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3rd year medicine > haem > Flashcards

haem Flashcards

1
Q

diagnosis?

A

thalassaemia trait

  • microcytosis and hypochromia with normal Hb
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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

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3
Q

polychromasia?

macro ovalocytes and hyperseg neutrophils?

A

reticulocytes

b12/folate deficiency

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4
Q

what parameter on blood count is likely to be raised in patient with spherocytosis?

A

MCHC because hyperchromic

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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

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6
Q

what blood count parameters would be raised in haemolytic anaemia? (4)

A

MCHC (spherocytes)

urinary haemosiderin

serum lactate dehydrogenase

DECREASED serum haptoglobin

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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

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8
Q

how to confirm autoimmune haemolysis?

A

DAT test (Coombs)

Dx = autoimmune haemolytic anaemia

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9
Q

Ax autoimmune haemolytic anaemia? (3)

Tx?

A

infection (CMV, HIV, EBV)

autoimmune disease (lupus)

lymphoma

Tx = steroids 1st line + FOLIC ACID!

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10
Q

blood film shows:

abnormally shaped red cells, neutrohpil segmentation

diagnosis?

A

myelodysplastic syndrome

i.e. macrocytic anaemia

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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

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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

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13
Q

steps in primary haemostasis

A

endothelial damage = expresses VWF

platelets adhere to VWF

aggregation of platelets

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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

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15
Q

whats this?

A

purpura (seen in thrombocytopenia)

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16
Q

causes of primary haemostasis FAILURE? (3)

A

scurvy, elderly

thrombocytopenia (or reduced platelet function)

VWF defieincy - most common inherited deficiency

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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

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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

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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

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20
Q

consequences of FAILURE of secondary haemostasis?

A

no characteristic clinical syndrome

bleeding into joints and muscles - haemophilia

DIC - severe bleeding

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21
Q

screening tests for fibrin clot formation

screening test for primary haemostasis?

A

prothrombin time

activated partial thromboplastin time

primary = platelet count

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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

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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)

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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)

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25
Q

thrombophilia?

A

deficiency of naturally occuring anticoagulants (antithrombin, protein C, protein S)

tendency to develop DVT/PE

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26
Q

markers of normal tissue perfusion?

A

Blood pressure

consciousness

urine output

lactate

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27
Q

causes of shock?

A

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

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28
Q

hypovolaemia classification

A
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29
Q

monitoring shock patients?

A

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

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30
Q

management shock?

A

ABCDE

wide bore IV access

Tx underlying cause

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31
Q

target MAP shock?

fluid challenge?

when fluids dont work?

when this fails?

A

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

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32
Q

2 types of fluids used in shock?

A

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

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33
Q

side effect of resuscitation?

Tx?

A

fluid overload - oedema, ARDS (wet lung), bowel oedema

young healthy people will just pee it out

elderly = diuretics, dialysis

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34
Q

what is massive haemorrhage?

massive haemorrhage protocol?

A

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

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35
Q

what is FFP?

cryoprecipitate?

transfusion target?

A

FFP = replaces clotting factors

cryoprecipitate = replaces fibrinogen

aim 2RBC : 1 FFP

in trauma = 1 : 1!!

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36
Q

Mx PPH?

A

most common cause = uterine atony

uterine massage

uterotonic drugs

cryoprecipitate (fibrinogen much higher in pregnant women)

+ tranexamic acid

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37
Q

trauma haemorrhage Tx?

Variceal bleed?

ruptured AAA?

A

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)

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38
Q

what should NOT be used in GI haemorrhage?

A

tranexamic acid!!

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39
Q

when to suspect DVT?

A

d-dimer

doppler

WELLS score

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40
Q

types of thrombocytopenia?

A

hereditary i.e. VWF deficiency (most common)

aquired:

reduced production (marrow problem) - pancytopenia

increased destruction = DIC, ITP, portal hypertension (hypersplenism)

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41
Q

Ax platelet functional deficits (i.e. normal number)?

A

hereditary

acquired = drugs (aspirin, NSAIDs), renal failure

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42
Q

von willebrand factor deficiency?

A

most common hereditary bleeding disorder (failure of platelet plug fomration but normal platelet count)

autosomal dominant

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43
Q

commonest cause of primary haemostatic failure?

A

thrombocytopenia - usually ITP or portal hypertension

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44
Q

clotting factor synthesis?

what is essential for function?

