Bleeding Disorders Associated Bleeding Disorders Associated Bleeding Disorders Associated Bleeding Disorders Associated Bleeding Disorders Associated

with Menorrhagia with Menorrhagia with Menorrhagia with Menorrhagia with Menorrhagia
Volume 17 , Number 1 Volume 17 , Number 1 Volume 17 , Number 1 Volume 17 , Number 1 Volume 17 , Number 1
J anuary 2003 J anuary 2003 J anuary 2003 J anuary 2003 J anuary 2003
Dorothy M. Adcock, MD
Objective: The reader will be able
to discuss the various bleeding
disorders associated with
menorrhagia and the laboratory
evaluation used to distinguish
among these disorders.
INTRODUCTION INTRODUCTION INTRODUCTION INTRODUCTION INTRODUCTION
Women with an underlying bleeding
disorder are at increased risk of a number
of untoward complications directly related
to menorrhagia. Women with undiag-
nosed bleeding disorders are also at risk
of suffering significant hemorrhage with
surgical procedures, trauma, and child-
birth. This may lead to prolonged hospi-
talizations and unnecessary transfusion
therapy. A study by Ragni, et al. reported
that post-operative bleeding in a cohort of
women could have been avoided in greater
than 85% of cases if proper history and
laboratory studies had been applied pre-
surgically.
Menorrhagia frequently impacts a
womans quality of life (QOL). Women
who suffer from menorrhagia frequently
report diminished QOL due to the exces-
sive bleeding. In a study performed by
Kouides et al., women with an underlying
hereditary bleeding disorder, specifically
von Willebrand Disease (vWD), were pro-
vided a questionnaire which evaluated
seven QOL parameters rated from 1-10
with 0 referring to no impact and 10
describing complete interference.
Women with vWD were compared to a
similar cohort of otherwise healthy men-
struating females. Results from the
Kouides questionnaire are listed in Table
1. QOL was statistically poorer in the
group with a bleeding disorder who suf-
fered menorrhagia. Although these
women described their general health as
very good, 39% reported lost time from
work or school secondary to heavy menses
and 47% reported accomplishing less
than their normal capability during this
time. Over 50% of women with a bleeding
disorder also complained of dysmenor-
rhea or painful menses, ranging in inten-
sity from moderate to very severe. Anemia
and resultant fatigue is reported in 64% of
women with vWD. Diminished QOL in
women with menorrhagia has also been
associated with a greater incidence of
psychological disturbances, most com-
monly generalized as anxiety disorders.
The Centers for Disease Control
(CDC) has initiated a research and edu-
cation program to increase both knowl-
edge and awareness of bleeding disor-
Heavy or prolonged menstrual bleeding or menorrhagia is defined as blood
loss of greater than 80cc per menstrual period. During their reproductive
years, as many as 5%10% of all women consult a physician complaining
of menorrhagia. Menorrhagia is the primary reason for approximately
30,000 hysterectomies every year. The incidence of menorrhagia is
higher in women with an underlying bleeding disorder and in fact, heavy
menses are frequently the first manifestation of a hemostatic disorder in
women.
