Immune Hematology Diagnosis and

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Immune
Hematology
Diagnosis and Management of
Autoimmune Cytopenias

Jenny M. Despotovic
Editor

123
Immune Hematology
Jenny M. Despotovic
Editor

Immune Hematology
Diagnosis and Management of Autoimmune
Cytopenias
Editor
Jenny M. Despotovic
Baylor College of Medicine
Texas Children's Hospital
Houston, TX
USA

ISBN 978-3-319-73268-8    ISBN 978-3-319-73269-5 (eBook)

https://doi.org/10.1007/978-3-319-73269-5

Library of Congress Control Number: 2018939554

© Springer International Publishing AG, part of Springer Nature 2018

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Preface

The autoimmune cytopenias are a fascinating and clinically challenging group of

disorders characterized by the development of autoantibodies against self-antigens
on the surface of hematopoietic cells. The pathophysiology of these disorders is
complex and incompletely understood but is generally related to loss of self-­
tolerance due to immune dysregulation. These disorders can be primary or second-
ary to underlying systemic autoimmunity or immune deficiency. The diagnosis of
these disorders can be challenging and varies significantly according to disease and
underlying pathology. While antibody testing is a cornerstone of diagnosis in some
autoimmune cytopenias, it offers low sensitivity and specificity for others.
This book offers an extensive overview of immune thrombocytopenia (ITP),
autoimmune hemolytic anemia (AIHA), Evans syndrome, thrombotic thrombocyto-
penic purpura (TTP), and autoimmune neutropenia (AIN). Each section contains
chapters covering historical background, pathophysiology, differential diagnosis,
diagnostic workup, and management, offering a much more in-depth review of
these disorders than is available in most hematology or immunology textbooks.
Readers will find many useful figures, tables, and diagnostic algorithms to comple-
ment the text.
The first part covers ITP, a condition in which autoantibodies are generated
against platelet antigens resulting in peripheral destruction of circulating platelets
and often profound thrombocytopenia. The trigger of the development of platelet
antibodies is often not identified but is typically thought to result from an environ-
mental stimulus such as infection. The pathophysiology of this disorder is complex
and involves the generation of antiplatelet antibodies, T-cell imbalance with a shift
in the T-cell profile favoring decreased self-tolerance, and abnormal production of
platelets. There are a variety of treatments available for both acute control of bleed-
ing symptoms and long-term management and each will be comprehensively
reviewed in Part I.
Part II covers AIHA and Evans syndrome. Autoimmune hemolytic anemia is a
rare but potentially life-threatening disorder resulting from antibodies against
endogenous erythrocytes and often severe hemolytic anemia. The complications of
hemolytic anemia can be devastating and this part highlights the importance of early

v
vi Preface

diagnosis and prompt treatment of the various forms of AIHA. As each type of
AIHA has a different pathophysiology, each requires a different management strat-
egy. Evans syndrome is historically defined as the combination of AIHA and ITP
but currently encompasses any two (or more) autoimmune cytopenias occurring
simultaneously or separately. The antibodies which cause the cytopenias are not
cross-reacting but discrete antibodies, and therefore highlight a more generalized
immune dysregulation which typically becomes a chronic disease with a number of
important complications often requiring immunomodulatory therapy.
Thrombotic thrombocytopenic purpura (TTP) is the focus of Part III. This is a
fascinating autoimmune cytopenia caused by autoantibodies against a disintegrin
and metalloproteinase with a thrombospondin type 1 motif, member 13
(ADAMTS13), resulting in microangiopathic hemolytic anemia and often severe
thrombocytopenia due to consumptive coagulopathy. Prior to the use of plasma
exchange, this disorder was almost universally fatal. Experts in this field provide
the latest information available on the pathophysiology and treatment of TTP in
this part.
Finally, Part IV covers autoimmune neutropenia (AIN), a common cause of
severe neutropenia in childhood with a typically benign clinical course. Given the
extensive differential diagnosis of severe neutropenia, the authors of this part pro-
vide critical information on the typical presentation and biology driving AIN, as
well as approach to workup and treatment, if needed.
Within this book, readers are offered an in-depth and comprehensive review of
the autoimmune cytopenias. Any hematologist, immunologist, general practitioner,
or trainee wanting better understanding of these entities from a historical and patho-
logical perspective, or requiring relevant and up-to-date information regarding diag-
nosis and management of the immune hematologic disorders, will benefit from
these expert contents.

Houston, TX Jenny M. Despotovic

Contents

Part I Immune Thrombocytopenia (ITP)

1 Background of Immune Thrombocytopenia ����������������������������������������    3
Kristina M. Haley
2 Pathophysiology of Immune Thrombocytopenia����������������������������������   17
Taylor Olmsted Kim
3 Presentation and Evaluation of Immune Thrombocytopenia��������������   35
Vicky R. Breakey
4 The Treatment of Immune Thrombocytopenia������������������������������������   45
Kandace L. Gollomp and Michele P. Lambert

Part II Autoimmune Hemolytic Anemia (AIHA)

5 Background, Presentation and Pathophysiology
of Autoimmune Hemolytic Anemia��������������������������������������������������������   83
Shawki Qasim
6 Treatment of Autoimmune Hemolytic Anemia ������������������������������������ 103
Omar Niss and Russell E. Ware
7 Evans Syndrome: Background, Clinical Presentation,
Pathophysiology, and Management�������������������������������������������������������� 125
Amanda B. Grimes

Part III Thrombotic Thrombocytopenic Purpura (TTP)

8 Background and Presentation of Thrombotic Thrombocytopenic
Purpura���������������������������������������������������������������������������������������������������� 153
Clay Cohen
9 Pathophysiology of Thrombotic Thrombocytopenic Purpura������������ 171
Sarah E. Sartain

vii
viii Contents

10 Evaluation and Treatment of Thrombotic

Thrombocytopenic Purpura�������������������������������������������������������������������� 189
Satheesh Chonat

Part IV Autoimmune Neutropenia (AIN)

11 Background and Pathophysiology of Autoimmune Neutropenia�������� 207
Jacquelyn M. Powers
12 Evaluation and Management of Autoimmune Neutropenia���������������� 213
Alicia K. Chang
Index������������������������������������������������������������������������������������������������������������������ 223
Contributors

