(PDF Download) Congenital and Acquired Bone Marrow Failure Mahmoud Aljurf Fulll Chapter

Download and Read online, DOWNLOAD EBOOK, [PDF EBOOK EPUB ], Ebooks
download, Read Ebook EPUB/KINDE, Download Book Format PDF
Congenital and Acquired Bone Marrow Failure

Mahmoud Aljurf
OR CLICK LINK
https://textbookfull.com/product/congenital-and-
acquired-bone-marrow-failure-mahmoud-aljurf/
Read with Our Free App Audiobook Free Format PFD EBook, Ebooks dowload PDF
with Andible trial, Real book, online, KINDLE , Download[PDF] and Read and Read
Read book Format PDF Ebook, Dowload online, Read book Format PDF Ebook,
[PDF] and Real ONLINE Dowload [PDF] and Real ONLINE
More products digital (pdf, epub, mobi) instant
download maybe you interests ...
Atlas of Bone Marrow Pathology 1st Edition Tracy I.

George
https://textbookfull.com/product/atlas-of-bone-marrow-
pathology-1st-edition-tracy-i-george/
The European Blood and Marrow Transplantation Textbook

for Nurses Michelle Kenyon
https://textbookfull.com/product/the-european-blood-and-marrow-
transplantation-textbook-for-nurses-michelle-kenyon/
Tumors and cancers : endocrine glands - blood - marrow

- lymph 1st Edition Dongyou Liu
https://textbookfull.com/product/tumors-and-cancers-endocrine-
glands-blood-marrow-lymph-1st-edition-dongyou-liu/
Acquired Brain Injury An Integrative Neuro

Rehabilitation Approach Jean Elbaum
https://textbookfull.com/product/acquired-brain-injury-an-
integrative-neuro-rehabilitation-approach-jean-elbaum/
Congenital disorders sourcebook. Fourth Edition Siva
Ganesh Maharaja
https://textbookfull.com/product/congenital-disorders-sourcebook-
fourth-edition-siva-ganesh-maharaja/
Diagnosis and Management of Adult Congenital Heart

Disease Michael A. Gatzoulis
https://textbookfull.com/product/diagnosis-and-management-of-
adult-congenital-heart-disease-michael-a-gatzoulis/
Dynamics of Lattice Materials Mahmoud I. Hussein
https://textbookfull.com/product/dynamics-of-lattice-materials-
mahmoud-i-hussein/
Fetal and Hybrid Procedures in Congenital Heart

Diseases 1st Edition Gianfranco Butera
https://textbookfull.com/product/fetal-and-hybrid-procedures-in-
congenital-heart-diseases-1st-edition-gianfranco-butera/
Invertebrate Embryology and Reproduction 1st Edition

Fatma Mahmoud El-Bawab
https://textbookfull.com/product/invertebrate-embryology-and-
reproduction-1st-edition-fatma-mahmoud-el-bawab/
CONGENITAL
AND ACQUIRED
BONE MARROW
FAILURE
Edited by
M.D. Aljurf
Adult Hematology and Bone Marrow Transplantation
Oncology Center, King Faisal Specialist Hospital
and Research Center, Riyadh, Saudi Arabia
E. Gluckman
Eurocord, Saint Louis Hospital, Paris, France
C. Dufour
Hematology Unit
G. Gaslini Children’s Hospital, Genova, Italy

Academic Press is an imprint of Elsevier
125 London Wall, London EC2Y 5AS, United Kingdom
525 B Street, Suite 1800, San Diego, CA 92101-4495, United States
50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States
The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom
Copyright © 2017 Elsevier Inc. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical,
including photocopying, recording, or any information storage and retrieval system, without permission in writing from the
publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrange-
ments with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our
website: www.elsevier.com/permissions.
This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may
be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understand-
ing, changes in research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any informa-
tion, methods, compounds, or experiments described herein. In using such information or methods they should be mindful
of their own safety and the safety of others, including parties for whom they have a professional responsibility.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any
injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or
operation of any methods, products, instructions, or ideas contained in the material herein.
Library of Congress Cataloging-in-Publication Data

A catalog record for this book is available from the Library of Congress
British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library
ISBN: 978-0-12-804152-9
For information on all Academic Press publications

visit our website at https://www.elsevier.com/
Publisher: Mica Haley

Acquisition Editor: Tari Broderick
Editorial Project Manager: Kathy Padilla
Production Project Manager: Karen East and Kirsty Halterman
Designer: Victoria Pearson
Typeset by Thomson Digital

List of Contributors
S.O. Ahmed Adult Hematology and Bone Marrow S. Elmahdi Department of Pediatrics, Graduate
Transplantation, Oncology Center, King Faisal School of Medicine, Nagoya University, Nagoya,
Specialist Hospital and Research Center, Riyadh, Japan
Saudi Arabia
P. Farruggia Pediatric Hematology and Oncology
G. Aldawsari Adult Hematology and Bone Marrow Unit, A.R.N.A.S. Ospedale Civico, Palermo, Italy
Transplantation, Oncology Center, King Faisal
F. Fioredda Hematology Unit, G. Gaslini Children’s
Specialist Hospital and Research Center, Riyadh,
Hospital; Unità di Ematologia Istituto Giannina
Saudi Arabia
Gaslini, Genova, Italy
M.D. Aljurf Adult Hematology and Bone Marrow
S. Gandhi Department of Haematological Medicine,
King’s College Hospital/King’s College London,
London, United Kingdom
Saudi Arabia
S. Giraudier Hematology Laboratory, Henri–
H. Alzahrani Adult Hematology and Bone Marrow
Mondor Hospital, Paris–Est–Creteil University,
Paris, France
Saudi Arabia E. Gluckman Eurocord, Hospital Saint-Louis, Paris,
France
M. Ayas Pediatric Hematology–Oncology and Stem
Cell Transplantation, King Faisal Specialist Hospital F. Grimaldi Hematology, Department of Clinical
and Research Center, Riyadh, Saudi Arabia Medicine and Surgery, Federico II University,
Naples, Italy
A. Bacigalupo Istituto di Ematologia, Policlinico
Universitario A. Gemelli, Universita’ Cattolica del B. Höchsmann Institute of Transfusion Medicine,
Sacro Cuore, Roma, Italy University of Ulm; Institute of Clinical Transfusion
Medicine and Immunogenetics, German Red Cross
F. Ciceri Hematology and BMT Unit, IRCCS San
Blood Transfusion Service Baden–Württemberg–
Raffaele Scientific Institute; University Vita-
Hessia, and University Hospital Ulm, Ulm,
Salute San Raffaele, IRCCS San Raffaele Scientific
Germany
Institute, Milano, Italy
K. Hosokawa National Institutes of Health, National
J.N. Cooper National Institutes of Health, National
Heart, Lung, and Blood Institute, Bethesda, MD,
Heart, Lung, and Blood Institute, Bethesda, MD,
United States
United States
S. Kojima Department of Pediatrics, Graduate
J.H. Dalle Hematology–Immunology Pediatric
School of Medicine, Nagoya University, Nagoya,
Department, Robert–Debre Hospital, Paris,
Japan
France
T. Leblanc Hematology–Immunology Pediatric
C. Dufour Hematology Unit, G. Gaslini Children’s
Department, Robert–Debre Hospital, Paris, France
ix
x List of Contributors
J.C.W. Marsh Department of Haematological P. Scheinberg Oncology Center, Hospital São José
Medicine, King’s College Hospital/King’s College National Institutes of Health, National Heart, Lung,
London, London, United Kingdom and Blood Institute, Bethesda, MD, United States
D. Meyran Hematology–Immunology Pediatric H. Schrezenmeier Institute of Transfusion
Department, Robert–Debre Hospital, Paris, France Medicine, University of Ulm; Institute of Clinical
Transfusion Medicine and Immunogenetics,
M. Miano Hematology Unit, G. Gaslini Children’s
German Red Cross Blood Transfusion Service
Baden–Württemberg–Hessia, and University
Hospital Ulm, Ulm, Germany
G.J. Mufti Department of Haematological
S. Sica Istituto di Ematologia, Policlinico
Medicine, King’s College Hospital/King’s College
Universitario A. Gemelli, Universita’ Cattolica del
London, London, United Kingdom
Sacro Cuore, Roma, Italy
J.R. Passweg Division of Hematology, University
M.T.L. Stanghellini Hematology and BMT Unit,
Hospital Basel, Basel, Switzerland
IRCCS San Raffaele Scientific Institute, Milano,
R. Peffault de Latour BMT Unit, French Reference Italy
Center for Aplastic Anemia and PNH, Saint-Louis
A. Tichelli Hematology, University Hospital of
Hospital, Paris, France
Basel, Basel, Switzerland
A.M. Risitano Hematology, Department of Clinical
M.T. Van Lint Divisione di Ematologia e Trapianto
Medicine and Surgery, Federico II University,
di Midollo Osseo, IRCCS AOU San Martino IST,
Naples, Italy
Genova, Italy
A. Rovó Hematology, University Hospital of Bern,
A.J. Warren Cambridge Institute for Medical
Bern, Switzerland
Research; The Department of Haematology,
A. Ruggeri Eurocord, Hospital Saint-Louis; University of Cambridge; Wellcome Trust–Medical
Hematology Department, Hospital Saint Antoine, Research Council Stem Cell Institute, University of
Paris, France Cambridge, Cambridge, United Kingdom
S. Samarasinghe Department of Haematology, N.S. Young National Institutes of Health, National

Great Hormond Street Hospital, London, United Heart, Lung, and Blood Institute, Bethesda, MD,
Kingdom United States

Introduction
From the first descriptions by Ehrlich over a haploidentical and cord blood transplants, and
century ago to where we are today, the under- in supportive care of hematopoietic stem cell
standing of the pathogenesis and biology and transplantation have lead not only to the expan-
of the diseases that are encompassed under sion of the potential donor pool, but also to re-
the umbrella of the “bone marrow failure syn- markable improvements in the outcome of he-
dromes” have witnessed tremendous progress. matopoietic stem cell transplantation for bone
This has been coupled with significant improve- marrow failure from related and unrelated stem
ments in the clinical care and outcomes of both cell sources with excellent rates of cure, par-
congenital and acquired forms of bone marrow ticularly in the younger patients, when a fully
failure. matched unrelated donor is used.
When considering acquired bone marrow Telomere shortening and telomeropathies
failure, in the last 4 decades, aplastic anemia have been increasingly recognized as contrib-
has progressed from a disease that was almost uting factors for bone marrow failure and stem
universally fatal to one in which the majority cell exhaustion in acquired states and causative
of patients can now expect to be cured and lead factors for the increasing number of entities of
normal lives. We have gained noteworthy in- congenital bone marrow failure.
sights in understanding the immune mechanism Several new treatment modalities have
of hematopoietic stem cell destruction, stem cell emerged during the last decade, most notable
niche, and T-cell dysregulation. This knowledge of which is the introduction of thrombopoietin
has placed immunosuppressive therapy at the mimetic agents. Possible interventions to rescue
center stage in the treatment of aplastic anemia, telomere length are being actively investigated.
and has facilitated the initiation of clinical trials Given the exciting progress in the field, this
for the use of new potential therapies to treat ac- book is a timely educational initiative produced
quired aplastic anemia. jointly by the Working Party of Severe Aplas-
Substantial progress in the knowledge about tic Anemia of the European Society for Blood
the role of somatic mutations and their relation and Marrow Transplantation and the European
to clonal hematopoiesis in acquired bone mar- School of Haematology.
row failure has been facilitated by the use of the The contents are a collection of up-to-date
next generation sequencing technologies, and contributions from world-renowned experts in
has allowed us to understand their relationship the field of congenital and acquired bone mar-
with myelodysplastic syndromes, paroxysmal row failure. The chapters in this book provide
nocturnal hemoglobinuria, and the risk of dis- extensive coverage for all aspects of congenital
ease progression. and acquired bone marrow failure, including bi-
Advances in HLA-typing technology, prog- ology, pathology, and treatments involving he-
ress in the field of alternate donor availability, matopoietic stem cell transplantation.
xi
xii Introduction
We hope this book will be an important re- With the endorsement of the European Soci-
source for scientists, clinicians, nurses, and all ety for Blood and Marrow Transplantation and
other health-related professionals involved in the European School of Haematology
research and patient care with the bone marrow
failure syndromes. Mahmoud Aljurf, Eliane Gluckman, Carlo Dufour

C H A P T E R
1
Epidemiology of Acquired Bone
Marrow Failure
F. Grimaldi*, S. Gandhi**, A.M. Risitano*
*Hematology, Department of Clinical Medicine and Surgery, Federico II University,
Naples, Italy; **Department of Haematological Medicine, King’s College Hospital/
King’s College London, London, United Kingdom
INTRODUCTION studies to gather data on the epidemiology of

