Hereditary spherocytosis

Parvovirus B 19 can cause transient red cell aplasia in patients with hemolytic disorders. It can cause aplastic crisis.

Ref: Harrisons principles of internal medicine, 18th edition, Page 874.

The presence of osmotic fragility is the main diagnostic test for hereditary spherocytosis.

Increased incidence of gallstones are seen in Hereditary spherocytosis, but they are pigment gallstones. This is almost the only condition where an elevated MCHC is seen.

CLinical features of hereditary spherocytosis:
 

Ans. ‘a’ i.e., Spectrin; ‘b’ i.e., Ankyrin

Defect in Hereditary spherocytosis

      Ankyrin (most common)                Band 3 (protein 3 or Anion transport channel)

      Spectrin                                        Band 4.2

Ans. is ‘b’ i.e., Reticulocytosis seen; ‘c’ i.e., Smaller size

Clinical features of hereditory spherocytosis

The clinical features are those of extravascular hemolysis : ‑

o Anemia —> Mild to moderate

o Jaundice (Mainly indirect bilirubin)

o Splenomegaly

o Gall stones -3  Elevated excretion of bilirubin promotes formation of pigment stone.

o Leg ulcer  —>  Rare clinical manifestation.

o Aplastic crisis —> Triggered by parvo-virus infection.

Laboratory findings

o Spherocytosis –> Peripheral smear shows microspherocytes which are small RBCs without central pallor (Normally central 1 /3 pallor is present in red cells).

o MCV  o Reticulocytosis —*As seen with any type of hemolytic anemia.

o MCHC T o Hemoglobin .1

o Increased unconjugate bilirubin o Serum Heptoglobin —> Normal to decreased.

o Urine urobilinogen T o Increased osmotic fragility.

o Stool stercobilinogen r

Ans. is ‘a’ i.e., Membrane skeleton abnormalities

Ans. is ‘a’ i.e., About 50% of affected infants have moderately severe neonatal jaundice

Answer is C (MCV Ted)

Mean corpuscular volume of RBC is decreased in patients with hereditary spherocytosis.

Hereditary spherocytosis is characterised by defect in one of the proteins in the cytoskeleton of Red cell membrane, leading to loss of membrane, and hence decreased ratio of surface area to volume and consequently spherocytosis.

Characteristic Laboratory abnormalities

• The mean corpuscular volume (MCV) : is decreased^Q
• The mean corpuscular Hb. concentration (MCHC) : is increased^Q
• Osmotic fragility is : increased^Q

Remember the following also :

Ans. A: Spectrin

Hereditary spherocytosis (HS) is due to a deficiency of a protein called ankyrin.

Ankyrins are cell membrane proteins (thought to interconnect integral proteins with the spectrin-based membrane skeleton)

The ankyrin of red blood cells (erythrocytic ankyrin) is called ankyrin-R/ankyrin-1/ ANK1.

Ans. D i.e. All of the above

Ans: C i.e. Spherocytosis is a pathognomic finding

Hereditary spherocytosis

• The characteristic clinical features are anemia, moderate splenomegaly (500-1000 gm), and jaundice.
• The most specific morphologic finding of hereditary spherocytosis is spherocytosis but spherocytosis is not pathognomic, since other forms of membrane loss, such as in autoimmune haemolytic anemias, also cause the formation of spherocytes
• Hereditary spherocytosis is an inherited disorder caused by intrinsic defects in the RBC membrane skeleton that render RBC spheroid, less deformable, and vulnerable to splenic sequestration and destruction.

Ans. B: Increased RBC surface area

Spherocytosis is caused by a molecular defect in one or more of the proteins of the red blood cell cytoskeleton, including, spectrin, ankyrin so blood cell contracts to its most surface-tension efficient and least flexible configuration, a sphere( spherocytes).

They have a high osmotic fragility and are more prone to physical degradation.

They are most commonly found in immunologically-mediated hemolytic anemias and in hereditary spherocytosis, but the former would have a positive direct Coombs test and the latter would not.

The misshapen but otherwise healthy red blood cells are mistaken by the spleen for old or damaged red blood cells and it thus constantly breaks them down, causing a cycle whereby the body destroys its own blood supply (auto-hemolysis). Chronic symptoms include anemia and splenomegaly. As a result of the broken-down blood cells — bilirubin — accumulates in the gallbladder and can cause pigmented gallstones to develop.

In peripheral blood smears, red blood cells will appear abnormally small.

The CBC will show elevated MCHC.

The bone marrow in its role of manufacturing red blood cells will display hyperplasia, the increased activity of replacing RBCs. As a result, immature red blood cell or reticulocyte counts will appear elevated.

Ans. is ‘b’ i.e., Ankyrin

Spherocytes: are nearly spherical erythrocytes which are nearly spherical erythrocytes which usually have a diameter smaller than normal. They lack the central pale area due to their spherical shape.Most commonly seen in cases of-

• Hemolytic anemia
• Post transfusion
• Hereditary sphercocytosis.

