Haemolytic Anaemias

Question 1

Define Haemolytic Anaemia

Answer 1

Haemolytic anaemia encompasses a number of conditions that result in the premature destruction/shortened survival of RBCs in circulation

Question 2

Classify the different types of HAs and give examples

Answer 2

EXTRINSIC/ACQUIRED

• Auto-immune Haemolysis (AIHA)
• Microangiopathic Haemolytic Anaemia (MAHA)
• Oxidative/Toxic damage to RBC ± Hb (drugs e.g. dapsone & chemicals)
• Prosthetic heart valves mechanically destroy RBC
• Parasitic Malaria infection

INTRINSIC/INHERITED

• Enzyme deficiencies
  
  • Glucose-6-Phosphate Dehydrogenase deficiency
  • Pyruvate Kinase Deficiency
• Membrane Issues
  
  • Hereditary Spherocytosis
  • Hereditary Elliptocytosis
• Haemoglobin Issues
  
  • Sickle Cell Trait
  • Beta-Thalassaemia Major

Question 3

Explain the risk factors for Haemolytic Anaemia

Answer 3

• Having autoimmune conditions (e.g. RA, SLE predispose to AIHA)
• Lymphoproliferative disorders (CLL. NHL predispose to AIHA)
• Prosthetic Heart valves (predispose to MAHA)
• Mediterranean, African, Middle-Eastern, SE Asia origin predispose to haemoglobinopathies
• FHx:
  
  • G6PD
  • Beta thalassaemia/Sickle cell
  • Hereditary Spherocytosis
• Exposure to oxidants like naphthalene/Fava beans/dapsone (mild haemolysis in normal pts but severe if G6PD)
• Paroxysmal Nocturnal Haemoglobinuria
  
  • rare genetic hemolysis due to increased susceptibility to intravascular complement-mediated destruction of erythrocytes
• Recent Cephalosporin use (causes anti-RBC antibody production/AIHA)

Question 4

Summarise the epidemiology of Haemolytic Anaemia

Answer 4

• HA is COMMON
• Genetic causes are prevalent if African, Mediterranean and Middle Eastern populations
• Hereditary spherocytosis is the most common inherited haemolytic anaemia in northern Europe

Question 5

Explain the pathophysiology of G6PD Deficiency & pathognomic features

Answer 5

• G6PD is involved in the pentose phosphate pathway which produces NADPH capable of reducing glutathione
• G6PD is an X-linked recessive disorder leading to a lack of G6PD & thus a lack of the protective effect of glutathione - tends to affect young boys
• The RBC are susceptible to INTRAVASCULAR HAEMOLYSIS due to infection or oxidant damage

PERIPHERAL BLOOD FILM FINDINGS:

• Irregularly contracted cells (due to oxidative damage - hyperchromic)
• Heinz bodies (remnants of denatured Hb)
• Bite cells (splenic macrophages remove the denatured Hb)

DIAGNOSIS: G6PD assay 3 months after initial attack as only the RBC with the most G6PD activity will remain and falsely overestimate G6PD activity

Question 6

Explain the pathophysiology of Hereditary Spherocytosis & give pathognomic findings

Answer 6

• Genetic defect in RBC membrane, cells lose part of their membrane during development without equivalent loss of cytoplasm so become spherical
• Function normally however when they reach the spleen they become trapped and haemolysed (EXTRAVASCULAR)
• If this is compensated then they are asymptomatic

PERIPHERAL FINDINGS

• Spherocytes on peripheral blood film
• EMA binding assay now used
• OSMOTIC FRAGILITY TEST:
  
  • normal RBC would haemolyse when placed in hypotonic solution as water moves in but spherocytes will heamolyse more readily at less hypotonic solutions (e.g. if normal RBC lyse at 2mM NaCl, spherocytes would lyse at 5mM)

Question 7

Explain the pathophysiology of Autoimmune Haemolytic Anaemia & pathognomic findings

Answer 7

• Results from the production of autoantibodies against RBC antigens
• The RBC-Antibody complex is recognised by splenic macrophages who rip off a bit of membrane –> spherocytes
  
  • Spherocytes are inflexible and are trapped & haemolysed in the spleen
• RBC-Antibody binding activates INTRAVASCULAR complement-mediated lysis
• Can be PRIMARY AIHA: Idiopathic or SECONDARY AIHA: due to drugs (penicillin, cephalosporin) or infection e.t.c