AA. Based on the two epidemiological studies
Paul Ehrlich in 1888 gave the first seminal carried out in Europe and Asia that used the
description of aplastic anemia (AA) in a preg- same methodology, the incidence of the disease
nant woman, where the normal hemopoietic is two- to threefold higher in Asia than in the
tissue was replaced by a fatty marrow and West [2–12]. This variability in incidence rates
empty spaces, the “hypocellular” marrow that may reflect differences in exposure to environ-
resulted in pancytopenia. Idiopathic AA is mental factors including viruses, drugs and
a rare form of acquired bone marrow failure, chemicals, genetic background, diagnostic cri-
where improved supportive care, early insti- teria, and study designs.
tution of immunosuppressive treatment, and In the following sections, a short review of
hematopoietic stem cell transplantation have studies performed and available in literature, in-
led to better treatment outcomes [1]. Several cluding case series and reports to determine the
retrospective studies from Europe, United epidemiology and demographics of AA across
States, South America, and Asia suggest that different centers of the world is presented. Dis-
the incidence is 0.6–6.1 cases per million popu- cussion is restricted to acquired cases of AA, and
lation. In addition, the incidence of AA shows hence the inherited bone marrow failure syn-
geographical variability, with lower rates re- dromes, the inevitable cases of marrow aplasia
ported in Europe, North America, and Brazil that follow intentional chemoirradiation treat-
and higher rates in Asia. However, the rarity of ments and cytopenias of nutritional deficiencies
disease means there have been few prospective or other causes have been excluded.

http://dx.doi.org/10.1016/B978-0-12-804152-9.00001-4
1 Copyright © 2017 Elsevier Inc. All rights reserved.
2 1. Epidemiology of Acquired Bone Marrow Failure
INCIDENCE OF AA IN DIFFERENT South Asia, in this study were found to have an

GEOGRAPHICAL REGIONS incidence even higher than their counterparts
AND RACE from East Asia, at 7.3 per million [13]. This study
suggested that Asian children have an increased
The annual incidence of AA varies from 0.6 incidence of AA, possibly as a result of a genetic
to 6 per million populations per annum across predisposition. Indeed, in a hospital based case
centers in different continents. Most findings control study from Lucknow (India), the annual
are from retrospective studies, and even retro- incidence of childhood AA was determined to be
spective reviews of death registries. However, 6.8 per million [14].
this incidence masks the variability that is seen Benzene has been found to be toxic to the
across continents and different ethnic groups; hemopoietic progenitor cells. In large collab-
for example, reports from the Barcelona group orative studies between the National Cancer
(2008), which was a detailed prospective study Institute and American and Chinese institutions
by Montané et al. [2] had an incidence of 2.34 per [15], hematologic susceptibility to benzene has
million population. This incidence rate is simi- been correlated to nucleotide polymorphism
lar to the 2.0 per million reported by the Inter- in key drug metabolic patways [16]. Thus, he-
national Agranulocytosis and Aplastic Anemia matotoxicity from exposure to benzene may be
Study (IAAAS) [3], which was conducted in Eu- particularly evident among genetically suscep-
rope and Israel from 1980 to 1984, and to rates re- tible populations, and it is plausible that the
ported in smaller national studies in Europe that increased incidence of AA seen in Asia may be
included United Kingdom [4], France [5], Scan- related not only to increased exposure but also
dinavia [6], and in South Americas and Brazil [7]. to key polymorphism in genes regulating the
The incidence was accurately determined to be 4 metabolism and cytokine expression.
cases per million population in Bangkok [8], but Similarly, although AA incidence reported
based on prospective studies, it may actually be in a multicenter Latin American study remains
closer to 5.6 cases per million population in the very low at 1.6 per million; this study corrobo-
rural areas of Thailand (Khonkaen region) [9]. rated the association between risk of exposure to
In the prospective Chinese Epidemiologic Study benzene, chloramphenicol, and also azithromy-
Group of Leukemia and Aplastic Anemia survey, cin and predisposition to AA in this area [17,18].
7.4 per million was reported as a national inci-
dence, which clearly is much on the higher side,
but may have been overestimated, as stringent AGE AND GENDER RELATED
criteria for the diagnosis of AA, as bone marrow DEMOGRAPHICS OF AA
study, were not strictly applied [10]. Increased
incidence in Eastern countries may be related to In nearly all modern studies of AA, the sex
environmental factors, such as increased expo- ratio has been close to 1:1, which is unusual for
sure to toxic chemicals and pesticides on agricul- immune-mediated diseases [2,19]. An exception
tural farms, practiced in the Far East and South to this has been a study from the Sabah prov-
Asia. However, the incidence of AA in children ince in Malaysia [12], where an unusually high
of immigrants from the East Asia in a pediat- male to female ratio was noted at 3:4. Similarly
ric population from the ages 0 to 14 years, in a a male preponderance was also noted in stud-
study from British Columbia (Canada) was sig- ies from Thailand [9], India [20], and Pakistan
nificantly higher at 6.9 per million, as compared [21]. This may reflect the underreporting of cases
to children of white/mixed ethnic descent at 1.7 of AA among females and access to adequate
per million [11]. Children of immigrants from healthcare services in Asia. However, it remains

AA and association with toxins/drugs 3
unclear why a female preponderance is not seen tries and Europe, where recently an incidence of
in a quintessential autoimmune disorder, such as 5.4%, stable across the years, has been reported
AA among studies in Europe and United States. in a large registry study from EBMT [25].
In all the largest studies available, including a Cases of AA associated with HAV, HBV, HGV,
series of 300 patients reported by Clinical Center parvovirus B19 [26–29], Epstein–Barr virus
at NIH by Young et al. [22], the Barcelona report (EBV) [30], transfusion-transmitted virus (TTV)
[2] and epidemiologic study from Thailand [9], [31] or echovirus [32] infections have been re-
2 patient age peaks of incidence are constantly ported. In a German–Austrian study of 213 pe-
observed, one among young adults and the sec- diatric cases aged 17 years or less of AA, 80% of
ond in the elderly. This characteristic biphasic cases were idiopathic, 9% followed posthepatitis
distribution shows two peaks, one from 10 to AA, 7% were following viral infections, and 4%
25 years and the second above 60 years. Within were associated with drugs/toxins [33].
the younger age group, a small peak in the in- Parvovirus B19 is the causative agent for fifth
cidence is observed in childhood, probably due disease, usually in the immunocompetent host.
to overlap with inherited marrow-failure syn- However, transient aplastic crises have been re-
dromes featured by a less penetrating pheno- ported in chronic hemolytic anemias, such as
type, where classical physicalanomalies of the sickle cell disease owing to reticulocytopenia,
inherited marrow-failure syndromes are not ob- and cases of severe AA have also been reported
vious. On the other hand, the second incidence in normal individuals during an acute episode
peak of AA seen above 60 years may reflect the of infection [34]. The actual incidence of acute
smaller pool of hematopoietic stem cell reserve parvovirus B19 infection at presentation in AA
left, with age-related telomeric attrition and its is not known, but in single case series of 27 pa-
capacity to maintain normal hemopoiesis, in the tients with AA from India, parvovirus B19 IgM
face of an immune insult against the hematopoi- and viral DNA was detected in nearly 40% of the
etic precursor cells [23]. cases [35]. This maybe an important etiological
factor, especially in immunocompromised host
or patients with chronic hemolytic anemias.
POSTHEPATITIS AA AND AA Very recently retrospective observations
OCCURRING AFTER VIRAL about eight AA cases occurring during HIV in-
INFECTIONS fection have been reported [36]. Even if AA ap-
pears to be a late rare complication in HIV pa-
Posthepatitis AA is a stereotypical syndrome, tients, report from Pagliuca et al. [36] highlights
where pancytopenia often presents 2–3 months that immunosuppressive therapy is a feasible
after an acute attack of seronegative severe but strategy in AA patients and that better outcome
self-limited liver inflammation. This distinct is observed in patients eligible to transplant,
variant has been commonly seen in 5–10% of while death for infection remain the principle
“classical” AA cases, typically occurring in ado- cause of mortality in undertreated patients.
lescent boys and young men [24]. Severe imbal-
ance of the T-cell immune system as seen with
“classical” AA, human leukocyte antigen (HLA) AA AND ASSOCIATION WITH
association, and effective response to immuno- TOXINS/DRUGS
suppressive therapy strongly suggest an im-
mune-mediated mechanism. As for other form There is no discernible difference in the de-
of AA, higher incidence is noted in East Asia mographics or clinical behavior, including re-
(4–10%), when compared to the Western coun- sponse to immunosuppressive therapy, between

patients classified as having “drug or toxin in- clined to the point that it has not been reported
duced” versus “idiopathic” AA [37]. as significant risk factor in any recent systematic
Benzene is the most widely studied and im- epidemiologic study of AA in Western countries.
plicated amongst toxins causing AA. The rela- Even in Thailand where the need for such effec-
tionship was initially brought to light by a case tive and inexpensive antibiotic is substantial, and
where a series of workers exposed through their usage is reported 100 times greater than in the
specific occupations [15] and has since been West, association with AA is infrequent, prob-
detected in some, but not all population-based ably due to lower-doses prescription [9].
case-control studies. An association has been In the IAAAS study [3] approximately 25%
seen in some case-control studies but even when of the identified AA cases were related to
present, the proportion of cases that can be at- drug use. Major drug associations were with
tributed to this chemical has been small. Studies gold salt (relative risk, RR of 29), antithyroid
on American workers earlier in this century sug- drugs (RR of 11), and nonsteroidal antiinflam-
gested that the risk of AA was about 3% in men matory agents (RR of 8.2 for Indomethacin).
exposed to concentration higher than 300 ppm, Similarly in 235 patients with AA prospec-
and in the more recent IAAAS study [3], benzene tively followed by the Barcelona group [2],
was accounted for about 1–3% of AA recorded 67 cases (28.5%) had a history of exposure to
cases. Similarly in Thailand population, benzene drugs or toxic agents that have been associated
carried a relative risk of 3.5 but accounted for an with AA, sometime in the preceding 6 months.
etiologic fraction of only 1% [9]. Forty nine (20.8%) cases had been exposed to
Pesticides have been associated with AA in a the following drugs (Table 1.1). In addition, 21
large number of medical records. In the Indian (8.9%) cases had been exposed to toxic agents:
cohort of pediatric AA, although significantly insecticides (n = 8), benzene (n = 6), and other
higher blood levels of organochlorine com- solvents (n = 10).
pounds were detected suggesting an associa-
tion, they were not entirely supported by statis- TABLE 1.1 Exposures to Drugs Reported to be
tical methods [14]. Anecdotal case reports of AA Associated With Aplastic Anemia in the
following use and pesticides, such as dichloro- 2–6 Months Prior to Hospital Admission
Among 235 Cases (Montané et al. [2])
diethyly-trichlorthane (DDT), chlordane or lin-
dane, or following exposure to organic solvents, Drug N (%)
such as toluene and other molecules resembling
Allopurinol 9 (3.8)
benzene, or containing benzene ring, again point
merely to an association. Unfortunately, system- Indomethacin 9 (3.8)
atic population case-control studies correlating Gold salts 9 (3.8)
level and duration of exposure of these identi- Sulfonamides 9 (3.8)
fied toxins and AA onset are lacking. Carbamazepine 5 (2.1)
Initially suggested by accumulation of case re- Ticlopidine 4 (1.7)
ports, specific drug associations have been estab-
Chloramphenicol 3 (1.2)
lished in different population based study and
have changed across time, mainly due to chang- Oxyphenbutazone 3 (1.2)
es in drugs diffusion and utilization. Chloram- Phenylbutazone 3 (1.2)
phenicol, for example, that gained notoriety for Penicillamine 3 (1.2)
its prominent association with AA in the 1950s Clopidogrel 2 (0.8)
and for decades was considered the common-
Methimazole 2 (0.8)
est cause of the disease, has progressively de-

