Haem 1: Haemolytic anaemias (normocytic things)

Question 1

What are the key differentials in normocytic anaemia?

Answer 1

Haemolytic: inherited or acquired (immune-mediated, non-immune-mediated)

Non-haemolytic: anaemia of chronic disease, failure of erythropoiesis

Question 2

What ix should be conducted in a normocytic anaemia?

Answer 2

Peripheral blood smear

DAT

CRP, ESR

Question 3

Causes of anaemia of chronic disease?

Answer 3

Infection, inflammation, malignancy

Question 4

Mechanism behind anaemia of chronic disease?

Answer 4

Cause of ACD is multifactorial and the origin is in the Immune system is activated by autoantigens, microbial molecules or tumour antigens

Increases cytokine production and free radicals that favour the increase of the hepcidin

This decreases inerythropoietin(EPO) and shortening of the half-life of red blood cells

Question 5

Ix findings in anaemia of chronic disease? + what is the mx?

Answer 5

Inflammatory markers – raised CRP, ESR (this is more raised than CRP as its chronic)

Iron studies – ↑iron, ↑ferritin, ↓transferrin, ↓TIBC

Treat underlying cause!

Question 6

How can haemolytic anaemias be classified + examples?

Answer 6

Inherited:

• Membrane - Hereditary spherocytosis
• Cytoplasm / enzymes - G6PD Deficiency + Pyruvate Kinase deficiency
• Hb - Thalassaemia, Sickle cell

Accquired (Immune):

• Autoimmmune - Warm v Cold haemolytic anaemia
• Alloimmune - ABO or Rhesus incompatability

Accquired (non-immune):

• Microangioapathic v macroangiopathic
• Infection

Question 7

How else can haemolytic anaemias be classified by anatomy?

Answer 7

Intravascular vs Extravascular

extravascular- destroyed in the circulation:

• Alloimmune
• Autoimmune
• Hereditary Spherocytosis

intravascular- destroyed in the reticuloendothelial system (phagocytic cells in liver, spleen and lung):

• Malaria(MOST COMMON)
• G6PD Deficiency
• Drugs
• Paroxysmal nocturnal hemoglobinuria (PNH)

Question 8

What is Paroxysmal nocturnal hemoglobinuria (PNH) caused by and how does it present?

Answer 8

This is caused by absence of protein on RBC wall meaning it is more likely to get broken down by oxidative stress

Presents w/ haemoglobinuria in morning, low haptoglobins, high free serum Hb and lactate dehydrogease?

Question 9

What is hereditary spherocytosis? + what clues are often given in questions to suggest this? inheritance?

Answer 9

AD inherited (membrane) cause of haemolytic anaemia

Caused by defect in the vertical interaction of the red cell membrane -> production of spherocytes

Questions may refer to parent having a splenectomy / similar symptoms at a young age

Question 10

What features are found in ix of hereditary spherocytosis + which test is most sensitive?

Answer 10

Peripheral blood smear: spherocytes, polychromasia

Positive osmotic fragility test - not used so much anymore

Positive eosin-5-maleimide (most sensitive test) - protein that binds to RBC membrane but in hereditary spherocytosis this is not taken up

Question 11

Mx of hereditary spherocytosis?

Answer 11

Folate supplementation, splenectomy

Question 12

What is G6PD deficiency? Where in the world is this more common? inheritance?

Answer 12

X-Linked recessive (usually affects males) cytoplasmic cause of haemolytic anaemia

This is caused by deficiency of Glucose-6-phosphate dehydrogenase

This is more common in areas w/ malaria as it is protective as the haemolysis means the parasite cannot go through its full life cycle

Question 13

Why is G6PD important?

Answer 13

G6PD generates NADPH via pentose phosphate pathway

NAPDH is important to maintain intracellular glutathione (GSH) which protects RBCs against oxidative stress

Question 14

What are the key features of G6PD deficiency in Ix and clinical presentation?

Answer 14

Presentation:
- Episodes following oxidative stress = fava beans, mothballs, drugs (anti-malarials + some abx), also some moth balls

Peripheral blood smear = Heinz bodies (denatured Hb in cells) + Bite cells

intravascular haemolysis hence -> : ↑unconjugated bilirubin, ↓haptoglobin, haemoglobinuria

Question 15

What is mx of G6PD deficiency?

Answer 15

Avoidance of triggers, supportive care

Question 16

When is haptoglobin generally low?

Answer 16

Generally in intravascular causes of haemolytic anaemia

Question 17

What is AIHA?

Answer 17

Auto-immune Haemolytic Anaemia is Immune-mediated destruction of red blood cells, DAT positive

There is warm AIHA and cold AIHA

Question 18

What is the difference between warm and cold AIHA?

