hemolytic anemoa

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HAEMOLYTIC ANAEMIAS

• DR.W.C.LWABBY (RESIDENT IM)

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INTRODUCTION

• Hemolysis is the destruction of RBCs with
  subsequent release of haemoglobin.
• Haemolytic anaemias are caused by increased
  destruction of red cells.
• The red cell normally survives about 120 days,
• In haemolytic anaemias the red cell survival
  are considerably shortened.
• Breakdown of normal red cells occurs in the
  macrophages of the bone marrow, liver and spleen.

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Sites of haemolysis

• Extravascular haemolysis
• In most haemolytic conditions red cell
  destruction is extravascular.
• 80-90 of RBC destruction.
• The damaged or Antibody-coated RBC are removed
  from the circulation by macrophages in spleen,
  liver, and marrow(RES)

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Sites of haemolysis..

• CAUSES OF EXTRAVASCULAR HEMOLYSIS
• Aged RBC as its life span is 120 days.
• Defects in membrane skeletal proteins eg lack of
  Vit B12 and FA
• Hemoglobin defects SCD, Thalassaemias
• Immune mediated transfusion reactions
• Defects in enzymes involved in energy production
  G6PD deficiency

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Sites of haemolysis.

• Intravascular haemolysis
• Involves rapid destruction of RBCs within the
  vasculature releasing free hemoglobin into the
  circulation.
• 10 of RBC destruction.
• Excess free plasma haemoglobin is filtered by the
  renal glomerulus.
• Then enters the urine, although small amounts are
  reabsorbed by the renal tubules.
• In the renal tubular, haemoglobin is broken down
  and becomes deposited in the cells as
  haemosiderin.

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Sites of haemolysis.

• CAUSES OF INTRAVASCULAR HEMOLYSIS
• Erythroparasites
• Babesia species and malaria parasite replicate
  inside erythrocytes.
• These rupture the cells when they exit to
  continue their life cycle.
• Oxidant injury
• Cu poisoning and Zn toxicity
• Metabolic conditions
• acute liver disease, hypophosphatemia

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INHERITED HAEMOLYTIC ANAEMIA

• Red cell membrane defects (Membrenopathies)
• Hereditary spherocytosis (HS)
• Hereditary elliptocytosis
• Haemoglobin abnormalities (Haemoglobinopathies)
• Qualitative abnormalities ( Sickle Cell Disease)
• Quantitative abnormalities (Thalassaemias)
• Metabolic disorders of the red cell (
  Enzymopathies)
• Glucose-6-phosphate dehydrogenase deficiency
• Pyruvate kinase deficiency
• Pyrimidine 5 nucleotidase deficiency

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Red cell membrane defects

• Hereditary spherocytosis (HS)
• Is the most common inherited haemolytic anaemia
  in northern Europeans.
• Affecting 1 in 5000.
• It is inherited in an autosomal dominant manner.
• Is due to defects in the red cell membrane.
• Resulting in the cells losing part of the cell
  membrane as they pass through the spleen.
• Possibly because the lipid bilayer is
  inadequately supported by the membrane skeleton.

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Hereditary spherocytosis (HS) cont.

• The best-characterized defect is a deficiency in
  the structural protein spectrin.
• The surface-to-volume ratio decreases.
• The cells become spherocytic.(sphere-shaped)
  rather than bi-concave disk shaped .
• Spherocytes are more rigid and less deformable
  than normal red cells.
• They are unable to pass through the splenic
  microcirculation so they have a shortened
  lifespan.

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Clinical features of HS

• The condition may present with
• Jaundice at birth--the onset of jaundice can be
  delayed for many years.
• Anaemia, splenomegaly and ulcers on the legs.
• Some patients may go through life with no
  symptoms
• are detected only during family studies.

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Clinical features of HS..

• The clinical course may be complicated by crises
• A haemolytic crisis
• Occurs when the severity of haemolysis increases.
  
• This is rare, and usually associated with
  infection.
• A megaloblastic crisis
• Follows the development of folate deficiency.
• It may occur as a first presentation of the
  disease in pregnancy.
• An aplastic crisis
• Occurs in association with parvovirus B19
  infection.
• The virus directly invades red cell precursors
  and temporarily switches off red cell production.
• Patients present with severe anaemia and a low
  reticulocyte count.