A

ALL synthsised in hepatocytes (reduced in liver failure)

factor 2, 7, 9 + 10 carboxylated by vitamin K whcih is essential for function

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45
Q

vitamin K absoprtion?

Ax vit K deficiency?

A

absortped in small bowel, requires bile salts for absorption

Ax deficiency

* poor diet

* malabsorption

* obstructive jaundice (no bile)

* Warfarin

* haemorrhagic disease of the newborn

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46
Q

disseminated intravascular coagulation?

S/s?

blood count will show?

coag screen?

A

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

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47
Q

Ax DIC?

Tx?

A

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

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48
Q

haemophillia?

inheritance?

Types?

severity?

A

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)

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49
Q

features haemophilia?

A

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

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50
Q

clinical features of severe haemophilia?

complication?

A

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)

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51
Q

isolated prolonged APTT?

A

suspect haemophillia

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52
Q

categories thrombosis?

A

Arterial = coronary, cerebral, peripheral

Venous = deep venous thrombosis, pulmonary embolism

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53
Q

arterial thrombosis Ax?

thrombus?

Tx?

A

Ax = atherosclerosis

platelet rich thrombus

Tx = aspirin and other antiplatelet drugs

modify risk factors for atherosclerosis - smoking, weight

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54
Q

venous thrombosis Ax?

thrombus?

A

Ax = Virchow’s triad

* stasis + endothelial damage + hypercoagulability

platelets not activated so fibrin-rich clot

Tx = anticoagulants e.g. heparin, wafarin, DOACs

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55
Q

risk factors VTE?

A

elderly

obesity

pregnancy + puerperium

HRT, COCP

previous DVT/PE

trauma, surgery

malignancy

thrombophillia

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56
Q

thrombophillia?

commonest thrombophillia?

A

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

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57
Q

Hereditary thrombophilias?

A

Factor V Leiden

Prothrombin 20210 mutation

Antithrombin deficiency

Protein C deficiency

Protein S deficiency

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58
Q

when to suspect hereditary thrombophillia?

Tx?

A

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

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59
Q

acquired thrombophillia?

S/s?

features?

Dx?

A

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)

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60
Q

conditions associated with APS?

Tx?

A

Autoimmune disorders

Lymphoprilifative disorders

Viral infections

Drugs

Primary - most common

Tx = aspirin + Warfarin

(remember different in pregnancy - LMWH)

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61
Q

indications for anticoagulant drugs?

Examples?

A

Venous thrombosis

Atrial fibrillation

anticoagulants = heparin + LMWH, Warfarin, DOACs

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62
Q

heparin mechanism?

benefit?

2 types?

mechanisms of types?

A

heparin = increases antithrombin effect

benefit = immediate effect

2 forms = unfractioned + LMWH

LMWH = antithrombin-Xa reaction

unfractioned = antithrombin-thrombin reaction

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63
Q

herpatin complications?

reversal?

A

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

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64
Q

mechanism of action Warfarin?

what do you have to give warfarin with initially?

why?

A

inhibition of vit K

warfarin must be given with herparin initially as inhibits protein C and protein S for a while

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65
Q

Warfarin therapy cons?

Benefits?

A

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)

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66
Q

DOACs?

benefits?

cons?

A

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)

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67
Q

DOACs used for?

A

DVT/PE

stroke prevention in AF patients

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68
Q
A

PSIS

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69
Q
A

immunophenotyping

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70
Q
A

ESRD and erythropoetin

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71
Q

haemopoesis?

types?

A

production of RBCs, WBCs + platelets

erythropoiesis = RBC

Thrombopoesis = platelets

Lymphopoiesis = WBC

granulopoiesis/myelopoiesis = production of granulocytes

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72
Q

lifespan of blood cells?

therefore?

A

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

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73
Q

ancestry of blood cells?

A

RBC

Pro-normoblast → late normoblast → reticulocyte → erythrocyte

Neutrophil

Myeloblast → promyelocyte → myelocyte → metamyelocyte → band neutrophil → mature neutrophil

Platelet = megakaryocyte

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74
Q

where do precursors (erythroblasts, myeloblasts) come from?

A

haemopoetic proginitor cells, which come from haemopoetic stem cells

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75
Q

myelocytes?

A

nucleated precursor between myeloblasts and neutrophils

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76
Q

myeloid terminology?

A
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77
Q

haemopoetic stem cells originate from?

sites of haemopoesis?

A

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

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78
Q

bone marrow cellularity?

A

subtract age from 100

so 20 year old has 80% cellularity

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79
Q

where to collect bone marrow biopsy?

