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Abnormal Erythrocyte Endothelial Adherence in Hereditary Stomatocytosis
By Brian D. Smith and George B. Segel
Hereditary stomatocytosis is a red cell membrane protein disorder, which results in hemolytic anemia. Some patients with
hereditary stomatocytosis experience dyspnea, chest pain, and
abdominal pain, particularly after splenectomy. These symptoms may represent vaso-occlusion secondary to adherence
of an abnormal erythrocyte membrane to vascular endothelium. We studied three members of a family with varying clinical expression of hereditary stomatocytosis. Adherence of red
cells to endothelium was quantified by measuring the shear
force required to separate individual cells from endothelial
monolayers using a micropipette technique. Two patients with
symptoms of in situ thromboses had a higher percentage of
adherent cells compared with their asymptomatic sibling and
normal controls. Correlation between this in vitro phenomenon and the clinical course suggests that flow abnormalities
in the microcirculation attributable to erythrocyte endothelial
adherence may play an important pathogenetic role in the
illness. When the proportion of adherent red cells was reduced
by a chronic transfusion program in one patient and pentoxifyllin therapy in another, the vaso-occlusive complications were
eliminated.
q 1997 by The American Society of Hematology.
H
left lower extremity pain, and platelet counts were 774,000/mL and
440,000/mL, respectively, and a venogram was normal. The third
crisis involved left sided abdominal pain, and the platelet count was
208,000/mL and an evaluation for thrombosis was unrevealing. Two
weeks after delivery her platelet count returned to her baseline of
1,100,000. J.W. had multiple admissions over the next 3 years for
severe abdominal pain or flank pain. Genitourinary (GU) and gastrointestinal (GI) evaluations were negative, and the pain was attributed
to possible omental infarction. Platelet counts ranged from
1,380,000/mL to 1,560,000/mL.
At age 24 in 1981, J.W. had a series of pulmonary episodes
initially thought to be pulmonary emboli because of positive ventilation-perfusion (VQ) scans and pulmonary arteriograms showing diffuse thrombi in small vessels. Platelet counts ranged from 960,000/
mL to 1,110,000/mL. An extensive workup for a potential source of
pulmonary emboli was unrevealing except for an echocardiogram,
which showed a right ventricular mass that was subsequently removed surgically. This mass was a calcified blood clot in the chordae
tendineae, but subsequent events indicated that it was not the source
of emboli. Despite taking aspirin and warfarin or subcutaneous heparin, she continued during the next 2 1/2 years to have episodes of
pulmonary compromise that were diagnosed as in situ pulmonary
thromboses, and these episodes required multiple hospital admissions. Platelet counts ranged from 260,000/mL to 928,000/mL and
there was no correlation between the height of the platelet count
and the onset or severity of the episodes of dyspnea. Platelet function
was normal, and protein C and S were normal, and antithrombin III
was normal. During this same time period, she had several hospital
admissions for severe abdominal pain, similar to sickle cell crises.
Platelet counts ranged from normal to elevated. GI and GU evaluations were again normal, and the patient was thought to have in situ
thromboses.
Since age 27, J.W. has been hypertransfused to minimize her
erythrocyte production, and since that time she has had no further
documented vascular events. Her platelet count has varied from
192,000/mL to 798,000/mL and her hematocrit has varied from 31%
to 41% with reticulocyte counts of 0.1% to 4.5%. She continues
EREDITARY stomatocytosis is a heterogeneous group
of congenital hemolytic anemias, characterized by red
cells that have an oval shape and slit-like central pallor on
a blood film.1-3 Studies in some families have revealed a
deficiency in integral membrane protein 7.2b4-10 as well as
abnormalities in cation permeability and intracellular cation
concentration, which alter intracellular water content and
cell morphology.11,12 These changes likely contribute to the
shortened in vivo survival of stomatocytes. We describe abnormal red cell endothelial adherence in three members of
a family with varying clinical expression of hereditary stomatocytosis. The percent of adherent cells appears to correlate with the severity of symptoms.