CLINICAL HEMOSTASIS REVIEW CLINICAL HEMOSTASIS REVIEW CLINICAL HEMOSTASIS REVIEW CLINICAL HEMOSTASIS REVIEW CLINICAL HEMOSTASIS REVIEW
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EDITOR IN CHIEF EDITOR IN CHIEF EDITOR IN CHIEF EDITOR IN CHIEF EDITOR IN CHIEF
Rebecca Jensen, MT(ASCP)
C CC CCLINICAL ADVISORS LINICAL ADVISORS LINICAL ADVISORS LINICAL ADVISORS LINICAL ADVISORS
Dorothy M. Adcock, MD
Alexander Duncan, MD, ChB
H. James Day, MD, FACP
Don W. Hill, MD, FACP
CONTRIBUTOR CONTRIBUTOR CONTRIBUTOR CONTRIBUTOR CONTRIBUTOR
Lynne Stevens, MT(ASCP)
ASSISTANT TO THE EDITOR ASSISTANT TO THE EDITOR ASSISTANT TO THE EDITOR ASSISTANT TO THE EDITOR ASSISTANT TO THE EDITOR
Kendra Sagar
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ISSN 0894-1025
ders in women. The primary goals of
the CDC program are to decrease un-
necessary surgeries, such as hyster-
ectomies, in women with bleeding dis-
orders and to improve QOL. As part of
this initiative, the CDC surveyed a co-
hort of obstetricians/gynecologists in
Georgia to determine the prevalence of
menorrhagia in their patient popula-
tions and to determine the etiologies of
heavy menses most often considered
by these physicians. There was a 54%
response rate to the survey. The aver-
age physician surveyed had been in
practice for 20 years and reported that
8% of their patient population com-
plained of menorrhagia. Respondents
reported that the most common etiol-
ogy of the bleeding was likely anovula-
tory in nature or secondary to a benign
lesion of the uterus (e.g. fibroids). An
underlying bleeding disorder such as
vWD was entertained by only 4% of the
physicians surveyed. This survey sug-
gests that physician awareness of
bleeding disorders, as a cause of
menorrhagia, must be heightened as
a number of studies suggest that the
actual incidence of an underlying bleed-
ing disorder is as high as 40% in this
population.
Realizing that there are many
women who go undiagnosed, and are
therefore at increased bleeding risk,
the National Hemophilia Foundation
(NHF) initiated Project Red Flag. This
public awareness program is designed
to inform and educate both the general
public and healthcare providers about
the high prevalence of womens bleed-
ing disorders such as vWD.
EVALUATION OF WOMEN EVALUATION OF WOMEN EVALUATION OF WOMEN EVALUATION OF WOMEN EVALUATION OF WOMEN
WITH MENORRHAGIA WITH MENORRHAGIA WITH MENORRHAGIA WITH MENORRHAGIA WITH MENORRHAGIA
It is very difficult for most women to
determine the quantity of blood lost
with menses and attempts to assist
quantitation through determining num-
ber of pads or tampons soaked have
not been well standardized or accepted
by clinicians. A significant problem is
that heavy bleeding is a relative con-
cept. This is compounded by the fact
that bleeding disorders tend to run in
families and families may consider
heavy menses to be normal since
women frequently learn about men-
struation from their mothers or sis-
ters. One good indicator of menor-
rhagia is the presence of iron defi-
ciency anemia.
Studies report that 17%-40% of
women with menorrhagia have an un-
derlying bleeding disorder. Non-he-
matologic causes of excessive uterine
bleeding, however, are also common
and should be excluded in the evalua-
tion of women complaining of menor-
rhagia. The most common causes of
heavy menses are uterine fibroids
(myomas) or hormonal disturbances
that frequently occur in women at the
beginning or end of their reproductive
age. Hormonal disturbances com-
monly lead to menometrorrhagia, which
refers to irregular yet heavy bleeding.
Menorrhagia is common in women
with low levels of thyroid hormone.
The American College of Gynecol-
ogy (ACOG) published a Committee
Opinion in December of 2001 stating
that inherited and acquired disorders
of hemostasis should be considered
in women with menorrhagia, particu-
larly those without obvious pelvic ab-
normalities to account for the bleeding.
While ACOG recommends screening
for vWD only as the initial evaluation, a
complete evaluation would include the
following assays: complete blood count
(CBC), activated partial thromboplas-
tin time (APTT), prothrombin time (PT),
and von Willebrand panel (factor VIII
activity, VWF antigen and activity). See
Table 2. A CBC is useful to screen for
anemia as well as thrombocytopenia.