A

adults = PSIS

children = anterior tibia

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80
Q

red vs yellow marrow?

myeloid:erythroid ratio?

normal ratio?

when will it change?

A

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

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81
Q

neutrophil precursor maturation regulated by?

platelets?

erythropoeisis?

A

neutrophil precursor maturation regulated by G-CSF (granulocyte colony stimulating factor)

thrombopoetin regulates development of magakaryocytes

erythropoesis = erythropoetin, iron (haem), folate, globin synthesis

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82
Q

Ix haemopoesis?

A

Routinely undertaken = FBC, cell indices, morphology (blood films)

Less common (specialist) - bone marrow examination

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83
Q

investigations for non-lymphoid cells vs lymphoid?

A

For non-lymphoid = blood count/morphological assessment often sufficient

lymphoid cells = immunophenotyping

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84
Q

how to harvest stem cells?

A

G-CSF injections stimulate mobilisation of stem cells form bone marrow into blood

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85
Q

ancestry lymphoid cells?

A
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86
Q

lymphoid system?

A

Central (primary) lymphoid tissues = bone marrow + thymus

Peripheral (secondary) lymphoid tissues = lymph nodes, spleen, tonsils (waldeyer’s ring), epithelio-lymphoid tissues

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87
Q

lymph node anatomy?

A

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

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88
Q

lymphoid system function?

A

immune function

prevents oedema

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89
Q

cell populations in lymph nodes?

A

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

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90
Q

lymphadenopathy Ax?

A

(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
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91
Q

red lines extending from inflamed node?

A

lymphangitis

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92
Q

generalised lymphadenopathy suggests?

A

systemic infection

lymphoma/leukemia - must check FBC

autoimmune

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93
Q

lymph node response to autoimmune? tumour? viral infection?

A
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94
Q

spleen palpable?

surfaces?

vascular supply?

rupture?

A

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

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95
Q

structure of spleen?

function?

A

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

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96
Q

how does spleen facilitate immune repsonse?

A

APCs in white pulp present antigen to immune cells

When stimulated by antigen, T and B cell responses may occur

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97
Q

splenomegaly symptoms?

Traid of hypersplenism?

A

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

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98
Q

causes of splenomegaly?

A

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

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99
Q

Ax hypersplenism vs hyposplenism?

A

hypersplenism

  • conditions associated with splenomegaly

hyposplenism

  • most commonly from splenectomy (need immunopsuppression)
  • other causes = coeliac disease, sickle cell, sarcoidosis, iatrogenic
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100
Q

features of hyposplenism?

A

Howell-Jolly bodies

also some immune deficiency

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101
Q

basophilia seen in?

A

polycythaemia rubra vera

chronic myeloid leukaemia

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102
Q

monocytosis seen in?

A

chronic bacterial infections

malignancy (chromic myelomonocytic leukaemia)

connective tissue disease (SLE + RA)

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103
Q

are monocytes raised in smoking?

A

No - will see mild neutrophilia tho

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104
Q

features of monocytes?

precursor?

A

large monolobular cells

same precursor as granulocytes but unlike granulocytes do not have prominent granules

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105
Q

functions monocytes?

A

phagocytosis + antigen presenting

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106
Q

lymphocyte origins and development?

lymphocytosis?

A

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

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107
Q

EBV mononucleosis characteristic appearance?

A

T cells blue cytoplasm wraps around neighbouring cells

(can also be seen in HIV, CMV, viral hepatitis + toxoplasma)

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108
Q

stable plaques can cause?

unstable plaques?

A

stable plaques = stable angina (coronary artery) + PVD claudication

unstable plaques = MI, stroke

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109
Q

risk factors arterial thrombosis?

A

Hypertension

Smoking

High cholesterol

Diabetes

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110
Q

platelets bind to?

platelet aggregation chemicals?

A

platelets bind to VWF (released by damaged vessel wall)

ADP, thromboxane A2

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111
Q

e.g. antiplatelet drugs?

A

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)

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112
Q

side effects aspirin?

A

Bleeding

Blocks production of prostaglandins

  • GI ulceration
  • Bronchospasm (contraindicated in asthma)
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113
Q

which drug is contraindicated in asthma?

A

aspirin!!!

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114
Q

side effects antiplatelet drugs?

Tx?

A

bleeding!

will affect platelets for 7-10 day lifespan so stop antiplatelets approx a week before surgery

in emergency = can reverse with platelet transfusion

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115
Q
A

A - acute leukemia

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116
Q
A

D - chronic lymphocytic leukemia

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117
Q
A

???

