Hemophilia

Hemophilia
The Royal Disease
Todd T. Eckdahl

Hemophilia: The Royal Disease

Copyright Momentum Press, LLC, 2017.
All rights reserved. No part of this publication may be reproduced, stored
in a retrieval system, or transmitted in any form or by any means
electronic, mechanical, photocopy, recording, or any otherexcept for
brief quotations, not to exceed 250 words, without the prior permission
of the publisher.
First published in 2017 by
Momentum Press, LLC
222 East 46th Street, New York, NY 10017
www.momentumpress.net
ISBN-13: 978-1-94474-963-7 (print)
ISBN-13: 978-1-94474-964-4 (e-book)
Momentum Press Human Diseases and Conditions Collection
DOI: 10.5643/9781944749644
Cover and interior design by S4Carlisle Publishing Services
Private Ltd., Chennai, India
First edition: 2017
10987654321
Printed in the United States of America

Abstract
Hemophilia is a genetic disease that impairs the normal process of blood
clotting and results in uncontrolled external and internal bleeding.
Injuries, surgeries, and dental procedures can result in prolonged external
bleeding in people with hemophilia. They also experience uncontrolled
bleeding of the joints, muscles, digestive system, and brain, either spontaneously or from accidents. The reader of the book will learn how a
definitive diagnosis of hemophilia is made by clinical tests of blood clotting time and measurements of clotting factor levels in blood. The book
describes how hemophilia A and B are caused by mutations in the genes
for clotting factor VIII and clotting factor IX, respectively. Both genes are
carried on X chromosome, resulting in a sex-linked recessive pattern of
inheritance. Almost all children born with hemophilia A and B are boys.
Hemophilia C is inherited in an autosomal recessive manner, is caused by
mutations in the clotting factor XI gene on chromosome 4, and occurs
in males and females with equal frequency. The book describes the use of
factor replacement therapy to treat hemophilia. It evaluates the prospects
for curing hemophilia through gene therapy and explains how genome
editing might be used in the future to correct the gene mutations underlying hemophilia.

Keywords
autosomal recessive genetic disease, bleeding disorder, clotting factors,
factor VIII deficiency, factor IX deficiency, factor XI deficiency, genetic
disease, hemophilia, hemophilia A, hemophilia B, hemophilia C, uncontrolled bleeding, X-linked genetic disease

Contents
Acknowledgments....................................................................................ix
Introduction...........................................................................................xi
Chapter 1
Chapter 2
Chapter 3
Chapter 4

Symptoms and Diagnosis...................................................1

Causes and Contributing Factors.....................................17
Treatment and Therapy....................................................37
Future Prospects...............................................................43

Conclusion............................................................................................47
Glossary................................................................................................49
Bibliography..........................................................................................53
About the Author...................................................................................55
Index....................................................................................................57

Acknowledgments
I am grateful to my friend Malcolm Campbell for encouraging me to take
a leap of faith on this project and on several others that have shaped my
career as a science educator. I value Malcolm as a teaching and research
collaborator, and I am proud of the positive impact that we have made
together on science education and the improvement of science literacy. I
am also grateful for the cheerful and professional support I received from
the publishing team at Momentum Press.
This book would not have been possible without the support of my
wife, Patty Eckdahl. She understands my passion for science and science
education and helps me to channel it in ways that benefit students and
others around me. I also appreciate the support and encouragement that
my parents, Tom and Bonnie Eckdahl, gave me in the pursuit of an education that would give me the privilege of sharing my love of DNA and
genetics with undergraduate students and everyone else I meet.
I am grateful to my undergraduate genetics professor at the University
of Minnesota, Duluth, Stephen Hedman, for helping to understand that
I could pursue my love of genetics in graduate school. Thanks to John
Anderson at Purdue University, who taught me to conduct molecular
genetics research and to value undergraduate education. I appreciate the
environment that Missouri Western State University provided me for following a path to becoming a science educator. I am grateful to my mentors in the Missouri Western Biology Department, Rich Crumley, Bill
Andresen, John Rushin, and Dave Ashley, who helped me to learn how to
engage students in the classroom and in the research lab. I appreciate the
many students that I have worked with in class and collaborated with on
research projects outside of class. I take pride in the contributions that my
former students have already made and will continue to make to society.

Introduction
The earliest known historical reference to inherited uncontrolled bleeding was written in the Talmud in the 2nd century CE. It warns that the
third male child should not be circumcised whose two older brothers
bled to death after circumcision. There is also a Biblical reference to a
woman whose uncontrolled bleeding was cured by Jesus. In the 10th
century, the Arab physician Albucasis made the first medical report of
inherited uncontrolled bleeding by describing a family in which males
died from hemorrhaging after minor injury. An article describing an inherited disposition to bleeding that primarily affects men was published
by John Conrad Otto in 1803, and a publication by John Hay in 1813
hypothesized that men could pass the uncontrolled bleeding trait on to
their unaffected daughters. Friedrich Hopff is credited with coining the
term haemorrhaphilia in 1828 to describe an inherited propensity for
hemorrhage, or uncontrolled bleeding. The term was later shortened to
hemophilia.
Public awareness of hemophilia increased in the late 19th and early
20th centuries when it affected several European royal families. A prominent member of the British royal family who suffered from hemophilia
was Prince Leopold. The prince suffered several life-threatening bleeding
episodes during his life, and died at the age of 30 in 1884 from uncontrolled bleeding of the brain after falling and hitting his head. The mother
of Prince Leopold was Queen Victoria, who did not have hemophilia but
was a hemophilia carrier. She passed on the condition of being a carrier to
two of her daughters, who married into other European royal families and
passed on hemophilia to three of their sons. Hemophilia cases occurred
in royal families from Russia, Germany, and Spain for three generations,
causing it to become widely known as the royal disease.
Bleeding disorder research accelerated in the 20th century, supported
by discoveries about the process of blood clotting. Normal blood clotting
begins when blood cells called platelets stick together to form a plug at
the site of a broken blood vessel. Blood proteins called clotting factors

