Pathology Thread

Inherited red cell membrane defects include hereditary spherocytosis, hereditary elliptocytosis, hereditary stomatocytosis, and pyropoikilocytosis. In each abnormalities of the red cell membrane result in hemolysis.

Hereditary spherocytosis is characterized by numerous spherocytes on the PBS (right).

Spherocytes have reduced surface membrane area relative to the RBC volume. Spherocytes are osmotically fragile compared to normal RBCs.

Spherocytes, being less flexible than normal RBCs, are destroyed in the spleen, often causing splenomegaly.

Hereditary spherocytosis is most common in people of northern European ancestry. Although a spectrin deficiency is seen in nearly all HS patients, it is thought that the principle defect is an abnormality of the membrane protein ankyrin.

Defects in vertical stabilization* of the phospholipid bilayer of the RBC membrane cause separation of the spectrin - phospholipid bilayer. Portions of the phospholipid bilayer form vesicles and are lost from the RBC surface resulting in decreased surface area and spherocytosis.

Defects may be in 1) the actin - spectrin - band 3 complex; 2) the spectrin - 4.1 -glycophorin complex or 3) the connection between the bilayer and spectrin.

Usually the osmotic fragility test results are graphed and reported as shown below.

Normal osmotic fragility is seen at top right.

Abnormal lysis of RBCs in mildly hypotonic solutions is seen at lower right (hereditary spherocytosis).

In other cases the defects are found in the horizontal junctions between the a-spectrin and b- spectrin dimers or between spectrin, actin and band 4.1.

These protein interactions normally maintain the structural strength and lateral stability of the RBC.

Defects of the junctions between the a-spectrin and b- spectrin dimers or between spectrin, actin and band 4.1 may cause the RBC cytoskeleton to loose its lateral integrity.

Such defects result in RBC shape alterations as in hereditary elliptocytosis or to fragmentation of the RBC as in hereditary pyropoikilocytosis.

Hereditary elliptocytosis is usually inherited as an autosomal dominant trait. The defect is a structural abnormality of spectrin or a deficiency of the RBC membrane protein 4.1, without anemia and usually with no splenomegaly and only mild hemolysis. Most patients are asymptomatic.

The PBS shows large numbers of elliptocytes and/or ovalocytes. The number of elliptocytes does not correlate with the severity of the hemolysis. Osmotic fragility is usually normal. Reticulocytes are mildly increased (<5%) and haptoglobin levels low.

RBC hemolysis occurs in the spleen, thus splenectomy corrects the hemolysis, but not the RBC membrane defect.

Hereditary stomatocytosis is an autosomal dominant disorder, in which a membrane abnormality leads to increased permeability to sodium. This causes water to move into the RBC decreasing the mean corpuscular hemoglobin concentration.

The PBS shows RBCs with narrow mouth-like areas of hypochromia. These RBCs are known as stomatocytes.

A mild hemolytic anemia and splenomegaly are typical clinical findings.

Acquired stomatocytosis may be seen in liver disease and hyperalimentation (lipid) therapy.

Severe hemolysis, bizarre poikilocytosis, and RBC fragmentation are the hallmarks of hereditary pyropoikilocytosis, a rare autosomal recessive disease.

A structural abnormality of spectrin is present in which RBCs fragment when heated to only 45°C. Normal RBCs fragment at 49°C.

Match patient A, B, and C with test results 1, 2, and 3 shown at right.

A. a 14 year lold boy who has lost blood from an auto accident is brought into the ER where Dr. Isbit Sloe orders an osmotic fragility test. The Hct is .44 L/L and the MCV 89fL.

B. a 12 year old girl who has always been a bit pale is seen in the clinic with a Hct of .32 L/L; MCV 90fL. Dr. Lisa Rotblut orders an osmotic fragility test.

C. a 15 year old boy is found to be mildly anemic in a camp physical. His Dad and several relatives also are repoorted to be anemic. His Hct is .34 L/L and the MCV 75 fL. Dr. I.M.A. Payne orders an osmotic fragility test.