Answer 18

Warm antibody hemolytic anemia and cold agglutinin disease based on the temperature at which the autoantibodies react with red blood cells (RBCs)

Warm is test that is positive at temperatures ≥ 37° C (can get in fevers)
Cold is 28–31.

Warm is more common tends to be more severe

Question 19

What are the features of Warm and Cold AIHA?

Answer 19

Warm

• Mediated by IgG
• Associated with CLL (Most likely), SLE, methyldopa
• Extravascular haemolysis

Cold

• Mediated by IgM
• Associated with Mycoplasma, EBV, hepatitis C
• Intravascular haemolysis

Its warm in GREECE and cold in MOSCOW

Both have DAT +ve

Question 20

Mx of warm / cold AIHA?

Answer 20

Treat underlying cause, steroids, rituximab (Anti-CD20)

Question 21

What is the difference between direct and indirect DAT?

Answer 21

Direct:
- Anti-Ig put directly into RBCs

Indirect:
- Anti-Ig put into serum and check for ab floating around

Question 22

What are some features of non-autoimmune HA?

Answer 22

DAT will benegative​- The red cell breakdown isNOTcaused by the immune system​

Infection(such asmalaria) can cause red cellhaemolysis​

This can also be caused byMicroangiopathicHaemolyticAnaemia(MAHA)​

Question 23

What is MAHA?

Answer 23

Microangiopathic haemolytic anaemia (MAHA) is a non-immune-mediated, small vessel disease

Question 24

What is the mechanism of disease in MAHA?

Answer 24

Damage to endothelial cells within the vasculature –> fibrin deposition and platelet aggregation –> fragmentation of red blood cells

Question 25

What are the findings of MAHA on ix + how to distinguish from DIC?

Answer 25

Peripheral blood smear: schistocytes, thrombocytopenia Disorders that cause MAHA – HUS, TTP, DIC Distinguish from DIC with normal APTT, PT, fibrinogen

Question 26

Mx of MAHA?

Answer 26

Treat underlying cause, supportive

Question 27

What is HUS?

Answer 27

Haemolytic uraemic syndrome (HUS) is a caused of MAHA that is commonly caused by E. Coli O157:H7 (Shiga-like toxin) More frequent but less severe in children

Question 28

What are the key clinical features of HUS and how might this appear on exam qs?

Answer 28

Symptoms occur after a diarrhoeal illness – do not give antibiotics to treat Triad of MAHA, thrombocytopenia, acute renal failure – self-limiting in children Features of MAHA on peripheral blood smear In questions you may see - child presenting following diarrhoeal illness w/ renal failure and MAHA

Question 29

Mx of HUS?

Answer 29

Usually supportive care?

Question 30

What is TTP?

Answer 30

Thrombotic Thrombocytopaenic Purpura is a cause of MAHA that occurs due to a deficiency of ADAMTS13 enzyme This can be inherited or accquired (?infection)

Question 31

How does TTP cause MAHA?

Answer 31

Deficiency of ADAMTS13 enzyme -> Reduced breakdown of long vWF multimers hence patients get massive clots and MAHA (due to forcing RBCs through these clots)

Question 32

What are the key clinical features of TTP? what is the most common site of ischaemia?

Answer 32

Pentad of MAHA, thrombocytopenia, acute renal failure, neurological symptoms (IMPORANT FOR Qs), fever High mortality rate Brain is the commonest target for ischaemia  -> develop headache, confusion, ataxia, seizures, and mental status and focal abnormalities

Question 33

How to distinguish between TTP and HUS?

Answer 33

TTP has all the symptoms of HUS + neurological symptoms!! In Qs if you see signs of uto-immune HA + neuro symptoms THINK TTP

Question 34

Mx of TTP?

Answer 34

Supportive care, plasma exchange

Question 35

What is DIC? MoA?

Answer 35

Disseminated intravascular Coagulation is an EMERGENCY (cause of MAHA) Systemic activation of coagulation leads to deposition of fibrin in small blood vessels -> The simultaneous depletion of platelets and coagulation factors leads to increased risk of bleeding 

Question 36

What are some common causes of DIC?

Answer 36

Sepsis (MOST COMMON)  ​ Trauma (e.g. head injury, fat embolism) ​ Obstetric complications (abruptio placentae, amniotic fluid embolism) ​ Malignancy ​(e.g. APML)

Question 37

What can be the complications of DIC?

Answer 37

Systemic activation of coagulation leads to deposition of fibrin in small blood vessels - which can cause kidney damage, brain damage and damage to the extremities requiring amputation

Question 38

Clotting studies findings in DIC?

