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Red blood cell mechanics
Author
Mohandas Narla, DSc
Section Editor
Stanley L Schrier, MD
Deputy Editor
Jennifer S Tirnauer, MD
Disclosures: Mohandas Narla, DSc Nothing to disclose. Stanley L Schrier, MD Nothing to disclose. Jennifer S
Tirnauer, MDNothing to disclose.
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Literature review current through: Feb 2015. | This topic last updated: Apr 24, 2013.
INTRODUCTION During its passage through the circulation, an erythrocyte that is 7 to 8 microns
in diameter must elongate, tank tread, and otherwise deform to pass through 3 micron diameter
capillaries and 1 micron wide and 0.5 micron thick endothelial slits in the red pulp of the spleen
(picture 1). Thus, during its 120-day life span, the erythrocyte must undergo extensive passive
deformation and must be mechanically stable to resist fragmentation [1,2].
Red cell deformability is influenced by three distinct cellular components [3,4]:
Cell shape or cell geometry, which determines the ratio of cell surface area to cell
volume (SA/V); higher values of SA/V facilitate deformation.
Cytoplasmic viscosity, which is primarily regulated by the mean corpuscular hemoglobin
concentration (MCHC) and is therefore influenced by alterations in cell volume.
Membrane deformability and mechanical stability, which are regulated by multiple membrane
properties, which include elastic shear modulus, bending modulus, and yield stress.
Importantly, increased sphericity due to loss of surface area is the dominant cause for removal from
the circulation of senescent normal red cells. Either directly or indirectly, membrane components
and their organization play an important role in regulating each of the factors that influence cellular
deformability. The factors affecting red blood cell mechanics (eg, cell shape, cytoplasmic viscosity,
membrane deformability and stability) will be discussed here.
CELL SHAPE The biconcave disc shape of the normal red cell (picture 1) creates an
advantageous SA/Vrelationship, allowing the red cell to undergo marked deformation while
maintaining a constant surface area. The normal human adult red cell has a volume of 90 fL and a
surface area of 140 2. If the red cell were a sphere of identical volume, it would have a surface
area of only 98 2. Thus, the discoid shape provides approximately 40 2 of excess surface area,
or an extra 43 percent, that allows the red cell to undergo extensive deformation.

Most deformations occurring in vivo and in vitro involve no increase in surface area. This is
important because the normal red cell can undergo large linear extensions of up to 230 percent of
its original dimension while maintaining its surface area, but an increase of even 3 to 4 percent in
surface area results in cell lysis.
Because the acquisition and maintenance of a favorable SA/V is crucial to red cell function, it is
useful to understand how the red cell acquires its discoid shape. The immediate precursor of the
mature discocytic red cell is the non-nucleated reticulocyte, which is produced when the normoblast
extrudes its nucleus. In contrast to red cells, immature reticulocytes are multilobular and motile,
contain mitochondria and ribosomes, and synthesize hemoglobin and certain membrane
components, including band 3, GLUT1 and protein 4.1. The deformability of these reticulocytes is
only about 10 percent that of discocytic red cells [5,6].
Both deformability and mechanical stability of reticulocytes improve during maturation [5]. In two to
three days, motile reticulocytes evolve further in the bone marrow, first to become deep cup-shaped
nonmotile cells that still contain ribosomes, and finally to mature fully hemoglobinized discocytic red
blood cells lacking organelles. Major reorganizations of membrane phospholipids, skeletal proteins,
and integral proteins accompany acquisition of the discoid shape and enhanced deformability.
These include loss of membrane lipids, loss of integral proteins, such as transferrin receptors,
insulin receptors, and fibronectin receptors, a major reorganization of the skeletal protein network,
and a progressive loss of volume and cell water. (See"Macrocytosis", section on 'Reticulocytosis'.)
Alterations in the SA/V ratio Having acquired the discoid shape, the mature red cell must
maintain this favorable SA/V relationship during its circulating life span. Either membrane loss,
leading to a reduction in surface area, or an increase in cell water content, leading to an increase in
cell volume, will create a more spherical shape with less redundant surface area. This loss of
surface area redundancy results in reduced cellular deformability, compromised red cell function,
and diminished survival. Increased osmotic fragility is a characteristic feature of all red cell
populations with less than normal surface redundancy.
Experimental manipulation of the SA/V ratio The importance of the SA/V ratio for red cell
survival was tested by incubating red cells in vitro with progressively increasing concentrations of
lysophosphatidylcholine (LPC) in order to reduce their surface area at constant volume. The treated
red cells were then perfused ex vivo into normal human spleens and the degree of splenic retention
measured. Results included the following [7]:
Treatment of red cells with progressively increasing concentrations of LPC resulted in
progressively decreased SA/V ratio, increased sphericity, increased osmotic fragility, and
decreased deformability. Splenic retention of treated red cells increased with increasing
surface area loss and decreasing SA/Vratio. Importantly, red cells with a >18 percent average
surface area loss (>27 percent reduced surface area-to-volume ratio) were rapidly and
completely entrapped in the spleen [7].
Surface area-deficient red cells that had escaped repeated passages through the spleen
appeared to undergo volume loss to compensate for their surface area loss. This reduction in
volume could represent an adaptive mechanism by which surface area-deficient red cells
increase their SA/V ratio to enable their subsequent transit through the spleen. Cell
deformation-mediated increase in membrane cation permeability could account for such