Vicky R. Breakey, MD, MEd, FRCPC (Peds) Department of Pediatrics,

McMaster University, Hamilton, ON, Canada
Alicia K. Chang, MD Section of Hematology-Oncology, Department of Pediatrics,
Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA
Satheesh Chonat, MD Pediatric Hematology, Department of Pediatrics, Emory
University School of Medicine and Aflac Cancer and Blood Disorders Center,
Children’s Healthcare of Atlanta, Atlanta, GA, USA
Clay Cohen, MD Department of Pediatric Hematology and Oncology, Baylor
College of Medicine, Houston, TX, USA
Kandace L. Gollomp, MD Division of Hematology, The Children’s Hospital of
Philadelphia, Philadelphia, PA, USA
Amanda B. Grimes, MD Baylor College of Medicine, Texas Children’s Hospital,
Houston, TX, USA
Kristina M. Haley, DO, MCR Pediatric Hematology/Oncology, Department of
Pediatrics, Oregon Health and Science University, Portland, OR, USA
Michele P. Lambert, MD Division of Hematology, The Children’s Hospital of
Philadelphia, Philadelphia, PA, USA
Omar Niss, MD Division of Hematology, Department of Pediatrics, Cincinnati
Children’s Hospital Medical Center and University of Cincinnati College of
Medicine, Cincinnati, OH, USA
Taylor Olmsted Kim, MD Section of Hematology/Oncology, Department of
Pediatrics, Texas Children’s Cancer and Hematology Centers, Baylor College of
Medicine, Houston, TX, USA
Jacquelyn M. Powers, MD, MS Pediatric Hematology/Oncology, Baylor College
of Medicine, Texas Children’s Cancer and Hematology Center, Houston, TX, USA

ix
x Contributors

Shawki Qasim, MD Baylor College of Medicine, Texas Children’s Hospital,

Houston, TX, USA
Sarah E. Sartain, MD Baylor College of Medicine, Texas Children’s Hospital,
Houston, TX, USA
Russell E. Ware, MD, PhD Division of Hematology, Department of Pediatrics,
Cincinnati Children’s Hospital Medical Center and University of Cincinnati College
of Medicine, Cincinnati, OH, USA
 Part I
Immune Thrombocytopenia (ITP)
Chapter 1
Background of Immune
Thrombocytopenia

Kristina M. Haley

Introduction

Immune thrombocytopenia (ITP, formerly idiopathic thrombocytopenic purpura) is

an acquired disease characterized by immune-mediated destruction of normal plate-
lets and suppression of platelet production that is associated with variable bleeding
symptoms [1]. Primary ITP is characterized by isolated thrombocytopenia in the
absence of any clear underlying cause or initiating factor [2]. Secondary ITP is
defined as ITP that is associated with an underlying cause or precipitating factor [3].
The variable disease definitions and the heterogeneity of symptoms suggest that the
actual incidence is not clear [1]. However, a 2009 study of published ITP literature
estimated the incidence of ITP in adults to be 3.3 per 100,000 adults/year, while the
incidence of ITP in children was estimated to be 1.9–6.4 per 100,000 children/year
[4]. There is a female preponderance in young adults, but in older adults, ITP affects
males and females equally [1]. In pediatric patients, ITP affects males more often in
the younger years and females more often in the older years [5].
Patients with ITP present with isolated thrombocytopenia (though anemia sec-
ondary to blood loss may be present) and variable bleeding symptoms which range
from asymptomatic to severe, life-threatening bleeding. The diagnosis of ITP is one
of exclusion [6]. The natural history in the majority of pediatric patients with ITP is
spontaneous resolution, and treatment is aimed at ameliorating symptoms while
awaiting spontaneous resolution. The majority of adult patients receive some
upfront treatment, but majority of many will not require ongoing therapy. The likeli-
hood of remission decreases as the duration of ITP increases [1].
The underlying etiology of ITP is immune dysregulation resulting in a combination
of increased platelet destruction and impaired platelet production [5, 7]. Antiplatelet

K. M. Haley, DO, MCR

Pediatric Hematology/Oncology, Department of Pediatrics, Oregon Health and Science
University, Portland, OR, USA
e-mail: haley@ohsu.edu

© Springer International Publishing AG, part of Springer Nature 2018 3

J. M. Despotovic (ed.), Immune Hematology,
https://doi.org/10.1007/978-3-319-73269-5_1
4 K.M. Haley

antibodies, directed at platelet and megakaryocyte surface glycoproteins, develop sec-

ondary to a loss of tolerance of these self-antigens [5]. Antiplatelet antibodies bind to
circulating platelets and result in their phagocytosis by splenic macrophages. In addi-
tion, antiplatelet antibodies bind to megakaryocytes and result in impaired mega-
karyocyte maturation and/or apoptosis [5, 7]. Dysregulation or dysfunction of T cells
likely also plays a role in impaired self-tolerance and in development of autoimmunity
[5, 8]. The understanding of the mechanisms at play in ITP is evolving and shaping the
understanding of the disease and the recommendations for treatments. The patho-
physiology of ITP will be comprehensively reviewed in Chap. 2.
In this chapter, the historical understanding of ITP, the evolution of the terminology
around ITP, and the clinical presentation including distinction between primary and
secondary ITP as well as the development of a differential diagnosis will be discussed.