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118
Q

how are proginitor/stem cells identified?

A

immunophenotyping

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119
Q

acute leukaemia pathophys?

Blood count?

bone marrow?

A

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

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120
Q

chronic myeloproliferative disorders pathophys?

e.g.?

blood count?

why?

A

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!!!

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121
Q

main cell type that differentiates CML and AML?

A

neutrophils!!

In AML = low

in CML = high

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122
Q

haematological malignancy divided into?

A

myeloid or lymphoid

developmental stage i.e. lymphoblastic vs lymphocytic vs myeloma

anatomical site

  • blood = leukemia
  • lymph node = lymphoma
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123
Q

myeloma?

A

malignancy of plasma cell in marrow

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124
Q

differences in histology/progression of haematological malignancies?

A

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

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125
Q

what do all leukemias present with?

A

All Leukaemias present (more commonly than chronic leukaemia) with significant bone marrow failure

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126
Q

malignant haemopoesis

myeloid vs lymphoid?

A

myeloid malignancies tend to involve more primitive progenitor cells

lymphoid malignancies can turn malignant at various stages

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127
Q

acute leukemia features?

Types?

A

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)
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128
Q

acute lymphoblastic leukemia?

clinical presentation?

A

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
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129
Q

commonest childhood cancer?

A

acute lymphoblastic leukemia

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130
Q

acute myeloid leukemia epidemiology?

S/s?

A

elderly >60 y/o

presentation same as ALL (marrow failure)

some have characteristic presentation

  • DIC in acute promyelocytic leukemia
  • gum infiltration
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131
Q

Ix acute leukemia?

A

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

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132
Q

Auer rods?

A

AML!!!

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133
Q

how to differentiate between AML and ALL?

why is this important?

bone marrow aspirate sub-optimal?

A

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

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134
Q

so definitive diagnosis of acute leukemia?

A

immunophenotyping!!

(only definitive way to distinguish between AML and ALL)

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135
Q

Tx acute leukaemia?

A

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
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136
Q

CVC placement for AML?

A

tip should sit at junction of SVC and right atrium

137
Q

acute leukaemia (marrow failure) complications?

Tx?

A

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
Q

chemo side effects

late effects?

A

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
Q
A

D - urgent biopsy followed by steroids

140
Q
A

B - excision biopsy of lymph gland

I THINK

141
Q

symptoms of lymphoma?

when to suspect Hodgkins?

A

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
Q

lymphadenopathy features

A
143
Q

Ix lymphadenopathy?

A

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
Q

diagnostic approach lymphadenopathy?

A
145
Q

imaging for lymphoma?

A

CANNOT be diagnosed by CT

but still useful

Dx = biopsy!!

146
Q

Dx lymphoma

A

Dx = incision biopsy!!!!

(FNA + core biopsy not acceptable)

147
Q
A

…

148
Q

immunohistochemistry lymphoma?

A

antibodies against proteins in biopsy

brown = positive

149
Q

reed sternberg cells?

A

Hodgkins lymphoma

150
Q

genetics analysis of lymphoma biopsy?

A

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
Q

types of B cell lymphoma?

A

Hodgkins

non-hodgkins:

Burkitt’s

diffuse large cell B cell lymphoma

Mantle cell lymphoma

Follicular lymphoma

152
Q

classifications of lymphoma?

A
153
Q

risk factors lymphoma?

A

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
Q

staging of lymphoma using?

system?

A

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
Q

prognosis lymphoma?

A

lactate dehydrogenase (LDH) = prognostic

156
Q

hodgkin’s lymphoma associated with?

spread?

hallmark?

Tx?

prognosis?

A

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
Q

complication chemo?

A

Bleomycin can cause pneumonitis

Long term toxicity including secondary cancers, cardiovascular disease, infertility

158
Q

non-Hodgkin’s subtype associated with high-grade lesions?

Extranodal disease?

Tx?

prognosis?

A

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
Q

burkitt’s lymphoma?

Ax?

disease sites?

genes?

complication?

A

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
Q

steroid use lymphoma?

A

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
Q

Dx?

A

pancytopenia - not a diagnosis on its own (must find cause)

162
Q

pancytopenia?

rules?

A

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
Q

erythrocyte precursor?

A
164
Q

pancytopenia Ax?