AA and association with HLA genes 5
Finally, incidence of drug-associated AA ap- Nimer et al. [39]. Subsequently, positive asso-
pears to be lower in East Asia [8,9]. ciation between HLA-DR2 (precisely DRB1*15
allele) and AA was confirmed in Chinese [40],
Japanese [41], Turkish [42], Pakistani [43], and
AA AND ASSOCIATION Malaysian [44] series. These data depict a clear
WITH HLA GENES role for HLA-DR2 gene as risk factor for AA,
and different distribution of this gene across
The (HLA) system is a crucial group of genes human population may probably account for
responsible for starting and regulating immune different incidence seen for AA inspecific geo-
response. Since antigen presentation and T-cell graphical areas and ethnic groups. Interestingly,
activation through HLA may represent the early when Maciejewski et al. [45] analyzed distribu-
step that precede global hematopoietic stem cell tion of HLA-DR2 (mainly DRB1*15 allele) across
destruction in AA, HLA polymorphism may disease subgroups (i.e., AA, hemolytic PNH
contribute to pathogenesis of the disease by: (1) and AA/PNH), they found an increased fre-
increasing or decreasing susceptibility to AA, quency in the ones where bone marrow failure
particularly for specific ethnic or age groups, was associated with a PNH clone. Other DR2 al-
(2) facilitating activity of drugs or viral antigen leles have been correlated with AA; in a single
to break immune tolerance and starting the dis- case report, Nakao et al. [46] showed a specific
ease, (3) influencing response to immunosup- T-cell cytotoxic response associated with the
pressive therapy. DRB1*0405 allele. The DRB1*07 allele has been
As for other autoimmune disease, a large reported in a single cohort of Iranian subjects
number of studies demonstrated an association [47], and DRB1*0901 in Chinese children [48].
between polymorphism of HLA class II genes Finally, evidences available correlate AA even
and AA susceptibility (Table 1.2, a). with other HLA-II class genes, such as Dpw3
An increased frequency of HLA-DR2 was [49] and DR4 [22].
first described in several studies for European Less data are available for HLA class I genes.
and American Caucasian patients [38], and Early reports suggested a correlation with HLA-
finally confirmed in a multiethnic cohort by A2 gene [50,51] and with HLA-B7 and HLA-B14
TABLE 1.2 Summary of AA and Incidence of Specific HLA Genes or Alleles

a. HLA and b. HLA and
increased risk increased risk c. HLA and d. HLA and e. HLA and drug/ f. HLA and
of AA (Class II) of AA (Class I) reduced risk of AA onset age of AA viral related AA AA outcome
HLA-DRB1*1501 HLA-A2 HLA-DRB1*13 HLA-DRB*09 Haplotype: -B38, HLA-DR2

-DR4, -DQ3
HLA-DRB1*0405 HLA-A*0206 HLA-DRB1*03:01 HLA-A26 Haplotype: HLA-DRB1*1501
-DRB1*0402,
-DQB1*0302
HLA-DRB1*07 HLA-B7 HLA-DRB1*11:01 HLA-B14 Haplotype: HLA-DR4-Ala74
-DRB1*1601,
-DQB1*0502
HLA-DRB1*0901 HLA-B14 HLA-DRB1*51:01 HLA-B48 HLA-DRB1*08
HLA-Dpw3 HLA-B*4002 HLA-DRB1*03
HLA-DR4 HLA-DRB1*13:02

genes at least in European patients [52,53]. More- tentially different HLA landscape in children
over, association between HLA-B14 alleles, HLA- with AA, even if further investigation involving
Cw7, and AA has been confirmed by Maciejewski a higher number of patient are needed to specifi-
et al. [45] in a multiethnic cohort of 212 American cally address this question (Table 1.2, c).
individuals. Finally Shichishima et al. [54] report- Association between agranulocytosis and
ed higher incidence of HLA-B*4002 and HLA- HLA genes has been reported for drugs expo-
A*0206 in 78 Japanese AA patients, suggesting sure in specific ethnic groups, suggesting that
a potential role of HLA class I genes even in Far certain alleles may facilitate the initiation of AA
East countries. through direct presentation of drug-derived an-
HLA genes revealing a protective role in devel- tigens to T-cells [37]. HLA-class II haplotypes
oping AA have been identified too (Table 1.2, b). have been reported to be associated with clozap-
Even if data refer mainly to small series of pa- ine-induced agranulocytosis in Askenazi Jewish
tients, and may reflect natural polymorphism [60,61] individuals, and association between
in HLA system, again a key role for HLA class HLA-DRB1*08 alleles and thionamide-induced
II genes and its alleles is suggested. HLA- AA has been described for Japanese patients
DRB1*13 appeared to be protective in a cohort [62]. A similar mechanism of disease can be sug-
of patients of Turkish origin [55], as well as gested for posthepatitis AA too, where associa-
HLA-DRB1*03:01, HLA-DRB1*11:01, and HLA- tion between HLA class I, specifically HLA-B8,
B1*51:01 alleles appear to be protective in co- and hematological disease have been document-
hort of Chinese children [48]. In a small cohort ed [24] (Table 1.2, d).
of Pakistani patients [43], HLA-DRB1*03 had an Finally, some groups have shown that re-
higher frequency in healthy control, suggesting sponse to immunosuppressive therapy can be
a putative protective role, and a similar observa- related to specific HLA genes. HLA-DRB1*1501
tion is available for allele DRB1*1302 in Korean is the most clearly allele associated with a better
population [56]. response to Cyclosporine [41], and the presence
Even if AA has a typical bimodal age of inci- of HLA-DR2 and a PNH clone independently
dence, majority of studies did not look specifi- predict response to therapy in patients under
cally into HLA frequency and age differences, immunosuppression [45]. On the other hand
mostly due to their retrospective nature and HLA-DRB1*1502 allele [63], that represents a dif-
rarity of disease. Therefore, a good assump- ferent allele variant of HLA-DR2, doesn’t seem
tion could be that data on HLA allele frequency to have same influence on treatment, even if its
could be inferred to the pediatric setting. How- incidence is increased among older Japanese pa-
ever Fuhrer et al. [57] in a recent study involv- tients with AA. High-resolution genotyping of
ing 181 Caucasian children observed a positive HLA-DRB1 showed that the HLA-DRB1*04 al-
association between HLA-A26 and HLA-B14 lele coding for alanine position 74 (HLA-DR4-
alleles, but not a higher incidence of HLA-DR2. Ala74) [64] predispose to AA independently
Similarly Chen et al. [48] in a retrospective sur- from HLA-DRB1*15 and that HLA-DRB1*04 al-
vey conducted on 80 Chinese children showed leles are associated with worse response to cy-
an higher than expected incidence of class I closporine and poorest prognosis (Table 1.2, e).
HLA-B48 alleles and class II HLA-DRB*09 al- Association between AA and HLA remains
lele. Finally, a frequency of HLA-DR2 B15 allele an intriguing field of interest. However studies
not different from normal population has been with larger patients populations from different
reported by Kook et al. [58] in North Korean AA ethnic backgrounds are needed to better address
children and by Yoshida et al. [59] in Japanese complex relations between HLA, environmental
AA children. These limited data suggest a po- factors, ethnicity, and AA incidence.

AA during pregnancy 7
AA AND AUTOIMMUNE among AA patients. Stalder et al. in a single cen-

DISORDERS ter series [71] of 253 individuals showed that
5.3% of patients with AA had a previous diagno-
Although AA is idiopathic in most cases, as- sis of AIDS, and 4.5% developed an AIDS after
sociations with other autoimmune disease (AID) AA was diagnosed. Similarly 4% of patients re-
have been shown in numerous single-case recorded in EBMT database [72] for AA have been
ports. In rheumatic diseases, such as systemic found diagnosed with a previous AIDS in a ret-
lupus erythematosus (SLE) and rheumatoid ar- rospective analysis. Most frequently diagnosed
thritis (RA), there is a recognized associations AIDS were autoimmune gastritis and thyroid-
with AA [65], with a true incidence not known, itis in Stalder series, and RA in EBMT analysis,
but presumed to be very low. respectively. Interestingly, in both studies pa-
Peripheral autoimmune cytopenias are com- tient’s age at diagnosis of AA seems to be higher
monly seen in SLE, and they are listed among (>50 years) than normal. Impact of immunosup-
diagnostic criteria for the disease in the revised pressive treatment for AA on concomitant AIDS,
American College of Rheumatology classifica- and effects on its natural history, remains at the
tion. Similarly, anemia of chronic disease, and moment a controversial topic.
cytopenias in relation to the use of cytotoxic
drugs are commonly seen in SLE patients [66].
Less frequently, case reports and small series AA DURING PREGNANCY
documented bone marrow abnormalities consis-
tent with AA, suggesting that in rare cases bone There are no prospective studies about the
marrow may also be a target organ of the disease, incidence of AA during pregnancy. Curiously
showing a full picture of acquired bone marrow AA was first described in a pregnant women
failure [67]. Very recently Chalayer et al. [68] re- by Ehrlich in 1888. Since then, there have been a
ported a MEDLINE methanalysis of 25 patients few published reports of AA during pregnancy.
with SLE and AA. In 12 of these 25 patients, di- Tichelli et al. [73] described a case series of 36
agnosis of AA was associated with long story of pregnancies in women with AA. Their study
SLE, extensive disease, and drug exposure, sug- showed that successful pregnancy with normal
gesting that drug-induced AA may represent a outcome is possible in women with AA who
consistent type of AA in these patients. have been previously treated with immuno-
Similarly the association of RA with AA is suppression. Nineteen percent of women were
better recognized because of the use of thera- found to have relapse of AA and a further 14%
peutic agents in RA, such as Methotrexate, gold needed transfusion support at the time of de-
salts, penicillamine, and Eternacept [69] causing livery. Complications appear to be more likely
AA, likely drug induced. in patients with low platelet counts and par-
Correlation with immune disorders is also oxysmal nocturnal hemoglobinuria-associated
highlighted by the strong link observed with AA. Similarly, Choudhry et al. [74] described
eosinophilic fasciitis (Shulman disease), a rare 10 cases of AA and concomitant pregnancies,
sclerodermiform syndrome that, in most cases, reporting successful delivery in 10 of 11 cases,
resolves spontaneously or after corticosteroid with adverse outcome related to fatal bleeding
therapy, and that is frequently reported in asso- in only 2 patients.
ciation with hematological diseases, especially Although pregnancy remains an immuno-
AA [70]. modulatory state, with an higher incidence of
Two large different studies have specifically autoimmune disease reported, causative rela-
looked into incidence of autoimmune conditions tionship with AA remains controversial.

AA POSTVACCINATION Ready availability of nucleotide variants

from the human genome project have defined
There have been three case reports of AA, new polymorphisms that are definitely patho-
following hepatitis B vaccination [75]. System- geneic and disease causing as opposed to vari-
atic case control studies for the incidence of AA ants that are disease predisposing and require
following vaccination are not known. Patients the interplay of other external factors for disease
with AA who have been treated with immu- causation. Furthermore, genetic tests have also
nosuppressive treatment, should better avoid defined how environmental influences, such as
vaccinations, if possible, including influenza, benzene play a role in the pathogenesis of AA
as there remains a theoretical risk of disease re- because of nucleotide polymorphisms that affect
lapse [1]. key drug metabolism pathways or cytokine sig-
naling molecules.
Following this theme, future epidemiological
PROBLEMS WITH studies for AA, are likely to better explain the
EPIDEMIOLOGICAL STUDIES IN association to causality in AA, precise diagno-
AA AND FUTURE STRATEGIES sis and staging prognostic information and also
unravel key molecular pathways for therapeutic
AA remains a rare disease with an annual inci- exploitation.
dence between 0.6 and 6 per million per annum. It
is innately difficult to conduct a population based References
study in a rare disease, such as AA. Reporting of
[1] Killick S, Brown N, Cavenagh J, et al. Guidelines for the
cases with AA is likely to be only from areas and
diagnosis and management of adult aplastic anemia. Br
centers that have a high coverage of health servic- J Haematol 2016;172:187–207.
es. It’s likely that there had been underreporting [2] Montané E, Ibanez L, Vidal X, et al. Epidemiology of
of cases with AA in regions with poor access to aplastic anaemia: a prospective multicenter study. Hae-
tertiary health care services or facilities for diag- matologica 2008;93:518–23.
[3] Kaufman DW, Kelly JP, Levy M, et al. The drug etiol-
nostic tests, including special diagnostic tests for
ogy of agranulocytosis and aplastic anemia. New York:
genomic and molecular analysis. Oxford University Press; 1991.
Drug recording and reporting to the medi- [4] Cartwright RA, McKinney PA, Williams L, et al. Aplas-
cines regulatory body for association studies tic anaemia incidence in parts of the United Kingdom
is not uniformly practiced, leading to under in 1985. Leuk Res 1988;12:459–63.
[5] Mary JY, Baumelou M, Guiguet M. The French Coop-
or over estimation of association and causality
erative Group for Epidemiological Study of Aplastic
(Chloramphenicol remains a case in point for an Anemia. Epidemiology of aplastic anemia in France: a
example of the latter). prospective multi-centric study. Blood 1990;75:1646–53.
The distinction between acquired and inher- [6] Clausen N, Kreuger A, Salmi T, et al. Severe aplastic
ited disease may present a clinical challenge, es- anaemia in the Nordic countries: a population based
study of incidence, presentation, course, and outcome.
pecially among pediatric cases.
Arch Dis Child 1996;74:319–22.
Multicenter clinical trials for newer thera- [7] Maluf EM, Pasquini R, Eluf JN, et al. Aplastic anemia
peutic agents or treatment strategies in AA may in Brazil: incidence and risk factors. Am J Hematol
provide on different countries a uniform panel 2002;71:268–74.
of recording data, including family history for [8] Issaragrisil S, Sriratanasatavorn C, Piankijagum A, et al.
Incidence of aplastic anemia in Bangkok. The Aplastic
inherited bone marrow failure syndromes, and
Anemia Study Group. Blood 1991;77(10):2166–8.
special tests, including T-cell subset repertoire [9] Issaragrisil S, Kaufman DW, Anderson T, et al. The
analysis and next-generation technique molecu- epidemiology of aplastic anemia in Thailand. Blood
lar analysis. 2006;107:1299–307.

