
Alpha thalassemia
Beta thalassemia
Sickle cell anaemia
277
forms of haemoglobin?
HbA (2 alpha chains and 2 beta chains)
HBA2 (2 alpha chains and 2 delta)
HbF (2 alpha 2 gamma)
278
genetics globin chains
Alpha genes on chromosome 16
* 2 alpha genes per chromosome (4 per cell)
Beta genes on chromosome 11
* One beta gene per chromosome (2 per cell)
279
when do Beta chain problems manifest?
6-12 months of age
280
haemaglobinopathies inheritance?
categories?
Autosomal RECESSIVE
2 main groups
* Thalassaemias - **decreased rate of globin chain synthesis**
* Structural haemoglobin variants - normal production of **ABNORMAL** globin chain (variant haemoglobin i.e. HbS, sickle)
281
types thalassemias?
consequences?
Alpha thalassemia - not making enough alpha chains
Beta chains - not making enough beta chains
Consequences:
* **Microcytic hypochromic anaemia! (TAILS)**
* If severe
* Unbalanced accumulation of globin chains (i.e. too many beta chains) which are toxic to cells!!!
* Ineffective erythropoiesis
* Haemolysis - jaundice
282
alpha thalassaemia affects?
types?
Alpha chains present in **HbA, HbA2 and HbF so all are affected**
* Unaffected = 4 normal alpha genes (aa/aa)
* Alpha thalassaemia trait = one or 2 alpha genes missing, **asymptomatic carrier state**, microcytic hypochromic red cells but **ferritin normal**
* HbH disease = only one alpha gene left (--/-a), moderate to severe anaemia
* **Hb Barts hydrops fetalis = no functional alpha genes, incompatible with life**
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beta thalassemia affects?
types?
Only B chains and hence only HbA (a2B2) affected
* B thalassaemia trait (B1/B or B0/B) = **asymptomatic**, no/mild anaemia, low MCV/MCH, **raised HbA2 diagnostic!!!**
* B thalassaemia intermedia (B+/B- or B0/B+) = moderate severity requiring occasional transfusion (similar phenotype to HbH disease)
* **B thalassaemia major = severe, lifelong transfusion dependency**
284
Tx alpha thalassemia trait?
important to?
Asymptomatic carrier state, no Tx needed
Important to distinguish from iron deficiency (ferritin will be normal)
285
HbH disease clinical features?
S/s?
HbH disease = more severe form of alpha thalassemia
clinical features:
* **Anaemia** with **very low MCV** and **MCH**
* excess B chains form tetramers called HbH
* **golf ball cells!!**
s/s
* jaundice
* splenomegaly
* anaemia
286
Tx HbH disease?
may req transfusions
287
Hb Barts Hydrops Foetalis syndrome?
pathophys
clinical features?
Dx?
**Severest form of alpha thalassaemia**
No alpha genes inherited from EITHER parent (--/--)
* no alpha chain production -\> HbF and HbA cant be made
* so tetramers produced - Hb Barts (y4) and HbH (B4)
Clinical features
* Profound anaemia
* Growth retardation
* Severe hepatosplenomegaly
* Skeletal and cardiac abnormalities
* **Almost all die in utero**
**Dx = nucleated, pale red cells on blood film**
288
beta thalassemia major presents?
S/s?
Hb content?
blood film?
presnets 6-24 months (as HbF falls)
s/s
* pallor + failure to thrive
* hepatosplenomegaly
* skeletal changes (frontal bossing)
Hb = mainly HbF (no HbA)
Blood film = very distorted mishapen red cells
289
Tx B thal major?
complication?
Regular transfusion programme to maintain Hb at 95-105g/l
complication = **iron overload** from transfusion
290
consequecnes of iron overload from transfusion?
Tx?
Endocrine dysfunction
* Impaired growth and pubertal development
* Diabetes
* Osteoporosis
Cardiac disease = cardiomyopathy + arrhythmias
Liver disease = cirrhosis + hepatocellular carcinoma
**Tx = iron chelating drugs (e.g. desferrioxamine)**
(venesection not feasible as already anaemic)
291
sickle cell trait?
s/s?
HPLC?
One normal, one abnormal B gene (B/BS)
**Asymptomatic carrier state**
Few clinical features as HbS level very very low
* may sickle in severe hypoxia e.g. **high altitude, under anesthesia**
* Blood film **NORMAL**
HPLC = mainly HbA, HbS \<50%
292
sickle cell anaemia?
s/s?
it is a haemolytic anaemia
2 abnormal B genes (BS/BS)
S/s
* Episodes of tissue infarction due to vascular occlusion - **sickle crisis!!** - extreme pain
* **Chronic haemolysis** - distorted red cells get stuck
* **Hyposplenism** due to repeated splenic infarcts
293
precipitants of sickle crisis?
Tx?
Precipitants of sickle crisis = hypoxia, dehydration, infection, cold exposure, stress/fatigue
Treatment of sickle crisis
* Opiate analgesia
* Hydration
* Rest
* Oxygen
* Antibiotics if evidence of infection
* **Red cell exchange transfusion in severe crisis e.g. lung crisis or brain (stroke)**
294
long term management of sickle cell anaemia?
