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Revised Prevalence Estimate of Possible Hereditary Xerocytosis as Derived from a Large U.S.
Laboratory Database
Harvey W. Kaufman1 , Justin K. Niles1, Denis R. Gallagher1, Alicia Rivera2, Seth L. Alper2 ,
Carlo Brugnara3 , L. Michael Snyder1.
1. Quest Diagnostics, Marlborough, MA 01752
2. Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess
Medical Center, and Department of Medicine, Harvard Medical School, Boston, MA 02215
3. Department of Laboratory Medicine, Boston Children's Hospital and Department of
Pathology, Harvard Medical School, Boston, MA 02115
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as an
‘Accepted Article’, doi: 10.1002/ajh.24923
This article is protected by copyright. All rights reserved.
American Journal of Hematology
To the Editor:
The rare autosomal dominant hemolytic anemia known as hereditary xerocytosis (HX) is
characterized by disease-causing mutations in one of two ion-channel proteins of the red cell
membrane. The mechanosensitive cation channel PIEZO1 is mutated in the majority of cases,
while a smaller subset of patients harbor mutations in the Ca2+-gated K+ channel, KCNN4
(Gardos channel) [1] [2]. When normal circulating erythrocytes undergo reversible distention
and distortion during their navigation through narrow tissue capillaries and hepatosplenic
sinuses, the mechanical stimuli activate PIEZO1, elevating intracellular [Ca2+]. The elevated
intracellular [Ca2+] in turn activates KCNN4 to allow K+ efflux and cell shrinkage. These two
channels thus constitute sequential steps in an erythrocyte Ca2+ signaling pathway [2, 3]. The
heterozygous missense mutations in either PIEZO1 or KCNN4 that cause autosomal dominant
HX appear to confer “gain-of-function,” manifested as abnormally increased channel activity
that is usually, but not uniformly, secondary to prolonged channel inactivation time [2-4].
Increased KCNN4 channel activity leads directly to erythrocyte dehydration via loss of K+, Cl-,
and water. In the case of PIEZO1 mutations, the dysfunction increases Ca2+ entry into
erythrocytes, in turn increasing KCNN4 activation and cellular dehydration [2-4].
The hemolytic anemia associated with HX varies from fully compensated to severe, and
is accompanied by chronic fatigue, muscle weakness, abdominal pain from splenic enlargement,
and pathological iron accumulation in body tissues [1]. However, while splenectomy can relieve
abdominal pain, it may be of no benefit for correcting anemia and carries an exceptionally high
risk of thromboembolic complications (at least in the context of PIEZO1 mutations) [5]. The
central role of KCNN4 in the red blood cell dehydration of HX has led to the proposed use of the
2
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American Journal of Hematology
KCNN4 (Gardos channel) blocker, senicapoc, to prevent dehydration and subsequent hemolysis
of red blood cells [6].
Evidence-based estimates of the number of HX patients would be of benefit in planning
clinical tests of senicapoc as a possible treatment for HX and in developing molecular
diagnostics for those patients. Classical estimates of HX prevalence of ~1:50,000 [1] have been
based on small numbers of reported patients. However, the study of HX cohorts in which
hemolytic disease occasionally cosegregates with disease variants (or disease-associated
variants) of higher allele frequency [6, 8] suggests that HX is more common than previously
believed. As the sometimes extreme red blood cell dehydration of HX is often revealed in
increased values of mean corpuscular hemoglobin concentration (MCHC) [1], we mined a large
commercial lab database for complete blood counts (CBCs) results.
All CBCs performed between January 2014 and December 2016 that included numerical
results for MCHC, hemoglobin, and mean corpuscular volume (MCV) were retrieved from the
Quest Diagnostics Health Trends™ Database. Individual patients were identified either by an
enterprise master patient identifier or by a combination of patient gender, date of birth, ZIP
Code®, and insurance provider. Patients from all 50 states and District of Columbia were
represented. The dataset was edited to include only the first CBC performed within the study
period for each individual patient of identified sex between the ages of 18 and 99 years.
Statistical significance testing of group proportions was conducted using the chi-square test. Data
were analyzed using SAS Studio (SAS Institute, Cary, N.C.). This Quest Diagnostics Health
Trends™ report was deemed exempt by the Western Institutional Review Board.
Median age was 51 years, and 59.1% of subjects were female. Hemoglobin and MCHC
values grouped by reference range (RR) are shown in Table 1. Of the 48,403,254 patients
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American Journal of Hematology
included in this analysis, 27,108 (0.056%) had MCHC values above the RR, of whom 4,029
(0.0083% of overall population) also had hemoglobin levels below the RR. This latter, smaller
group includes anemic patients with possible HX, referred to as "candidate HX (anemia)."