CASE REPORTS
J.W., E.M., and A.M. are siblings of Swiss-German ancestry
whose paternal and maternal great-great grandmothers were sisters.
The pedigree spanning 6 generations previously has been reported.13
J.W. was asymptomatic until age 5 in 1962, when she required
hospital admission for profound anemia, which occurred after a respiratory infection. Her physical exam revealed hepatosplenomegaly,
and laboratory evaluation included a hematocrit of 19% and a reticulocyte count of 31%. Subsequent evaluations revealed: persistent
hepatosplenomegaly; chronic hematocrits of 30%, reticulocyte
counts of 20%; blood films with 35% stomatocytes; negative direct
and indirect coombs tests; normal hemoglobin electrophoresis; and
negative tests for paroxysmal nocturnal and cold hemoglobinuria.
Two siblings (E.M. and A.M.) were noted to have similar hematologic findings, and all were diagnosed with hereditary stomatocytosis.13
In 1970 at age 13, J.W. had her spleen removed to improve the
red cell survival, but the procedure was not helpful and her anemia
was not improved. Preoperative platelet count was 430,000/mL. Nine
days after her splenectomy she had a laparotomy for a subdiaphragmatic hematoma and her platelet count was 3,826,000/mL. Three
weeks later she had a third laparotomy for portal vein thrombosis
with a platelet count of 1,101,000/mL. She was treated with aspirin,
and 1 month later her platelet count was 1,236,000/mL. Over the
next 4 years she remained asymptomatic with platelet counts ranging
from 518,000/mL to 1,484,000/mL with a median platelet count of
1,225,000/mL. In 1974, she developed left shoulder pain exacerbated
by deep inspiration. Her hematocrit was 27% with 15% reticulocytes
and a platelet count of 1,340,000/mL. Pulmonary angiogram and
lower extremity venograms were negative. Symptoms resolved and
she was maintained with aspirin therapy.
J.W. had one pregnancy in 1977, which was managed with hypertransfusion and prophylactic subcutaneous heparin to minimize the
risk of thrombotic complications. However, in her third trimester
she had three admissions for painful crises. Two crises involved
From the Departments of Medicine and Pediatrics, University of
Rochester School of Medicine, Rochester, NY.
Submitted August 28, 1996; accepted December 5, 1996.
Address reprint requests to Brian D. Smith, MD, University of
Rochester, Highland Hospital, 1000 South Ave, Rochester, NY
14620.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
‘‘advertisement’’ in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
q 1997 by The American Society of Hematology.
0006-4971/97/8909-0106$3.00/0
Blood, Vol 89, No 9 (May 1), 1997: pp 3451-3456
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3452
SMITH AND SEGEL
Fig 1. Mean percentage of erythrocytes that are
adherent to cultured endothelial monolayers at various shear stresses. (m), Patient A.M.; (●), patient
J.W.; (j), patient E.M.; (s), age- and sex-matched
controls. V, maximum venule shear stress; C, maximum capillary shear stress; A, maximum arteriole
shear stress.
taking warfarin with an international normalized ratio (INR) of 2.5,
and she is hypertransfused with 2 U of packed red cells every 2 to
3 weeks. Iron overload has caused mild biventricular congestive
heart failure and cardiac arrhythmias and has been treated with desferoxamine since 1985.
E.M. was admitted at age 4 in 1963 with pallor, hepatosplenomegaly, and anemia. His hematocrit was 12% and reticulocyte count 0%.
He was transfused and given folic acid and recovered uneventfully.
Subsequent hematological evaluation as part of a family study13
revealed a hematocrit of 27%, a reticulocyte count of 15% and blood
film with 35% stomatocytes. He did well until 1992 when he noted
increased fatigue after an infection. He was seen at his local hospital
and given 2 U of packed red cells. Currently he is asymptomatic
and working full-time. Physical examination is significant for splenomegaly with the spleen 4 cm below the left costal margin. His
hematocrit is 22.5%, reticulocyte count 18.7%, and platelet count
244,000/mL.