Hyposplenism - reduce risk of infection
* Prophylactic penicillin
* Vaccination
Folic acid supplementation (increase RBC turnover to increased demand)
**Hydroxycarbamide** can reduce severity of disease by inducing HbF production
Regular transfusion to prevent stroke in selected cases
295
Dx haemoglobinopathies (alpha, beta, sickle)?
Simple things first:
* FBC, Hb
* Blood film
* Ethnic origin
**High performance liquid chromaopgraphy (HPLC)** or electrophoresis to quantify haemoglobins
* Identifies abnormal haemoglobins e.g. HbS
* **Raised HbA2 diagnostic of beta thal trait**
296
raised HbA2?
diagostic of beta thal **trait**
297
when to suspect thalassemia?
microcytic anaemia with **normal ferritin**
298
IAT?
use IAT to determine patient's blood type
299
clinical use blood transfusion?
**Symptomatic** anemia Hb \<70g/L (80g/L if cardiac disease)
Major bleeding
(Transfuse single unit then reassess patient)
300
indications for platelet transfusion?
Prophylaxis in patients with bone marrow failure and very low platelet counts
Treatment of bleeding in thrombocytopenic patient
Prophylaxis prior to surgery/procedure (e.g. biopsy) in thrombocytopenic patient
(again 1 unit usual dose)
301
indications for FFP transfusion?
Treatment of bleeding in patient with **coagulopathy** (PT ratio \>1.5)
Prophylaxis prior to surgery or procedure in patient with coagulopathy
Management of massive haemorrhage
Transfuse early in trauma (1:1 within 4 hours)
(NOT used in absence of bleeding/planned procedure - even if abnormal coagulation screen)
302
observations blood transfusion?
Observations before blood is commenced
Observations at 15 minutes
Observations within 60 minutes of completion
* Acute transfusion reactions
303
next steps?
Tx given likely diagnosis?
microcytic anaemia with normal ferritin so thinking **thalassemia**
nex steps = HPLC
Tx for B thal major = regulat transfusions to maintain minimum Hb (beware iron overload)
304
spherocytes seen in?
hereditary spherocytosis + autoimmune haemolytic anaemia
305
sickle cell microcytic?
NO you will NOT be microcytic in sickle cell
in other haemoglobinopathies i.e. thalassemias you will be
306
consequences of haemolysis?
**Erythroid hyperplasia** (increased bone marrow red cell production)
Excess red cell breakdown products e.g. **bilirubin**
307
...
308
classification haemolysis?
**Extravascular**
* Red cells taken up by spleen and liver
**Intravascular**
* Red cells destroyed within circulation
They have different breakdown products = useful in determining cause of haemolysis
309
extravascular haemolysis s/s?
breakdown products?
S/s = **splenomegaly + hepatomegaly,** jaundice, gallstones
breakdown products:
* **Unconjugated** bilirubin (jaundice, gallstones)
* Urobilinogenuria
(they are normal products but found in EXCESS)
310
intravascular haemolysis breakdown products?
Haemoglobinaemia (free Hb in circulation)
Methaemalbuminaemia
Haemoglobinuria - **pink urine, turns black if left for a while**
Hemosiderinuria
(abnormal products unlike extravascular = **life-threatening**)
311
Ax intravscular haemolysis?
extravascular?
Intravascular Ax
* ABO incompatible blood transfusion (immediate, IgM)
* G6PD deficiency
* Severe falciparum malaria (blackwater fever)
* Rarer still - PNH, PCH
extravascular Ax = all other causes
312
Ix haemolysis?
Confirm haemolytic state
* FBC + blood film
* Reticulocyte count
* Serum unconjugated bilirubin
* Serum haptoglobins
* Urinary urobilinogen
Identify cause
* History + examination - FHx, organomegaly
* Blood film - membrane damage (spherocytes)
* Mechanical damage (red cell fragments)
* Oxidative damage (Heinz bodies)
* Others e.g. HbS (sickle cells)
* Specialist investigations e.g. direct Coomb’s (ATR)
313
acquired causes of haemolysis?
Immune
* Autoimmune haemolysis
* Alloimmune haemolysis (from blood transfusion)
Mechanical
Abnormal cell membrane
Abnormal red cell metabolism
Abnormal haemoglobin
314
autoimmue haemolysis Ax
Warm or cold autoantibody
* Warm (IgG)
* Idiopathic - commonest
* Autoimmune disorders (SLE)
* Lymphoproliferative disorders - CLL
* Drugs (penicillins)
* Infections
* Cold (IgM)
* Idiopathic
* Infections (EBV, mycoplasma)
* Lymphoproliferative disorders
315
alloimmune haemolysis Ax?
Dx?
Haemolytic transfusion reaction
* Immediate (IgM) - intravascular
* Delayed (IgG) - extravascular
Passive transfer of antibody
* Haemolytic disease of the newborn!!
* RhD, ABO incompatibility, others e.g. anti-Kell
Dx = DAT Coombs???
316
mechanical haemolysis Ax?