xii INTRODUCTION

form a fibrous clot that holds the platelets in place and stops the bleeding.
It became clear that prolonged bleeding could be attributed to deficiencies in factors that are needed for blood to clot. The factors were identified as proteins that circulate in the blood and interact with each other
in a cascade of enzymatic reactions that results in blood coagulation, or
blood clotting. A deficiency in factor I was reported in 1920, followed by
descriptions in the 1940s through 1960s of deficiencies in factors II, V,
VII, X, XII, and XIII. The diseases that result from deficiencies of these
factors are listed in the table entitled Genetic bleeding disorders. The
diseases are rare, occurring at a frequency between 1 in 500,000 and 1
in 3,000,000 people, and they cause prolonged bleeding symptoms that
range from mild to severe. The pattern of inheritance for the diseases is
autosomal recessive, which means that two mutant copies of a gene must
be present to cause disease and that the diseases affect males and females
with equal frequency.
The most common bleeding disorder is von Willebrand disease
(vWD), which was determined in 1957 to be caused by insufficient levels of a protein named von Willebrand factor. Approximately 1 in 100
people have vWD, which is actually a family of diseases. Some people
have such mild symptoms that they are unaware that they have vWD. For
other people, bleeding episodes after trauma, surgery, or dental work can
be severe. The pattern of inheritance of vWD is autosomal, which means
that males and females are affected in equal numbers. Some types of vWD
are recessive, and two dysfunctional genes encoding vWF must be present
to cause disease. Other types of vWD are dominant, and only one version
of a mutated vWF gene must be present to cause disease. Rarely, vWD
can develop in people without a family history of uncontrolled bleeding,
and this is called acquired vWD. The sudden appearance of uncontrolled
bleeding symptoms is usually associated with dysfunction of the immune
system that results in the production of antibodies that interfere with the
normal function of von Willebrand factor in the clotting cascade.
Hemophilia A is the most common form of hemophilia, affecting
about 400,000 people globally each year. Hemophilia A is also known as
classic hemophilia and about 80 percent of people with hemophilia have
hemophilia A. Hemophilia A occurs in about 1 in 5,000 males and affects
people of all races and ethnic backgrounds. Symptoms ranging from mild

 INTRODUCTION
xiii

Genetic bleeding disorders

Bleeding
disorder

Clotting
deficiency

Severity Occurrence Inheritance

von Willebrand
disease

von
Willebrand
factor

Mild to
severe

1 in 100

Autosomal
recessive or
dominant

Hemophilia A

Factor VIII

Mild to
severe

1 in 5,000
males

X-linked
recessive

Hemophilia B

Factor IX

Mild to
severe

1 in 34,000
males

X-linked
recessive

Hemophilia C

Factor XI

Mild to
moderate

1 in 100,000

Autosomal
recessive

Stuart-Prower factor
deficiency

Factor X

Moderate
to severe

1 in 500,000

Autosomal
recessive

Fibrinogen deficiency

Factor I

Mild

1 in 1,000,000

Autosomal
recessive

Prothrombin
deficiency

Factor II
(prothrombin)

Mild

1 in 1,000,000

Autosomal
recessive

Parahemophilia

Factor V

Mild

1 in 1,000,000

Autosomal
recessive

Proconvertin
deficiency

Factor VII

Mild to
severe

1 in 1,000,000

Autosomal
recessive

Hageman factor
deficiency

Factor XII

Mild

1 in 1,000,000

Autosomal
recessive

Fibrin stabilizing
factor deficiency

Factor XIII

Severe

1 in 3,000,000

Autosomal
recessive

to severe uncontrolled bleeding are caused by deficiency of clotting factor

VIII. The predominance of hemophilia A in males is due to the fact that
the gene encoding factor VIII is on the X chromosome. Rarely, females
can also inherit hemophilia A, if they carry a defective factor VIII gene on
both X chromosomes.
Hemophilia B was first described in 1952 as a disease caused by deficiency of clotting factor IX. It also became known as Christmas disease
after Stephen Christmas, the original patient. Hemophilia B affects about
1 in 34,000 males, and like hemophilia A, affects people of all races and
ethnicities. It is caused by defects in the gene encoding factor IX located
on the X chromosome, explaining the predominance of male cases. Females can inherit hemophilia B under rare circumstances if they inherit

xiv INTRODUCTION

two X chromosomes that have a defective version of the factor IX gene.

The symptoms of hemophilia B vary from mild to severe uncontrolled
bleeding.
A deficiency in clotting factor XI was described during the 1950s that
later become known as hemophilia C. Unlike hemophilia A and B, hemophilia C affects males and females in equal frequencies because the gene
encoding factor XI is not on the X chromosome. It is on chromosome 4.
Hemophilia C affects about 1 in 100,000 people and its symptoms range
from mild to moderate uncontrolled bleeding. Spontaneous bleeding
does not usually occur. Hemophilia C is more prevalent in some ethnic
groups than others, such as people of Ashkenazi Jewish descent.
The chapters that follow describe the royal disease of hemophilia as a
collection of inherited bleeding disorders. Chapter 1 presents the primary
symptoms of hemophilia that range from occasional minor uncontrolled
bleeding to severe external or internal bleeding that occurs spontaneously,
after traumatic injury, or during surgical procedures. It describes the normal process of blood coagulation and how hemophilia is diagnosed by
careful measurement of the time required for blood to clot. Chapter 2
presents the pattern of inheritance of hemophilia A and hemophilia B
as X-linked recessive, which explains why almost all patients are male. It
describes the cause of hemophilia A as mutations in the gene for clotting
factor VIII and the cause of hemophilia B as mutations in the clotting factor IX gene. Chapter 2 describes the pattern of inheritance of hemophilia
C as autosomal recessive and explains how it is caused by mutations in
the gene for clotting factor XI. The chapter presents several scenarios by
which hemophilia can arise for the first time in families, and how genetic
testing can provide information that prospective parents can use to make
reproductive decisions. Chapter 3 presents treatment and therapy for hemophilia, including clotting factor replacement therapy. Chapter 4 describes future prospects for diagnosing, treating, and curing hemophilia,
including maternal blood screening, preimplantation genetic diagnosis,
gene therapy, and genome editing.