Ans. is ‘a’ i.e., Direct Coomb’s positive

Hereditary Spherocytosis

• Membrane cytoskeleton that lies closely opposed to the internal surface of the plasma membrane, is responsible for elasticity and maintenance of RBC shape.

Membrane skeleton consists :‑

Spectrin  →  The chief protein component responsible for biconcave shape.

Ankyrin and band 4-2     →  Binds spectrin to band 3

Band 3    →  A transmembrane ion transport protein.

Band 4^.1 →  Binds spectrin to glycophorin A, atransmembrane protein.

• Hereditary spherocytosis is an autosomal dominant disorder characterized by intrinsic defects in red cell membrane. This results in production of red cells that are sphere (spherocytes) rather than biconcave.
• The mutation most commonly involves the gene coding for ankyrin, followed by Band-3 (anionic transport channel), spectrin, and Band 4^.2 (also called palladin).

Also know

Most common, defect in hereditary elliptocytosis is in spectrin

Pathogensis of Hereditary spherocytosis

• Loss of membrane cytoskeleton proteins (ankyrin, spectrin, Band 3, 4.2) results in reduced membrane stability. Reduced membrane stability leads to spontaneous loss of membrane fragments during exposure to shear stresses in the circulation. The loss of membrane relative to cytoplasm forces the cells to assume the smallest possible diameter for a given volume cells become microspherocytes.
• Because of their spheroidal shape and reduced membrane plasticity, red cells become less deformable and are trapped in to spleen as they are unable to pass through the interendothelial fenestrations of the venous sinusoids. In the splenic sinusoides, red cells are phagocytosed by RE cells  Extravascular hemolysis.

Clinical features of Hereditory spherocytosis

The clinical features are those of extravascular hemolysis :

Anemia  →  Mild to moderate

Jaundice (Mainly indirect bilirubin)→ Splenomegaly

Gall stones     →  Elevated excretion of bilirubin promotes formation of pigment stone.

Leg ulcer  → Rare clinical manifestation.

Aplastic crisis  → Triggered by parvo-virus infection.

Laboratory findings

• Spherocytosis –> Peripheral smear shows microspherocytes which are small RBCs without central pallor (Normally central 1/3 pallor is present in red cells).
• MCV4
• MCHC r
• Increased unconjugate bilirubin
• Urine urobilinogen 1′
• Stool stercobilinogen
• Reticulocytosis -4 As seen with any type of hemolytic anemia.
• Hemoglobin 1
• Serum Heptoglobin –> Nonnal to decreased.
• Increased osmotic fragility on pink test.
• Coomb’s test is used to distinguish hereditary spherocytosis from autoimmune hemolytic anemias.
• Autoimmune hemolytic anemias are coomb’s positive_ whereas hereditary spherocytosis is coomb’s negative.

Ans. is ‘b’ i.e., Aplastic crisis

• Parvovirus B19 selectively infects erythroid precursors and is the most common aetiological agent that induces
• aplastic crisis in patients with hereditary spherocytosis (and other Hemolytic disorders).

Transient aplastic crisis

• Persons with decreased erythrocytes caused by conditions such as iron deficiency anemia, human immunodeficiency virus sickle cell disease, spherocytosis or thalassemia are at risk of transient aplastic crisis if infected with parvovirus B19.
• The virus causes a cessation of erythrocyte production.
• Parvovirus infection may be the first manifestation in HS.
• It begins with reticulocytosis and thrombocytosis

Ans. is ‘d’ i.e., Aplastic Crisis are common

Aplastic crisis are a rare/uncommon complication of Hereditary Spherocytosis typically caused by virally induced

bone marrow suppression.

• The most common aetiological agent that induces Aplastic Crisis in patients with Hereditary Spherocytosis is Parvovirus B19

Hereditary spherocvtosis usually has autosomal dominant inheritance caused by mutation in genes for proteins such as spectrin. ankrin or band 3.

• The genes responsible for HS include akyrin, b spectrin, band-3-protein, a-spectrin, and protein 4.2. In approximately two-thirds to three-quarter of HS patients, inheritance is autosomal dominant. In the remaining patients, inheritance is non-dominant due to autosomal recessive inheritance of a de novo mutation.

In patients with hereditary spherocvtosis Red blood cells are destroyed in the spleen

• The spleen plays a critical role in the pathobiology of HS, as destruction of spherocytes in the spleen is the primary cause of hemolysis in HS patients.

Aplastic Crisis is an Uncommon Complication

• Aplastic crisis following virally induced bone marrow suppression are uncommon, but may result in severe anaemia with serious complications including congestive heart failure or even death.
• The most common aetiological agent in these cases is parvovirus B19.
• Parvovirus selectively infects erythropoietic progenitor cells and inhibits their growth

Ans. is ‘c’ i.e., Decreased MCHC