Among subjects less than 50 years of age, the criteria for "candidate HX (anemia)" were more
commonly present in females than in males (0.0059% vs. 0.0036%; p<0.01). In contrast, those
criteria in subjects 50 or older were more common in males than in females (0.0129% vs
0.0100%; p<0.01).
Table 2 shows concurrent CBC values and indicators of hemolysis for subjects with high
MCHC in whose samples cold agglutinins had been ruled out. Among subjects with in-range or
elevated hemoglobin values, 52.5% had elevated reticulocyte counts, 10.5% had elevated total
bilirubin concentrations, and 12.9% had elevated serum levels of lactate dehydrogenase (LD). In
addition, 15.9% of patients with high MCHC had elevated serum ferritin levels, consistent with
the systemic iron overload of HX, exceeding that expected from the degree of hemolysis. Also
notable among these patients were elevated MCH values in 46.8%, consistent with the
macrocytosis commonly noted in HX patients. Patients with combinations of elevated MCHC,
in-range or elevated hemoglobin, and elevated total bilirubin, ferritin, LD, or reticulocyte count
were defined as having possible HX with compensated hemolysis, and referred to as "candidate
HX (compensated hemolysis)." For subjects of all ages, elevated MCHC was more frequent in
males than in females (0.0831% vs. 0.0372%; p<0.01), as was also true for the group "candidate
HX (compensated hemolysis)" (0.0103% vs. 0.0019%; p<0.01).
These data suggest that the number of subjects with hematological indices consistent with
HX is higher than would be predicted by previous estimates of HX prevalence based on sporadic
clinical presentation [1]. Extrapolation of this analysis to the 2010 US Census population
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American Journal of Hematology
between the ages of 18-99 (243,226,274; https://www.census.gov/2010census/) suggests that
approximately 146,000 US residents have elevated MCHC values (Table 3). Among these
individuals, 18,718 exhibit additional hematological parameters consistent with "candidate HX
(anemia)", and 15,531 have indices consistent with "candidate HX (compensated hemolysis)"
(Table 3). Thus, an extrapolated 34,249 people in the US exhibit elevated MCHC accompanied
by compensated, mild, or severe anemia, representing ~1:7,000 U.S. adults aged 18-99 years. We
therefore suggest that patients with unexplained anemia or compensated hemolysis accompanied
by elevated MCHC, as well as symptomatic patients with elevated MCHC in the absence of
anemia, may, be candidates for genetic screening for mutations associated with HX.
However, elevated MCHC values cannot be attributed exclusively to HX. MCHC can be
elevated by hyperlipidemia, hyperbilirubinemia, hyponatremia, and hemolysis, none of which
factors have been systematically controlled for in our analysis [9]. Fewer than 4% of hereditary
spherocytosis (HS) patients have elevated MCHC [10]. This is equivalent to the 3.67% of our
subjects with both elevated MCHC and anemia, who also have low MCV (Table 2), representing
~750 patients within our extrapolated US population estimate. The ~10% or more of sickling
hemoglobinopathy patients (SS and SC) with elevated MCHC [11] may represent as many as
1,850 patients among our extrapolated US population estimate, assuming a US sickle cell disease
population of 100,000. Moreover, homozygous HbC disease affects 0.02% of the approximately
29,000,000 American adults of self-described African descent aged 18-99 (2010 US Census),
and accounts for 5,800 additional patients with elevated MCHC. However, the "candidate HX"
groups capture only that ~15% of HbC disease patients with MCV within or above RR [12],
numbering ~900 patients. Thus, subtracting the above ~3,500 patients with HS or with
hemoglobinopathies SS, SC, or CC from the extrapolated 34,249 US subjects with elevated
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American Journal of Hematology
MCHC and either anemia or compensated hemolysis leaves ~31,000 subjects from our
extrapolated study population in the category of "candidate HX." This value suggests a possible
HX prevalence in the US population (the "anemia" group plus the "compensated hemolysis"
group) of 1:8,000 US adults, or ~6-fold greater than classical estimates based on clinical
presentation. However, even this estimated prevalence is likely a conservative one, since a not
insubstantial minority of HX patients have MCHC within RR. In addition, several PIEZO1
variants genetically linked to HX [6, 8] have minor allele frequencies of 0.0033 or higher in the
general population (exac.broadinstitute.org)
The main strength of this study is its evaluation of nearly 20% of American adults,
providing a broad window into the laboratory findings associated with anemia and compensated
hemolysis accompanied by elevated MCHC. The main weakness of the study is that subject
ascertainment reflects the variations in degree of clinical suspicion of anemia and other medical
conditions by healthcare providers, as reflected in ordering of CBC testing. Thus, the study is
limited by the large proportion of patients who did not undergo tests of the additional parameters
contributing to our definition of "presumed HX (compensated hemolysis)," likely rendering these
estimates somewhat conservative. Another limitation is extrapolating prevalence from a
population who received medical care to the entire U.S. population. In contrast, possible
interference with MCHC measurement by concomitant hyperbilirubinemia, hyperlipidemia,
hyponatremia, or intravascular or post-collection hemolysis would contribute to overestimation
of the candidate HX population.