REFERENCES 9
[10] Yang C, Zhang X. Incidence survey of aplastic anemia [26] Gonzalez-Casas R, Garcia-Buey L, Jones EA, et al. Sys-
in China. Chin Med Sci J 1991;6:203–7. tematic review: hepatitis-associated aplastic anaemia—
[11] Szklo M, Sesenbrenner L, Markowitz J, et al. Incidence a syndrome associated with abnormal immunological
of aplastic anemia in Metropolitan Baltimore. A popu- function. Aliment Pharmacol Ther 2009;30:436–43.
lation based study. Blood 1985;66:115–9. [27] Adachi Y, Yasui H, Yuasa H, Ishi Y, Imai K, Kato Y. Hep-
[12] Yong AS, Goh M, Rahman J, et al. Epidemiology of atitis B virus-associated aplastic anemia followed by
aplastic anemia in the state of Sabah, Malaysia. Cell Im- myelodysplastic syndrome. Am J Med 2002;112:330–2.
munol 1996;1284:S75. [28] Byrnes JJ, Banks AT, Piatack M Jr, Kim JP. Hepatitis G-
[13] McCahon E, Tang K, Rogers PC, McBride ML, et al. The associated aplastic anaemia. Lancet 1996;348:472.
impact of Asian descent on the incidence of acquired [29] Pardi DS, Romero Y, Mertz LE, Douglas DD. Hepatitis-
severe aplastic anaemia in children. Br J Haematol associated aplastic anemia and acute parvovirus B19
2003;121(1):170–2. infection: a report of two cases and a review of the lit-
[14] Ahamed M, Anand M, Kumar A, Siddiqui MK. Child- erature. Am J Gastroenterol 1998;93:468–70.
hood aplastic anaemia in Lucknow, India: incidence, [30] Lau YL, Srivastava G, Lee CW, et al. Epstein–Barr virus
organochlorines in the blood and review of case re- associated aplastic anaemia and hepatitis. J Paediatr
ports following exposure to pesticides. Clin Biochem Child Health 1994;30:74–6.
2006;39(7):762–6. [31] Poovorawan Y, Tangkijvanich P, Theamboonlers A,
[15] Qing L, Luoping Z, Guilan L, et al. Hematotoxicity et al. Transfusion transmissible virus (TTV) and its pu-
in workers exposed to low levels of benzene. Science tative role in the etiology of liver disease. Hepatogas-
2004;306(5702):1774–6. troenterology 2001;48:256–60.
[16] Qing L, Luoping Z, Min S, et al. Polymorphisms in cy- [32] Imai T, Itoh S, Okada H, et al. Aplastic anemia follow-
tokine and cellular adhesion molecule genes and sus- ing hepatitis associated with echovirus 3. Pediatr Int
ceptibility to hematotoxicity among workers exposed 2002;44:522–4.
to benzene. Cancer Res 2005;65:9574–81. [33] Führer M, Rampf U, Baumann I, et al. Immunosup-
[17] Maluf E, Hamerschlak N, Cavalcanti AB, et al. In- pressive therapy for aplastic anemia in children: a
cidence and risk factors of aplastic anemia in Latin more severe disease predicts better survival. Blood
American countries: the LATIN case-control study. 2005;106:2102–4.
Haematologica 2009;94(9):1220–6. [34] Young NS, Brown KE. Mechanisms of disease: parvovi-
[18] Young N, Kaufman D. The epidemiology Of acquired rus B19. N Engl J Med 2004;350:586–97.
aplastic anemia. Haematologica 2008;93:489–92. [35] Mishra B, Malhotra P, Ratho RK, et al. Human parvovi-
[19] Heimpel H. Epidemiology and aetiology of aplastic rus B19 in patients with aplastic anemia. Am J Hematol
anaemia. In: Schrezenmeier H, Bacigalupo A, editors. 2005;79:166–7.
Aplastic anaemia: pathophysiology and treatment. [36] Pagliuca S, Gérard L, Kulasekararaj A, et al. Character-
Cambridge, UK: Cambridge University Press; 2000. istics and outcomes of aplastic anemia in HIV patients:
p. 97–116. a brief report from the severe aplastic anemia work-
[20] Mahapatra M, Singh PK, Agarwal M, et al. Epidemiol- ing party of the European Society of Blood and Bone
ogy, clinico-haematological profile and management of Marrow Transplantation. Bone Marrow Transplant
aplastic anaemia: AIIMS experience. J Assoc Physicians 2016;51:313–5.
India 2015;63(3 Suppl):30–5. [37] Young NS, Alter BP, Young NS. . In: Young NS, Alter BP,
[21] Adil SN, Kakepoto GN, Khurshi M. Epidemiological editors. Aplastic anemia, acquired and inherited, drugs
features of aplastic anaemia in Pakistan. J Pak Med As- and chemicals. Philadelphia: W.B. Saunders; 1994.
soc 2001;51:443. p. 100–32.
[22] Young NS. Bone marrow failure syndromes. Philadel- [38] Chapuis B, Von Fliedner VE, Jeannet M, et al. Increased
phia: W.B. Saunders; 2000. frequency of DR2 in patients with aplastic anaemia and
[23] Hao LY, Armanios M, Strong MA, et al. Short telomeres, increased DR sharing in their parents. Br J Haematol.
even in the presence of telomerase, limit tissue renewal 1986;63:51–7.
capacity. Cell 2005;123:1121–31. [39] Nimer SD, Ireland P, Meshkinpour A, et al. An in-
[24] Brown KE, Tisdale J, Barrett AJ, et al. Hepatitis-associ- creased HLA DR2 frequency is seen in aplastic anemia
ated aplastic anemia. N Engl J Med 1997;336:1059–64. patients. Blood 1994;84:923–7.
[25] Locasciulli A, Bacigalupo A, Bruno B. Hepatitis-as- [40] Shao W, Tian D, Congyan L, et al. Aplastic anemia is
sociated aplastic anaemia: epidemiology and treat- associated with HLA-DRB1*1501 in northern Han Chi-
ment results obtained in Europe. A report of The nese. Int J Hematol 2000;71:350–2.
EBMT aplastic anaemia working party. Br J Haematol [41] Nakao S, Takamatsu H, Chuhjo T, et al. Identification
2010;6:890–5. of a specific HLA class II haplotype strongly associated

with susceptibility to cyclosporine-dependent aplastic [57] Fuhrer M, Durner J, Brunnler G, et al. HLA association
anemia. Blood 1995;84:4257–61. is different in children and adults with severe acquired
[42] Ilhan O, Beksac M, Arslan O, Koc H, et al. HLA-DR aplastic anemia. Pediatr Blood Cancer 2007;48:186–91.
frequency in Turkish aplastic anemia patients and the [58] Kook H, Hwang TJ, Seo JJ, et al. The frequency of
impact of HLA-DR2 positivity in response rate in pa- HLA alleles in Korean children with aplastic anemia
tients receiving immunosuppressive therapy. Blood and the correlation with the response to immunosup-
1995;86:2055. pressive treatment. Korean J Pediatr Haematol Oncol
[43] Rehman S, Saba N, Khalilullah, et al. The frequency 2003;10:177–88.
of HLA class I and II alleles in Pakistani patients with [59] Yoshida N, Yagasaki H, Takahashi Y, et al. Clinical im-
aplastic anemia. Immunol Investig 2009;38:251–4. pact of HLA-DR15, a minor population of paroxysmal
[44] Dhaliwal JS, Wong L, Kamaluddin MA. Susceptibility nocturnal haemoglobinuria-type cells, and an aplastic
to aplastic anemia is associated with HLA-DRB1* 1501 anaemia-associated autoantibody in children with ac-
in an aboriginalpopulation in Sabah, Malaysia. Hum quired aplastic anemia. Br J Haematol 2008;142:427–35.
Immunol 2011;72:889–92. [60] Yunis JJ, Corzo D, Salazar M, et al. HLA associa-
[45] Maciejewski JP, Follmann D, Nakamura R. Increased tions with clozapine-induced agranulocytosis. Blood
frequency of HLA-DR2 in patients with paroxysmal 1995;86:1777.
nocturnal hemoglobinuria and the PNH/aplastic ane- [61] Corzo D, Yunis JJ, Salazar M, et al. The major histo-
mia syndrome. Blood 2001;98:3513–9. compatibility complex region marked by HSP70-1 and
[46] Nakao S, Takami A, Takamatsu H. Isolation of a T-cell HSP70-2 varisnts is associated with clozapine induced
clone showing HLA-DRB1*0405-restricted cytotoxicity agranulocytosis in two different ethnic groups. Blood
for hematopoietic cells in a patient with aplastic ane- 1995;86:3835–40.
mia. Blood 1997;89:3691. [62] Tamai H, Sudo T, Kimura A, et al. Association be-
[47] Yari F, Sobhani M, Vaziri MZ, et al. Association of aplas- tween the DRB1*08032 histocompatibility antigen
tic anemia and Fanconi’s disease with HLA-DRB1 al- and methimazole-induced agranulocytosis in Japa-
leles. Int J Immunogenet 2008;35:453–6. nese patients with Graves disease. Ann Intern Med
[48] Chen C, Lu S, Luo M, et al. Correlations between HLA- 1996;124:490–4.
A, HLA-B and HLA-DRB1 allele polymorphism to ac- [63] Sugimori C, Yamazaki H, Feng X, et al. Roles of
quired aplastic anemia. Acta Haematol 2012;128:23–7. DRB1*1501 and DRB1*1502 in the pathogenesis of
[49] Odum N, Platz P, Morling N, et al. Increased frequency aplastic anemia. Exp Hematol 2007;35:13–20.
of HLA-DPw3 in severe aplastic anemia. Tissue Anti- [64] Kapustin SI, Popova TI, Lyshchov AA, et al. HLA-
gens 1987;29:184–5. DR4-Ala74 beta is associated with high risk and poor
[50] Albert E, et al. HLA antigens and haplotypes in outcome of severe aplastic anemia. Ann Haematol
200 patients with aplastic anemia. Transplantation 2001;80:66–71.
1976;22:528–31. [65] Bacigalupo A. Aetiology of severe aplastic anaemia and
[51] Dausset J, Gluckman E, et al. Excess of HLA-A2 and outcome after allogeneic bone marrow transplantation
HLA-A2 homozygotes in patients with aplastic anemia or immunosuppression. Eur J Haematol 1996;57(Sup-
Fanconi’s anemias. Nouv Rev Fr Hematol Blood Cells pl):16–9.
1977;18:315–24. [66] Bhatt AS, Berliner N. Hematologic Manifestations of
[52] Gluckman E. HLA markers in patients suffering from SLE. In: Schur P, Massarotti E, editors. Lupus erythe-
aplastic anaemia. Haematologia 1981;14:165–72. matosus: clinical evaluation and treatment. New York:
[53] D’Amaro J, et al. HLA associations in Italian and non- Springer; 2012. p. 127–40.
Italian Caucasoid aplastic anemia patients. Tissue Anti- [67] Alishiri GH, Saburi A, Bayat N, et al. The initial pre-
gens 1983;21:184–91. sentation of systemic lupus erythematosis with aplastic
[54] Shichishima T, Noji H, Ikeda K, et al. The frequency of anemia successfully treated with rituximab. Clin Rheu-
HLA class I alleles in Japanese patients with bone mar- matol 2012;31(2):381.
row failure. Haematologica 2006;91:857. [68] Chalayer É, Ffrench M, Cathébras P. Aplastic anemia as
[55] Oguz FS, Yalman N, Diler S, et al. HLA-DR15 and a feature of systemic lupus erythematosus: a case report
pediatric aplastic anemia patients. Haematologica and literature review. Rheumatol Int 2015;35(6):1073–
2002;87:772–4. 82.
[56] Song EY, Park S, Lee DS, et al. Association of human [69] Kozak N, Friedman J, Schattner A. Etanercept-asso-
leukocyte antigen-DRB1 alleles with disease suscep- ciated transient bone marrow aplasia: a review of
tibility and severity of aplastic anemia in Korean pa- the literature and pathogenetic mechanisms. Drugs
tients. Hum Immunol 2008;69:354–9. 2014;14(2):155–8.

REFERENCES 11
[70] De Masson. Severe aplastic anemia associated with eo- [73] Tichelli A, Socié G, Marsh J, et al. Outcome of preg-
sinophilic fasciitis: report of 4 cases and review of the nancy and disease course among women with aplastic
literature. Medicine (Baltimore) 2013;2:69–81. anemia treated with immunosuppression. Ann Intern
[71] Stalder MP, Rovó A, Halter J, et al. Aplastic anemia Med 2002;137(3):164.
and concomitant autoimmune disease. Ann Hematol [74] Choudhry VP, Gupta S, Gupta M, et al. Pregnancy asso-
2009;88:659–65. ciated aplastic anemia—a series of 10 cases with review
[72] Cesaro S, Marsh JC, Tridelli G, et al. Retrospective of the literature. Haematology 2002;7:233–8.
survey on the prevalence and outcome of prior au- [75] Shah C, Lemke S, Singh V, et al. Case reports of aplas-
toimmune diseases in patients with aplastic anemia tic anemia after vaccine administration. Am J Hematol
reported to the registry of the European group for 2004;77(2):204.
blood and marrow transplantation. Acta Haematol
2010;124:19–22.