A

reduced production or increased destruction

  • reduced production = acquired or inherited
  • increased destruction = hypersplenism
165
Q

triad inherited bone marrow syndromes?

A

congenital anomalies + impaired haemopoeisis (pancytopenia) + cancer predisposition

166
Q

Ax reduced production pancytopenia?

A

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
Q

Fanconi’s anaemia S/s?

Ax?

A

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
Q

idiopathic aplastic anaemia?

Ax?

features?

A

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 hypercellular marrow)

169
Q

myelodysplastic syndromes?

feature?

why do you get pancytopenia?

compliation MDS?

A

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
Q

why can acute leukaemia cause pancytopenia?

A
171
Q

secondary bone marrow failure?

Ax?

A

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
Q

increased destruction pancytopenia?

S/s?

Ax?

A

HYPERSPLENISM

s/s = splenomegaly

Ax:

  • splenic congestion - portal hypertension
  • systemic diseases - rheumatoid arthritis
  • haematological = splenic lymphoma
173
Q

summary pancytopenia

A
174
Q

s/s pancytopenia?

A

Anaemia

  • Fatigue
  • SOB

Neutropenia = infections

Thrombocytopenia

  • Bleeding
  • Purpura
  • Petechiae
  • “Wet” bleeds i.e. visceral bleeds
175
Q

Ix cause of pancytopenia?

A

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
Q

marrow cellularity in pancytopenia?

A

Hypocellular in aplastic anaemia

Hypercellular in:

  • Myelodysplastic syndromes
  • B12/folate deficiency
  • Hypersplenism
177
Q

Tx pancytopenia?

A

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
Q

immediate cytotoxic drug side effects?

long term?

Tx?

A

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
Q

what is used to monitor response to therapy in Hodgkin’s lymphoma?

A

PET scan

180
Q

haematological uses of biologics?

e.g.?

A

multiple myeloma!!

e.g. thalidomide, lenalidomide (revlimid)

181
Q

Tx CML?

A

tyrosine kinase inhibitors

182
Q

myeloproliferative disorders (neoplasms)?

what do they result in?

A

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
Q

myeloproliferative neoplasm types?

A

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
Q

when to consider MPN?

A

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
Q
A

suspect MPN - polycythaemia vera?

  • raised Hb
  • raised eosinophils + basophils
  • significantly raised haematocrit
186
Q

this patient has severe COPD

A

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
Q

chronic myeloid leukaemia?

clinical features?

A

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
Q

lab features CML?

A

Blood count changes

  • normal/decreased Hb
  • Leukocytosis with neutrophilia and myeloid precursors (myelocytes)
  • eosinophilia, basophilia
  • thrombocytosis

Bone marrow biopsy

  • Increased cellularity
  • Increased granulocytes
189
Q

early satiety + weight loss

A

Dx = CML

  • weight loss
  • moderate anaemia
  • very high WCC (neutrophillia, eosinophillia + basophilia)
  • raised platelets
190
Q

empyema

A

Dx = reactive picture seconary to empyema

  • moderate anaemia
  • high WCC (neutrophilia)
  • thrombocytosis
191
Q

hallmark of CML?

A

philadelphia chromosome

(chromosome 9 + 22 translocation)

BCR-ABL1 positive!!

192
Q

pathophys CLM?

thus Tx?

A

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
Q

BCR-ABL1 negative MPN?

symptoms?

A

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
Q

polycythaemia vera features?

must distinguish from?

A

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
Q

pseudopolycythaemia?

A

actually a normal amount of red blood cells - however haematocrit high due to decreased volume of blood

196
Q

clinical features polycythaemia vera?

A

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
Q

Ix polycythaemia vera?

A

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
Q

JAK2 mutation?

A

Present in >95% of patients with PV

NOT present in patients with secondary or pseudopolycythaemia

199
Q

Tx polycythaemia vera?

A

Venesect to haematocrit <0.45

Aspirin (thrombosis risk)

Cytotoxic oral chemotherapy e.g. hydroxycarbamide (also used in sickle)

200
Q

essential thrombocythaemia?

A

overproduction of platalets + abnormally large platelets

i.e. uncontrolled production of abnormal platelets

201
Q
  • clinical features ET?
A

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
Q

does high platelet count = essential thrombocytopenia?

example

A

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
Q

ET diagnosis?

A

Exclude reactive thrombocytosis - IMPORTANT (blood loss, inflammation, malignancy, iron deficiency)

Exclude CML - can present with high platelet count

Genetics (about 50% have JAK2)

204
Q

ET Tx?