Historical Perspective

Long before platelets were identified, clinical symptoms associated with thrombo-
cytopenia were noted and recorded. Early descriptions of otherwise healthy indi-
viduals with purpura likely fit our current definition of ITP and are recorded as early
as 1025 [9]. The classical clinical description of ITP was first noted by Paul Gottlieb
Werlhof in 1735, as he described a 16-year-old female with mucosal bleeding which
developed following an infection [9, 10]. The link to thrombocytopenia was not
made until years later, as platelets were not described until the 1800s, with the
advent of improved microscopy techniques [11]. The first drawing of platelets
occurred in 1841, but it was not until 1882 that the term “platelets” was used to
describe an independent blood cell line with hemostatic function [11, 12]. The first
report connecting thrombocytopenia and petechiae or purpura was published in
1883 [9]. Just a few years later, it was observed that the appearance of petechiae
correlated with thrombocytopenia and the disappearance correlated with resolution
of thrombocytopenia [9]. Despite these observations, the underlying pathophysiol-
ogy of the thrombocytopenia remained unknown.
Two theories emerged in the early twentieth century regarding the etiology of
thrombocytopenia: decreased platelet production vs. increased platelet destruction
[10, 13]. In support of impaired production, Ernest Frank posited that a toxic sub-
stance produced by the spleen resulted in impaired platelet production by mega-
karyocytes [9, 10]. And, in opposition, Paul Kaznelson proposed that there was
increased platelet destruction in the spleen [9, 10]. Though still a student, Kaznelson
convinced his mentor to perform a splenectomy on one of his patients with chronic
ITP, and the patient’s thrombocytopenia improved [9]. This debate over decreased
production vs. increased destruction continued over the next few decades. In 1942,
Troland and Lee suggested that a substance produced by the spleen, what they called
“thrombocytopen,” caused ITP. Observations by Dameshek and Miller, ­published in
1946, ultimately led to the conclusion that ITP was due to an abnormality of the
spleen which led to impaired megakaryocyte production of platelets [10, 14].
1 Background of Immune Thrombocytopenia 5

A series of experiments conducted by William Harrington and James Hollingsworth

in 1951 provided evidence in support of peripheral destruction as the etiology of
ITP. Dr. Harrington infused whole blood from a patient with known ITP into himself
and others in order to determine the effect on circulating platelets. He became severely
thrombocytopenic and developed bleeding symptoms soon after the infusion. Bone
marrow examination done before and after the infusion demonstrated increased
megakaryocytes at the time of thrombocytopenia. His platelet count recovered within
1 week. Of note, he had a generalized seizure soon after the infusion and was hospi-
talized due to his bleeding symptoms and thrombocytopenia. He performed this
experiment again on volunteers from his lab and non-ITP patients and found similar
findings in a subset of those infused. This was the first study to demonstrate the
importance of host factors in the development of ITP. He later demonstrated that the
factor resulting in thrombocytopenia was in the gamma-globulin fraction of plasma
[9, 10, 12]. While these series of experiments would never be approved in today’s
research milieu, they led to a significant improvement in our understanding of the
pathophysiology of ITP, specifically highlighting the role of decreased platelet sur-
vival secondary to a humoral factor [9]. In the same year as the Harrington and
Hollingsworth experiments, Evans and colleagues attributed the syndrome to an anti-
platelet antibody [10]. Several years later, additional work demonstrated that the anti-
platelet antibody was associated with immunoglobulin G (IgG) [9] and directed
against platelet glycoproteins [13].
Interestingly, the debate of increased destruction vs. decreased production con-
tinued even once antiplatelet antibodies were identified. Studies with radiolabeled
platelets demonstrated significant heterogeneity in platelet turnover, with many
patients producing less platelets than expected for the degree of thrombocytopenia
[15]. These experiments revitalized the idea that decreased platelet production con-
tributed to the thrombocytopenia seen in ITP. Experiments performed evaluating the
effect of antiplatelet antibodies on megakaryocytopoiesis confirmed impaired plate-
let production in ITP [16, 17]. Evaluation of megakaryocyte ultrastructure using
electron microscopy has added additional data in support of impaired platelet pro-
duction in ITP [18]. However, the absence of antiplatelet antibodies in a proportion
of patients spurred an additional hypothesis to explain the thrombocytopenia in ITP:
cytotoxic T-lymphocyte (CTL)-mediated platelet lysis. Early experiments demon-
strated increased CTL expression of cytotoxic genes as well as increased platelet
lysis by CTLs in patients with active ITP and no platelet lysis in patients with ITP
in remission [19]. Further, improved understanding of the immune system as well as
further study of chronic ITP resulted in appreciation for the importance of immune
dysregulation in the development of ITP.
6 K.M. Haley

Terminology

The abbreviation ITP has been defined in a number of ways over the years, includ-
ing idiopathic thrombocytopenic purpura, immune thrombocytopenic purpura,
and immune thrombocytopenia. In addition, other aspects of ITP, such as response
criteria or bleeding symptoms, have been variably defined. These inconsistencies
have resulted in difficulty in standardization of research, in applicability of research
results to different clinical populations, and in communications regarding ITP. An
International Working Group (IWG) was formed and convened in 2007 to address
the inconsistencies and develop standardization in terminology.
In 2009, the culmination of the collaborative efforts of the International Working
Group (IWG) was published and provided a reference for terminology [3]. The
2011 American Society of Hematology (ASH) guidelines on ITP call for the utiliza-
tion of the IWG standard terminology as well as refinement of the terminology in
areas of continued debate [20].
The IWG proposed that the acronym ITP stands for immune thrombocytopenia
[3]. The term “idiopathic” was removed from the definition, while the term
“immune” was kept in order to highlight the known pathophysiologic mechanisms.
Purpura was removed due to the variability of this clinical finding. Immune throm-
bocytopenia is defined as isolated thrombocytopenia in the absence of any underly-
ing cause [2]. The threshold for diagnosis was set at a platelet count of 100 × 109/L
[3, 19, 20]. The IWG also proposed that secondary immune thrombocytopenia be
broadly defined as all immune-mediated thrombocytopenia that is not primary ITP

Table 1.1 Examples of conditions associated with secondary ITP

Autoimmune and immune Evans syndrome
dysregulation disorders Autoimmune lymphoproliferative syndrome (ALPS)
Systemic lupus erythematosus (SLE)
Antiphospholipid antibody syndrome (APS)
Autoimmune thyroid disease
Combined variable immunodeficiency (CVID)
Malignant Chronic lymphocytic leukemia (CLL)
lymphoproliferative Large granular T-lymphocytic leukemia
disorders Hodgkin lymphoma
Infections Helicobacter pylori
Human immunodeficiency virus (HIV)
Hepatitis C
Cytomegalovirus (CMV)
Varicella zoster virus (VZV)
Drug effects Strong evidence for quinine, quinidine, trimethoprim/
sulfamethoxazole, vancomycin, penicillin, rifampin, carbamazepine,
ceftriaxone, ibuprofen, mirtazapine, oxaliplatin, suramin,
glycoprotein IIb/IIIa inhibitors (abciximab, tirofiban, eptifibatide),
heparin
Others Vaccine side effect (MMR)
Post bone marrow or solid organ transplantation
1 Background of Immune Thrombocytopenia 7