C H A P T E R
2
Pathophysiology of Acquired Bone
Marrow Failure
K. Hosokawa*, P. Scheinberg**, N.S. Young*
*National Institutes of Health, National Heart, Lung, and Blood Institute, Bethesda,
MD, United States; **Oncology Center, Hospital São José National Institutes of
Health, National Heart, Lung, and Blood Institute, Bethesda, MD, United States
INTRODUCTION: EVIDENCE AND therapy (IST) alone is strong evidence of an im-

INFERENCES FROM THE CLINIC mune mechanism in most patients with AA: 60–
70% respond to one course of horse hATG/cyclo-
Acquired aplastic anemia (AA) is the proto- sporine (CsA) and an additional 30% of primary
typical bone marrow (BM) failure syndrome. nonresponders will respond to a second course
AA is characterized by pancytopenia of pe- of IST. Similarly, patients’ blood counts often are
ripheral blood and BM hypoplasia. Low blood dependent on continued administration of CsA,
counts and “empty” marrow pathology implies as would be expected of a T-cell driven disease.
the absence of stem and progenitor cells, which Eltrombopag, a thrombopoietin (TPO) mimetic,
is consistent with, the success of BM transplan- has activity in refractory SAA as single agent
tation (BMT), in which replacement of hemato- and in increasing the response rate and com-
poietic stem cells (HSCs) (and immune cells) is pleteness of the response when combined with
adequate to cure disease. There is little evidence IST as first therapy. These results suggest that
that AA is mediated by BM stromal cells. If stem there are residual HSCs that can repopulate BM,
cell absence were the only defect, twin donor or even if they are not detectable. Recent genomic
syngeneic transplants should be successful with data applying whole exome sequencing in AA
infusion of BM, but a large proportion suffer show that hematopoiesis can be sustained from
graft failure; that conditioning eliminates graft a single or very few HSC clones. Clonal hemato-
failure suggests an immune pathophysiology poiesis has also been inferred from the frequent
[1]. Immunosuppressive regimens were devel- and unique association of paroxysmal nocturnal
oped in the context of graft failure and now are hemoglobinuria (PNH), the origin of which is a
widely employed when stem- cell transplant is somatic mutation in an X-linked gene, with ac-
not feasible. The efficacy of immunosuppressive quired AA.

http://dx.doi.org/10.1016/B978-0-12-804152-9.00002-6
13 Copyright © 2017 Elsevier Inc. All rights reserved.
14 2. Pathophysiology of Acquired Bone Marrow Failure
In vitro experiments with patients’ cells are fected patients at presentation. There are few or
consistent with clinical observations in support- no CD34+ cells on flow cytometry [8].
ing an immune mechanism of AA. The presence Recent HSC fate-mapping analyses in mice
of PNH or acquired copy number-neutral loss of have suggested that progenitors and not HSCs
heterozygosity of the 6p arms (6pLOH) clones are fundamental for hematopoiesis under ho-
support clonal escape from immune-mediated meostatic conditions [11,12]. Physiological
BM destruction. Immune-mediated destruction studies to experimentally test this hypothesis
of BM can be modeled in animals and animal ex- are not possible in normal human subjects.
periments employing myelotoxic drugs or with However, certain disease states may indicate
myeloablative transplants show that very limit- the consequences of HSC loss on progenitors
ed numbers of HSCs can support hematopoiesis and the role of HSCs in human blood produc-
for very prolonged time periods. tion under nontransplant conditions. Using a
Clonal evolution, the development of myelo- flow cytometric gating scheme to define MPPs
dysplastic syndrome (MDS) and acute myeloid (CD34+CD38–Thy1–CD45RA–CD49f–), CMPs
leukemia (AML) in a patient with typical AA, of- (CD34+CD38+CD10–FLT3+CD45RA–), and MEPs
ten after successful IST, demonstrates genomic (CD34+CD38+CD10–FLT3- CD45RA–), the pro-
instability in the setting of immune or inflamma- genitor hierarchy was examined in a few cases
tory disease environment (and occurs in other of AA [13]. Consistent with previous reports,
immune diseases, such as inflammatory bowel the proportion of CD34+ cells within the over-
disease and chronic hepatitis). Short telomeres all mononuclear cell pool was much lower
appear to predispose to genomic instability, in AA compared with normal BM [6,9]. The
with tissue culture and animal model experi- CD34+CD38– stem-cell compartment in AA was
ments providing a mechanism of chromosome more significantly depleted compared with the
derangement. In some cases of clonal evolution, CD34+CD38+ progenitor compartment. HSCs
there is evidence of origin from a tiny clone of and MPPs were virtually undetectable in the
cells harboring a recurrent mutation in an MDS/ residual CD34+CD38– compartment, confirming
AML candidate gene. that HSCs are lost in AA, as determined by phe-
notype. Despite the loss of phenotypic HSCs,
the CD34+CD38+ compartment was detectable
in all cases. The percentage of myeloid progeni-
PATHOPHYSIOLOGY tors was equivalent compared with normal BM.
In contrast, erythroid progenitors were low, like
Hematopoiesis in AA HSCs, in all patients. These results suggest that
AA is a BM failure syndrome characterized ongoing erythropoiesis is more reliant on HSC
by pancytopenia of the peripheral blood and input compared with myelopoiesis. Consistent
BM hypoplasia [2–4]. Profound reduction in he- with these findings, clinical data suggested that
matopoietic stem and progenitor cells (HSPCs) the baseline absolute reticulocyte count (ARC)
is a consistent finding [5–9]. Stem cells/early and absolute lymphocyte count (ALC) together
progenitor cells can be assayed by long-term serve as a simple predictor of response to IST
culture-initiating cell assays (LTC-ICs) [7,9], or and greater rate of 5-year survival [14].
cobblestone area-forming cells [10], these cells In AA, BM is not truly empty but replaced by
are also markedly deficient in AA. The scant fat cells [15]. BM adipocytes were reported to
numbers of LTC-ICs per mononuclear cell sug- be possible negative regulators in the hemato-
gest that only a small percentage of residual poietic microenvironment [16]. To examine the
early hematopoietic cells remain in severely af- role of adipocytes in BM failure, recent study

Pathophysiology 15
investigated peroxisomal proliferator-activated of the AA patients, in a limited number of genes
receptor gamma (PPARγ), a key transcription and at low initial variant allele frequency [26].
factor in adipogenesis, utilizing an antagonist of Clonal hematopoiesis was detected in 47% of the
this factor [17]. While PPARγ antagonists inhib- AA, most frequently as acquired mutations. The
ited adipogenesis as expected, it also suppressed prevalence of the mutations increased with age.
T-cell infiltration of BM, reduced plasma in- DNMT3A-mutated and ASXL1-mutated clones
flammatory cytokines, decreased expression of tended to increase in size over time; the size of
multiple inflammasome genes, and ameliorated BCOR- and BCORL1-mutated and PIGA-mutat-
marrow failure. These results suggested that ed clones decreased or remained stable. How-
PPARγ antagonists acted as negative regulators ever, clonal dynamics were highly variable and
of T cells in addition to their inhibition of BM did not determine the response to therapy and
adipogenesis. long-term survival among individual patients.
AA is strongly associated with PNH [18]. These results were consistent with those of re-
PNH is a rare acquired disorder of HSCs, char- cent studies in which candidate-gene targeted
acterized by hemolytic anemia, BM failure, and sequencing also showed recurrent mutations in
venous thrombosis. The etiology of PNH is a a similar spectrum of genes [28,29]. Two hun-
somatic mutation in the X-linked phosphati- dred and nineteen genes were screened in 39 pa-
dylinositol glycan class A gene (PIG-A), result- tients, and found somatic mutations in 9 (23%),
ing in global deficiency of glycosyl phosphati- comprising ASXL1, DNMT3A, and BCOR. The
dylinositol–anchored proteins (GPI–APs) [19]. median allele burden was <10% in 7 patients
Clinically, AA may coexist or appear to evolve [28]. In 2 of 38 patients (SLIT1, and SETBP1 with
to other hematologic diseases that are character- ASXL1) using a smaller panel of 42 genes, 3 mu-
ized by proliferation of distinctive cell clones, as tations were found. However, the patient with
in PNH or MDS [2]. Nearly half of AA patients SETBP1 and ASXL1 was tested at time of pro-
have clonal populations of cells lacking GPI–APs gression to MDS.
because of somatic mutations in the PIG-A gene; These results show parallels between BM
these are called PNH clones [20,21]. Most clones failure and normal aging of the hematopoietic
are small and do not lead to clinical manifesta- compartment. The characteristic mutation sig-
tions of hemolysis or thrombosis [22], but classic nature and correlation of mutations with patient
PNH can be dominated by marrow failure (the age suggested age-related, spontaneous conver-
“AA/PNH syndrome”). PIG-A mutant cells can sion of methylated cytosine to thymidine at CpG
support hematopoiesis for long term, despite sites as major source of nucleotide alternations
accumulation of somatic mutations associated in AA [30]. Similar C-to-T conversion muta-
with clonal evolution to MDS/AML [23–25]. tions accumulate in hematopoietic progenitors
Recent studies have demonstrated clonal he- in healthy persons [31–33]. Mutations generally
matopoiesis in the majority of AA [26,27]. To appeared at a low variant allele frequency and
clarify the origin, importance, and dynamics involved common mutational targets in my-
over time of clonal hematopoiesis in AA, and its eloid cancers, which suggests that the origin and
relationship to the development of MDS, AML, clonal selections of these mutations are similar
or both, targeted deep-sequencing, SNP array to those in AA.
karyotyping, and whole-exome sequencing, However, the exact mechanism of selection
were performed to identify genetic alterations in of mutated cells in AA is unclear. DNMT3A is
AA and described their dynamics over long clin- essential for hematopoietic stem-cell differen-
ical courses [26]. Somatic mutations in myeloid tiation [34]. DNMT3A loss predisposes murine
cancer candidate genes were present in one-third HSCs to malignant transformation [35]. Deletion

of ASXL1 results in myelodysplasia in vivo BM [44–50]; CD8+ CTLs are expanded

[36,37]. Cells containing DNMT3A or ASXL1 in AA, leading to the production of
mutations may preferentially self-renew rather proinflammatory cytokines (e.g., IFN-γ) that
than differentiate in response to extrinsic sig- induces apoptosis of CD34+ cells [47,50].
nals. In contrast, striking overrepresentation of 2. Oligoclonal skewing of the T-cell repertoire
BCOR and BCORL1 and PIGA mutations as well indicating expansion of pathogenic CD8+
as frequent 6pUPD involving the specific HLA T cells [51–53]. In general, patients at
classes suggest a mechanism of protection of presentation demonstrate oligoclonal
mutated cells from immune-mediated destruc- expansions of a few Vβ subfamilies, which
tion by pathogenic T cells [38,39]. diminish or disappear with successful
IST; original clones reemerge with relapse,
sometimes accompanied by new clones,
Immune Mechanisms in AA consistent with spreading of the immune
Clinical Data response. Very occasionally, a large clone
An immune mechanism was inferred de- persists in remission, perhaps evidence of
cades ago from the recovery of hematopoiesis T-cell tolerance.
in patients who failed to engraft after stem-cell 3. A reduction of regulatory T cells (Treg) and
transplantation, when renewal of autologous an increase in Th17 related T cells resulting
blood-cell production was credited to the con- in a high Th17/Treg ratio at diagnosis which
ditioning regimen. Also, the majority of synge- tends to normalize in responding patients
neic transplantations in which BM was infused to IST [54,55]; reduction in Treg numbers
without conditioning failed due to rejection im- correlates with disease severity, and the
plying a disease immune mechanism [40]. The defect is most prominent in severe and very
responsiveness of AA to IST in most patients severe AA [56].
is the best evidence of an underlying immune 4. Increased transcription of Th1-related genes
pathophysiology: the majority of patients show in activated T cells of AA patients [57,58];
hematologic improvement after only transient recent study in BM failure mouse models
T-cell depletion by ATGs; relapse also usually identified NOTCH signaling as a primary
responds to ATG; and dependence of adequate driver of Th1-mediated pathogenesis in
blood counts on administration of very low dos- AA and may represent a novel target for
es of CsA is not infrequent [2]. therapeutic intervention.
5. Confirmation in murine models on the role
T Cells and Cytokines of Th1 and Th17 cells and related cytokines
In early laboratory experiments, removal of to producing destruction of marrow
lymphocytes from aplastic BMs improved colony progenitor cells and the positive effects of
numbers in tissue culture, and their addition to Th17 blocking antibodies and infusion of
normal marrow inhibited hematopoiesis in vitro regulatory T cells in reversing BM failure in
[41]. Immunity to HSCs by activated T cells has these models [55,59–63].
been considered to be responsible for the patho- The impact of T-cell attack on BM can be mod-
genesis of AA [42,43]. Laboratory in vitro data eled in vitro and in vivo. IFN-γ (and tumor necro-
has further reinforced the immune pathogenesis sis factor-α) in increasing doses reduce numbers
in AA with the principal findings including: of human hematopoietic progenitors assayed in
1. An increased cytokine (IFN-γ) of activated vitro; the cytokines efficiently induce apoptosis
T cells identified both in the blood and in CD34+ target cells, at least partially through