volume loss. This phenomenon could explain the decreased cell volume of senescent normal
red cells and of hereditary spherocytic red cells with decreased surface area.
Clinical examples As examples, protein defects involving alpha- and beta-spectrin, ankyrin,
band 3, or protein 4.1R lead to a loss of cohesion between the lipid bilayer and the spectrin-based
membrane skeleton, resulting in membrane vesiculation and/or a mechanically unstable membrane.
Both of these processes lead to membrane fragmentation and the generation of cells with reduced
surface area, as seen in congenital hemolytic anemias such as hereditary spherocytosis and
hereditary elliptocytosis [2,8,9]. (See "Hereditary spherocytosis: Mechanism of hemolysis and
pathogenesis" and "Hereditary elliptocytosis: Genetics and pathogenesis".)
Loss of the favorable SA/V ratio is also seen in several other disorders:
Partial phagocytosis of the red cell by macrophages leads to reduced surface area and the
generation of spherocytes in certain immune hemolytic anemias.
In some forms of hereditary stomatocytosis, the membrane defect results in increased cell
volume due to impaired volume regulation. (See "Stomatocytosis".)
A different type of red cell abnormality occurs in other disorders in which the SA/V ratio
is increased above normal:
In patients with liver disease, increased membrane cholesterol content raises the cell surface
area which, in the presence of normal cell volume, increases the degree of surface area
redundancy. This excess surface area is manifested morphologically by a target or spur cell
appearance and functionally by increased osmotic resistance (decreased osmotic fragility).
(See "Spiculated cells (echinocytes and acanthocytes) and target cells".)
In certain hemoglobinopathies (eg, thalassemia and hemoglobin CC), the same abnormality
is induced by decreased cell volume in the face of normal membrane surface area.
(See "Pathophysiology of beta thalassemia".)
CYTOPLASMIC VISCOSITY Cytoplasmic viscosity, another regulatory component of red cell
deformability, is largely determined by the mean corpuscular hemoglobin concentration (MCHC),
which is determined in part by cell water content [3]. The lipid components and integral proteins of
the red cell membrane involved in transport function play a crucial role in volume homeostasis of
the red cell, maintaining the cell hemoglobin concentration at levels that do not unduly influence the
ability of the cell to deform.
As the hemoglobin concentration rises from 27 to 35 g/dL (the normal range for red blood cell
hemoglobin concentration or MCHC), the viscosity of hemoglobin solution increases from 5 to 15
centipoise (cP), 5 to 15 times that of water (figure 1). At these levels, the contribution of cytoplasmic
viscosity to cellular deformability is negligible. However, viscosity increases exponentially at
hemoglobin concentrations greater than 37 g/dL,reaching 45 cP at 40 g/dL, 170 cP at 45 g/dL, and
650 cP at 50 g/dL. At these levels, cytoplasmic viscosity may become the primary determinant of
cellular deformability. Thus, cellular dehydration, usually due to the failure of normal volume
homeostasis mechanisms, can severely impair cellular deformability and thus decrease optimal
oxygen delivery by impairing the ability of red cells to undergo rapid deformation necessary for
passage through the microvasculature. (See "Control of red blood cell hydration".)