A.M. had no childhood hospitalizations, but had intermittent episodes of pallor and icterus and had predictable fatigue with exercise.
At age 7, in 1969, an enlarged spleen, 5 cm below the costal margin
was noted. His hematocrit was 33%, reticulocyte count was 16.1%,
and stomatocytes 21%, and he along with his siblings J.W. and E.M.,
was diagnosed with hereditary stomatocytosis.13
A.M. began noting progressive fatigue, shortness of breath, and
arthralgias in 1991, and he has been unable to work since March
1993. In 1992, he was admitted with severe chest pain, but cardiac
and pulmonary evaluations were normal. In 1993 he had increasing
episodes of shortness of breath and was admitted to rule out pulmonary embolus when one of these episodes was witnessed by his
primary medical doctor. The VQ scan was negative and symptoms
resolved spontaneously. He also has noted intermittent episodes of
abdominal pain, primarily localized to the left upper quadrant. Evaluation has been unrevealing except for persistent splenomegaly with
the spleen palpable 4 cm below the left costal margin. His hematocrit
has averaged 36.9% and reticulocyte count 18.9% and platelet count
226,000/mL. In March 1993 he was treated with low-dose pentoxifyllin, 400 mg/d, and although he continues to note fatigue and infrequent recurrences of abdominal discomfort, he has had no further
episodes of acute shortness of breath or severe abdominal pain except
on two occasions when he stopped taking the pentoxifylline. Symptoms, which persisted for 1 to 2 days, resolved when the pentoxifylline was restarted.
MATERIALS AND METHODS
Endothelial cell cultures. Veins from human umbilical cords
were cannulated and infused with isotonic phosphate buffer to re-
Table 1. Adherence Studies on Patients With Matched Controls
Patient
Reticulocyte
Count (%)
Shear Force
(dynes/cm2)
Total No. of
RBC Observed
No. of Adherent
RBC for Patient
No. of Adherent RBC
Matched Control
P
J.W.
1.1
10
20
30
55
5,600
4,200
2,800
1,400
39
27
18
7
17
9
5
1
.002
.002
.005
.035
A.M.
18.9
10
20
30
55
8,400
6,300
4,200
2,100
61
44
29
12
17
10
7
3
õ.0001
õ.0001
.0002
.02
E.M.
18.7
10
20
30
55
5,600
4,200
2,800
1,400
22
15
8
4
13
8
4
2
.09
.11
.19
.34
Abbreviation: RBC, red blood cell.
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RBC ADHERENCE IN HEREDITARY STOMATOCYTOSIS
3453
Fig 2. Sequential mean percent RBC adherence
studies for patient AM at physiologic shear force in
the microcirculation. (A) Initial 6 months corresponding to progressive symptoms. (B) While taking pentoxifylline for 2 years. (C) Two occasions when pentoxifylline was stopped. (D) Age and sex matched
controls. (h), Percent adherent for shear stress of 20
dynes/cm2; ( ), percent adherent for shear stress of
30 dynes/cm2; (j) percent adherent for shear stress
of 55 dynes/cm2.
move erythrocytes then filled with 15 mL of Collagenase 0.045 g/
50 mL isotonic phospate buffer (Sigma, St Louis, MO) and incubated
at 377C for 10 minutes to loosen endothelial cells. The veins were
flushed with phosphate buffer, and the endothelial cells collected,
then mixed with Sigma medium 199 (Sigma) and 20% fetal calf
serum (Sigma), E0760 endothelial cell growth supplement 30 mg/
mL of culture media (Sigma) and 20 mL/L antibiotic/ antimycotic
A9909 (Sigma). The cells were layered on 1-cm squares of glass.
The culture medium was changed at 24- to 48-hour intervals until
the endothelium formed a confluent monolayer.
Erythrocytes. Venous blood was collected in citrate anticoagulant from J.W., E.M., and A.M. and simultaneously from five normal
controls that were age and sex matched for each patient. A minimum
of two samples were collected from each patient over an interval of
several months. Cells were suspended in isotonic phosphate buffer
plus albumin (5 g/L), for a final hematocrit of less than 1% to aid
visualization.