DIC
Haemolytic uraemic syndrome (E.coli 0157)
thrombotic thrombocytopenic purpura (TTP)
Leaking heart valve
Infections e.g. malaria
317
abnormal cell membrane haemolysis Ax?
Liver disease (Zieve’s syndrome)
Vitamin E deficiency
Paroxysmal nocturnal haemoglobinuria
318
red cell membrane haemolysis Ax?
heriditary spherocytosis
319
abnormal red cell metabolism haemolysis Ax?
Dx?
G6PD deficiency = makes RBCs more prone to oxidative damage
thus haemolysis
Dx = **Heinz bodies**
320
ABO incompatible vs delayed haemolysis
Delayed haemolysis - extravascular
ABO incompatible would be intravascular and immediate
321
iron absoprtion enhanced by?
Inhibited by?
Enhanced by
* Ascorbic acid (reduces iron to Fe2+ form)
* Alcohol
Inhibited by
* Tannins e.g. tea
* Phytates e.g. cereals, bran, nuts and seeds
* Calcium e.g. dairy produce
322
process of iron absoprtion at duodenum
Duodenal cytochrome B
* Found in luminal surface
* Reduces ferric iron to ferrous form
DMT (divalent metal transporter)-1
* Transports ferrous iron **into** duodenal enterocyte
Ferroportin
* Facilitates iron **export** from enterocyte
* Passes on to transferrin
323
how is iron absorbtion regulated?
**Hepcidin!!!**
* Major **negative** regulator of iron uptake
* Produced in liver in response to
* Increased iron level
* **Inflammation**
* Binds to ferroportin and causes its degradation
Hepcidin levels decrease when iron deficient
324
raised ferritin?
rises when iron levels high BUT ALSO in infection + malignancy (acts as an acute phase protein)
325
GI blood loss iron deficiency?
GI blood loss of 8-10ml per day (4-5mg iron) can occur **without any symptoms or signs of bleeding**
326
iron malutilisation?
anaemia of chronic disease
(due to increased hepcidin - **remember ferritin may be high too** due to inflammation)
327
hereditary heamochromatosis Ax?
pathophys
S/s?
mutation in HFE gene
Decreased synthesis of hepcidin so increased iron absorption
Clinical features
* weakness/fatigue
* Joint pains
* Impotence
* Arthritis
* Cirrhosis
* Diabetes (bronze diabetic)
* Cardiomyopathy
328
Dx haemochromatosis?
Tx?
HFE gene (C282Y mutation)
transferrin sat \>50%
raised serum ferritin
Tx
* weekly venesection
329
acute transfusion reactions?
s/s?
happen early in transfusion (within 1st hour)
Symptoms
* Chills, rigors, rash, flushing
* Feeling of impending doom
* Collapse
* Loin pain
* Respiratory distress
Signs
* Fever
* Tachycardia
* Hypotension
* Tachyopnoia
EMERGENCY Tx!!
330
Tx ATR?
Treatment for ALL transfusion reactions
* 1 - STOP the transfusion
* 2 - ABCDE
* 3 - re-check compatibility tag against patient details
* 4 - document event in medical notes
acute haemolytic transfusion reaction:
* same as above
* FBC, coag screen, renal function, haemolysis products, blood cultures (to rule out infection)
331
pathophys AHTR?
Binding of IgM anti-A or B antibodies to transfused cells (intravascular haemolysis)
Release of inflammatory cytokines
* Shock, DIC, renal failure!!
* Often fatal
332
trasnfusion associated circulatory overload (TACO) clinical features?
Risk factors?
Tx?
Clinical features
* respiratory distress within 6 hours of transfusion
* Raised blood pressure
* Raised JVP
* oedema
Risk factors = **elderly patients**, cardiac failure, low albumin, renal impairment
Tx of TACO
* Oxygen + supportive care
* Diuretics
(consider slowing the rate of future transfusions + diuretic)
333
Mild transfusion reactions?
tx?
Isolated temp rise \>38 or rash only
Management
* Continue transfusion - consider slowing rate
* Close monitoring of patient in case condition worsens
* Consider paracetamol/antihistamine
334
delayed haemolytic transfusion reactions?
Dx?
**Extravascular** haemolysis 5-10 days post transfusion
Dx = positive DAT (alloantibody)
335
if see reticulocytosis on blood film?
look for red cell breakdown products
if none = bleeding rather than haemolysis
336
normochromic normocytic anaemia?
Marrow failure - drug induced, aplastic anaemia (can be macrocytic)
Hypometabolic (can be macrocytic)
Marrow infiltration (metastatic malignancy, fibrosis)
Renal impairment (failure of erythropoetin)
**Chronic disease** (infective, inflammatory, malignant)
337
commonest causes of anaemia?
how to distinguish?
iron deficiency + anaemia of chronic disease
in anaemia of chronic disease ferritin will be **normal**
338
could be iron deficient or thalassemia
need ferritin to find out
339
oral vs IV iron?
oral iron 1st line in most patients
IV only used in certain circumstances
* 3rd trimester of pregnancy
* imminent surgery
* malasbsorption
* chronic renal failure or heart failure?