A

Antiplatelets = aspirin

Cytotoxic = hydroxycarbamide, anagrelide, interferon alpha

205
Q

myelofibrosis?

Ax?

A

rare cause of BCR-ABL1 negative MPN

Ax

  • primary = idiopathic
  • secondary = post-polycythaemia vera or post-ET
206
Q

idiopathic myelofibrosis clincal features?

A

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
Q

myelofibrosis symptoms?

A

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
Q

myelofibrosis Dx?

A

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
Q

leukoerythroblastic blood film?

Ax?

A

neutrophil precursors (myelocytes) + red cell precursors (erythroblasts) in peripheral blood

Ax

  • reactive - sepsis
  • marrow infilration
  • myelofibrosis
210
Q

fibrosis in bone marrow trephines?

A

Dx = myelofibrosis

211
Q

myelofibrosis Tx?

A

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
Q
A

….

213
Q
A

….

214
Q

neutrophil maturation?

A

myeloblast > promyelocyte > myelocyte > neutrophil

215
Q

RBC maturation?

earliest site of entry to bloodstream?

A

pronormoblast > normoblast > reticulocyte > eryethrocyte

earliest site of entry to blood = reticulocyte (also first nucleus free cell)

216
Q

granulocytes?

A

Eosinophils

Basophils

Neutrophils

217
Q

neutrophil features?

function?

A

Segmented nucleus (polymorph)

function = phagocytose invaders, kill with granule contents, attract other cells

218
Q

eosinophil features?

function?

A

Bi-lobed + bright orange/red granules

Function = fight parasitic infections, allergic reactions

219
Q

basophil features?

function?

A

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
Q

monocytes features?

function?

A

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
Q

lymphocytes mature vs atypical?

A

Mature

  • Small with condensed nucleus

Activated (atypical) - seen in glandular fever!!

  • Large with plentiful blue cytoplasm

Atypical shown here:

222
Q

structure of RBCs

A

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
Q

oxidation RBC?

A

Oxidation (Fe3+) is BAD for RBCs!!

224
Q

Hb structure?

A

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
Q

red cell production regulated by?

A

Red cell production regulated by erythropoietin

  • Hypoxia sensed by kidney

Erythropoietin produced

Stimulates RBC production

226
Q

red cell destruction?

A

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
Q

redistribution of blood cells?

A

Low cell count

  • Chronic liver disease -> portal hypertension -> splenomegaly

High cell count

  • Steroids - neutrophils will leave tissues and enter circulation instead
  • Splenic trauma
228
Q
A

…

229
Q

erythroid hyperplasia?

A

hypoxia results in increased erythropoetin production

result is erythroid hyperplasia

230
Q
A

…

231
Q

glycolysis pathway

A
232
Q

free radicals?

what protects body?

what is needed to regenerate?

problem?

A

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
Q

G6PD deficiency?

A

X-linked male disorder

  • oxidative damage to RBCs, thus ANAEMIA
234
Q

CO2 transport?

A

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
Q

foetal Hb?

A

2 alpha, 2 gamma

236
Q

allosteric effect?

A

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
Q

oxygen dissociation curve?

A

Dissociation curve for haemoglobin is sigmoidal!

238
Q

curve shifted right by?

results in?

significance?

A

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
Q

what shifts curve to the left?

A

increased pH (low H+), low DPG, low temperature

240
Q

when are Hb/hct not a good marker of anaemia?

A

rapid haemorrhage

or when fluids are given

241
Q

polychromasia?

A

reticulocytes!!

242
Q

classifying anaemia?

A

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
Q

haemoglobin synthesis

A

occurs in cytoplasm

porphyrin made in mitochondria

244
Q

hypochromic microcytic anaemias?

A

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
Q

iron states?

A

Can exist in Fe2+ (ferrous) or Fe3+ (ferric) state

246
Q

iron stored as?

transported by? - where?

A

Iron stored as ferritin in liver

Iron transported by transferrin

  • transported to bone marrow, where macrophages “feed it” to red cell precursors
247
Q

tests to assess iron?

A

Functional iron = haemoglobin

Transported iron = serum iron + transferrin

Storage iron = serum ferritin

248
Q

% saturation transferrin?

A

%saturation of transferrin with iron measures iron supply

  • Reduced in iron deficiency
  • Reduced in anemia of chronic disease
  • Increased in haemochromatosis
249
Q

ferritin stores?

measures?

low?