CHAPTER 1

Symptoms and Diagnosis

The main symptoms of hemophilia are uncontrolled internal and external bleeding. Once started, bleeding in a person with hemophilia is not
faster, but the process of clotting to stop the bleeding takes longer. The
risk of uncontrolled bleeding depends on the levels of clotting factor in
the bloodstream. The lower the level of clotting factor, the higher the
risk of uncontrolled bleeding. Similarly, the severity of bleeding episodes
is determined by clotting factor levels. Lower levels of clotting factor
in the blood result in more severe and longer lasting bleeding episodes.
Hemophilia patients who have clotting factor levels less than 1 percent
of normal levels are described as having severe hemophilia. Severe cases
represent about 60 percent of all hemophilia patients. Severe hemophilia
results in prolonged external and internal bleeding initiated by injury or
surgery. It can also result in frequent spontaneous bleeding, for which the
cause is not obvious. Severe hemophilia is usually diagnosed at birth or
within two years of life. Clotting factor levels between 1 and 5 percent
result in moderate hemophilia, and 15 percent of hemophilia patients
are in this category. Moderate hemophilia can cause prolonged bleeding
episodes after injuries or spontaneous bleeding. It is most often diagnosed
by the age of six years. The remaining 25 percent of hemophilia patients
have clotting factor levels between 6 and 30 percent of normal levels and
are described as having mild hemophilia. People with mild hemophilia
usually have prolonged bleeding only after serious injury, trauma, tooth
extraction, or surgery. They often do not know that they have hemophilia
until one of these events occurs and their first uncontrolled bleeding episode might not occur until adulthood. Women with mild hemophilia
often have unusually heavy menstrual periods and can experience excessive hemorrhaging after childbirth.

2 HEMOPHILIA

External Bleeding from Hemophilia

Minor injuries to the skin that result in external bleeding are usually not a
problem for people with hemophilia. The biochemical challenge of forming a clot to stop bleeding from a minor cut or scrape can often be overcome. In cases of severe hemophilia, it might take longer for the clotting
process to stop the bleeding. The bleeding might also stop and then start
again. Extensive injuries such as deep cuts and lacerations are a more
serious problem for people with hemophilia. The uncontrolled bleeding
that results can make accidental injury to the skin much harder to treat.
Injuries to the gums and other tissues in the mouth can also cause uncontrolled bleeding episodes in people with hemophilia. A fall might cause
biting of the tongue, mouth, or lips. Losing a baby tooth or cutting of the
gums by a new adult tooth often causes bleeding that might be a problem
for children with moderate or severe hemophilia. Tooth brushing or eating can also initiate uncontrolled bleeding of the gums. Dental procedures
that cause bleeding can also be dangerous for people with hemophilia,
and so special procedures are used to minimize the extent of bleeding.
Another symptom of hemophilia is frequent and heavy nosebleeds that
occur without any obvious cause. Many women with hemophilia experience prolonged and heavy menstrual bleeding, called menorrhagia. They
might also have more severe menstrual cramps. Newborn males with severe hemophilia might bleed heavily after circumcision.

Internal Bleeding from Hemophilia

Although prolonged external bleeding can be a problem for people living
with hemophilia, internal bleeding represents a greater health risk. Frequent internal hemorrhaging results in blood loss and damage to organs
and tissues throughout the body that require frequent medical attention
and can be life-threatening. The most common sites of internal bleeding
for patients with hemophilia are the joints. Bleeding in the shoulders,
elbows, wrists, ankles, knees, and hips can occur after slight injuries or
spontaneously without any apparent cause. The first sign of joint bleeding
might be an unusual bubbly or tingly feeling in the joint. Swelling soon
follows as blood accumulates in the joint, which restricts its motion and
causes it to feel tight. Continued bleeding causes the joint to become hot

Symptoms and Diagnosis

to the touch and very painful to move. It might become impossible to flex
the joint at all. Adults with hemophilia learn to recognize these symptoms
and seek medical attention. Symptoms of joint bleeding in children with
hemophilia are more difficult to discern, although they may be seen to
hold the affected joint or avoid using it. Very young children might resort
to crawling instead of walking because of the pain from joint bleeding.
Severe joint bleeding requires immediate medical attention to prevent
damage to the joint and curb the loss of blood. Repeated episodes of joint
bleeding can cause long-term damage to joints. The lining of connective
tissue in joints can become thickened, reducing the joint space and resulting in arthritis. The bones might also develop cysts. Hemophilia patients
sometimes have joints and limbs of different sizes and appearances on one
side of their bodies compared to the other side. Repeated episodes of joint
bleeding might damage joints to the point where they must be replaced
with an artificial joint or fused to preclude any further movement and
risk of bleeding.
Hemophilia can also result in uncontrolled internal bleeding of the
large muscles. Muscle bleeding can begin after a fall, a collision with a
solid object, or even a slight bump or blow. It might start as a result of
exercise or recreation that strains or tears muscles. Spontaneous bleeding
of the large muscles might also begin for no apparent reason. Once the
capillaries that supply large muscles are ruptured, hemophilia makes it
difficult for the clotting process to stop the bleeding. The symptoms of
prolonged large muscle bleeding are pain, swelling, and restricted movement in the abdomen, hips, knees, or back. Large bruises appear and
persist much longer than normal. The accumulation of blood in the large
muscles can generate pressure on the nerves that control them, which can
result in permanent nerve damage.
People with hemophilia can also experience bleeding from internal
organs. Bleeding in the kidneys or bladder leads to blood in the urine.
Although this type of bleeding might be caused by an accident or a blow
to the abdomen or lower back, it is more common for it to begin spontaneously. A gross hematuria is uncontrolled bleeding of the kidneys or
bladder that produces pink, red, or brown urine. If the bleeding is not as
severe, it is called a microscopic hematuria because red blood cells in the
urine can only be detected by microscopic examination. Passing blood in

4 HEMOPHILIA

the urine is not usually painful unless there are blood clots that form in
the urethra. This can cause sharp pain in the lower abdomen.
Bleeding from the digestive system can also be a problem for people
with hemophilia. Bleeding in the mouth and throat can swell the tongue
to the point where it obscures the airway and makes breathing difficult.
Bleeding from the stomach or intestines can be started by a fall, an accident, a blow to the abdomen, or unknown causes. Conditions such
as appendicitis, pancreatitis, or a peptic ulcer can cause anyone to have
digestive system bleeding, but for people with hemophilia, the bleeding
is more dangerous. The accumulation of blood in the digestive tract can
cause vomiting. Another common symptom is blood in the feces that
gives it a black and tarry appearance. Bleeding of the digestive system
can also result in abdominal pain. Prolonged loss of blood causes anemia,
with symptoms of light-headedness, weakness, and fatigue.
Of special concern for patients with hemophilia is internal bleeding
in the brain. Bleeding can start after a traumatic injury to the head, or a
simple bump to the head from a minor accident or a fall. Spontaneous
bleeding of the brain can also occur. Bleeding in the brain, known as an
intracranial hemorrhage, can cause a severe headache that lasts for a long
time and is not responsive to pain medications. A brain bleed can cause
unusual behaviors such as irritability, lethargy, and sleepiness. It might result in an inability to coordinate movement of the arms and hands or difficulty in maintaining balance or walking. Additional symptoms include
frequent vomiting, double vision, convulsions, and seizures. Persistent
bleeding of the brain poses a risk of brain damage or death, and is a health
emergency.

