Haematology - Haemolytic Anaemias Flashcards
What is haemolytic anaemia?
The breakdown of red blood cells before their normal life span of ~120 days
What is intravascular haemolytic anaemia and three causes?
Where red blood cells are destroyed in circulation (they rupture and release their contents)
- Alloimmune
- Autoimmune
- Hereditary spherocytosis
What is extravascular haemolytic anaemia and four causes?
Where red blood cells are destroyed in the reticuloendothelial system
- Malaria
- Drugs
- G6PD deficiency
- PNH (Paroxysmal Nocturnal Haemoglobinuria)
What are the biochemical features of all haemolytic anaemias?
- Increased unconjugated bilirubin
- Increased urobilinogen (in urine)
- Increased LDH
- Reticulocytosis (Macro/normocytic + Polychromasia)
- ?Pigmented gallstones
What are the biochemical features of intravascular haemolytic anaemia?
- Increased Hb
- Decreased Haptoglobin (binds free Hb)
- Haemoglobinuria (dark red urine)
- Methaemalbuminaemia (Haem + albumin in blood)
- Increased LDH
- Decreased haptoglobin
- Diptick = Blood +
What are the biochemical features of extravascular haemolytic anaemia?
- Urobilinogen
- Dipstick = Blood -
- Spherocytes (on blood smear)
What is a clinical feature of extravascular haemolytic anaemia?
Splenomegaly
What is erythroid hyperplasia?
An increased count of erythroid precursor cells as a response to peripheral RBC loss/destruction.
What are erythroid hyperplasia states susceptible to?
- Parvovirus B19 (aplastic crisis)
- Iron overload
- Osteoporosis
What are reticulocytes?
Immature RBCs halted in the process of maturation
What is a normal reticulocyte count?
0.5-2.5%
What happens to the reticulocyte count of a patient who is acutely anaemia and why?
- It increases (high reticulocyte count)
- Bone marrow is responding and working harder to produce more RBCs
When is a reticulocyte count raised?
With peripheral causes of anaemia
What are the inherited causes of haemolytic anaemia and some examples?
Membrane Defect:
- Hereditary spherocytosis
- Hereditary elliptocytosis
Enzyme Defect:
- G6PD Deficiency
- Pyruvate kinase deficiency
Haemaglobinopathies:
- Sickle cell disease
- Thalassaemias
What are acquired causes of haemolytic anaemia and some examples?
Immune:
- Autoimmune (e.g. Warm + Cold)
- Alloimmune (e.g. Haemolytic transfusion reactions + ABO/Rhesus incompatibility)
Non-immune:
- Mechanical (e.g. Metal valves + trauma)
- Paroxysmal Nocturnal Haemaglobinuria
- Microangiopathic Haemolytic Anaemia
- Infections (e.g. Malaria)
- Drugs
What is hereditary spherocytosis?
A defect in the vertical interaction of RBC membrane
What inheritance pattern is hereditary spherocytosis?
Autosomal Dominant
What is hereditary spherocytosis susceptible to?
Effects of Parvovirus B19
Often develop gallstones
Which membrane proteins is hereditary spherocytosis deficient in?
Spectrin / Ankyrin
What type of haemolysis does hereditary spherocytosis show and what clinical sign would it present with?
Extravascular haemolysis
Splenomegaly
What test results would hereditary spherocytosis show?
- Blood Film: Spherocytes + Polychromasia
- Increased osmotic fragility (lysis in hypotonic solutions)
- Coombs/DAT negative
- Flow cytometry/EMA binding test: Positive Eosin-5-maleimide (MOST SENSITIVE)
What is the treatment for hereditary spherocytosis?
Folic acid
Splenectomy in some cases
What is hereditary elliptocytosis?
A defect in the horizontal transmission of RBCs membrane
What type of inheritance pattern does hereditary elliptocytosis have?
Autosomal Dominant (mostly)
EXCEPT: Hereditary pyropoikilocytosis (Autosomal Recessive)
What type of mutation is present in hereditary elliptocytosis?
Spectrin mutation (membrane protein)
What is hereditary pyropoikilocytosis?
