Page 743 - Hematology_ Basic Principles and Practice ( PDFDrive )

630 Part V Red Blood Cells

Although the clinical severity of HS is highly variable among
Entrapment of Nondeformable Spherocytes different kindred, in general it is relatively uniform within a given
in the Spleen family, in which HS is typically inherited as an autosomal dominant
disorder. However, HS kindred have been described in which there
The importance of the spleen in the pathophysiology of hemolysis in was great variability in the clinical severity of affected family members.
HS was appreciated in the original description of the disease and has Several explanations might account for these observations, including
been substantiated by subsequent studies. HS cells are selectively variable penetrance of the genetic defect, a de novo mutation, pres-
destroyed in the spleen because of their poor deformability and ence of a mild recessive HS in the kindred, presence of a modifier
because of the unique anatomy of the splenic vasculature that acts as allele that influences the expression of a membrane protein, or a
a microcirculation filter. tissue-specific mosaicism of the defect.
The poor RBC deformability is principally a consequence of
a decreased cell surface/cell volume ratio resulting from the loss
of surface material. Normal discocytes have an excess surface, Clinical Manifestations
which allows them to deform and pass through narrow microcir-
culation openings. In contrast, HS RBCs lack this extra surface, Typical Forms
and their poor deformability may be further impaired by cellular
dehydration. The typical HS patient is relatively asymptomatic. As noted in the
The principal sites of RBC entrapment in the spleen are fenestra- earliest descriptions of HS, mild jaundice can be the only symptom
tions in the wall of splenic sinuses, where blood from the splenic of the disease. Anemia is usually mild to moderate but may be absent
cords of the red pulp enters the venous circulation. In rat spleen, the because of compensatory bone marrow hyperplasia manifest by
length and width of these fenestrations, 2 to 3 µm and 0.2 to 0.5 µm, reticulocytosis. Splenomegaly gradually develops in most patients,
respectively, are approximately half the RBC diameter. Electron with the spleen occasionally reaching large dimensions.
micrographs show that very few HS RBCs traverse these slits. Con-
sequently, the nondeformable spherocytes accumulate in the red
pulp, which becomes grossly engorged. Mild Forms and Carrier State
In some families, anemia is absent, the reticulocyte count is normal
Splenic Conditioning and Destruction or only minimally elevated, laboratory evidence of hemolysis is
minimal or absent, and the changes in RBC shape can be mild,
Once trapped in the spleen, HS erythrocytes undergo additional escaping detection on the peripheral blood film. The presence of HS
damage or conditioning with further loss of surface area and an is detected only by laboratory testing or during evaluation of a relative
increase in cell density, as is evident in cells removed from the spleen with a more symptomatic form of the disease. Some patients are first
at splenectomy. Some of these conditioned RBCs reenter the systemic diagnosed during transient viral infections such as infectious mono-
circulation, as revealed by the “tail” of the osmotic fragility curve, nucleosis or parvovirus infection, during pregnancy, or even in the
indicating the presence of a subpopulation of cells with a markedly 7th to 9th decades of life as the bone marrow’s ability to compensate
reduced surface area. After splenectomy, this RBC population for hemolysis wanes.
disappears.
Contributions to conditioning may include a relatively low pH in
the spleen as well as in the sequestered RBCs that may further Severe and Atypical Forms
compromise the poor HS RBC deformability, and contact of RBCs
with macrophages that may inflict additional damage on the RBC The relatively uncommon patients with nondominant forms of HS
membrane. The conditioning effect of the spleen appears to represent can present with a severe life-threatening hemolysis early in life. Some
a cumulative injury. The average residence time of HS RBCs in the patients can be transfusion dependent during early infancy and child-
splenic cords is between 10 and 100 minutes compared with 30 to 40 hood. The underlying molecular defects include severe spectrin or
seconds for normal RBCs, and only 1% to 10% of blood entering band 3 deficiency.
the spleen is temporarily sequestered in the congested cords, whereas
the remaining 90% of blood flow is rapidly shunted into the venous
circulation. Hereditary Spherocytosis and
Nonerythroid Manifestations

Inheritance In most HS cases, the clinical manifestations are confined to the
erythroid lineage, probably because many of the nonerythroid coun-
The HS genes are assigned to several chromosomes, including chro- terparts of the RBC membrane proteins (e.g., spectrin and ankyrin)
mosome 1 (α-spectrin), chromosome 8 (ankyrin), chromosome 14 are encoded by separate genes or because some proteins (e.g., protein
(β-spectrin), chromosome 15 (protein 4.2), and chromosome 17 4.1R, β-spectrin, ankyrin) are subject to tissue-specific alternative
(band 3). In approximately two-thirds of HS patients, inheritance is splicing. However, several HS kindred have been reported with a
autosomal dominant. In the remaining patients, inheritance is non- cosegregating neurologic or muscular abnormality, such as a degen-
dominant. In many of these patients, HS is caused by a de novo erative disorder of the spinal cord, cardiomyopathy, or mental
mutation, which is inherited in an autosomal recessive fashion in retardation. The observation that both erythrocyte ankyrin and
subsequent generations. Recessively inherited HS cases manifesting β-spectrin are also expressed in muscles and the brain, particularly
with severe hemolytic anemia have been reported. The majority of the cerebellum, and spinal cord raises the possibility that these HS
the affected patients were found to be severely deficient in RBC patients may have a defect in one of these proteins. This hypothesis
spectrin, associated with α-spectrin defects. The remaining cases is further supported by studies of nb/nb mice, a mouse model of HS
characterized by a recessive inheritance pattern are caused by a defect caused by an ankyrin mutation. These mice develop a neurologic
in protein 4.2, a deficiency that is associated with relatively mild syndrome with a progression that coincides with the loss of ankyrin
hemolysis. from the Purkinje cells of the cerebellum.
Only a few cases of homozygous HS have been reported. These Mutations of band 3 without HS have been described in patients
patients have a severe hemolytic anemia, whereas their mostly con- with distal renal tubular acidosis. With a few rare exceptions, most
sanguineous parents have a mild to moderate form of the disease or patients with heterozygous mutations of band 3 and HS have normal
are asymptomatic. renal acidification.