Although no specific treatment for HX is currently available, the KCNN4 inhibitor
senicapoc, has been well tolerated in previous phase III clinical trials [7] and has been proposed
as a targeted therapy for HX [2, 6, 8]. Future studies of senicapoc and of other nascent
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American Journal of Hematology
therapeutic approaches for patients with elevated MCHC and anemia or compensated hemolysis ,
will evaluate the utility of PIEZO1 and KCNN4 genetic screening in defining eligibility for
treatment with senicapoc or other drugs. These studies may define patient subsets who may most
benefit from genetic testing.
Acknowledgements:
We thank Dr. Jay Wohlgemuth and Jeff Radcliff for support and critical comment.
Conflict of interest disclosure:
Drs. Alper, Brugnara, and Snyder are co-investigators in a clinical project for the treatment of
HX (dehydrated stomatocytosis) with Springworks Therapeutics. Dr. Brugnara and Boston
Children’s Hospital hold patents potentially related to senicapoc. Dr. Alper has received research
funding from Quest Diagnostics. Dr. Kaufman, Mr. Niles, Mr. Gallagher, and Dr. Snyder are
employees of Quest Diagnostics.
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American Journal of Hematology
References
1.
Andolfo I, Russo R, Gambale A, et al. New insights on hereditary erythrocyte membrane
defects. Haematologica 2016;101:1284-1294.
2.
Andolfo I, Russo R, Manna F, et al. Novel Gardos channel mutations linked to
dehydrated hereditary stomatocytosis (xerocytosis). American Journal of Hematology
2015;90:921-926.
3.
Cahalan SM, Lukacs V, Ranade SS, et al. Piezo1 links mechanical forces to red blood
cell volume. eLife 2015;4.
4.
Alper SL. Genetic Diseases of PIEZO1 and PIEZO2 Dysfunction. Current Topics in
Membranes 2017;79:97-134.
5.
Iolascon A, Andolfo I, Barcellini W, et al. Recommendations regarding splenectomy in
hereditary hemolytic anemias. Haematologica 2017;102:1304-1313.
6.
Rapetti-Mauss R, Picard V, Guitton C, et al. Red blood cell Gardos channel
(KCNN4):the essential determinant of erythrocyte dehydration in Hereditary Xerocytosis.
Haematologica 2017.
7.
Ataga KI, Reid M, Ballas SK, et al. Improvements in haemolysis and indicators of
erythrocyte survival do not correlate with acute vaso-occlusive crises in patients with sickle cell
disease: a phase III randomized, placebo-controlled, double-blind study of the Gardos channel
blocker senicapoc (ICA-17043). British journal of haematology 2011;153:92-104.
8.
Glogowska E, Schneider ER, Maksimova Y, et al. Novel mechanisms of PIEZO1
dysfunction in hereditary xerocytosis. Blood 2017.
9.
Berda-Haddad Y, Faure C, Boubaya M, et al. Increased mean corpuscular haemoglobin
concentration: artefact or pathological condition? International journal of laboratory hematology
2017;39:32-41.
10.
Rocha S, Costa E, Rocha-Pereira P, et al. Complementary markers for the clinical
severity classification of hereditary spherocytosis in unsplenectomized patients. Blood cells,
molecules & diseases 2011;46:166-170.
11.
Parrow NL, Tu H, Nichols J, et al. Measurements of red cell deformability and hydration
reflect HbF and HbA2 in blood from patients with sickle cell anemia. Blood cells, molecules &
diseases 2017;65:41-50.
12.
Murphy JR. Hemoglobin CC disease: rheological properties or erythrocytes and
abnormalities in cell water. The Journal of clinical investigation 1968;47:1483-1495.