Reticulocytes. For separation of low density or young cells,
whole blood was layered on a solution consisting of 16.75 parts
Tris-NaCl (5 mmol/L Tris, 16 mmol/L NaCl, 300 MOSM, pH 7.4)
and 13.25 40% Hypaque (Sodium diatrizoate), then centrifuged at
4,480g for 40 minutes in a Beckman model TJ-6 centrifuge (Beckman Industries Inc, Fullerton, CA). This separated the erythrocytes
into two bands: the least dense comprising less than 1% of the total
volume of erythrocytes on the top and the remaining red cells beneath
the Tris-Hypaque solution. Plasma and buffy coats were discarded,
and the band of least dense erythrocytes was washed and suspended
in isotonic Tris-NaCl plus albumin. Reticulocyte counts were performed on cells stained with methylene blue.
Quantitation of erythrocyte adherence. Erythrocytes were allowed to settle on the endothelial monolayer. Then under direct
microscopic visualization, adhesion was quantitated for 7,000 cells
per sample for each patient and control. Local wall shear stress was
induced by flow from a 12-m glass pipette filled with phosphate
buffer. The pipette was placed adjacent to cells and fluid velocity
produced a shear force, which caused unattached cells to move out
of the field.13a
Calculation of shear stress is based on the Poiseuille-Hagen Law
that characterizes laminar flow of a Newtonian fluid in a uniform
diameter tube: DP Å 8hLQ/pr4; DP Å pressure difference, L Å tube
length, h Å fluid viscosity, r Å tube radius, Q Å volumetric flow
rate. Poiseuille flow is characterized by a parabolic velocity profile
with zero flow at the wall and maxium flow velocity at the axis.
Wall shear rate (gw ) is gw Å 4Q/pr3 . Wall shear stress Tw , equals
the product of viscosity and wall shear rate Tw Å hgw . By substituting into the initial equation Tw Å DPr/2L. Wall shear stress calcula-
Table 2. Sequential Adherence Studies on Patient A.M. Compared With Matched Controls
Shear Force
(dynes/cm2)
Total No. of
RBC Observed
No. of Adherent
RBC for A.M.
No. of Adherent RBC
Matched Control
P
Increased frequency of symptoms
over 6 mo of observation
20
30
55
6,300
4,200
2,100
44
29
12
10
7
3
õ.0001
.0002
.02
Low dose pentox
over 2 yrs. no
acute crises
20
30
55
4,200
2,800
1,400
21
11
5
14
5
3
.16
.14
.36
Pentox stopped on 2 occasions
and crises recurred
20
30
55
4,200
2,800
1,400
44
22
11
6
2
1
õ.0001
õ.0001
.003
Clinical Presentation
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3454
SMITH AND SEGEL
Table 3. Adherence for High Reticulocyte Samples
Patient
Reticulocyte
Count (%)
Shear Force
(dynes/cm2)
Total No. of
RBC Observed
J.W.
80
10
20
30
55
2,800
2,100
1,400
700
A.M.
83
10
20
30
55
E.M.
78
10
20
30
55
No. of Adherent
RBC for Patient
Control Reticulocyte
Count (%)
No. of Adherent RBC
Matched Control
P
8
4
2
1
78
5
3
1
0
.29
.50
.50
.50
2,800
2,100
1,400
700
12
8
5
2
78
8
4
0
0
.25
.19
.03
.25
2,800
2,100
1,400
700
8
5
3
1
87
4
1
0
0
.19
.11
.13
.50
tions for in vivo model pressure and vessel dimension measurements14,15 provided approximate ranges for arterioles, capillaries, and
venules. The wall shear stress may also be calculated from the
formula Tw Å hdV/dZ, V Å axial velocity, and Z Å radial distance
from the center line of the pipette.