[3]. Further, the IWG recommended that secondary ITP should be designated by the
terminology “secondary ITP” followed by the associated disease or drug in paren-
theses [3]. Secondary causes of ITP include medications, viral infections such as
hepatitis C or human immunodeficiency virus, and autoimmune disorders such as
systemic lupus erythematosus or antiphospholipid antibody syndrome (Table 1.1—
causes of secondary ITP).
ITP was previously split into two groups: acute ITP and chronic ITP. Acute ITP
was described as a self-limited disease lasting less than 6 months, and persistent
thrombocytopenia beyond 6 months was termed chronic ITP. A challenge to these
definitions was that acute ITP could only truly be defined retrospectively. The IWG
proposed three phases of ITP which can be used both prospectively and retrospec-
tively: newly diagnosed (0–3 months), persistent (3–12 months), and chronic ITP
(>12 months) [3]. These distinctions have been widely implemented and are impor-
tant as they may help guide therapy or prognostication. For example, there is still a
significant chance of remission in those with persistent ITP, which may help guide
decisions regarding aggressiveness of therapy [22]. Definitions of disease severity
are less well-defined. Historically, disease severity (mild, moderate, severe) has
been correlated solely with degree of thrombocytopenia. The IWG recommended
that the designation of severe ITP should be reserved for clinically significant bleed-
ing that necessitates intervention [3]. This definition may result in decreased inter-
vention in a patient with significant thrombocytopenia but no clinical bleeding [21].
Response criteria were a major focus of the IWG to facilitate comparison of
clinical studies and to guide therapy. While they acknowledged that clinically rele-
vant endpoints would be ideal, surrogate endpoints like platelet count are objective
and more easily compared [3]. The IWG proposed the following definitions [3]:
• Complete response (CR): any platelet count of at least 100 × 109/L
• Response (R): any platelet count between 30 and 100 × 109/L PLUS resolution
of bleeding symptoms
• No response (NR): any platelet count less than 30 × 109/L or less than doubling
of the baseline count
• Corticosteroid dependence: ongoing need for continuous corticosteroid or fre-
quent courses of corticosteroids beyond 2 months to maintain a platelet count at
or above 30 × 109/L and to avoid bleeding
Notably, patients with corticosteroid dependence are considered nonresponders.
Duration of response is measured from the achievement of CR or R to loss of CR or
R. Patients with refractory ITP are defined as those who fulfill two criteria: (1) non-
responder to splenectomy or relapse after splenectomy and (2) severe ITP or high
risk for bleeding [3]. The various types of therapy were also more clearly defined by
the IWG. On-demand therapy was defined as any therapy used to temporarily
increase the platelet count to safely perform invasive procedures or to treat major
bleeding or in the event of trauma. Adjunctive therapy includes any therapy that is
not ITP specific. For example, antifibrinolytics, hormonal therapy, and DDAVP are
considered adjunctive therapies [3].
8 K.M. Haley

The standardized terminology developed by the IWG has been incorporated into
treatment guidelines [2, 20], facilitating communications between treating provid-
ers. In addition, the establishment of clear definitions and terms for ITP has helped
to classify patients into subgroups, to design clinical trials, and to interpret and
apply results [6]. The adaptability of the IWG consensus terminology was evaluated
in a clinical population of pediatric patients in 2012 [23]. In this study, the majority
of patients with ITP could be easily classified using the new criteria. However, the
investigators noted a few limitations. Specifically, the authors found the exclusion
of secondary ITP by the IWG in the application of the standardized terminology to
result in exclusion of several patients with Evans syndrome. This population of
patients often has symptomatic ITP that is challenging to treat and would benefit
from inclusion in clinical studies as well as from comparison using standardized
terminology. Further, the authors found that the duration of response criteria was
difficult to apply retrospectively. Finally, the authors note that the IWG terminology
is limited in its definition of refractory ITP in a pediatric patient [23].

Presentation

ITP should be suspected in a patient presenting with an isolated thrombocytopenia,

an otherwise unremarkable peripheral smear, and exam findings significant for
expected bleeding for platelet count [8]. Bleeding is the most common presenting
symptom in ITP [7] and is typically mucocutaneous, resulting in petechiae, purpura,
and bruising. Examples of more significant bleeding include epistaxis, oral bleed-
ing, urinary bleeding, gastrointestinal bleeding, and/or heavy menstrual bleeding
[7]. Intracranial hemorrhage is a rare but life-threatening complication. Pediatric
patients typically have an acute onset of bleeding symptoms and are otherwise clini-
cally well. A preceding viral infection is seen in approximately two-thirds of pedi-
atric patients [25]. In contrast, ITP can be insidious in adults and more frequently
becomes a chronic disease [26].
Severe hemorrhage is rare in patients with platelet counts >30 × 109/L [5, 22]. A
recent systematic review analyzed the incidence of severe hemorrhage across sev-
eral prospective ITP studies [21]. Intracranial hemorrhage (ICH) occurred in 0.4%
of newly diagnosed pediatric patients with ITP and 0.6% of adult patients with ITP
[21]. There is a higher incidence of ICH in chronic ITP, occurring in 1.3% and 1.8%
of pediatric and adult patients, respectively [21]. Other severe bleeding occurred in
20.2% of pediatric patients and 9.6% of adult patients with ITP [21]. In the system-
atic review, no predictors of severe bleeding were identified, but association of
severe bleeding with lower platelet counts (below 10–20 × 109/L) and minor bleed-
ing was observed [21]. The heterogeneous nature of ITP and the lack of prediction
tools make application of treatment algorithms difficult.
2 Pathophysiology of Immune Thrombocytopenia 21

morphology [20]. In the 1970s, Rolovic et al. [21] used a rat model to show that
infusion of antiplatelet antibody-rich serum resulted in thrombocytopenia, but also
decreased maturation of megakaryocytes as well as the absolute number of stage III,
mature megakaryocytes [21]. After assays for specific antibodies against GPIIB/IIIa
and GPIIb/IX were created, these antibodies were discovered to target megakaryo-
cytes directly. Cultured CD34+ cells from healthy human donors with serum from
ITP patients [22]. Megakaryocyte production in culture was decreased, ranging
from 26 to 90% reduction as compared to cells cultured in control plasma [22]. As
with the prior rat studies carried out by Rolovic et al., in this model, megakaryocytes
showed impaired maturation [11, 21, 22].