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Investigations

• Blood count
• Anaemia. This is usually mild, but occasionally
  can be severe.
• BLOOD FILM
• spherocytes and reticulocytes.
• Evident of Haemolysis
• Raised the serum bilirubin
• Raised urinary urobilinogen
• Direct antiglobulin (Coombs) test
• Is negative in hereditary spherocytosis,
  virtually ruling out autoimmune haemolytic
  anaemia.

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Investigations cont

• Osmotic fragility.
• When red cells are placed in solutions of
  increasing hypotonicity
• They take in water, swell, and eventually lyse.
• Spherocytes tolerate hypotonic solutions less
  well than do normal biconcave red cells.

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Treatment HS

• Splenectomy
• Helps to
• relieve symptoms due to anaemia or splenomegaly.
  
• reverse growth failure and prevent recurrent
  gallstones.
• Following splenectomy
• The spherocytes persist.
• Hb usually returns to normal as the red cells
  are no longer destroyed.
• Splenectomy should be
• Preceded by appropriate immunization
• Followed by lifelong penicillin prophylaxis.

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Haemoglobin abnormalities

• Sicklecell disease
• Results from
• a single glutamic acid to valine substitution at
  position 6 of the beta globin polypeptide chain.
• It is inherited as an autosomal recessive trait.
• Homozygotes only produce abnormal beta chains
  that make haemoglobin S (HbS, termed SS).
• This results in the clinical syndrome of
  sicklecell disease.
• Heterozygotes produce a mixture of normal and
  abnormal beta chains that make normal HbA and HbS
  (termed AS).
• This results in the clinically asymptomatic
  sickle cell trait.

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Epidemiology

• The disease usually does not manifest itself
  until the HbF decreases to adult levels at about
  6 months of age.
• The heterozygote frequency is over 20 in
  tropical Africa.
• In black American populations sicklecell trait
  has a frequency of 8.
• Individuals with sickle cell trait are relatively
  resistant to the lethal effects of falciparum
  malaria in early childhood.
• The high prevalence in equatorial Africa can be
  explained by
• the survival advantage it confers in areas where
  falciparum malaria is endemic.

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Pathogenesis

• When haemoglobin S is deoxygenated
• the molecules of haemoglobin polymerise to form
  pseudocrystalline structures known as tactoids.
• These distort the red cell membrane and produce
  characteristic sickleshaped cells
• The polymerisation is reversible when
  reoxygenation occurs.
• However, may become permanent and the red cell
  irreversibly sickled.

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Precipitating factors

• Sickling is precipitated by
• Infection
• Dehydration
• Coldness
• Acidosis or hypoxia.
• Sickling can produce
• A shortened red cell survival.
• Impaired passage of cells through the
  microcirculation, leading to
• obstruction of small vessels and tissue
  infarction.

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Clinical features

• Irreversibly sickled cells have a shortened
  survival and plug vessels in the
  microcirculation.
• This results in
• Acute syndromes termed crises.
• Chronic organ damage.
• These crises include
• Painful vaso-occlusive crisis.
• Sickle chest syndrome.
• Sequestration crisis.
• Aplastic crisis.

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Clinical features

• Painful Vaso-occlusive crises
• Plugging of small vessels in the bone produces
  acute severe bone pain.
• This affects areas of active marrow
• The hands and feet in children (so called
  dactylitis)
• The femora, humeri, ribs, pelvis and vertebrae in
  adults.
• Patients usually have a systemic response with
  tachycardia, sweating and a fever.
• This is the most common crisis.

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Clinical features

• Sickle chest syndrome
• This occurs in up to 30 .
• It may follow a vaso-occlusive crisis.
• Is the most common cause of death in adult
  sickle disease.
• Bone marrow infarction results in fat emboli to
  the lungs
• which cause further sickling and infarction,
  leading to ventilatory failure if not treated.
• It comprises shortness of breath, chest pain,
  hypoxia and new chest X-ray changes due to
  consolidation.
• The presentation may be gradual or very rapid,
  leading to death in a few hours.

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Clinical features

• Sequestration crisis.
• Thrombosis of the venous outflow from an organ
• causes loss of function and acute painful
  enlargement.
• In children, the spleen is the most common site.
• Massive splenic enlargement may result in
• severe anaemia, circulatory collapse and death.