How Does Hemophilia Impair Blood Clotting?

Internal or external bleeding occurs when the integrity of the delicate
walls of blood vessels is broken. Blood flows in the circulatory system
because it is under pressure, which exacerbates uncontrolled bleeding. The
loss of blood can range from insignificant to life-threatening. Bleeding
into surrounding tissues and organs disrupts their functions. The process
by which the body prevents and curbs bleeding is called hemostasis. Once
the lining of a blood vessel is compromised, blood cells called platelets

Symptoms and Diagnosis

attach to the site of damage. Platelets are made in the bone marrow. Like
human red blood cells, platelets lack a nucleus, but they are only one-fifth
as big. The number of platelets in the circulatory system is normally 5 to
10 percent of the number of red blood cells. Once bleeding begins, platelets first adhere to the site of a hole or tear in a blood vessel. They undergo
activation, which involves changes in their shape and secretion of chemical messengers. The platelets then connect to each other in a process called
aggregation to block the hole or tear in the blood vessel. The construction
of a platelet plug is the first step in hemostasis and it activates the second
step, coagulation. Coagulation results in the accumulation of fibrin, a
protein that forms a network that crosslinks platelets into a clot that plugs
the site of bleeding until wound healing can occur.
The coagulation cascade is a series of biochemical reactions that comprise
a pathway to the formation of a blood clot. As shown in Figure 1.1, the
coagulation cascade is composed of the intrinsic pathway, the extrinsic
pathway, and the common pathway. The intrinsic pathway and the extrinsic pathway converge on the common pathway. Biochemical reactions
in general are catalyzed by enzymes, which are almost always proteins. The
activity of a given enzyme can be controlled by the chemical addition of
small groups of atoms, or by protein cleavage that causes the enzyme to
change from an inactive form to an active one. The biochemical reaction
by which cleavage occurs is often catalyzed by another enzyme. The coagulation cascade is a series of steps in which an inactive enzyme is converted
into an active one, that in turn catalyzes the conversion of the next enzyme
from its inactive to its active form. The enzymes are called coagulation
factors, or clotting factors, and each is designated by a different Roman
numeral (e.g., factor VIII), with an appended lowercase a for the active
form (e.g., factor VIIa). Most coagulation factors are enzymes that cleave
the next protein enzyme in the cascade to generate its active form. The
exceptions to this are factor VIII and factor V, which are glycoproteins that
function as cofactors to assist clotting cascade enzymes, and factor XIII,
which is an enzyme that crosslinks fibrin protein to form a clot.
The intrinsic pathway of the clotting cascade is also known as the contact activation pathway because it is initiated by surface contact. It begins
when factor XII is activated by the release of anions from activated platelets, exposure to a protein called collagen that forms a matrix underneath

Factor Xa

Factor X

Fibrinogen

Fibrin

Tissue
Factor

Fibrin Clot

Factor XIIIa

Factor XIII

Factor VII

Extrinsic Pathway
Factor VIIa

Thrombin

Common
Pathway

Prothrombin

Factor Va

Factor VIIIa

Factor VIII

Factor V

Factor IXa

Factor XIa

Factor IX

Factor XI

Factor XIIa

Figure 1.1 The blood coagulation cascade

Factor XII

Intrinsic Pathway

6 HEMOPHILIA

Symptoms and Diagnosis

the epithelial lining of blood vessels and other tissues, or contact with
lipopolysaccharides on the surface of bacteria. Activated factor XII starts
the intrinsic pathway cascade, which involves all three of the clotting factors involved in hemophilia A, B, and C. The intrinsic pathway leads to
the formation of an important enzyme complex that includes activated
factor VIII and activated factor IX. Because this complex converts factor
X into its activated form, it is often called the tenase complex, a word
composed of ten and the suffix ase that is used to designate enzymes.
Activated factor X converts prothrombin (factor II) to thrombin. Factor
X is the point of convergence of the intrinsic and extrinsic pathways and
is the first step in the common pathway.
The extrinsic pathway is also known as the tissue factor pathway, and
it is considered to be a more important route to the common pathway
than the intrinsic pathway. Damage to blood vessels causes circulating
factor VII to come into contact with a protein called tissue factor that is
found on the surface of cells. This proteinprotein interaction activates
factor VII, allowing it to catalyze the activation of factor X. The active
form of factor X combines with active factor V to form the prothrombinase complex, so-named because it converts prothrombin into thrombin.
Thrombin is considered to be the most important protein of the coagulation cascade. Thrombin is the major activator of platelets and several
upstream coagulation factors, including factors V, VII, and VIII. Activation of thrombin has a positive feedback effect, because an increase in
thrombin activity causes an increase in the level of activated coagulation
factors that lead to the production of more activated thrombin.
Thrombin is a serine protease that cleaves fibrinogen to produce fibrin
monomers. Thrombin also activates factor XIII, which catalyzes the polymerization of fibrin monomers into an interwoven fibrin clot that serves
as a hemostatic plug to stop bleeding. The coagulation cascade is said to
be in a prothrombotic state as long as activation of factor VIII and factor
IX continues to produce the tenase complex that leads to the activation
of factor X and the production of thrombin from prothrombin. Natural
anticoagulant pathways are responsible for shutting down the coagulation
cascade to prevent circulatory problems associated with too much clotting. There is a delicate balance between the procoagulant pathways of
the clotting cascade and the anticoagulant pathways. Whereas failure of

8 HEMOPHILIA

procoagulant pathways results in hemophilia, dysfunction of anticoagulant pathways results in thrombotic disorders in which too much clotting
disrupts normal blood flow and damages blood vessels.
People with hemophilia have low levels of one of the clotting factors
required for the normal function of the coagulation cascade. Hemophilia
A is caused by low levels of factor VIII, which sometimes is called antihemophilic factor. Factor VIII is a protein that is made in the liver
and endothelial cells throughout the body. Factor VIII is secreted into
the bloodstream, where it circulates in an inactive form bound to von
Willebrand factor (vWF). Activation of factor VIII occurs by interaction
with already activated factor IX. Hemophilia B is caused by low levels of
factor IX, a protein that is made in the liver and secreted into the blood.
Factor IX is inactive in serum until it is cleaved by activated factor XI or
activated factor VII. Hemophilia C is caused by low levels of factor XI.
Activated by factor XII, factor XI protein is made in the liver before being
secreted into the bloodstream.