Inadequate Thrombopoietin Levels

Megakaryocyte progenitor growth and maturation is impacted by multiple cyto-

kines, but most significantly by thrombopoietin (TPO). In ITP, the capacity of the
megakaryocytes to produce new platelets is inadequate for the rate of platelet
destruction [10, 23], and insufficient TPO levels may contribute to this inability to
adequately respond to the thrombocytopenia.
TPO is constitutively expressed by the liver; however, it is produced to a lesser
degree in other organs such as the bone marrow and spleen [23]. Intuitively, endog-
enous TPO levels should have a compensatory increase in the setting of thrombocy-
topenia. However, in the setting of ITP, TPO levels are not appropriately elevated.
In 1998 Nichol et al. [23] measured TPO levels in healthy controls, aplastic anemia,
and ITP patients [23]. Though the patients with aplastic anemia had appropriately
high TPO levels in the setting of severe thrombocytopenia, the ITP patient popula-
tion did not [23]. Studies in mice monitoring radiolabeled TPO showed a twofold
increase in clearance for platelet-bound TPO in ITP as opposed to mice who were
thrombocytopenic due to sublethal radiation [23]. It is theorized that in the setting
of ITP, platelets may have more thrombopoietin receptors (Mpl receptor), thereby
allowing for increased TPO binding and subsequent clearance [23]. Therefore, it
appears that in ITP, there is not inadequate production of TPO, but rather inadequate
levels due to excessive clearance by platelets prior to their destruction.

T Cell-Mediated ITP

T Cell-Propagated Autoantibody Production

The production of autoantibodies against platelet surface glycoproteins requires inter-

action with CD4+ T cells. Following exposure to GPIIb/IIIa fragments by antigen-­
presenting cells, CD4+ T cells stimulate antibody synthesis through interaction with
B cells. CD4+ cells do not react in the same way to native platelet glycoproteins. The
Another random document with
no related content on Scribd:
of temples in the sacred enclosure at Thebes (this enclosure itself
meant order and protection), and then we shall have all the
materials requisite for enabling us to understand every particular
of Homer’s statement. Jupiter goes to the Ethiopians, because he
was the chief god of Thebes. But there are temples enough for all
the gods, and so they all accompany him. Here they meet, we
see why, Oceanus. It is a great festival of many days. This is
intelligible. We see why these Ethiopians are irreproachable. In an
age of piracy and violence they enforce, with all the authority of
Religion, the order, fair dealing, and abstinence from all kinds of
violence, and ensure the security, necessary for trade; and which
had made the trade they were protecting and fostering the
greatest, at that time, in the world. Their singular
irreproachableness might be measured by their unparalleled
prosperity, and their unparalleled prosperity accounted for by their
singular irreproachableness; and both might be explained by their
profound and all-embracing piety. This made them irreproachable.
This made them prosperous. This ensured the presence of all the
gods at their twelve days’ Feast.
[5] Throughout this chapter I distinguish between the idea, and
the doctrine, of a future life. There may be some traces of the
idea in the Old Testament; though I believe that they are not so
numerous, or so distinct, as many suppose. And what there may
be of this kind is certainly counterbalanced by the general tenor of
the documents with respect to this subject, and by some distinct
statements in the opposite sense. What I affirm is, that there is no
trace of a doctrine of a future life. A doctrine on such a subject is
a categorical averment of it, unmistakably announced, and
unmistakably used as a motive for shaping the whole life. Of such
an averment, so used, I assert, and endeavour to account for, the
absence.
[6] It has been pointed out to me by a reader of the first edition
of this book, that there is a great similarity between the above
paragraph and a passage in Bishop Butler’s Analogy. But as I
have not seen that great work since my Oxford days, now thirty-
two years ago, I think I may be allowed to leave it standing with
an acknowledgment of unconscious reminiscence.
[7] Note.—After the foregoing Chapter was in type, it occurred
to me to apply the light of the fact it accounts for to some
prominent particulars of the Old Testament. Here are a few of the
results: Moses gives as a reason for our first parents having been
driven out of Paradise, that God desired to preclude the possibility
of their eating of the fruit of a certain tree, whereof if they were to
eat they would become immortal; and that He afterwards carefully
guarded the tree from them by Cherubims, and a flaming sword
that turned every way. This was to prevent their becoming
immortal. Previously, too, God had threatened that, if they
disobeyed a certain commandment, they should become
incapable of immortality (for the context shows that this was the
meaning intended); and, on their disobedience, God had passed
on them the sentence that they should return to the dust out of
which they had been made. There can be no reasonable doubt
but that in this part of the introductory history a foundation is
designedly laid for the absence of the doctrine of a future life from
the dispensation; and objections to its absence answered by
anticipation. Popular hermeneutics, however, are incapable of
explaining these particulars, notwithstanding the significant
prominency assigned them in the narrative.
Again, on the theory of the popular interpretation, we can see
no reason why Isaiah should have placed the ultimate
suppression of evil, and the complete triumph of good, on this
earth. That would be of no advantage to the generation to which
he had to address himself; and it would be an arrangement that
would give nothing to those who had borne the heat and burden
of the day, and everything to those who had done nothing. The
difficulty, however, vanishes, when we remember that he had no
doctrine of a future life, or of any other stage than this earth for
man. Everything, therefore, that was to be brought about, must be
brought about on this earth, and during this earthly life, which
were all.
Our fact also accounts for the conspicuous, and otherwise
inexplicable, want of proselytizing zeal in the old Israelites. They
quite believed that the best thing for man was the knowledge of
God; but they had no disposition to communicate this knowledge.
The reason was that the advantages of this knowledge were
temporal. Had, therefore, Jehovah been brought to give
protection, wealth, and strength to their neighbours, with whom
they were generally in a state of hostility, it would have been a
hurt to themselves. So soon as the objects of religion became
moral only, and not of this world, Israelites had abundance of zeal
for making proselytes among their neighbours.
 Doubtless other particulars will occur to the reader, which, like
those I have just noted, are explicable only by the aid of the direct
opposite to that which the popular interpretation assumes, this
direct opposite being, in fact, the most prominent and distinctive
of the peculiarities of the dispensation.
[8] Moses was learned in all the wisdom of the Egyptians.—
Acts vii. 22.
[9] In ‘Land and Water,’ of February 3rd, 1872, may be found an
interesting account of the way in which D. (Lord Ducic) stalked,
killed, and ultimately secured the sunken carcass of one of the
few stragglers that may now occasionally be seen to the north of
the cataract. It was a full-grown specimen, and, as the evidence
of its stomach proved, a child-eater. Jure occisus est. The scene
was 3° 32´ north of the cataract.
[10] M. de Lesseps has lately raised these charges 50 per
cent., having made the discovery that the chargeable tonnage of
a steamship includes the space required for engines and fuel. As
well might he, after having charged a sailing vessel for its cargo-
space, assess at so much more the scantling of its spars, and the
spread of its canvas. At all events this method of charging is not
after the fashion in which he himself originally interpreted those
terms of the concession, which fix the rate at which ships using
the Canal may be charged.
 INDEX.