PATHOGNOMIC FINDINGS

• Direct Antiglobulin Test (DAT/Coombe’s Test)+: An antibody against the anti-RBC antibody is used to detect the presence of anti-RBC antibodies
• Cold agglutinin test: This detects causes of AIHA that are precipitated by temperatures below 37 (Mycoplasma, & Infectious Mononucleosis, lyphoMa) - these autoantibodies are IgM –> Raynaud’s symptoms are seen
• Warm agglutinin test: This detects causes of AIHA that are precipitated by temperatures equal to or above 37 (Idiopathic, SLE & CLL, Myelodysplasia) - these autoantibodies are IgG
• Spherocytes on peripheral blood film
• Management:
  
  • Warm: steroids (± rituximab)
  • Cold: avoidance of cold, warming (plasma exchange in severe disease)

Question 8

Explain the pathophysiology of Microangiopathic Haemolytic Anaemia and pathognomic findings

Answer 8

Microangiopathic haemolysis is a subgroup of HA that result in physical trauma to RBC, such as:

• DIC
• Thrombotic Thrombocytopenic Purpura
• Haemolytic Uraemic Syndrome
  
  • (Thrombocytopenia, AKI, MAHA)
• Pregnancy complications
• In these conditions, the endothelial layer of small vessels is damaged with resulting platelet aggregation and fibrin deposition.
• As red blood cells travel through these damaged vessels, they are fragmented via platelet aggregates resulting in intravascular hemolysis.

PATHOGNOMIC FINDINGS

• Schistocytes on peripheral blood film

Question 9

Give examples of Intravascular Haemolysis and explain how free Hb is handled

Answer 9

• G6PD deficiency/Oxidative damage (Naphthalene, Broad beans, dapsone)
• AIHA
• Malaria infection (Blackwater fever)
• Pyruvate Kinase deficiency
• Sickle Cell Anaemia
• MAHA conditions (DIC, HUS, TTP, Artificial heart valve)

Once the free Hb is in the blood, it can be:

• Sequestered by plasma proteins (Haptoglobin = free Hb, Hemopexin = free haem) that carry it to the spleen and liver where macrophages (reticulo-endothelial system) can break the globin into AAs and the haem into iron & unconjugated bilirubin
• If the intravascular haemolysis is chronic or excessive, then the above mechanisms fail to reduce free Hb so it is filtered via the glomerulus and ends up in the urine, causing HAEMOGLOBINURIA (as well as iro-filled necrotic renal cells) which gives it a characteristic DARK BROWN COLOUR

Question 10

Recognise the presenting symptoms of haemolytic anaemia

Answer 10

Can be ASYMPTOMATIC

• Fatigue
• Shortness of Breath
• Dizzy
• Fever (due to ongoing infection e.g. malaria)
• Sickle cell crisis presentation (priapism, splenic sequestration, painful crisis etc)

Question 11

Recognise the signs of haemolytic anaemia on physical examination

Answer 11

• Bone deformities (sickle cell & thalassaemia, due to extramedullary haematopoiesis)
• Jaundice & Scleral Icterus
• Hepatosplenomegaly
• Conjunctival Pallor
• Increased BP (in pregnancy this indicates eclampsia)
• Tachycardia
• Fever in infectious causes
• Cutaneous & joint signs in autoimmune disease (SLE, RA)

Question 12

Identify appropriate investigations for haemolytic anaemia and interpret the results

Answer 12

Bloods

• FBC:
  
  • Reticulocytes & Low RCC
  • NORMOCYTIC/MACROCYTIC (due to reticulocytosis)
  • Thrombocytopaenia (TTP/HUS)
• Elevated LDH
• Elevated unconjugated bilirubin
• Low haptoglobin (this mops up free Hb)
• U & E
  
  • may indicate ACUTE renal failure/injury in HUS & TTP
• Urinalysis may show haemoglobinuria indicating intravascular haemolysis
• Direct Antiglobulin test/Coombs
• Haemoglobin electrophoresis detects haemoglobinopathies
• Peripheral Blood Smear may identify specific abnormal cells pointing to the diagnosis such as:
  
  • Hypochromic microcytic anaemia - thalassemia
  • Spherocytes – hereditary spherocytosis or AIHA
  • Elliptocytes – hereditary elliptocytosis
  • Sickle cells – sickle cell anaemia
  • Schistocytes - Microangiopathic processes
  • Malarial parasite
  • Heinz bodies (& ‘bite cells’) – G6PD deficiency
  • Howell-Jolly bodies (Sickle Cell)
  • Irregularly contracted cells - G6PD deficiency