APTT may be increased in women with
vWD or due to a factor VIII, factor IX, or
factor XI deficiency. Factor XI levels
should be evaluated in women with
menorrhagia to rule out hemophilia C
(factor XI deficiency). APTT values,
however, may be normal in women
TABLE 1. TABLE 1. TABLE 1. TABLE 1. TABLE 1. Quality of LIfe Assessment
2 2 2 2 2 CLINICAL HEMOSTASIS REVIEW / OCTOBER 2003
Controls
n =150
vWD patients
(Type 1) n =81

P-value*
Impact of menses on
general activity

1.1 +1.8

4.1 +3.0

<0.0001
ability to work or go to school 0.5 +1.4 3.1 +3.3 <0.0001
family activities 0.6 +1.4 3.5 +2.9 <0.0001
ability to enjoy life 0.9 +1.5 3.9 +3.3 <0.0001
sleep 1.3 +2.3 3.6 +3.1 <0.0001
mood 3.5 +2.8 5.6 +3.3 <0.0001
overall quality of life 1.7 +1.8 4.3 +3.1 <0.0001

with vWD, factor XI deficiency, and in
women who are carriers of hemophilia
A and B (deficiencies of factors VIII and
IX, respectively). APTT and PT assays
that are normal, therefore, do not ex-
clude a bleeding disorder. For this rea-
son, it may be necessary to evaluate
specific factor levels in women with
menorrhagia.
In women with normal screening
studies (CBC, PT/PTT, vW panel and
factor XI activity) who complain of men-
orrhagia, should be evaluated for factor
VIII and factor IX levels especially if there
is a family history of bleeding. Of course,
hereditary deficiencies of factors VII, V,
and II may cause menorrhagia and
should be considered in certain fami-
lies, although these deficiencies are
rare. Some form of platelet function
analysis should be considered such as
bleeding time, platelet aggregation stud-
ies, or the use of an automated platelet
function analyzer (PFA) such as the PFA-
100 (Dade Behring, Marburg, Germany).
In those women in whom the cause of
bleeding still remains elusive, consid-
eration should be given to performance
of euglobulin clot lysis time, fibrinogen
activity, PAI-1, and 2-antiplasmin to
rule out hyperfibrinolysis or dysfibrino-
genemia as a cause of bleeding. See
Table 2.
In women with menorrhagia, thy-
roid function tests should be consid-
ered, as hypothyroidism may lead to
heavy menses. Hypothyroidism rep-
resents an acquired form of vWD, as
these patients typically have low vWF
levels, which increase into the normal
range with appropriate thyroid supple-
mentation therapy.
MENORRHAGIA AND vWD MENORRHAGIA AND vWD MENORRHAGIA AND vWD MENORRHAGIA AND vWD MENORRHAGIA AND vWD
Menorrhagia is the most common
manifestation of bleeding in women
with vWD and is reported in up to 80%.
Most women with vWD report onset of
menorrhagia with menarche.
VWD is the most common heredi-
tary bleeding disorder affecting 1%-
3% of all people. This means that
about 2.6 million persons in the United
States have vWD. Bleeding in individu-
als with vWD can be mild or life threat-
ening, can occur with injury or trauma
only, or be spontaneous. The most
common symptoms of vWD include
recurrent nosebleeds, menorrhagia,
easy bruising, unusual or excessive
bleeding from the mouth or gums, and
unusual or excessive bleeding after
surgery, dental procedures, or injury.
VWD is equally common in men
and women because it is inherited in
an autosomal dominant manner. A
parent with vWD has a 50% chance of
passing the gene to each child. Some
cases of vWD represent a spontane-
ous mutation and there are rare cases
of acquired vWD due to certain malig-
nancies, autoimmune disorders, or
drug therapies.