Abraham, his genealogy, 29.

At the Pyramids, 83.
At Heliopolis, 119.
Bargaining with Ephron, 337
Abydos, 97-104.
Ride to, 98.
Its Palace and Temple, 100;
its Tablet, 101.
Antiquity of its civilisation, 102-104
Acacia, 411
Achmed and Hodge, 396-401
Agriculture, Egyptian, favoured early civilization, 13-15.
Syrian, 245
Alexandria, 448-457
Alkali, Egyptians used, in washing, 367
Amasis, 277
Amenemha III., his register of risings of the Nile, 5, 114.
Engineered Lake Mœris, 114
American, an, on the Pyramids, 85.
The ⸺ pig, 433
Amunoph, 124.
His Colossus, 150
Apries, or Pharaoh Hophra, 277
Arabs sleep in the open air, 99.
Truthfulness and honesty of, 176.
Superstitions, 359-364
Arch, date of the, in Egypt, 142.
Why not used, 294.
Date of the pointed, 464
Art, style of Egyptian, 36
Arts, antiquity of useful, 44
Aryan ancestors of Egyptians might have come from the Persian
Gulf, 38.
Date, 40.
Their belief in a future state, 35, 195
Ashdod, siege of, 275
Ass, the, 424
Assassef, 151
Assyrian Dynasty at Bubastis, 271.
They overrun Egypt, 272
Assouan, Governor of, 168.
Camel-riding at, 421
Astronomer Royal for Scotland on the Pyramids, 63, 65
Awe, its place in religion of Egypt, 127

Backsheesh, 45-51
Bahr Jusuf, 103, 106, 475
Bargaining, 337, 469
Basques, possible origin of, 40, 44
‘Beginning’ of 1st Ch. of Genesis, 264
Belief, travel and, 244-256
Belzoni, 138
Benihassan, 173
Bethany, girl of, 47-49
Bethlehem, women of, 50
Birds in Egypt, 436-440
Birket el Keiroon, 106, 111, 112
Bitter Lakes, 486
Bottled-up labour, Capital is, 59
Boulak Museum, wooden statue in, 72-74.
Chephren’s statue in, 74
Brotherhood, doctrine of, 318.
Overthrew Egyptianism, 320.
Its subsequent history, 322
Bubastis, 270.
Festival of, 278.
Canal of, 473, 475
Buffalo, the, 433
Builders, Orientals great, 467
Buildings, cause of disappearance of, 77.
Destruction of, in Egypt, 79.
In the Delta, 266-289.
Preservation of, in Upper Egypt, 290-298.
Why large, and constructed of large stones, 293
Bunyan’s ‘Pilgrim’s Progress,’ 190

Cairo, 458-471
Caliphs, tombs of the, 467
Camel, 417-423
Canalization of the Isthmus, 472-493
Capital, what ⸺ is, and how it acts, 59.
What it will do for the East, 394
Caste, origin of, 34.
 How used by the Egyptians, 311.
Survey of the phenomena of, 332-336
Christianity has no written law, 211, 213, 215, 217, 220, 229,
233, 318.
Why ⸺ triumphed in Egypt, 320.
Why ⸺ failed, 321.
Was a protest, 509.
What it dealt with, 516
Chronology, early, 75, 81
Church and State, 514.
Its relation to religion, 515.
Its conflicts with the State, 516.
Originally included the State, 517.
Its usurpations stopped, 519.
Who look to the, for the education of the people, 525.
Its inability to educate, 526.
Its sphere, 528.
What it should teach, 532
Civilization, early hindrances to, 13.
What it was before the date of the Pyramids, 52-56.
Anterior to Abydos, 102
Cleanliness, Oriental, 365-369
Cleopatra, 164, 286.
Needle of, 455
Climates, Egypt has the ⸺ of two zones, 15
Clothes pawned returned at sunset, 340
Colchis, Egyptian colony at, 160
Colossus of Memnon, 150
Communications easy in Egypt, 13.
In direction of latitude, 14
Conclusion, 494-540
Concrete, early thought, 259
Constantinople, 492
Contemporaneous, Egyptian documents, 94, 101
Copts at Thebes, 148
Cosmogony, Mosaic, how to be taken, 261
Crabs, their business, 145
Criticism, Biblical, 82, 257
Crocodiles, why worshipped, 109.
The last killed below the Cataract, 435
Custom, persistency of, 337.
Change of, an European characteristic, 340

Darius completes the Canal to the Red Sea, 477

‘Day’ of the 1st Ch. of Genesis, 263
Dead, Book of the, 186
Deceased, the, 103
Della, its dynasties, 266-284.
Overthrow and disappearance of its monuments, 266-289
Dendera, 286
Despotism, how nature aided, in Egypt, 18-20.
How formerly checked, 21
Dish, dipping in the, 340
Divorce, 378, 383
Doctrine differs from idea, 193
Dodecarchs, connexion of, with Labyrinth, 115
Dog, the, 428
Dôm Palm, 413
Donkey-boys, 170-176