Blood Screening Diagnostic Tests

Diagnosis of hemophilia usually begins with observation of uncontrolled
bleeding episodes. Prolonged external bleeding by a newborn might occur
after a heel stick during routine newborn screening, or after circumcision. Unusually prolonged internal bleeding of the scalp or brain might
occur in a newborn after the use of a vacuum or forceps during delivery.
Bruising of other parts of the body caused by delivery might persist in a
newborn with hemophilia. Even if none of these observations is made,
hemophilia may be suspected in a baby or toddler if bruising appears
too often and lasts too long. When hemophilia is suspected, a series of
blood screening diagnostic tests is performed to rule out other causes of
uncontrolled bleeding.
Blood screening tests require taking a blood sample from a vein in the
arm, and this must be done carefully with patients who have a bleeding
disorder because of the risk of uncontrolled bleeding. After a blood sample is obtained, a complete blood count (CBC) is performed to measure
the amount of hemoglobin and the size and number of red blood cells,
white blood cells, and platelets in the blood. As indicated in Table 1.1,

Symptoms and Diagnosis

Table 1.1 Blood screening diagnostic tests

Blood screening
test

Result for hemophilia Result for other

diagnosis
diagnoses

Red blood cell count/

hemoglobin

Normal or low from recent

prolonged bleeding

Low for anemias, liver disease,

kidney disease, some cancers

Platelet count

Normal

Low for leukemia, hepatitis,

autoimmune disease

Prothrombin time
(PT)

Normal

Prolonged for factor II/V/VII/X

deficiency, vitamin K deficiency,
liver disease, warfarin therapy

Partial
thromboplastin time
(PTT)

Normal for mild hemophilia

Prolonged for moderate and
severe hemophilia

Prolonged for vitamin K

deficiency, liver disease, factor
VII deficiency

Activated partial
thromboplastin time
(APTT)

Normal for mild or

moderate hemophilia
Prolonged for severe
hemophilia

Prolonged for factor XII/vWF

deficiency, heparin therapy,
inhibitors of clotting factors

Thrombin time (TT)

Normal

Prolonged for liver disease,

malnutrition, disseminated
intravascular coagulation

Fibrinogen test

Normal

Low levels for liver disease,

malnutrition
High levels for coronary heart
disease, heart attack, peripheral
arterial disease, some cancers

patients with hemophilia usually have normal red blood cell counts and
normal hemoglobin levels. An exception to this can occur after heavy or
prolonged bleeding episodes that deplete the number of red blood cells
and the concentration of hemoglobin. A low red blood cell count can
be caused by liver disease, kidney disease, anemias, and some cancers.
Of particular importance for normal blood clotting is the platelet count.
Because platelets are a key cellular component in blood clotting, a low
platelet count might explain uncontrolled bleeding. As listed in Table 1.1,
the platelet count is normal for hemophilia, but a low platelet count can
be caused by leukemia, hepatitis, or an autoimmune disease. Medications
such as heparin, sulfa antibiotics, and chemotherapy drugs can also lower
the platelet count.
If uncontrolled bleeding cannot be explained by low platelet count,
the next blood screening test to be performed is prothrombin time (PT),

10 HEMOPHILIA

which is alternatively known as pro-time, anticoagulant-prothrombin

time, or clotting time. The PT test was originally developed to detect abnormally low levels of the prothrombin clotting factor, but later it became
clear that it also measured deficiencies in several other clotting factors.
The PT test begins with adding an anticoagulant such as sodium citrate
to a withdrawn blood sample maintained at body temperature. The anticoagulant binds calcium ions needed for blood clotting. The sample
is then placed in a centrifuge to separate blood cells from plasma, producing what is referred to as platelet-poor plasma. The plasma is transferred to a new tube and a solution of calcium ions is added to replace
the calcium ions previously bound by sodium citrate. A source of
phospholipids is added to the sample as a surrogate for platelets, followed by
tissue factor to activate the clotting cascade pathway. Tissue factor used in
PT tests is manufactured with recombinant DNA technology or isolated
from human or rabbit blood. Clotting causes the sample to become
opaque and this can be measured by direct observation or by passing light
through the sample and determining how much light is absorbed. A timer
carefully measures how long it takes for the sample to clot, which is the
PT. There are slight variations in the way a PT test can be conducted. Different medical labs use human or rabbit tissue factor to initiate clotting,
and the test can be performed manually or with an automated system.
Even with a standardized procedure, timing of clot formation in a given
medical lab can vary because of batch differences in the tissue factor and
other reagents used. The international normalized ratio (INR) was developed to address the variability of PT test results. Sometimes PT results
are described as INR results. As indicated in Table 1.1, abnormally long
PT times are an indication of slower blood clotting that can be caused
by liver disease, vitamin K deficiency, or warfarin anticoagulant therapy.
Because PT measures blood clotting by the extrinsic pathway, PT times
are normal for people with hemophilia.
Blood screening tests called partial thromboplastin time (PTT) and
activated partial thromboplastin time (APTT) are also conducted in the
course of diagnosing hemophilia and other bleeding disorders. Like the
PT test, PTT and APTT measure the time it takes for blood to clot.
Unlike PT tests that are initiated by tissue factor, PTT and APTT clotting
is initiated by surface contact. The use of the word partial in the name