There are three
common catego-
ries of vWD. Type 1
comprises 70%-
80% of cases and
is characterized by
decreased vWF
activity and anti-
gen. As the vW pro-
tein serves as a
carrier of factor VIII,
factor VIII levels are
decreased to
about the same
level as the vWF
antigen. Degrees
of deficiency in type
1 vWD can be mild,
moderate, or se-
vere. Type 2 vWD
is characterized by
an abnormal vWF
protein a qualita-
tive abnormality. In
type 2, the vWF
antigen to activity
ratio is usually in
the range of 2:1.
Type 3 vWD is char-
acterized by es-
sentially no circulating vWF. This se-
vere form of deficiency is rare and bleed-
ing manifestations can be life threaten-
ing. In a 16-center study of women with
either type 2 or 3 vWD, 80% required
transfusion with blood products be-
cause of excessive bleeding and in
23%, menorrhagia necessitated hys-
terectomy, primarily for control of men-
strual bleeding.
In patients with vWD, childbirth may
present a unique challenge. During
pregnancy, especially in the third tri-
mester, levels of factor VIII and vWF
increase, in both normal women and
those with type 1 vWD. These levels,
however, may not increase to the same
degree in normal women as those with
vWD. Postpartum hemorrhage occurs
in 16%-30% with vWD, while rates of
3%-5% are reported in the general
population. Red cell transfusions are
administered to 7%-17% of these
women carrying the risk of transfusion
reaction, sensitization, and disease
transmission to the mother.
Diagnosis of vWD is dependent
on assimilation of clinical features and
laboratory results. The clinical and
laboratory diagnosis of vWD, however,
can be difficult. This is, in part, due to
natural variations in vWF levels as these
proteins are acute phase reactants and
levels also vary with hormone status. In
addition, vWF and factor VIII levels are
dependent on ABO blood type, age,
and race. Higher vWF levels occur in
non-0 blood types and in African Ameri-
cans, and levels tend to increase with
age. There is no consensus as to the
effect of menstrual cycle and exog-
enous hormone effect of vWF antigen
and activity levels. It has been sug-
gested, although inconclusively, that
vWF antigen and activity levels are low-
est during menstruation. In the early
follicular phase of the menstrual cycle
(less than day 7) most sex hormones
are at their baseline and vW levels
show little variation between days 5-7.
When vW testing is performed in
women, day of the menstrual cycle
should be noted. In women that have
borderline results suggestive of vWD,
repeat vW testing during days 5-7 of the
cycle should be considered. The ma-
jority of studies evaluating the effect on
female sex hormones on vWF levels
suggest that estrogens increase vWF
levels in a dose dependent manner.
For this reason, there is concern that a
diagnosis of vWD may be missed if
women are tested while on hormone
therapy, including oral contraceptive
therapy, or during pregnancy. Until
further data are published, it is best to
OCTOBER 2003 / CLINICAL HEMOSTASIS REVIEW 3 33 33
TABLE 2. TABLE 2. TABLE 2. TABLE 2. TABLE 2. Recommended Screening Tests for Menorrhagia
1
st
Tier Tests for Menorrhagia
Prothrombin Time
Activated Partial Thromboplastin
Time
Complete Blood Count
von Willebrand Panel
Factor VIII Activity
von Willebrand Factor Antigen
von Willebrand Factor Activity
Factor XI Activity
2
nd
Tier Tests for Menorrhagia
Factor IX Activity
Evaluation of Platelet Function
Platelet Aggregation
PFA-100
3
rd
Tier Tests for Menorrhagia
Fibrinogen Activity
2-Antiplasmin
Factor XIII
test women at least two months off of
hormone therapy and at times other
than during pregnancy or the postpar-
tum period, when possible.
MENORRHAGIA AND MENORRHAGIA AND MENORRHAGIA AND MENORRHAGIA AND MENORRHAGIA AND
BLEEDING DISORDERS OTHER BLEEDING DISORDERS OTHER BLEEDING DISORDERS OTHER BLEEDING DISORDERS OTHER BLEEDING DISORDERS OTHER
THAN vWD THAN vWD THAN vWD THAN vWD THAN vWD
Menorrhagia is reported in 57% of
women who are carriers of hemophilia
A and B, and in 60% of women with
factor XI deficiency. Menorrhagia also
occurs in women deficient in factors VII,
V, or II, although these deficiencies are
rare. Most women with these inherited
bleeding disorders also report onset of
menorrhagia with menarche.