A

Stores up to 4000 ferric ions (fe3+)

Serum ferritin = measure of storage iron

Low ferritin means iron deficiency!!

250
Q

iron deficiency Dx?

A

reduced Hb + reduced ferritin

251
Q

iron deficiency consequences?

A

Microcytic anaemia!!

Epithelial changes

  • Skin
  • Koilonychia
  • Angular chelitis
252
Q

causes of iron deficiency?

A
  • 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
Q

where is iron absorbed?

A

duodenum

254
Q
A

B12 deficiency (macrocytic)

255
Q
A

life-style

256
Q

causes of macrocytosis?

A

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
Q

what is a megaloblast?

A

Megaloblast - an abnormally large nucleated red cell precursor with an immature nucleus

258
Q

megaloblastic anaemia occurs due to?

explain process

A

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
Q

causes of megaloblastic anaemia?

A

B12 deficiency or folate deficiency (essential DNA synthesis and nuclear maturation)

260
Q

how B12 absorbed?

A

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
Q

causes of B12 deficiency?

(thus megaloblastic anaemia)

A

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
Q

what is pernicious anaemia?

asociated with?

A

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
Q

folate absorbed?

causes of folate deficiency?

A

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
Q

B12 + folate sources, stores, abdorbed, daily req

A
265
Q

clinical features B12/folate deficiency?

A

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
Q

Dx B12 + folate deficiency?

A

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
Q

problems with B12 + folate interpretation?

A
268
Q

Tx megaloblastic anaemia?

A

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
Q

non-megaloblastic macrocytic anaemia Ax?

A
270
Q

spurious macrocytosis Dx?

Ax?

A

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
Q

approach to macrocytic anaemia

A
272
Q

what chemicals are released from dead red cells?

A

Haemoglobin and lactate dehydrogenase (LDH)

273
Q

earliets part of haem ring synthesised where?

A

Earliest part of haem ring synthesised in mitochondria

274
Q

pernicious anaemia Tx?

A

lifelong B12 IM injections

275
Q

Tx alcoholic with macrocytic anaemia?

A

folic acid 5mg/day

276
Q

haemglobinopathies e.g.?

A

Alpha thalassemia

Beta thalassemia

Sickle cell anaemia

277
Q

forms of haemoglobin?

A

HbA (2 alpha chains and 2 beta chains)

HBA2 (2 alpha chains and 2 delta)

HbF (2 alpha 2 gamma)

278
Q

genetics globin chains

A

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
Q

when do Beta chain problems manifest?

A

6-12 months of age

280
Q

haemaglobinopathies inheritance?

categories?

A

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
Q

types thalassemias?

consequences?

A

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
Q

alpha thalassaemia affects?

types?

A

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
283
Q

beta thalassemia affects?

types?

A

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
Q

Tx alpha thalassemia trait?

important to?

A

Asymptomatic carrier state, no Tx needed

Important to distinguish from iron deficiency (ferritin will be normal)

285
Q

HbH disease clinical features?

S/s?

A

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
Q

Tx HbH disease?

A

may req transfusions

287
Q

Hb Barts Hydrops Foetalis syndrome?

pathophys

clinical features?

Dx?

A

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
Q

beta thalassemia major presents?

S/s?

Hb content?

blood film?

A

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
Q

Tx B thal major?

complication?

A

Regular transfusion programme to maintain Hb at 95-105g/l

complication = iron overload from transfusion

290
Q

consequecnes of iron overload from transfusion?

Tx?

A

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
Q

sickle cell trait?

s/s?

HPLC?

A

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
Q

sickle cell anaemia?

s/s?

A

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
Q

precipitants of sickle crisis?

Tx?

A

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
Q

long term management of sickle cell anaemia?

A

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
Q

Dx haemoglobinopathies (alpha, beta, sickle)?

A

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
Q

raised HbA2?

A

diagostic of beta thal trait

297
Q

when to suspect thalassemia?

A

microcytic anaemia with normal ferritin

298
Q

IAT?

A

use IAT to determine patient’s blood type

299
Q

clinical use blood transfusion?

A

Symptomatic anemia Hb <70g/L (80g/L if cardiac disease)

Major bleeding

(Transfuse single unit then reassess patient)

300
Q

indications for platelet transfusion?

A

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
Q

indications for FFP transfusion?

A

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
Q

observations blood transfusion?

A

Observations before blood is commenced

Observations at 15 minutes

Observations within 60 minutes of completion

  • Acute transfusion reactions
303
Q

next steps?

