Haem 1: Haemolytic anaemias (normocytic things) Flashcards
What are the key differentials in normocytic anaemia?
Haemolytic: inherited or acquired (immune-mediated, non-immune-mediated)
Non-haemolytic: anaemia of chronic disease, failure of erythropoiesis
What ix should be conducted in a normocytic anaemia?
Peripheral blood smear
DAT
CRP, ESR
Causes of anaemia of chronic disease?
Infection, inflammation, malignancy
Mechanism behind anaemia of chronic disease?
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
Ix findings in anaemia of chronic disease? + what is the mx?
Inflammatory markers – raised CRP, ESR (this is more raised than CRP as its chronic)
Iron studies – ↑iron, ↑ferritin, ↓transferrin, ↓TIBC
Treat underlying cause!
How can haemolytic anaemias be classified + examples?
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
How else can haemolytic anaemias be classified by anatomy?
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)
What is Paroxysmal nocturnal hemoglobinuria (PNH) caused by and how does it present?
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?
What is hereditary spherocytosis? + what clues are often given in questions to suggest this? inheritance?
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
What features are found in ix of hereditary spherocytosis + which test is most sensitive?
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
Mx of hereditary spherocytosis?
Folate supplementation, splenectomy
What is G6PD deficiency? Where in the world is this more common? inheritance?
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
Why is G6PD important?
G6PD generates NADPH via pentose phosphate pathway
NAPDH is important to maintain intracellular glutathione (GSH) which protects RBCs against oxidative stress
What are the key features of G6PD deficiency in Ix and clinical presentation?
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
What is mx of G6PD deficiency?
Avoidance of triggers, supportive care
When is haptoglobin generally low?
Generally in intravascular causes of haemolytic anaemia
What is AIHA?
Auto-immune Haemolytic Anaemia is Immune-mediated destruction of red blood cells, DAT positive
There is warm AIHA and cold AIHA
What is the difference between warm and cold AIHA?
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
What are the features of Warm and Cold AIHA?
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
Mx of warm / cold AIHA?
Treat underlying cause, steroids, rituximab (Anti-CD20)
What is the difference between direct and indirect DAT?
Direct:
- Anti-Ig put directly into RBCs
Indirect:
- Anti-Ig put into serum and check for ab floating around
What are some features of non-autoimmune HA?
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)
What is MAHA?
Microangiopathic haemolytic anaemia (MAHA) is a non-immune-mediated, small vessel disease
What is the mechanism of disease in MAHA?
Damage to endothelial cells within the vasculature –> fibrin deposition and platelet aggregation –> fragmentation of red blood cells
What are the findings of MAHA on ix + how to distinguish from DIC?
Peripheral blood smear: schistocytes, thrombocytopenia
Disorders that cause MAHA – HUS, TTP, DIC
Distinguish from DIC with normal APTT, PT, fibrinogen
Mx of MAHA?
Treat underlying cause, supportive
What is HUS?
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
What are the key clinical features of HUS and how might this appear on exam qs?
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
Mx of HUS?
Usually supportive care?
What is TTP?
Thrombotic Thrombocytopaenic Purpura is a cause of MAHA that occurs due to a deficiency of ADAMTS13 enzyme
This can be inherited or accquired (?infection)
How does TTP cause MAHA?
Deficiency of ADAMTS13 enzyme -> Reduced breakdown of long vWF multimers hence patients get massive clots and MAHA (due to forcing RBCs through these clots)
What are the key clinical features of TTP? what is the most common site of ischaemia?
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
How to distinguish between TTP and HUS?
TTP has all the symptoms of HUS + neurological symptoms!!
In Qs if you see signs of uto-immune HA + neuro symptoms THINK TTP
Mx of TTP?
Supportive care, plasma exchange
What is DIC? MoA?
Disseminated intravascular Coagulation is an EMERGENCY (cause of MAHA)
Systemic activation of coagulation leadstodeposition of fibrin in small bloodvessels-> The simultaneous depletion of plateletsand coagulation factors leadstoincreased risk of bleeding
What are some common causes of DIC?
Sepsis (MOST COMMON)
Trauma (e.g.head injury, fat embolism)
Obstetric complications (abruptio placentae, amniotic fluid embolism)
Malignancy(e.g. APML)
What can be the complications of DIC?
Systemic activation of coagulation leadstodeposition of fibrin in small bloodvessels- which can cause kidney damage,brain damage and damage to theextremities requiring amputation
Clotting studies findings in DIC?
↑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 meshin the small blood vessels
How the generally differentiate between the different causes of MAHA?
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
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
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 asPK 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)
What is LDH raised in?
Intravascular haemolysis
Which anaemias are:
Microcytic, normocytic and macrocytic?
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
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?
Folate Deficiency
High MCV and low Hb = Megaloblastic anaemia
More folate is needed during pregnancy as well
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?
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)
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
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
Which lab finding would you not expect to see in autoimmune haemolytic anaemia?
Reticulocytes Raised conjugated bilirubin Positive DAT Low Hb Raised LDH
Raised conjugated bilirubin
- The rest are all features found in AI haemolytic anaemia
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
TTP
This patient shows signs of MAHA (schistocytes) and neurological symptoms making TTP the most likely cause
How do you mx TTP?
Plasma exchange
What protein is classically mutated in hereditary spherocytosis?
Spectrin