Answer 38

↑ PT (intrinsic) and ↑ APTT (extrinsic) - both raised THINK DIC ↑ D-dimer - made when body breaks down clots ↑ TT ↑ FDP ↓ platelets ↓ Fibrinogen Schistocytes - Due to fragmentation of red blood cells as they pass through the fibrin mesh in the small blood vessels  

Question 39

How the generally differentiate between the different causes of MAHA?

Answer 39

HUS: Think: E. coli, renal failure, thrombocytopenia, MAHA TTP: Think neurological symptoms, MAHA, renal failure, fever DIC: Think: clotting is screwed + MAHA + ↑ APTT + ↑PT, Amniotic Fluid Embolus

Question 40

``` What are the following ix used for in assessment of haemolytic anaemias? DAT  Urinary haemosiderin/haemoglobin  Osmotic fragility ​ G6PD +/- PK activity Haemoglobin separation A and F% ​ Heinz body stain ​ Ham's test/Flow cytometry of GPI-linked proteins  ​ Thick and thin blood film  ```

Answer 40

DAT - Autoimmune haemolysis Urinary haemosiderin/haemoglobin  - Intravascular haemolysis Osmotic fragility ​- suggests hereditary spherocytosis (dye binding test more commonly used) G6PD +/- PK activity - characterised by episodic haemolysis, where as PK deficiency causes chronic haemolytic anaemia  ​ Haemoglobin separation A and F% ​ Heinz body stain ​- Oxidative haemolysis (eg G6PD) Ham's test/Flow cytometry of GPI-linked proteins  ​- Paroxysmal nocturnal haemoglobinuria  ​ Thick and thin blood film  Malaria (thick = if parasites present, thin = which parasite causing malaria)

Question 41

What is LDH raised in?

Answer 41

Intravascular haemolysis

Question 42

Which anaemias are: | Microcytic, normocytic and macrocytic?

Answer 42

Microcytic: - IDA - Thalassemia - Haemoglobinopathies - Sideroblastic Anaemia Normocytic: - Early IDA - Primary marrow disorders - Bleeding - Anaemia of Chronic Disease - Haemoloytic anaemia Macrocytic: - Megaloblastic Anaemia - Liver Disease - Increased Destruction

Question 43

A pregnant lady is in her first trimester, and is found to have a High MCV, and a low Hb. She informs you that she hasn’t started taking any multivitamins, or supplements, since finding out she is pregnant. What is the likely cause?

Answer 43

Folate Deficiency High MCV and low Hb = Megaloblastic anaemia More folate is needed during pregnancy as well

Question 44

A 5 year old boy presented to A&E with fatigue and shortness of breath. Patient is also mildly jaundiced. Peripheral blood film shown below. His father had a splenectomy when he was younger. What is most sensitive investigation?

Answer 44

Eosin-5-maleimide test Father had splenectomy whilst younger suggesting hereditary spherocytosis Eosin-5-maleimide test is binding test is a flow cytometric test widely used to detect hereditary spherocytosis (HS)

Question 45

An 18-year-old man has just returned from a holiday to Malawi and arranges a GP appointment. He said during the holiday he turned yellow, his urine turned brown and he felt more tired than normal. No PMH. He took antimalarial prophylaxis as directed. Blood tests reveal a normocytic anaemia with unconjugated bilirubinemia. DAT negative. What is the most likely reason for the haemolysis? ``` Malaria  Beta Thalassemia G6PD Deficiency Hereditary Spherocytosis Warm autoimmune hemolytic anemia ```

Answer 45

G6PD Deficiency DAT -ve tell you it is a non-autoimmune cause The use of anti-malarials represents an oxidative stress that can trigger episodes of acute haemolysis in G6PD deficiency

Question 46

Which lab finding would you not expect to see in autoimmune haemolytic anaemia? ``` Reticulocytes  Raised conjugated bilirubin  Positive DAT  Low Hb Raised LDH ```

Answer 46

Raised conjugated bilirubin  | - The rest are all features found in AI haemolytic anaemia

Question 47

A confused patient presents to A&E. She is noted to be extremely lethargic, and she is oliguric. Blood film shows schistocytes. Her bloods show a thrombocytopenia and a rapid rise in urea and creatinine What is the most likely diagnosis? ``` MAHA DIC TTP HUS Acute Intermittent Porphyria ```

Answer 47

TTP This patient shows signs of MAHA (schistocytes) and neurological symptoms making TTP the most likely cause

Question 48

How do you mx TTP?

Answer 48

Plasma exchange

Question 49

What protein is classically mutated in hereditary spherocytosis?

Answer 49

Spectrin