Calculation of shear stress on the erythrocytes resting on the endothelial surface was based on the assumption that the parabolic distribution of the velocity profile in the pipette is maintained approximately over the short interval between the pipette tip and the
individual erythrocyte under observation. In this study the pipette
was placed 1 m from the erythrocyte and positive pressure was
applied to the pipette to produce flow which impinged on the cell.
The flow velocity, V, a function of applied pressure, was determined
by observation of the velocity of small axially flowing particles in
the buffer. Since the pipette axis is nearly parallel to the endothelial
surface the actual force on the cell is approximately equal to the
product of the wall shear stress and the projected area of the erythrocyte, F Å Tw Ap . However, since the projected area or cross-section
of the cell perpendicular to the direction of flow is fairly uniform
due to the similarity of erythrocyte diameter and volume, the wall
shear stress proportional to the force is a practical expression of the
force on the cell and permits estimation of in vivo dynamics from
the in vitro experiment.
Statistical analysis. Results are expressed as the mean { SE.
Statistical analysis of the data was calculated using the comparison
of two Poisson distributed observations.
RESULTS
Each of the three study subjects has had a different clinical
course during the past 30 years, ranging from relatively
asymptomatic (E.M.), to progressive symptoms (A.M.), and
life-threatening thrombotic complications post splenectomy
(J.W.).
As shown in Fig 1, all three patients have an increased
percentage of erythrocytes which are abnormally adherent
to endothelial cells, compared with age- and sex-matched
controls.
Patients with symptoms (J.W. and A.M.) have a higher
percentage of adherent cells compared with their asymptomatic sibling (E.M.) and controls. The absolute numbers of
adherent cells for each patient on repeated testing, as well
as age and sex matched controls are depicted in Table
1. A.M. and J.W., unlike E.M., are significantly different
from controls. The increased adherence seen for J.W. is particularly notable because she is hypertransfused to reduce
her erythroid production, implying that a high proportion of
her native cells are abnormally adherent.
Many of the bound red cells remained adherent to endothelial cells despite exposure to fluid shear force that exceeded
physiologic shear force normally present in the microcircula-
Fig 3. Mean percentage of reticulocytes that are
adherent to cultured endothelial monolayers at various shear stresses. (m), Patient A.M.; (j), patient
E.M.; (●), patient J.W.; (s), age- and sex-matched
controls. V, maximum venule shear stress; C, maximum capillary shear stress; A, maximum arteriole
shear stress.
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RBC ADHERENCE IN HEREDITARY STOMATOCYTOSIS
tion. Adherent red cells that separated from endothelial cells
frequently reattached to adjacent endothelial cells, implying
that their inherently adhesive properties do not require prolonged contact time.
A longitudinal study of patient A.M. is depicted in Fig 2.
Figure 2A shows mean red cell endothelial adherence of
repeated tests during several months when symptoms consisted of fatigue, arthralgias, intermittent abdominal pain,
and occasional episodes of shortness of breath and severe
chest pain. Because A.M. had progressive symptoms of compromised blood flow without identifiable etiology other than
his abnormal erythrocyte endothelial adherence, we postulated that there may have been increased cytokine mediated
erythrocyte endothelial adherence, and treated him with low
dose pentoxifylline. This resulted in resolution of the acute
episodes of chest and abdominal pain and, as shown in Fig
2B, a decrease in erythrocyte-endothelial adherence on repeated testing over the next 2 years. On two occasions A.M.
reported decreased compliance in taking his pentoxifylline,
which resulted in recurrence of his symptoms and a significant increase in red cell adherence (see Fig 2C). Table 2
lists the absolute numbers of adherent cells and P values for
patient A.M. and controls. Patient A.M. had significantly
greater erythrocyte adherence compared to control both before taking pentoxifylline and when the pentoxifylline was
stopped.
To assess the possible contribution of reticulocytes to the
adherence process, erythrocyte endothelial interaction was
studied in density separated patient and control samples. As
shown in Table 3, the separation procedure resulted in a high
percentage of reticulocytes (78% to 87%) and these cells
shown in Fig 3 were less adherent than the nonseparated
cells shown in Fig 1.