A type of hereditary elliptocytosis where erythrocytes are abnormal sensitive to heat
What symptoms are present with hereditary elliptoocytosis?
Most asymptomatic
What is seen on the blood film of hereditary elliptocytosis
Elliptocytes (elliptical RBCs)
What is South Asian Ovalocytosis and it’s mode of inheritance?
An autosomal recessive, heterozygote defect that is similar to hereditary elliptocytosis that presents with ovalocytes on blood film.
Can offer malarial protection
What is the commonest RBC enzyme defect?
Glucose-6-phosphate dehydrogenase deficiency
What is the mode of inheritance of glucose-6-phosphate dehydrogenase deficiency?
X-linked
Where is glucose-6-phosphate dehydrogenase deficiency prevalent?
In areas of malarial endemicity
- Africa
- Mediterranean
- Middle East
What are the symptoms of glucose-6-phosphate dehydrogenase deficiency?
Rapid anaemia + jaundice
What causes rapid anaemia in glucose-6-phosphate dehydrogenase deficiency?
Acute haemolysis following an exposure to oxidative stres
What is seen on a blood film for glucose-6-phosphate dehydrogenase deficiency?
- Bite cells
- Heinz bodies (blue deposits, oxidized Hb)
What is the action and role of glucose-6-phosphate dehyrogenase?
It generates NADPH via the pentose phosphate pathway
It helps RBCs make glutathione which protects them from oxidant damage?
What are some precipitants for Glucose-6-phosphate dehydrogenase deficiency?
- Drugs (2-3 days after starting - primaquine, sulfonamides, aspirin)
- Broad/Fava beans (1 day after eating - favism)
- Acute stressors
- Moth Balls
- Acute Infection
What are some clinical findings of glucose-6-phosphate dehydrogenase deficiency?
Intravascular haemolysis
- Dark urine
- Haemoglobinuria
- Decreased haptoglobin
- Increased unconjugated bilirubin
How is glucose-6-phosphate dehydrogenase deficiency diagnosed?
Enzyme assay ~2-3months post-crisis
- Young RBCs may have sufficient enzyme results so may appear normal
What is the treatment for Glucose-6-phosphate dehydrogenase deficiency?
AVOID PRECIPITANTS
- Transfuse if severe
- Genetic screening (rare subtypes give chronic haemolysis for which splenectomy can be needed)
- Supportive treatment
What is the mode of inheritance of pyruvate kinase deficiency?
Autosomal Recessive
(AD has been observed with the disorder)
What are the clinical features of pyruvate kinase deficiency?
- Severe neonatal jaundice
- Splenomegaly
- Haemolytic anaemia
What is the treatment of pyruvate kinase deficiency?
?Blood transfusion
?Splenectomy
Most don’t require treatment
What blood test is used to identify an Autoimmune Acquired Haemolytic Anaemia?
- Direct Antiglobulin Test (DAT) / Coombs Test
- Positive
What are the two types of Autoimmine Acquired Haemolytic Anaemia and which is more common?
Warm (WAIHA) - MOST COMMON
Cold agglutinin disease
What are some features of WAIHA?
- 37C
- IgG (Warm in Greece)
- Positive Coombs Test
What type of haemolysis does WAIHA show?
Extravascular
What is seen on the blood film of WAIHA?
Spherocytes
What are some features of Cold agglutinin disease?
- <37C
- IgM (Cold in Moscow)
- Often with Raynaud’s
What type of haemolysis does cold agglutinin disease show?
Intravascular
What are some causes of WAIHA?
- Idiopathic (main cause)
- Lymphoma
- CLL
- SLE
- Methyldopa
What are some causes of Cold agglutinin disease?
- Idiopathic (main cause)
- Lymphoma infections: EBV, Mycoplasma, Hepatitis C
What is the Management of WAIHA?
- Treat underlying cause
- Steroids
- Splenectomy
- Immunosuppression
What is the management of cold agglutini disease?
- Treat underlying conditino
- Avoid the cold
- Chemotherapy if lymphoma
- Steroids
What are some symptoms of haemolytic anaemia?