Symptoms and Diagnosis

11

of the PTT and APTT tests indicates that clotting is initiated without
the addition of tissue factor. For both PTT and APTT, a blood sample
is treated with an anticoagulant that binds the calcium ions needed for
clotting. Platelet-poor plasma is prepared by centrifugation. The plasma
is transferred to a tube maintained at body temperature and calcium is
added back to facilitate clotting, along with a substance called cephalin
that is a phospholipid substitute for platelets. For PTT, the next step is
to measure the time it takes for the blood to clot. For APTT, an activator
of micronized silica, or a type of clay called kaolin, is added to accelerate
the clotting process before clotting time is measured. As listed in Table
1.1, prolonged PTT clotting times are found for moderate and severe
hemophilia. They might also be caused by vitamin K deficiency, liver
disease, or factor VII deficiency. Abnormally long APTT clotting times
can be caused by severe hemophilia. Other causes of prolonged APTT
times include factor XII deficiency and vWF deficiency. It is important
to determine if the cause of prolonged PTT and APTT clotting times
is the absence of clotting factors due to hemophilia, or the presence of
clotting inhibitors in the blood. A simple way to distinguish between
these two alternatives is to mix blood plasma with normal plasma and
repeat the PTT or APTT test. If the clotting time is still abnormally long,
then a clotting inhibitor is likely. If clotting time falls within the normal
range, a clotting factor deficiency is suspected, which might be caused by
hemophilia.
Two additional blood screening tests can be performed to facilitate
diagnosis of bleeding disorders. The thrombin time (TT) test involves
the addition of thrombin to platelet-poor plasma and measurement
of the clotting time. The TT test is sensitive to inhibitors of the last
step in the coagulation cascade, which converts fibrinogen to fibrin.
As stated in Table 1.1, people with hemophilia have normal TT test
results. Prolonged TTs can be caused by liver disease, malnutrition,
or disseminated intravascular coagulation, which results in too much
blood clotting. The fibrinogen test measures the level of fibrinogen in
the blood, but hemophilia does not affect the level of fibrinogen. Low
fibrinogen levels can be caused by fibrinogen deficiency, liver disease,
and malnutrition. High fibrinogen levels are caused by coronary heart
disease, heart attack, peripheral arterial disease, and some cancers.

12 HEMOPHILIA

The results of blood screening tests clarify the cause of abnormal

clotting and contribute to a definitive hemophilia diagnosis. As shown
in Table 1.1, severe hemophilia is indicated when all of these tests give
normal results except PT and APTT, which will produce prolonged
times. Moderate hemophilia is indicated by an isolated result of prolonged APTT. Abnormal PT and APPT results indicate that direct testing for clotting factor deficiencies known to cause hemophilia should be
performed.

Clotting Factor Assays for Hemophilia Diagnosis

Clotting factor assays are used to measure clotting factor deficiencies.
The results enable a diagnosis of one of the three types of hemophilia and
indicate its severity, both of which are needed for the development of
an appropriate treatment plan. Clotting factor tests involve performing a
series of APTT tests that compare the clotting time of platelet-depleted
serum from a patient to the clotting time of serum that has a specific clotting factor removed. For hemophilia diagnosis, the process requires commercially prepared normal serum as well as three serum preparations from
which factors VIII, IX, or XI have been removed. A series of dilutions of
the factor-depleted serum is prepared. Each of the dilutions is mixed with
an equal volume of normal serum and the APTT test is performed. The
time to clot is plotted on a graph versus the dilution factor. The graphs
show the relationship between clotting time and known levels of factors
VIII, IX, or XI. The same procedure is applied to platelet-depleted serum
from the patient. The serum is serially diluted, and each dilution is mixed
with an equal volume of normal serum before APTT clotting time is
determined and graphed. A comparison of the clotting time graphs using
patient serum to the clotting time graphs using commercially prepared
factor-depleted serum reveals the level of factors VIII, IX, and XI in the
serum from the patient. For people who do not have hemophilia and have
normal blood clotting, the levels of factors VIII, IX, and XI vary from 50
to 150 percent of the average factor level. Abnormally low factor levels
cause hemophilia, and they generally correlate with the severity of symptoms. As listed in Table 1.2, factor levels between 5 and 50 percent are
usually associated with mild hemophilia and cause prolonged bleeding

Symptoms and Diagnosis

13

Table 1.2 Hemophilia severity depends on clotting factor levels

Severity of Levels of factors Symptoms
hemophilia VIII, IX, or XI
Normal (no
hemophilia)

50150%

None

Mild
hemophilia

550%

Uncontrolled bleeding after major surgery or

severe injury

Moderate
hemophilia

15%

One or more bleeding episodes per month;

uncontrolled bleeding after surgery, dental
procedures, or slight injury; joint disease

Severe
hemophilia

Less than 1%

One or more bleeding episodes per week; joint

and muscle bleeding; high risk of digestive
system and brain bleeding; uncontrolled
external bleeding after slight injury;
spontaneous bleeding

only after major surgery or severe injury. Factor levels between 1 and 5
percent of normal levels usually cause moderate hemophilia, with one or
more bleeding episode per month after dental procedures or slight injury.
Factor levels below 1 percent are associated with severe hemophilia. The
symptoms of severe hemophilia include weekly bleeding episodes in the
joints and muscles, digestive system, and brain. Spontaneous bleeding or
bleeding after slight injury can occur.
Clotting factor assays are sensitive to variables associated with the laboratory procedures and to differences in patients. Degradation of the factor proteins by freezing and thawing of serum samples can adversely a ffect
assay results. Use of alternative commercially prepared factor-depleted
serum samples can also affect factor assay results. Factor VIII clotting
activity in plasma is increased with oral contraceptive use, aerobic exercise, and chronic inflammation. Factor VIII levels also rise in response
to pregnancy and estrogen therapy. Factor VIII clotting activity in plasma
is about 25 percent lower in people with blood type O than people with
blood types A, B, or AB. Factor VIII levels might be decreased in patients
that have von Willebrand disease, which is not hemophilia. Liver diseases can cause an increase of factor VIII activity. Low factor IX levels are
associated with liver disease, vitamin K deficiency, and warfarin therapy.
Normal full-term newborn infants and healthy premature infants might
have decreased factor IX levels that typically increase with age.

14 HEMOPHILIA

What Are Common Health Complications of

Hemophilia?
Chronic joint disease, especially of the elbows, knees, and ankles, is a
common health complication of people living with hemophilia. The
synovium is a membranelike sac that provides lubrication to joints, and
removes fluid and debris from them. Frequent spontaneous bleeding into
the synovium causes it to thicken and become susceptible to more bleeding. Uncontrolled joint bleeding causes the cartilage that protects the
surface of bones in joints to degrade. Joint bleeding produces additional
symptoms of warmth and swelling of joints, moderate to severe pain, and
loss of joint flexibility. Joints that bleed frequently are also more susceptible
to infections. The effects of chronic joint disease can be e xacerbated by
being overweight. The function of badly damaged joints can be improved
by removal of the synovium in a surgical process called synovectomy. For
knees and hips, joint replacement is also an option.
Women with hemophilia can experience menorrhagia, which is heavy
and prolonged menstrual periods associated with unusually severe cramping and pain. Some women are diagnosed with mild to moderate hemophilia once they enter puberty and develop menorrhagia. Menorrhagia is
useful in the diagnosis of factor XI deficiency (hemophilia C) and vWF deficiency (von Willebrand disease). Prolonged bleeding can cause low iron
levels and anemia. Hemophilia and other bleeding disorders are also problematic in pregnant women. Miscarriages or abortions, as well as normal
child birth, can result in prolonged bleeding in women with hemophilia.
Some people have health complications arising from immune responses
to clotting factor treatment. Part of the normal immune response is to generate antibodies that bind to foreign proteins and direct their d
estruction.
Antibodies to coagulation factors are referred to as inhibitors. Although
antibody inhibitors of other coagulation factors also develop, inhibitors to
factor VIII are the most common. Inhibitors can be a problem for people
receiving clotting factor injections to treat their hemophilia. About onethird of people with severe hemophilia A develop antibodies against factor
VIII protein within their first 20 injections of the protein. The antibodies
bind to the factor VIII, making it ineffective in the c oagulation cascade.
Once inhibitors have developed, they render clotting factor treatments