Mutations in proteins involved in transport processes, acquired alterations in these proteins due to
membrane oxidation, or other changes induced by mutant hemoglobin interacting with the
membrane can lead to marked cellular dehydration. As examples, cellular dehydration reduces red
cell deformability in hereditary xerocytosis, sickle cell anemia, hemoglobin CC, and beta
thalassemia [3,10,11]. (See "Xerocytosis" and "Hydroxyurea and other disease-modifying therapies
in sickle cell disease", section on 'Mechanism of erythrocyte dehydration'and "Pathophysiology of
beta thalassemia", section on 'Red blood cell dehydration'.)
MEMBRANE DEFORMABILITY AND STABILITY As mentioned above, the red cell membrane
has two important properties related to the passage of red cells through the circulation:
deformability and mechanical stability.
The property of membrane deformability determines the extent of membrane deformation
that can be induced by a defined level of applied force. The more deformable the membrane,
the less force that is required for the cell to pass through the capillaries and other narrow
openings, such as fenestrations in the splenic cords.
The property of mechanical membrane stability is defined as the maximum extent of
deformation that a membrane can undergo, beyond which it cannot completely recover its
initial shape. This is the point at which the membrane fails. Normal membrane stability allows
human red cells to circulate for 120 days without fragmenting, while decreased stability leads
to cell fragmentation under normal circulating stresses.
Studies of both biochemically perturbed membranes and membranes from particular disease states
have shown that deformability and stability can change with no fixed relation to one another [1]. This
observation implies that these two properties are regulated by different skeletal proteins and their
interactions.
Membrane mechanical properties The mechanical behavior of the red cell membrane is
complex and depends upon the magnitude and duration of applied stresses [3,4,12-14]. At small
values of applied force for short duration, the red cell membrane behaves as a viscoelastic solid,
since it is capable of undergoing large elastic extensions and completely recovers its initial shape.
In the nondeformed state, spectrin molecules exist in a folded conformation. During reversible
deformation, the change in geometric shape occurs at a constant surface area. This process is
characterized by rearrangement of the skeletal network in which some spectrin molecules become
uncoiled and extended, while others are more compressed and folded [1,14].
In contrast, when small forces are applied over a long period of time, or when large forces are
applied for a shorter period, the membrane yields and is unable to recover its initial shape. Under
these circumstances, the membrane exhibits permanent "plastic" deformation due to the inability of
the skeletal network to recover its prestressed configuration. Failure of recovery may also be due to
defects in the membrane itself (see 'Failure of membrane deformability and stability' below).
In addition to its contribution to the elastic behavior of the membrane, the membrane skeleton plays
a crucial role in the regulation of membrane mechanical stability, particularly junctional complexes in
the skeletal network, as will be outlined in the following section. (See "Red blood cell membrane
dynamics and organization", section on 'Structural organization'.)
Failure of membrane deformability and stability The preceding observations indicate that
membrane deformability can be reduced by an increase in intermolecular or intramolecular

associations of the skeletal proteins or by an increased association of integral membrane proteins