East, can anything be done for the? 389-395

Edfou, 285
Education, the, which the State should undertake, 524
Egypt, how formed, 1-9.
Its agriculture made civilization possible, 13.
Has two climates, 15.
Its configuration and agriculture aided despotism, 12-20.
What hope for modern, 21.
Antiquity of its civilization, 26.
Its relation to Israel, 239.
Its prosperity under Amasis, 277.
What its history teaches, 536
Egyptians, how their character affected by nature, 12-20.
Hard lot of modern, 22-24.
Not mainly African, or Semitic, 27.
Mixed Aryan and Ethiopian, 32.
Their style of art, 36.
Aptitude for science and organization, 37.
Might have arrived by the Red Sea, 38.
Not Turanian, 41.
Resembled the Japanese, 42-44.
Their belief in a future life, 182-192.
Their wisdom and its fall, 299-322
England, how want of wood in Egypt affects, 408.
Advantage of the Canal to, 491
English thought practical, 120-123.
Language in Egypt, 171
Equus, why not Latin for horse, 263
Esbekeyeh, 464
Esné, 287
Established Churches, 214
Ethiopians, connexion with Egypt, 33.
Why irreproachable, 162 (note)
Etruscans, possible origin of, 40, 44
Evil eye, 360-363
Exclusiveness, national, 312.
Abrogation of, 318
Exodus, date of, 474

Faioum, 105-116.
Remoteness of its reclamation, 105.
How reclaimed, 106-112.
Why crocodiles were worshipped in, 109
Fellah, his hard case, 22
Festivals, at Bubastis, 278.
At Sais, 279
Finns, possible origin of, 40, 44
Free trade and independence, 43
French policy in Egypt, 480
Fuel, how manufactured in Egypt, 407
Future life, Egyptian belief in, 35.
Whence derived, 182.
Basis of Egyptian civilization, 184.
Why not a doctrine of the Mosaic Dispensation, 193-243.
Why necessary for Christianity, 211-220.
Why Moses could not have taught it, 221.
Logical basis of the doctrine, 238.
Buddhist doctrine of, 240.
Jewish morality unsupported by, 240, 500
Gardening in Egypt, 414-416
Genesis, 1st Ch. of, 261-265
Geese, ancient and modern, 438
Germanicus at Thebes, 164-167, 502
Girl of Bethany, 47-49.
At Thebes, 172.
At Benihassan, 173
Goats, 434
Gods, materials from which ⸺ were made, 290
Granite, why used, 267
Greece compared with Egypt, 501.
What it achieved, 539
Greeks keep pigs in the East, 431, 432

Hareem, the atmosphere of the, 387

Harrow, my young friend late from, 47, 51, 87, 91
Harvests, Egypt has two, 15
Hebrew Scriptures not primarily historical, 81-84.
Their chronology, 81.
Why ⸺ have no doctrine of a future life, 193-243.
How to be interpreted, 257.
Right of interpretation, 259
Heliopolis, 117-123.
The Holy Family at, 117.
The University of Egypt, 119.
Obelisk of, 119
Herodotus upon the formation of Egypt, 3.
Mentions a register of risings of the Nile, 5.
His account of Lake Mœris explained, 110.
Of Egyptian colony in Colchis, 160.
 What he says of Bubastis, 270.
Of the Egypt of Amasis, 277.
Of Necho’s circumnavigation, 274.
Of feasts of Bubastis and Sais, 278
Herod’s temple and palace, 246
Hippopotamus, 435
Hodge compared with Achmed, 396-401
Homer acquainted with the greatness of Thebes, 124.
Why ⸺ sends the gods to the irreproachable Ethiopians,
160-162.
Mentions the Island of Pharos, 453
Homœopathy, 364
Hophra, or Apries, 276
Horse, the, in Egypt, 426
Houriism, 381-388

Ideas make men and women, 385.

Change slowly, 519
Imagination, its relation to history and religion, 461
Immortality, how the working of society confirmed the idea of,
17.
How the river and the sun, 18.
How Christ brought it to light, 211-234.
Why mankind not immortal, 243 (note)
Insects in Egypt, 443
Instincts, moral sentiments are, 306.
What are ⸺, 308.
Egyptian study of, 310
Interpretation, historical method of, 257-265
Isaiah, why ⸺ anticipated a new earth, 243 (note)
Iseum, 280
Ismailia, 483
Israel compared with Egypt, 499.
What it achieved, 539
Israelites, who they were, 29.
Their ethnology, 199.
Not unimaginative, 204.
Their moral heroism, 241.
When ⸺ built Pithom and Ramses, 474

Jacob’s deception, 250

Japan, Egypt compared to, 42-44
Jerusalem, aspect of the city, 246.
Only a Bible word, 256.
Pilgrims at, 357.
Camels at, 419
Jesus Christ, the situation to which His teaching was addressed,
207.
What He taught, 210-220.
Argumentative position of, 216, 229.
Why He taught a future life, 229.
Why He impugned the doctrine of immediate judgments,
239.
His doctrine, in part, a protest, 509
Jews, a mixed people, 29, 199.
Moral heroism of, 241.
Why not proselytisers, 243 (note)
Jezebel’s last toilet, 338
Joseph, story of, 338
Josiah defeated by Necho, 276
Kagabu, 339
Karnak, 125-132.
Hypostyle hall of, 129
Kêf, 95
Koran, 345

Labour, why squandered on Pyramids and Temples, 57-63

Labourer, English, why held to labour all the year round, 399
Labyrinth, 114-116
Lamps, Feast of, 279
Landlordism Eg., 328-331
Language, morality compared to, 242
Laps, possible origin of, 40, 44
Law, Semitic idea of, 31.
Separation of Municipal from Religion, 212-216.
General laws the same as particular Providence, 235
Legislatures, Orientals have no, 347, 371
Letters, discovery of, 184.
Results, 185, 391
Liberty, Oriental systems extinguish, 372
Library of Rameses, 146.
Of Alexandria, 455
Light, Symbol of the Divine Spirit, 280
Literature, effects of, 390-392.
Alexandrian, 451
Livingstone, 2
London, a contemplation of, 506, 534
Luncheon at the Pyramids, 92-96
Luxor, 124
Luxury, Oriental, 383