Symptoms and Diagnosis

15

ineffective in controlling bleeding. Some mutations of the gene encoding

factor VIII are associated with an increased risk of inhibitor d
evelopment.
For reasons that are not clear, inhibitors of factor VIII are more common
in people of African and Hispanic decent than those of Caucasian ethnicity.
Sometimes, an immune response to coagulation factors is generated in
people who have not inherited hemophilia. The inhibitors impair the function of the coagulation cascade and result in acquired hemophilia. Acquired hemophilia is rare, occurring in about 1 in 500,000 people.
Uncontrolled bleeding in and around the brain is called an intracranial hemorrhage and is a serious complication of hemophilia that can
occur spontaneously, or as a result of a fall or blow to the head. The
symptoms of intracranial hemorrhage in newborns and young children
include irritability, sleepiness, vomiting, and seizures. In severe cases, prolonged bleeding can noticeably enlarge the head and lead to system shock
from blood loss. For older children and adults, symptoms of intracranial
hemorrhage include weakness, impaired vision, inability to communicate, and cognitive dysfunction. As soon as intracranial hemorrhage is
diagnosed, clotting factor treatment is given and a CT scan is performed
to assess the extent of uncontrolled bleeding. Neurosurgery might be required to relieve pressure on the brain and remove excess blood from
inside the skull. The long-term effects of intracranial hemorrhage include
paralysis, vision loss, speech impairment, and symptoms normally associated with stroke. Childhood intracranial hemorrhaging has been linked
to the development of learning disabilities.
Another health complication for people living with hemophilia is an
increased risk of infections from contaminated blood products. Beginning in the 1960s, methods were developed to purify factor VIII from
donated human plasma. Inadvertent viral infections resulted from concentrated factor VIII used to treat hemophilia A. Many people receiving
tainted factor VIII concentrates developed hepatitis B virus infections or
became chronic hepatitis C carriers. Thousands of people contracted HIV
from contaminated factor concentrates from 1979 to 1885, and about
half of them died of AIDS. From 1997 to 2007, 19 percent of deaths of
hemophilia patients were related to HIV infection, and 22 percent were
related to hepatitis C infection. By contrast, only 12 percent of deaths
of hemophilia patients during the same period were directly caused by

16 HEMOPHILIA

uncontrolled bleeding. Methods to inactivate viruses in factor concentrates and improved donor screening procedures greatly reduced the risk
of infection by known viral pathogens from factor concentrates. The risk
of opportunistic infections was eliminated by the use recombinant DNA
clotting factor instead of donor plasma-purified clotting factor. Since
1992, no new infections of hepatitis A, hepatitis B, hepatitis C, or HIV
have been traced to blood products.

Index
Acquired hemophilia, 15
Acquired von Willebrand disease
(vWD), xii
Activated partial thromboplastin time
(APTT) test, 8, 10
Adeno-associated virus, 44
Albucasis, xi
Albumin, 46
Alleles, 17
Amino acids, 26
Aminocaproic acid, 40
Amniocentesis, 35
Anticoagulant-prothrombin time
test. See Prothrombin
time (PT) test
Antifibrolytic medication, 40
Antihemophilic factor, 8
Autosomal recessive, xii
Autosomes, 23
Base pairing, 26
Beneficial mutations, 28
Blastomere biopsy, 43
Bleeding, prolonged, 1314
Bleeding disorder, xixiii
Blood coagulation cascade, 6
Blood plasma, 38
Blood screening diagnostic tests, 912
Bypassing products, 40
Carriers, 18
Center for Disease Control
Hemophilia A Mutation
Project (CHBMP), 29
Center for Disease Control
Hemophilia B Mutation
Project (CHBMP), 31
Cephalin, 11
Chaperones, 27
Chorionic villus sampling (CVS), 35
Christmas, Stephen, xiii

Christmas disease. See Hemophilia B

Chromosomes, 1718
Chronic joint disease, 14
Classic hemophilia. See Hemophilia A
Clotting factors, xixii, 5, 7
assays, 1213
hemophilia treatment with,
3839
Clotting time. See Prothrombin
time (PT) test
Coagulation, 5
factors, 5
Coagulation cascade, 5, 6, 7
common pathway, 5
extrinsic pathway, 5, 7
intrinsic pathway, 5, 7
Codons, 2627
Collagen, 5, 7
Contact activation pathway, 5
CRISPR/Cas technology, 46
Cryoprecipitate, 37, 38
Cytokines, 36
Deleterious mutations, 28
Desmopressin acetate (DDAVP), 40
Dominant alleles, 17
Endoplasmic reticulum (ER), 27
Ex vivo gene therapy, 45
Exons, 26
F8 gene, 17, 27, 44
mutations of, causing Hemophilia
A, 2831
F8 transcriptional promoter, 31
F9 gene, 17, 27, 44
mutations of, causing Hemophilia
B, 31
F11 gene, 28
mutations of, causing Hemophilia C,
3233