DISCUSSION
The etiology of abnormal erythrocyte endothelial interaction in these patients with the dehydrated form of hereditary
stomatocytosis is not clear. The most consistent structural
abnormality in hydrocytic stomaotcytosis is a deficiency in
the integral membrane protein band 7.2b.4-9 Protein band
7.2b is present but has not been quantitated for this family
and recent studies of J.W. and E.M. using an informative
polymorphic marker identified in the 7.2b gene have excluded linkage of hereditary stomatocytosis to the band 7.2b
gene in these two patients.16
The clinical episodes of J.W. and A.M. resemble those
seen in sickle cell anemia patients with vaso-occlusive crises.
Standard clinical tests for documenting large vessel thromboses are often negative for in situ thromboses in the microcirculation, but J.W. had documented in situ pulmonary thromboses. Her thrombotic events began following splenectomy
at the time of puberty and progressed with time but did
not correlate with thrombocytosis. She had multiple vasoocclusive crises at times when her platelet counts were normal and conversely, she has had no vaso-occlusive episodes
since beginning hypertransfusion despite platelet counts to
800,000/mL. J.W.’s thrombotic events were not improved
by antiplatelet or warfarin anticoagulation therapy but did
respond to hypertransfusion, which suppressed erythroid
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production. A population of adherent red cells remains evident in J.W.’s blood before her transfusions. Splenectomy
may have allowed circulation of a large proportion of pathologically adherent stomatocytes, which precipitated her vasoocclusive episodes. These episodes and the proportion of
adherent cells appear to be decreased by chronic transfusion.
Data from this and several other kindred underscores the
hazard of splenectomy in hereditary stomatocytosis because
of the increased frequency of thrombotic events following
splenectomy.17
Similar to patient J.W., patient A.M.’s symptoms progressed with time. A.M. was relatively asymptomatic until
age 29 then had progressive symptoms of vaso-occlusion
during the following 2 years. His platelet count remained
normal, and his reticulocytosis and splenomegaly were constant. The potential influence of reticulocytes on the adherence measurements was studied using high reticulocyte samples from both patients and controls. Reticulocyte adherence
was less than nonseparated red cell adherence making it
unlikely that physiologically significant abnormal adherence
could be attributed to a reticulocyte-rich population of cells.18
This conclusion also is supported clinically by the asymptomatic course of E.M. whose baseline reticulocytosis resembles that of patient A.M. and greatly exceeds the reticulocyte
count of patient J.W.
Patient A.M.’s red cells were significantly more adherent
to endothelium than those of his asymptomatic brother E.M.
The factors resulting in this increased adherent population
are unknown in A.M., but specific receptors and plasma
factors that participate in erythrocte endothelial adherence
may be operative.19-28 Pentoxifyllin, a pharmaceutical agent
initially developed to promote improved red cell passage
through the microcirculation in patients with compromised
blood flow secondary to atherosclerotic vascular disease, decreases production of tumor necrosis factor-a and inhibits
inflammatory cytokine mediated adherence.29-32 For patient
A.M. the postulated downregulation of red cell adherence
factors by pentoxifylline correlated with his improved clinical course, and on two occasions when there was poor compliance in taking medication his symptoms recurred and red
cell-endothelial adherence significantly increased. However,
this finding is in a single patient with a limited number of
observations and there is no direct experimental evidence
for therapeutic efficacy for pentoxyfylline.
The specific etiology of abnormal red cell-endothelial interaction in this family remains to be identified. Additional
studies are planned in a larger number of hereditary stomatocytosis patients and the use of potential antagonists to this
adherence process may further elucidate the mechanism of
abnormal erythrocyte endothelial adherence.
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SMITH AND SEGEL
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WBS: Blood
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
1997 89: 3451-3456
Abnormal Erythrocyte Endothelial Adherence in Hereditary Stomatocytosis
Brian D. Smith and George B. Segel
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