Carriers of hemophilia A and B can
demonstrate a wide range of factor VIII
and IX levels respectively. Women with
factor VIII or IX levels below 50% may
have an increased bleeding tendency.
Menorrhagia, prolonged hemorrhage
with trauma, childbirth, or surgery and
easy bruising has been reported in
female carriers of hemophilia A and B.
Factor XI deficiency is inherited in
an autosomal manner in which ho-
mozygotes have factor levels below
15% while heterozygous deficients may
have levels in the low normal range.
Bleeding in factor XI deficiency is vari-
able and does not always correlate well
with factor XI levels. Factor XI deficiency
is rare.
Platelet abnormalities due to ei-
ther decreased number (thrombocy-
topenia) or dysfunction are an impor-
tant cause of menorrhagia. Idiopathic
thrombocytopenic purpura is a frequent
cause of thrombocytopenia in women
of reproductive age. Abnormalities of
platelet function can be inherited or
acquired. Medications such as aspirin
and non-steroidal anti-inflammatory
agents are common causes of platelet
dysfunction. It is important to consider
drug effect as women with menorrhagia
commonly suffer dysmenorrhea for
which they may take non-steroidal anti-
inflammatory agents. Hereditary
causes of platelet dysfunction include
surface glycoprotein receptor abnor-
malities (Glanzmanns thrombasthe-
nia and Bernard Soulier Syndrome)
and storage pool defects.
TREATMENT TREATMENT TREATMENT TREATMENT TREATMENT
Intranasally administered desmo-
pressin (DDAVP) for the treatment of
menorrhagia in women with vWD is
successful 92% of the time. Intranasal
DDAVP is typically given as a 2-8 day
course with each menstrual cycle. This
therapy is also beneficial in women
who are carriers of hemophilia A and in
some forms of platelet function defects
such as storage pool disease. Side
effects of DDAVP therapy include nau-
sea, headache, and hyponatremia may
develop if water intake is not restricted.
The use of exogenous hormones
in the form of combined oral contracep-
tives has been reported to decrease
menstrual flow and decrease the inci-
dence of iron deficiency anemia in
women with vWD. This mechanism of
menorrhagia control is most likely due
in part to inhibition of endometrial
growth. Diminished menstrual bleed-
ing may also be secondary to eleva-
tions of factor VIII and vWF levels asso-
ciated with the administration of estro-
gen.
The use of antifibrinolytic therapy
has also been effective in the treatment
of menorrhagia in women with vWD.
Epsilon-amino caproic acid given orally
for four days during the menstrual cycle
is associated with decreased men-
strual blood loss. Tranexamic acid,
another form of antifibrinolytic therapy,
has also been used effectively to con-
trol blood loss with menstruation in
Europe regardless of the type of under-
lying hemostatic disorder. This drug is
not available as an oral compound in
the U.S.
Women with factor XI deficiency
and menorrhagia may respond to
tranexamic acid therapy. Oral contrac-
tive agents may also be used and likely
reduce bleeding due to their atrophic
effects on the endometrium. Thera-
peutic interventions for women with
factor VII or V deficiency or carriers of
hemophilia B require further study.
CONCLUSION CONCLUSION CONCLUSION CONCLUSION CONCLUSION
Menorrhagia occurs in up to 10%
of women. An underlying bleeding dis-
order, most commonly vWD, should be
considered and investigated in women
with a normal pelvic examination. Ap-
propriate diagnosis and therapy of an
underlying bleeding disorder in this
population can improve QOL and de-
crease morbidity.
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