Tx given likely diagnosis?

A

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
Q

spherocytes seen in?

A

hereditary spherocytosis + autoimmune haemolytic anaemia

305
Q

sickle cell microcytic?

A

NO you will NOT be microcytic in sickle cell

in other haemoglobinopathies i.e. thalassemias you will be

306
Q

consequences of haemolysis?

A

Erythroid hyperplasia (increased bone marrow red cell production)

Excess red cell breakdown products e.g. bilirubin

307
Q
A

…

308
Q

classification haemolysis?

A

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
Q

extravascular haemolysis s/s?

breakdown products?

A

S/s = splenomegaly + hepatomegaly, jaundice, gallstones

breakdown products:

  • Unconjugated bilirubin (jaundice, gallstones)
  • Urobilinogenuria

(they are normal products but found in EXCESS)

310
Q

intravascular haemolysis breakdown products?

A

Haemoglobinaemia (free Hb in circulation)

Methaemalbuminaemia

Haemoglobinuria - pink urine, turns black if left for a while

Hemosiderinuria

(abnormal products unlike extravascular = life-threatening)

311
Q

Ax intravscular haemolysis?

extravascular?

A

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
Q

Ix haemolysis?

A

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
Q

acquired causes of haemolysis?

A

Immune

  • Autoimmune haemolysis
  • Alloimmune haemolysis (from blood transfusion)

Mechanical

Abnormal cell membrane

Abnormal red cell metabolism

Abnormal haemoglobin

314
Q

autoimmue haemolysis Ax

A

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
Q

alloimmune haemolysis Ax?

Dx?

A

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
Q

mechanical haemolysis Ax?

A

DIC

Haemolytic uraemic syndrome (E.coli 0157)

thrombotic thrombocytopenic purpura (TTP)

Leaking heart valve

Infections e.g. malaria

317
Q

abnormal cell membrane haemolysis Ax?

A

Liver disease (Zieve’s syndrome)

Vitamin E deficiency

Paroxysmal nocturnal haemoglobinuria

318
Q

red cell membrane haemolysis Ax?

A

heriditary spherocytosis

319
Q

abnormal red cell metabolism haemolysis Ax?

Dx?

A

G6PD deficiency = makes RBCs more prone to oxidative damage

thus haemolysis

Dx = Heinz bodies

320
Q

ABO incompatible vs delayed haemolysis

A

Delayed haemolysis - extravascular

ABO incompatible would be intravascular and immediate

321
Q

iron absoprtion enhanced by?

Inhibited by?

A

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
Q

process of iron absoprtion at duodenum

A

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
Q

how is iron absorbtion regulated?

A

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
Q

raised ferritin?

A

rises when iron levels high BUT ALSO in infection + malignancy (acts as an acute phase protein)

325
Q

GI blood loss iron deficiency?

A

GI blood loss of 8-10ml per day (4-5mg iron) can occur without any symptoms or signs of bleeding

326
Q

iron malutilisation?

A

anaemia of chronic disease

(due to increased hepcidin - remember ferritin may be high too due to inflammation)

327
Q

hereditary heamochromatosis Ax?

pathophys

S/s?

A

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
Q

Dx haemochromatosis?

Tx?

A

HFE gene (C282Y mutation)

transferrin sat >50%

raised serum ferritin

Tx

  • weekly venesection
329
Q

acute transfusion reactions?

s/s?

A

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
Q

Tx ATR?

A

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
Q

pathophys AHTR?

A

Binding of IgM anti-A or B antibodies to transfused cells (intravascular haemolysis)

Release of inflammatory cytokines

  • Shock, DIC, renal failure!!
  • Often fatal
332
Q

trasnfusion associated circulatory overload (TACO) clinical features?

Risk factors?

Tx?

A

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
Q

Mild transfusion reactions?

tx?

A

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
Q

delayed haemolytic transfusion reactions?

Dx?

A

Extravascular haemolysis 5-10 days post transfusion

Dx = positive DAT (alloantibody)

335
Q

if see reticulocytosis on blood film?

A

look for red cell breakdown products

if none = bleeding rather than haemolysis

336
Q

normochromic normocytic anaemia?

A

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
Q

commonest causes of anaemia?

how to distinguish?

A

iron deficiency + anaemia of chronic disease

in anaemia of chronic disease ferritin will be normal

338
Q
A

could be iron deficient or thalassemia

need ferritin to find out

339
Q

oral vs IV iron?

A

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?

3rd year medicine (13 decks)

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