such as band 3 with the skeletal network (figure 2) [3,4]. While normal red cells completely recover
their shape following repeated cycles of deformation in the circulation, pathologic red cells with
weakened or abnormal junctions between skeletal proteins fail to recover their initial shape and
undergo plastic deformation (figure 3). Although substantial changes in lipid composition of the
membrane have little effect on membrane mechanical properties, small changes in individual
protein components can profoundly alter membrane behavior.
One type of membrane failure occurs with increasing degrees of deformation in which the
membrane becomes more extended and some of the spectrin molecules attain their maximal linear
extension. This point is the limit of reversible deformability. A continued application of force would
require an increase in surface area and the breaking of junctional complexes; this occurs at the
weakest of the lateral protein-protein associations (spectrin-spectrin junction or spectrin-actinprotein 4.1R junction), leading to loss of membrane stability and membrane fragmentation.
As an example, decreased membrane mechanical stability in hereditary elliptocytosis is due to
either weakened spectrin-spectrin association, resulting from mutations in either alpha- or betaspectrin, or a weakened spectrin-actin-protein 4.1 junction due to mutations in protein 4.1 (figure 2)
[2,3]. The generation of irreversibly sickled cells in sickle cell anemia is also the result of plastic
deformation of the membrane due to skeletal protein reorganization during repeated cycles of
sickling and unsickling in the circulation. (See "Hereditary elliptocytosis: Genetics and
pathogenesis", section on 'Pathophysiology of hemolysis' and "Red blood cell membrane dynamics
and organization", section on 'Structural organization'.)
SUMMARY During its passage through the circulation, the erythrocyte must undergo extensive
passive deformation and must be mechanically stable to resist fragmentation. These functions are
influenced by three distinct cellular components: cell shape (surface to volume ratio), cytoplasmic
viscosity, and membrane properties.
Decreased SA/V ratio Membrane loss or increased cell volume create a more spherical shape,
resulting in reduced cellular deformability, compromised red cell function, increased osmotic fragility,
and diminished survival. Examples include:
Inherited membrane protein defects lead to a loss of cohesion between the lipid bilayer and
the membrane skeleton or decreased membrane mechanical stability, generating cells with
reduced surface area. (See"Hereditary spherocytosis: Mechanism of hemolysis and
pathogenesis" and "Hereditary elliptocytosis: Genetics and pathogenesis".)
Partial phagocytosis of antibody-coated red cells by macrophages leads to reduced surface
area and the generation of spherocytes. (See "Pathogenesis of autoimmune hemolytic
anemia: Warm agglutinins and drugs", section on 'Immunoadherence'.)
In some forms of hereditary stomatocytosis, the membrane defect results in increased cell
volume due to impaired volume regulation. (See "Stomatocytosis".)
Increased SA/V ratio An increased SA/V ratio is seen in the following conditions:
In patients with liver disease, increased membrane cholesterol content raises the cell surface
area, manifested by a target or spur cell appearance with decreased osmotic fragility.
(See "Spiculated cells (echinocytes and acanthocytes) and target cells".)

In thalassemia and hemoglobin CC disease, an increased SA/V ratio is induced by

decreased cell volume. (See "Pathophysiology of beta thalassemia".)
Increased cytoplasmic viscosity Cytoplasmic viscosity is largely determined by the mean
corpuscular hemoglobin concentration (MCHC), which is determined in part by cell water content. At
MCHC levels greater than 37 g/dL, cytoplasmic viscosity may become the primary determinant of
cellular deformability. (See'Cytoplasmic viscosity' above.)
Examples include hereditary xerocytosis, sickle cell anemia, hemoglobin CC, and beta thalassemia.
(See"Xerocytosis" and "Hydroxyurea and other disease-modifying therapies in sickle cell disease",
section on 'Mechanism of erythrocyte dehydration' and "Pathophysiology of beta thalassemia",
section on 'Red blood cell dehydration'.)
Red cell membrane properties The red cell membrane has two important properties related to
the passage of red cells through the circulation. (See 'Membrane deformability and stability' above.)
Membrane deformability determines the extent of membrane deformation that can be
induced by a defined level of applied force.
Mechanical membrane stability is the extent of deformation that a membrane can undergo,
beyond which it cannot completely recover its initial shape.
As an example, the generation of irreversibly sickled cells in sickle cell anemia is also the result of
plastic deformation of the membrane due to skeletal protein reorganization during repeated cycles
of sickling and unsickling in the circulation.
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