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Clinical features

• Sequestration crisis.
• Recurrent sickling in the spleen in childhood
  results
• in infarction and adults may have no functional
  spleen.
• In adults
• The liver may undergo sequestration with severe
  pain due to capsular stretching.
• Priapism is a complication seen in affected men.

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Clinical features

• Aplastic crisis
• Infection with human parvovirus B19 results in a
  severe but selflimiting red cell aplasia.
• This produces a very low haemoglobin, which may
  cause heart failure.
• Unlike in all other sickle crises the
  reticulocyte count is low.

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Investigations

• Patients with sicklecell disease have a
  compensated anaemia, usually around 68 g/dL.
• The blood film shows
• Sickle cells
• Target cells (dark ring surrounding a dark
  central spot)
• Features of hyposplenism.
• A reticulocytosis is present.
• Sickling test is positive
• Exposing red cells to a reducing agent such as
  sodium dithionite
• polymerises to produce a turbid solution.

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Investigations.

• The definitive diagnosis requires
• Haemoglobin electrophoresis to demonstrate the
  absence of
• HbA
• 220 HbF
• The predominance of HbS.

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Clinical and laboratory features of sickle-cell
disease.
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Treatment

• All patients with sickle cell disease should
  receive prophylaxis
• With daily folic acid
• Penicillin V to protect against pneumococcal
  infection which may be lethal in the presence of
  hyposplenism.
• These patients should be vaccinated against
• Pneumococcus
• Meningococcus
• Haemophilus influenzae B
• Hepatitis B
• Seasonal influenza.

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Treatment.

• Vasoocclusive crises are managed by
• Aggressive rehydration
• Oxygen therapy
• Adequate analgesia (which often requires opiates)
  
• Antibiotics.
• Transfusion may be used in a sequestration or
  aplastic crisis.
• Some agents are able to increase synthesis of HbF
• This has been used to reduce the frequency of
  severe crises.
• Oral cytotoxic agent hydroxycarbamide has been
  shown to have
• clinical benefit with acceptable side effects in
  children and adults
• who have recurrent severe crises.

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Treatment.

• Allogeneic stem cell transplants from HLA
  matched siblings have been performed.
• This procedure appears to be potentially curative
• Prognosis
• In Africa
• Few children with sickle cell anemia survive to
  adult life without medical attention.
• Even with standard medical care approximately
• 15 die by the age of 20 years.
• 50 die by the age of 40 years.

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Metabolic disorders of the red cell
(Enzymopathies)

• Glucose-6-phosphate dehydrogenase deficiency
• The enzyme glucose6phosphate dehydrogenase
  (G6PD) is pivotal in the hexose monophosphate
  shunt pathway.
• Deficiencies result in the most common human
  enzymopathy
• affecting 10 of the worlds population,
• with a geographical distribution which parallels
  the malaria belt
• because heterozygotes are protected from malarial
  parasitisation.
• Pathogenesis

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Treatment

• Aims to stop any precipitant drugs and treat any
  underlying infection.
• Acute transfusion support may be lifesaving.

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ACQUIRED HAEMOLYTIC ANAEMIA

• These anaemias may be due to
• Immune
• Non-immune
• Other causes.
• Causes of immune destruction of red cells
• Autoantibodies
• Drug-induced antibodies
• Alloantibodies.

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ACQUIRED HAEMOLYTIC ANAEMIA.

• Causes of non-immune destruction of red cells
• Acquired membrane defects (e.g. paroxysmal
  nocturnal haemoglobinuria)
• Mechanical factors (e.g. prosthetic heart
  valves, or microangiopathic haemolytic anaemia)
• Secondary to systemic disease (e.g. renal and
  liver disease)

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ACQUIRED HAEMOLYTIC ANAEMIA.

• Miscellaneous causes
• Various toxic substances can disrupt the red
  cell membrane and cause haemolysis (e.g. arsenic,
  and products of Clostridium welchii).
• Malaria frequently causes anaemia owing to a
  combination of
• a reduction in red cell survival
• Reduced production of red cells.
• Hypersplenism- results in a reduced red cell
  survival, which may also contribute to the
  anaemia seen in malaria.
• Some drugs (e.g. dapsone, sulfasalazine) cause
  oxidative haemolysis with Heinz bodies

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