- Pallor
- Jaundice
- Splenomegaly
- Pigmenturia
- FHx
What is the cause of haemoglobinuria in Paroxysmal Cold Haemoglobinuria?
Viral infection:
- Measles
- Syphilis
- VZV
What type of antibodies are found in Paroxysmal Cold Haemoglobinuria?
Donath-Landsteiner antibodies
What is the pathophysiology of Paroxysmal Cold Haemoglobinuria?
Donath-Lansteiner antibodies stick to RBCs in the cold and cause complement-mediated haemolysis on rewarming.
Self-limiting: IgG dissociates at higher temperatures than IgM
What test is used to determine a non-immune acquired haemolytic anaemia?
Direct Antiglobulin Test (DAT)/Coombs Test
NEGATIVE
What are some general signs of non-immune acquired haemolytic anaemias?
- Mechanical trauma
- Infections
- Hypersplenism
How is Paroxysmal Nocturnal Haemoglobinuria caused?
An acquired loss of protective surface GPI markers on RBCs (platelets + neutrophils) cause complement-mediated lysis leading to chronic intravascular haemolysis, especially at night.
What are some signs/symptoms of paroxysmal nocturnal haemoglobinuria?
- Morning haemoglobinuria
- Thrombosis (+ Budd-chiari syndrome)
How is paroxysmal nocturnal haemoglobinuria diagnosed?
- Immunophenotype shows altered GPI
- HAM’S TEST (in vitro acid-induced lysis)
What is the treatment for paroxysmal nocturnal haemoglobinuria?
- Iron/folate supplements
- Prophylactic vaccines/antibiotics
- Expensive monoclonal antibodies (ECULIZUMAB) that prevents complement from binding RBCs
What is microangiopathic haemolytic anaemia?
A non-immune-mediated, small vessel disease
What is the pathophysiology of microangiopathic haemolytic anaemia?
Damage to endothelial cells causes fibrin deposition and platelet aggregation (TBCs forced through fibrin/platelet mesh) leading to RBC fragmentation
What is seen on a blood film/tests for microangiopathic haemolytic anaemia?
- Schistocytes
- Thrombocytopaenia
What are some causes of microangiopathic haemolytic anaemia?
- HUS (Haemolytic Uraemic Syndrome)
- TTP (Thrombotic Thrombocytopaenic Purpura)
- Pre-eclampsia
- Eclampsia
- Reactions (usually plasma exchange)
What is the management of microangiopathic haemolytic anaemia?
- Treat underlying cause
- Supportive
What are the pentad of symptoms of thrombotic thrombocytopaenic purpura?
- MAHA
- Fever
- Renal impairment (less pronounced than HUS)
- Neuro abnormalities
- Thrombocytopaenia
What are the causes of thrombotic thrombocytopaenic purpura?
- Inherited
- Acquired
What is the treatment of thrombotic thrombocytopaenic purpura?
Emergency plasma exchange (Haematological emergency)
+ Supportive Management
What is the autoimmune pathophysiology of thrombotic thrombocytopaenic purpura?
ADAMTS13 defiency causes a breakdown of multimers of vWF leading to long strands of vWF which act like cheese wire in the blood vessels, cutting up RBCs
Which protein is associated with TTP?
ADAMTS13
What are some features of haemolytic uraemic syndrome?
- Common in children + elderly
- Less severe in children
- Usually self-limiting
What is the primary cause of haemolytic uraemic syndrome?
Escherichia Coli 0157:H7 shiga-like-toxin
How is haemolytic uraemic syndrome caused?
The E. coli (Esherichia coli 0157:H7) shiga-like-toxin damages endothelial cells, forms a fibrin mesh and damages RBCs + impaired renal function + MAHA
What are the symptoms of haemolytic uraemic syndrome?
- Diarrhoea
- Renal failure
- No neuro problems
When do the symptoms appear in haemolytic uraemic syndrome?
After diarrhoea-illness
DO NOT GIVE ABX
What is the management of haemolytic uraemic syndrome?
Supportive
What is the triad of haemolytic uraemic syndrome?
- MAHA
- Acute renal failure
- Thrombocytopaenia