58 INDEX

Factor V, 5, 7
Factor VII, 7
Factor VIII, 5, 7, 8, 13, 14, 15, 22, 38
Factor IX, 7, 8, 13, 22, 27, 38
Factor X, 7
Factor XI, 89, 14, 39
Factor XII, 5, 7
Factor XIII, 5, 7
Factor concentrates, 1516
Factor replacement therapy, 3940
Fibrin glue, 40
Fibrin stabilizing factor deficiency, xiii
Fibrinogen deficiency, xiii
Fibrinogen test, 8, 11
Founder effect, 24
Frameshift mutations, 30, 31
Fresh frozen plasma, 3940
Gene modifiers, 36
Gene therapy, 4445
Genetic bleeding disorders, xii, xiii
Genetic code, 27
Genetic testing, for hemophilia,
3335
Genome editing, 4546
Genotypes, 1819
Global Treatment Centre Directory, 37
Glycoproteins, 5
Gross hematuria, 3
Haemorrhaphilia, xi
Hageman factor deficiency, xiii
Hay, John, xi
Hemophilia, xi
blood screening diagnostic tests, 912
causes and contributing factors,
1736
clotting factor assays, 1213
coagulation cascade, 57
contributing factors, 3536
external bleeding from, 2
factor replacement therapy, 3940
gene therapy for, 4445
genetic testing for, 3335
genome editing for, 4546
health complications of, 1416
hemophilia A. See Hemophilia A
hemophilia B. See Hemophilia B

hemophilia C. See Hemophilia C

internal bleeding from, 24
molecular basis of, 2628
preimplantation genetic diagnosis
of, 4344
risk of infections, 15, 16
severity of, 12
symptoms and diagnosis, 116
treatment and therapy, 3741
Hemophilia A, xiixiii, 8
F8 gene mutations causing, 2831
inheritance, 1723
Hemophilia B, xiiixiv, 8
F9 gene mutations causing, 31
inheritance, 1723
Hemophilia C, xiii, xiv, 8, 14
F11 gene mutations causing, 3233
inheritance, 2326
Hemophilia treatment centers
(HTCs), 37
Hemostasis, 4
Heterozygous genotype, 23
High-responding inhibitors, 40
Homology-directed repair, 46
Homozygous dominant, 23
Homozygous recessive, 23
Hopff, Friedrich, xi
Human genome, 26
Immune tolerance therapy, 41
In vitro fertilization (IVF), 34
Incomplete dominance, 18, 23
Inherited uncontrolled bleeding, xi
Inhibitors, 14, 3536
low-responding/high-responding, 40
Interleukins, 36
International normalized ratio (INR), 10
Intracranial hemorrhage, 4, 15
Introns, 26
Inversions, 29
Kaolin, 11
Lipopolysaccharides, 7
Low-responding inhibitors, 40
Maternal blood screening, 35
Mendel, Gregor, 17

 INDEX
59

Menorrhagia, 2, 14
Messenger RNA (mRNA), 26
Microscopic hematuria, 3
Mild hemophilia, 1, 12, 13
Missense mutations, 29
Moderate hemophilia, 1, 12, 13, 14
Monogenic X-linked recessive
diseases, 17
Mutations, 28
Neurosurgery, 15
Neutral mutations, 28
Newborn screening, 9
Nonhomologous end joining, 46
Nonsense mutations, 30, 31
Obligate carrier, 22
Otto, John Conrad, xi
Padua allele, 45
Parahemophilia, xiii
Partial thromboplastin time (PTT)
test, 8, 10
Pathogenic mutations, in F8 gene, 29
Phenotypes, 19
Plasmapheresis, 40
Platelet count, 8, 9
Platelet-poor plasma, 10, 11
Platelets, xi, 45
Pool, Judith, 38
Posttranslational modification, 27
Preimplantation genetic diagnosis
(PGD), 34, 4344
Prenatal diagnostic testing (prenatal
screening), 35
Pro-time. See Prothrombin time (PT)
test
Proconvertin deficiency, xiii
Prophylaxis, 39
Prothrombin deficiency, xiii
Prothrombin time (PT) test,
8, 910
Punnett square, 1920, 24

Recessive alleles, 17
Red blood cell count/hemoglobin test,
8, 9
RNA splicing, 26
Royal disease. See Hemophilia
Sangamo Biosciences Incorporated, 46
Serine, 29, 32
Severe hemophilia, 1, 11, 12, 13
Sex chromosomes, 18
Sex-linked inheritance, 18
Sodium citrate, 10
Spontaneous mutations, 22, 32
Stuart-Prower factor deficiency, xiii
Substitution mutations, of F8 gene,
29
Synovectomy, 14
Synovium, 14
Talmud, xi
Tenase complex, 7
Thrombin, 7
Thrombin time (TT) test, 8, 11
Tissue factor, 7, 1011
pathway, 7
Transcription, 26
Translation, 26
Translational reading frame, 30, 31
Trophectoderm biopsy, 43
Tumor necrosis factor-alpha
(TNF), 36
Uncontrolled bleeding, xi, 2, 910, 15
von Willebrand disease (vWD), xii,
xiii, 13, 14
World Federation of Hemophilia, 37
X chromosome, 18
X-linked inheritance, 18
Y chromosome, 18

OTHER TITLES IN OUR HUMAN DISEASES

AND CONDITIONS COLLECTION
A. Malcolm Campbell, Editor
Genetic Diseases or Conditions: Cystic Fibrosis, The Salty Kiss by Todd T. Eckdahl
Gradual Loss of Mental Capacity from Alzheimers by Mary E. Miller

FORTHCOMING TITLES IN THIS COLLECTION

Nerve Disease ALS and Gradual Loss of Muscle Function: Amytrophic Lateral Sclerosis
by Mary E. Miller
Auto-Immunity Attacks the Body by Mary E. Miller
Sickle Cell Disease by Todd T. Eckdahl
Brain Degeneration from Huntingtons Disease by Todd T. Eckdahl
Momentum Press offers over 30 collections including Aerospace, Biomedical, Civil,
Environmental, Nanomaterials, Geotechnical, and many others. We are a leading book
publisher in the field of engineering, mathematics, health, and applied sciences.
Momentum Press is actively seeking collection editors as well as authors. For more
information about becoming an MP author or collection editor, please visit
http://www.momentumpress.net/contact

Announcing Digital Content Crafted by Librarians

Concise e-books business students need for classroom and research
Momentum Press offers digital content as authoritative treatments of advanced engineering
topics by leaders in their field. Hosted on ebrary, MP provides practitioners, researchers,
faculty, and students in engineering, science, and industry with innovative electronic content
in sensors and controls engineering, advanced energy engineering, manufacturing, and
materials science.
Momentum Press offers library-friendly terms:
perpetual access for a one-time fee
no subscriptions or access fees required
unlimited concurrent usage permitted
downloadable PDFs provided
free MARC records included
free trials
The Momentum Press digital library is very affordable, with no obligation to buy in future
years.
For more information, please visit www.momentumpress.net/library or to set up a trial in the
US, please contact mpsales@globalepress.com.