Mad, are all Orientals, 341

Mandeville, his account of the Pyramids, 64-66
Marriages, Oriental, 338, 374.
Why early in the East, 378
Master-mind, the, 122
Medinet Haboo, 148
Memnon, 150
Mendes, 266
Metaphysical solutions of physical problems, 3
Metaphysics, Hebrew, 261.
Early, 232
Mississippi compared with the Amazon, 15
Modern societies, prospects of, 540
Mœris, Lake, 108.
Abundance of fish, 110.
Herodotus’ account of, 110
Mohamed, 66, 342
Mohamed Adamanhoury, 470
Money not known at date of the Pyramids, 58
Monogamists, early Egyptians were, 37.
Nature made us, 379
Monuments, why disappeared in the Delta, 266-289.
Why not in Upper Egypt, 285-289.
Rationale of, 290-298
Moral being is a growth, 253.
Moral sentiments instincts, 306-310.
 Aims of society must be, 536
Morality not dependent on future life, 240.
How congenital, 242.
Grounds of, 242.
Progressive, 251.
What should be taught by the State, 524.
What by the Church, 532
Moses, his wife, 168.
Aim of his legislation, 201.
First historical protestant, 509
Mosks of Omar, 246.
Of Cairo, 464.
Of Ebn e’ Tooloon, 464.
Of Hassam, 465.
Of El Azar, 466
Mosquitoes, 443
Mounds of old cities, 404
Mouské, 461
Municipal religion when impossible, 227

Nature, how ⸺ affected the Egyptians, 12-20.

What it presented to the Egyptians, 16.
Variety of, 495.
Intelligence seen in, 496
Necho, extends the Canal to the Bitter Lakes, 273.
Circumnavigates Africa, 274.
His Asiatic campaign, 275.
Extends the Canal of Rameses, 477.
Necropolis of Pyramid era, 91-95.
Of Thebes, 133-143
Nile, how the, formed Egypt, 1-9.
Three colours of its water, 9.
 Contrast of past and present value of its work, 10.
Facilities for up and down traffic, 14.
Important that it flows in the direction of latitude, 14
Norfolk Island Pine, 415

Obelisk of Heliopolis, 119.

Of Luxor, 125.
Of Alexandria, 281, 455.
Were books, 298
Omar destroys the library of Alexandria, 456.
Re-opens canal to Red Sea, 479
Orientals, are they mad? 341.
Intellectual inferiority of, accounted for, 343
Originality of the Egyptians, 153
Osiris, temple of, at Abydos, 101.
Mysteries of his sufferings, 271
Ositarsen, first name at Karnak, 130.
At Tanis, 267
Ox, the, 434

Palace of Westminster, what it suggests, 512, 514

Palm-trees, tax on, 23.
Character of, 110
Paradise, Hebrew, 205.
Mahomedan, 381
Parliament, history of the English, 513
Paul, St., what he taught, 220
Pearls, real, 121
Pelicans, 437
Persian invasion, 163
Petamenap, his tomb, 141
Pharos, 453
Philæ, Great Pyramid looks down on, 70.
Ride to, 421
Physical Geography, bearing of, on national history, 12
Pigeons in Egypt, 437
Pilgrimage, 355-358
Pilgrims, Greek and Latin, at Jerusalem, 357
Pithom, 473
Platte, resemblance of valley of, to Egypt, 4
Pointed Arch, 464
Polygamy, 374-380.
The polygamic region, 376
Population, Commerce supports, 245
Pork, why forbidden in the East, 433
Port Saïd, 482
Post-Pharaohnic temples, 285-289
Prayer, Oriental, what it is, 349.
Connexion of, with morality, 351.
Variation in its object, 352.
Repetitions in, 354.
Women not taught, 374
Printing-press, its use to the East, 392
Progress, in arts, 137.
In religion, 231.
In moral being, 253.
Historical progress, 325.
Ordained by God, 233.
Rendered possible by letters, 184, 392
Property, value of security for, 389.
Exists amongst animals, 429
Prophets, the Hebrew, have no doctrine of a future life, 194.
Anti-Egyptian policy of, 276.
Their hopefulness, 315.
Their self-devotion, 500
Protestant, the first, 509
Providence, identity of particular, and general laws, 235
Psalm, the 109th, 250
Psammetichus, 272
Ptolemy Philadelphus re-opens the canal to the Red Sea, 478
Pyramids, contemporary civilization implied by, 52-56.
Why labour was squandered on, 57-63.
Why so formed, 63-69.
Sir J. Mandeville’s account of, 64-67.
Inscriptions on the Great, 65.
Great Pyramid higher than the Cataract of Philæ, 70.
Ascent of Great Pyramid, 85-91.
Luncheon at, 92-96.
Necropolis of Pyramid era, 94-95

Railway, a mid-European, 492

Rameseum, 146
Rameses II. at Luxor and Karnak, 125.
His temple-palace, 145, 146.
His library, 146.
His great expedition, 154-163.
His inscription in Syria, 162.
Cut the Pithom-Ramses Canal, 473
Rameses III., his tomb, 135.
His temple-palace, 148
Ramses, city of, 473
Rationale of the monuments, 290-298
Register of Nile risings, 5, 114
Religion, Aryan character of that of Egypt, 27, 35.
Aim of that delivered by Moses, 201.
A municipal, when impossible, 227.
A chapter in its history, 231.
Same as truth, 237.
Its great rôle in Egypt, 299.
Why it did not spread, 302.
Its aims moral, 303.
Why it fell, 320.
Reverts in Egypt to Theocracy, 321.
An organism of thought, 341.
A distinction between Christianity and Mahomedanism, 342.
What it is, 515.
Its aims, 532
Republicans, why Orientals are not, 370-373.
Conditions disposing them to be, 370
Ritualists, where those, get their ideas, 465
Rome compared with Egypt, 502.
What it achieved, 539
Rooks, 439

Sais, its temple, 271.

Connexion with the Greeks, 271.
Festival of, 279
Sakia, 446
Sandstone-buildings long-lived, 289
Saul’s sons hanged, 250
Scarabs, 177-181
Scene, the, in England, 495.
Must be associated with man, 496.