Pathophysiology 17
the Fas-dependent pathway of cell death [43,64]. Immune Escape Clones (PNH, 6pLOH)
In long-term culture of human BM, in which Certain clones may escape the immune attack
stromal cells were engineered to constitutively within the BM environment and proliferate and
express IFN-γ, the output of long-term-culture- attain a survival advantage over normal HSCs.
initiating cells (LTCI-ICs) was markedly dimin- The global absence of a large number of cell-sur-
ished, despite low concentrations of the cytokine face proteins in PNH has been hypothesized to
in the media, consistent with local amplification allow escape and survival of a preexisting mutant
of toxicity in the marrow milieu [49]. clone. Association of present PNH clone with a
Measurements of soluble circulating mediat- predictor of responsiveness to IST suggests that
ing factors in BM failure were limited largely to the escape is from immune attack [20,80–83].
one or two cytokines in AA [65–68]. High TPO Small PNH clones present at diagnosis usually
levels have been observed in patients with AA, remain stable over time, but may expand suffi-
and these abnormal levels correlate with disease ciently to produce symptomatic hemolysis [84].
severity [66,68]. Comprehensive analysis of 31 Comparison by microarray shows that residual
cytokines by an immuno-bead-based multiplex cells of normal phenotype in the PNH BM upreg-
assay (Luminex) identified that high levels of ulate the same apoptosis and cell-death genes as
TPO and granulocyte colony-stimulating fac- do CD34+ cells in aplastic marrow, while the PIG-
tor, with low levels of CD40 ligand, CXCL5, A mutant clone appears transcriptionally similar
CCL5, CXCL11, epidermal growth factor, vascu- to CD34+ cells from healthy donors [85]. Alter-
lar endothelial growth factor, and CCL11 were natively, NK cell mediated cytotoxicity may play
a signature profile for AA [69]. An increase in a role; immunoglobulin-like receptors (KIR) may
IL-17-producing Th17 cells in the peripheral be differentially expressed in PNH compared to
blood and BM of patients with AA has also been normal, resulting in cytotoxicity of normal HSCs
reported [55,70,71]. Recent study showed that [86]. Recent work has suggested expansion of au-
TPO and IL-17 levels are useful for differentiat- toreactive, CD1d-restricted, GPI-specific T cells
ing hypocellular refractory cytopenia of child- in PNH [38]. These data suggested important
hood (RCC) from pediatric AA [72]. roles for cell-extrinsic factors in clonal expansion
of PNH cells.
HLA and Cytokine Gene Polymorphisms
It was recently reported that AA patients po
There have been a number of studies on the ssessing clonal/oligoclonal hematopoiesis who
human leukocyte antigens (HLA) and their as- had specifically lost either HLA haplotype con-
sociation with AA. HLA-DR2 is overrepresent- taining the HLA-B*40:02, HLA-A*31:01, HLA-
ed among patients [73], suggesting a role for A*02:01, and HLA-A*02:06 [87]. Approximately
antigen recognition, and its presence is predic- 10% of AA have acquired copy number neutral
tive of a better response to CsA [74]. Further re- loss of heterozygosity (CN-LOH) in chromo-
search showed HLA-DRB1*1501 was associated some arm 6p (6pLOH), postulated to emerge by
with a good response to IST in Japanese cohorts immune selection against specific HLA alleles
[75,76]. [87–89]. This clonal hematopoiesis may repre-
Polymorphisms in cytokine genes, associated sent a signature of an escape from cytotoxic T-
with an increased immune response, also may cells autoimmunity targeting autoantigens and
be more prevalent: a nucleotide polymorphism strengthen the hypothesis of the immune-me-
in the TNF-α (TNF2) promoter at −308 [77], ho- diated pathogenesis of AA, although the exact
mozygosity for a variable number of dinucleo- mechanism is still unclear. Recent report showed
tide repeats in the gene encoding IFN-γ [78], and the PNH patient that had acquired CN-6pLOH
polymorphisms in the CTLA4 [79]. in GPI–AP+ granulocytes, but not in GPI–AP−

granulocytes, supporting the hypothesis that a matory bowel disease. Recent work described
hostile immune environment drives selection previously unknown potential regulatory roles
of resistant hematopoietic cell clones [90]. Re- of the miR-145-5p and miR-126-3p in T-cell ac-
cent study reported successful isolation of HLA- tivation in AA, in which MYC and PIK3R2 are
B*40:02-restricted CTLs specific for HSCs that the respective targets of these miRNA [99]. Dys-
were present in AA patient peripheral blood or regulated miR-145-5p and miR-126-3p promote
BM [91]. T-cell proliferation and increase GZMB and IFN-
γ production. Targeting or employing miRNA
STAT3 Mutant Clones mimics might be novel molecular therapeutic
Large granular lymphocyte leukemia (LGL) approaches in AA.
is often associated with immune cytopenias and
can occur in BM failure, such as AA and MDS Autoantibodies
[92,93]. STAT3 mutations in LGL clonal expan- Autoantibodies are frequently detected in
sions are detected [94,95]. STAT3 clones can be patients with AA [100–103]. Antimoesin [100],
not only in known LGL concomitant cases, but diazepam-binding inhibitor-related protein 1
in a small population of other BM failure cases [101], kinectin [102], postmeiotic segregation in-
(7% AA and 2.5% MDS) [72]. In STAT3-mutat- creased 1 [102], and HNRNPK antibodies [103]
ed AA patients, trend toward better responses were reported to be expressed in AA. Recent
of IST and an association with the presence of study using SEREX identified autoantibodies
HLA-DR 15 were found. STAT3-mutant clones that are expressed in AA accompanied by im-
may facilitate a persistently dysregulated auto- mune abnormality [104]. Eight candidates were
immune activation, responsible for the primary identified: CLIC1, SLIRP, HSPB11, NHP2L1,
induction of BM failure in a subset of AA and SLC50A1, RPL41, RPS27, and SNRPF.
MDS.
Immune-Mediated BM Failure
Innate Immunity Mouse Models
Transcriptional analysis of T cells from AA Mouse models of AA, produced by the de-
has implicated some components of innate im- struction of BM cells using radiation, cytotoxic
munity in AA, including toll-like receptors and drugs, and immune cells, have been useful in
natural killer cells [96]. defining the hematopoietic stem cell and illus-
There are some experimental results that sup- trating the potency of small numbers of lympho-
port the natural killer cells involvement in AA cytes in specifically inducing apoptosis of BM
[97,98]. KIR and KIR ligand (KIR-L) genotype targets and their cytokines (e.g., IFN-γ-) as nega-
study showed that AA and PNH showed de- tive effector molecules [105–108]. Murine mod-
creased frequency of KIR-2DS1 and KIR-2DS5 els mimicking AA have used exposure to agents
genes [98]. The reduced frequency of these KIRs that result in marrow destruction through a
in AA and PNH may indicate an immunogenetic direct toxic effect, but models that explore anti-
relationship between these diseases. genic disparities between strains have resulted
in immune-mediated destruction of the marrow,
microRNAs more closely modeling human AA [109]. Infu-
There is emerging evidence that microRNA sion of parental lymph node cells into F1 hybrid
(miRNA) play crucial roles in controlling and donors caused pancytopenia, profound mar-
modulating immunity. Dysregulation of miRNA row aplasia, and death [63]. Not only a murine
can lead to autoimmune diseases, such as rheu- version of ATG and CsA but also monoclonal
matoid arthritis, multiple sclerosis, and inflam- antibodies to IFN-γ and tumor necrosis factor

Pathophysiology 19
abrogated hematologic disease, rescuing ani- and continued until days 91 and 112 posttreat-
mals. A powerful “innocent bystander” effect, ment [113].
in which activated cytotoxic T cells kill geneti-
cally identical targets, was present in second-
ary transplantation experiments [62]. In a minor Genetic Risk Factors in AA
histocompatibility antigen-discordant model, Telomeres are DNA sequences with a struc-
marrow destruction resulted from activity of an ture that protects chromosomes from erosion and
expanded H60 antigen-specific T-cell clone [61]. that a specific enzyme, telomerase, is involved
Treatment with the CsA abolished H60-specific in their repair after mitosis [114,115]. Telomeres
T-cell expansion and rescued animals from fatal are repeated nucleotide sequences that cap the
pancytopenia. The development of BM failure ends of chromosomes and protect them from
was associated with a significant increase in ac- damage. Acquired and congenital AA have been
tivated CD4+CD25+ T cells that did not express linked molecularly and pathophysiologically
intracellular FoxP3, whereas inclusion of normal by abnormal telomere maintenance [116,117].
CD4+CD25+ regulatory T cells in combination Telomeres are eroded with cell division, but in
with C57BL/6 LN cells aborted H60-specific T- HSCs, maintenance of their length is mediated
cell expansion and prevented BM destruction. by telomerase. Accelerated telomere shorten-
Trafficking of T cells to the marrow has also been ing is virtually universal in dyskeratosis con-
shown to be important in AA pathogenesis in genita, caused by mutations in genes encoding
murine models [110]. components of telomerase or telomere-binding
protein (TERT, TERC, DKC1, NOP10, or TINF2)
Mouse Models of Chemical and Drug [118–122]. Short telomeres were found in leuko-
Hematopoietic Toxicity cytes from approximately one-third of patients
In a few instances, mouse models have been with AA, especially those who do not have a re-
utilized to examine chemical and drug toxicity sponse to IST [123,124]. Systematic screening of
for hematopoiesis. Industrial exposure to ben- patients with apparently AA showed a few pa-
zene has numerous deleterious hematologic tients with TERT or TERC mutations [125,126].
effects in human workers. When benzene was Mutation of SBDS underlie Shwachman–
subcutaneously injected into CD1 mouse, they Diamond syndrome (SDS), inherited syndrome
showed lethargy, irritability, and weight loss, featuring BM failure [127]. Heterozygosis for
with decreased hemoglobin, erythrocytes, leu- 258 + 2 T > C SBDS gene was associated with
kocytes, and BM cells indicative of BM failure AA (4 of 91 AA) and telomere shortening of
[111]. leukocytes [128]. These mutations cause low
Chronic, delayed hematotoxicity of the che- telomerase activity, accelerated telomere short-
motherapy drug busulfan was recapitulated in ening, and diminished proliferative capacity of
a mouse model: following a course of therapy, hematopoietic progenitors. Sex hormones in-
animals maintained normal blood and BM cell crease telomerase activity by upregulating the
counts for 1 year before developing pancytope- TERT gene [129]. Blood count improvement can
nia and frank marrow aplasia, with significant be obtained with androgen therapy in patients
decline in splenic colony-forming units (CFU) with mutation in telomere repair complex genes
[112]. BALB/c mice were treated 8 times with [130]. For more information about telomeres,
busulfan over 23 days and found reductions please refer Chapter 15.
in nucleated marrow cells, granulocyte-macro- Germ-line GATA2 gene mutations, lead-
phage (CFU-GM), CFU-erythroid, erythrocytes, ing to haploinsufficiency, have been identi-
leukocytes, platelets, and reticulocytes on day 1 fied in patients with familial MDS/AML [131],

monocytopenia and mycobacterial infections dyskeratosis congenita (DC), and Diamond–