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American Journal of Hematology
Table 1: Hemoglobin and MCHC Reference Range Groups
MCHC Values
(g/dL)
Hemoglobin Values (g/dL)
Male: >17.1
Female: >15.5
Male: 13.1 - 17.1
Female: 12.2 - 15.5
Male: <13.1
Female: <12.2
Total
>36
2,605 (0.0054)
20,474 (0.0423)
4,029 (0.0083)
27,108 (0.0560)
32-36
807,177 (1.67)
35,640,342 (73.63)
5,917,868 (12.23)
42,365,387 (87.53)
<32
57,626 (0.12)
3,456,431 (7.14)
2,496,702 (5.16)
6,010,759 (12.42)
Total
867,408 (1.79)
39,117,247 (80.82)
8,418,599 (17.39)
48,403,254 (100)
______________________________________________________________________________
Parentheses indicate values in % of total population tested.
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Page 10 of 11
Table 2: Select Hematologic Indices in Patients with Elevated MCHC and with Hemoglobin Values either
Below Reference Range or Within or Above Reference Range
MCH
MCV
RBC
RDW
Total
Bilirubin
Ferritin
LD
Reticulocyte
Count
Hemoglobin Below Reference Range
Below
Above
Reference
Within
Reference
TOTAL
Range, N
Reference
Range, N
N
(%) Range, N (%)
(%)
1,301
2,691
4,029
37 (0.92)
(32.29)
(66.79)
2,924
4,029
148 (3.67)
(72.57)
957 (23.75)
3,689
3,895
(94.71)
205 (5.26)
1 (0.03)
1,970
1,662
3,632
0 (0)
(54.24)
(45.76)
1,918
2,449
4 (0.16)
(78.32)
527 (21.52)
306
24 (7.84)
189 (61.76)
93 (30.39)
121
5 (4.13)
77 (63.64)
39 (32.23)
88
6 (6.82)
33 (37.50)
Hemoglobin Normal or Above Reference Range
Below
Above
Reference
Within
Reference
TOTAL
Range, N
Reference
Range, N
N
(%)
Range, N (%)
(%)
12,238
10,800
23,079
41 (0.18)
(53.03)
(46.8)
21,071
23,079
306 (1.33)
(91.30) 1,702 (7.37)
3,512
16,294
20,219
(17.37)
(80.59)
413 (2.04)
16,083
17,577
5 (0.03)
(91.50)
1489 (8.47)
15,704
1,838
17,553
11 (0.06)
(89.47)
(10.47)
774
15 (1.94)
636 (82.17)
123 (15.89)
518
13 (2.51)
438 (84.56)
67 (12.93)
49 (55.68)
59
5 (8.47)
23 (38.98)
______________________________________________________________________________
N, Number of patients in each category for whom laboratory value was available in the database.
Parentheses indicate % of "TOTAL N".
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31 (52.54)
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American Journal of Hematology
Table 3: Extrapolated Population Prevalence Estimates by Age and Sex
Estimated U.S.
Population Prevalence
Candidate HX
(Compensated
hemolysis)
Candidate HX
(anemia)
Elevated
MCHC
N (%)
Age Group
(Years)
Female
Male
Female Male
18-49
4,594 (0.0318)
7,696 (0.0888)
21,692
60,610 82,302
50-99
6,036 (0.0427)
8,782 (0.0787)
24,501
39,257 63,757
TOTAL
10,630 (0.0372)
16,478 (0.0831)
46,193
99,867 146,059
18-49
851 (0.0059)
316 (0.0036)
4,047
2,471
6,518
50-99
1,421 (0.0100)
1,441 (0.0129)
5,873
6,327
12,200
TOTAL
2,272 (0.0079)
1,757 (0.0089)
9,920
8,798
18,718
18-49
171 (0.0020)
879 (0.0124)
1,406
8,820
10,226
50-99
187 (0.0017)
772 (0.0087)
974
4,331
5,305
TOTAL
358 (0.0019)
1,651 (0.0103)
2,380
13,151 15,531
Total
______________________________________________________________________________
Total United States population estimates for the categories Elevated MCHC, "Candidate HX
(anemia)", and "Candidate HX (compensated hemolysis)" were based on extrapolations from
2010 U.S. Census data (https://www.census.gov/2010census/) stratified by sex and age, Sexstratified prevalence data for the groups aged 18-49 and 50-99 were adjusted by corresponding
U.S. population estimates. Parentheses indicate values in % of total population tested.
11
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