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Chapter 45 Red Blood Cell Membrane Disorders 643

stomatocytes in Duchenne dystrophy, or a choreiform disorder in areas of the two halves of the lipid bilayer. Conversely, agents that
some patients with the McLeod phenotype. asymmetrically expand the inner half of the lipid bilayer, such as
The Kell antigen consists of two protein components: a 37-kDa chlorpromazine, lead to stomatocytic shape transformation. In the
protein that carries the Kx antigen, a precursor molecule necessary case of echinocytes produced by ATP depletion or calcium loading,
for the Kell antigen expression, and a 93-kDa protein that carries the the altered phospholipid distribution between the two bilayer hemile-
Kell blood group antigen. RBCs with the McLeod phenotype have aflets may be a consequence of calcium-induced phospholipid
no detectable Kx antigen, and they have a marked deficiency of the scrambling or a decrease in the activity of aminophospholipid trans-
93-kDa protein that carries the Kell antigen. McLeod RBCs should locase, an ATP-dependent enzyme that actively translocates amino-
be distinguished from Kell null (K 0) RBCs, which have a normal phospholipids from the outer leaflet to the inner hemileaflet.
shape. In K 0 cells, only the Kell antigen carrying the 93-kDa glyco-
protein is absent, whereas these cells have twice the amount of the
Kx antigen. As in the other acanthocytic disorders, the surface projec- Keratocytes, Bizarre Poikilocytes, and Schistocytes
tions of acanthocytes may be related to asymmetry of the surface area
of the two lipid bilayer hemileaflets, as indicated by correction of the Mechanical trauma of circulating RBCs has occasionally produced
acanthocytosis by agents that expand the inner lipid layer, as well as bizarre shapes resembling acanthocytes, such as cells with horny
the finding of an increased rate of exchange of phosphatidylcholine projections (keratocytes). Some acanthocyte-like cells are also seen in
(localized preferentially in the outer lipid hemileaflet) with an exog- splenectomized HE and HS patients. Similar shape changes are seen
enous source. in heated RBCs, in which spectrin has been damaged by thermal
denaturation, suggesting that these cells are bizarre poikilocytes rather
than true acanthocytes.
Acanthocytosis in Other Conditions
RED BLOOD CELL MEMBRANE DISORDERS MANIFESTED
Acanthocytes have also been noted in malnourished patients, includ-
ing those with anorexia nervosa and cystic fibrosis. In these patients, BY TARGET CELL FORMATION
RBC shape normalizes after restoration of the nutritional status.
Likewise, a small number of cells with long spicules resembling The common feature of target cells is an increase in the ratio of the
acanthocytes are found in patients with hypothyroidism, after sple- cell surface area to cell volume. In microcytic RBCs of patients with
nectomy, and with myelodysplasia. various forms of thalassemia and hemoglobinopathies, the increased
surface to volume ratio, and consequently the target cell shape, reflect
Differentiation of Acanthocytes From Other Spiculated at least in part the relative abundance of cell surface area. In liver disease
Red Blood Cells and other disorders discussed subsequently, the target cell formation
reflects an absolute expansion of the cell surface area because of a net
accumulation of membrane phospholipids and cholesterol.
Echinocytes (Burr Cells)
In contrast to acanthocytes, echinocytes, also called burr cells, have Liver Disease
rather uniform surface projections. Although early echinocytic forms
have a regularly scalloped cell contour, advanced forms of echinocytes The presence of target cells in association with either normal or
have a spheroidal shape and the surface projections appear as short, slightly increased cell volume is characteristically found in patients
narrow spikes (see Fig. 45.8). Although the finding of echinocytes on with obstructive jaundice, including various forms of liver disease
a peripheral blood film is often an artifact related to blood storage, associated with intrahepatic cholestasis. These target cells have a
contact with glass, or an elevated pH, several hemolytic anemias have normal survival in the peripheral circulation and do not typically
been reported in association with echinocytosis on peripheral blood account for the anemias often encountered in patients with liver
films. These conditions include mild hemolytic anemia in long- disease.
distance runners and in patients with hypomagnesemia and hypo- In these patients, target cell formation is a consequence of a net
phosphatemia (presumably because of decreased intracellular ATP uptake of both free cholesterol and phospholipids into the RBC
stores), uremia because of an unknown plasma factor, and pyruvate membrane from the plasma because of abnormalities in the
kinase deficiency. cholesterol/phospholipid/protein ratios of low-density lipoproteins.
Inspection of wet blood preparations (but not dried blood films) Target cells have a decreased osmotic fragility, because the excess of
reveals echinocytosis in most patients with liver disease. In contrast membrane surface area leads to an increase in the critical hemolytic
to spur cells in patients with severe liver disease, these echinocytes volume.
have a normal cholesterol content, and the molecular abnormality
may be related to the binding of abnormal echinocytogenic high-
density lipoproteins to the RBC surface. Lecithin-Cholesterol Acyltransferase Deficiency
The mechanisms of echinocytosis in these diverse disorders are
likely to be heterogeneous, as suggested by findings that many diverse The lecithin-cholesterol acyltransferase (LCAT) enzyme catalyzes the
factors, such as exposure of RBCs to certain drugs, calcium loading, formation of cholesterol esters in lipoproteins. It circulates in plasma
or ATP depletion, can induce the transformation of discocytes to as a complex with components of high-density lipoproteins. LCAT
echinocytes in vitro. However, in vitro studies of the discocyte- deficiency, caused by mutations in the LCAT gene, is a rare autosomal
echinocyte-stomatocyte equilibrium have suggested a possible dominant disorder manifested by hyperlipidemia, premature athero-
common denominator. As discussed earlier, the lipid bilayer of sclerosis, corneal opacities, chronic nephritis, proteinuria, mild
normal RBCs is asymmetric in lipid composition: The outer half of anemia, and the presence of target cells on the blood film. The anemia
the lipid bilayer is relatively enriched in sphingomyelin and phospha- is caused by mild hemolysis together with a diminished compensatory
tidylcholine, whereas the inner half is preferentially enriched in the erythropoiesis. As in obstructive jaundice, the target cells in LCAT
negatively charged phosphatidylserine and phosphatidylethanol- deficiency have a marked increase in both cholesterol and phospho-
amine. Agents that preferentially bind to one or another class of these lipids. In addition, the membrane phosphatidylcholine is increased
phospholipids dramatically influence RBC shape. Consequently, at the expense of sphingomyelin and phosphatidylethanolamine.
agents that preferentially accumulate in the outer half of the RBC Bone marrow aspiration and biopsy reveal the presence of sea-blue
lipid bilayer, expanding this lipid bilayer, produce an echinocytic histiocytes. Analysis of plasma lipoproteins reveals multiple abnor-
shape, presumably by creating an asymmetry between the two surface malities secondary to the underlying enzyme deficiency. Inherited