[132,133], Emberger syndrome [134], and den- Blackfan anemia (DBA) are sequenced by this
dritic cell, monocyte, B-, and NK-cell deficien- method [144].
cy [135,136]. GATA2 mutations have also been
identified in a subset of patients presenting with
chronic neutropenia [137], and young adults Clonal Evolution in AA
with AA [138,139], highlighting the clinical With improved survival, the late develop-
heterogeneity and variable hematologic phe- ment of MDS, AML, or both has been noted in
notypes associated with a single genetic defect. about 15% of AA patients and termed “clonal
The BM from patients with GATA2 deficiency evolution” [145]. AA patients with clonal cy-
is typically hypocellular, with varying degrees togenetic patterns are heterogenous; unlike in
of dysplasia. The marrow had severely reduced primary MDS, aberrancies of chromosome 5
monocytes, B cells, and NK cells; absent hema- and 20 were infrequent [146]. The clinical course
togones; and inverted CD4:CD8 ratios. Atypi- depended on the specific abnormal cytogenetic
cal megakaryocytes and abnormal cytogenetics pattern. Most deaths related to leukemic trans-
were more common in GATA2 marrows. Routine formation occur in patients with abnormalities
BM flow cytometry, morphology, and cytogenet- of chromosome 7 or complex cytogenetic altera-
ics in patients who present with cytopenias can tions or both [146]. In contrast, +8 and del13q,
identify patients for whom GATA2 sequencing may appear in AA that is responsive to IST and
is indicated [139]. If GATA2 mutations are iden- associated with good prognosis [146–149]. In AA
tified, it is important to screen family members patients with PNH clone, cytogenetic abnormal-
who may be potential donors, as BM transplan- ities usually occur in hematopoietic cells that are
tation is the only definitive therapy for GATA2 normal phenotype (GPI–AP positive), suggest-
deficiency [140,141]. ing these cells have different origin [25,148].
Familial AA is an extremely rare inherited Telomere dynamics play a role in the devel-
subtype affecting multiple individuals in a fam- opment of myeloid cancers in patients with AA
ily. Patients typically only have features of AA; not associated with a telomeropathy. In adult
the absence of any somatic features making it patients with severe AA undergoing IST (with-
distinct from other inherited AA. By exome se- out a known genetic telomeropathy), pretreat-
quencing, the causative homozygous MPL mu- ment telomere length in the bottom quartile for
tation in a family with familial AA is reported age was a significant risk factor for evolution to
[142]. Biallelic constitutional mutations in MPL MDS [150]. Patients with the shortest telomeres
have been described in congenital amegakaryo- had more uncapped telomere-free chromosome
cytic thrombocytopenia (CAMT) [143]. MPL ends as compared to the patients with the lon-
mutations can be found in children with famil- gest telomeres [151]. Analysis of patients, with-
ial AA in whom CAMT was not diagnosed or out telomeropathies and with normal telomere
suspected. Additional studies will be needed to length at the time of diagnosis, who developed
further clarify the relationship between CAMT, to monosomy 7 found these patients had dra-
AA, and MPL. matically accelerated telomere attrition before
For screening, genomic panels of large num- developing MDS [152]. Rapid telomere loss
bers of genes are now available and routinely led to an accumulation of individual chromo-
used in the clinic to molecularly characterize somes bearing extremely short telomeres prior
patients with suspected inherited bone marrow to the development of monosomy 7 as detected
failure syndromes (IBMFS); multiple genes from by STELA. Dependence on a limited stem-cell
pathways involved in, Fanconi anemia (FA), pool to support hematopoiesis would require

Another random document with
no related content on Scribd:
struggled to keep his footing. Between them the girl uncomplainingly
picked her way upward.
And then they came to a place, as Stephen had hoped, where it was
necessary to scale a sheer scarp of six or seven feet in order to gain
a shelf near the summit. He had to kneel in order to help the girl up.
Turpan, not tall enough to pull himself up with his arms, cursed as his
boots slipped.
"Extend the barrel of your rifle to me," Stephen said, "and I will pull
you up until you are able to reach that overhanging bush. It will
support your weight."
Turpan nodded curtly. He was not happy about this. He was never
happy when playing a minor role, but he appreciated the urgency of
the moment.
Stephen pulled and the Bedchamber Assassin strained upward. Then
he grasped at the bush, and at the same moment Stephen gave a
sharp, Herculean tug.
Turpan snatched for the bush with both hands. "Got it," he said, and
swung himself upon the ledge.
"Yes," agreed Stephen, "but I have the rifle."
Turpan, fettered like a common criminal, lay upon his couch in the
tent where he had sat not long ago, a conqueror. The powerful
floodlight that shone in his face did nothing to sooth his raw temper.
Someone entered the tent and he strained in his bonds to see who it
was. Stephen came and stood over him.
Turpan licked his dry lips. "What time is it?" he asked.
"It is almost midnight. They have destroyed your rifle, but it has been
decided that, in view of your predatory nature, it would be dangerous
to release you again upon this colony. Are you prepared to meet your
fate?"
Turpan sneered. "Destroy me, fool—eunuch! It will not change your
lot here. You will remain an untouchable—an odd man out. May your
books comfort your cold bed for the rest of your life. I prefer death."
Stephen removed the hypodermic needle from the kit which they had
furnished him and filled it. He bared Turpan's arm. The muscles of
that arm were tense, like cords of steel. Turpan was lying. He was
frightened of death.
Stephen smiled a little. He looked a good deal younger when he
smiled. "Please relax," he said. "I am only a biological technician; not
an executioner."
Two hours later Stephen emerged from the tent, perspiring, and
found that the revel in the encampment continued unabated even at
this time of morning. Few suspected what had been going on in
Turpan's tent. These few now anxiously awaited his verdict.
"How did it go?" the former Planner of Flight One asked. "Was—the
equipment satisfactory? The drugs and chalones sufficient?"
He nodded wearily. "The character change appears to have been
complete enough. The passivity will grow, of course." A group of men
and women were playing a variety of hide-and-seek, with piercing
shouts and screams, among the shadows of the tents, and it was no
child's game.
"Don't worry about them," the Planner said. "They'll be over it in the
morning. Most of them have never had anything to drink before. Our
dictator's methods may have been cruder than we intended, but
they've certainly broken the ice."
"When will we see—Turpan?" someone asked. It was Ellen.
Stephen had not known that she was waiting. "Any moment now, I
believe," he said. "I will go in and see what is keeping him."
He returned in a few seconds. "A matter of clothing," he said with a
smile. "I warned you that there would be a complete character
change."
The garments were supplied. Stephen took them in. The floodlight
had been turned off now, and it was fairly dark in the tent.
"Hurry up," Stephen said gently.
"I can't—I cannot do it!"
"Oh, but you can. You can start all over now. Few of the colonists
ever knew you by sight. I am sure that you will be warmly enough
received."
Stephen came out. Ellen searched his face. "It will not be much
longer now," he told her.
"And to think that I doubted you!"
"I am only a technician," he said.
"There are one hundred and sixty-two male high scientists upon this
island," she said, coming forward and putting her arms around him,
"but only one, solid, unimaginative, blessed technician. It makes a
nice, even arrangement for us women, don't you think?"
"Even enough," he said. And at that moment Turpan stepped out of
the tent, and all of them looked. And looked. And Turpan, unable to
face that battery of eyes, ran.
Ran lightly and gracefully through the tent village toward the cliffs
beyond. And all along that gauntlet there were catcalls and wolf
whistles.
"Don't worry," the Planner said. "She will come back to us. After all,
there is a biological need."
*** END OF THE PROJECT GUTENBERG EBOOK EVEN
STEPHEN ***
Updated editions will replace the previous one—the old editions will
be renamed.
Creating the works from print editions not protected by U.S.

copyright law means that no one owns a United States copyright in
these works, so the Foundation (and you!) can copy and distribute it
in the United States without permission and without paying copyright
royalties. Special rules, set forth in the General Terms of Use part of
this license, apply to copying and distributing Project Gutenberg™
electronic works to protect the PROJECT GUTENBERG™ concept
and trademark. Project Gutenberg is a registered trademark, and
may not be used if you charge for an eBook, except by following the
terms of the trademark license, including paying royalties for use of
the Project Gutenberg trademark. If you do not charge anything for
copies of this eBook, complying with the trademark license is very
easy. You may use this eBook for nearly any purpose such as
creation of derivative works, reports, performances and research.
Project Gutenberg eBooks may be modified and printed and given
away—you may do practically ANYTHING in the United States with
eBooks not protected by U.S. copyright law. Redistribution is subject
to the trademark license, especially commercial redistribution.
START: FULL LICENSE

THE FULL PROJECT GUTENBERG LICENSE
PLEASE READ THIS BEFORE YOU DISTRIBUTE OR USE THIS WORK
To protect the Project Gutenberg™ mission of promoting the free

distribution of electronic works, by using or distributing this work (or
any other work associated in any way with the phrase “Project
Gutenberg”), you agree to comply with all the terms of the Full
Project Gutenberg™ License available with this file or online at
www.gutenberg.org/license.
Section 1. General Terms of Use and

Redistributing Project Gutenberg™
electronic works
1.A. By reading or using any part of this Project Gutenberg™
electronic work, you indicate that you have read, understand, agree
to and accept all the terms of this license and intellectual property
(trademark/copyright) agreement. If you do not agree to abide by all
the terms of this agreement, you must cease using and return or
destroy all copies of Project Gutenberg™ electronic works in your
possession. If you paid a fee for obtaining a copy of or access to a
Project Gutenberg™ electronic work and you do not agree to be
bound by the terms of this agreement, you may obtain a refund from
the person or entity to whom you paid the fee as set forth in
paragraph 1.E.8.
1.B. “Project Gutenberg” is a registered trademark. It may only be

used on or associated in any way with an electronic work by people
who agree to be bound by the terms of this agreement. There are a
few things that you can do with most Project Gutenberg™ electronic
works even without complying with the full terms of this agreement.
See paragraph 1.C below. There are a lot of things you can do with
Project Gutenberg™ electronic works if you follow the terms of this
agreement and help preserve free future access to Project
Gutenberg™ electronic works. See paragraph 1.E below.
1.C. The Project Gutenberg Literary Archive Foundation (“the
Foundation” or PGLAF), owns a compilation copyright in the
collection of Project Gutenberg™ electronic works. Nearly all the
individual works in the collection are in the public domain in the
United States. If an individual work is unprotected by copyright law in
the United States and you are located in the United States, we do
not claim a right to prevent you from copying, distributing,
performing, displaying or creating derivative works based on the
work as long as all references to Project Gutenberg are removed. Of
course, we hope that you will support the Project Gutenberg™
mission of promoting free access to electronic works by freely
sharing Project Gutenberg™ works in compliance with the terms of
this agreement for keeping the Project Gutenberg™ name
associated with the work. You can easily comply with the terms of
this agreement by keeping this work in the same format with its
attached full Project Gutenberg™ License when you share it without
charge with others.
1.D. The copyright laws of the place where you are located also
govern what you can do with this work. Copyright laws in most
countries are in a constant state of change. If you are outside the
United States, check the laws of your country in addition to the terms
of this agreement before downloading, copying, displaying,
performing, distributing or creating derivative works based on this
work or any other Project Gutenberg™ work. The Foundation makes
no representations concerning the copyright status of any work in
any country other than the United States.
1.E. Unless you have removed all references to Project Gutenberg:
1.E.1. The following sentence, with active links to, or other

immediate access to, the full Project Gutenberg™ License must
appear prominently whenever any copy of a Project Gutenberg™
work (any work on which the phrase “Project Gutenberg” appears, or
with which the phrase “Project Gutenberg” is associated) is
accessed, displayed, performed, viewed, copied or distributed:
This eBook is for the use of anyone anywhere in the United
States and most other parts of the world at no cost and with
almost no restrictions whatsoever. You may copy it, give it away
or re-use it under the terms of the Project Gutenberg License
included with this eBook or online at www.gutenberg.org. If you
are not located in the United States, you will have to check the
laws of the country where you are located before using this
eBook.
1.E.2. If an individual Project Gutenberg™ electronic work is derived

from texts not protected by U.S. copyright law (does not contain a
notice indicating that it is posted with permission of the copyright
holder), the work can be copied and distributed to anyone in the
United States without paying any fees or charges. If you are
redistributing or providing access to a work with the phrase “Project
Gutenberg” associated with or appearing on the work, you must
comply either with the requirements of paragraphs 1.E.1 through
1.E.7 or obtain permission for the use of the work and the Project
Gutenberg™ trademark as set forth in paragraphs 1.E.8 or 1.E.9.
1.E.3. If an individual Project Gutenberg™ electronic work is posted

with the permission of the copyright holder, your use and distribution
must comply with both paragraphs 1.E.1 through 1.E.7 and any
additional terms imposed by the copyright holder. Additional terms
will be linked to the Project Gutenberg™ License for all works posted
with the permission of the copyright holder found at the beginning of
this work.
1.E.4. Do not unlink or detach or remove the full Project

Gutenberg™ License terms from this work, or any files containing a
part of this work or any other work associated with Project
Gutenberg™.
1.E.5. Do not copy, display, perform, distribute or redistribute this

electronic work, or any part of this electronic work, without
prominently displaying the sentence set forth in paragraph 1.E.1 with
active links or immediate access to the full terms of the Project
Gutenberg™ License.
1.E.6. You may convert to and distribute this work in any binary,
compressed, marked up, nonproprietary or proprietary form,
including any word processing or hypertext form. However, if you
provide access to or distribute copies of a Project Gutenberg™ work
in a format other than “Plain Vanilla ASCII” or other format used in
the official version posted on the official Project Gutenberg™ website
(www.gutenberg.org), you must, at no additional cost, fee or expense
to the user, provide a copy, a means of exporting a copy, or a means
of obtaining a copy upon request, of the work in its original “Plain
Vanilla ASCII” or other form. Any alternate format must include the
full Project Gutenberg™ License as specified in paragraph 1.E.1.
1.E.7. Do not charge a fee for access to, viewing, displaying,

performing, copying or distributing any Project Gutenberg™ works
unless you comply with paragraph 1.E.8 or 1.E.9.
1.E.8. You may charge a reasonable fee for copies of or providing

access to or distributing Project Gutenberg™ electronic works
provided that:
• You pay a royalty fee of 20% of the gross profits you derive from
the use of Project Gutenberg™ works calculated using the
method you already use to calculate your applicable taxes. The
fee is owed to the owner of the Project Gutenberg™ trademark,
but he has agreed to donate royalties under this paragraph to
the Project Gutenberg Literary Archive Foundation. Royalty
payments must be paid within 60 days following each date on
which you prepare (or are legally required to prepare) your
periodic tax returns. Royalty payments should be clearly marked
as such and sent to the Project Gutenberg Literary Archive
Foundation at the address specified in Section 4, “Information
about donations to the Project Gutenberg Literary Archive
Foundation.”
• You provide a full refund of any money paid by a user who

notifies you in writing (or by e-mail) within 30 days of receipt that
s/he does not agree to the terms of the full Project Gutenberg™
License. You must require such a user to return or destroy all
copies of the works possessed in a physical medium and
discontinue all use of and all access to other copies of Project
Gutenberg™ works.
• You provide, in accordance with paragraph 1.F.3, a full refund of

any money paid for a work or a replacement copy, if a defect in
the electronic work is discovered and reported to you within 90
days of receipt of the work.
• You comply with all other terms of this agreement for free
distribution of Project Gutenberg™ works.
1.E.9. If you wish to charge a fee or distribute a Project Gutenberg™

electronic work or group of works on different terms than are set
forth in this agreement, you must obtain permission in writing from
the Project Gutenberg Literary Archive Foundation, the manager of
the Project Gutenberg™ trademark. Contact the Foundation as set
forth in Section 3 below.
1.F.
1.F.1. Project Gutenberg volunteers and employees expend

considerable effort to identify, do copyright research on, transcribe
and proofread works not protected by U.S. copyright law in creating
the Project Gutenberg™ collection. Despite these efforts, Project
Gutenberg™ electronic works, and the medium on which they may
be stored, may contain “Defects,” such as, but not limited to,
incomplete, inaccurate or corrupt data, transcription errors, a
copyright or other intellectual property infringement, a defective or
damaged disk or other medium, a computer virus, or computer
codes that damage or cannot be read by your equipment.
1.F.2. LIMITED WARRANTY, DISCLAIMER OF DAMAGES - Except

for the “Right of Replacement or Refund” described in paragraph
1.F.3, the Project Gutenberg Literary Archive Foundation, the owner
of the Project Gutenberg™ trademark, and any other party
distributing a Project Gutenberg™ electronic work under this
agreement, disclaim all liability to you for damages, costs and
expenses, including legal fees. YOU AGREE THAT YOU HAVE NO
REMEDIES FOR NEGLIGENCE, STRICT LIABILITY, BREACH OF
WARRANTY OR BREACH OF CONTRACT EXCEPT THOSE
PROVIDED IN PARAGRAPH 1.F.3. YOU AGREE THAT THE
FOUNDATION, THE TRADEMARK OWNER, AND ANY
DISTRIBUTOR UNDER THIS AGREEMENT WILL NOT BE LIABLE
TO YOU FOR ACTUAL, DIRECT, INDIRECT, CONSEQUENTIAL,
PUNITIVE OR INCIDENTAL DAMAGES EVEN IF YOU GIVE
NOTICE OF THE POSSIBILITY OF SUCH DAMAGE.
1.F.3. LIMITED RIGHT OF REPLACEMENT OR REFUND - If you

discover a defect in this electronic work within 90 days of receiving it,
you can receive a refund of the money (if any) you paid for it by
sending a written explanation to the person you received the work
from. If you received the work on a physical medium, you must
return the medium with your written explanation. The person or entity
that provided you with the defective work may elect to provide a
replacement copy in lieu of a refund. If you received the work
electronically, the person or entity providing it to you may choose to
give you a second opportunity to receive the work electronically in
lieu of a refund. If the second copy is also defective, you may
demand a refund in writing without further opportunities to fix the
problem.
1.F.4. Except for the limited right of replacement or refund set forth in
paragraph 1.F.3, this work is provided to you ‘AS-IS’, WITH NO
OTHER WARRANTIES OF ANY KIND, EXPRESS OR IMPLIED,
INCLUDING BUT NOT LIMITED TO WARRANTIES OF
MERCHANTABILITY OR FITNESS FOR ANY PURPOSE.
1.F.5. Some states do not allow disclaimers of certain implied

warranties or the exclusion or limitation of certain types of damages.
If any disclaimer or limitation set forth in this agreement violates the
law of the state applicable to this agreement, the agreement shall be
interpreted to make the maximum disclaimer or limitation permitted
by the applicable state law. The invalidity or unenforceability of any
provision of this agreement shall not void the remaining provisions.
1.F.6. INDEMNITY - You agree to indemnify and hold the
Foundation, the trademark owner, any agent or employee of the
Foundation, anyone providing copies of Project Gutenberg™
electronic works in accordance with this agreement, and any
volunteers associated with the production, promotion and distribution
of Project Gutenberg™ electronic works, harmless from all liability,
costs and expenses, including legal fees, that arise directly or
indirectly from any of the following which you do or cause to occur:
(a) distribution of this or any Project Gutenberg™ work, (b)
alteration, modification, or additions or deletions to any Project
Gutenberg™ work, and (c) any Defect you cause.
Section 2. Information about the Mission of

Project Gutenberg™
Project Gutenberg™ is synonymous with the free distribution of
electronic works in formats readable by the widest variety of
computers including obsolete, old, middle-aged and new computers.
It exists because of the efforts of hundreds of volunteers and
donations from people in all walks of life.
Volunteers and financial support to provide volunteers with the

assistance they need are critical to reaching Project Gutenberg™’s
goals and ensuring that the Project Gutenberg™ collection will
remain freely available for generations to come. In 2001, the Project
Gutenberg Literary Archive Foundation was created to provide a
secure and permanent future for Project Gutenberg™ and future
generations. To learn more about the Project Gutenberg Literary
Archive Foundation and how your efforts and donations can help,
see Sections 3 and 4 and the Foundation information page at
www.gutenberg.org.
Section 3. Information about the Project

Gutenberg Literary Archive Foundation
The Project Gutenberg Literary Archive Foundation is a non-profit
501(c)(3) educational corporation organized under the laws of the
state of Mississippi and granted tax exempt status by the Internal
Revenue Service. The Foundation’s EIN or federal tax identification
number is 64-6221541. Contributions to the Project Gutenberg
Literary Archive Foundation are tax deductible to the full extent
permitted by U.S. federal laws and your state’s laws.
The Foundation’s business office is located at 809 North 1500 West,

Salt Lake City, UT 84116, (801) 596-1887. Email contact links and up
to date contact information can be found at the Foundation’s website
and official page at www.gutenberg.org/contact
Section 4. Information about Donations to

the Project Gutenberg Literary Archive
Foundation
Project Gutenberg™ depends upon and cannot survive without
widespread public support and donations to carry out its mission of
increasing the number of public domain and licensed works that can
be freely distributed in machine-readable form accessible by the
widest array of equipment including outdated equipment. Many small
donations ($1 to $5,000) are particularly important to maintaining tax
exempt status with the IRS.
The Foundation is committed to complying with the laws regulating

charities and charitable donations in all 50 states of the United
States. Compliance requirements are not uniform and it takes a
considerable effort, much paperwork and many fees to meet and
keep up with these requirements. We do not solicit donations in
locations where we have not received written confirmation of
compliance. To SEND DONATIONS or determine the status of
compliance for any particular state visit www.gutenberg.org/donate.
While we cannot and do not solicit contributions from states where

we have not met the solicitation requirements, we know of no
prohibition against accepting unsolicited donations from donors in
such states who approach us with offers to donate.
International donations are gratefully accepted, but we cannot make

any statements concerning tax treatment of donations received from
outside the United States. U.S. laws alone swamp our small staff.
Please check the Project Gutenberg web pages for current donation
methods and addresses. Donations are accepted in a number of
other ways including checks, online payments and credit card
donations. To donate, please visit: www.gutenberg.org/donate.
Section 5. General Information About Project

Gutenberg™ electronic works
Professor Michael S. Hart was the originator of the Project
Gutenberg™ concept of a library of electronic works that could be
freely shared with anyone. For forty years, he produced and
distributed Project Gutenberg™ eBooks with only a loose network of
volunteer support.
Project Gutenberg™ eBooks are often created from several printed

editions, all of which are confirmed as not protected by copyright in
the U.S. unless a copyright notice is included. Thus, we do not
necessarily keep eBooks in compliance with any particular paper
edition.
Most people start at our website which has the main PG search
facility: www.gutenberg.org.
This website includes information about Project Gutenberg™,

including how to make donations to the Project Gutenberg Literary
Archive Foundation, how to help produce our new eBooks, and how
to subscribe to our email newsletter to hear about new eBooks.

(PDF Download) Congenital and Acquired Bone Marrow Failure Mahmoud Aljurf Fulll Chapter

Uploaded by

Copyright:

Available Formats

(PDF Download) Congenital and Acquired Bone Marrow Failure Mahmoud Aljurf Fulll Chapter

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

(PDF Download) Congenital and Acquired Bone Marrow Failure Mahmoud Aljurf Fulll Chapter

Uploaded by

Copyright:

Available Formats

Download and Read online, DOWNLOAD EBOOK, [PDF EBOOK EPUB ], Ebooks

download, Read Ebook EPUB/KINDE, Download Book Format PDF

Congenital and Acquired Bone Marrow Failure

Atlas of Bone Marrow Pathology 1st Edition Tracy I.

The European Blood and Marrow Transplantation Textbook

Tumors and cancers : endocrine glands - blood - marrow

Acquired Brain Injury An Integrative Neuro

Diagnosis and Management of Adult Congenital Heart

Dynamics of Lattice Materials Mahmoud I. Hussein

Fetal and Hybrid Procedures in Congenital Heart

Invertebrate Embryology and Reproduction 1st Edition

Copyright © 2017 Elsevier Inc. All rights reserved.

Library of Congress Cataloging-in-Publication Data

British Library Cataloguing-in-Publication Data

For information on all Academic Press publications

Publisher: Mica Haley

Typeset by Thomson Digital

S. Samarasinghe Department of Haematology, N.S. Young National Institutes of Health, National

INTRODUCTION studies to gather data on the epidemiology of

Congenital and Acquired Bone Marrow Failure

INCIDENCE OF AA IN DIFFERENT South Asia, in this study were found to have an

TABLE 1.2 Summary of AA and Incidence of Specific HLA Genes or Alleles

HLA-DRB1*1501 HLA-A2 HLA-DRB1*13 HLA-DRB*09 Haplotype: -B38, HLA-DR2

AA AND AUTOIMMUNE among AA patients. Stalder et al. in a single cen-

AA POSTVACCINATION Ready availability of nucleotide variants

INTRODUCTION: EVIDENCE AND therapy (IST) alone is strong evidence of an im-

Congenital and Acquired Bone Marrow Failure

of ASXL1 results in myelodysplasia in vivo BM [44–50]; CD8+ CTLs are expanded

monocytopenia and mycobacterial infections dyskeratosis congenita (DC), and Diamond–

Creating the works from print editions not protected by U.S.

START: FULL LICENSE

To protect the Project Gutenberg™ mission of promoting the free

Section 1. General Terms of Use and

1.B. “Project Gutenberg” is a registered trademark. It may only be

1.E. Unless you have removed all references to Project Gutenberg:

1.E.1. The following sentence, with active links to, or other

1.E.2. If an individual Project Gutenberg™ electronic work is derived

1.E.3. If an individual Project Gutenberg™ electronic work is posted

1.E.4. Do not unlink or detach or remove the full Project

1.E.5. Do not copy, display, perform, distribute or redistribute this

1.E.7. Do not charge a fee for access to, viewing, displaying,

1.E.8. You may charge a reasonable fee for copies of or providing

• You provide a full refund of any money paid by a user who

• You provide, in accordance with paragraph 1.F.3, a full refund of

1.E.9. If you wish to charge a fee or distribute a Project Gutenberg™

1.F.1. Project Gutenberg volunteers and employees expend

1.F.2. LIMITED WARRANTY, DISCLAIMER OF DAMAGES - Except

1.F.3. LIMITED RIGHT OF REPLACEMENT OR REFUND - If you

1.F.5. Some states do not allow disclaimers of certain implied

Section 2. Information about the Mission of

Volunteers and financial support to provide volunteers with the

Section 3. Information about the Project

The Foundation’s business office is located at 809 North 1500 West,

Section 4. Information about Donations to

The Foundation is committed to complying with the laws regulating

While we cannot and do not solicit contributions from states where

International donations are gratefully accepted, but we cannot make

Section 5. General Information About Project

Project Gutenberg™ eBooks are often created from several printed

TABLE 1.2 Summary of AA and Incidence of Specific HLA Genes or Alleles

HLA-DRB11501 HLA-A2 HLA-DRB113 HLA-DRB*09 Haplotype: -B38, HLA-DR2